psychiatric times april 2011 vol xxviii, no 4

by Ronald W. Pies, MD

T he title of Gardiner Harris’s front-page story in the March 6 New York Times was blunt: “Talk

Doesn’t Pay, So Psychiatry Turns Instead to Drug Therapy.” For those of us who see our profession as a human-istic calling, this piece is likely to provoke a mixture of sadness and anger. After all, its depiction of psychiatric practice was one of grim, damage control, in which maintaining the fi-nancial bottom line and keeping pa-tients functional seem to be the prime directives. The main character in this sorry tale appears to be a decent soul, overwhelmed by the demands of his practice, and ashamed of his own ther-a peutic apostasy. The besieged and beleaguered psychiatrist, trained in the “old style” of in-depth therapy, describes his office as resembling “a bus station” and concludes that psy-chotherapy is no longer “economically viable.”

The declining use of psychotherapy in psychiatric practice is unquestion-ably worrisome. Unfortunately, the New York Times article uses the anec-dotal experience of one psychiatrist to

create, at best, a partial picture of psychiatric practice, and at worst, a caricature that perpetuates a number of myths and misconceptions. Among the most injurious of these myths is that

psychiatrists have essentially aban-doned psychotherapy; that pharmaco-therapy is something psychiatrists typically provide “instead of” psycho-therapy; and that in the course of a 15-minute medication visit, there is little one can do for the patient’s emotional suffering, beyond referring him or her to a “real” psychotherapist. The article also perpetuates the pop-ular but mistaken impression that pharmacotherapy is a rather crude and simple-minded intervention. Perhaps worst of all, this saga of an overworked psychiatrist may leave millions of read-ers with the fear that most psychiatrists are now “training” themselves not to get “too interested” in their patients’ problems.

First of all, what is the reality of psychiatry’s use of psychotherapy in recent years? The Times cited a 2005 government survey showing that “just 11% of psychiatrists provide talk therapy to all patients. . . .” Presumably,

(Please see Psychotherapy, page 9)

www.PsychiatricTimes.comA UBM Medica Publication® April 2011 • Vol. XXVIII, No. 4

Issue Highlights

Antipsychotics and the Shrinking Brain

Donald C. Goff, MD

Severe Funding Shortfalls Likely for Mental Health Programs

Stephen Barlas

Antidrug Vaccines: Fact or Science Fiction?

Daryl Shorter, MD and

Thomas R. Kosten, MD

Custom-Made Neural Stem Cells

John J. Medina, PhD

COMPLETE CONTENTS, PAGE 10

Psychotherapy Is Alive and Talking in Psychiatry

16 Practice Management How to Protect Patient Information 26 Special Report

Clinical Pharmacology 50 Category 1 CMECardiovascular Risks of Psychotropics

by Arline Kaplan

Encouraged by recent studies showing that a single IV infusion of ketamine can have antidepres-

sant effects within hours in patients with treatment-resistant major depres-sion (TRD) or bipolar depression, a psychiatric team at the University of California, San Diego (UCSD) Medical Center has begun offering ketamine infusions to patients who “are running out of options.”

“We are not studying ketamine per se,” said David Feifel, MD, PhD, asso-

ciate professor of psychiatry and neurosciences at UCSD and director of the Medical Center’s Neuropsy-chiatry and Behavioral Medicine Service. Rather, he and his team have developed a protocol of IV ketamine for severely depressed patients who have unsuccessfully run the gamut of medications and possibly ECT. It is one of several approaches offered in their Treatment Refractory Program.

According to Feifel, patients are informed that ketamine is not approved for this use, that insurance does not

(Please see Ketamine, page 10)

Ketamine: A Possible Role for Patients Who Are Running Out of Options?

Senior Executive Sales Representative(cuts to the chase)

Sarah

DD68601 0311 PRINTED IN USA. © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED.

Cymbalta is a registered trademark of Eli Lilly and Company.

• The treatment of major depressive disorder (MDD). The efficacy of Cymbalta was established in 4 short-term trials and 1 maintenance trial.

• The treatment of general anxiety disorder (GAD). The efficacy of Cymbalta was established in 3 short-term trials and 1 maintenance trial.

• The management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain (CLBP) and chronic pain due to osteoarthritis (OA).

• The management of diabetic peripheral neuropathic pain (DPNP).

• The management of fi bromyalgia (FM).

Cymbalta is indicated in adults for:

48168_eldd_DD68601_ad_sarah_tab_fa.indd 148168_eldd_DD68601_ad_sarah_tab_fa.indd 1 2/3/11 5:04:13 PM2/3/11 5:04:13 PM

I will support your goal of doing what’s best for your patients.

We provide clinical and educational resources designed to help appropriate patients at the start

of and throughout their treatment plan with Cymbalta. To fi nd out more, speak with your

Cymbalta sales representative or visit insidecymbalta.com.

O ff er educational resources that may support your patientsR ealize I’m not the most important person you’ll see today

R emember that small talk is best in small doses

I Will :

Warning: Suicidality and Antidepressant Drugs—Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients.

Important Safety Information About Cymbalta

See Important Safety Information, including Boxed Warning, above and on next page, and Brief Summary of Prescribing Information on following pages.

(cont.)


Important Safety Information About Cymbalta (Cont.)

Contraindications

• Concomitant use in patients taking Monoamine Oxidase Inhibitors (MAOIs) is contraindicated due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. These interactions may include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome.

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI.

• Cymbalta was associated with an increased risk of mydriasis; therefore, it should not be used in patients with uncontrolled narrow-angle glaucoma and used cautiously in patients with controlled narrow-angle glaucoma.

Warnings and Precautions

• Clinical Worsening and Suicide Risk

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially within the first few months of treatment and when changing the dose. Consider changing the therapeutic regimen, including possibly discontinuing the medication in patients whose depression is persistently worse or includes symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, or suicidality that are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If discontinuing treatment, the medication should be tapered. Families and caregivers of patients being treated with antidepressants for any indication should be alerted about the need to monitor patients. Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

• Hepatic failure, sometimes fatal, has been reported in patients treated with Cymbalta. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.

• Because it is possible that Cymbalta and alcohol may interact to cause liver injury or that Cymbalta may aggravate pre-existing liver disease, Cymbalta should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

• Orthostatic hypotension and syncope have been reported with therapeutic doses of Cymbalta. This tends to occur within the first week of therapy but can occur at any time during Cymbalta treatment, particularly after dose increases. Consideration should be given to discontinuing Cymbalta in patients who experience symptomatic orthostatic hypotension and/or syncope.

• The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Cymbalta treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. Concomitant use with serotonin precursors (e.g., tryptophan) is not recommended. Treatment with duloxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. (cont.)


Important Safety Information About Cymbalta (Cont.)

Warnings and Precautions (Cont.)

• SSRIs and SNRIs, including Cymbalta, may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with concomitant use of Cymbalta and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation.

• On abrupt or tapered discontinuation, spontaneous reports of adverse events, some of which may be serious, have been reported during the marketing of SSRIs and SNRIs. A gradual reduction in dose rather than abrupt cessation is recommended when possible.

• Cymbalta should be used cautiously in patients with a history of mania or with a history of a seizure disorder.

• In clinical trials across indications relative to placebo, treatment with Cymbalta was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.4 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment.

• Co-administration of Cymbalta with potent CYP1A2 inhibitors or thioridazine should be avoided.

• SSRIs and SNRIs, including Cymbalta, have been associated with cases of clinically significant hyponatremia that appeared to be reversible when Cymbalta was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs.

• The effect that alterations in gastric motility may have on the stability of the enteric coating of Cymbalta is unknown. As duloxetine is rapidly hydrolyzed in acidic media to naphthol, caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics).

• Cymbalta should ordinarily not be administered to patients with any hepatic insufficiency or patients with end-stage renal disease (requiring dialysis) or severe renal impairment (creatinine clearance <30 mL/min).

• As observed in DPNP trials, Cymbalta treatment worsens glycemic control in some patients with diabetes. In the extension phases (up to 52 weeks) of the DPNP studies, an increase in HbA1c in both the Cymbalta (0.5%) and the routine care groups (0.2%) was noted.

• Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during Cymbalta treatment, this effect may be drug-related. In postmarketing experience, urinary retention has been observed.

Use in Specific Populations

• Pregnancy and Nursing Mothers: Use only if the potential benefit justifies the potential risk to the fetus or child.

Most Common Adverse Events

• The most commonly reported adverse events (≥5% and at least twice placebo) for Cymbalta vs placebo in controlled clinical trials (N=6020 vs 3962) were: nausea (24% vs 8%), dry mouth (13% vs 5%), somnolence* (10% vs 3%), fatigue (10% vs 5%), constipation* (10% vs 4%), dizziness (10% vs 5%), decreased appetite* (8% vs 2%), and increased sweating (7% vs 2%).

* Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies that did not have a placebo lead-in period or dose titration.

• In placebo-controlled clinical trials, the overall discontinuation rates due to adverse events were: MDD: 9% vs 5%; GAD: 15% vs 4%; DPNP: 13% vs 5%; FM: 20% vs 12%; OA: 16% vs 6%; CLBP: 17% vs 6%.

The common adverse events reported as a reason for discontinuation and considered to be drug related were: MDD: nausea (1.3% vs 0.5%). GAD: nausea (3.7% vs 0.2%), vomiting (1.3% vs 0%), dizziness (1.0% vs 0.2%). DPNP: nausea (3.5% vs 0.7%), dizziness (1.2% vs 0.4%), somnolence (1.1% vs 0%). FM: nausea (1.9% vs 0.7%), somnolence (1.5% vs 0%), fatigue (1.3% vs 0.2%). OA: nausea (2.9% vs 0.8%), asthenia (1.3% vs 0%). CLBP: nausea (3.0% vs 0.7%), somnolence (1.0% vs 0%).

For more safety information, please see Brief Summary of Prescribing Information, including Boxed Warning, on following pages.

DD HCP ISI 4NOV10

DD68601 0311 PRINTED IN USA. © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED.

Cymbalta is a registered trademark of Eli Lilly and Company.


CYMBALTA® (duloxetine hydrochloride) PV 7213 AMP CYMBALTA® (duloxetine hydrochloride) PV 7213 AMP CYMBALTA® (duloxetine hydrochloride) PV 7213 AMP

CYMBALTA (duloxetine hydrochloride) Delayed-Release CapsulesBrief Summary: Consult the package insert for complete prescribing information.

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients. [See Warnings and Precautions and Use in Specific Populations.]

INDICATIONS AND USAGE: Major Depressive Disorder—Cymbalta is indicated for the acute and maintenance treatment of major depressive disorder (MDD). The efficacy of Cymbalta was established in four short-term trials and one maintenance trial in adults.

Generalized Anxiety Disorder—Cymbalta is indicated for the treatment of generalized anxiety disorder (GAD). The efficacy of Cymbalta was established in three short-term trials and one maintenance trial in adults.

Diabetic Peripheral Neuropathic Pain—Cymbalta is indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy.

Fibromyalgia—Cymbalta is indicated for the management of fibromyalgia (FM).Chronic Musculoskeletal Pain—Cymbalta is indicated for the management

of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain (CLBP) and chronic pain due to osteoarthritis.

CONTRAINDICATIONS: Monoamine Oxidase Inhibitors—Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. These interactions may include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome [see Warnings and Precautions].

Uncontrolled Narrow-Angle Glaucoma—In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma [see Warnings and Precautions].

WARNINGS AND PRECAUTIONS: Clinical Worsening and Suicide Risk—Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1

Age Range Drug-Placebo Difference in Number of Cases of Suicidality

per 1000 Patients Treated

Increases Compared to Placebo

<18 14 additional cases

18-24 5 additional cases

Decreases Compared to Placebo

25-64 1 fewer case

≥65 6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see Warnings and Precautions for descriptions of the risks of discontinuation of Cymbalta].

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder—A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Cymbalta (duloxetine) is not approved for use in treating bipolar depression.

Hepatotoxicity—There have been reports of hepatic failure, sometimes fatal, in patients treated with Cymbalta. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.

Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.

Cymbalta increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (89/29,435) of Cymbalta-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.37% (132/9611) of Cymbalta-treated patients compared to 0.49% (35/7182) of placebo-treated patients. In placebo-controlled studies using a fixed-dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.

Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Cymbalta should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

Orthostatic Hypotension and Syncope—Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during duloxetine treatment, particularly after dose increases. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see Warnings and Precautions and Drug Interactions] and in patients taking duloxetine at doses above 60 mg daily. Consideration should be given to discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or syncope during duloxetine therapy.

Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions—The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Cymbalta treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant

syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

The concomitant use of Cymbalta with MAOIs intended to treat depression is contraindicated [see Contraindications].

If concomitant treatment of Cymbalta with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions].

The concomitant use of Cymbalta with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions].

Treatment with duloxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Abnormal Bleeding—SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation.

Discontinuation of Treatment with Cymbalta—Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, fatigue, vomiting, irritability, insomnia, diarrhea, anxiety, and hyperhidrosis.

During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration].

Activation of Mania/Hypomania—In placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (2/2489) of duloxetine-treated patients and 0.1% (1/1625) of placebo-treated patients. No activation of mania or hypomania was reported in GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, Cymbalta should be used cautiously in patients with a history of mania.

Seizures—Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In placebo-controlled clinical trials, seizures/convulsions occurred in 0.03% (3/10,524) of patients treated with duloxetine and 0.01% (1/7699) of patients treated with placebo. Cymbalta should be prescribed with care in patients with a history of a seizure disorder.

Effect on Blood Pressure—In placebo-controlled clinical trials across indications from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.4 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of duloxetine on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing.

Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment [see Adverse Reactions].

Clinically Important Drug Interactions—Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Potential for Other Drugs to Affect CymbaltaCYP1A2 Inhibitors—Co-administration of Cymbalta with potent CYP1A2

inhibitors should be avoided [see Drug Interactions].CYP2D6 Inhibitors—Because CYP2D6 is involved in duloxetine metabolism,

concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine [see Drug Interactions].

Potential for Cymbalta to Affect Other DrugsDrugs Metabolized by CYP2D6—Co-administration of Cymbalta with drugs

that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines, and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Cymbalta. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Cymbalta and thioridazine should not be co-administered [see Drug Interactions].



Other Clinically Important Drug InteractionsAlcohol—Use of Cymbalta concomitantly with heavy alcohol intake may

be associated with severe liver injury. For this reason, Cymbalta should not be prescribed for patients with substantial alcohol use [see Warnings and Precautions and Drug Interactions].

CNS Acting Drugs—Given the primary CNS effects of Cymbalta, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action [see Warnings and Precautions and Drug Interactions].

Hyponatremia—Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Cymbalta. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Cymbalta was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations]. Discontinuation of Cymbalta should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

Use in Patients with Concomitant Illness—Clinical experience with Cymbalta in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Cymbalta’s enteric coating. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics).

Cymbalta has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing.

Hepatic Insufficiency—Cymbalta should ordinarily not be used in patients with hepatic insufficiency [see Warnings and Precautions and Use in Specific Populations].

Severe Renal Impairment—Cymbalta should ordinarily not be used in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min). Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) [see Use in Specific Populations].

Controlled Narrow-Angle Glaucoma—In clinical trials, Cymbalta was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma [see Contraindications].

Glycemic Control in Patients with Diabetes—As observed in DPNP trials, Cymbalta treatment worsens glycemic control in some patients with diabetes. In three clinical trials of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, Cymbalta was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the Cymbalta group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the Cymbalta group and by 0.2% in the routine care groups.

Urinary Hesitation and Retention—Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug-related.

In postmarketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed.

Laboratory Tests—No specific laboratory tests are recommended.

ADVERSE REACTIONS: Clinical Trial Data Sources—The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=2489), GAD (N=910), OA (N=239), CLBP (N=600), DPNP (N=906), and FM (N=876). The population studied was 17 to 91 years of age; 65.5%, 62.5%, 61.5%, 42.9%, and 94.9% female; and 86.5%, 81.2%, 86.2%, 74.0%, and 88% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day [see Clinical Studies (14)].

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials—Major Depressive Disorder—Approximately 9% (209/2327) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.7% (68/1460) of the patients receiving placebo. Nausea (duloxetine 1.3%, placebo 0.5%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo).

Generalized Anxiety Disorder—Approximately 15.3% (102/668) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 4.0% (20/495) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.7%, placebo 0.2%), and vomiting (duloxetine 1.3%, placebo 0.0%), and dizziness (duloxetine 1.0%, placebo 0.2%).

Diabetic Peripheral Neuropathic Pain—Approximately 12.9% (117/906) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0.0%).

Fibromyalgia—Approximately 19.6% (172/876) of the patients who received duloxetine in 3- to 6-month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 11.8% (63/535) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 1.9%, placebo 0.7%), somnolence (duloxetine 1.5%, placebo 0.0%), and fatigue (duloxetine 1.3%, placebo 0.2%).

Chronic Pain due to Osteoarthritis—Approximately 16.3% (39/239) of the patients who received duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 5.6% (14/248) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.9%, placebo 0.8%) and asthenia (duloxetine 1.3%, placebo 0.0%).

Chronic Low Back Pain—Approximately 16.5% (99/600) of the patients who received duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.0%, placebo 0.7%), and somnolence (duloxetine 1.0%, placebo 0.0%).

Most Common Adverse Reactions—Pooled Trials for all Approved Indications—The most commonly observed adverse reactions in Cymbalta-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, fatigue, constipation, decreased appetite, and hyperhidrosis.

Diabetic Peripheral Neuropathic Pain—The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.

Fibromyalgia—The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.

Chronic Pain due to Osteoarthritis—The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, fatigue, and constipation.

Chronic Low Back Pain—The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.

Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials—Table 2 in full PI gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials (N=6020 Cymbalta; N=3962 placebo) for approved indications that occurred in 5% or more of patients treated with duloxetine and with an incidence greater than placebo. These adverse events were: nausea, headache, dry mouth, fatigue (includes asthenia), somnolence* (includes hypersomnia and sedation), insomnia* (includes middle insomnia, early morning awakening, and initial insomnia), dizziness, constipation*, diarrhea, decreased appetite* (includes anorexia), and hyperhidrosis.

*Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration.

Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials—Pooled MDD and GAD Trials—Table 3 in full PI gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials (N=2995 Cymbalta; N=1955 placebo) for approved indications that occurred in 2% or more of patients treated with duloxetine and with an incidence greater than placebo. These adverse events were: Cardiac Disorders—palpitations; Eye Disorders—vision blurred; Gastrointestinal Disorders—nausea, dry mouth, diarrhea, constipation*, abdominal pain (includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain), vomiting; General Disorders and Administration Site Conditions—fatigue (includes asthenia); Investigations—weight decreased*; Metabolism and Nutrition Disorders—decreased appetite (includes anorexia); Nervous System Disorders—dizziness, somnolence (includes hypersomnia and sedation), tremor; Psychiatric Disorders—insomnia (includes middle insomnia, early morning awakening, and initial insomnia), agitation (includes feeling jittery, nervousness, restlessness, tension, and psychomotor agitation), anxiety, libido decreased (includes loss of libido), orgasm abnormal (includes anorgasmia), abnormal dreams (includes nightmare); Reproductive System and Breast Disorders—erectile dysfunction, ejaculation delayed*, ejaculation disorder (includes ejaculation failure and ejaculation dysfunction); Respiratory, Thoracic, and Mediastinal Disorders—yawning; Skin and Subcutaneous Tissue Disorders—hyperhidrosis; Vascular Disorders—hot flush.

*Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration.

DPNP, FM, OA, and CLBP—Table 4 in full PI gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled trials (N=2621 Cymbalta; N=1672 placebo) and with an incidence greater than placebo. These adverse events were: Gastrointestinal Disorders—nausea, dry mouth*, constipation*, diarrhea, abdominal pain (includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain), vomiting, dyspepsia (includes stomach discomfort); General Disorders and Administration Site Conditions—fatigue (includes asthenia); Infections and Infestations—nasopharyngitis, upper respiratory tract infection, influenza; Metabolism and Nutrition Disorders—decreased appetite* (includes anorexia); Musculoskeletal and Connective Tissue Disorders—musculoskeletal pain* (includes myalgia and neck pain), muscle spasm; Nervous System Disorders—headache, somnolence* (includes hypersomnia and sedation), dizziness, paraesthesia (includes hypoaesthesia, hypoaesthesia facial, and paraethesia

oral), tremor*; Psychiatric Disorders—insomnia* (includes middle insomnia, early morning awakening, and initial insomnia), agitation (includes feeling jittery, nervousness, restlessness, tension, and psychomotor hyperactivity); Reproductive System and Breast Disorders—erectile dysfunction*, ejaculation disorder; Respiratory, Thoracic, and Mediastinal Disorders—cough, oropharyngeal pain*; Skin and Subcutaneous Tissue Disorders—hyperhidrosis; Vascular Disorders—flushing (includes hot flush).

*Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day.

Effects on Male and Female Sexual Function—Changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Cymbalta than on placebo as measured by ASEX total score. Physicians should routinely inquire about possible sexual side effects. (See Table 5 in full PI for specific ASEX results.)

Vital Sign Changes—In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.07 mm Hg in systolic blood pressure and 0.62 mm Hg in diastolic blood pressure compared to mean decreases of 1.31 mm Hg systolic and 0.73 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions].

Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.40 beats per minute.

Weight Changes—In placebo-controlled clinical trials, MDD and GAD patients treated with Cymbalta for up to 10 weeks experienced a mean weight loss of approximately 0.5 kg compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In studies of DPNP, FM, OA, and CLBP, patients treated with Cymbalta for up to 26 weeks experienced a mean weight loss of approximately 0.6 kg compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In one long-term fibromyalgia 60-week uncontrolled study, duloxetine patients had a mean weight increase of 0.7 kg. In one long-term CLBP 54-week study (13-week, placebo-controlled acute phase and 41-week, uncontrolled extension phase), duloxetine patients had a mean weight decrease of 0.6 kg in 13 weeks of acute phase compared to study entry, then a mean weight increase of 1.4 kg in 41 weeks of extension phase compared to end of acute phase.

Laboratory Changes—Cymbalta treatment in placebo-controlled clinical trials across approved indications, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Cymbalta-treated patients when compared with placebo-treated patients [see Warnings and Precautions].

Electrocardiogram Changes—Electrocardiograms were obtained from duloxetine-treated patients and placebo-treated patients in clinical trials lasting up to 13 weeks. No clinically significant differences were observed for QTc, QT, PR, and QRS intervals between duloxetine-treated and placebo-treated patients. There were no differences in clinically meaningful QTcF elevations between duloxetine and placebo. In a positive-controlled study in healthy volunteers using duloxetine up to 200 mg twice daily, no prolongation of the corrected QT interval was observed.

Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine—Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials of all indications, 29,435 patients were treated with duloxetine. Of these, 30.4% (8953) took duloxetine for at least 6 months, and 14.7% (4317) for at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Cardiac Disorders—Frequent: palpitations; Infrequent: myocardial infarction and tachycardia. Ear and Labyrinth Disorders—Frequent: vertigo; Infrequent: ear pain and tinnitus. Endocrine Disorders—Infrequent: hypothyroidism. Eye Disorders—Frequent: vision blurred; Infrequent: diplopia and visual disturbance. Gastrointestinal Disorders—Frequent: flatulence; Infrequent: eructation, gastritis, halitosis, and stomatitis; Rare: gastric ulcer, hematochezia, and melena. General Disorders and Administration Site Conditions—Frequent: chills/rigors; Infrequent: feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance. Infections and Infestations—Infrequent: gastroenteritis and laryngitis. Investigations—Frequent: weight increased; Infrequent: blood cholesterol increased. Metabolism and Nutrition Disorders—Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia. Musculoskeletal and Connective Tissue Disorders—Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching. Nervous System Disorders—Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria. Psychiatric Disorders—Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide. Renal and Urinary Disorders—Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal. Reproductive System and Breast Disorders—Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, and sexual dysfunction. Respiratory, Thoracic and Mediastinal Disorders—Frequent: yawning; Infrequent: throat tightness. Skin and Subcutaneous Tissue Disorders—Infrequent:



cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis. Vascular Disorders—Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.

Postmarketing Spontaneous Reports—The following adverse reactions have been identified during postapproval use of Cymbalta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, erythema multiforme, extrapyramidal disorder, galactorrhea, glaucoma, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.

Serious skin reactions including Stevens-Johnson Syndrome that have required drug discontinuation and/or hospitalization have been reported with duloxetine.

DRUG INTERACTIONS: Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Inhibitors of CYP1A2—When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions].

Inhibitors of CYP2D6—Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see Warnings and Precautions].

Dual Inhibition of CYP1A2 and CYP2D6—Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.

Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)—Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued [see Warnings and Precautions].

Lorazepam—Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration.

Temazepam—Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration.

Drugs that Affect Gastric Acidity—Cymbalta has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of Cymbalta with aluminum- and magnesium-containing antacids (51 mEq), or Cymbalta, with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption [see Warnings and Precautions].

Drugs Metabolized by CYP1A2—In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily).

Drugs Metabolized by CYP2D6—Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50-mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see Warnings and Precautions].

Drugs Metabolized by CYP2C9—Duloxetine does not inhibit the in vitro enzyme activity of CYP2C9. Inhibition of the metabolism of CYP2C9 substrates is therefore not anticipated, although clinical studies have not been performed.

Drugs Metabolized by CYP3A—Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.

Drugs Metabolized by CYP2C19—Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.

Monoamine Oxidase Inhibitors—[See Contraindications and Warnings and Precautions.] Switching Patients to or from a Monoamine Oxidase Inhibitor—At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI [see Contraindications and Warnings and Precautions].

Serotonergic Drugs—Based on the mechanism of action of SNRIs and SSRIs, including Cymbalta, and the potential for serotonin syndrome, caution is

advised when Cymbalta is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort. The concomitant use of Cymbalta with other SSRIs, SNRIs, or tryptophan is not recommended [see Warnings and Precautions].

Triptans—There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Cymbalta with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions].

Alcohol—When Cymbalta and ethanol were administered several hours apart so that peak concentrations of each would coincide, Cymbalta did not increase the impairment of mental and motor skills caused by alcohol. In the Cymbalta clinical trials database, three Cymbalta-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see Warnings and Precautions].

CNS Drugs—[See Warnings and Precautions.] Drugs Highly Bound to Plasma Protein—Because duloxetine is highly

bound to plasma protein, administration of Cymbalta to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions.

USE IN SPECIFIC POPULATIONS: Pregnancy—Teratogenic Effects, Pregnancy Category C—In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.

When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (7 times the maximum recommended human dose [MRHD, 60 mg/day] and 4 times the human dose of 120 mg/day on a mg/m2 basis, in rat; 15 times the MRHD and 7 times the human dose of 120 mg/day on a mg/m2 basis in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (2 times the MRHD and ≈1 times the human dose of 120 mg/day on a mg/m2 basis in rats; 3 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis in rabbits).

When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.

There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects—Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions].

When treating pregnant women with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Cymbalta in the third trimester.

Lilly maintains a pregnancy registry to monitor the pregnancy outcomes of women exposed to Cymbalta while pregnant. Healthcare providers are encouraged to register any patient who is exposed to Cymbalta during pregnancy by calling the Cymbalta Pregnancy Registry at 1-866-814-6975 or by visiting www.cymbaltapregnancyregistry.com.

Labor and Delivery—The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers—Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics. (See Nursing Mothers section in full PI for additional information.)

Pediatric Use—Safety and effectiveness in the pediatric population have not been established [see Boxed Warning and Warnings and Precautions]. Anyone considering the use of Cymbalta in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use—Of the 2418 patients in premarketing clinical studies of Cymbalta for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. Of the 1761 patients in FM premarketing studies, 7.9% (140) were 65 years of age or over. Premarketing clinical studies of GAD did not include sufficient numbers of subjects age 65 or over to determine whether they respond differently from younger subjects. In the MDD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Cymbalta, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions]. (See Geriatric Use section in full PI for additional information.)

Gender—Duloxetine’s half-life is similar in men and women. Dosage adjustment based on gender is not necessary.

Smoking Status—Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.

Race—No specific pharmacokinetic study was conducted to investigate the effects of race.

Hepatic Insufficiency—[See Warnings and Precautions-Use in Patients with Concomitant Illness.] (See Use in Patients with Concomitant Illness-Hepatic Insufficiency section in full PI for additional information.)

Severe Renal Impairment—[See Warnings and Precautions-Use in Patients with Concomitant Illness.] (See Use in Patients with Concomitant Illness-Severe Renal Impairment section in full PI for additional information.)

DRUG ABUSE AND DEPENDENCE: Abuse—In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential. While Cymbalta has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Cymbalta (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Dependence—In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

OVERDOSAGE: Signs and Symptoms—In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

Management of Overdose—There is no specific antidote to Cymbalta, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. (See Management of Overdose section in full PI for additional information.)

NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility—Carcinogenesis—Duloxetine was administered in the diet to mice and rats for 2 years. In female mice receiving duloxetine at 140 mg/kg/day (11 times the maximum recommended human dose [MRHD, 60 mg/day] and 6 times the human dose of 120 mg/day on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (8 times the MRHD and 4 times the human dose of 120 mg/day on a mg/m2 basis).

In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis) and up to 36 mg/kg/day in males (6 times the MRHD and 3 times the human dose of 120 mg/day on a mg/m2 basis) did not increase the incidence of tumors.

Mutagenesis—Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo.

Impairment of Fertility—Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (7 times the maximum recommended human dose of 60 mg/day and 4 times the human dose of 120 mg/day on a mg/m2 basis) did not alter mating or fertility.

PATIENT COUNSELING INFORMATION: See FDA-approved Medication Guide and Patient Counseling Information section of full PI.

Additional information can be found at www.Cymbalta.com.

Literature revised: November 8, 2010

Eli Lilly and CompanyIndianapolis, IN 46285, USA

Copyright © 2004, 2010, Eli Lilly and Company. All rights reserved.

PV 7213 AMP

DD HCP BS 17NOV10


psychotherapist. Furthermore, with respect to the treatment of major depression, there is reasonably good evidence that the combination of psychotherapy and medication works better than either treatment alone, at least in chronically or severely depressed patients.6,7

Yet in the Times article, there is a not-too-subtle disparagement of pharmacotherapy. Our harried psychiatrist, estranged from his psychotherapeutic training, opines that “. . . there’s not a lot to master” in psychopharmacology, and that he often feels like “the ape with the bone.” It’s true that the kind of complexity involved in medication treatment is quite different from that of, say, psychoanalysis or object-relations theory. But psychopharma-cology has its own complexity, if—to borrow a phrase from Woody Allen—“you are doing it right.” Quite aside from the innumerable drug-drug interactions one needs to sort through, there are the issues of medicating patients with comorbid illnesses, such as diabetes or heart disease; understanding how psychi-atric medications affect the very young and the very old; monitoring potential metabolic effects of medi-cations; and mitigating adverse effects without undermining other-wise successful pharmacotherapy.8

Then there is the realm of medi-cation’s “psychodynamics”—the hopes, fears, and fantasies the pa-tient often attaches both to the physi-cian’s prescribing a medication and to the particular drug prescribed. A failure to understand these often unconscious issues can spell disaster for pharmacotherapy. As Dewan has put it:

Some patients derive a psy-chological benefit from being given medications, because they consider it a caring, nur-turing act that feeds their dependency needs or validates their suffering as genuine. Other patients may see the prescription of medications as an imposition of external con-trol, or as a statement by the therapist that they are not strong enough to solve their problems by themselves. These feelings may contribute to non-compliance with both medica-tions and brief therapy.9(pp257-264)

To be sure, given a 15-minute time slot, the harried psychiatrist focusing only on medication adverse effects is at a severe disadvantage—and so is the patient. Based on the principles

sensitivity of the psychiatrist’s inter-vention. Faced with a patient who is experiencing a painful issue in her marriage or job, there is a good deal more we can do in 5 to 10 minutes besides saying, “Sorry, I’m not your therapist. That stuff is not in my bailiwick.” We can offer understand-ing, empathy, and clarification—and I believe most psychiatrists do just that, during a medication visit. Similarly, Dr Glen Gabbard has described how psychodynamic prin-ciples and an understanding of the patient’s urgent personal concerns are necessary parts of the much-maligned “15-minute med check.” He notes the following:

Psychiatry has probably made far too much of a distinction between psychotherapy and pharmacotherapy in training and in practice. Psychother-apeutic skills are needed in every context in psychiatry because the same phenomena that emerge in psychother-apy—transference, resistance, countertransference, schema, automatic thoughts—appear in other contexts. . . . Psychiatry residents need to be taught that psychotherapeutic principles apply in all settings where psychiatric treatment is deliv-ered [italics added].4

The other unfortunate aspect of the Harris article is its implicit rein-forcement of the “mind-body” split that has so bedeviled psychiatry for the past 50 years, as Tanya Luhrmann documented in her classic study, Of Two Minds: The Growing Disorder in American Psychiatry. Thus, phar-macotherapy is portrayed as some-thing psychiatrists do “instead of” psychotherapy, rather than as part of an integrated and holistic form of treatment. But in my experience, many psychiatrists continue to provide such comprehensive medi-cal-psychological care, although the Mojtabai-Olfson data do not tell us what percentage do so (M. Olfson, personal communication, March 8, 2011). In truth, there are often reasons—including cost-effective-ness—for preferring a “single provider” model of combined treat-ment. Dr Mantosh Dewan5 showed, for example, that when treatment requires both psychotherapy and medication, combined treatment by a psychiatrist costs about the same or less than split treatment with a social worker psychotherapist and is usually less expensive than split treatment with a psychologist

this was a reference to the study by Mojtabai and Olfson,1 based on data from the 1996 - 2005 cross-sectional National Ambulatory Medical Care Survey (NAMCS). Indeed, the study found a decline in the number of psychiatrists who provided psycho-therapy to all of their patients, from 19.1% in 1996 - 1997 to 10.8% in 2004 - 2005. The study also found that the percentage of visits involving psychotherapy declined from 44.4% in 1996 - 1997 to 28.9% in 2004 - 2005, which “. . . coincided with changes in reimbursement, increases in managed care, and growth in the prescription of medications.”

So far, all this is in line with the New York Times piece. But the article failed to mention that most psychia-trists (59.4%) continue to provide psychotherapy to at least some of their patients.1 Moreover, when we read the discussion section of the Mojtabai-Olfson study, we find an important caveat. Their study re-quired that “psychotherapy visits” had to be longer than 30 minutes and had to be “explicitly designated as a psychotherapy visit by the psychi-atrist or office staff.” The authors added this telling observation:

Some visits likely involved use of psychotherapeutic tech-niques but were not classified as psychotherapy in the current analysis. Psychotherapeutic techniques can be effectively taught and used in brief medi-cation management visits by psychiatrists and other health care providers. 1(p968),2,3

Furthermore, the NAMCS survey did not examine the type of psycho-therapy provided. As Mojtabai and Olfson1 note, “Examining the types of psychotherapy would be of special interest as there has been an expan-sion in the use of more structured short-term therapies in recent years.” Indeed, not all psychotherapy corre-sponds to, or necessarily requires, the classic “50-minute hour” asso-ciated with psychoanalytically ori-ented therapy. My colleague, James P. Gustafson, MD, has developed a form of “very brief psychother-apy” that sometimes involves 5- or 10-minute interventions. Surpris-ingly, these very brief encounters can be transformative on a very deep level, for carefully selected patients.3

Indeed, while I am no fan of the 15-minute “med check,” the critical issue is not so much the available minutes as it is the deftness and

of beneficence and non-malfeasance, one might argue that it is frankly unethical to limit an emotionally distraught or suicidal patient to such a procrustean time slot, if her medi-cal and psychological needs demand more thorough evaluation and management. (Our beleaguered New York Times psychiatrist nearly fails to detect suicidal ideation in a patient who initially complained of “ADD” and, to his credit, winds up extending the session to 55 minutes.) Speaking of ethics: we should remind ourselves that there are still over 45 million Americans who lack health insur-ance, and that most patients with major depression do not receive any professional treatment10—never mind, psychotherapy.

Finally, even the constraints of a 15-minute session are no excuses for putting off patients with comments such as “I’m not your therapist.” Like it or not, our patients often do not make a sharp distinction between “therapist” and “psychiatrist,” and we continue to be seen by them as sources of advice, comfort, and solace.4 As even our harried psychi-atrist observed of his patients, “The sad thing is that I’m very important to them. . . .” But it really isn’t sad, Doctor—it is hopeful, and our patients should not be discouraged from seeing us as compassionate healers. After all, this is probably the image we had of ourselves when we entered this profession, our human-itarian ideals still intact.

No, a brief medication check is hardly a substitute for the revered 50-minute therapy hour. But even in a 15-minute meeting, we can still engage in what Theodor Reik called “listening with the third ear.” Fur-thermore, we can and must convey to our patients that we are intensely interested in their problems.

Dr Pies is editor in chief emeritus of Psy-chiatric Times and professor in the psychiatry departments of SUNY Upstate Medical Uni-versity, Syracuse, NY, and Tufts University School of Medicine, Boston. He is the au-thor, most recently, of Becoming a Mensch: Timeless Talmudic Ethics for Everyone; The Judaic Foundations of Cognitive-Behavioral Therapy; and a collection of short stories, Ziprin’s Ghost.

Acknowledgments—I would like to thank Susan Kweskin, Dr Glen Gabbard, Dr James Knoll, and Dr Mark Olfson for their helpful comments on earlier drafts of this piece.

References

1. Mojtabai R, Olfson M. National trends in psycho-therapy by office-based psychiatrists. Arch Gen Psy-chiatry. 2008;65:962-970.

9PSYCHIATRIC TIMES APRIL 2011www.psychiatr ic t imes.com

PsychotherapyContinued from page 1

(Please see Psychotherapy, page 10)

APRIL 2011

2. Castelnuovo-Tedesco P. The twenty-minute “hour”: an experiment in medical education. N Engl J Med. 1962;266:283-289.3. Gustafson JP. Very Brief Psychotherapy. New York: Routledge; 2005.4. Gabbard GO. Deconstructing the “med check.” Psychiatric Times. September 3, 2009. http://www.psychiatrictimes.com/display/article/10168/1444238. Accessed March 8, 2011.5. Dewan M. Are psychiatrists cost-effective? An analysis of integrated versus split treatment. Am J Psychiatry. 1999;156:324-326.6. Keller MB, McCullough JP, Klein DN, et al. A com-parison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combi-nation for the treatment of chronic depression [pub-lished correction appears in N Engl J Med. 2001;345:232]. N Engl J Med. 2000;342:1462-1470.7. Friedman MA, Detweiler-Bedell JB, Leventhal HE, et al. Combined psychotherapy and pharmacother-apy for the treatment of major depressive disorder. Clin Psychol Sci Pract. 2004;11:47-68.8. Jacobson SA, Pies RW, Katz IR. Clinical Manual of Geriatric Psychopharmacology. Washington, DC: American Psychiatric Publishing, Inc; 2007.9. Dewan MJ, Steenbarger BN, Greenberg RP, eds. In: Gabbard GO, series ed. The Art and Science of Brief Psychotherapies. Washington, DC: American Psychi-atric Publishing, Inc; 2004.10. Wang SS. Studies: mental ills are often over-treated, undertreated. Wall Street Journal. January 5, 2010. http://online.wsj.com/article/SB10001424052748703580904574638750777038042.html. Accessed March 9, 2011.

Further reading:

Manring J. No, psychiatry has not lost its “mind”: here, psychotherapy training thrives. Psychiatric Times. June 2, 2010. http://www.psychiatrictimes.com/display/article/10168/1579811. Accessed March 9, 2010. ❒

cover its use, and that optimal use of ketamine in depression is still being studied. Patients are also warned that if they do respond to ketamine, its effects are temporary, and that staff will work with them on how to maintain a treatment response.

What the research showsThe impetus for ketamine research stems from the need for rapid-response antidepressants. Many patients do not benefit from standard antidepressants; others may take weeks or months to respond, said Carlos Zarate Jr, MD, chief of the Experimental Therapeutics and Pathophysiology Branch of the Division of the Intramural Research Program at the NIMH and lead investigator on several ketamine studies.

The Sequenced Treatment Alternatives to Relieve Depression Trial (STAR*D), for example, showed that only a third of patients with major depressive disorder achieved remission (ie, minimal/no residual symptoms) after 1 adequate treatment trial with a traditional antidepressant.1

We can rapidly control blood sugar or high blood pressure in a matter of minutes or hours, Zarate

PsychotherapyContinued from page 9

KetamineContinued from page 1

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PSYCHIATRIC TIMES

said. Similarly, we need interven-tions that can work rapidly in de-pressed patients, he added.

Evidence indicates that the gluta-matergic system is involved in the pathophysiology and treatment of mood disorders, Zarate said. Earlier studies found altered glutamate lev-els in serum and cerebrospinal fluid from patients with mood disorders.2 Postmortem studies found altered glutamate levels in diverse brain areas in individuals with mood dis -orders.3 Ketamine increases the firing rate of glutamatergic neurons and the presynaptic release of glutamate.

Much is known about ketamine, a high-affinity N-methyl-d-aspartate (NMDA) receptor antagonist, ac-cording to Zarate. “It is an approved anesthetic that is used worldwide, particularly in ED settings as well as in children, so it has a good track record of safety,” he said. “Using ketamine as an experimental drug, we tested the hypothesis of whether directly going to the NMDA receptor complex target would bring about rapid antidepressant effects, and indeed we found it to be the case,” he said.

The first small, preliminary inves-tigation by Berman and colleagues4 found significant antidepressant effects within 72 hours after keta-mine infusion in 7 individuals with TRD. Zarate and coworkers5 subse-quently confirmed the rapid anti-depressant response with ketamine. Zarate’s team conducted a double-blind, crossover, placebo-controlled study involving 18 patients; those with TRD experienced symptom relief in as little as 2 hours with a single IV dose of ketamine (0.5 mg/kg over 40 minutes).

Of the 17 patients treated with ketamine (1 patient dropped out), 71% met response criteria (50% improvement on 21-item Hamilton Depression Rating Scale) and 29% met remission criteria the day follow-ing the infusion. The response was sustained for at least 1 week in 35% of patients.

“We have conducted a series of other studies,” Zarate told Psychiat-ric Times. Some looked at bipolar depression, suicidal ideation, and predictors of response.

His team recently completed a placebo-controlled study in treat-ment-resistant bipolar depression with 18 subjects.6 “After a single IV infusion, we found very rapid anti-depressant effects starting within 1 hour, which lasted most of the week,” Zarate said. In the randomized, placebo-controlled, double-blind, crossover, add-on study, 12 of 17

(Please see Ketamine, page 12)

CATEGORY 1 CME ARTICLEProarrhythmic Risks of Antidepressant and Antipsychotic Drugs

W. Victor R. Vieweg, MD, Mehrul Hasnain, MD, Mark A. Wood, MD, Antony Fernandez, MD,

Edward J. Lesnefsky, MD, and Ananda K. Pandurangi, MD

DEPARTMENTS

COVER STORIESPsychotherapy Is Alive and Talking in Psychiatry

Ronald W. Pies, MD

Ketamine: A Possible Role for Patients Who Are Running Out of

Options? Arline Kaplan

NEWSAntipsychotics and the Shrinking Brain Donald C. Goff, MD

Excavation in Austria Uncovers Mass Grave

Thought to Hold Nazi Psychiatric Victims Susan Kweskin

PRACTICE MANAGEMENTHow to Protect Patient Information—and What to Do if It Gets

Lost or Stolen Rick Kam, CIPP

Managing Risks When Practicing in Three-Party Care Settings

Robindra K. Paul, MD, DPH, MBA, Christopher Lockey, MD, Ryan C. W. Hall, MD,

and Harold J. Bursztajn, MD

SPECIAL REPORT

CLINICAL PSYCHOPHARMACOLOGY, PART 1

Introduction: Looking to the Future of Psychopharmacology

Thomas L. Schwartz, MD

Antidrug Vaccines: Fact or Science Fiction?

Daryl Shorter, MD and Thomas R. Kosten, MD

Novel Treatment Avenues for Bipolar Depression

Roger S. McIntyre, MD and Danielle S. Cha

COLUMNS

MOLECULES OF THE MINDCustom-Made Neural Stem Cells John J. Medina, PhD

POETRY OF THE TIMESExpert Witness Richard M. Berlin, MD

BOOK REVIEWSThe Judaic Foundations of Cognitive-Behavioral Therapy:

Rabbinical and Talmudic Underpinnings of CBT and REBT

Reviewed by H. Steven Moffic, MD and Rabbi Evan Moffic

We’ve Got Issues: Children and Parents in the Age of Medication

Reviewed by Gabrielle A. Carlson, MD

WASHINGTON REPORTSevere State and Federal Funding Shortfalls Likely for Local

Mental Health Programs Stephen Barlas

Cover Image © iStockphoto.com

In This Issue

Please read Brief Summary of Full Prescribing Information on adjacent page.

www.Daytrana.com

Daytrana is indicated for the treatment of Attention Defi cit Hyperactivity Disorder (ADHD) in children (ages 6-12) and adolescents (ages 13-17). The effi cacy of Daytrana was estab-lished in controlled clinic studies: two 7-week trials in children and one 7-week trial in adolescents. Daytrana is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social).

Important Safety Information

WARNING: DRUG DEPENDENCEDaytrana should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

Contraindications: The Daytrana patch should not be used by patients who have an allergy to methylphenidate or other patch components; marked anxiety, tension, and agitation; glaucoma; motor tics or with a diagnosis or a family history of Tourette’s syndrome; seizures; are being treated (or within 14 days after treatment) with monoamine oxidase inhibitors (MAOIs).

Serious Cardiovascular Effects: Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. A careful patient history, including family history, and physical exam should be performed to assess the presence of cardiac disease. Stimulant products generally should not be used in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious heart problems. Patients who develop symptoms (i.e., exertional chest pain, unexplained syncope) suggestive of cardiac disease while using or wearing the Daytrana patch should be promptly evaluated. Use with caution in patients whose underlying medical condition might be affected by increases in blood pressure or heart rate. Use cautiously with pressor agents. Hematologic monitoring is advised during prolonged treatment.

Psychiatric and Long-Term Suppression of Growth: Use with caution in patients with a history of psychosis, EEG abnormalities, bipolar disorder, and depression. New psychosis, mania, aggression, visual disturbances, and growth suppression have been associated with the use of stimulants. Growth should be monitored in children during treatment with stimulants, and patients who are not growing (gaining height or weight) as expected may need to have their treatment interrupted.

Contact Sensitization: Use of the Daytrana patch may lead to contact sensitization. Erythema has been commonly reported and is not by itself an indication of sensitization. If contact sensitization is suspected (erythema with edema, papules and/or vesicles spread beyond the patch site and/or lack of improvement within 48 hours), treatment should be discontinued. Patients should avoid applying external heat to the Daytrana patch; application of heat can increase the extent and rate of absorption.

Most Common Adverse Events: The most common adverse reactions associated with the Daytrana patch (at least 5% and twice the rate of placebo-treated patients) in clinical trials were: children – decreased appetite, insomnia, nausea, vomiting, decreased weight, tics, affect lability, and anorexia; adolescents – decreased appetite, nausea, insomnia, decreased weight, dizziness, abdominal pain, and anorexia. In addition, the majority of subjects in these studies had minimal to defi nite skin erythema at the patch application site. Leaving the patch on for longer than the recommended 9 hours has resulted in an increased incidence of adverse events.

Daytrana® and the Graphic Design are registered trademarks of Noven Therapeutics, LLC. ©2011 Noven Therapeutics, LLC. All rights reserved. Printed in USA DAY-2011 02/11

Removable Daytrana® controls ADHD symptoms… You control the duration of effect.

PM REMOVE PATCH*

AM APPLY PATCH*

*The maximum wear time for Daytrana is 9 hours. Effi cacy observed at two hours after application. The effects from the patch continue for up to three hours after removal.1

Reference: 1. Daytrana package insert. Miami, FL: Noven Pharmaceuticals Inc; 11/2010.

DAY_3872_PSYT_APR11.indd 1 3/10/11 3:53 PM

that acute improvements in suicidal-ity could be sustained through re-peated ketamine infusions.7

DiazGranados and others,8 part of Zarate’s team, showed that in pa-tients with major depressive disor-der who had significant suicidal ideation, improvement occurred within 40 minutes of a ketamine infusion. Predictors of response to IV ketamine, Zarate said, include a family history of alcohol depen-

past decade there has been a signif-icant increase in ED visits for suicidal ideation or attempts. Suicides have occurred even in inpatient psychiat-ric units and have become an urgent issue for the US military.

At the Mount Sinai School of Medicine in New York, researchers found that a single subanesthetic dose of IV ketamine had rapid effects (1 day after infusion) on suicidal ideation in patients with TRD and

(71%) patients responded to keta-mine; 3 patients had a response that lasted 2 weeks or more.

Ketamine also has an anti-suicidal effect, which is critically important given that individuals with mood disorders are often at risk for suicide within the first month of starting a medication, Zarate said. Adding to the challenge, he said, is that in the

dence,9,10 increased pretreatment rostral anterior cingulate cortex activity,11 and anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task.12

In the next few months, Zarate said his team will start a ketamine mechanism of action study (http://patientinfo.nimh.nih.gov). “We will be looking at people who have failed only one adequate antidepressant trial in their lifetime, so it will be a much less treatment refractory group,” he said. “We will be studying several hundred people with unipo-lar depression or bipolar depression and using novel technologies, includ-ing multimodal brain imaging, poly-somnography, genetics, and cogni-tive measures.”

The reason for this extensive battery, according to Zarate, is to better understand how ketamine works and to tease out who might respond and what might be the mark-ers for predicting response.

“We hope to be able to identify signatures of rapid response which then could be utilized to develop other similar types of compounds,” Zarate said.

The team’s research has also prompted investigation of ketamine for other mental disorders. “We have not published these data yet, but ke-tamine has significant anti-anxiety effects,” said Zarate. People with certain symptoms of anxiety or trauma and those with obsessive symptom profiles appear to benefit from the ketamine infusion, he noted.

The NIH’s Web site (www.clinicaltrials.gov) indicates that some studies of ketamine in obses-sive-compulsive disorder and PTSD, and as augmentation of ECT for severe major depression, are under way. Other researchers are looking at the feasibility of repeated-dose IV ketamine for acute management of TRD. In one recent study, symp-toms relapsed, on average, 19 days after the sixth ketamine infusion; however, 1 patient remained antide-pressant-free with minimal symp-toms for more than 3 months.13

Asked about the notoriety keta-mine gained as the abusable club drug known as “K,” Zarate said that during its infusion, ketamine can cause dissociative side effects. He noted that his team has safely ad-ministered ketamine to more than 100 patients in a controlled setting. We are trying to determine “which subunit of the NMDA receptor is responsible for side effects and which is responsible for improvement,” he said, explaining that there are ma-

KetamineContinued from page 10

12 APRIL 2011www.psychiatr ic t imes.com

PSYCHIATRIC TIMES

DAYTRANA - methylphenidate patch Noven Therapeutics, LLCBrief Summary. Consult Package Insert for complete Prescribing Information.

WARNING: DRUG DEPENDENCEDaytrana should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

INDICATIONS AND USAGE Daytrana (methylphenidate transdermal system) is indicated for the treatment of Attention Deficit Hyperac-tivity Disorder (ADHD). The efficacy of Daytrana in patients diagnosed with ADHD was established in two 7-week controlled clinical trials in children (ages 6-12) and one 7-week, controlled clinical trial in adolescents (ages 13-17). CONTRAINDICATIONS Hypersensitivity to Methylphenidate - Daytrana is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product (polyester/ethylene vinyl acetate laminate film backing, acrylic adhesive, silicone adhesive, and fluoropolymer-coated polyester). Agitation - Daytrana is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. Glaucoma - Daytrana is contraindicated in patients with glaucoma. Tics - Daytrana is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome [see Adverse Reactions (6.1)]. Monoamine Oxidase Inhibitors - Daytrana is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result).WARNINGS and PRECAUTIONS Serious Cardiovascular Events Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents: Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults: Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia [see Adverse Reactions (6.1)]. Assessing Cardiovascular Status in Patients Being Treated With Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis: Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness: Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms: Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to none in placebo-treated patients. Aggression: Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Seizures - There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Long-Term Suppression of Growth - Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylpheni-date or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Visual Disturbance - Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. Contact Sensitization - In an open-label study of 305 subjects conducted to characterize dermal reactions in children with ADHD treated with Daytrana using a 9-hour wear time, one subject (0.3%) was confirmed by patch testing to be sensitized to methylphenidate (allergic contact dermatitis). This subject experienced erythema and edema at Daytrana application sites with concurrent urticarial lesions on the abdomen and legs resulting in treatment discontinuation. This subject was not transitioned to methylphenidate. Use of Daytrana may lead to contact sensitization. Daytrana should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of Daytrana and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the patch site. Confirmation of a diagnosis of contact sensitization (allergic contact dermatitis) may require further diagnostic testing. Patients sensitized from use of Daytrana, as evidenced by development of an allergic contact dermatitis, may develop systemic sensitization or other systemic reactions if methylphenidate-containing products are taken via other routes, e.g., orally. Manifestations of systemic sensitization may include a flare-up of previous dermatitis or of prior positive patch-test sites, or generalized skin eruptions in previously unaffected skin. Other systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting. No cases of systemic sensitization have been observed in clinical trials of Daytrana. Patients who develop contact sensitization to Daytrana and require oral treatment with methylphenidate should be initiated on oral medication under close medical supervision. It is possible that some patients sensitized to methylphenidate by exposure to Daytrana may not be able to take methylphenidate in any form. Patients Using External Heat - Patients should be advised to avoid exposing the Daytrana application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the patch. When heat is applied to Daytrana after patch application, both the rate and extent of absorption are significantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold. This increased absorption can be clinically significant and can result in overdose of methylphenidate [see Overdosage (10)]. Hematologic Monitoring - Periodic CBC, differential, and platelet counts are advised during prolonged therapy.ADVERSE REACTIONS Detailed information on serious and adverse reactions of particular importance is provided in the "OXED�7ARNING�AND�7ARNINGS�AND�0RECAUTIONS��SECTIONS��s�$RUG�DEPENDENCE�;SEE�"OXED�7ARNING=�s�(YPERSENSITIVITY�TO�-ETHYLPHENIDATE�;SEE�#ONTRAINDICATIONS��=�s�-ARKED�ANXIETY��TENSION��OR�AGITATION�;SEE�#ONTRAINDICATIONS��=�s�'LAUCOMA�;SEE�#ONTRAINDICATIONS��=�s�4ICS�OR�A�FAMILY�HISTORY�OF�4OURETTE�S�SYN-DROME�;SEE�#ONTRAINDICATIONS��=��s�-ONOAMINE�/XIDASE�)NHIBITORS�;SEE�#ONTRAINDICATIONS��AND�$RUG�)NTERACTIONS��=�s�3ERIOUS�#ARDIOVASCULAR�%VENTS�;SEE�7ARNINGS�AND�0RECAUTIONS��=��s�)NCREASE�IN�"LOOD�0RESSURE�;SEE�7ARNINGS�AND�0RECAUTIONS��=�s�0SYCHIATRIC�!DVERSE�%VENTS�;SEE�7ARNINGS�AND�0RECAUTIONS��=�s�3EIZURES�;SEE�7ARNINGS�AND�0RECAUTIONS��=�s�,ONG 4ERM�3UPPRESSION�OF�'ROWTH�;SEE�7ARNINGS�AND�0RECAUTIONS��=�s�6ISUAL�$ISTURBANCE�;SEE�7ARNINGS�AND�0RECAUTIONS��=�s�#ONTACT�3ENSITIZATION�;SEE�7ARNINGS�AND�0RECAUTIONS��=�s�%XTERNAL�(EAT�;SEE�7ARNINGS�AND�0RECAUTIONS��=�s�(EMATOLOGIC�-ONITOR-ing [see Warnings and Precautions (5.8)] The most commonly reported (frequency * 5% and twice the rate of placebo) adverse reactions in a controlled trial in children aged 6-12 included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affect lability, and anorexia. The most commonly reported (fre-quency * 5% and twice the rate of placebo) adverse reactions in a controlled trial in adolescents aged 13-17 were appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain and anorexia [see Adverse Reactions (6.1)]. The most common (* 2% of subjects) adverse reaction associated with discontinu-ations in double-blind clinical trials in children or adolescents was application site reactions15 [see Adverse Reactions (6.3)]. The overall Daytrana development program included exposure to Daytrana in a total of 2,152 participants in clinical trials, including 1,529 children aged 6-12, 223 adolescents aged 13-17, and 400 adults. The 1,752 child and adolescent subjects aged 6-17 years were evaluated in 10 controlled clinical studies, 7 open-label clinical studies, and 5 clinical pharmacology studies. In a combined studies pool of children using Daytrana with a wear time of 9 hours, 212 subjects were exposed for * 6 months and 115 were exposed for * 1 year; 85 adolescents have been exposed for * 6 months. Most patients studied were exposed to Daytrana patch sizes of 12.5 cm2, 18.75 cm2, 25 cm2 or 37.5 cm2, with a wear time of 9 hours. In the data presented below, the adverse reactions reported during exposure were obtained primarily by general inquiry at each visit, and were recorded by the clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reac-tions without first grouping similar types of events into a smaller number of standardized event categories. Throughout this section adverse reactions reported are events that were considered to be reasonably associated with the use of Daytrana based on comprehensive assessment of the available adverse event

information. A causal association for Daytrana often cannot be reliably established in individual cases. Further, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.Clinical Trials Experience Adverse Reactions Associated With Discontinuation of Treatment In a 7-week double-blind, parallel-group, placebo-controlled study in children with ADHD conducted in the outpatient setting, 7.1% (7/98) of patients treated with Daytrana discontinued due to adverse events compared with 1.2% (1/85) receiving placebo. The most commonly reported (* 1% and twice the rate of placebo) adverse reactions leading to discontinuation in the Daytrana group were application site reaction (2%), tics (1%), headache (1%), and irritability (1%). In a 7-week double-blind, parallel-group, placebo-controlled study in adolescents with ADHD conducted in the outpatient setting, 5.5% (8/145) of patients treated with Daytrana discontinued due to adverse reactions compared with 2.8% (2/72) receiving placebo. The most commonly reported adverse reactions leading to discontinuation in the Daytrana group were application site reaction (2%) and decreased appetite/anorexia (1.4%). Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Trials Skin Irritation and Application Site Reactions: Daytrana is a dermal irritant. In addition to the most commonly reported adverse reactions pre-sented in Table 2, the majority of subjects in those studies had minimal to definite skin erythema at the patch application site. This erythema generally caused no or minimal discomfort and did not usually interfere with therapy or result in discontinuation from treatment. Erythema is not by itself a manifestation of contact sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the patch site [see Warnings and Precautions (5.6)]. Most Commonly Reported Adverse Reactions: Table 2 lists treatment-emergent adverse reactions reported in * 1% Daytrana-treated children or adolescents with ADHD in two 7 week double-blind, parallel-group, placebo-controlled studies conducted in the outpatient setting. Overall, in these studies, 75.5% of children and 78.6% of adolescents experienced at least 1 adverse event. Adverse Reactions With the Long-Term Use of Daytrana: In a long-term open-label study of up to 12 months duration in 326 children wearing Daytrana 9 hours daily, the most common (* 10%) adverse reactions were decreased ap-petite, headache, and weight decreased. A total of 30 subjects (9.2%) were withdrawn from the study due to adverse events and 22 additional subjects (6.7%) discontinued treatment as the result of an application site reaction. Other than application site reactions, affect lability (5 subjects, 1.5%) was the only additional adverse reaction leading to discontinu-ation reported with a frequency of greater than 1%. In a long-term open-label study of up to 6 months duration in 162 adolescents wearing Daytrana 9 hours daily, the most common (* 10%) adverse reactions were decreased appetite and headache. A total of 9 subjects (5.5%) were withdrawn from the study due to adverse events and 3 additional subjects (1.9%) discontinued treatment as the result of an application site reaction. Other adverse reactions leading to discontinuation that occurred with a frequency of greater than 1% included affect lability and irritability (2 subjects each, 1.2%). Postmarketing Experience In addition, the following adverse reactions have been identified during the post-approval use of Daytrana. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to Daytrana exposure. Cardiac Disorders: palpitation. Eye Disorders: visual disturbances, blurred vision, mydriasis, accommodation disorder. General Disorders and Administration Site Disorders: application site reactions such as bleeding, bruising, burn, burning, dermatitis, discharge, discoloration, discomfort, dryness, eczema, edema, erosion, erythema, excoriation, exfoliation, fissure, hyperpigmentation, hypopigmentation, induration, infection, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, scab, swelling, ulcer, urticaria, vesicles, and warmth. Immune System Disorders: hypersensitivity reactions including generalized erythematous and urticarial rashes, allergic contact derma-titis, angioedema, and anaphylaxis. Investigations: blood pressure increased. Nervous System Disorders: convulsion, dyskinesia. Psychiatric Disorders: transient depressed mood, hallucination, nervousness. Skin and Subcutaneous Tissue Disorders: alopecia Adverse Reactions With Oral Methylphenidate Products Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur. Other reactions include: Cardiac: angina, arrhythmia, pulse increased or decreased. Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura. Metabolism/Nutrition: anorexia, weight loss during prolonged therapy. Nervous System: drowsiness, rare reports of Tourette’s syndrome, toxic psychosis. 6ASCULAR��blood pressure increased or decreased, cerebral arteritis and/or occlusion. Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate: Blood/lymphatic: leukopenia and/or anemia. Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma. Psychiatric: transient depressed mood. Skin/Subcutaneous: scalp hair loss. Neuroleptic Malignant Syndrome:�6ERY�RARE�reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause.DRUG INTERACTIONS MAO Inhibitors - Daytrana should not be used in patients being treated (currently or within the preceding two weeks) with monoamine oxidase inhibitors [see Contraindications (4.5)]. Vasopressor Agents - Because of a possible effect on blood pressure, Daytrana should be used cautiously with pressor agents. Hypotension Agents - Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors - Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticon-vulsants (e.g., phenobarbital, phenytoin, primidone), and some tricyclic drugs (e.g., imipramine, clomipramine, desipramine) and selective serotonin reuptake inhibitors. Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing methylphenidate.USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C - Animal reproduction studies with transdermal methylphenidate have not been performed. In a study in which oral methylphenidate was given to pregnant rabbits during the period of organogenesis at doses up to 200 mg/kg/day no teratogenic effects were seen, although an increase in the incidence of a variation, dilation of the lateral ventricles, was seen at 200 mg/kg/day; this dose also produced maternal toxicity. A previously conducted study in rabbits showed teratogenic effects of methylphenidate at an oral dose of 200 mg/kg/day. In a study in which oral methylphenidate was given to pregnant rats during the period of organogenesis at doses up to 100 mg/kg/day, no teratogenic effects were seen although a slight delay in fetal skeletal ossification was seen at doses of 60 mg/kg/day and above; these doses caused some maternal toxicity. In a study in which oral methylphenidate was given to rats throughout pregnancy and lactation at doses up to 60 mg/kg/day, offspring weights and survival were decreased at 40 mg/kg/day and above; these doses caused some maternal toxicity. Adequate and well-controlled studies in pregnant women have not been conducted. Daytrana should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery - The effect of Daytrana on labor and deliv-ery in humans is unknown. Nursing Mothers - It is not known whether methylphenidate is excreted in human milk. Daytrana should be administered to a nursing woman only if the potential benefit justifies the potential risk to the child. Pediatric Use - Daytrana should not be used in children under six years of age, since safety and efficacy in this age group have not been established. Long-term effects of methylphenidate in children have not been well established. Studies with transdermal methylphenidate have not been performed in juvenile animals. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose. The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day. The clinical significance of the long-term behavioral effects observed in rats is unknown. Geriatric Use: Daytrana has not been studied in patients greater than 65 years of age.DRUG ABUSE AND DEPENDENCE Controlled Substance - Daytrana is classified as a Schedule II controlled substance by federal regulation. Abuse - See warning containing drug abuse information [see Boxed Warning]. Dependence - See warning containing drug dependence information [see Boxed Warning]. Manufactured for: Noven Therapeutics, LLC, Miami, FL 33186 By: Noven Pharmaceuticals, Inc., Miami, FL 33186. For more information call 1-877-567-7857 or visit WWW.DAYTRANA.COM. Dot Matrix™ is a trademark of Noven Pharmaceuticals, Inc. Daytrana® is a registered trademark of Noven Therapeutics, LLC. © 2009, 2010 Noven Pharmaceuticals, Inc. This product is covered by US patents including for use with 6,905,016. Last Modified: 11/2010 102086-12 Revised: 11/2010 Noven Therapeutics, LLC DAY-2011-A 03/11

Table 2 - Number (%) of Subjects with Commonly Reported Adverse Reactions (* 1% in the Daytrana Group) in 7-Week Placebo-controlled

Studies in Either Children or Adolescents - Safety Population

Adolescents Children

System Organ Class Preferred term

Placebo N = 72

Daytrana N = 145

Placebo N = 85

Daytrana N = 98

Cardiac Disorders Tachycardia

0 (0) 1 (0.7) 0 (0) 1 (1.0)

Gastrointestinal disorders Abdominal pain Nausea ��6OMITING

0 (0)2 (2.8)1 (1.4)

7 (4.8)14 (9.7)5 (3.4)

5 (5.9)2 (2.4)4 (4.7)

7 (7.1)12 (12.2)10 (10.2)

Investigations Weight decreased 1 (1.4) 8 (5.5) 0 (0) 9 (9.2)

Metabolism and nutrition disorders Anorexia Decreased appetite

1 (1.4)1 (1.4)

7 (4.8)37 (25.5)

1 (1.2)4 (4.7)

5 (5.1)25 (25.5)

Nervous system disorders Dizziness Headache

1 (1.4)9 (12.5)

8 (5.5)18 (12.4)

1 (1.2)10 (11.8)

0 (0)15 (15.3)

Psychiatric disorders Affect lability Insomnia Irritability Tic

1 (1.4)2 (2.8)5 (6.9)0 (0)

0 (0)9 (6.2)16 (11)0 (0)

0 (0)4 (4.7)4 (4.7)0 (0)

6 (6.1)*13 (13.3)7 (7.1)7 (7.1)

* Six subjects had affect lability, all judged as mild and descibed as increased emotionally sensitive, emotionality, emotional instability, emotional lability, and

intermittent emotional

Increased anterior cingulate cortical activity in re-sponse to fearful faces: a neurophysiological bio-marker that predicts rapid antidepressant response to ketamine. Biol Psychiatry. 2009;65:289-295.12. Salvadore G, Cornwell BR, Sambataro F, et al. Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine. Neuropsychopharmacology . 2010;35:1415-1422.13. aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67:139-145. ❒

jor efforts in academia and the phar-maceutical industry to find safer ketamine-like drugs.

Zarate added that his NIMH program is “geared to looking at rapid treatments.” He hopes that having ketamine and scopolamine, which temporarily block the musca-rinic cholinergic receptor, “will serve as a great model to better understand what mechanism is involved in the beginning of an antidepressant re-sponse. We hope this will lead to the development of treatments with a rapid onset of action.”

Clinical practiceAs regards his clinical work with ketamine at UCSD, Dr Feifel had this to say:

You have patients who have been severely depressed for years and nothing has helped. Both patients and their provid-ers wonder whether there is any possibility that patients will ever be free of their depres-sion. Part of our goal is to see whether their nervous system is amenable to turning off depression through some sort of biological intervention, such as ketamine. So if ketamine is able to turn off a patient’s depression, even for one day, you have accomplished some-thing important, whether or not you can maintain it. This is because you have at least given the patient hope . . . that in itself is very significant from a therapeutic perspective.

References1. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psy-chiatry. 2006;163:28-40.2. Machado-Vieira R, Salvadore G, Ibrahim LA, et al. Targeting glutamatergic signaling for the develop-ment of novel therapeutics for mood disorders. Curr P harm Des. 2009;15:1595-1611.3. Hashimoto K, Sawa A, Iyo M. Increased levels of glutamate in brains from patients with mood disor-ders. Biol Psychiatry. 2007;62:1310-1316.4. Berman RM, Cappiello A, Anand A, et al. Antide-pressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.5. Zarate CA Jr, Singh JB, Carlson PJ, et al. A ran-domized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.6. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793-802.7. Price RB, Nock MK, Charney DS, Mathew SJ. Ef-fects of intravenous ketamine on explicit and im-plicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66:522-526.8. DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71:1605-1611.9. Machado-Vieira R, Zarate CA Jr. Proof of concept trials in bipolar disorder and major depressive disor-der: a translational perspective in the search for im-proved treatments. Depression Anxiety. In press.10. Phelps LE, Brutsche N, Moral JR, et al. Family history of alcohol dependence and initial antidepres-sant response to an N-methyl-D-aspartate antago-nist. Biol Psychiatry. 2009;65:181-184.11. Salvadore G, Cornwell BR, Colon-Rosario V, et al.


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NEWS 15PSYCHIATRIC TIMES APRIL 2011www.psychiatr ic t imes.com

by Donald C. Goff, MD

In the February 2011 issue of the Archives of General Psychiatry, Ho and colleagues1 published an

article that examined the relation-ship between long-term antipsychot-ic treatment and brain volume in first-episode schizophrenia patients. That paper triggered considerable media attention. Because it was widely in-terpreted as showing that antipsy-chotics damage the brain, it may have caused many people—both patients and family members—to reconsid-er whether to take their prescribed medication.

As is so often the case, the picture is far from clear.

Ho and colleagues performed structural brain imaging every 3 years for up to 14 years in 211 first-episode patients who had been treated natural-istically. In the beginning, 15% were medication-naive and the majority were treated with first-generation antipsychotics; by the third scan, this had changed to most receiving sec-ond-generation antipsychotics and 23% receiving clozapine. On aver-age, each subject was scanned 3 times and had already been treated for 5 months before the first scan.

The investigators found that gray matter volumes of all brain regions except for the cerebellum decreased over time; white matter volume on average was unchanged. Subjects who had received higher average life-time doses of an antipsychotic had less gray matter at baseline and at all future time points. Neither antipsy-chotic dose nor type of antipsychotic (first-generation, second-generation, or clozapine) appeared to influence the rate at which gray matter loss pro-gressed over time. In contrast, pa-tients who received a low-dose anti-psychotic tended to have modest increases in white matter volume over time compared with modest white matter loss in patients whose lifetime average dose was higher. The only advantage for second-generation antipsychotics over typical antipsy-chotics was a reduction in parietal white matter loss over time.

If we were to draw conclusions from this study alone, it would appear that gray matter loss can’t be altered by reducing antipsychotic exposure or by switching antipsychotic class—it just happens. The one possible benefit of a low-dose antipsychotic,

the preservation of white matter, is of unclear clinical significance, as is the possible increase in parietal white matter with second-generation agents. However, the story gets more complicated as we look earlier in the course of treatment.

Back in 2007, Ho and colleagues2 published a report based on roughly half their current sample. In this anal-ysis, they discovered that antipsy-chotic dose was related to the rate of loss of frontal gray matter, but only in medication-naive patients. Frontal gray matter loss, in turn, correspond-ed with cognitive decline. These rela-tionships disappeared if subjects had been treated with medication before baseline scanning—in these sub-jects, brain-derived neurotrophic fac-tor (BDNF) genotype predicted the rate of gray matter loss and the pattern of cognitive deficits. This suggests that gray matter loss associated with antipsychotic dose may have been missed entirely in the recent publica-tion by Ho and colleagues because it may occur very early in treatment—before the baseline scan in the great majority of subjects.

Many additional potential con-founds complicate these findings. First, it’s not possible to determine whether higher antipsychotic doses are contributing to the progression of brain loss or are merely a response to it. In the absence of an untreated control group, it’s also not possible to detect neurotoxic effects of drugs that are not related to dose and, with-out a healthy control group, it is not clear which changes in brain volume are pathological.

Animal studies can begin to ad-dress these issues. A study in mon-keys conducted by David Lewis’ group prompted concern about anti-psychotic neurotoxicity several years ago. Monkeys treated with haloper-idol and olanzapine for 17 to 27 months lost roughly 10% of their total brain volume, both gray and white matter, compared with sham-treated controls, with greatest volume loss in frontal and parietal cortex.3 Further examination revealed a reduction in the number of glial cells4; a similar postmortem finding in schizophrenia brains previously had been attributed to the illness. However, this study in-cluded only 6 monkeys per treatment group and did not provide informa-tion on the time course of neurotoxic changes.

Other studies suggest that antipsy-chotic effects on brain volume may occur rapidly. For example, Vernon and colleagues5 found a significant loss of frontal cortical volume after only 8 weeks in rats given haloperidol or olanzapine.

Evidence of the rapidity at which antipsychotics can affect brain vol-ume in humans was recently provided by Tost and associates.6 These inves-tigators found a significant, revers-ible decrease in striatal volume in healthy subjects within 2 hours after they were treated intravenously with haloperidol. Loss of striatal volume powerfully predicted neurological adverse effects.

Taken together, these studies sug-gest that antipsychotics may contrib-ute to early gray matter loss and, later in the course of treatment, to white matter loss. These effects may be dose-related and probably are not prevented by the use of second-gen-eration agents. This argues for mini-mizing antipsychotic exposure both

acutely and long-term. However, we are left with the additional dilemma that a longer duration of untreated psychosis (DUP) may also be neuro-toxic. Longer DUP has been associ-ated with poorer symptomatic and functional outcomes7 as well as brain volume loss.8 Studies of DUP have their own methodological limitations and controversies, but they should serve to warn us that the rapid control of psychosis may also be important.

Psychosis at any phase of the ill-ness can be extremely distressing, disruptive, and potentially dangerous for patient and family. New approach-es for early intervention are needed and, with existing drugs, the potential for neurotoxicity must be weighed against short-term and long-term clinical gains. In the meantime, clini-cians should avoid using antipsychot-ics unnecessarily and, when needed, use the lowest effective dose.

Antipsychotics and the Shrinking Brain

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(Please see Antipsychotics, page 16)

AntipsychoticsContinued from page 15

by Rick Kam, CIPP

As a practicing psychiatrist, your day is spent with your pa-tients; you listen to them de-

scribe their health histories and you administer mental health tests, pre-scribe medication, engage in therapy, and review patients’ records. When do you have time to think about the best way to protect all of the patient information you gather daily? And in the event your laptop computer, per-sonal digital assistant (PDA), or smart phone is lost or stolen, what do you need to do if any of these devices contained patient information?

My objective is to give the practic-ing psychiatrist a short primer on how to address these 2 questions: • How do you protect the patient

information you have on your laptop computer, PDA, or smart phone?

• What should you do if any of

these devices get lost or stolen and have patient information stored on them?

You are well aware that the psychi-atric patient information you hold is some of the most sensitive and per-sonal health information that exists. At a recent conference where I spoke, many of your colleagues told me they refuse to store patient information on a laptop, PDA, or smart phone, and instead maintain confidential and se-cure paper-based records. While this may reduce the risk of this informa-tion being stolen by electronic means (ie, a hacker breaking into your server or identity thief stealing your laptop), in several states, the unauthorized dis-closure due to loss or theft of paper-based patient records requires legal notification to the affected patients. In California, notification needs to be made within 5 business days from the day a breach is discovered.

What changed on February 17,

2009? Federal legislation called the Health Information Technology for Economic and Clinical Health (HITECH) Act was enacted as part of the American Recovery and Rein-vestment Act. It promotes the adop-tion and meaningful use of health information technology. It also ad-dresses privacy and security concerns with the electronic transmission of health information by strengthening civil and criminal enforcement of the Health Insurance Portability and Ac-countability Act (HIPAA). In short, this act requires that all covered enti-ties or business associates protect pa-tient information and promptly notify individuals if their information is dis-closed in an unauthorized way (ie, lost or stolen with the potential to cre-ate reputational, medical, financial, or other harm, such as identity theft or health care fraud). Within the context of this legislation, you, the psychia-trist, are considered the “covered en-

How to Protect Patient Information—and What to Do if It Gets Lost or Stolen

Risk Analysis

by Eric Nelson, CIPP, Director, Breach Prevention

Any health care practitioner who collects, manages, and stores

patient information faces the risk that his or her data may be

lost, misused, or accessed by or disclosed to unauthorized indi-

viduals. While technology (eg, encryption) may provide some

level of protection, it is only one component of an effective

security program.

The Health Insurance Portability and Accountability Act

(HIPAA) Security and Privacy Rules apply to all covered entities,

regardless of size, and require the implementation of adminis-

trative, technical, and physical safeguards. The fi rst step, and

required under the Security Rule–Administrative Safeguards,

is to perform a risk analysis. The HIPAA risk analysis require-

ment specifi cally states:

Conduct an accurate and thorough assessment of the

potential risks and vulnerabilities to the confi dentiality,

integrity, and availability of electronic protected health

information held by the organization.

Although the Security Rule applies only to electronic health

information, the Privacy Rule requires safeguarding any type

or medium of protected health information (PHI). Steps to per-

form a risk analysis are:

1. Identify the information that your practice collects, man-

ages, and shares. How can you protect something when you

don’t know what you have to protect? Many health care orga-

nizations perform some type of security assessment and de-

velop privacy and security policies, but many don’t take the

crucial fi rst step and actually perform an inventory of their or-

ganization’s personal information and understand the internal

and external fl ow of that information.

2. Identify third-party risks. What are the external sources

of PHI? Do you work with vendors or consultants who create,

receive, maintain, or share the personal information of your

patients? Have you implemented third-party agreements re-

quiring information safeguards and HIPAA compliance?

3. Identify and document potential threats and vulnerabil-

ities. How do employees access personal information? How

do you restrict unauthorized access to information? Have your

employees been trained to access and protect PHI appropri-

ately? Do you currently encrypt the information that you store

or transmit?

4. Assess security measures, policies, and procedures. Do

you have the appropriate policies and procedures in place to

reduce risks and vulnerabilities? Have you assigned security

responsibility? Do you have policies and procedures in place

regarding access and storage of PHI? Do you share informa-

tion with third parties and have agreements in place that re-

quire them to safeguard your information?

5. Determine the level of risk and potential impact of threats.

A smaller organization (eg, a solo practice) may have more

control. However, such organizations are still required to deter-

mine their level of risk and the impact of all threats and vulner-

abilities that may affect the “confi dentiality, integrity, and avail-

ability of electronic protected health information held by the

organization.”

HIPAA security compliance requirements provide some fl ex-

ibility, which is based on an organization’s size and complexi-

ty. However, performing a risk analysis and documenting risks

and steps taken to mitigate those risks is a requirement of the

Security Rule. Finally, risk analysis is not a one-time exercise.

Rather, it is an ongoing process that should provide an organi-

zation with a detailed understanding of its risks and informa-

tion necessary to address those risks in a timely manner, and

the means to reduce associated risks to reasonable and appro-

priate levels.

Additional information can be found at the US Department of

Health and Human Services Web site (http://www.hhs.gov/ocr/

privacy/hipaa/understanding/srsummary.html). ■

SIDEBAR

PRACTICE MANAGEMENT16 APRIL 2011www.psychiatr ic t imes.com

PSYCHIATRIC TIMES

Dr Goff is director of the Schizophrenia Pro-

gram at Massachusetts General Hospital and

professor of psychiatry at Harvard Medical

School in Boston.

References

1. Ho BC, Andreasen NC, Ziebell S, et al. Long-term antipsychotic treatment and brain volumes: a longi-tudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011;68:128-137.2. Ho BC, Andreasen NC, Dawson JD, Wassink TH. Association between brain-derived neurotrophic fac-tor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psy-chiatry. 2007;164:1890-1899.3. Dorph-Petersen KA, Pierri JN, Perel JM, et al. The influence of chronic exposure to antipsychotic med-ications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in ma-caque monkeys. Neuropsychopharmacology. 2005;30:1649-1661.4. Konopaske GT, Dorph-Petersen KA, Pierri JN, et al. Effect of chronic exposure to antipsychotic medica-tion on cell numbers in the parietal cortex of ma-caque monkeys. Neuropsychopharmacology. 2007;32:1216-1223.5. Vernon AC, Natesan S, Modo M, Kapur S. Effect of chronic antipsychotic treatment on brain structure: a serial magnetic resonance imaging study with ex vivo and postmortem confirmation. Biol Psychiatry. 2010 Dec 30; [Epub ahead of print].6. Tost H, Braus DF, Hakimi S, et al. Acute D2 receptor blockade induces rapid, reversible remodeling in hu-man cortical-striatal circuits. Nat Neurosci. 2010;13:920-922.7. Marshall M, Lewis S, Lockwood A, et al. Associa-tion between duration of untreated psychosis and outcome in cohorts of first-episode patients: a sys-tematic review. Arch Gen Psychiatry. 2005;62:975-983.8. Malla AK, Bodnar M, Joober R, Lepage M. Duration of untreated psychosis is associated with orbital-frontal grey matter volume reductions in first episode psychosis. Schizophr Res. 2011;125:13-20. ❒

Erratum

In “Demystifying Health Re-form Legislation” in our March 2011 issue (page 26), James C. Pyles, JD, presents an update on the status of implementation of health care reform legislation. An error appears in the section entitled “The need for health re-form.” Mr Pyles notes that a December 2010 report from the Bipartisan Deficit Reduction Committee concludes (among other things) that federal health spending represents our single largest fiscal challenge and goes on to say that “The legislation includes specific recommenda-tions to reduce health care spend-ing between now and 2020.” That sentence should have read, “The report includes specific recommendations to reduce health care spending between now and 2020.” We regret the error. ❒

17APRIL 2011 PRACTICE MANAGEMENT

e-mail from being intercepted and read without your or your patient’s authorization.

Privacy policy. Implement a pri-vacy policy not to accept patient in-formation over the Web or by unse-cured e-mail. Have a written policy that you and your staff adhere to spe-cific electronic transmission of pa-tient information. While this may not stop all of your patients from sending you information in this way, it makes it clear that you do not want to receive it in this form.

Security assessment. Perform a se-curity assessment and determine where your patient information is. The HITECH Act requires an annual security assessment to determine vul-nerabilities in your security of patient information. This assessment should also help you understand where your office stores patient information to-day and how it is shared or transmit-ted to other providers, payers, and your patients. Many breaches occur because doctors do not know where these data are kept and how the in-formation flows to others in day-to-day practice. There are experts who can help with this assessment (see Sidebar, “Risk Analysis,” by Eric Nelson).

Buy data breach insurance. A new insurance product has emerged over the past few years to mitigate the financial cost of a breach of patient information. It covers the majority of costs associated with responding to a breach—including computer fo rensics investigation, consumer notification, legal advice, identity

tity.” An example of a business asso-ciate would be the company where you host and manage your e-mail and practice management systems.

Protecting patient information is an essential part of maintaining pa-tient trust. Yet you might ask, does the HITECH Act apply to me and my practice or small clinic? The answer is more than likely “yes”—especially if you use an electronic health record system to bill your patients or for in-surance claims. And, remember: the state data breach notification laws also apply to your practice. So where do you start with regard to protecting your patient information? The sug-gestions I outline here are for solo practitioners.

Protecting patient informationData encryption. Implement data en-cryption on your laptop, PDA, or smart phone. Data encryption makes information unreadable on these de-vices by unauthorized persons (ie, someone who stole your laptop). It also provides safe harbor under the HITECH Act and state breach notifi-cation laws. This means that the data are considered secure; as such, the re-quirement to notify individuals is eliminated. You can buy data encryp-tion software at your local computer store.

Use secure e-mail. E-mail services are available that provide encrypted transmission and other protections to ensure security and regulatory com-pliance. Free e-mail tools are avail-able that provide adequate privacy and security controls and protect your

theft monitoring, and victim resto-ration services. Talk to your insur-ance professional to understand your options and obtain a policy that is right for your practice (see Sidebar, “Data Breach Insurance,” by Mark Camillo).

What to do if you discover a data breachNow that you have taken reasonable steps to protect patient information, let’s talk about what you do if you dis-cover a data breach. Let me start by highlighting a few examples that might alert you that a data breach has occurred. • You walk into your office in the

morning and your office assistant tells you that someone has stolen all the computers and backup disk drives

• You are sitting on an airplane get-ting ready to fly home from a con-ference and suddenly realize you forgot your smart phone in the taxi . . . or was it the restaurant

• You return to your car after at-tending to several patients at your clinic and realize your car has been broken into and your back-pack containing paper-based pa-tient files is missing

• Your home computer with patient records is displaying a flashing message telling you it has been taken over by a virus and all of the files have been forwarded to everyone in your electronic ad-dress book

If you find yourself facing any of these scenarios, this doesn’t neces-sarily mean you have a data breach situation. If your patient information was encrypted and you implemented the suggestions outlined in this ar-ticle, your patient information is se-cure and would not trigger federal or state data breach notification laws. However, read on for suggestions if this was not the case.

Determine what the laws are. Call your attorney to determine whether there are federal or state data breach notification laws that apply to the sit-uation. The circumstances of each data breach are unique and the laws that apply are evolving. Your attorney can determine the specific laws that apply and provide legal advice on how to comply.

Determine what data were lost. Engage a computer forensics expert to determine what data were lost or stolen and whether there is a potential for misuse. It is important to first un-derstand whether there was patient information on the affected device. This is easier said than done, because in many cases, you may not know

what information was on your device. Patient information may have been in a spreadsheet or document or an in-surance claim file. A forensics expert can also determine whether any of the information was accessed and who accessed the information. You may be able to confirm that there was no pa-tient data on the device or that no one accessed it, which reduces the risk of it being misused.

Deploy the breach response team. This is the group of professionals who you designate to manage the response to the data breach. It includes your at-torney, forensics expert, office man-ager, and others who can provide an effective response so you can remain productive in your practice. The re-sponse team provides crisis manage-ment and manages all of the vendors who help with consumer notification; call center services; and identity pro-tection services that mitigate the reg-ulatory, reputational, legal, and other risks of a data breach. You can engage an organization that manages this process if the available resources are not available to you or your practice. It is best to engage such an organiza-tion before a breach and to get an agreement for services.

Notify affected patients and the ap-propriate regulatory agencies. This step is the foundation for both federal and state compliance with the breach notification provisions of the various laws. It helps the patients affected by a breach take action to protect them-selves from identity theft and other forms of health care fraud. If the breach involved 500 or more records, you will be required to notify Health and Human Services and in some cases local media concurrently. Many organizations also notify the state at-torneys general and insurance com-missioners where affected individu-als live. Expect the Office of Civil Rights to initiate an investigation of a breach of more than 500 records and be prepared to show the steps your practice had taken to protect patient information and to close se-curity gaps that caused the breach.

Mr Kam is president and co-founder of ID

Experts, which is a leader in comprehensive

data breach solutions. The company contrib-

utes to relevant legislation and rules, includ-

ing HITECH, and is a corporate member of

Healthcare Information and Management

Systems Society (HIMSS). ID Experts is ac-

tive with privacy organizations, including

ANSI/Identity Theft Prevention, Identity Man-

agement Standards Panel, and the Inter-

national Association of Privacy Profession-

als. For more information, visit http://www.

idexpertscorp.com. ❒

17PSYCHIATRIC TIMES

www.psychiatr ic t imes.com

Data Breach Insurance

by Mark Camillo, Vice President—Professional Liability, Chartis Insurance

The demand for security/privacy insurance is growing rapidly as health care prac-

titioners realize that traditional insurance does not address privacy exposures.

The cost to notify affected individuals adds up quickly, particularly if the clinician

must provide some form of credit monitoring, hire legal and public relations fi rms

to mitigate reputational damage, and pay for a computer forensic investigation.

Lawsuits that may arise from a breach are costly to defend, even if groundless,

and class action lawsuits are on the rise. Regulatory actions are becoming more

common and can impose a signifi cant fi nancial burden on even a well-capitalized

practice.

Applying for coverage has been simplifi ed, and the cost has come down dra-

matically over the past few years. As such, security/privacy insurance has become

a good value for most organizations. Specialty risk protection insurance is sold

by coverage part, so you can buy what you need and have access to the latest en-

hancements, including:

• Express coverage for claims arising from breaches of confi dential informa-

tion considered “electronic-protected health information”

• Coverage for regulatory actions and fi nes/penalties (where insurable by law)

• Flexible event management options (eg, covering forensic investigation ex-

penses, costs to notify and provide identity monitoring for individuals whose

personal information is compromised)

For additional information, go to http://www.chartisinsurance.com or e-mail [email protected]. ■

SIDEBAR

Helping Your Patients While Minimizing Your Risks

PRACTICE MANAGEMENT

by Robindra K. Paul, MD, DPH, MBA, Christopher Lockey, MD,

Ryan C. W. Hall, MD, and Harold J. Bursztajn, MD

Following trends in medicine, psychiatry is faced with limited resources and third-party ad-

ministration of resource allocation. This has affected psychiatric practice in many ways and altered the doc-tor-patient relationship. Trends to-ward resource-sensitive, third-party–related psychiatric practice may be accelerated by the current social con-cerns regarding the economy. Thus, an awareness of social context and the growing recognition that autonomy-enhancing alternatives to paternalis-tic care are fundamental to improve both the effectiveness and accessibil-ity of care in limited-resource en-vironments are each becoming vital for an informed clinical and risk-management practice perspective.1

To increase the likelihood of effec-tive help for patients, psychiatrists need to know how third-party admin-istration and limited resources influ-ence their practice. It is also important to ask whether an individual who presents for help is actually willing to as-sume sufficient responsibility for his or her care to benefit from what help is available. Psychiatrists must also understand how to follow up if treat-ments are not covered or claims are denied. In addition, when a psychia-trist leaves a preferred provider net-work, he also needs to know what steps can be taken to ensure continu-ity of care for patients.

Practicing within the standard of carePsychiatric practice is affected by limited resources administered by third parties such as managed care organizations.2 The persistence of ir-rational beliefs—such as the convic-tion that medical care (including psy-chiatric care) occurs in a vacuum of unlimited resources—is among the biggest impediments to adequate care and risk management for clinicians and patients.3 As Voltaire recognized, “the better [perfect] is the enemy of the good.”4

The limited resources that face psychiatrists include relatively short face-to-face time with patients, a fi-

nite number of sessions budgeted to treat insured patients on an inpatient and outpatient basis, and the ongoing struggle to provide care for the unin-sured. One way to cope is to practice in a more cost-effective manner. This may include using screening instru-ments such as patient questionnaires, using limited time more effectively, and prescribing generic equivalents instead of brand-name medications whenever possible. Used critically, evidence-based practice guidelines may offer direction for more cost-effective treatment.5 Other mental health providers, such as physician assistants or psychiatric nurses, can see patients for routine visits at a lower overall cost.

Screening instruments help sepa-rate persons who may benefit from psychiatric care from those for whom it may not be helpful or may even be counterproductive. For example, in-dividuals who are actively abusing substances need to commit to being substance-free before they will bene-fit from psychiatric care. Similarly, the autonomy of long-standing para-noid patients with schizoid or avoid-ant traits who drop in and out of treat-ment needs to be respected.

Even in an environment of limited resources, psychiatrists can make treatment recommendations that fit the patient’s problems. This means being informed about laws, profes-sional ethics, and standards of care that can be learned through training, continuing education, and consulta-tion with colleagues.

Malpractice standards vary state by state. In California, for example, a representative standard for medical

malpractice was described in the 1976 California Supreme Court case of Landeros v Flood.6 The case stan-dard states: “A physician is required to exercise, in both diagnosis and treatment, that reasonable degree of knowledge and skill which is ordinar-ily possessed and exercised by other members of his profession in similar circumstances.” A key phrase here is “in similar circumstances.”6

A psychiatrist’s care may fall below the standard of care if, for ex-ample, he fails to conduct an adequate risk assessment of a suicidal patient, or if he prescribes a medication—eg, a neuroleptic—without informing the competent patient about the potential for tardive dyskinesia or metabolic

syndrome. It is important to distin-guish optimal care from care that is sufficient to meet the standard of care. The standard of care can be met in a variety of ways. What a physician can do may be limited by considerations that range from respect for a patient’s autonomy to resources that are avail-able when a problem arises.

It helps for the clinician to be flex-ible in coordination and communi-cation and to consider the limits of doctor-patient confidentiality. For ex-ample, in the outpatient setting, en-listing help from other office mem-bers in dealing with a patient in crisis can bring about efficient transfer to the hospital. Coordinating the man-agement of a patient’s acute psycho-social stressors with social workers may allow more time for a treatment session.

Physicians should avoid unrealis-tic expectations about available re-sources and the utility of those re-

sources. This includes refraining from expressing unrealistic hope that certain treatments will be successful when research data indicate other-wise or from practicing defensive medicine by considering hospitaliza-tion inevitably to be the best treat-ment. For some, hospitalization can be counterproductive insofar as it undermines a patient’s ability or mo-tivation to be responsible for his own treatment. Similarly, any short-term benefit of a forced hospitalization must be weighed against the potential risk of undermining the potential for a therapeutic alliance with a care-avoiding patient.

When working with limited re-sources, it is important to use ap-proaches that respect patient autono-my and are cost-effective. Approach-es that respect patient autonomy promote good clinical practice and, with proper documentation and con-sultation, good risk management. Critical consideration of evidence-based guidelines and being open to the use of decision aids and systems approaches to patient care can also be of help.5,7

Understanding health plans to provide care and anticipate risksPsychiatrists should be knowledge-able about the benefits provided un-der their patients’ health care plans. There are significant differences among plans, whether they are pri-vate or government-sponsored orga-nizations. Most health care plans, in-cluding HMOs and PPOs, use evi-dence-based guidelines as a road map to decide what treatments are ap-proved and in their review of phy-sicians’ recommendations. Under-standing the basics of each plan, such as the recommended formularies and approved treatment, will allow you and your patients to make more in-formed decisions.

Plans list certain mental illnesses as “coverable.” For each illness, plans specify approved treatments and the contexts in which those treatments can be prescribed. Although medica-tion may be covered, many brand-name medications will not be ap-proved until there have been trials of generic alternatives. A patient may not be able to continue to take certain


PSYCHIATRIC TIMES

CHECK POINTS

The persistence of irrational beliefs—such as the conviction that medical care, including psychiatric care, occurs in a vacuum of unlimited re sources—is among the biggest impediments to adequate care and risk management.

Practicing in a more cost-effective manner may include use of screening instruments, using limited time more effectively, and using generic equivalents instead of brand-name medications whenever possible.

In light of third-party administration and the need for more efficiency amid limited resources, respecting patient autonomy has become increasingly important in clinical practice.

Managing Risks When Practicing in Three-Party Care Settings

PRACTICE MANAGEMENT

protect the managed care organiza-tion when benefits are denied but may not protect the clinician. In sum, understanding covered conditions and treatment allows both psychia-trists and patients to better under-stand the most cost-effective ways to proceed with treatment. This also allows psychiatrists and patients to anticipate any potential denial of benefits and, therefore, prospectively plan for potential alternatives to care.

brand-name medications started as an inpatient when outpatient use of those medications is not covered by his plan. In this situation, switching to a generic or other alternative treat-ment may lead to the loss of any short-term gain as the patient transitions to outpatient care. That is, such transi-tions may involve hidden transaction costs, such as when the patient is uninformed of the potential conse-quences of switching from a brand-name to a generic medication. For example, patients may be left without medications for a while, until they can see their outpatient provider. Also, alternative treatments may not be as effective as the inpatient treat-ment. In both of these cases, the trans-action cost is the increased risk of decompensation of the patient. Thus, a lack of planning, information, and communication increases the risk of an eventual negative outcome, in-cluding possible rehospitalization.

In light of third-party administra-tion and the need for more efficiency amid limited resources, respect for patient autonomy has become in-creasingly important in clinical prac-tice. Encouraging patients to learn about their illness, to reduce stress, to take responsibility for avoidance of substance use, and to understand their plan promotes thoughtful pa-tient decisions about where to access care.8 This also allows patients to make more informed decisions about treatment, including when they may be required, or may even elect, to pay for services out-of-pocket.

If benefits are denied by a health care plan, psychiatrists may appeal on behalf of patients or, alternative-ly, educate patients about their rights so that patients can pursue their own appeals. This is especially important in cases where there is no adequate alternative to care. However, the like-lihood of a successful appeal must be considered in light of informa-tion such as that from the New York Insurance Department, which indi-cates that of 11,179 appealed deci-sions to 15 HMOs, only 38% were successful.9

Even in cases where an insurance company acts egregiously, such as by denying standard care, patients who sue their health care plan providers may be limited to recovering only the benefit itself or a monetary equivalent under the Employee Retirement In-come Security Act of 1974 (ERISA).10 Recovery cannot be gained from plans covered under ERISA for ex-penses lost and personal injury, in-cluding pain and suffering, because of an inappropriate denial of benefits.10

Administrative guidelines may

How to provide for continuity of care when leaving an insurance panelPsychiatrists occasionally choose to leave a third-party insurance panel. When this occurs, the psychiatrist must continue to address issues such as limited resources available to pro-vide continued mental health treat-ment; obligations to patients, includ-ing guarding against actual and per-ceived abandonment; and following

contractual specifications and ethical guidelines in providing a smooth transition to another mental health provider.

When psychiatrists leave insur-ance panels, patients must receive adequate notification and continuity of care to reduce the risk that a patient will decompensate or “be lost to fol-low-up.” More planning and assis-

(Please see Three-Party Care Settings, page 20)


• When added to a stimulant, extended-release Kapvay™ demonstrated statistically signifi cant improvement of ADHD symptoms compared with a stimulant alone at the end of 5 weeks of treatment, as measured by the ADHD RS-IV total score

IndicationKapvay™ (clonidine hydrochloride) extended-release tablets are indicated for the treatment of attention defi cit/hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications in children and adolescents ages 6-17. The effi cacy of Kapvay™ is based on the results of 2 clinical trials in children and adolescents.

Kapvay™ is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome.

The effectiveness of Kapvay™ for longer-term use (more than 5 weeks) has not been systematically evaluated in controlled trials; therefore, the physician electing to use Kapvay™ for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Important Safety Information• Kapvay™ should not be used in patients with known hypersensitivity to clonidine

• Kapvay™ can cause dose-related decreases in blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope

• Somnolence/Sedation were commonly reported adverse reactions in clinical studies with Kapvay™. Potential for additive sedative effects with CNS-depressant drugs. Advise patients to avoid use with alcohol. Caution patients against operating heavy equipment or driving until they know how they respond to Kapvay™

• Patients should be instructed not to discontinue Kapvay™ therapy without consulting their physician due to the potential risk of withdrawal effects. Kapvay™ should be discontinued slowly in decrements of no more than 0.1 mg every 3 to 7 days

• In patients who have developed localized contact sensitization or other allergic reaction to clonidine in a transdermal system, substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash, urticaria, or angioedema. Use cautiously in patients with vascular disease, cardiac conduction disease, or chronic renal failure: Monitor carefully and uptitrate slowly

• Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs

• Use caution when Kapvay™ is administered concomitantly with antihypertensive drugs, due to the additive pharmacodynamic effects (e.g., hypotension, syncope)

• Kapvay™ should not be used during pregnancy unless clearly needed. Since clonidine hydrochloride is excreted in human milk, caution should be exercised when Kapvay™ is administered to a nursing woman

• Caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers) due to a potential for additive effects, such as bradycardia and AV block

• Clonidine, the active ingredient in Kapvay™, is also approved as an antihypertensive. Do not use Kapvay™ in patients concomitantly taking other clonidine-containing products, (e.g., Catapres® [clonidine hydrochloride], JENLOGA)

• Common adverse reactions (incidence at least 5% and twice the rate of placebo) include: somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain

Extended-Release Formulation

© 2011 Shionogi Pharma, Inc. Atlanta, Georgia. All rights reserved. KAP10-PAD-002-00

* Kapvay™ was FDA approved on September 28, 2010.

Kapvay™ is a trademark of Shionogi Pharma, Inc.Catapres® is a registered trademark of Boehringer Ingelheim.

Please see Brief Summary of full Prescribing Information on the adjacent page.

When you treat Attention Defi cit/Hyperactivity Disorder (ADHD) with stimulants, for some patients, a question may be...

PRACTICE MANAGEMENT

a patient is in crisis, he may need to refer to the initial insurance panel contract or review the contract with a lawyer to determine his obligation to the patient and the steps required for the patient’s transition. The following recommendations assume a “stable” patient population.

Many of the notification steps that a medical practitioner should take when leaving a panel are similar to

tance during transitions of care may be required for patients in crisis. Some insurance panels require that treating psychiatrists continue to care for a patient in crisis even if the psy-chiatrist leaves the panel. Therefore, if a psychiatrist leaves a panel while

those that psychiatrists take when re-tiring from practice. For example, when psychiatrists retire, they need to notify their patients of the closure of their practice, help patients find a new psychiatrist, offer to forward records to the new treating psychia-trist and, if possible, be available for emergencies for a reasonable period while the patient is transitioning to a new therapist.11 The difference be-

tween retiring from practice and leaving a panel is that in the latter case a patient may choose to continue to be treated by the psychiatrist, but the patient needs to be notified of the change and how it may affect the doctor-patient relationship.12,13

Patients can be notified that a phy-sician has retired or has left an insur-ance panel via letter, by informing patients during a session, or by post-

Three-Party Care SettingsContinued from page 19


PSYCHIATRIC TIMES

KAPVAY (clonidine hydrochloride) extended-release tablets, oral, Rx only INDICATIONS AND USAGE

KAPVAY™ is a centrally acting alpha2-adrenergic agonist indicated for the treatment of

attention deficit hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications. (1)

The efficacy of KAPVAY is based on the results of two clinical trials in children and adolescents. (14) Maintenance efficacy has not been systematically evaluated, and patients who are continued on longer-term treatment require periodic reassessment. (1)

This extended-release formulation of clonidine hydrochloride is also approved for the treatment of hypertension under the trade name JENLOGA. (1)

CONTRAINDICATIONSKAPVAY should not be used in patients with known hypersensitivity to clonidine.

WARNINGS AND PRECAUTIONS

Hypotension/BradycardiaTreatment with KAPVAY can cause dose related decreases in blood pressure and heart rate. In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -8.8 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -7.3 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on KAPVAY 0.2 mg/day and -7.7 beats per minute on KAPVAY 0.4 mg/day.During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on KAPVAY 0.2 mg/day and -5.6 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on KAPVAY 0.2 mg/day and -5.4 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on KAPVAY 0.2 mg/day and -3.0 beats per minute on KAPVAY 0.4 mg/day.Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use KAPVAY with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, because it can decrease blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use KAPVAY with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated.

Sedation and SomnolenceSomnolence and sedation were commonly reported adverse reactions in clinical studies. In patients that completed 5 weeks of therapy in a controlled fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day vs 7% of placebo treated patients reported somnolence as an adverse event. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with KAPVAY+stimulant vs 8% treated with placebo+stimulant reported somnolence. Before using KAPVAY with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with KAPVAY. Advise patients to avoid use with alcohol.

Abrupt DiscontinuationNo studies evaluating abrupt discontinuation of KAPVAY in children with ADHD have been conducted. In children and adolescents with ADHD, physicians should gradually reduce the dose of KAPVAY in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue KAPVAY therapy without consulting their physician due to the potential risk of withdrawal effects.In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety.In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.

Allergic ReactionsIn patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash.In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

Patients with Vascular Disease, Cardiac Conduction Disease, or Renal FailureClonidine hydrochloride should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease or chronic renal failure.

Other Clonidine-Containing ProductsClonidine, the active ingredient in KAPVAY, is also approved as an antihypertensive. Do not use KAPVAY in patients concomitantly taking other clonidine-containing products, (e.g. Catapres®).

ADVERSE REACTIONS

Clinical Trial ExperienceTwo KAPVAY ADHD clinical studies evaluated 256 patients who received active therapy, in one of the two placebo-controlled studies (Studies 1 and 2) with primary efficacy end-points at 5-weeks.

Study 1: Fixed-dose KAPVAY Monotherapy Study 1 was a multi-center, randomized, double-blind, placebo-controlled study with primary efficacy endpoint at 5 weeks, of two fixed doses (0.2 mg/day or 0.4 mg/day) of KAPVAY in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes.Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2.

Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Treatment period (Study 1)

Preferred Term

Percentage of Patients Reporting Event KAPVAY

0.4 mg/day N=78

KAPVAY 0.2 mg/day

N=76

Placebo (N=76)

Somnolence1 31% 38% 5% Headache 19% 29% 18% Upper Abdominal Pain 13% 20% 17% Fatigue2 13% 16% 1% Upper Respiratory Tract Infection 6% 11% 4% Irritability 6% 9% 3% Throat Pain 6% 8% 3% Nausea 8% 5% 4% Nightmare 9% 3% 0 Dizziness 3% 7% 5% Insomnia 6% 4% 1% Emotional Disorder 5% 4% 1% Constipation 6% 1% 0 Dry Mouth 5% 0 1% Nasal Congestion 5% 3% 1% Body Temperature Increased 1% 5% 3% Gastrointestinal Viral 0% 7% 4% Diarrhea 1% 4% 3% Ear Pain 0 5% 1% Nasopharyngitis 3% 3% 1% Abnormal Sleep-Related Event 1% 3% 0 Aggression 1% 3% 1% Asthma 1% 3% 1% Bradycardia 4% 0 0 Enuresis 4% 0 0 Influenza like Illness 3% 1% 1% Tearfulness 3% 1% 0 Thirst 3% 1% 0 Tremor 3% 1% 0 Epistaxis 0 3% 0 Lower Respiratory Tract Infection

0 3% 1%

Pollakiuria 0 3% 0 Sleep Terror 0 3% 0

1. Somnolence includes the terms “somnolence” and “sedation”.2. Fatigue includes the terms “fatigue” and “lethargy”.Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3.

Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Taper period* (Study 1)

Preferred Term

Percentage of Patients Reporting Event KAPVAY

0.4 mg/day N=78

KAPVAY 0.2 mg/day

N=76

Placebo (N=76)

Abdominal Pain Upper 6% 0 3% Headache 2% 5% 3% Gastrointestinal Viral 5% 0 0 Somnolence 3% 2% 0 Heart Rate Increased 3% 0 0 Otitis Media Acute 0 3% 0

*Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6-8; Placebo dose, weeks 6-8

Study 2: Flexible-dose KAPVAY as Adjunctive Therapy to PsychostimulantsStudy 2 was a multi-center, randomized, double-blind, placebo-controlled study, with primary efficacy endpoint at 5 weeks, of a flexible dose of KAPVAY as adjunctive therapy to a psychostimulant in children and adolescents (6 to 17 years) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. KAPVAY was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most KAPVAY treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day.

Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 4.

PRACTICE MANAGEMENT 21PSYCHIATRIC TIMES APRIL 2011www.psychiatr ic t imes.com

ing an announcement in the office. The last 2 methods can be problem-atic. In terms of risk management, it may be helpful to inform patients in writing with a letter to ensure that the patient has been notified. It is advisable to send patients at high risk for adverse transition-of-care events a certified letter at least 30 days be-fore leaving the panel to en-sure its receipt. The letter should in-

able psychiatrists still in the panel.• Records will be sent to the patient’s

new doctor on request.The earlier the notification before

the actual termination the better, be-cause it allows the patient more time to decide whether he wishes to con-tinue with the psychiatrist or find a new one. It can be a lengthy process to find a new therapist (depending on the availability of psychiatrists in the

community). While it may be thera-peutic to inform a patient during a session, oral communication does not provide sufficient documentation to prevent a malpractice suit (since it may become a “he said, she said” issue). It is not enough to inform pa-tients merely with an announcement in the office because patients can le-gitimately claim not to have noticed the announcement.

Electronic means such as e-mails, instant messaging, blogs, or Web sites may soon become an acceptable way to notify patients. However, from a risk management stance, electronic communication is not currently the best means of communication be-cause of potential confidentiality is-sues and Health Insurance Portabil-ity and Accountability Act (HIPAA) concerns.14-17 Also, if a psychiatrist corresponds electronically, he needs to respond as quickly to an e-mail as to a telephone call. For some psychi-atrists, this means of communication is less practical or less efficient.16,17

If a patient “chooses” to terminate his relationship with a psychiatrist when the psychiatrist leaves the panel, the patient may be asked to sign a “voluntary termination of treat-ment” form during the final visit. This form should clearly indicate that the patient:• Is choosing to leave treatment.• Has been given a list of referrals or

has been referred to the insurance provider to obtain a list.

• Understands that the psychiatrist with whom he is terminating will be available for emergencies for at least 30 days or until he finds a new psychiatrist.This practice encourages sound

documentation for rebuttal for any subsequent allegation of abandon-ment made by the patient.

It is not a psychiatrist’s obligation to find a new psychiatrist for the pa-tient but rather to “assist” the patient in doing so. This is usually accom-plished by providing names and num-bers of other practitioners or contact information for the local mental health department. It is important to provide patients with as much fore-warning as possible because in some locations it may take 6 to 8 weeks to obtain an appointment with a new therapist.

SummaryIn third-party, resource-adminis-tered, time-limited environments, it is vital to be mindful of fundamental principles, particularly in the midst of the stress of decision making under conditions of uncertainty.7 This in-

(Please see Three-Party Care Setting, page 22)

form the patient that:• The psychiatrist is leaving the

panel.• The patient may continue to be

seen at the office but may be sub-ject to a different fee schedule.

• If the patient does not express an intention to continue at the office, then his file will be closed.

• The patient can contact the insur-ance company for a list of avail-

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category C: Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day on a mg/m2 basis) produced no evidence of teratogenic or embryotoxic potential. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m2 basis) were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the dams was restricted to gestation days 6-15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the lowest dose employed in this study. No adequate and well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless clearly needed.

Nursing MothersSince clonidine hydrochloride is excreted in human milk, caution should be exercised when KAPVAY is administered to a nursing woman.

Pediatric UseA study was conducted in which young rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood at doses of up to 300 mcg/kg/day, which is approximately 3 times the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis. A slight delay in onset of preputial separation was seen in males treated with the highest dose (with a no-effect dose of 100 mcg/kg/day, which is approximately equal to the MRHD), but there were no drug effects on fertility or on other measures of sexual or neurobehavioral development.

KAPVAY has not been studied in children with ADHD less than 6 years old.

Patients with Renal ImpairmentThe impact of renal impairment on the pharmacokinetics of clonidine in children has not been assessed. The initial dosage of KAPVAY should be based on degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental KAPVAY following dialysis.

Adult Use in ADHDKAPVAY has not been studied in adult patients with ADHD.

DRUG ABUSE AND DEPENDENCEControlled SubstanceKAPVAY is not a controlled substance and has no known potential for abuse or dependence.

OVERDOSAGESymptomsClonidine overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure.

TreatmentConsult with a Certified Poison Control Center for up-to-date guidance and advice.

© 2010 Shionogi Pharma, Inc. Florham Park, NJ 07932 Last modified 10/2010

Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Treatment Period (Study 2)

Preferred Term Percentage of Patients Reporting Event

KAPVAY+STM (N=102)

PBO+STM (N=96)

Somnolence1 19% 8% Fatigue2 16% 4%

Abdominal Pain Upper 12% 7% Nasal Congestion 6% 5% Throat Pain 6% 3% Decreased Appetite 5% 4% Body Temperature Increased 4% 2% Dizziness 4% 2% Insomnia 4% 2% Epistaxis 3% 0 Rhinorrhea 3% 0 Abdominal Pain 2% 1% Anxiety 2% 0 Pain in Extremity 2% 0

1. Somnolence includes the terms: “somnolence” and “sedation”.

2. Fatigue includes the terms “fatigue” and “lethargy”.

Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5.

Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Taper Period* (Study 2)

Preferred TermPercentage of Patients Reporting EventKAPVAY+STM

(N=102)PBO+STM

(N=96)Nasal Congestion 4% 2% Headache 3% 1% Irritability 3% 2% Throat Pain 3% 1% Gastroenteritis Viral 2% 0 Rash 2% 0

*Taper Period: weeks 6-8.

Most common adverse reactions, defined as events that were reported in at least 5% of drug-treated patients and at least twice the rate as in placebo patients, during the treatment period were somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain. The most common adverse reactions that were reported during the taper phase were upper abdominal pain and gastrointestinal virus.Adverse Reactions Leading to DiscontinuationThirteen percent (13%) of patients receiving KAPVAY discontinued from the pediatric monotherapy study due to adverse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of KAPVAY monotherapy treated patients were from somnolence/sedation (5%) and fatigue (4%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: formication, vomiting, prolonged QT, increased heart rate, and rash. In the pediatric adjunctive treatment to stimulants study, one patient discontinued from KAPVAY + stimulant group because of bradyphrenia.

Effects on Laboratory Tests, Vital Signs, and ElectrocardiogramsKAPVAY treatment was not associated with any clinically important effects on any laboratory parameters in either of the placebo-controlled studies.

Mean decreases in blood pressure and heart rate were seen [see Warnings and Precautions (5.1)].

There were no changes on ECGs to suggest a drug-related effect.

DRUG INTERACTIONSNo drug interaction studies have been conducted with KAPVAY in children. The following have been reported with other oral immediate release formulations of clonidine.

Interactions with CNS-depressant DrugsClonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs.

Interactions with Tricyclic AntidepressantsIf a patient is receiving clonidine hydrochloride and also taking tricyclic antidepressants the hypotensive effects of clonidine may be reduced.

Interactions with Drugs Known to Affect Sinus Node Function or AV Nodal ConductionDue to a potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers).

Use with other products containing clonidineDo not use KAPVAY concomitantly with other products containing clonidine (e.g. Catapres®).

Antihypertensive DrugsUse caution when KAPVAY is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope) [see Warnings and Precautions (5.2)].

PRACTICE MANAGEMENT

respect for patients’ autonomy is cru-cial. When clinical time or resources are limited, it is vital to distinguish between patients who want to take responsibility and pseudopatients who are not interested in treatment by reason of character or motive. The

psychiatrist who respects a patient’s autonomy is in the best position to provide wise, effective, nondefensive clinical care while also being able to manage the risks for the practice in resource-constrained third-party treatment environments.

Dr Paul is board-certified in psychiatry and

is a forensic psychiatrist in practice in San

Diego. He completed a fellowship in forensic

psychiatry at Case Western Reserve Uni-

versity in Cleveland and is a past GlaxoSmith-

Kline and Rappeport Fellow. Dr Lockey is

assistant professor of psychiatry at Oregon

Health and Science University in Portland.

He completed a fellowship in forensic psy-

chiatry at Case Western Reserve University.

Dr Hall is an affiliate instructor of psychiatry

at the University of South Florida and a past

Rappeport Fellow of the American Academy

of Psychiatry and the Law. Dr Bursztajn is

cofounder of the Program in Psychiatry and

the Law at Beth Israel Deaconess Medical

Center, department of psychiatry, Harvard

Medical School, Boston. He has an active

clinical and forensic neuropsychiatric prac-

tice. He has been a consulting and testifying

expert for attorneys representing physicians,

patients, and third-party organizations and is

a consultant for independent peer-review or-

ganizations. He is a recipient of the Clifford A.

Barger Excellence in Mentoring Award from

Harvard Medical School.

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Chair in Bioethics. Psychiatric ethics and the rights of

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polfind/Hlth-Ethics.pdf. Accessed January 22, 2009.

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16. Spielberg AR. On call and online: sociohistorical,

legal, and ethical implications of e-mail for the pa-

tient-physician relationship. JAMA. 1998;280:1353-

1359.

17. Recupero PR, Rainey SE. Websites and e-mail in

medical practice: suggestions for risk management.

Med Health R I. 2007;90:173-177. ❒

cludes recognizing that clinical de-cision making in real time contains elements of uncertainty, and thus shared responsibility expressed as a

Three-Party Care SettingContinued from page 21


PSYCHIATRIC TIMES

by Susan Kweskin

United Press International recently reported

that construction workers in Hall, Austria, have

exhumed what may turn out to be grim re-

mains of the Third Reich’s Action T4 program

that sought to exterminate mentally and physi-

cally disabled men, women, and children.1

During recent excavations near a psychiatric

hospital, workers uncovered a mass grave of

220 bodies that had been buried between 1942

and 1945. Those buried may have been victims

of the Nazi’s infamous “euthanasia” program.

They are to be exhumed and efforts will be

made to identify each person and the cause of

death. This process may take up to 2 years.

Under the direction of Philip Bouhler and Dr

Karl Brandt, Hitler’s personal physician, the se-

cret Action T4 program was launched in 1939

to kill disabled children. Later that year, the pro-

gram was expanded to include disabled adults.

Between 70,000 and 200,000 physically or mentally ill men, women, and chil-

dren judged to be “undeserving of life” are believed to have been murdered.

A public outcry led the program to be halted in 1941; nevertheless, evidence

presented at the Nuremberg trials showed that German and Austrian physi-

cians continued to exterminate patients after 1941.2,3 At the psychiatric hospi-

tal at Hall, for example, there was a marked increase in the number of deaths

during the last years of the war.

Between 1940 and 1944, an estimated 30,000 disabled people were killed in

Hartheim castle—the most notorious euthanasia facility in Austria during the

war. The physically and mentally disabled who died there succumbed to gas-

sing or lethal injection. Dr Brandt, then professor of psychiatry at Würzburg

University, made regular visits to the castle.2,3

Action T4 had its roots in Nazi “racial hygienist” policies, which the party

be gan to implement as early as 1933. During that year, the “Law for the Pre-

vention of Hereditarily Diseased Offspring” mandated compulsory steriliza-

tion for people with a range of conditions believed to be hereditary; these

included schizophrenia, “manic depressive insanity,” “congenital mental

defi ciency,” epilepsy, Huntington chorea, blindness, deafness, and severe

deformity.

References

1. Scally D. Mass grave in Austria believed to contain Nazi euthanasia victims. The Irish Times.

January 5, 2011. http://www.irishtimes.com/newspaper/world/2011/0105/1224286779725.html. Ac-

cessed March 8, 2011.

2. Action T4. Wikipedia. http://en.wikipedia.org/wiki/Action_T4. Accessed March 8, 2011.

3. Law for the prevention of hereditarily diseased offspring. http://en.wikipedia.org/wiki/Law_for_

the_Prevention_of_Hereditarily_Diseased_Offspring. Accessed March 14, 2011.

For more information

Lifton RJ. The Nazi Doctors: Medical Killing and the Psychology of Genocide. New York: Basic Books; 2000. ■

Excavation in Austria Uncovers Mass Grave Thought to Hold Nazi Psychiatric Victims

Residents,Do You Like to Write?

Do you have an experience you have learned from during your residency that you would like to share with your colleagues?

Is there a patient interaction that has helped you to become a better doctor? A meaningful lesson you learned from a patient, nurse, or supervisor? A difficulty you en-countered that raised questions about your career path or your ap-proach to patients?

Is there an aspect of your career development you have been think-ing about that may interest other residents as well as practicing psychiatrists?

Psychiatric Times invites con-tributions from residents concern-ing their experiences, challenges, frustrations, and triumphs.

Residents are encouraged to send a brief description of the top-ic they would like to write about, a sample of their writing, and their curriculum vitae to Editor, Psy chiatric Times, 535 Connecti-cut Avenue, Suite 300, Norwalk, CT 06854, or by e-mail to editor@ psychiatrictimes.com. ❒

The poster shown here (from around 1938) reads: “60,000 Reichsmarks is what this per-son suffering from a hereditary disease costs the People’s community during his lifetime. Comrade, that is your money too. Read ‘[A] New People,’ the monthly magazine of the Bureau for Race Politics of the NSDAP.” Courtesy of Wikipedia.

IMPORTANT SAFETY INFORMATION

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo. GEODON is not approved for the treatment of patients with dementia-related psychosis.

GEODON is contraindicated in patients with a known history of QT prolongation, recent acute myocardial infarction, or uncompensated heart failure, and should not be used with certain other QT-prolonging drugs. GEODON has a greater capacity to prolong the QTc interval than several antipsychotics. In some drugs, QT prolongation has been associated with torsade de pointes, a potentially fatal arrhythmia. In many cases this would lead to the conclusion that other drugs should be tried fi rst. Hypokalemia may increase the risk of QT prolongation and arrhythmia.

As with all antipsychotic medications, a rare and potentially fatal condition known as neuroleptic malignant syndrome (NMS) has been reported with GEODON. NMS can cause hyperpyrexia, muscle rigidity, diaphoresis, tachycardia, irregular pulse or blood pressure, cardiac dysrhythmia, and altered mental status. If signs and symptoms appear, immediate discontinuation, treatment, and monitoring are recommended.

Prescribing should be consistent with the need to minimize tardive

dyskinesia (TD), a potentially irreversible dose- and duration-dependent syndrome. If signs and symptoms appear, discontinuation should be considered since TD may remit partially or completely.

Hyperglycemia-related adverse events, sometimes serious, have been reported in patients treated with atypical antipsychotics. There have been few reports of hyperglycemia or diabetes in patients treated with GEODON, and it is not known if GEODON is associated with these events. Patients treated with an atypical antipsychotic should be monitored for symptoms of hyperglycemia.

Precautions include the risk of rash, orthostatic hypotension, and seizures.

Neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery. GEODON should be used during pregnancy only if the potential benefi t justifi es the potential risk to the fetus. Breast feeding is not recommended.

The most common adverse events (≥5%) associated with GEODON in the bipolar maintenance study were tremor and insomnia.

Please see brief summary of prescribing information on adjacent page.

For more information, please visit www.pfi zerpro.com/GEODON

GEODON is indicated for acute treatment as monotherapy of manic or mixed episodes associated with bipolar I disorder and for maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate. For full symptoms and diagnostic criteria, see the DSM-IV-TR® (2000).

BIPOLAR I MAINTENANCE TREATMENT

02-07634E_R1_GEOD.JA_King.indd 1 12/22/10 4:32 PM

GEODON® (ziprasidone HCl) Capsules

GEODON® (ziprasidone mesylate) injection for intramuscular use

BRIEF SUMMARY: See package insert for full prescribing information.

INDICATIONS GEODON is indicated for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as an adjunct to lithium or valproate for the maintenance treatment of bipolar disorder. GEODON intramuscular is indicated for acute agitation in schizophrenic patients.

DOSAGE AND ADMINISTRATION Schizophrenia GEODON Capsules should be administered at an initial daily dose of 20 mg twice daily with food. In some patients, daily dosage may subsequently be adjusted on the basis of individual clinical status up to 80 mg twice daily. Dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, as steady-state is achieved within 1 to 3 days. In order to ensure use of the lowest effective dose, patients should ordinarily be observed for improvement for several weeks before upward dosage adjustment. Efficacy in schizophrenia was demonstrated in a dose range of 20 mg to 100 mg twice daily in short-term, placebo-controlled clinical trials. There were trends toward dose response within the range of 20 mg to 80 mg twice daily, but results were not consistent. An increase to a dose greater than 80 mg twice daily is not generally recommended. The safety of doses above 100 mg twice daily has not been systematically evaluated in clinical trials. Maintenance Treatment—While there is no body of evidence available to answer the question of how long a patient treated with ziprasidone should remain on it, a maintenance study in patients who had been symptomatically stable and then randomized to continue ziprasidone or switch to placebo demonstrated a delay in time to relapse for patients receiving GEODON. No additional benefit was demonstrated for doses above 20 mg twice daily. Patients should be periodically reassessed to determine the need for maintenance treatment. Bipolar I Disorder Acute Treatment of Manic or Mixed Episodes—Dose Selection: Oral ziprasidone should be administered at an initial daily dose of 40 mg twice daily with food. The dose may then be increased to 60 mg or 80 mg twice daily on the second day of treatment and subsequently adjusted on the basis of tolerance and efficacy within the range 40 mg to 80 mg twice daily. In the flexible-dose clinical trials, the mean daily dose administered was approximately 120 mg. Maintenance Treatment (as an adjunct to lithium or valproate)—Continue treatment at the same dose on which the patient was initially stabilized, within the range of 40 mg to 80 mg twice daily with food. Patients should be periodically reassessed to determine the need for maintenance treatment. Acute Treatment of Agitation in Schizophrenia Intramuscular Dosing —The recommended dose is 10 mg to 20 mg administered as required up to a maximum dose of 40 mg per day. Doses of 10 mg may be administered every two hours; doses of 20 mg may be administered every four hours up to a maximum of 40 mg/day. Intramuscular administration of ziprasidone for more than three consecutive days has not been studied. If long-term therapy is indicated, oral ziprasidone hydrochloride capsules should replace the intramuscular administration as soon as possible. Since there is no experience regarding the safety of administering ziprasidone intramuscular to schizophrenic patients already taking oral ziprasidone, the practice of co-administration is not recommended. Ziprasidone intramuscular is intended for intramuscular use only and should not be administered intravenously. Intramuscular Preparation for Administration GEODON for Injection (ziprasidone mesylate) should only be administered by intramuscular injection and should not be administered intravenously. Single-dose vials require reconstitution prior to administration. Add 1.2 mL of Sterile Water for Injection to the vial and shake vigorously until all the drug is dissolved. Each mL of reconstituted solution contains 20 mg ziprasidone. To administer a 10 mg dose, draw up 0.5 mL of the reconstituted solution. To administer a 20 mg dose, draw up 1.0 mL of the reconstituted solution. Any unused portion should be discarded. Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final solution. This medicinal product must not be mixed with other medicinal products or solvents other than Sterile Water for Injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Dosing in Special Populations Oral: Dosage adjustments are generally not required on the basis of age, gender, race, or renal or hepatic impairment. GEODON is not approved for use in children or adolescents. Intramuscular: Ziprasidone intramuscular has not been systematically evaluated in elderly patients or in patients with hepatic or renal impairment. As the cyclodextrin excipient is cleared by renal filtration, ziprasidone intramuscular should be administered with caution to patients with impaired renal function. Dosing adjustments are not required on the basis of gender or race.

CONTRAINDICATIONSQT Prolongation Because of ziprasidone’s dose-related prolongation of the QT interval and the known association of fatal arrhythmias with QT prolongation by some other drugs, ziprasidone is contraindicated in patients with a known history of QT prolongation (including congenital long QT syndrome), with recent acute myocardial infarction, or with uncompensated heart failure (see WARNINGS). Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have not been performed. An additive effect of ziprasidone and other drugs that prolong the QT interval cannot be excluded. Therefore, ziprasidone should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. Ziprasidone is also contraindicated with other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects and have this effect described in the full prescribing information as a contraindication or a boxed or bolded warning [see WARNINGS]. Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.

WARNINGSIncreased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. GEODON is not approved for the treatment of dementia-related psychosis (see BOXED WARNING).

QT Prolongation and Risk of Sudden Death Ziprasidone use should be avoided in combination with other drugs that are known to prolong the QTc interval. Additionally, clinicians should be alert to the identification of other drugs that have been consistently observed to prolong the QTc interval. Such drugs should not be prescribed with ziprasidone. Ziprasidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias (see CONTRAINDICATIONS).

QT Prolongation in Clinical Trials A study directly comparing the QT/QTc prolonging effect of oral ziprasidone with several other drugs effective in the treatment of schizophrenia was conducted in patient volunteers. The mean increase in QTc from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (risperidone, olanzapine, quetiapine, and haloperidol), but was approximately

14 msec less than the prolongation observed for thioridazine. In this study, the effect of ziprasidone on QTc length was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg twice daily). In placebo-controlled trials, oral ziprasidone increased the QTc interval compared to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg. In clinical trials the electrocardiograms of 2/2988 (0.06%) patients who received GEODON and 1/440 (0.23%) patients who received placebo revealed QTc intervals exceeding the potentially clinically relevant threshold of 500 msec. In the ziprasidone-treated patients, neither case suggested a role of ziprasidone. QT Prolongation and Torsade De Pointes Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsade de pointes and with sudden unexplained death. The relationship of QT prolongation to torsade de pointes is clearest for larger increases (20 msec and greater) but it is possible that smaller QT/QTc prolongations may also increase risk, or increase it in susceptible individuals. Although torsade de pointes has not been observed in association with the use of ziprasidone in premarketing studies and experience is too limited to rule out an increased risk, there have been rare post-marketing reports (in the presence of multiple confounding factors) (see ADVERSE REACTIONS). A study evaluating the QT/QTc prolonging effect of intramuscular ziprasidone, with intramuscular haloperidol as a control, was conducted in patient volunteers. In the trial, ECGs were obtained at the time of maximum plasma concentration following two injections of ziprasidone (20 mg then 30 mg) or haloperidol (7.5 mg then 10 mg) given four hours apart. Note that a 30 mg dose of intramuscular ziprasidone is 50% higher than the recommended therapeutic dose. The mean change in QTc from baseline was calculated for each drug, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone was 4.6 msec following the first injection and 12.8 msec following the second injection. The mean increase in QTc from baseline for haloperidol was 6.0 msec following the first injection and 14.7 msec following the second injection. In this study, no patients had a QTc interval exceeding 500 msec. As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported in patients taking ziprasidone at recommended doses. The premarketing experience for ziprasidone did not reveal an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo, but the extent of exposure was limited, especially for the drugs used as active controls and placebo. Nevertheless, ziprasidone’s larger prolongation of QTc length compared to several other antipsychotic drugs raises the possibility that the risk of sudden death may be greater for ziprasidone than for other available drugs for treating schizophrenia. This possibility needs to be considered in deciding among alternative drug products. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval. Electrolyte Disturbances May Increase The Risk of QT Prolongation It is recommended that patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances, hypokalemia in particular, have baseline serum potassium and magnesium measurements. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. Hypokalemia may result from diuretic therapy, diarrhea, and other causes. Patients with low serum potassium and/or magnesium should be repleted with those electrolytes before proceeding with treatment. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment. Persistently prolonged QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients. Rather, ziprasidone should be avoided in patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec. Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients undergoing treatment with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. If signs and symptoms of tardive dyskinesia appear in a patient on ziprasidone, drug discontinuation should be considered. Hyperglycemia and Diabetes Mellitus Hyperglycemia-related adverse events, sometimes serious, have been reported in patients treated with atypical anti-psychotics. There have been few reports of hyperglycemia or diabetes in patients treated with GEODON, and it is not known if GEODON is associated with these events. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia.

PRECAUTIONSLeukopenia, Neutropenia, and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis (including fatal cases) have been reported temporally related to antipsychotic agents. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue GEODON at the first sign of decline in WBC in the absence of other causative factors. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue GEODON and have their WBC followed until recovery. Rash In premarketing trials with ziprasidone, about 5% of patients developed rash and/or urticaria, with discontinuation of treatment in about one-sixth of these cases. The occurrence of rash was related to dose of ziprasidone, although the finding might also be explained by the longer exposure time in the higher dose patients. Several patients with rash had signs and symptoms of associated systemic illness, e.g., elevated WBCs. Most patients improved promptly with adjunctive treatment with antihistamines or steroids and/or upon discontinuation of ziprasidone, and all patients experiencing these reactions were reported to recover completely. Upon appearance of rash for which an alternative etiology cannot be identified, ziprasidone should be discontinued. Orthostatic Hypotension Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia, and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its

1-adrenergic antagonist properties. Syncope was reported in 0.6% of the patients

treated with ziprasidone. Ziprasidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications). Seizures In clinical trials, seizures occurred in 0.4% of patients treated with ziprasidone. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. As with other antipsychotic drugs, ziprasidone should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia, and ziprasidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia (see BOXED WARNING and Increased Mortality in Elderly Patients with Dementia-Related Psychosis in WARNINGS). Hyperprolactinemia As with other drugs that antagonize dopamine D2 receptors, ziprasidone elevates prolactin levels in humans. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is

INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS—Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. GEODON (ziprasidone) is not approved for the treatment of patients with Dementia-Related Psychosis (see WARNINGS).


contemplated in a patient with previously detected breast cancer. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time. Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction in patients treated with ziprasidone. In the 4- and 6-week placebo-controlled trials, somnolence was reported in 14% of patients on ziprasidone compared to 7% of placebo patients. Somnolence led to discontinuation in 0.3% of patients in short-term clinical trials. Since ziprasidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that ziprasidone therapy does not affect them adversely. Priapism One case of priapism was reported in the premarketing database. Body Temperature Regulation Although not reported with ziprasidone in premarketing trials, disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Suicide The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for ziprasidone should be written for the smallest quantity of capsules consistent with good patient management in order to reduce overdose risk. Patients With Concomitant Illnesses Clinical experience with ziprasidone in patients with certain concomitant systemic illnesses is limited. Ziprasidone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of QTc prolongation and orthostatic hypotension with ziprasidone, caution should be observed in cardiac patients (see QT Prolongation and Risk of Sudden Death in WARNINGS and Orthostatic Hypotension in PRECAUTIONS). Information for Patients To assure safe and effective use of GEODON, the information and instructions provided in the patient information should be discussed with patients. Laboratory Tests Patients being considered for ziprasidone treatment who are at risk of significant electrolyte disturbances should have baseline serum potassium and magnesium measurements. Low serum potassium and magnesium should be replaced before proceeding with treatment. Patients who are started on diuretics during Ziprasidone therapy need periodic monitoring of serum potassium and magnesium. Discontinue ziprasidone in patients who are found to have persistent QTc measurements >500 msec (see WARNINGS).

DRUG INTERACTIONS (1) Ziprasidone should not be used with any drug that prolongs the QT interval. (2) Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs. (3) Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain antihypertensive agents. (4) Ziprasidone may antagonize the effects of levodopa and dopamine agonists. Effect of Other Drugs on Ziprasidone Carbamazepine, 200 mg bid for 21 days, resulted in a decrease of approximately 35% in the AUC of ziprasidone. Ketoconazole, a potent inhibitor of CYP3A4, 400 mg qd for 5 days, increased the AUC and Cmax of ziprasidone by about 35-40%. Cimetidine, 800 mg qd for 2 days, did not affect ziprasidone pharmacokinetics. Co-administration of 30 mL of Maalox® did not affect ziprasidone pharmacokinetics. Population pharmacokinetic analysis of schizophrenic patients enrolled in controlled clinical trials has not revealed evidence of any clinically significant pharmacokinetic interactions with benztropine, propranolol, or lorazepam. Effect of Ziprasidone on Other Drugs In vitro studies revealed little potential for ziprasidone to interfere with the metabolism of drugs cleared primarily by CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and little potential for drug interactions with ziprasidone due to displacement. Ziprasidone 40 mg bid administered concomitantly with lithium 450 mg bid for 7 days did not affect the steady-state level or renal clearance of lithium. In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of estrogen or progesterone components. Ziprasidone 20 mg bid did not affect the pharmacokinetics of concomitantly administered oral contraceptives, ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg). Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite, dextrorphan. There was no statistically significant change in the urinary dextromethorphan/dextrorphan ratio.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Lifetime carcinogenicity studies were conducted with ziprasidone in Long Evans rats and CD-1 mice. In male mice, there was no increase in incidence of tumors relative to controls. In female mice, there were dose-related increases in the incidences of pituitary gland adenoma and carcinoma, and mammary gland adenocarcinoma at all doses tested. Increases in serum prolactin were observed in a 1-month dietary study in female, but not male, mice. Ziprasidone had no effect on serum prolactin in rats in a 5-week dietary study at the doses that were used in the carcinogenicity study. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown (see Hyperprolactinemia in PRECAUTIONS). Mutagenesis: There was a reproducible mutagenic response in the Ames assay in one strain of S. typhimurium in the absence of metabolic activation. Positive results were obtained in both the in vitro mammalian cell gene mutation assay and the in vitro chromosomal aberration assay in human lymphocytes. Impairment of Fertility: Ziprasidone increase time to copulation in Sprague-Dawley rats in two fertility and early embryonic development studies at doses of 10 to 160 mg/kg/day (0.5 to 8 times the MRHD of 200 mg/day on a mg/m2 basis). Fertility rate was reduced at 160 mg/kg/day (8 times the MRHD on a mg/m2 basis). There was no effect on fertility at 40 mg/kg/day (2 times the MRHD on a mg/m2 basis). The fertility of female rats was reduced.

USE IN SPECIFIC POPULATIONSPregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Ziprasidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery The effect of ziprasidone on labor and delivery in humans is unknown. Nursing Mothers It is not known whether ziprasidone or its metabolites are excreted in human milk. It is recommended that women receiving ziprasidone should not breastfeed. Pediatric Use The safety and effectiveness of ziprasidone in pediatric patients have not been established. Geriatric Use Of the total number of subjects in clinical studies of ziprasidone, 2.4 percent were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Nevertheless, the presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period for some elderly patients.

ADVERSE REACTIONS Adverse Findings Observed in Short-term, Placebo-Controlled Trials The following findings are based on the short-term placebo-controlled premarketing trials for schizophrenia (a pool of two 6-week, and two 4-week fixed-dose trials) and bipolar mania (a pool of two 3-week flexible-dose trials) in which GEODON was administered in doses ranging from 10 to 200 mg/day. Adverse Events Associated With Discontinuation Schizophrenia: Approximately 4.1% (29/702) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 2.2% (6/273) on placebo. The most common reaction associated with dropout was rash, including 7 dropouts for rash among ziprasidone patients (1%) compared to no placebo patients (see PRECAUTIONS). Bipolar Mania: Approximately 6.5% (18/279) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 3.7% (5/136) on placebo. The most common reactions associated with dropout in the ziprasidone-treated patients were akathisia, anxiety, depression, dizziness, dystonia, rash and vomiting, with 2 dropouts for each of these reactions among ziprasidone patients (1%) compared to one placebo patient each for dystonia and rash (1%) and no placebo patients for the remaining adverse events. Adverse Events at an Incidence of ≥5% and at Least Twice the Rate of Placebo The most commonly observed adverse events associated with GEODON in schizophrenia trials were somnolence (14%) and respiratory tract infection (8%). The most commonly observed adverse events associated with the use of GEODON in bipolar mania trials were somnolence (31%), extrapyramidal symptoms (31%), dizziness (16%),

akathisia (10%), abnormal vision (6%), asthenia (6%), and vomiting (5%). The following list enumerates the treatment-emergent adverse events that occurred during acute therapy, including only those events that occurred in 2% of GEODON patients and at a greater incidence than in placebo. Schizophrenia: Body as a Whole—asthenia, accidental injury, chest pain. Cardiovascular—tachycardia. Digestive—nausea, constipation, dyspepsia, diarrhea, dry mouth, anorexia. Nervous—extrapyramidal symptoms, somnolence, akathisia, dizziness. Respiratory—respiratory tract infection, rhinitis, cough increased. Skin and Appendages—rash, fungal dermatitis. Special Senses—abnormal vision. Bipolar Mania: Body as a Whole—headache, asthenia, accidental injury. Cardiovascular—hypertension. Digestive—nausea, diarrhea, dry mouth, vomiting, increased salivation, tongue edema, dysphagia. Musculoskeletal—myalgia. Nervous—somnolence, extrapyramidal symptoms, dizziness, akathisia, anxiety, hypesthesia, speech disorder. Respiratory—pharyngitis, dyspnea. Skin and Appendages—fungal dermatitis. Special Senses—abnormal vision. Dose Dependency An analysis for dose response in the schizophrenia 4-study pool revealed an apparent relation of adverse reaction to dose for the following reactions: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision. Extrapyramidal Symptoms (EPS) The incidence of reported EPS for ziprasidone patients in the short-term, placebo-controlled schizophrenia trials was 14% vs. 8% for placebo. Objectively collected data from those trials on the Simpson-Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference between ziprasidone and placebo. Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. Elevated risk of acute dystonia is observed in males and younger age groups. Vital Sign Changes Ziprasidone is associated with orthostatic hypotension (see PRECAUTIONS). Weight Gain In short-term schizophrenia trials, the proportions of patients meeting a weight gain criterion of ≥7% of body weight were compared, revealing a statistically significantly greater incidence of weight gain for ziprasidone (10%) compared to placebo (4%). A median weight gain of 0.5 kg was observed in ziprasidone patients compared to no median weight change in placebo patients. Weight gain was reported as an adverse event in 0.4% of both ziprasidone and placebo patients. During long-term therapy with ziprasidone, a categorization of patients at baseline on the basis of body mass index (BMI) revealed the greatest mean weight gain and highest incidence of clinically significant weight gain (>7% of body weight) in patients with low BMI (<23) compared to normal (23-27) or overweight patients (>27). There was a mean weight gain of 1.4 kg for those patients with a “low” baseline BMI, no mean change for patients with a “normal” BMI, and a 1.3 kg mean weight loss for patients who entered the program with a “high” BMI. ECG Changes Ziprasidone is associated with an increase in the QTc interval (see WARNINGS). In the schizophrenia trials, ziprasidone was associated with a mean increase in heart rate of 1.4 beats per minute compared to a 0.2 beats per minute decrease among placebo patients. Other Adverse Events Observed During the Premarketing Evaluation of Ziprasidone in Schizophrenia Frequent adverse events are those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare adverse events are those occurring in fewer than 1/1000 patients. Body as a Whole—Frequent: abdominal pain, flu syndrome, fever, accidental fall, face edema, chills, photosensitivity reaction, flank pain, hypothermia, motor vehicle accident. Cardiovascular System—Frequent: tachycardia, hypertension, postural hypotension. Infrequent: bradycardia, angina pectoris, atrial fibrillation. Rare: first degree AV block, bundle branch block, phlebitis, pulmonary embolus, cardiomegaly, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, myocarditis, thrombophlebitis. Digestive System—Frequent: anorexia, vomiting. Infrequent rectal hemorrhage, dysphagia, tongue edema. Rare: gum hemorrhage, jaundice, fecal impaction, gamma glutamyl trans-peptidase increased, hematemesis, cholestatic jaundice, hepatitis, hepatomegaly, leukoplakia of mouth, fatty liver deposit, melena. Endocrine—Rare: hypothyroidism, hyperthyroidism, thyroiditis. Hemic and Lymphatic System—Infrequent: anemia, ecchymosis, leukocytosis, leukopenia, eosinophilia, lymphadenopathy. Rare: thrombocytopenia, hypochromic anemia, lymphocytosis, monocytosis, basophilia, lymphedema, polycythemia, thrombocythemia. Metabolic and Nutritional Disorders—Infrequent: thirst, transaminase increased, peripheral edema, hyperglycemia, creatine phosphokinase increased, alkaline phosphatase increased, hypercholesteremia, dehydration, lactic dehydrogenase increased, albuminuria, hypokalemia. Rare: BUN increased, creatinine increased, hyperlipemia, hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, glucose tolerance decreased, gout, hyperchloremia, hyperuricemia, hypocalcemia, hypoglycemic reaction, hypomagnesemia, ketosis, respiratory alkalosis. Musculoskeletal System—Frequent: myalgia. Infrequent: tenosynovitis. Rare: myopathy. Nervous System—Frequent: agitation, extrapyramidal syndrome, tremor, dystonia, hypertonia, dyskinesia, hostility, twitching, paresthesia, confusion, vertigo, hypokinesia, hyperkinesia, abnormal gait, oculogyric crisis, hypesthesia, ataxia, amnesia, cogwheel rigidity, delirium, hypotonia, akinesia, dysarthria, withdrawal syndrome, buccoglossal syndrome, choreoathetosis, diplopia, incoordination, neuropathy. Infrequent: paralysis. Rare: myoclonus, nystagmus, torticollis, circumoral paresthesia, opisthotonos, reflexes increased, trismus. Respiratory System—Frequent: dyspnea Infrequent pneumonia, epistaxis. Rare: hemoptysis, laryngismus. Skin and Appendages—Infrequent: maculopapular rash, urticaria, alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous rash. Special Senses—Frequent: fungal dermatitis. Infrequent: conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia. Rare: eye hemorrhage, visual field defect, keratitis, keratoconjunctivitis. Urogenital System—Infrequent: impotence, abnormal ejaculation, amenorrhea, hematuria, menorrhagia, female lactation, polyuria, urinary retention, metrorrhagia, male sexual dysfunction, anorgasmia, glycosuria. Rare: gynecomastia, vaginal hemorrhage, nocturia, oliguria, female sexual dysfunction, uterine hemorrhage. Adverse Findings Observed in Trials of Intramuscular Ziprasidone In these studies, the most commonly observed adverse reactions associated with the use of intramuscular ziprasidone (≥5%) and observed at a rate on intramuscular ziprasidone (in the higher dose groups) at least twice that of the lowest intramuscular ziprasidone group were headache (13%), nausea (12%), and somnolence (20%). Adverse Events at an Incidence of ≥1% in Short-Term Fixed-Dose Intramuscular Trials The following list enumerates the treatment-emergent adverse events that occurred in ≥1% of patients during acute therapy with intramuscular ziprasidone: Body as a Whole—headache, injection site pain, asthenia, abdominal pain, flu syndrome, back pain. Cardiovascular—postural hypotension, hypertension, bradycardia, vasodilation. Digestive—nausea, rectal hemorrhage, diarrhea, vomiting, dyspepsia, anorexia, constipation, tooth disorder, dry mouth. Nervous—dizziness, anxiety, insomnia, somnolence, akathisia, agitation, extrapyramidal syndrome, hypertonia, cogwheel rigidity, paresthesia, personality disorder, psychosis, speech disorder. Respiratory—rhinitis. Skin and Appendages—furunculosis, sweating. Urogenital—dysmenorrhea, priapism. Other Events Observed During Post-marketing Use Adverse reaction reports not listed above that have been received since market introduction include rare occurrences of the following—Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of multiple confounding factors), (see WARNINGS); Digestive System Disorders: Swollen Tongue; Reproductive System and Breast Disorders: Galactorrhea, priapism; Nervous System Disorders: Facial Droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with serotonergic medicinal products), tardive dyskinesia; Psychiatric Disorders: Insomnia, mania/hypomania; Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash; Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension, syncope.

DRUG ABUSE AND DEPENDENCE Controlled Substance Class Ziprasidone is not a controlled substance.

OVERDOSAGE In premarketing trials in over 5400 patients, accidental or intentional overdosage of oral ziprasidone was documented in 10 patients. All patients survived without sequelae. In the patient taking the largest confirmed amount (3240 mg), the only symptoms reported were minimal sedation, slurring of speech, and transitory hypertension (200/95).

GZU00989E © 2011 Pfizer Inc. All rights reserved. Revised January 2011


26 APRIL 2011

Introduction: Looking to the Future of Psychopharmacology

The focus of this Special Report is on some future-oriented aspects of psy-chopharmacology. First, it is an eclectic set of articles

that cover treating resistant depres-sion, using currently illegal drugs to treat psychiatric problems, and fi-nally the potential of using vaccines to treat substance use disorders. Frankly, each of these topics can fill its own Special Report.

One of the considerations in a dis-cussion of the ethics of psychophar-macology is the use of brand-name, expensive drugs versus generics. Sometimes the generics are not equal; there may be a 30% sway in bioavailability between the brand-name drug and available generics. The slow-release technology also differs from brand name to generics and allows for differential adverse-effect issues in practice. This must be weighed against the clear cost difference. Monotherapy approaches are the FDA norm and are speci-fied as first-line treatments in most guidelines. However, monotherapy

does not often yield true remission of symptoms.

Polypharmacy certainly drives up cost and adverse effects, but it ap-pears to be more of the norm in clini-cal practice despite a relative lack of empirical evidence that polypharma-cy is inherently more effective. One could discuss off-label prescribing and the use of this rational polyphar-macy approach. Does the FDA ap-proval process that ultimately allows advertising provide enough evidence to move more risky drugs into early treatment phases in guidelines in-stead of using less risky agents that have less empirical data?

Should unipolar antidepressants be used in bipolar, depressed pa-tients? There is an increased risk of manic escalation with formal antide-pressants; however, they seem to be devoid of the risk of movement dis-orders and severe metabolic dis or-ders that are possible adverse effects of the current bipolar depression–approved atypical antipsychotics. Perhaps we will find nonmonoamine, nonmania-escalating bipolar depres-

CLINICAL PSYCHOPHARMACOLOGY

ALSO IN THIS SPECIAL REPORT:

Special Report Chairperson:Thomas L. Schwartz, MD

by Thomas L. Schwartz, MD

Antidrug VaccinesDaryl Shorter, MD

Thomas R. Kosten, MD

Novel Treatment Avenues for Bipolar DepressionRoger S. McIntyre, MD

Danielle S. Cha

28 37

© Jean Francois Podevin/theispot.com

We'd like to thank David A. Osser, MD, associate professor of psychiatry, Harvard Medical School,

and one of our Editorial Board members for his contributions to this Special Report.

Dr Schwartz is associate professor in the

department of psychiatry at SUNY Upstate

Medical University in Syracuse, NY. He re-

ports that he is on the Speaker’s Bureau for

AstraZeneca and Merck; he has received

research grants from Forest, Cephalon, and

Cyberonics; and he is a consultant for

PamLab. ❒

sues associated with the greater reli-ance and application of psychotropic medications and the risks associated with their use, such as the reverse ef-fects of some antidepressants on the pediatric population and the serious metabolic effects associated with atypical antipsychotics, as well as what some see as overprescription of psychotropic medications.

sion drugs in the research pipeline. In their article, Roger S. McIntyre, MD, and Danielle S. Cha review some novel approaches to the treatment of bipolar depression that include insu-lin sensitizers, anti-inflammatory agents, and glutamate-modulating drugs such as ketamine. Ketamine is a legally prescribed drug, but it also has street value and abuse potential. Investigators are looking into this product, and other glutamate modu-lators, for the treatment of resistant unipolar and bipolar depression.

The article by Daryl Shorter, MD, and Thomas R. Kosten, MD, deals with one of the most interesting ad-vances in psychopharmacological approaches: a vaccine to treat sub-stance use disorders. Simplistically, when we ingest or inject drugs, they enter our bloodstream and make their way across the blood-brain bar-rier where they cause addiction path-ways to fire, allowing for reward pathways and behaviors to occur. A vaccine would allow antibodies in the patient’s system to bind to the ad-dictive drug and mitigate the drug’s ability to cross the blood-brain bar-rier and, thus, reduce the addiction/reward pathway response in the CNS. This might promote less illicit drug use and help promote sobriety.

Upcoming in Part 2In Part 2 of the Special Report com-ing in the May 2011 issue of Psychi-atric Times, Michael C. Mithoefer, MD, reviews the evidence for an-other controlled substance that is not legally prescribed—MDMA (3,4-methylenedioxy-methamphet-amine), or ecstasy. This Class I Drug Enforcement Administration drug was once considered for lower cate-gory III status. It promotes seroto-nergic facilitation, and phase 1 and 2 regulatory data are being collected. Findings from these studies on anxi-ety disorders indicate that MDMA may facilitate psychotherapeutic re-sponse. A whole special issue could be dedicated to illegal drugs or drugs of abuse that are used in psychophar-macology practice, ie, ketamine for depression, MDMA for anxiety, so-dium oxybate (a GHB derivative) for anxiety and, of course, our currently widespread use of sedatives, hypnot-ics, and stimulants.

The availability of psychotropic medications has improved the lives of millions of patients with severe mental illness. However, the in-creased use of these medications has created ethical and societal concerns. Laura Roberts, MD, explores the is-

CLINICAL PSYCHOPHARMACOLOGYAPRIL 2011 27PSYCHIATRIC TIMES


At Western Psychiatric Institute and Clinic ofUPMC, we take on complex disorders that otherswon’t even attempt to treat.

Whether a patient has a difficult-to-treat disorderor one more easily treated, teams of specialistsin psychiatry, psychopharmacology, clinicalpsychology, and medicine craft complete,individualized treatment plans that draw uponthe latest clinical research, much of it conductedby our own investigators. Our work to advancethe understanding and treatment of bipolardisorder, eating disorders, autism, and geriatricbehavioral health issues is world-class. In fact,

we have one of themost comprehensive programsfor mood disorders, with research-basedtreatments for patients at every level of need, atevery stage of life.

With nearly 400 inpatient psychiatric beds and 50ambulatory programs, we care for people whenthey’re feeling their worst and support themwhen they’re at their best, back with their familiesin their communities. Each year, WesternPsychiatric helps people of all ages — at allstages of recovery, from all over the world —live healthier andmore productive lives. To learnmore, visit UPMCPhysicianResources.com.

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Looking for ResidentsResi dents are encouraged to send their CVs along with topic pro-posals and writ ing samples to Editor, Psychiatric Times, 535 Connec ticut Avenue, Suite 300, Norwalk, CT 06854, or e-mail to [email protected]. ❒

by Daryl Shorter, MD and Thomas R. Kosten, MD

S ubstance use disorders (SUD) are recognized worldwide as causes of negative medical,

psychological, and social outcomes, and they result in significant person-al consequences for affected persons, their families, and society at large. Treatment of SUD has focused on a combination of pharmacotherapy and behavioral therapies in an effort to improve patients’ chances of suc-cessfully entering and maintaining recovery.

Antidrug vaccines are a poten-tially important class of medications currently under investigation. They represent yet another frontier in the ongoing quest for novel pharmaco-logical strategies that could be easily integrated into treatment plans to re-duce substance use and establish ab-stinence. Ultimately, these vaccines reflect an important shift in our con-ceptualization of drugs of abuse, ie, that these substances are “foreign” and that the body’s own defenses can be used against them.

Mechanisms of actionDrugs of abuse act centrally on the reward and reinforcement pathways of the brain. After introduction into the body, via oral, intranasal, inha-lation, or intravenous route, these substances rapidly enter the brain to

activate target neurotransmitter sys-tems. One factor of particular impor-tance in addiction pharmacology re-lates to the size of the molecule, because substances of abuse must be small enough to traverse the blood-brain barrier. Once in the brain, the initial common pathway of the ad-dictive process is through stimula-tion of dopamine release from the ventral tegmental area to the nucleus accumbens; this, in part, determines the addictive liability of a substance.

Although the use of a vaccine to treat chemical dependency—an ill-ness characterized by its multifacto-

rial etiology and biopsychosocial underpinnings—sounds like a con-cept from the pages of a science fic-tion novel, the field of addictions treatment is much closer than many may realize. Interestingly, the idea of treating SUD using immunological means was introduced almost 40 years ago.

In 1972, based on an animal study, Berkowitz and Spector1 published their findings on the creation of a morphine vaccine. In rats, adminis-tration of a morphine hapten–bovine serum albumin (a carrier protein) was found to result in the creation of antimorphine antibodies. These anti-bodies were observed to reduce the plasma concentration of the drug in rats and to decrease self-administra-tion of heroin in rhesus monkeys.2

Fact or Science Fiction?

Antidrug Vaccines

CLINICAL PSYCHOPHARMACOLOGY APRIL 2011PSYCHIATRIC TIMES www.psychiatr ic t imes.com

28

What is already known about antidrug vaccines?

They are medically safe and effective in reducing abuse of cocaine and nicotine in humans through a mechanism of competitive antagonism.

What new information does this article add?

It provides a brief summary of the studies done with these vaccines over the past 15 years when they were first tested in humans and updates the status of their development in ongoing multisite randomized clinical trials.

What are the implications for psychiatric practice?

Addictions, particularly nicotine dependence in psychotic patients, are the most common disorders in psychiatric practice. Nicotine has a few pharmacotherapies, but no blocking therapies, and the efficacy of existing treatments is relatively lim-ited. Medical safety issues have also arisen with varenicline, the most effective agent, which is a partial blocker. Cocaine addiction has no FDA-approved therapies. For both these disorders, vaccines are significant additions to the treatment options and should be available commercially within a few years.

I’m driving the MassPike west

just before sunset, blacktop cleared

of snow, the only car for miles

after a late April storm. The distant

silhouettes of bare trees line up

along the Berkshire hills like the stubble

of my three-day beard, and wild clouds

spin arcs of steel-bar-blue, Creedence

on the radio singing “Fortunate Son,”

me remembering my father

like I always do at dusk on the highway,

1954, riding shotgun in our new Olds-

mobile sedan on Route 1, traffic

streaming toward us from the glow

of New York City, my father warning

me that twilight and dawn are the most

dangerous times to drive. In a few days

I will listen for his voice again when

I turn around and drive east at sunrise,

rehearsing my testimony for the trial

of a drug dealer accused of murder.

“Crazy or sane?” they will ask me,

“Life in a hospital ward or slow death

in a prison yard?” The defendant’s father

will be speeding down the MassPike, too,

the sun’s glare filling our eyes with tears,

both of us driving blind.

Dr Berlin is associate professor of psychiatry at the University of Massachusetts Medical School. E-mail: [email protected]. He is the author of The Prophecy, published by Pudding House Press. ❒

Expert Witness

by Richard M. Berlin, MD

Poetry of theTimes

(Please see Vaccines, page 30)

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and symptoms of toxicity, and to pro-tect against overdose. These agents are akin to other immunoglobulin treatments for a wide array of ill-nesses, including malignancies and infectious diseases.

Antidrug vaccines work via active immunization, where administration of the vaccine triggers an immuno-logical response against the agent.5 Immunological memory is created, whereby re-exposure to the agent (ie, through booster injection) results in amplification of the initial response. Because the immune system has been primed by vaccination, later in-troduction of the agent produces an antigen-specific, IgG-mediated anti-body response. These antibodies bind the substance of abuse and cre-ate immune complexes too large to cross the blood-brain barrier; as such, they trap the drug in the circu-lation and allow it to be cleared from the system. The individual’s subjec-tive experience (ie, euphoria) and reward are reduced, which also af-fects the reinforcing nature of the drug.

Drugs of abuse do not typically cause the user to mount an immuno-logical response with the creation of antibodies capable of binding and clearing the substance. Thus, in cre-ating antidrug vaccines, the targeted substance of abuse (ie, drug hapten) must be conjugated to a molecule that carries immunogenicity—such as a foreign carrier protein (eg, inac-tivated cholera toxin, bovine serum albumin). The effectiveness of the vaccine is then measured by its abil-ity to create antibodies with specific-ity and high binding affinity for the drug of abuse and the robustness of the antibody response, ie, the con-centration of antibody produced.6

Clinical trials of substance abuse vaccines that targ et both cocaine and nicotine dependence are ongo-ing. Phase 1 and 2 clinical trials of these new medications are dis-cussed below.

Cocaine vaccineThe cocaine vaccine, TA-CD, is a cocaine hapten conjugated to inacti-vated cholera toxin B (Table 1). The vaccine induces a cocaine-specific antibody response. Antibody-bound cocaine molecules are then broken down by cholinesterases in the circu-lation, which convert cocaine into inactive metabolites that are subse-quently excreted.7

In the phase 1 trial (N = 34), TA-CD demonstrated an ability to in-duce the creation of cocaine-specific antibodies in all vaccinated subjects.8

fragments to bind the drug, confining it to the plasma and limiting its distri-bution into tissue.3

Since that time, additional studies of passive immunization for treat-ment of SUD have been conducted. Antibodies specific for methamphet-amine, heroin, and morphine were shown to bind these drugs in the cir-culation, to reduce euphoric effects

followed this study by creating anti-gen-binding fragments through a process of passive immunization. Goats were immunized with PCP, which generated high-affinity anti-body proteins that were then collect-ed from the animal serum and puri-fied. In their final experiment, they administered PCP to dogs and used the PCP-specific antigen-binding

In 1986, Owens and Mayersohn3 highlighted the ability of antibodies to sequester substances of abuse within the circulatory system. The researchers first characterized the pharmacokinetics and clearance of phencyclidine (PCP) in dogs.4 They

VaccinesContinued from page 28


30

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of the high-dose group). Sixteen of 18 participants (89%) successfully completed the study; there were no hospitalizations, deaths, or serious adverse effects.7 The 2 participants who did not complete the study re-ceived only 1 vaccination and did not report any adverse effects before discontinuing treatment.

In the initial phase 2b trial (N = 115), either TA-CD, at a single dose

5 injections). The vaccine demon-strated an ability to elicit an immu-nological response in participants from both the low- and high-dose groups.7 Participants from both groups developed cocaine-specific antibodies that persisted for at least 6 months.10 Mean antibody levels were higher in the high-dose group. Per-sons in this group were also more likely to remain abstinent at 6-month follow-up (89% of the low-dose group experienced a relapse vs 43%

cal pain and/or tenderness at the in-jection site, with no difference be-tween active-treatment and placebo groups. Treatment-related systemic adverse effects that occurred in both groups included tachycardia, elevat-ed temperature, and hypertension.8 It is important to note that there were no serious adverse effects during the 12 months of follow-up.7

In the phase 2a trial (N = 18), TA-CD was administered at 2 dose levels (100 μg � 4 injections, or 400 μg �

Participants reported attenuation in their subjective experience and eu-phoria from smoked cocaine.7,9 The antibody levels did not persist be-yond 1 year; the immunological ef-fect appeared to last approximately 2 to 4 months following the final vac-cination, as evidenced by a decline in the level of circulating antibody within that time span.

Overall, the safety profile for the vaccine was quite favorable. Almost all recipients (33 of 34) reported lo-



Summary of cocaine vaccine trials

Phase Participants Completion rate Dosage(s) Results

1 N = 34, former cocaine abusers 27/34 received all 3 injections • 6 received placebo Cocaine-specific antibody (Ab) • 8 received 13 µg production in all vaccinated • 10 received 82 µg subjects; significantly higher • 10 received 709 µg Ab response in highest-dose group

2a N = 18, treatment-seeking, 16/18 • 9 received 100 µg � 4 injections Subjects in the higher-dose groupcocaine-dependent subjects • 7 received 400 µg � 5 injectionsa produced a more robust Ab response and had a better treatment outcome as measured by proportion of cocaine- positive urine samples submitted throughout treatment; reduction in cocaine use and euphoric effects were reported in both groups

2b N = 115, cocaine-dependent, 94/115 • 47 received placebo Vaccinated subjects stratified into high- methadone-maintained subjects • 47 received 360 µg � 5 injections and low-Ab responders; high-Ab responders with more cocaine-negative urine samples had longer period of abstinence

2b Large-scale multicenter To be completed in 2011 • 400-µg injections at weeks Ongoing 1, 3, 5, 9, and 13

a 8 subjects received booster vaccines (2 subjects received 400 mg and 6 subjects received 2000 µg) between 9 and 12 months.

Nicotine vaccine trials

Vaccine Carrier Completion rate Dosage Results

NicVAXa Pseudomonas aeruginosa 56/68 • Placebo � 4 injections All vaccinated subjects mounted antibody

exoprotein A • 45 vaccine group • 50 µg � 4 injections (Ab) response; Ab titer increased as dose

• 23 placebo group • 100 µg � 4 injections increased; reduced smoking behavior and

• 200 µg � 4 injections higher rates of abstinence in high-dose

group

NicQba Virus-like particle 239/340 • Placebo � 5 injections High-Ab responders’ rate of continuous

• 159/229 vaccine group • 100 µg � 5 injections abstinence found to be statistically

• 80/111 placebo group significant (P > .05) and clinically relevant

in comparison with placebo group

TA-NICb Cholera toxin B 50 smokers, 10 nonsmokers • Placebo � 4 - 6 injections Higher quit rates were observed in the

• 10 g � 4 - 6 injections high-dose vaccine group in comparison

• 50 g � 4 - 6 injections with the control group (38% vs 8%);

however, statistical analysis not reported

because of small cohort size

a Only phase 2 clinical trial information included.b Participants were randomized to 1 of 4 dosing regimens, ranging from a total of 6 to 20 weeks in trial duration and an additional booster injection at week 32.

Table 1

Table 2


demonstrated the ability to mount an immunological response, with serum antibody levels that increased sig-nificantly (P > .05) after each subse-quent dose. Higher quit rates were observed in the high-dose vaccine group than in the control group (38% vs 8%). Note, however, that because of the small cohort size, statistical analysis was not reported.15.17

27%), nasopharyngitis (32% vs 26%), rigors (13.5% vs 0%), and myalgia (13.5% vs 5%).16 NicQb is in phase 2b/3 clinical trials.16

Similar to the cocaine vaccine, TA-NIC is composed of a nicotine hapten conjugated with inactivated cholera toxin B. During the clinical trial to assess safety and immunoge-nicity of the vaccine, participants

The safety of NicQb was found to be favorable overall, although there was a significantly higher rate of re-ported “flu-like symptoms” among recipients of the vaccine than among recipients of placebo (70% vs 12.5%). Other commonly reported adverse effects in the vaccine group included pyrexia (42% vs 8% in the control group), headache (40% vs

level (360 μg � 5 injections), or pla-cebo was administered to cocaine-dependent, methadone-maintained participants. Those who received the vaccine were analyzed according to response and stratified into high- and low-antibody–producing groups. The high-antibody group showed a greater percentage of cocaine-free urine samples.11 The safety profile of the vaccine was favorable: all severe adverse effects were deemed unre-lated to the vaccine. At present, TA-CD is undergoing large-scale, multi-center, phase 2b clinical testing.

Nicotine vaccineThere are 3 nicotine conjugate vac-cines, NicVAX, NicQb, and TA-NIC (Table 2). NicVAX is composed of a nicotine hapten linked to Pseudo-monas aeruginosa exoprotein A. NicVAX is currently in the second of 2 phase 3 clinical trials; in pre-vious studies, it has been found to produce antibody titers in a linear dose-response fashion.12,13 The nico-tine-specific IgG antibodies pro-duced resulted in a reduction of smoking among vaccinated persons, rather than compensatory smoking behavior.13

NicVAX was well tolerated from a safety standpoint. Local reactivity at the site of vaccination was seen in both placebo and treatment groups, which suggests that these events were related to the adjuvant, rather than vaccine, components. There were no significant differences be-tween groups in terms of commonly reported systemic adverse effects (ie, malaise, headache, myalgia).13

A nicotine hapten structurally similar to that used in NicVAX makes up the core of NicQb. With the NicQb vaccine, however, the nicotine hapten is conjugated to a virus-like particle formed by recom-binant expression of the protein coat of bacteriophage Qb.14 Moreover, this vaccine is not mixed with an alu-minum adjuvant, as is the case with most vaccines.15 In a phase 2 trial, there was no statistically significant difference in rates of continuous ab-stinence between vaccinated persons and controls (P > .05).14 However, when stratified according to anti-body response, those with high anti-body production had higher continu-ous abstinence rates than those who received placebo (56.6% vs 31.3%); the difference between the groups was statistically significant.



32

RISPERDAL® CONSTA® provides ConstaCoverage*—

assurance that antipsychotic medication is on board

when administered every 2 weeks.

*Based on pharmacokinetic properties/plasma concentrations.

RISPERDAL® CONSTA® (risperidone) FOR THE MAINTENANCE TREATMENT

OF BIPOLAR I DISORDER

IMPORTANT SAFETY INFORMATION FOR RISPERDAL® CONSTA® (risperidone)

WARNING: Increased Mortality in Elderly Patients with Dementia-Related

Psychosis Elderly patients with dementia-related psychosis treated with

antipsychotic drugs are at an increased risk of death. Analyses of 17

placebo-controlled trials (modal duration of 10 weeks), largely in patients

taking atypical antipsychotic drugs, revealed a risk of death in the drug-

treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated

patients. Over the course of a typical 10-week controlled trial, the rate of

death in drug-treated patients was about 4.5%, compared to a rate of about

2.6% in the placebo group. Although the causes of death were varied, most

of the deaths appeared to be either cardiovascular (e.g., heart failure,

sudden death) or infectious (e.g., pneumonia) in nature. Observational

studies suggest that, similar to atypical antipsychotic drugs, treatment with

conventional antipsychotic drugs may increase mortality. The extent to

which the findings of increased mortality in observational studies may be

attributed to the antipsychotic drug as opposed to some characteristic(s) of

the patients is not clear. RISPERDAL® CONSTA® is not approved for the

treatment of patients with dementia-related psychosis.

Contraindications: RISPERDAL® CONSTA® is contraindicated in patients with a known hypersensitivity to the product.Cerebrovascular Adverse Events (CAEs): CAEs (e.g., stroke, transient ischemia attacks), including fatalities, were reported in placebo-controlled trials in elderly patients with dementia-related psychosis taking oral risperidone. The incidence of CAEs was significantly higher than with placebo. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications. Clinical manifestations include muscle rigidity, fever, altered mental status,

and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical monitoring, and treatment of any concomitant serious medical problems. Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose, but can develop after relatively brief treatment at low doses. Elderly women patients appeared to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Hyperglycemia and Diabetes: Hyperglycemia, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death has been reported in patients treated with atypical antipsychotics (APS), including RISPERDAL® CONSTA®. Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of anti-diabetic treatment despite discontinuation of the suspect drug.Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

between the practical implications of vaccines, ethical considerations of treatment, and financial realities within society.

Dr Shorter is assistant professor in the

Menninger Department of Psychiatry and Be-

havioral Science at the Baylor College of Med-

may be a day when those persons at increased risk for chemical depen-dency (because of factors such as family history) may elect to prophy-lactically receive antidrug vaccines in an effort to reduce their likelihood of progression to addiction. There-fore, it is important that our ongo-ing conversation about this pharma-cotherapeutic option strike a balance

tions for vaccine trials will likely fo-cus on the use of booster injections to prolong antibody effects and meth-ods for combining immunotherapy with current behavioral approaches.

As we think about the implica-tions of this treatment, alleviating the suffering of those struggling with ac-tive addiction might only be the first step. Although years away, there

ConclusionAntidrug vaccines represent an ex-citing area of development in the pharmacological treatment of chemi-cal dependency. In addition to the clinical trials being conducted on vaccines for cocaine and nicotine de-pendence, preclinical development of vaccines for methamphetamine and heroin is ongoing. Future direc-



In a 52-week adjunctive therapy trial

RISPERDAL® CONSTA®, when added to lithium or valproate, signifi cantly delayed time to relapse vs placebo plus lithium or valproate (P=0.01)1,2

Demonstrated in a 52-week, multicenter,

randomized, double-blind, placebo-controlled

study in 124 patients with Bipolar I Disorder.

Doses of 25, 37.5, or 50 mg were given by

intramuscular injection every 2 weeks, in

addition to their individually defi ned

adjunctive treatment, which consisted

of mood stabilizers (primarily lithium

and/or valproate), antidepressants, and/or

anxiolytics. All other antipsychotics were

discontinued after the fi rst 3 weeks of the

initial injection. Patients who were judged

to be stable for at least the last 4 weeks of

a 16-week, open-label phase were randomized

in the double-blind phase. The primary endpoint

was time to relapse to any new mood episode.1

23.1%

RISPERDAL® CONSTA®

+ lithium or valproate(N=65)

Placebo+ lithium or valproate

(N=59)

30

15

0

45

60

45.8%

Pe

rce

nta

ge

Percentage of patients who relapsed2

References: 1. RISPERDAL® CONSTA® [Prescribing Information]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2. Macfadden W, Alphs L, Haskins JT, et al. A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord. 2009;11:827-839.

Orthostatic Hypotension and Syncope: RISPERDAL® CONSTA® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period. RISPERDAL® CONSTA® should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of MI or ischemia, conduction abnormalities), cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia) and additionally elderly patients with renal or hepatic impairment. Monitoring should be considered in patients for whom this may be of concern. Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including RISPERDAL® CONSTA®. Patients with a history of clinically significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of RISPERDAL® CONSTA® should be considered. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue RISPERDAL® CONSTA® and have their WBC followed until recovery.Potential for Cognitive and Motor Impairment: Somnolence was reported in multiple trials in subjects treated with RISPERDAL® CONSTA®. Since RISPERDAL® CONSTA® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that RISPERDAL® CONSTA® does not adversely affect them. Seizures: RISPERDAL® CONSTA® should be used cautiously in patients with a history of seizures.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Use cautiously in patients at risk for aspiration pneumonia.Priapism has been reported. Severe priapism may require surgical intervention. Thrombotic Thrombocytopenic Purpura (TTP) has been reported.Administration: For intramuscular injection only. Care should be taken to avoid inadvertent injection into a blood vessel. Suicide: The possibility of suicide attempt is inherent in bipolar disorder. Close supervision of high-risk patients should accompany drug therapy.Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies has been reported. Manifestations and features are consistent with NMS.Use RISPERDAL® CONSTA® with caution in patients with conditions and medical conditions that could affect metabolism or hemodynamic responses (e.g., recent myocardial infarction or unstable cardiac disease).Commonly Observed Adverse Reactions for RISPERDAL® CONSTA®:

The most common adverse reactions in clinical trials in patients with bipolar disorder were weight increased (5% in monotherapy trial) and tremor and Parkinsonism (≥10% in adjunctive therapy trial).

Please see accompanying brief summary of full Prescribing

Information for RISPERDAL® CONSTA®.

Visit our Web site at www.JanssenCNS.com/risperdal

© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2011 March 2011 01CS11029

Text CONSTA4 to 30333 or

scan this code with your

smartphone, using a 2D

code reader app, to visit

the RISPERDAL® CONSTA®

mobile Web site.

Standard text and data rates may apply.


RISPERDAL® CONSTA®(risperidone) LONG-ACTING INJECTION

Brief SummaryBEFORE PRESCRIBING RISPERDAL® CONSTA®, PLEASE SEE FULL PRESCRIBING INFORMATION,INCLUDING BOXED WARNING.

RISPERDAL® CONSTA® is indicated as monotherapy or as adjunctive therapy to lithium or valproate forthe maintenance treatment of Bipolar I Disorder [see Clinical Studies (14.2, 14.3) in full PI].

CONTRAINDICATIONS: RISPERDAL® CONSTA® (risperidone) is contraindicated in patients with a knownhypersensitivity to the product.

WARNINGS AND PRECAUTIONS: Increased Mortality in Elderly Patients with Dementia-RelatedPsychosisElderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increasedrisk of death. RISPERDAL® CONSTA® (risperidone) is not approved for the treatment of dementia-relatedpsychosis (see Boxed Warning).Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis:Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reportedin patients (mean age 85 years; range 73-97) in trials of oral risperidone in elderly patients withdementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence ofcerebrovascular adverse events in patients treated with oral risperidone compared to patients treatedwith placebo. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementia-relatedpsychosis. [See also Boxed Warning and Warnings and Precautions] Neuroleptic Malignant Syndrome(NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome(NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS arehyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulseor blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may includeelevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnosticevaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identifycases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemicinfection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Otherimportant considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke,drug fever, and primary central nervous system pathology. The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy;(2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant seriousmedical problems for which specific treatments are available. There is no general agreement aboutspecific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychoticdrug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefullyconsidered. The patient should be carefully monitored, since recurrences of NMS have been reported.Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may developin patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to behighest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimatesto predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. Therisk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed toincrease as the duration of treatment and the total cumulative dose of antipsychotic drugs administeredto the patient increase. However, the syndrome can develop, although much less commonly, afterrelatively brief treatment periods at low doses. There is no known treatment for established cases oftardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatmentis withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs andsymptoms of the syndrome and thereby may possibly mask the underlying process. The effect thatsymptomatic suppression has upon the long-term course of the syndrome is unknown. Given theseconsiderations, RISPERDAL® CONSTA® should be prescribed in a manner that is most likely to minimizethe occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved forpatients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) forwhom alternative, equally effective, but potentially less harmful treatments are not available orappropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration oftreatment producing a satisfactory clinical response should be sought. The need for continued treatmentshould be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient treatedwith RISPERDAL® CONSTA®, drug discontinuation should be considered. However, some patients mayrequire treatment with RISPERDAL® CONSTA® despite the presence of the syndrome. Hyperglycemiaand Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated withketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypicalantipsychotics including RISPERDAL®. Assessment of the relationship between atypical antipsychoticuse and glucose abnormalities is complicated by the possibility of an increased background risk ofdiabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in thegeneral population. Given these confounders, the relationship between atypical antipsychotic use andhyperglycemia-related adverse events is not completely understood. However, epidemiological studiessuggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patientstreated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse eventsin patients treated with atypical antipsychotics are not available. Patients with an established diagnosisof diabetes mellitus who are started on atypical antipsychotics, including RISPERDAL®, should bemonitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g.,obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, includingRISPERDAL®, should undergo fasting blood glucose testing at the beginning of treatment and periodicallyduring treatment. Any patient treated with atypical antipsychotics, including RISPERDAL®, should bemonitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including RISPERDAL®, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL®, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of RISPERDAL®.Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone elevatesprolactin levels and the elevation persists during chronic administration. Risperidone is associated withhigher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppresshypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibitreproductive function by impairing gonadal steroidogenesis in both female and male patients.Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving

prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadismmay lead to decreased bone density in both female and male subjects. Tissue culture experiments indicatethat approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potentialimportance if the prescription of these drugs is contemplated in a patient with previously detected breastcancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammaryadenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicitystudies conducted in mice and rats [see Nonclinical Toxicology]. Neither clinical studies nor epidemiologicstudies conducted to date have shown an association between chronic administration of this class ofdrugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive atthis time. Orthostatic Hypotension: RISPERDAL® CONSTA® may induce orthostatic hypotension associatedwith dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration periodwith oral risperidone, probably reflecting its alpha-adrenergic antagonistic properties. Syncope wasreported in 0.8% (12/1499 patients) of patients treated with RISPERDAL® CONSTA® in multiple-dose studies.Patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence oforthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to standin the morning and slowly rising from a seated position). RISPERDAL® CONSTA® should be used withparticular caution in (1) patients with known cardiovascular disease (history of myocardial infarction orischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which wouldpredispose patients to hypotension, e.g., dehydration and hypovolemia, and (2) in the elderly and patientswith renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all suchpatients, and a dose reduction should be considered if hypotension occurs. Clinically significanthypotension has been observed with concomitant use of oral RISPERDAL® and antihypertensivemedication. Leukopenia, Neutropenia, and Agranulocytosis: Class Effect: In clinical trial and/orpostmarketing experience, events of leukopenia/neutropenia have been reported temporally related toantipsychotic agents, including RISPERDAL® CONSTA®. Agranulocytosis has also been reported. Possiblerisk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and a historyof drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or adrug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequentlyduring the first few months of therapy and discontinuation of RISPERDAL® CONSTA® should be consideredat the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patientswith clinically significant neutropenia should be carefully monitored for fever or other symptoms or signsof infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia(absolute neutrophil count <1000/mm3) should discontinue RISPERDAL® CONSTA® and have their WBCfollowed until recovery. Potential for Cognitive and Motor Impairment: Somnolence was reported by 5% of patients treated with RISPERDAL® CONSTA® in multiple-dose trials. Since risperidone has thepotential to impair judgment, thinking, or motor skills, patients should be cautioned about operatinghazardous machinery, including automobiles, until they are reasonably certain that treatment withRISPERDAL® CONSTA® does not affect them adversely. Seizures: During premarketing testing, seizuresoccurred in 0.3% (5/1499 patients) of patients treated with RISPERDAL® CONSTA®. Therefore,RISPERDAL® CONSTA® should be used cautiously in patients with a history of seizures. Dysphagia:Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspirationpneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia.RISPERDAL® CONSTA® and other antipsychotic drugs should be used cautiously in patients at risk foraspiration pneumonia. [See also Boxed Warning and Warnings and Precautions] Priapism: Priapism hasbeen reported during postmarketing surveillance [see Adverse Reactions (6.9) in full PI]. Severe priapismmay require surgical intervention. Thrombotic Thrombocytopenic Purpura (TTP): A single case of TTPwas reported in a 28 year-old female patient receiving oral RISPERDAL® in a large, open premarketingexperience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventuallyrecovered after receiving plasmapheresis. The relationship to RISPERDAL® therapy is unknown. BodyTemperature Regulation: Disruption of body temperature regulation has been attributed to antipsychoticagents. Both hyperthermia and hypothermia have been reported in association with oral RISPERDAL® orRISPERDAL® CONSTA® use. Caution is advised when prescribing RISPERDAL® CONSTA® for patientswho will be exposed to temperature extremes. Administration: RISPERDAL® CONSTA® should be injectedinto the deltoid or gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel.[See Dosage and Administration (2) and Adverse Reactions (6.8) in full PI] Antiemetic Effect: Risperidonehas an antiemetic effect in animals; this effect may also occur in humans, and may mask signs andsymptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye’ssyndrome, and brain tumor. Suicide: There is an increased risk of suicide attempt in patients withschizophrenia or bipolar disorder, and close supervision of high-risk patients should accompany drugtherapy. RISPERDAL® CONSTA® is to be administered by a health care professional [see Dosage andAdministration (2) in full PI]; therefore, suicide due to an overdose is unlikely. Use in Patients withConcomitant Illness: Clinical experience with RISPERDAL® CONSTA® in patients with certain concomitantsystemic illnesses is limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receiveantipsychotics, including RISPERDAL® CONSTA®, are reported to have an increased sensitivity toantipsychotic medications. Manifestations of this increased sensitivity have been reported to includeconfusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinicalfeatures consistent with the neuroleptic malignant syndrome. Caution is advisable when usingRISPERDAL® CONSTA® in patients with diseases or conditions that could affect metabolism orhemodynamic responses. RISPERDAL® CONSTA® has not been evaluated or used to any appreciableextent in patients with a recent history of myocardial infarction or unstable heart disease. Patients withthese diagnoses were excluded from clinical studies during the product’s premarket testing. Increasedplasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renalimpairment (creatinine clearance <30 mL/min/1.73 m2) treated with oral RISPERDAL®; an increase in thefree fraction of risperidone is also seen in patients with severe hepatic impairment. Patients with renalor hepatic impairment should be carefully titrated on oral RISPERDAL® before treatment withRISPERDAL® CONSTA® is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriatewhen clinical factors warrant dose adjustment, such as in patients with renal or hepatic impairment [seeDosage and Administration]. Osteodystrophy and Tumors in Animals: RISPERDAL® CONSTA® producedosteodystrophy in male and female rats in a 1-year toxicity study and a 2-year carcinogenicity study at adose of 40 mg/kg administered IM every 2 weeks. RISPERDAL® CONSTA® produced renal tubular tumors(adenoma, adenocarcinoma) and adrenomedullary pheochromocytomas in male rats in the 2-yearcarcinogenicity study at 40 mg/kg administered IM every 2 weeks. In addition, RISPERDAL® CONSTA®

produced an increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicitystudy and in renal tumor-bearing males in the 2-year carcinogenicity study at 40 mg/kg administered IMevery 2 weeks. (Cellular proliferation was not measured at the low dose or in females in either study.) Theeffect dose for osteodystrophy and the tumor findings is 8 times the IM maximum recommended humandose (MRHD) (50 mg) on a mg/m2 basis and is associated with a plasma exposure (AUC) 2 times theexpected plasma exposure (AUC) at the IM MRHD. The no-effect dose for these findings was 5 mg/kg(equal to the IM MRHD on a mg/m2 basis). Plasma exposure (AUC) at the no-effect dose was one thirdthe expected plasma exposure (AUC) at the IM MRHD. Neither the renal or adrenal tumors, norosteodystrophy, were seen in studies of orally administered risperidone. Osteodystrophy was notobserved in dogs at doses up to 14 times (based on AUC) the IM MRHD in a 1-year toxicity study. Therenal tubular and adrenomedullary tumors in male rats and other tumor findings are described in moredetail in Section 13.1 in full PI (Carcinogenicity, Mutagenesis, Impairment of Fertility). The relevance ofthese findings to human risk is unknown. Monitoring: Laboratory Tests: No specific laboratory tests are recommended.ADVERSE REACTIONS: The following are discussed in more detail in other sections of the labeling: • Increased mortality in elderly patients with dementia-related psychosis • Cerebrovascular adverseevents, including stroke, in elderly patients with dementia-related psychosis • euroleptic malignantsyndrome • Tardive dyskinesia • Hyperglycemia and diabetes mellitus • Hyperprolactinemia • Orthostatichypotension • Leukopenia/Neutropenia and Agranulocytosis • Potential for cognitive and motor impairment• Seizures • Dysphagia • Priapism • Thrombotic Thrombocytopenic Purpura (TTP) • Disruption of bodytemperature regulation • Avoidance of inadvertent injection into a blood vessel • Antiemetic effect• Suicide • Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSISElderly patients with dementia-related psychosis treated with antipsychotic drugs are at anincreased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largelyin patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients ofbetween 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to arate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deathsappeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia)in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug asopposed to some characteristic(s) of the patients is not clear. RISPERDAL® CONSTA® (risperidone)is not approved for the treatment of patients with dementia-related psychosis. [See Warnings and Precautions]

Risp Consta Brief:Layout 1 3/4/11 12:46 PM Page 1

bodies • Diseases or conditions that could affect metabolism or hemodynamic responses • Osteodystrophyand tumors in animals. The most common adverse reactions in the double-blind, placebo-controlledperiods of the bipolar disorder trials were weight increased (5% in the monotherapy trial) and tremor andparkinsonism (≥ 10% in the adjunctive treatment trial). Adverse reactions that were associated withdiscontinuation from the double-blind, placebo-controlled periods of the bipolar disorder trials werehyperglycemia (one patient in the monotherapy trial) and hypokinesia and tardive dyskinesia (one patienteach in the adjunctive treatment trial). The data described in this section are derived from a clinical trial database consisting of 2392 patients exposed to one or more doses of RISPERDAL® CONSTA®

for the treatment of schizophrenia. Of these 2392 patients, 332 were patients who receivedRISPERDAL® CONSTA® while participating in a 12-week double-blind, placebo-controlled trial. Twohundred two (202) of the 332 were schizophrenia patients who received 25 mg or 50 mgRISPERDAL® CONSTA®. The conditions and duration of treatment with RISPERDAL® CONSTA® in theother clinical trials varied greatly and included (in overlapping categories) double-blind, fixed- andflexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients andoutpatients, and short-term (up to 12 weeks) and longer-term (up to 4 years) exposures. Safety wasassessed by collecting adverse events and performing physical examinations, vital signs, body weights,laboratory analyses, and ECGs. In addition to the studies in patients with schizophrenia, safety data arepresented from a trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administeredas monotherapy for maintenance treatment in patients with bipolar I disorder. The subjects in thismulti-center, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria forBipolar Disorder Type I and who were stable on risperidone (oral or long-acting injection), were stableon other antipsychotics or mood stabilizers, or were experiencing an acute episode. After a 3-week periodof treatment with open-label oral risperidone (n=440), subjects who demonstrated an initial response tooral risperidone in this period and those who were stable on risperidone (oral or long-acting injection) atstudy entry entered into a 26-week stabilization period of open-label RISPERDAL® CONSTA® (n=501).Subjects who demonstrated a maintained response during this period were then randomized into a24-month double-blind, placebo-controlled period in which they received RISPERDAL® CONSTA® (n=154)or placebo (n=149) as monotherapy. Subjects who relapsed or who completed the double-blind periodcould choose to enter an 8-week open-label RISPERDAL® CONSTA® extension period (n=160). Safetydata are also presented from a trial assessing the efficacy and safety of RISPERDAL® CONSTA® whenadministered as adjunctive maintenance treatment in patients with bipolar disorder. The subjects in thismulti-center, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria forBipolar Disorder Type I or Type II and who experienced at least 4 episodes of mood disorder requiringpsychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6 monthsprior to the start of the study. At the start of this study, all patients (n = 275) entered into a 16-weekopen-label treatment phase in which they received RISPERDAL® CONSTA® in addition to continuing theirtreatment as usual, which consisted of various mood stabilizers (primarily lithium and valproate),antidepressants, and/or anxiolytics. Patients who reached remission at the end of this 16-week open-labeltreatment phase (n = 139) were then randomized into a 52-week double-blind, placebo-controlled phasein which they received RISPERDAL® CONSTA® (n = 72) or placebo (n = 67) as adjunctive treatment inaddition to continuing their treatment as usual. Patients who did not reach remission at the end of the16-week open-label treatment phase could choose to continue to receive RISPERDAL® CONSTA® asadjunctive therapy in an open-label manner, in addition to continuing their treatment as usual, for up toan additional 36 weeks as clinically indicated for a total period of up to 52 weeks; these patients (n = 70)were also included in the evaluation of safety. Adverse events during exposure to study treatment wereobtained by general inquiry and recorded by clinical investigators using their own terminology.Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverseevents, events were grouped in standardized categories using MedDRA terminology. Throughout thissection, adverse reactions are reported. Adverse reactions are adverse events that were considered tobe reasonably associated with the use of RISPERDAL® CONSTA® (adverse drug reactions) based on thecomprehensive assessment of the available adverse event information. A causal association forRISPERDAL® CONSTA® often cannot be reliably established in individual cases. Further, because clinicaltrials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trialsof a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflectthe rates observed in clinical practice. The majority of all adverse reactions were mild to moderate inseverity. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials –Bipolar Disorder: Table 2 lists the treatment-emergent adverse reactions reported in 2% or more ofRISPERDAL® CONSTA®-treated patients in the 24-month double-blind, placebo-controlled treatmentperiod of the trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administered asmonotherapy for maintenance treatment in patients with Bipolar I Disorder. Table 2. Adverse Reactionsin ≥2% of Patients with Bipolar I Disorder Treated with RISPERDAL® CONSTA® as Monotherapy in a24-Month Double-Blind, Placebo-Controlled Trial, System/Organ Class, Percentage of Patients ReportingEvent, RISPERDAL® CONSTA® (N=154) first, Placebo (N=149) second, Adverse Reaction, Investigations:Weight increased 5, 1; Nervous system disorders: Dizziness 3, 1; Vascular disorders: Hypertension 3, 1.Table 2 lists the treatment-emergent adverse reactions reported in 4% or more of patients in the 52-weekdouble-blind, placebo-controlled treatment phase of a trial assessing the efficacy and safety ofRISPERDAL® CONSTA® when administered as adjunctive maintenance treatment in patients with bipolardisorder. Table 2. Adverse Reactions in ≥ 4% of Patients with Bipolar Disorder Treated withRISPERDAL® CONSTA® as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled Trial,System/Organ Class, Percentage of Patients Reporting Event, RISPERDAL® CONSTA® + Treatment asUsuala (N=72) first, Placebo + Treatment as Usuala (N=67) second, Adverse Reaction, General disordersand administration site conditions: Gait abnormal 4, 0; Infections and infestations: Upper respiratory tractinfection 6, 3; Investigations: Weight increased 7, 1; Metabolism and nutrition disorders: Decreasedappetite 6, 1; Increased appetite 4, 0; Musculoskeletal and connective tissue disorders: Arthralgia 4, 3;Nervous system disorders: Tremor 24, 16; Parkinsonismb 15, 6; Dyskinesiab 6, 3; Sedationc 7, 1; Disturbancein attention 4, 0; Reproductive system and breast disorders: Amenorrhea 4, 1; Respiratory, thoracic andmediastinal disorders: Cough 4, 1. a Patients received double-blind RISPERDAL® CONSTA® or placeboin addition to continuing their treatment as usual, which included mood stabilizers, antidepressants, and/oranxiolytics. b Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia.Dyskinesia includes muscle twitching and dyskinesia. c Sedation includes sedation and somnolence.Other Adverse Reactions Observed During the Premarketing Evaluation of RISPERDAL® CONSTA®:Thefollowing additional adverse reactions occurred in < 2% of the RISPERDAL® CONSTA®-treated patients in the above schizophrenia double-blind, placebo-controlled trial dataset, in < 2% of theRISPERDAL® CONSTA®-treated patients in the above double-blind, placebo-controlled period of themonotherapy bipolar disorder trial dataset, or in < 4% of the RISPERDAL® CONSTA®-treated patients inthe above double-blind, placebo-controlled period of the adjunctive treatment bipolar disorder trialdataset. The following also includes additional adverse reactions reported at any frequency inRISPERDAL® CONSTA®-treated patients who participated in the open-label phases of the above bipolardisorder studies and in other studies, including double-blind, active controlled and open-label studies inschizophrenia and bipolar disorder. Blood and lymphatic system disorders: anemia, neutropenia Cardiacdisorders: tachycardia, atrioventricular block first degree, palpitations, sinus bradycardia, bundle branchblock left, bradycardia, sinus tachycardia, bundle branch block right Ear and labyrinth disorders: ear pain,vertigo Endocrine disorders: hyperprolactinemia Eye disorders: conjunctivitis, visual acuity reducedGastrointestinal disorders: diarrhea, vomiting, abdominal pain upper, abdominal pain, stomach discomfort,gastritis General disorders and administration site conditions: injection site pain, chest discomfort, chestpain, influenza like illness, sluggishness, malaise, induration, injection site induration, injection siteswelling, injection site reaction, face edema Immune system disorders: hypersensitivity Infections andinfestations: nasopharyngitis, influenza, bronchitis, urinary tract infection, rhinitis, respiratory tractinfection, ear infection, pneumonia, lower respiratory tract infection, pharyngitis, sinusitis, viral infection,infection, localized infection, cystitis, gastroenteritis, subcutaneous abscess Injury and poisoning: fall,procedural pain Investigations: blood prolactin increased, alanine aminotransferase increased,electrocardiogram abnormal, gamma-glutamyl transferase increased, blood glucose increased, hepaticenzyme increased, aspartate aminotransferase increased, electrocardiogram QT prolonged, glucoseurine present Metabolism and nutritional disorders: anorexia, hyperglycemia Musculoskeletal,connective tissue and bone disorders: posture abnormal, myalgia, back pain, buttock pain, muscular

weakness, neck pain, musculoskeletal chest pain Nervous system disorders: coordination abnormal,dystonia, tardive dyskinesia, drooling, paresthesia, dizziness postural, convulsion, akinesia, hypokinesia,dysarthria Psychiatric disorders: insomnia, agitation, anxiety, sleep disorder, depression, initial insomnia,libido decreased, nervousness Renal and urinary disorders: urinary incontinence Reproductive systemand breast disorders: galactorrhea, oligomenorrhea, erectile dysfunction, sexual dysfunction, ejaculationdisorder, gynecomastia, breast discomfort, menstruation irregular, menstruation delayed, menstrualdisorder, ejaculation delayed Respiratory, thoracic and mediastinal disorders: nasal congestion,pharyngolaryngeal pain, dyspnea, rhinorrhea Skin and subcutaneous tissue disorders: rash, eczema,pruritus generalized, pruritus Vascular disorders: hypotension, orthostatic hypotension AdditionalAdverse Reactions Reported with Oral RISPERDAL®: The following is a list of additional adverse reactionsthat have been reported during the premarketing evaluation of oral RISPERDAL®, regardless of frequencyof occurrence: Blood and Lymphatic Disorders: granulocytopenia Cardiac Disorders: atrioventricularblock Ear and Labyrinth Disorders: tinnitus Eye Disorders: ocular hyperemia, eye discharge, eye rolling,eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucomaGastrointestinal Disorders: abdominal pain upper, dysphagia, fecaloma, abdominal discomfort, fecalincontinence, lip swelling, cheilitis, aptyalism General Disorders: thirst, feeling abnormal, gait disturbance,pitting edema, edema, chills, discomfort, generalized edema, drug withdrawal syndrome, peripheralcoldness Immune System Disorders: drug hypersensitivity Infections and Infestations: tonsillitis, eyeinfection, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tractinfection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, heart rateincreased, eosinophil count increased, white blood cell count decreased, hemoglobin decreased, bloodcreatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressuredecreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia Musculoskeletal,Connective Tissue, and Bone Disorders: joint swelling, joint stiffness, rhabdomyolysis, torticollis NervousSystem Disorders: hypertonia, balance disorder, dysarthria, unresponsive to stimuli, depressed level ofconsciousness, movement disorder, hypokinesia, parkinsonian rest tremor, transient ischemic attack,cerebrovascular accident, masked facies, speech disorder, loss of consciousness, muscle contractionsinvoluntary, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome,diabetic coma Psychiatric Disorders: blunted affect, confusional state, middle insomnia, listless,anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria Reproductive System and BreastDisorders: vaginal discharge, retrograde ejaculation, ejaculation disorder, ejaculation failure, breastenlargement Respiratory, Thoracic, and Mediastinal Disorders: epistaxis, wheezing, pneumonia aspiration,dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratorydisorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skindiscoloration, skin lesion, skin disorder, rash erythematous, rash papular, hyperkeratosis, dandruff,seborrheic dermatitis, rash generalised, rash maculopapular Vascular Disorders: flushing DiscontinuationsDue to Adverse Reactions: Bipolar Disorder In the 24-month double-blind, placebo-controlled treatmentperiod of the trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administered as monotherapy for maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154RISPERDAL® CONSTA®-treated patients discontinued due to an adverse reaction (hyperglycemia). In the52-week double-blind phase of the placebo-controlled trial in which RISPERDAL® CONSTA® wasadministered as adjunctive therapy to patients with bipolar disorder in addition to continuing with theirtreatment as usual, approximately 4% (3/72) of RISPERDAL® CONSTA®-treated patients discontinuedtreatment due to an adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adversereactions associated with discontinuation in RISPERDAL® CONSTA®-treated patients were: hypokinesia(one patient) and tardive dyskinesia (one patient). Dose Dependency of Adverse Reactions in ClinicalTrials: Extrapyramidal Symptoms: Two methods were used to measure extrapyramidal symptoms (EPS) inthe 12-week double-blind, placebo-controlled trial comparing three doses of RISPERDAL® CONSTA®

(25 mg, 50 mg, and 75 mg) with placebo in patients with schizophrenia, including: (1) the incidence ofspontaneous reports of EPS symptoms; and (2) the change from baseline to endpoint on the total score(sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal SymptomRating Scale (ESRS). The overall incidence of EPS-related adverse reactions (akathisia, dystonia,parkinsonism, and tremor) in patients treated with 25 mg RISPERDAL® CONSTA® was comparable to thatof patients treated with placebo; the incidence of EPS-related adverse reactions was higher in patientstreated with 50 mg RISPERDAL® CONSTA®. The median change from baseline to endpoint in total ESRSscore showed no worsening in patients treated with RISPERDAL® CONSTA® compared with patientstreated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the placebo group); and0 (50-mg group). Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of musclegroups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptomsinclude: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowingdifficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at lowdoses, they occur more frequently and with greater severity with high potency and at higher doses offirst generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and youngerage groups. Changes in Body Weight: In the 24-month double-blind, placebo-controlled treatment periodof a trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administered as monotherapyfor maintenance treatment in patients with bipolar I disorder, 11.6% of patients treated withRISPERDAL® CONSTA® compared with 2.8% of patients treated with placebo experienced a weight gainof >7% of body weight at endpoint. In the 52-week double-blind, placebo-controlled trial in patients withbipolar disorder, 26.8% of patients treated with RISPERDAL® CONSTA® as adjunctive treatment in additionto continuing their treatment as usual, compared with 27.3% of patients treated with placebo in additionto continuing their treatment as usual, experienced a weight gain of >7% of body weight at endpoint.Changes in ECG: The electrocardiograms of 227 patients with Bipolar I Disorder were evaluated in the24-month double-blind, placebo-controlled period. There were no clinically relevant differences in QTcintervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL® CONSTA®

compared to placebo. The electrocardiograms of 85 patients with bipolar disorder were evaluated in the52-week double-blind, placebo-controlled trial. There were no statistically significant differences in QTcintervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL® CONSTA®

25 mg, 37.5 mg, or 50 mg when administered as adjunctive treatment in addition to continuing treatmentas usual compared to placebo. Pain Assessment and Local Injection Site Reactions: The mean intensityof injection pain reported by patients with schizophrenia using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo:16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratingsindicated that 1% of patients treated with 25 mg or 50 mg RISPERDAL® CONSTA® experienced redness,swelling, or induration at the injection site. In a separate study to observe local-site tolerability in whichRISPERDAL® CONSTA® was administered into the deltoid muscle every 2 weeks over a period of 8 weeks,no patient discontinued treatment due to local injection site pain or reaction. Clinician ratings indicatedthat only mild redness, swelling, or induration at the injection site was observed in subjects treated with37.5 mg or 50 mg RISPERDAL® CONSTA® at 2 hours after deltoid injection. All ratings returned to baselineat the predose assessment of the next injection 2 weeks later. No moderate or severe reactions wereobserved in any subject. Postmarketing Experience: The following adverse reactions have been identifiedduring postapproval use of risperidone; because these reactions are reported voluntarily from a populationof uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia,anaphylactic reaction, angioedema, atrial fibrillation, diabetes mellitus, diabetic ketoacidosis in patientswith impaired glucose metabolism, hypoglycemia, hypothermia, inappropriate antidiuretic hormonesecretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apneasyndrome, thrombocytopenia, urinary retention, and water intoxication. In addition, the following adversereactions have been observed during post approval use of RISPERDAL® CONSTA®: cerebrovasculardisorders, including cerebrovascular accidents, and diabetes mellitus aggravated.DRUG INTERACTIONS: The interactions of RISPERDAL® CONSTA® with coadministration of other drugshave not been systematically evaluated. The drug interaction data provided in this section is based onstudies with oral RISPERDAL®. Centrally-Acting Drugs and Alcohol: Given the primary CNS effects ofrisperidone, caution should be used when RISPERDAL® CONSTA® is administered in combination withother centrally-acting drugs or alcohol. Drugs with Hypotensive Effects: Because of its potential forinducing hypotension, RISPERDAL® CONSTA® may enhance the hypotensive effects of other therapeutic


agents with this potential. Levodopa and Dopamine Agonists: RISPERDAL® CONSTA® may antagonizethe effects of levodopa and dopamine agonists. Amitriptyline: Amitriptyline did not affect thepharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone combined followingconcomitant administration with oral RISPERDAL®. Cimetidine and Ranitidine: Cimetidine and ranitidineincreased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine didnot affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased theAUC of risperidone and 9-hydroxyrisperidone combined by 20%. Clozapine: Chronic administration ofclozapine with risperidone may decrease the clearance of risperidone. Lithium: Repeated doses of oralRISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax)of lithium (n=13). Valproate: Repeated doses of oral RISPERDAL® (4 mg once daily) did not affect thepre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divideddoses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasmaconcentration (Cmax) after concomitant administration of oral RISPERDAL®. Digoxin: Oral RISPERDAL®

(0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin.Topiramate: Oral RISPERDAL® administered at doses from 1-6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone Cmax and a 33% decrease in risperidone AUC0-12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidonecombined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be ofclinical significance. There was no clinically relevant effect of oral RISPERDAL® on the pharmacokineticsof topiramate. Drugs That Inhibit CYP 2D6 and Other CYP Isozymes: Risperidone is metabolized to9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can beinhibited by a variety of psychotropic and other drugs [see Clinical Pharmacology (12.3) in full PI]. Druginteractions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasmaconcentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinicalstudies involving a modest number of poor metabolizers (n=̃70 patients) does not suggest that poor andextensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the twogroups has been made. In vitro studies showed that drugs metabolized by other CYP isozymes, including1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. Fluoxetine andParoxetine: Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, havebeen shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively.Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered theconcentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetineis initiated or discontinued, the physician should re-evaluate the dose of RISPERDAL® CONSTA®. Wheninitiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose ofRISPERDAL® CONSTA® between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapyto adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetineis initiated in patients receiving the recommended dose of 25 mg RISPERDAL® CONSTA®, it isrecommended to continue treatment with the 25-mg dose unless clinical judgment necessitates loweringthe RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA®

treatment. When RISPERDAL® CONSTA® is initiated in patients already receiving fluoxetine or paroxetine,a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigatedin clinical trials. [See also DOSAGE AND ADMINISTRATION (2.5) in full PI]. The effects of discontinuationof concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and9-hydroxyrisperidone have not been studied. Erythromycin: There were no significant interactionsbetween oral RISPERDAL® and erythromycin. Carbamazepine and Other CYP 3A4 Enzyme Inducers:Carbamazepine co-administration with oral RISPERDAL® decreased the steady-state plasmaconcentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations ofcarbamazepine did not appear to be affected. Co-administration of other known CYP 3A4 enzyme inducers(e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in thecombined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreasedefficacy of RISPERDAL® CONSTA® treatment. At the initiation of therapy with carbamazepine or otherknown hepatic enzyme inducers, patients should be closely monitored during the first 4–8 weeks, sincethe dose of RISPERDAL® CONSTA® may need to be adjusted. A dose increase, or additional oralRISPERDAL®, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepaticenzyme inducers, the dosage of RISPERDAL® CONSTA® should be re-evaluated and, if necessary,decreased. Patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeksbefore the planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for theexpected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treatedwith the recommended dose of 25 mg RISPERDAL® CONSTA® and discontinuing from carbamazepine orother CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unlessclinical judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitatesinterruption of RISPERDAL® CONSTA® treatment. The efficacy of the 12.5 mg dose has not beeninvestigated in clinical trials. [See also DOSAGE AND ADMINSTRATION (2.5) in full PI] Drugs Metabolizedby CYP 2D6: In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore,RISPERDAL® CONSTA® is not expected to substantially inhibit the clearance of drugs that are metabolizedby this enzymatic pathway. In drug interaction studies, oral RISPERDAL® did not significantly affect thepharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category C.: The teratogenic potential of oralrisperidone was studied in three embryofetal development studies in Sprague-Dawley and Wistar rats(0.63-10 mg/kg or 0.4 to 6 times the oral maximum recommended human dose [MRHD] on a mg/m2 basis)and in one embryofetal development study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the oralMRHD on a mg/m2 basis). The incidence of malformations was not increased compared to control inoffspring of rats or rabbits given 0.4 to 6 times the oral MRHD on a mg/m2 basis. In three reproductivestudies in rats (two peri/post-natal development studies and a multigenerational study), there was anincrease in pup deaths during the first 4 days of lactation at doses of 0.16-5 mg/kg or 0.1 to 3 times theoral MRHD on a mg/m2 basis. It is not known whether these deaths were due to a direct effect on thefetuses or pups or to effects on the dams. There was no no-effect dose for increased rat pup mortality. Inone peri/post-natal development study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kgor 1.5 times the oral MRHD on a mg/m2 basis. In a cross-fostering study in Wistar rats, toxic effects onthe fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the numberof dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed.In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless ofwhether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior inthat pup body weight gain and survival (from Days 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidonetested, i.e., 5 mg/kg or 3 times the oral MRHD on a mg/m2 basis. No studies were conducted withRISPERDAL® CONSTA®. Placental transfer of risperidone occurs in rat pups. There are no adequate andwell-controlled studies in pregnant women. However, there was one report of a case of agenesis of thecorpus callosum in an infant exposed to risperidone in utero. The causal relationship to oral RISPERDAL®

therapy is unknown. Non-Teratogenic Effects: Neonates exposed to antipsychotic drugs (includingRISPERDAL®) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawalsymptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor,somnolence, respiratory distress, and feeding disorder in these neonates. These complications havevaried in severity; while in some cases symptoms have been self-limited, in other cases neonates haverequired intensive care unit support and prolonged hospitalization. RISPERDAL® CONSTA® should beused during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor andDelivery: The effect of RISPERDAL® CONSTA® on labor and delivery in humans is unknown. NursingMothers: Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, womenshould not breast-feed during treatment with RISPERDAL® CONSTA® and for at least 12 weeks after thelast injection. Pediatric Use: RISPERDAL® CONSTA® has not been studied in children younger than 18 years old. Geriatric Use: In an open-label study, 57 clinically stable, elderly patients (≥ 65 years old)with schizophrenia or schizoaffective disorder received RISPERDAL® CONSTA® every 2 weeks for up to12 months. In general, no differences in the tolerability of RISPERDAL® CONSTA® were observed betweenotherwise healthy elderly and nonelderly patients. Therefore, dosing recommendations for otherwise

healthy elderly patients are the same as for nonelderly patients. Because elderly patients exhibit a greatertendency to orthostatic hypotension than nonelderly patients, elderly patients should be instructed innonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g.,sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowlyrising from a seated position). In addition, monitoring of orthostatic vital signs should be considered inelderly patients for whom orthostatic hypotension is of concern [see Warnings and Precautions (5.7) infull PI]. Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis In two offour placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence ofmortality was observed in patients treated with furosemide plus oral risperidone when compared topatients treated with oral risperidone alone or with oral placebo plus furosemide. No pathologicalmechanism has been identified to explain this finding, and no consistent pattern for cause of death wasobserved. An increase of mortality in elderly patients with dementia-related psychosis was seen with theuse of oral risperidone regardless of concomitant use with furosemide. RISPERDAL® CONSTA® is notapproved for the treatment of patients with dementia-related psychosis. [See Boxed Warning andWarnings and Precautions]DRUG ABUSE AND DEPENDENCE: Controlled Substance: RISPERDAL® CONSTA® (risperidone) is not acontrolled substance.Abuse: RISPERDAL® CONSTA® has not been systematically studied in animals or humans for its potentialfor abuse. Because RISPERDAL® CONSTA® is to be administered by health care professionals, thepotential for misuse or abuse by patients is low.Dependence: RISPERDAL® CONSTA® has not been systematically studied in animals or humans for itspotential for tolerance or physical dependence.OVERDOSAGE: Human Experience: No cases of overdose were reported in premarketing studies withRISPERDAL® CONSTA®. Because RISPERDAL® CONSTA® is to be administered by health careprofessionals, the potential for overdosage by patients is low. In premarketing experience with oralRISPERDAL®, there were eight reports of acute RISPERDAL® overdosage, with estimated doses rangingfrom 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting froman exaggeration of the drug’s known pharmacological effects, i.e., drowsiness and sedation, tachycardiaand hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg,was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case,involving an estimated overdose of 36 mg, was associated with a seizure. Postmarketing experience withoral RISPERDAL® includes reports of acute overdose, with estimated doses of up to 360 mg. In general,the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug’sknown pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidalsymptoms. Other adverse reactions reported since market introduction related to oral RISPERDAL®

overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported inassociation with combined overdose of oral RISPERDAL® and paroxetine.Management of Overdosage: In case of acute overdosage, establish and maintain an airway and ensureadequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately andshould include continuous electrocardiographic monitoring to detect possible arrhythmias. Ifantiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoreticalhazard of QT prolonging effects that might be additive to those of risperidone. Similarly, it is reasonableto expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resultingin problematic hypotension. There is no specific antidote to risperidone. Therefore, appropriate supportivemeasures should be instituted. The possibility of multiple drug involvement should be considered.Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenousfluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since betastimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases ofsevere extrapyramidal symptoms, anticholinergic medication should be administered. Close medicalsupervision and monitoring should continue until the patient recovers.

10130507BRevised December 2010© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007

Risperidone is manufactured by: Microspheres are manufactured by:Janssen Pharmaceutical Ltd. Alkermes, Inc.Wallingstown, Little Island, Wilmington, OhioCounty Cork, IrelandDiluent is manufactured by:Vetter Pharma Fertigung GmbH & Co. KGRavensburg or Langenargen, Germany or Cilag AGSchaffhausen, Switzerland or Ortho Biotech Products, L.P.Raritan, NJ RISPERDAL® CONSTA® is manufactured for:Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.Titusville, NJ 08560


icine and staff psychiatrist at the Michael E.

DeBakey Veterans Administration Medical

Center (MEDVAMC) in Houston. Dr Kosten is

JH Waggoner Chair and professor of psychi-

atry, pharmacology, and neuroscience in the

Menninger Department of Psychiatry and Be-

havioral Science at the Baylor College of Med-

icine and research director of the Na tional VA

Substance Use Disorders, Quality Enhance-

ment Research Initiative (QUERI) in Houston.

The authors report no conflicts of interest

concerning the subject matter of this article.

Acknowledgments—Research support was provided by VA SUD-QUERI, DOD, NIH grants K05-DA0454, P50-DA18197.

References

1. Berkowitz B, Spector S. Evidence for active im-munity to morphine in mice. Science. 1972;178:1290-1292.2. Bonese KF, Wainer BH, Fitch FW, et al. Changes in heroin self-administration by a rhesus monkey after morphine immunisation. Nature. 1974;252:708-710.3. Owens SM, Mayersohn M. Phencyclidine-specific Fab fragments alter phencyclidine disposition in dogs. Drug Metab Dispos. 1986;14:52-58.4. Woodworth JR, Owens SM, Mayersohn M. Phen-cyclidine (PCP) disposition kinetics in dogs as a func-tion of dose and route of administration. J Pharmacol Exp Ther. 1985;234:654-661.5. Kosten T, Owens SM. Immunotherapy for the treat-ment of drug abuse. Pharmacol Ther. 2005;108:76-85.6. Orson FM, Kinsey BM, Singh RA, et al. Substance abuse vaccines. Ann N Y Acad Sci. 2008;1141:257-269.7. Martell BA, Mitchell E, Poling J, et al. Vaccine phar-macotherapy for the treatment of cocaine depen-dence. Biol Psychiatry. 2005;58:158-164.8. Kosten TR, Rosen M, Bond J, et al. Human thera-peutic cocaine vaccine: safety and immunogenicity. Vaccine. 2002;20:1196-1204.9. Haney M, Kosten TR. Therapeutic vaccines for substance dependence. Expert Rev Vaccines. 2004;3:11-18.10. Orson FM, Kinsey BM, Singh RA, et al. Vaccines for cocaine abuse. Hum Vaccin. 2009;5:194-199.11. Martell BA, Orson FM, Poling J, et al. Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double blind, placebo-controlled efficacy trial. Arch Gen Psychiatry. 2009;66:1116-1123.12. Riedmann EM. NicVAX: pivotal phase III study initiated. Hum Vaccin. 2010;6:430-435.13. Hatsukami DK, Rennard S, Jorenby D, et al. Safety and immunogenicity of a nicotine conjugate vaccine in current smokers [published correction appears in Clin Pharmacol Ther. 2006;79:396]. Clin Pharmacol Ther. 2005;78:456-467.14. Cornuz J, Zwahlen S, Jungi WF, et al. A vaccine against nicotine for smoking cessation: a random-ized controlled trial. PLoS One. 2008;3:e2547.15. LeSage MG, Keyler DE, Pentel PR. Current status of immunologic approaches to treating tobacco de-pendence: vaccines and nicotine-specific antibodies. AAPS J. 2006;8:E65-E75.16. Heading CE. Drug evaluation: CYT-002-NicQb, a therapeutic vaccine for the treatment of nicotine ad-diction. Curr Opin Investig Drugs. 2007;8:71-77.17. St Clair Roberts J, Dobson J, Wood D, Settles M. Safety and immunogenicity of a human nicotine conjugate vaccine. Drug Alcohol Depend. 2002;66:S148. ❒




by Roger S. McIntyre , MD and Danielle S. Cha

B ipolar disorders are heteroge-neous in phenomenology, pathoetiology, comorbidity,

and treatment. These disorders are highly prevalent and often misdiag-nosed and underrecognized. For bi-polar patients who are correctly identified, the time from onset of symptoms to correct identification is often 10 to 15 years. It is disquieting that mortality studies indicate that bipolar disorder is associated with approximately 15 to 25 years of life lost largely because of associated cardiometabolic disorders.1

Despite the development and widespread use of several novel pharmacological, psychosocial, and neuromodulatory approaches for bi-polar disorder during the past de-cade, outcomes remain rather disap-pointing. For example, results from efficacy as well as effectiveness studies indicate that the majority of individuals with bipolar disorder who receive guideline-concordant measurement-based care fail to achieve symptomatic, syndromal, or functional recovery. Moreover, phe-nomenological studies indicate that the longitudinal course in bipolar disorder largely consists of depres-sive symptoms and episodes.

Research into bipolar depression symptoms is particularly important because bipolar depression symp-toms carry a much higher illness bur-den—these symptoms are by far more prevalent than manic symp-toms.2-4 This latter observation pro-vides the impetus for developing genuinely novel disease-modifying treatment strategies.

Except for lithium, most treat-ments for bipolar disorder symptoms were not primarily developed as “an-tibipolar therapies” (eg, anticonvul-sants, conventional unimodal antide-pressants). Most were initially used off-label and only later were evalu-ated in bipolar disorder (eg, atypical antipsychotics). Still others continue to be frequently prescribed off-label (eg, antidepressants). A major limita-tion to genuinely novel drug discov-ery in bipolar disorder is the absence of a consensually agreed-on neuro-

pathology as well the unavailability of a sufficient animal model with ap-propriate face, construct, and patho-logical and pharmacological validity.5

Although the field continues to be preoccupied with the monoamine hypothesis, it is abundantly clear that monoamine dysregulation has never been established as a central distur-bance in bipolar disorder and that targeting monoamines is not sine qua non for symptom relief. Other mod-els that have been proposed to exist alongside the monoamine hypothesis include the excitotoxicity, neuro-trophic/neuroplasticity, neuroin-flammatory, metabolic, and cellular redox (ie, oxidative stress to the cell) models. Novel treatments for bipolar disorder that are a focus of clinical research attempt to target one or more of the effector systems within these pathophysiological models.

Currently, only quetiapine, que-tiapine XR, and an olanzapine/flu-oxetine combination are FDA-approved for the acute treatment of bipolar depression. Although these agents are highly beneficial for some individuals, most fail to sufficiently benefit and/or are intolerant of these agents, which underscores the need for novel alternatives. This article aims to provide a succinct summary of novel pharmacological treatment avenues that are under investigation as treatment for bipolar depression. We present some of these novel treatments according to the over-arching disease model that they de-rive from.

ExcitotoxicitySeveral lines of evidence suggest that glutamatergic system dysfunc-tion (eg, N-methyl d-aspartate [NMDA] receptor complex) may play a critical role in the pathophysi-ology of bipolar disorder. In keeping with this view, the use of glutamater-gic modulators may be predicted to alleviate symptoms and modify the disease process. Postmortem studies indicate that altered NMDA receptor complexes are observed in the brain tissue of patients with bipolar disor-der. Moreover, genetic polymor-phisms for genes implicated in the glutamate receptor complex have been associated with this disorder.6

Riluzole, an inhibitor of gluta-mate release, is approved by the FDA for the treatment of amyo-trophic lateral sclerosis. This agent, at a dosage of 50 to 200 mg/d, was evaluated in an 8-week add-on study in combination with lithium in 14 adults with bipolar depression, 6 of whom had bipolar I disorder, and 8 of whom had bipolar II disorder. Eight patients completed the 8-week trial.6 Significant improvement in depressive symptoms was noted in weeks 5 through 8 as measured by the Montgomery Asberg Depression Rating Scale (MADRS).

Ketamine is a noncompetitive NMDA antagonist that has been evaluated in subanesthetic doses in persons with bipolar disorder.7 Re-sults from a double-blind, random-ized, placebo-controlled, crossover study indicate that a single intrave-nous infusion of ketamine combined with lithium or valproate was capa-ble of alleviating depressive symp-toms within 40 minutes of admin-istration when compared with pla-cebo.7 The benefit of ketamine was sustained through day 3. Overall, 71% of patients responded to keta-mine and 6% responded to placebo at some point during the trial. Keta-mine was not associated with signifi-cant increases in hypomania or ma-nia but was associated with disso-ciative symptoms.

Inflammatory networkAbnormal activation in function of the inflammatory network has been implicated as causative and conse-quential in bipolar depression symp-tomatology. For example, elevated concentrations of proinflammatory cytokines (interleukin-6 and tumor necrosis factor [TNF]-�) have been implicated in bipolar depression and mania.8,9 Conventional pharmaco-therapy for bipolar disorder (eg, lith-ium) exerts a modulatory effect on the proinflammatory–anti-inflam-matory network.8 Proinflammatory cytokines are known to induce be-havioral symptoms (eg, anorexia, psychomotor retardation) in humans that are thought to mimic sickness behavior described in animals.8

Cyclooxygenase-2 (COX-2) in-

Going Beyond Lithium

Novel Treatment Avenues for Bipolar Depression

(Please see Novel Treatment, page 38)

well tolerated. Adverse events re-ported in more than 15% of the N-acetylcysteine group included change in energy, headaches, heart-burn, and increased joint pain.

ModafinilModafinil is currently approved by the FDA for improving wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea-hypopnea syndrome and shift work sleep disorder. This drug’s mechanism of action is not fully characterized but is thought to in-volve multiple neurochemical sys-tems that include dopamine signal-ing.15 Modafinil at a dosage of 100 to 200 mg/d has been shown to allevi-ate depressive symptoms when com-pared with placebo in adults with bipolar disorder across 6 weeks of treatment.16 Improvement in depres-sive symptoms was statistically sig-nificantly greater (P = .01) in the modafinil group by week 2, with greater response and remission rates. Modafinil was not associated with treatment-emergent hypomania or mania.

Armodafinil is the longer-lasting isomer of modafinil, and its thera-peutic indications are similar to those of the racemic agent modafinil. Ar-modafinil at a dosage of 150 mg/d was evaluated as an antidepressant in adults with bipolar disorder who re-ceived either olanzapine, lithium, or valproic acid as part of an 8-week double-blind placebo-controlled study.17 Patients who received armo-dafinil exhibited greater improve-ment of depressive symptoms as measured by the 30-item Inventory of Depressive Symptomatology, Cli-nician-Rated score. The rate of new-onset hypomania or mania did not differ between groups. The most fre-quently reported adverse events among armodafinil recipients were headache, diarrhea, and insomnia.

ConclusionsThe treatment of adults with bipolar depression may begin with an FDA-approved agent such as quetiapine or an olanzapine/fluoxetine combina-tion. The evidence-based approach to bipolar depression includes treat-ment with lithium, conventional uni-modal antidepressants, lamotrigine, or divalproex. The evidence base does not provide sufficient guidance for next treatment steps in bipolar disorder and, as such, treatment deci-sions are made empirically. Pharma-cological options that are commonly considered are pramipaxole, modaf-inil, and armodafinil.

Insulin is transported into the CNS across the blood-brain barrier by a saturable insulin receptor–medi-ated transport process.11-13 Long-term potentiation, the neurobiological model of learning, is partially modu-lated by insulin. Insulin deficiency in diabetic rats triggers a retraction of dendrites and reduces NMDA trans-mission of hippocampal neurons, with associated decrements in mem-ory performance. Taken together, cellular, molecular, and physiologi-cal data indicate that insulin is im-portant for normal (and pathological) memory processes.12

Several case reports and case se-ries suggest that insulin sensitizers (eg, rosiglitazone) may offer an anti-depressant effect in persons with ma-jor depressive disorder. Studies are currently under way in bipolar disor-der. For example, several studies are evaluating the antidepressant effects of intranasal insulin and insulin secretagogues (eg, incretins) in bipo-lar disorder. Moreover, there is ongo-ing research to determine whether weight loss, bariatric surgery, and di-etary modification (eg, ketogenic diet) improve depressive symptoms in persons with bipolar disorder.

Antioxidant implicationsAvailable evidence implicates oxida-tive stress and abnormalities in cel-lular redox in the pathophysiology of bipolar disorder. Evidence also indi-cates that lithium and valproate may protect neurons from oxidative stress. Glutathione is an antioxidant distributed throughout multiple tis-sues; levels of this antioxidant have been reported to be abnormal in indi-viduals with bipolar disorder. Glu-tathione production rate is limited by its precursor, cysteine.14

N-acetylcysteine is the acetylated derivative of cysteine and is more efficiently bioavailable. N-acetyl-cysteine has been reported to be neu-roprotective in preclinical neuro-degenerative disease models. Results from a randomized, double-blind, multicenter, placebo-controlled study of adults with bipolar disorder (N = 75) indicate that N-acetyl-cysteine (1 g bid) adjunctive to usual medications was capable of alleviat-ing depressive symptoms as mea-sured by the MADRS.14 The benefit on depressive symptoms was noted at week 20 as part of this 24-week study. Benefits were noted by week 8 on the Global Assessment of Func-tioning Scale and Social and Occu-pational Functioning Assessment Scale. N-acetylcysteine did not in-duce hypomania or mania and was

proach may offer a rapid onset of antidepression action in bipolar dis-order. More work is needed to repli-cate/extend or refute these findings, however.

Metabolic actionNeuronal insulin mediates multiple biological actions characterized as metabolic (eg, increases in glucose uptake), neuromodulatory (eg, inhi-bition of neuronal reuptake of nor-adrenaline), growth regulatory (eg, promotion of neurite outgrowth and synaptogenesis), and neuroendo-crine. For example, insulin modu-lates the CNS concentration of neu-ropeptides, monoamines, and other neurotransmitters (eg, acetylcholine) implicated in the pathophysiology of mood disorders, schizophrenia, and Alzheimer disease. Insulin inhibits the firing of neurons in the hippo-campus and hypothalamus, inhibits the reuptake of noradrenaline in rat brains, modulates catecholamine turnover in the hypothalamus, stimu-lates phosphoinositide turnover in the hippocampus, and regulates the noradrenaline and dopamine trans-porter messenger RNA concentra-tion in neurons.

hibitors have been shown to protect against glutamate-induced neurotox-icity; to prevent normal aging-relat-ed increases of cytokines, prosta-glandins, and TNF in neurons; and to modulate the hypothalamic adrenal axis.10 The COX-2 inhibitor celecox-ib was evaluated as a potential anti-depressant in adults with bipolar I/II depression (N = 28).10 This drug was administered at a dosage of 400 mg daily in combination with a mood stabilizer or antipsychotic medica-tion as part of a 6-week, randomized, double-blind, placebo-controlled study. Depressive symptoms in both the treatment group and the placebo group improved, with a statistically significant (P = .01) advantage at week 1 in patients treated with cele-coxib compared with patients who received placebo. Although there was an advantage in favor of the treatment group at week 1, both the active-treatment and placebo groups had similar reductions for each of the remaining observation points.

Taken together, the results sug-gest that an anti-inflammatory ap-

Novel TreatmentContinued from page 37


38

in this article) are equivocal in bipo-lar depression but can be considered. The role of exercise, weight loss, and dietary modification are research vista for the future.

and easier to use treatments that also target glutamate (eg, lamotrigine) in bipolar depression. Results with N-acetylcysteine look promising and could be considered; however, repli-cation in other studies is warranted. Results with omega-3 (not reviewed

Although ketamine and riluzole are not considered standard treat-ments for bipolar depression, they are proof of concept of the role of glutamate systems. These proof of concept studies provide indirect pharmacodynamic support for safer

CLINICAL PSYCHOPHARMACOLOGYAPRIL 2011 39

Book Review

The Judaic Foundations of Cognitive-Behavioral Therapy:

Rabbinical and Talmudic Underpinnings of CBT and REBT

by Ronald W. Pies, MD; Bloomington, IN: iUniverse Books; 2010

• 208 pages • $17.95 (softcover)

Reviewed by H. Steven Moffic, MD and Rabbi Evan Moffic

The upshot for consumers: medical wisdom

that has stood the test of time—and large,

randomized, controlled trials—is more

likely to be right than the latest news flash

about a single food or drug. —S. Begley1

The above is not a quote by Ronald Pies, author of The Judaic Foundations of Cognitive-Behavioral Therapy: Rabbinical and Talmudic Underpinnings of CBT and REBT. Rather, it is by well-known jour-nalist, Sharon Begley, as she con-cluded her recent Newsweek arti-cle, “Why Almost Everything You Hear About Medicine Is Wrong.” She focuses on the work of Dr John P. A. Ioannidis, who questions the very framework of medical investigation. Recent ex-amples of questionable findings include hormone replacement therapy, prostate-specific antigen testing for prostate cancer, and even antidepressant medication for mild to moderate depression.

Pies must have known the flawed nature of scientific stud-ies. Cognitive-behavioral therapy (CBT) has been extensively test-ed, and the author’s timely new book creatively places CBT in the context of time-tested religious wisdom. By doing so, Pies even goes beyond this important psychiatric confirmation to expand the im-plications to morality, ethics, and character.

Of course, the title itself would imply its rele-vance. It should be of interest to any clinician prac-ticing today’s most popular form of psychotherapy. Even here, the potential interest is broader. Rather than focus on Aaron Beck’s legacy (as so many other

writers do), Pies concentrates on the relatively ne-glected work of Albert Ellis, founder of Rational Emotive Behavioral Therapy. It may also be of inter-est to psychoanalytic therapists, given that Freud was known to have studied and incorporated other Jewish teachings, especially on mysticism, into his theories.

From the religious side, pastoral counselors of almost any religious denomination may find the un-derlying principles of CBT to be applicable. Al-though his main focus is Judaic foundations, Pies also touches on Christian, Islamic, Hindu, and Zen Buddhist beliefs. He quotes the Ma harishi Mahesh Yogi: “For the forest to be green, each tree must be green.” In other words, society won’t change for the better unless we as individuals change our self-defeating habits. As Pies himself concludes, both rabbinical Judaism and CBT share “the conviction that human beings can exercise their reason in the service of self-improvement, self-control, and self-discipline.”

For CBT to work, there needs to be a positive therapeutic alliance in which the clinician conveys empathy, warmth, and a positive regard toward the patient. It would have been helpful if Pies had added this infor mation to this relatively brief book. Along with a faith in shared positive expectations and be-

liefs, this relationship will con-tribute to a baseline placebo benefit.

There is no evidence that the founders of CBT used rabbinical and Talmudic insights to devel-op their treatments, but the over-lap is striking. See if you can tell if the following quote comes from religious wisdom or a CBT therapist: “To defeat depression, you must introduce a fresh per-spective to your thinking. You must begin to replace troubling, destructive thoughts with posi-tive, constructive ones.” To this, we say, “Amen.”

Dr Moffic is a tenured professor in the departments of psychiatry and behav-ioral sciences and of family and com-

munity medicine at the Medical College of Wisconsin in Mil-waukee. He is a regular blogger on www.psychiatrictimes.com. Rabbi Moffic is the Senior Rabbi at Congregation Solel, Highland Park, Chicago. Dr and Rabbi Moffic are father and son.

Reference

1. Begley S. Why Almost Everything You Hear About Medicine Is Wrong. http://www.newsweek.com/2011/01/23/why-almost-everything-you-hear-about-medicine-is-wrong.html. Accessed February 14, 2011. ❒

(Please see Novel Treatment, page 40)

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new insight into the biology of depression. Am J Psy-chiatry. 2010;167:1305-1320.6. Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipo-lar depression. Biol Psychiatry. 2005;57:430-432.7. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793-802.8. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the phenomenology, patho-physiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry. 2009;70:1078-1090.9. Soczynska JK, Kennedy SH, Goldstein BI, et al. The effect of tumor necrosis factor antagonists on mood and mental health-associated quality of life: novel hypothesis-driven treatments for bipolar depres-sion? Neurotoxicology. 2009;30:497-521.10. Nery FG, Monkul ES, Hatch JP, et al. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, ran-domized, placebo-controlled study. Hum Psycho-pharmacol. 2008;23:87-94.11. McIntyre RS, Kenna HA, Nguyen HT, et al. Brain volume abnormalities and neurocognitive deficits in diabetes mellitus: points of pathophysiological com-monality with mood disorders? Adv Ther. 2010;27:63-80.12. McIntyre RS, Soczynska JK, Konarski JZ, et al. Should depressive syndromes be reclassified as “metabolic syndrome type II”? Ann Clin Psychiatry. 2007;19:257-264.13. McIntyre RS, Soczynska JK, Lewis GF, et al. Man-aging psychiatric disorders with antidiabetic agents: translational research and treatment opportunities. Expert Opin Pharmacother. 2006;7:1305-1321.14. Berk M, Copolov DL, Dean O, et al. N-acetyl cys-teine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64:468-475.15. Andersen ML, Kessler E, Murnane KS, et al. Do-pamine transporter-related effects of modafinil in rhesus monkeys. Psychopharmacology (Berl). 2010;210:439-448.16. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164:1242-1249.17. Calabrese JR, Ketter TA, Youakim JM, et al. Ad-junctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2010;71:1363-1370. ❒

Remember that electroconvulsive therapy is a highly effective treat-ment in bipolar depression and is probably underused in some centers. Results with transcranial magnetic stimulation look promising in bipo-lar depression; several academic centers are evaluating the role of deep brain stimulation.

As for all patients with bipolar disorder, the pharmacological treat-ment of bipolar depression is part of a multicomponent chronic disease management approach. A critical component of this model includes psychoeducation and in many cases the provision of manual-based psy-chotherapy, such as cognitive-behav-ioral therapy, interpersonal therapy, social rhythm therapy, or family-focused therapy.

Dr McIntyre is associate professor of psychia-

try and pharmacology, University of Toronto,

and head of the Mood Disorders Psychophar-

macology Unit, University Health Network,

Toronto. Ms Cha is a research assistant in the

Mood Disorders Psychopharmacology Unit,

University Health Network. Dr McIntyre re-

ports that he is on the Advisory Boards for

AstraZeneca, Bristol-Myers Squibb, France

Foundation, GlaxoSmithKline, Janssen-Ortho,

Solvay/Wyeth, Eli Lilly, Organon, Lundbeck,

Biovail, Pfizer, Shire, and Schering-Plough. He

is on the Speakers Bureau for Janssen-Ortho,

AstraZeneca, Eli Lilly, Lundbeck, Biovail, and

Wyeth. He has been a faculty member for

CME activities for AstraZeneca, Bristol-Myers

Squibb, France Foundation, I3 CME, Solvay/

Wyeth, Physicians Postgraduate Press, CME

Outfitters, OptumHealth, Schering-Plough,

and Eli Lilly. He has received research

grants from Eli Lilly, Janssen-Ortho, Shire, and

AstraZeneca. He has received travel funds

from Bristol-Myers Squibb. Ms Cha reports

that she has no conflicts of interest concern-

ing the subject matter of this article.

References

1. McIntyre RS, Konarski JZ. Bipolar disorder: a na-tional health concern. CNS Spectr. 2004;9(11 suppl 12):6-15.2. Judd LL, Schettler PJ, Solomon DA, et al. Psycho-social disability and work role function compared across the long-term course of bipolar I, bipolar II and unipolar major depressive disorders. J Affect Disord. 2008;108:49-58.3. Judd LL, Akiskal HS, Schettler PJ, et al. Psychoso-cial disability in the course of bipolar I and II disor-ders: a prospective, comparative, longitudinal study. Arch Gen Psychiatry. 2005;62:1322-1330.4. Judd LL, Schettler PJ, Akiskal HS, et al. Long-term symptomatic status of bipolar I vs. bipolar II disor-ders. Int J Neuropsychopharmacol. 2003;6:127-137.5. Krishnan V, Nestler EJ. Linking molecules to mood:

Novel TreatmentContinued from page 39

APRIL 2011PSYCHIATRIC TIMES www.psychiatr ic t imes.com

40

Opinionated Psychiatrists Wanted

Psychiatric Times invites readers to suggest Commentaries and Point/Counterpoint articles. Topics should be relevant to practicing psychiatrists and mental health care profession-als. Point/Counterpoint issues should have 2 distinct view-points with a corresponding au-thor for each. Proposals and ar-ticles should be grounded in scientific literature and include ref erences. Send proposals to [email protected]. Please note that manuscripts may be sent for peer review. ❒

MOLECULES OF THE MIND 41PSYCHIATRIC TIMES APRIL 2011www.psychiatr ic t imes.com

In this column, we explore how the judicious use of neural stem cells (NSCs) has led to a research Holy Grail: the creation of research-ready, patient-specific neurons. This tech-nology did not use the famously con-troversial embryonic stem cells. These custom-made NSCs were cre-ated from politically neutral adult tissues (fibroblasts), which were originally isolated from an affected patient. With no embryo in sight, sci-entists genetically reprogrammed fi-broblasts into stem cells, which were then induced to develop into NSCs. This is an extraordinary finding with many topics to be discussed here:• The potential research utility for

patient-specific neurons• An explanation of how stem

cells can be made from adult tissues

• A striking set of results that involve one of the most commonly inher-ited and lethal childhood neuro-logical disorders: spinal muscular atrophy (SMA)

Research utility for NSCsOf what possible utility could mo-lecular investigations of a motor dis-order have for the mental health community? Before getting into the specifics of the breakthrough, it might be useful to address a real-world psychiatric need, using de-pression and SSRIs as an example, to see where these data fit.

When we consider the molecular mechanisms of SSRI interactions, it is easy to resort to commonly taught ideas about interactions that involve a single synapse. Nothing could be further from the truth. The most comprehensive neurological view of SSRI interactions must take into account the participation of thou-sands of individual neurons strung together in coordinated, complex neural networks.

And not just serotonergic neu-rons. These cells are in contact with many other central nervous deni-zens, from adjacent glial cells to the extracellular matrix into which the cells are embedded. What do these

circuits actually look like in patients who are vulnerable to depression? Is their architecture all that differ-ent from patients who do not exhibit this vulnerability? If there are differ-ences, could they eventually predict drug efficacy? Could these differ-ences only be detected by construct-ing parts of the circuit from scratch, or could they be observed at the level of a single cell?

The first step in answering these questions involves growing a cus-tom-made batch of serotonergic neu-rons derived only from the affected patients, and then asking relevant structure/function questions. From attempting to understand molecular mechanisms of disease to testing the efficacy of potential medications, such patient-specific test beds would have a powerful research utility. Un-til recently, the creation of such tai-lor-made neural substrates had been an impossible goal.

While it will certainly be quite some time before we can grow entire parkinsonian dopaminergic path-ways in a dish, it is now possible to create individual patient-specific neurons in culture. The technology comes from that end-run I mentioned earlier, through the use of a certain type of stem cell. It is to these inter-esting cellular substrates that we now turn.

Inducible stem cellsTo say that embryonic stem cell re-search has been subject to heated po-litical debate is an understatement. The bugaboo has been the source materials from which the stem cells would be isolated—human embry-os—many left over from embryos generated in in vitro fertilization laboratories.

In 2006, researchers found a way to create stem cells that bypassed the need for human embryos. The origi-nal technique involved the introduc-tion of 4 specific gene products into mature mouse fibroblasts. Surpris-ingly, this cocktail was found to re-program adult stem cells and re-verse-engineer them into pluripotent

I t is ironic that an attempt to do a molecular end-run around a politically hot topic could result in an impor-tant breakthrough in the treatment of neurological dis-ease with potentially strong implications for the psychi-

atric community. Ironic maybe, but true.

ulation of func-tional protein. This interaction explains in part why there can be so much varia-tion in the clinical presentation.

The great mys-tery is why SMN protein loss results in motor cell alterations that lead to the disease state in the first place. The protein is known to be essential for normal messenger RNA process-ing and is expressed throughout the body. Yet its absence most severely affects spinal motor neurons.

The most exacting way to attack this “black box” would be to isolate the motor neuron populations from the patient, then compare these pop-ulations with unaffected controls and look for differences, of which there are many. These include responses to various medications. It is well known that the application of val-proic acid (an anticonvulsant and/or mood stabilizer) or tobramycin (an aminoglycoside) to cultured cells, for example, leads to changes in the expression patterns of both full-length SMN protein and truncated forms. What is the molecular basis of this unusual interaction? And could such differences be used as a “molecular flashlight” to ferret out other secrets regarding the SMN pro-tein? Creating custom-made neu-rons—one population from an af-fected individual, another from an unaffected control—would certainly give a test bed capable of answering this question.

The dataStudying these 2 populations is pre-cisely what a group of investigators did. The researchers isolated fibro-blasts from an affected child and also from the child’s healthy unaffected mother.

The next step was to generate custom-made neurons. Several steps would be required (Figure). First, using the iPSC protocols I men-tioned, the researchers would at-tempt to create stem cells from both child and parent sources. If that worked, the researchers would then try to induce these patient-derived stem cells into motor neurons—ones that would carry the same biological mechanisms observed in both the

stem cells. Like embryonic stem cells, the altered stem cells had the ability to differentiate into any cell type. Eventually, a protocol was de-veloped that did the same thing in human tissues. The cells were called iPSCs, short for induced pluripotent stem cells.

This was quite a breakthrough. No longer would researchers need to harvest cells from extant human em-bryos to do stem cell research. Skin cells would do. Scientists were soon able to regenerate—and then cor-rect—molecular dysfunction in a mouse model of sickle cell anemia using this technology.

Could any of this work apply to humans, specifically to human neu-ral tissue? Another successful round of experiments (with amyotrophic lateral sclerosis neurons) prompted researchers to study motor disease, ie, SMA.

Of those hereditary neurological disorders capable of causing death in pediatric populations, SMA is easily the most common. The disease is unique to humans and associated with 2 genes, SMN1 and SMN2. For reasons that are not well understood, the absence of the survival motor neuron (SMN) protein results in an alteration of the function of spinal motor neurons. The primary feature is muscle weakness and atrophy. Death occurs at infancy in the most severe forms of the disease, with symptoms generally presenting sev-eral weeks after birth. There are many other, nonlethal forms of the disorder, however, with a wide spec-trum of symptoms that range from trivial motor effects to catastrophic impairment.

Why this variation? Both genes express in unaffected individuals, but the biological heavy lifting be-longs to the SMN1 gene. Because of structural constraints, the expression pattern of the SMN2 gene normally results in only 10% of its protein be-ing processed as a full-length (and functional) polypeptide; 90% of its protein output is truncated (and nonfunctional). That is okay, as long as the SMN1 gene is intact. But when SMN1 is mutated and silent, the dis-ease condition results. Assuming there is a damaged SMN1, the sever-ity of SMA varies according to the number of other SMN2 copies the infant may carry. The more copies of SMN2 gene, the greater the pop-

by John J. Medina, PhD

Custom-Made Neural Stem Cells

(Please see Neural Stem Cells, page 42)

MOLECULES OF THE MIND42 APRIL 2011www.psychiatr ic t imes.com

PSYCHIATRIC TIMES

of motor neurons.There are ways to gain greater

reassurance. One way to assay the success of the protocol is to look for bona fide molecular markers of developing spinal neurons. It is known, for example, that extant mo-tor neurons express the protein SMI032 and choline acetyltrans-ferase. Did these induced cells ex-press such proteins? The answer turned out to be yes, both for the af-fected child and for the unaffected parent. Developing cells in these populations possess transcription factors such as HOXB4, ISLET1, HB9, and OLIG2 as well. Did the induced populations express these markers? They did indeed. While not completely conclusive, it ap-peared that the researchers had generated patient-specific motor neurons from known affected and

diseased and the healthy popula-tions. If successful, the researchers would have their custom-made test beds. They could begin characteriza-tion studies; reactions to valproic acid and tobramycin would make obvious first choices to try.

The first step worked. The re-searchers were able to generate cus-tom-made stem cells from both child and parent. The researchers then tackled the hard part: manufacturing spinal motor neurons from these stem cell populations. They certain-ly generated promising cellular pop-ulations. But the iPSC technolo-gies are new enough that a visual inspection of the generated cells might be necessary—but certainly not sufficient—to show the presence

unaffected sources.The next characterization experi-

ments also yielded fruit. They were able to find that the child and parent neurons reacted very differently to the normally stimulating effects of valproic acid and tobramycin. The child’s cells showed elevated levels of SMN protein, both of the truncat-ed form and full-length version. In addition, SMN-containing nuclear structures were altered. No such el-evation occurred in the unaffected maternal line of cells.

These differences were signifi-cant for 2 reasons. First, it gave the investigators a toehold in their at-tempts to characterize at a more inti-mate level the differences between affected and unaffected cells. Sec-ond, the differences were discovered as reactions to known medications. The hope is that similar approaches

could be used to test the efficacy of various medications before commit-ting to human trials.

ConclusionsThese data, full of promising impli-cations as they are, need to be treated with some caution. First, the experi-mental cells are pure populations de-rived from stem cells. This hardly reflects the physical in vivo situa-tion. The cells and matrix compo-nents that normally surround such cells in nature, including skeletal muscle tissues and even other neu-rons, are not present in these studies.

Another objection concerns the fidelity of the conversion process it-self. The differentiation pattern seen in various molecular markers hinted that the investigators generated real live spinal motor neurons; however, one cannot a priori say they have in every way created a motor neuron that precisely mimics the real-world situation. These cells may lack many subtle molecular processes—and a few extra, equally subtle interac-tions—that could easily escape de-tection, at least by current technolo-gies. Because subtle differences can profoundly influence intracellular molecular interactions, especially when we think about reactions to medications, this is a true concern.

The most exciting aspect of these studies comes from what the future holds. A great deal of speculation has gone into thinking about how to tai-lor medications to individual pa-tients. That certainly is a psychiatric issue . . . I need not talk to this audi-ence about the variable effects of, say, fluoxetine on clinical outcomes. We have visited this topic in past col-umns. The ability to create patient-specific cellular test beds may go a long way toward solving some of these problems. Indeed, clinics of the future might routinely screen to decide what medications their pa-tients should receive—and in what concentrations.

There is much work to do. To date, none has been applied to neuro-logical systems relevant to mental health professionals. Even given the cautions mentioned above, there is no reason why it couldn’t. That’s not bad for having to do with an end-run around a hostile, politically charged issue such as stem cell debates. Would that all ethical issues could be decided so cleanly, or with so much fruit.

Dr Medina is a developmental molecular bi-ologist and private consultant, with research interests in the genetics of psychiatric disor-ders. For more about Dr Medina, visit http://brainrules.net. ❒

MI

Custom-made motor neurons

Fibroblasts isolated

From affectedinfant (I)

From related unaffectedadult (mother [M])

1. With theintroduction ofspecific gene

transcription factors,iPSCs were

generated fromfibroblast substrates

I M

2. These iPSCs wereused to generatepatient-specific

spinal motorneurons

M

3. Putative spinalneurons were

assayed for motor-specific neurons

4. Cells weretested for reactions

to medications;differences were

observed

I

I

I

I

I

M

M M

M

I M

OLIG2

HOXB4

ISLET1

SM1-32

OLIG2

HOXB4

ISLET1

SM1-32

VALPROIC ACID

TOBRAMYCIN

VALPROIC ACID

TOBRAMYCIN

TF TF

Figure

The ability to create patient-specific neurons from stem cells holds great promise in elucidating the molecular

mechanisms behind many neurological disorders, including, as shown below, spinal muscular atrophy. (iPSCs,

induced pluripotent stem cells; TF, transcription factor.)

Neural Stem CellsContinued from page 41

In adults with MDD and Generalized

Anxiety Disorder (GAD)1

In adolescents aged 12 to 17 with

Major Depressive Disorder (MDD)1

Treat your patients with the demonstrated effi cacy of LEXAPRO1-5

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Lexapro or any other antidepressant in a child, adolescent or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Lexapro is not approved for use in pediatric patients less than 12 years of age.

Please see additional Important Safety Information on following pages.

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See the effect of LEXAPRO

Proven effi cacy in MDD in

adolescents aged 12 to 17,*

and in MDD and GAD in adults1-5

• Signifi cantly improved MDD symptoms in adolescents2

There is no generic available for LEXAPRO

• Signifi cantly higher rates of response and remission vs placebo in MDD and GAD in adults4,5

IMPORTANT SAFETY INFORMATION (continued)

Contraindications

Lexapro is contraindicated in patients taking monoamine • oxidase inhibitors (MAOIs). There have been reports of serious, sometimes fatal, reactions with some cases resembling neuroleptic malignant syndrome (NMS) and serotonin syndrome. Features may include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fl uctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on an MAOI. Serotonin syndrome was reported for two patients who were concomitantly receiving linezolid, an antibiotic which has MAOI activity. Lexapro should not be used in combination with an MAOI or within 14 days of discontinuing an MAOI. MAOIs should not be initiated within 14 days of discontinuing Lexapro.

Lexapro is contraindicated in patients taking pimozide • or with hypersensitivity to escitalopram or citalopram.

Warnings and Precautions

All patients treated with antidepressants should be • monitored appropriately and observed closely for clinical worsening, suicidality and unusual changes in behavior, especially within the fi rst few months of treatment or when changing the dose. Consideration should be given to changing the therapeutic regimen, including discontinuing medication, in patients whose depression is persistently worse, who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients treated with antidepressants should be alerted about the need to monitor patients daily for the emergence of agitation, irritability, unusual changes in behavior, or the emergence of suicidality, and report such symptoms immediately. Prescriptions for Lexapro should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose.

Lexapro (escitalopram oxalate) is indicated for the acute and maintenance treatment of major depressive disorder (MDD) in adults and adolescents aged 12-17 years. Lexapro is also indicated for the acute treatment of generalized anxiety disorder (GAD) in adults. disturbances (e.g., paresthesias), anxiety, confusion,

headache, lethargy, emotional lability, insomnia and hypomania. A gradual dose reduction rather than abrupt cessation is recommended whenever possible.

SSRIs and SNRIs have been associated with clinically • signifi cant hyponatremia. Elderly patients and patients taking diuretics or who are otherwise volume-depleted appear to be at a greater risk. Discontinuation of Lexapro should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Please see Boxed Warning on fi rst page and additional Important Safety Information on next page.

A major depressive episode may be the initial presentation • of bipolar disorder. In patients at risk for bipolar disorder, treating such an episode with an antidepressant alone may increase the likelihood of precipitating a mixed/manic episode. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder. Lexapro should be used cautiously in patients with a history of mania or seizure disorder. Lexapro is not approved for use in treating bipolar depression.

The concomitant use of Lexapro with other SSRIs, SNRIs, • triptans, tryptophan, antipsychotics or other dopamine antagonists is not recommended due to potential development of life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions. Reactions have been reported with SNRIs and SSRIs alone, including Lexapro, but particularly with drugs that impair metabolism of serotonin (including MAOIs). Management of these events should include immediate discontinuation of Lexapro and the concomitant agent and continued monitoring.

Patients should be monitored for adverse reactions • when discontinuing treatment with Lexapro. During marketing of Lexapro and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation, including dysphoric mood, irritability, agitation, dizziness, sensory Visit the LEXAPRO website at www.lexapro.com

* LEXAPRO is indicated as an integral part of a total treatment program for MDD. Drug treatment may not be indicated

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Warnings and Precautions (continued)

SSRIs (including Lexapro) and SNRIs may increase • the risk of bleeding. Patients should be cautioned that concomitant use of aspirin, NSAIDs, warfarin or other anticoagulants may add to the risk.

Patients should be cautioned about operating hazardous • machinery, including automobiles, until they are reasonably certain that Lexapro does not affect their ability to engage in such activities.

Lexapro should be used with caution in patients with • severe renal impairment or with diseases or conditions that alter metabolism or hemodynamic responses. In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of Lexapro in hepatically impaired patients is 10 mg/day.

For pregnant or nursing mothers, Lexapro should be • used only if the potential benefi t justifi es the potential risk to the fetus or child.

Adverse Reactions

In clinical trials of MDD, the most common adverse • reactions in adults treated with Lexapro (approximately 5% or greater and at least twice the incidence of placebo) were nausea (15% vs 7%), insomnia (9% vs 4%), ejaculation disorder (9% vs <1%), fatigue (5% vs 2%), somnolence (6% vs 2%), and increased sweating (5% vs 2%). In pediatric patients, the overall profi le of adverse reactions was similar to that seen in adults; however, the following additional adverse reactions were reported at an incidence of at least 2% for Lexapro and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion.

In clinical trials of GAD, the most common adverse reactions • in adults treated with Lexapro (approximately 5% or greater and at least twice the incidence of placebo) were nausea (18% vs 8%), ejaculation disorder (14% vs 2%), insomnia (12% vs 6%), fatigue (8% vs 2%), decreased libido (7% vs 2%) and anorgasmia (6% vs <1%).

Please see accompanying brief summary of Prescribing Information for LEXAPRO, including Boxed Warning.

Visit the LEXAPRO website at www.lexapro.com

© 2010 Forest Laboratories, Inc. Printed in U.S.A. 41-1016226hR2 3/10

LEXAPRO: Proven effi cacy in MDD in adolescents

aged 12 to 17, and in MDD and GAD in adults1-5

References: 1. LEXAPRO [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2009. 2. Emslie GJ, Ventura D, Korotzer A, Tourkodimitris S. Escitalopram in the treatment of adolescent depression: a randomized placebo-controlled multisite trial. J Am Acad Child Adolesc Psychiatry. 2009;48:721-729. 3. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry. 2002;63:331-336. 4. Davidson JRT, Bose A, Korotzer A, Zheng H. Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, fl exible dose study. Depress Anxiety. 2004;19:234-240. 5. Wade A, Lemming OM, Hedegaard KB. Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol. 2002;17:95-102.

LEXAPRO® (escitalopram oxalate) TABLETS/ORAL SOLUTION Rx OnlyBrief Summary: For complete details, please see full Prescribing Information for Lexapro.

WARNINGS: SUICIDALITY AND ANTIDEPRESSANT DRUGSAntidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder(MDD) and other psychiatric disorders. Anyone considering the use of Lexapro or any other antidepressantin a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies didnot show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyondage 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 andolder. Depression and certain other psychiatric disorders are themselves associated with increases in therisk of suicide. Patients of all ages who are started on anti depressant therapy should be monitored appro-priately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Familiesand caregivers should be advised of the need for close observation and communication with the pre-scriber. Lexapro is not approved for use in pediatric patients less than 12 years of age. [See Warnings andPrecautions: Clinical Worsening and Suicide Risk, Patient Counseling Information: Information forPatients, and Used in Specific Populations: Pediatric Use].

INDICATIONS AND USAGE: Major Depressive Disorder-Lexapro (escitalopram) is indicated for the acute andmaintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age [seeClinical Studies]. A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearlyevery day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, andincludes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, signif-icant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation,increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attemptor suicidal ideation. Generalized Anxiety Disorder-Lexapro is indicated for the acute treatment of GeneralizedAnxiety Disorder (GAD) in adults [see Clinical Studies]. Generalized Anxiety Disorder (DSM-IV) is characterizedby excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which theperson finds difficult to control. It must be associated with at least 3 of the following symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability,muscle tension, and sleep disturbance. CONTRAINDICATIONS: Monoamine oxidase inhibitors (MAOIs)-Concomitant use in patients taking monoamineoxidase inhibitors (MAOIs) is contraindicated [see Warnings and Precautions]. Pimozide-Concomitant use in patients taking pimozide is contraindicated [see Drug Interactions]. Hypersensitivity to escitalopram orcitalopram-Lexapro is contraindicated in patients with a hypersensitivity to escitalopram or citalopram or any ofthe inactive ingredients in Lexapro. WARNINGS AND PRECAUTIONS: Clinical Worsening and Suicide Risk-Patients with major depressive disorder(MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking anti-depressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk ofdepression and certain other psychiatric disorders, and these disorders themselves are the strongest predictorsof suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducingworsening of depression and the emergence of suicidality in certain patients during the early phases of treat-ment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents,and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo inadults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 andolder. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compul-sive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressantdrugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psy-chiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressantdrugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tenden-cy toward an increase in the younger patients for almost all drugs studied. There were differences in absoluterisk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drugvs. placebo), however, were relatively stable within age strata and across indications. These risk differences(drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

TABLE 1Age Range Drug-Placebo Difference in Number of Cases

of Suicidality per 1000 Patients TreatedIncreases Compared to Placebo

<18 14 additional cases18-24 5 additional cases

Decreases Compared to Placebo 25-64 1 fewer case

65 6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was notsufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extendsto longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlledmaintenance trials in adults with depression that the use of anti-depressants can delay the recurrence of depres-sion. All patients being treated with anti-depressants for any indication should be monitored appropriately andobserved closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initialfew months of a course of drug therapy, or at times of dose changes, either increases or decreases. The follow-ing symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity,akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patientsbeing treated with antidepressants for major depressive disorder as well as for other indications, both psychiatricand nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worseningof depression and/or the emergence of suicidal impulses has not been established, there is concern that suchsymptoms may represent precursors to emerging suicidality. Consideration should be given to changing the ther-apeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistentlyworse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depres-sion or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, asrapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms[see Dosage and Administration]. Families and caregivers of patients being treated with antidepressants for majordepressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need tomonitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptomsdescribed above, as well as the emergence of suicidality, and to report such symptoms immediately to health careproviders. Such monitoring should include daily observation by families and caregivers [see also PatientCounseling Information]. Prescriptions for Lexapro should be written for the smallest quantity of tablets consis-tent with good patient management, in order to reduce the risk of overdose. Screening Patients for BipolarDisorder-A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed(though not established in controlled trials) that treating such an episode with an anti depressant alone mayincrease the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, priorto initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screenedto determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history,including a family history of suicide, bipolar disorder, and depression. It should be noted that Lexapro is notapproved for use in treating bipolar depression. Serotonin Syndrome or Neuroleptic Malignant Syndrome(NMS)-like Reactions-The development of a potentially life-threatening serotonin syndrome or NeurolepticMalignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Lexaprotreatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs whichimpair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists.Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g.,hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia,muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. Theconcomitant use of Lexapro with MAOIs intended to treat depression is contraindicated. If concomitant treatmentof Lexapro with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of thepatient is advised, particularly during treatment initiation and dose increases. The concomitant use of Lexapro with

serotonin precursors (such as tryptophan) is not recommended. Treatment with Lexapro and any concomitantserotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if theabove events occur and supportive symptomatic treatment should be initiated. Discontinuation of Treatment withLexapro-During marketing of Lexapro and other SSRIs and SNRIs (serotonin and norepinephrine reuptakeinhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs,particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory distur-bances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotionallability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of seri-ous discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatmentwith Lexapro. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resum-ing the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing thedose but at a more gradual rate [see Dosage and Administration]. Seizures-Although anticonvulsant effects ofracemic citalopram have been observed in animal studies, Lexapro has not been systematically evaluated inpatients with a seizure disorder. These patients were excluded from clinical studies during the product’s premar-keting testing. In clinical trials of Lexapro, cases of convulsion have been reported in association with Lexaprotreatment. Like other drugs effective in the treatment of major depressive disorder, Lexapro should be introducedwith care in patients with a history of seizure disorder. Activation of Mania/Hypomania-In placebo-controlled tri-als of Lexapro in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715patients treated with Lexapro and in none of the 592 patients treated with placebo. One additional case of hypo-mania has been reported in association with Lexapro treatment. Activation of mania/hypomania has also beenreported in a small proportion of patients with major affective disorders treated with racemic citalopram and othermarketed drugs effective in the treatment of major depressive disorder. As with all drugs effective in the treatmentof major depressive disorder, Lexapro should be used cautiously in patients with a history of mania.Hyponatremia-Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Lexapro. Inmany cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormonesecretion (SIADH), and was reversible when Lexapro was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIsand SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [seeGeriatric Use]. Discontinuation of Lexapro should be considered in patients with symptomatic hyponatremia andappropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache,difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope,seizure, coma, respiratory arrest, and death. Abnormal Bleeding-SSRIs and SNRIs, including Lexapro, mayincrease the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin,and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohortdesign) have demonstrated an association between use of drugs that interfere with serotonin reuptake and theoccurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchy-moses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned aboutthe risk of bleeding associated with the concomitant use of Lexapro and NSAIDs, aspirin, or other drugs that affectcoagulation. Interference with Cognitive and Motor Performance-In a study in normal volunteers, Lexapro 10 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned aboutoperating hazardous machinery, including automobiles, until they are reasonably certain that Lexapro therapydoes not affect their ability to engage in such activities. Use in Patients with Concomitant Illness-Clinical expe-rience with Lexapro in patients with certain concomitant systemic illnesses is limited. Caution is advisable in usingLexapro in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.Lexapro has not been systematically evaluated in patients with a recent history of myocardial infarction or unsta-ble heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product’spremarketing testing. In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of Lexapro in hepatically impaired patients is10 mg/day [see Dosage and Administration]. Because escitalopram is extensively metabolized, excretion ofunchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renalimpairment have been evaluated during chronic treatment with Lexapro, however, it should be used with cautionin such patients [see Dosage and Administration]. Potential for Interaction with Monoamine Oxidase Inhibitors-In patients receiving serotonin reuptake inhibitor drugs in combination with a monoamine oxidase inhibitor(MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity,

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myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes thatinclude extreme agitation progressing to delirium and coma. These reactions have also been reported in patientswho have recently discontinued SSRI treatment and have been started on an MAOI. Some cases presented withfeatures resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combineduse of SSRIs and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evokebehavioral excitation. Therefore, it is recommended that Lexapro should not be used in combination with an MAOI,or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping Lexapro before starting an MAOI. Serotonin syndrome has been reported in two patients who were concomitantly receiving linezolid, an antibiotic which is a reversible non-selective MAOI.ADVERSE REACTIONS: Clinical Trials Experience-Because clinical studies are conducted under widely varyingconditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to ratesin the clinical studies of another drug and may not reflect the rates observed in practice. Clinical Trial DataSources; Pediatrics (6 -17 years)-Adverse events were collected in 576 pediatric patients (286 Lexapro, 290 placebo) with major depressive disorder in double-blind placebo-controlled studies. Safety and effectivenessof Lexapro in pediatric patients less than 12 years of age has not been established. Adults-Adverse events information for Lexapro was collected from 715 patients with major depressive disorder who were exposed to escitalopram and from 592 patients who were exposed to placebo in double-blind, placebo-controlled trials. Anadditional 284 patients with major depressive disorder were newly exposed to escitalopram in open-label trials.The adverse event information for Lexapro in patients with GAD was collected from 429 patients exposed to esc-italopram and from 427 patients exposed to placebo in double-blind, placebo-controlled trials. Adverse eventsduring exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminol-ogy of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion ofindividuals experiencing adverse events without first grouping similar types of events into a smaller number ofstandardized event categories. In the tables and tabulations that follow, standard World Health Organization(WHO) terminology has been used to classify reported adverse events. The stated frequencies of adverse reac-tions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse eventof the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened whilereceiving therapy following baseline evaluation. Adverse Events Associated with Discontinuation of Treatment;Major Depressive Disorder; Pediatrics (6 -17 years)-Adverse events were associated with discontinuation of3.5% of 286 patients receiving Lexapro and 1% of 290 patients receiving placebo. The most common adverseevent (incidence at least 1% for Lexapro and greater than placebo) associated with discontinuation was insomnia(1% Lexapro, 0% placebo). Adults-Among the 715 depressed patients who received Lexapro in placebo-controlled trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies, the rate of discontinuation for adverse events in patients receiving10 mg/day Lexapro was not significantly different from the rate of discontinuation for adverse events in patientsreceiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/dayLexapro was 10%, which was significantly different from the rate of discontinuation for adverse events in patientsreceiving 10 mg/day Lexapro (4%) and placebo (3%). Adverse events that were associated with the discontinua-tion of at least 1% of patients treated with Lexapro, and for which the rate was at least twice that of placebo, werenausea (2%) and ejaculation disorder (2% of male patients). Generalized Anxiety Disorder; Adults-Among the429 GAD patients who received Lexapro 10-20 mg/day in placebo-controlled trials, 8% discontinued treatmentdue to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse events that were associ-ated with the discontinuation of at least 1% of patients treated with Lexapro, and for which the rate was at leasttwice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%). Incidence of Adverse Reactions inPlacebo-Controlled Clinical Trials; Major Depressive Disorder; Pediatrics (6 -17 years)-The overall profile ofadverse reactions in pediatric patients was generally similar to that seen in adult studies, as shown in Table 2.However, the following adverse reactions (excluding those which appear in Table 2 and those for which the codedterms were uninformative or misleading) were reported at an incidence of at least 2% for Lexapro and greater thanplacebo: back pain, urinary tract infection, vomiting, and nasal congestion. Adults-The most commonly observedadverse reactions in Lexapro patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweatingincreased, fatigue, and somnolence. Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 715 depressed patients who received Lexapro at dosesranging from 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more ofpatients treated with Lexapro and for which the incidence in patients treated with Lexapro was greater than theincidence in placebo-treated patients.

TABLE 2Treatment-Emergent Adverse Reactions Observed with a Frequency of ≥ 2%

and Greater Than Placebo for Major Depressive Disorder

Adverse Reaction Lexapro Placebo(N=715) (N=592)

Autonomic Nervous System DisordersDry Mouth 6% 5%Sweating Increased 5% 2%Central & Peripheral Nervous System DisordersDizziness 5% 3%Gastrointestinal DisordersNausea 15% 7%Diarrhea 8% 5%Constipation 3% 1%Indigestion 3% 1%Abdominal Pain 2% 1%GeneralInfluenza-like Symptoms 5% 4%Fatigue 5% 2%Psychiatric DisordersInsomnia 9% 4%Somnolence 6% 2%Appetite Decreased 3% 1%Libido Decreased 3% 1%Respiratory System DisordersRhinitis 5% 4%Sinusitis 3% 2%UrogenitalEjaculation Disorder1,2 9% <1%Impotence2 3% <1%Anorgasmia3 2% <1%

1Primarily ejaculatory delay.2Denominator used was for males only (N=225 Lexapro; N=188 placebo).3Denominator used was for females only (N=490 Lexapro; N=404 placebo).

Generalized Anxiety Disorder; Adults-The most commonly observed adverse reactions in Lexapro patients (inci-dence of approximately 5% or greater and approximately twice the incidence in placebo patients) were nausea,ejaculation disorder (primarily ejaculatory delay), insomnia, fatigue, decreased libido, and anorgasmia. Table 3enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse events that occurredamong 429 GAD patients who received Lexapro 10 to 20 mg/day in placebo-controlled trials. Events included arethose occurring in 2% or more of patients treated with Lexapro and for which the incidence in patients treatedwith Lexapro was greater than the incidence in placebo-treated patients.

TABLE 3Treatment-Emergent Adverse Reactions Observed with a Frequency of ≥ 2%

and Greater Than Placebo for Generalized Anxiety Disorder

Adverse Reactions Lexapro Placebo(N=429) (N=427)

Autonomic Nervous System DisordersDry Mouth 9% 5%Sweating Increased 4% 1%

Central & Peripheral Nervous System DisordersHeadache 24% 17%Paresthesia 2% 1%

Gastrointestinal DisordersNausea 18% 8%Diarrhea 8% 6%Constipation 5% 4%Indigestion 3% 2%Vomiting 3% 1%Abdominal Pain 2% 1%Flatulence 2% 1%Toothache 2% 0%

GeneralFatigue 8% 2%Influenza-like Symptoms 5% 4%

Musculoskeletal System DisorderNeck/Shoulder Pain 3% 1%

Psychiatric DisordersSomnolence 13% 7%Insomnia 12% 6%Libido Decreased 7% 2%Dreaming Abnormal 3% 2%Appetite Decreased 3% 1%Lethargy 3% 1%

Respiratory System DisordersYawning 2% 1%

UrogenitalEjaculation Disorder1,2 14% 2%Anorgasmia3 6% <1%Menstrual Disorder 2% 1%

1Primarily ejaculatory delay.2Denominator used was for males only (N=182 Lexapro; N=195 placebo).3Denominator used was for females only (N=247 Lexapro; N=232 placebo).

Dose Dependency of Adverse Reactions-The potential dose dependency of common adverse reactions (definedas an incidence rate of ≥5% in either the 10 mg or 20 mg Lexapro groups) was examined on the basis of thecombined incidence of adverse events in two fixed-dose trials. The overall incidence rates of adverse events in 10 mg Lexapro-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day Lexapro-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day Lexapro group with an incidence that was approximately twice that ofthe 10 mg/day Lexapro group and approximately twice that of the placebo group.

TABLE 4Incidence of Common Adverse Reactions in Patients with Major Depressive Disorder

Adverse Reaction Placebo 10 mg/day 20 mg/day(N=311) Lexapro Lexapro

(N=310) (N=125)Insomnia 4% 7% 14%Diarrhea 5% 6% 14%Dry Mouth 3% 4% 9%Somnolence 1% 4% 9%Dizziness 2% 4% 7%Sweating Increased <1% 3% 8%Constipation 1% 3% 6%Fatigue 2% 2% 6%Indigestion 1% 2% 6%

Male and Female Sexual Dysfunction with SSRIs-Although changes in sexual desire, sexual performance, andsexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence ofpharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexualexperiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire,performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence.

TABLE 5Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials

Adverse Event Lexapro PlaceboIn Males Only

(N=407) (N=383)Ejaculation Disorder(primarily ejaculatory delay) 12% 1%Libido Decreased 6% 2%Impotence 2% <1%

In Females Only(N=737) (N=636)

Libido Decreased 3% 1%Anorgasmia 3% <1%

There are no adequately designed studies examining sexual dysfunction with escitalopram treatment. Priapismhas been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associatedwith the use of SSRIs, physicians should routinely inquire about such possible side effects. Vital Sign Changes-Lexapro and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse,systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for poten-tially clinically significant changes from baseline in these variables. These analyses did not reveal any clinicallyimportant changes in vital signs associated with Lexapro treatment. In addition, a comparison of supine andstanding vital sign measures in subjects receiving Lexapro indicated that Lexapro treatment is not associatedwith orthostatic changes. Weight Changes-Patients treated with Lexapro in controlled trials did not differ fromplacebo-treated patients with regard to clinically important change in body weight. Laboratory Changes-Lexaproand placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry,hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinicallysignificant changes from baseline in these variables. These analyses revealed no clinically important changes inlaboratory test parameters associated with Lexapro treatment. ECG Changes-Electrocardiograms from Lexapro(N=625), racemic citalopram (N=351), and placebo (N=527) groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria forpotentially clinically significant changes from baseline in these variables. These analyses revealed (1) a decreasein heart rate of 2.2 bpm for Lexapro and 2.7 bpm for racemic citalopram, compared to an increase of 0.3 bpmfor placebo and (2) an increase in QTc interval of 3.9 msec for Lexapro and 3.7 msec for racemic citalopram,compared to 0.5 msec for placebo. Neither Lexapro nor racemic citalopram were associated with the develop-ment of clinically significant ECG abnormalities. Other Reactions Observed During the Premarketing Evaluationof Lexapro-Following is a list of treatment-emergent adverse events, as defined in the introduction to theADVERSE REACTIONS section, reported by the 1428 patients treated with Lexapro for periods of up to one yearin double-blind or open-label clinical trials during its premarketing evaluation. The listing does not include thoseevents already listed in Tables 2 & 3, those events for which a drug cause was remote and at a rate less than 1%or lower than placebo, those events which were so general as to be uninformative, and those events reportedonly once which did not have a substantial probability of being acutely life threatening. Events are categorized bybody system. Events of major clinical importance are described in the Warnings and Precautions section.Cardiovascular - hypertension, palpitation. Central and Peripheral Nervous System Disorders - light-headed feel-ing, migraine. Gastrointestinal Disorders - abdominal cramp, heartburn, gastroenteritis. General - allergy, chestpain, fever, hot flushes, pain in limb. Metabolic and Nutritional Disorders - increased weight. MusculoskeletalSystem Disorders - arthralgia, myalgia jaw stiffness. Psychiatric Disorders - appetite increased, concentrationimpaired, irritability. Reproductive Disorders/Female - menstrual cramps, menstrual disorder. RespiratorySystem Disorders - bronchitis, coughing, nasal congestion, sinus congestion, sinus headache. Skin andAppendages Disorders - rash. Special Senses - vision blurred, tinnitus. Urinary System Disorders - urinary frequency, urinary tract infection. Post-Marketing Experience; Adverse Reactions Reported Subsequent to theMarketing of Escitalopram-The following additional adverse reactions have been identified from spontaneousreports of escitalopram received worldwide. These adverse reactions have been chosen for inclusion because ofa combination of seriousness, frequency of reporting, or potential causal connection to escitalopram and havenot been listed elsewhere in labeling. However, because these adverse reactions were reported voluntarily froma population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causalrelationship to drug exposure. These events include: Blood and Lymphatic System Disorders: anemia, agranulo-cytis, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia purpura, leukopenia, thrombocytopenia.Cardiac Disorders: atrial fibrillation, bradycardia, cardiac failure, myocardial infarction, tachycardia, torsade depointes, ventricular arrhythmia, ventricular tachycardia. Ear and Labyrinth Disorders: vertigo EndocrineDisorders: diabetes mellitus, hyperprolactinemia, SIADH. Eye Disorders: diplopia, glaucoma, mydriasis, visualdisturbance. Gastrointestinal Disorders: dysphagia, gastrointestinal hemorrhage, gastroesophageal reflux, pancreatitis, rectal hemorrhage. General Disorders and Administration Site Conditions: abnormal gait, asthenia,edema, fall, feeling abnormal, malaise. Hepatobiliary Disorders: fulminant hepatitis, hepatic failure, hepaticnecrosis, hepatitis. Immune System Disorders: allergic reaction, anaphylaxis. Investigations: bilirubin increased,decreased weight, electrocardiogram QT prolongation, hepatic enzymes increased, hypercholesterolemia, INRincreased, prothrombin decreased. Metabolism and Nutrition Disorders: hyperglycemia, hypoglycemia,hypokalemia, hyponatremia. Musculoskeletal and Connective Tissue Disorders: muscle cramp, muscle stiffness,muscle weakness, rhabdomyolysis. Nervous System Disorders: akathisia, amnesia, ataxia, choreoathetosis,cerebrovascular accident, dysarthria, dyskinesia, dystonia, extrapyramidal disorders, grand mal seizures (or convulsions), hypoaesthesia, myoclonus, nystagmus, Parkinsonism, restless legs, seizures, syncope, tardivedyskinesia, tremor. Pregnancy, Puerperium and Perinatal Conditions: spontaneous abortion. PsychiatricDisorders: acute psychosis, aggression, agitation, anger, anxiety, apathy, completed suicide, confusion, deper-sonalization, depression aggravated, delirium, delusion, disorientation, feeling unreal, hallucinations (visual andauditory), mood swings, nervousness, nightmare, panic reaction, paranoia, restlessness, self-harm or thoughtsof self-harm, suicide attempt, suicidal ideation, suicidal tendency. Renal and Urinary Disorders: acute renal failure, dysuria, urinary retention. Reproductive System and Breast Disorders: menorrhagia, priapism.Respiratory, Thoracic and Mediastinal Disorders: dyspnea, epistaxis, pulmonary embolism, pulmonary hyperten-sion of the newborn. Skin and Subcutaneous Tissue Disorders: alopecia, angioedema, dermatitis, ecchymosis,erythema multiforme, photosensitivity reaction, Stevens Johnson Syndrome, toxic epidermal necrolysis,urticaria. Vascular Disorders: deep vein thrombosis, flushing, hypertensive crisis, hypotension, orthostatichypotension, phlebitis, thrombosis. DRUG INTERACTIONS: Serotonergic Drugs-Based on the mechanism of action of SNRIs and SSRIs includingLexapro, and the potential for serotonin syndrome, caution is advised when Lexapro is coadministered with otherdrugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic whichis a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort [see Warnings and Precautions]. Theconcomitant use of Lexapro with other SSRIs, SNRIs or tryptophan is not recommended. Triptans-There havebeen rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treat-ment of Lexapro with a triptan is clinically warranted, careful observation of the patient is advised, particularlyduring treatment initiation and dose increases [see Warnings and Precautions]. CNS Drugs- Given the primaryCNS effects of escitalopram, caution should be used when it is taken in combination with other centrally actingdrugs. Alcohol-Although Lexapro did not potentiate the cognitive and motor effects of alcohol in a clinical trial,as with other psychotropic medications, the use of alcohol by patients taking Lexapro is not recommended.Monoamine Oxidase Inhibitors (MAOIs)-[see Contraindications and Warnings and Precautions]. Drugs ThatInterfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)-Serotonin release by platelets plays an importantrole in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated anassociation between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence ofupper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate therisk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs andSNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored whenLexapro is initiated or discontinued. Cimetidine-In subjects who had received 21 days of 40 mg/day racemiccitalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopramAUC and Cmax of 43% and 39%, respectively. The clinical significance of these findings is unknown. Digoxin-Insubjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of citalopram anddigoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.Lithium-Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days)had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levelsshould be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical prac-tice. Because lithium may enhance the serotonergic effects of escitalopram, caution should be exercised whenLexapro and lithium are coadministered. Pimozide and Celexa-In a controlled study, a single dose of pimozide2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a meanincrease in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did notalter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.Sumatriptan-There have been rare postmarketing reports describing patients with weakness, hyperreflexia, andincoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and anSSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram) is clinically warranted,appropriate observation of the patient is advised. Theophylline-Combined administration of racemic citalopram(40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not

evaluated. Warfarin-Administration of 40 mg/day racemic citalopram for 21 days did not affect the pharmaco -kinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance ofwhich is unknown. Carbamazepine-Combined administration of racemic citalopram (40 mg/day for 14 days) andcarbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given theenzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearanceof escitalopram should be considered if the two drugs are coadministered. Triazolam-Combined administrationof racemic citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam. Ketoconazole-Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor,decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect thepharmacokinetics of citalopram. Ritonavir-Combined administration of a single dose of ritonavir (600 mg), botha CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmaco -kinetics of either ritonavir or escitalopram. CYP3A4 and -2C19 Inhibitors-In vitro studies indicated that CYP3A4and -2C19 are the primary enzymes involved in the metabolism of escitalopram. However, coadministration ofescitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the phar-macokinetics of escitalopram. Because escitalopram is metabolized by multiple enzyme systems, inhibition of asingle enzyme may not appreciably decrease escitalopram clearance. Drugs Metabolized by CytochromeP4502D6-In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady statelevels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metab-olizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, ofa drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism.However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (singledose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC ofdesipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6. Metoprolol-Administration of 20 mg/dayLexapro for 21 days in healthy volunteers resulted in a 50% increase in Cmax and 82% increase in AUC of the beta-adrenergic blocker metoprolol (given in a single dose of 100 mg). Increased metoprolol plasma levels havebeen associated with decreased cardioselectivity. Coadministration of Lexapro and metoprolol had no clinicallysignificant effects on blood pressure or heart rate. Electroconvulsive Therapy (ECT)-There are no clinical studies of the combined use of ECT and escitalopram.USE IN SPECIFIC POPULATIONS: Pregnancy; Pregnancy Category C-In a rat embryo/fetal development study,oral administration of escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organo-genesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses(approximately ≥ 56 times the maximum recommended human dose [MRHD] of 20 mg/day on a body surfacearea [mg/m2] basis). Maternal toxicity (clinical signs and decreased body weight gain and food consumption),mild at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day isapproximately 28 times the MRHD on a mg/m2 basis. No teratogenicity was observed at any of the doses test-ed (as high as 75 times the MRHD on a mg/m2 basis). When female rats were treated with escitalopram (6, 12,24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growthretardation were noted at 48 mg/kg/day which is approximately 24 times the MRHD on a mg/m2 basis. Slightmaternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose.Slightly increased offspring mortality was also seen at 24 mg/kg/day. The no-effect dose was 12 mg/kg/daywhich is approximately 6 times the MRHD on a mg/m2 basis. In animal reproduction studies, racemic citalopramhas been shown to have adverse effects on embryo/fetal and postnatal development, including teratogeniceffects, when administered at doses greater than human therapeutic doses. In two rat embryo/fetal developmentstudies, oral administration of racemic citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidenceof fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. This dose was also asso-ciated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses ofracemic citalopram of up to 16 mg/kg/day. Thus, teratogenic effects of racemic citalopram were observed at amaternally toxic dose in the rat and were not observed in the rabbit. When female rats were treated with racemiccitalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose.The no-effect dose was 12.8 mg/kg/day. Similar effects on offspring mortality and growth were seen when damswere treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day. A no-effect dose was not determined in that study. There are no adequate and well-controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Pregnancy-Nonteratogenic Effects-Neonates exposed to Lexapro and other SSRIs or SNRIs, late in the thirdtrimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respi-ratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia,hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. Itshould be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warningsand Precautions]. Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general popu-lation and is associated with substantial neonatal morbidity and mortality. In a retrospective, case-control studyof 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the riskfor developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of ges-tation compared to infants who had not been exposed to antidepressants during pregnancy. There is currentlyno corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the firststudy that has investigated the potential risk. The study did not include enough cases with exposure to individ-ual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman withLexapro during the third trimester, the physician should carefully consider both the potential risks and benefitsof treatment [see Dosage and Administration]. Physicians should note that in a prospective longitudinal study of201 women with a history of major depression who were euthymic at the beginning of pregnancy, women whodiscontinued antidepressant medication during pregnancy were more likely to experience a relapse of majordepression than women who continued antidepressant medication. Labor and Delivery-The effect of Lexapro onlabor and delivery in humans is unknown. Nursing Mothers-Escitalopram is excreted in human breast milk.Limited data from women taking 10-20 mg escitalopram showed that exclusively breast-fed infants receiveapproximately 3.9% of the maternal weight-adjusted dose of escitalopram and 1.7% of the maternal weight-adjusted dose of desmethylcitalopram. There were two reports of infants experiencing excessive somnolence,decreased feeding, and weight loss in association with breastfeeding from a racemic citalopram-treated mother;in one case, the infant was reported to recover completely upon discontinuation of racemic citalopram by itsmother and, in the second case, no follow-up information was available. Caution should be exercised and breast-feeding infants should be observed for adverse reactions when Lexapro is administered to a nursing woman.Pediatric Use-Safety and effectiveness of Lexapro has not been established in pediatric patients (less than 12years of age) with Major Depressive Disorder. Safety and effectiveness of Lexapro has been established in adolescents (12 to 17 years of age) for the treatment of major depressive disorder [see Clinical Studies].Although maintenance efficacy in adolescent patients with Major Depressive Disorder has not been systematical-ly evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitaloprampharmacokinetic parameters in adults and adolescent patients. Safety and effectiveness of Lexapro has not beenestablished in pediatric patients less than 18 years of age with Generalized Anxiety Disorder. Geriatric Use-Approximately 6% of the 1144 patients receiving escitalopram in controlled trials of Lexapro in major depressivedisorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of Lexaprobetween 10 and 20 mg. The number of elderly patients in these trials was insufficient to adequately assess forpossible differential efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of someelderly individuals to effects of Lexapro cannot be ruled out. SSRIs and SNRIs, including Lexapro, have beenassociated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for thisadverse event [see Hyponatremia]. In two pharmacokinetic studies, escitalopram half-life was increased byapproximately 50% in elderly subjects as compared to young subjects and Cmax was unchanged [see ClinicalPharmacology]. 10 mg/day is the recommended dose for elderly patients [see Dosage and Administration]. Of4422 patients in clinical studies of racemic citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457were 75 and over. No overall differences in safety or effectiveness were observed between these subjects andyounger subjects, and other reported clinical experience has not identified differences in responses between theelderly and younger patients, but again, greater sensitivity of some elderly individuals cannot be ruled out. DRUG ABUSE AND DEPENDENCE: Abuse and Dependence; Physical and Psychological Dependence-Animalstudies suggest that the abuse liability of racemic citalopram is low. Lexapro has not been systematically stud-ied in humans for its potential for abuse, tolerance, or physical dependence. The premarketing clinical experiencewith Lexapro did not reveal any drug-seeking behavior. However, these observations were not systematic and itis not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will bemisused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate Lexapropatients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse(e.g., development of tolerance, incrementations of dose, drug-seeking behavior).OVERDOSAGE: Human Experience-In clinical trials of escitalopram, there were reports of escitalopram over-dose, including overdoses of up to 600 mg, with no associated fatalities. During the postmarketing evaluation ofescitalopram, Lexapro overdoses involving overdoses of over 1000 mg have been reported. As with other SSRIs,a fatal outcome in a patient who has taken an overdose of escitalopram has been rarely reported. Symptomsmost often accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol,included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somno-lence, and ECG changes (including QT prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose. Management of Overdose-Establish and maintainan airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended,along with general symptomatic and supportive care. Due to the large volume of distribution of escitalopram,forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for Lexapro. In managing overdosage, consider the possibility of multiple-drug involvement.The physician should consider contacting a poison control center for additional information on the treatment ofany overdose.

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Severe State and Federal Funding Shortfalls Likely for Local Mental Health ProgramsA political tsunami threatens access to mental health care for individuals who depend on community pro-grams. States are axing Medicaid recipients and/or reducing Medicaid

funding to community mental health centers. Meanwhile, Republicans in Congress are intent on budget cuts that would make major reductions to the federal mental health block grant that supplements state programs be-yond state Medicaid funding.

Chuck Ingoglia, MSW, vice pres-ident, public policy, National Coun-cil for Community Behavioral Healthcare, explained that Medicaid funds 50% of outpatient mental health care provided in total—in lo-

cal, state, federal, and private-pay programs—in the United States.

In Arizona, for example, Gover-nor Janice Brewer has announced that she will eliminate 280,000 Med-icaid recipients from the program. Perhaps 140,000 of those adults and children are receiving some form of out-patient psychiatric care.

Other Medicaid recipients around the country have been and will be losing access to psychiatrists and other mental health providers be-

cause of state Medicaid funding cuts occasioned by the lingering results of the 2008-2009 recession. On Feb-ruary 16, 2011, Kevin Martone, dep-uty commissioner of the New Jersey division of mental health and addic-tion services, keynoted a congressio-nal staff briefing in Washington. He noted that states have been forced to cut mental health agency budgets

by Stephen Barlas

WASHINGTON REPORT48 APRIL 2011www.psychiatr ic t imes.com

PSYCHIATRIC TIMES

We invite you to listen to succinct discussions on www.psychiatrictimes.com.

www.PsychiatricTimes.com/podcasts

Second-Generation Antipsychotics and Schizophrenia

Dr David Osser focuses on a meta-analysis of the relative magnitude and risk of QT pro-longation posed by several agents in this class in patients with schizophrenia.

Antidepressants for Acute Treatment of Bipolar Disorder

Dr Ronald Pies discusses a meta-analysis that sheds new light on the safety and efficacy of antidepressants in the acute treatment of bi-polar disorder.

Suicide Risk AssessmentSince suicide is almost impossible to predict, why is it that a psychiatrist could be held liable for a bad outcome? Have any suicide assessment forms been validated in the prediction of sui-cide risk? Is it risky for a psychiatrist to accept a patient’s denial of suicidal ideas at face value? Forensic psychiatrist Phillip Resnick addresses these 3 questions in the first in his podcast series.

Special Report Chair Discusses Suicide

Dr Eric Caine discusses the things physicians need to know about suicide, including the myths that surround it, who is at increased risk, and prevention strategies.

Book Review

We’ve Got Issues: Children and Parents

in the Age of Medication

by Judith Warner; New York:

Penguin Group; 2010

336 pages • $25.95 (hardcover)

Reviewed by Gabrielle A. Carlson, MD

For those of us who treat seriously emotionally disturbed children, We’ve Got Issues is a welcome change from the invectives of those who believe that the use psycho-tropic medication is virtually crim-inal. Ms Warner began with that supposition—and when she dug deep er into the matter, she found that most parents and doctors do the best they can for children whose psychological problems are any-thing but trivial.

“Issues” is a clever word. I had first heard the term from the mother of a boy with high-functioning au-tism. She called his explosive melt-downs “issues.” I thought, “What kind of euphemism is that?” It is a nice disguise, though, for the many behavioral difficulties parents face with their children when they don’t want to use a more stigmatizing label.

Ms Warner turns out to have other “issues” too. Her first was finding that much of the ambient information that depicts doctors as “drugging and pathologizing kids,” “profit-mad scientists” and parents who are looking for a quick fix comes from uninformed and over-simplified “public opinion and most media treatment.”

Hunkering down with well-ref-erenced research, she fills her chap-ters with “observation, scores of interviews with mental health ex-perts, critical thinking and, above all, the compassion gained from talking to dozens and dozens of the parents who stare at the whole ‘is-sue’ of chil dren’s mental health.”

Ms War ner then returns to a discus-sion of how public understanding of children’s mental health treat-ment has gone wrong.

Among other things, the author recognizes that “kids with serious problems are no longer routinely institutionalized . . . they’re kept functioning with medication,” and there are real risks in not being properly treated. She debunks what she calls the MedScare—the “now common conviction that psychiat-ric drugs are being used to control and denature normal and healthy children and adults who don’t con-form to society’s expectations.”

Ms Warner says “Industry/Big-Pharma” has corrupted medicine and psychiatry. However, her under standing of how drugs are studied is naive, and her notion of “conflicts of interest” is limited only to financial ones. Like many in the public sector, she doesn’t recog-nize that more is broken than over-zealous marketing. She fails to real-ize that if there were no connection between academic clinicians and pharmaceutical companies, drug development would be seriously compromised.

Any practicing child psychiatrist can get behind the book’s most seri-ous concern that “science has out-paced our capacity to use it well. Progress has been betrayed by com-mercial interests, political complai-sance, and a lack of policy directed at making sure that new scientific advances are safely . . . made avail-able to . . . the public.” While Ms Warner tends to be redundant and oversimplifies matters—and die-hard opponents of the practice of mental health medicalization will not be persuaded—worried parents and caring doctors have an articu-late champion in their corner.

Dr Carlson is professor of psychiatry and pediatrics and director of child and adoles-cent psychiatry at Stony Brook University School of Medicine in New York. ❒

WASHINGTON REPORTSAMHSA activities. If H.R. 1 is ulti-mately passed, SAMHSA would take a 7% overall cut since last year. There is no chance that Obama’s SAMHSA budget request for ’12 will be enacted.” So the $14 million increase to the $420 million Obama proposed for fiscal 2012 is dead.

The only question is whether Congress will cut the mental health block grant again, in 2012—and by how much. Ingoglia explained that Sen Debbie Stabenow (D-Mich)

by a combined total of nearly $2.2 billion over the past 3 fiscal years. “Many states have been forced to re-duce funding for a wide array of community-based interventions, in-cluding crisis services, targeted case management, prescription medica-tions, and outpatient clinics,” he said. “These services are at the heart of every public mental health system in the country.”

Martone was in Washington to help build congressional support for President Obama’s proposed fiscal 2012 budget for the Substance Abuse and Mental Health Services Admin-istration (SAMHSA), which, next to Medicaid, is the second largest fed-eral source of mental health funding. SAMHSA’s main contribution in that regard is its community mental health block grant program. That money is distributed to states on a formula basis, and the states then divvy their portion up among their cities and counties. In fiscal 2012, beginning October 1, 2011, an in-crease from $420.8 million in fiscal 2011 to $434.7 million is proposed.

Congress, however, has not yet approved a fiscal 2011 budget. It has been passing a series of continuing resolutions that have kept all federal 2011 budgets at 2010 levels. For the mental health block grant program, that is $420.8 million—the same level Obama has proposed for 2011.

Congress has delayed passing a 2011 budget because Republicans want to make reductions across the board in discretionary programs to-taling $61 billion below 2010 levels. In the Continuing Resolution (H.R. 1) the House passed by a vote of 235 to 189 on February 19, 2011, the SAMHSA budget for fiscal 2011 was cut by $200 million below the 2010 budget of $3.43 billion. There was an additional cut of $2.9 million for mental health programs of regional and national significance, a catchall category that funds a variety of local mental health programs. H.R. 1 did not prescribe how SAMHSA should apportion that $200 million in cuts. But mental health lobbyists believe that most, if not all, of that $200 mil-lion would be cut from the mental health ($420 million) and substance abuse ($1.45 billion) block grants, probably proportionally.

Two things seem certain at this point. When Congress finally passes a 2011 budget for SAMHSA, there will be a significant cut in mental health block grants below 2010 lev-els. James K. Finley, senior asso-ciate government relations, National Association of Social Workers, ex-plained, “The cuts under discus-sion now would certainly impact

planned to lead an effort in the Sen-ate to ward off severe cuts to the mental health block grant program. He noted, however, that given the political pressure to cut the federal budget deficit, the debate over SAMHSA spending and spending for other discretionary programs—whether those be food stamps or home heating subsidies for the poor—will “not be about if we cut, it will be about how much we cut, and both Republicans and Democrats

will support some level of reductions in these programs.”

Very doubtful, too, is funding for the new $90 million program for state mental health prevention grants the President proposed for 2012. According to Ingoglia, that initiative is meant to run parallel to the Ac-countable Care Act’s (that was the controversial health care reform bill passed in 2010) programs dedicated to upgrading primary care preven-tion services. ❒


November 7-10, 2011

CME LLC Announces Charles Raison, MD as the Program Chair of 2011 Psych Congress

Charles Raison, MD* 2011 Psych Congress Chair

Charles Raison, MD* 2011 Psych Congress Chair

For more information about Dr. Raison, the Steering Committee, and to register with special Early Bird discounts, please visit:

PsychCongress.com or call (800) 447-4474.

* Dr. Raison is paid by CME LLC to chair Psych Congress. The opinions expressed are those of Dr. Raison and do not necessarily reflect the views of Emory University or Emory Healthcare. Dr. Raison’s participation in this activity does not constitute or imply endorsement by Emory University or Emory Healthcare.

Official Coverage ProviderJoin our communities

TWPTWP

CME LLC’s goal is to provide an optimal educational experience. One of the key aspects

is focusing on the endeavor of how we can more involve providers who are going to come

to the conference not just as a listener or a learner, but also as a participant.”

“We plan to make this year’s program a collective process through community development in order to best teach each other using our shared knowledge and wisdom to establish better practices in

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“I’m very excited about this year’s Psych Congress and I really think we’re going to knock

this one out of the park.”

CATEGORYSPONSORED BY CME LLC • PSYCHIATRIC TIMES • APRIL 2011

Cardiometabolic Risks of Antidepressant and Antipsychotic Drugs, Part 1Proarrhythmic Risks of Antidepressant and Antipsychotic Drugs

50

CREDITS: 1.5

RELEASE DATE: April 20, 2011

EXPIRATION DATE: April 20, 2012

FACULTYW. Victor R. Vieweg, MDClinical Professor, Departments of Psychiatry and Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond

Mehrul Hasnain, MDClinical Associate Professor, Department of Psychiatry, Memorial University of Newfoundland, Wateford Hospital, St John’s, Newfoundland

Mark A. Wood, MDProfessor, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond

Antony Fernandez, MDProfessor, Department of Psychiatry, Virginia Commonwealth University School of Medicine, Staff Psychiatrist, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond

Edward J. Lesnefsky, MDProfessor, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Chief of Cardiology, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond

Ananda K. Pandurangi, MDProfessor, Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond

FACULTY DISCLOSURESDrs Vieweg, Hasnain, Wood, Fernandez, and Lesnefsky have no relationships to disclose relating to the subject matter of this article. Dr Pandurangi reports that she is a consultant for Prophase Inc and principal investigator for Eli Lilly & Co.

This activity has been independently reviewed for balance.

TARGET AUDIENCEThis continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, nurse practitioners, and other health care professionals who seek to improve their care for patients requiring treatment with antidepressant and antipsychotic drugs.

GOAL STATEMENTThis activity will provide participants with an understanding of the life-threatening proarrhythmic risks associated with antidepressant and antipsychotic drug administration and how to monitor and protect patients from these risks.

ESTIMATED TIME TO COMPLETEThe activity in its entirety should take approximately 90 minutes to complete.

LEARNING OBJECTIVESAfter completing this activity, participants should be able to:• Identify the proarrhythmic risks associated with

antidepressant and antipsychotic medications• Understand the underlying causes for these

proarrhythmic risks• Monitor their patients for adverse proarrhythmic

effects associated with antidepressant and antipsychotic drugs

COMPLIANCE STATEMENTThis activity is an independent educational activity under the direction of CME LLC. The activity was planned and implemented in accordance with the Essential Areas and policies of the ACCME, the Ethical Opinions/Guidelines of the AMA, the FDA, the OIG, and the PhRMA Code on Interactions with Healthcare Professionals, thus assuring the highest degree of independence, fair balance, scientific rigor, and objectivity.

ACCREDITATION STATEMENTThis activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of CME LLC and Psychiatric Times. CME LLC is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATIONCME LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

DISCLAIMERThe opinions and recommendations expressed by faculty and other experts whose input is included in this activity are their own and do not necessarily reflect the views of the sponsors or supporter. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the faculty or may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Activity participants are encouraged to refer to primary references or full prescribing information resources.

METHOD OF PARTICIPATIONParticipants are required to read the entire article and to complete the posttest and evaluation to earn a certificate of completion. A passing score of 80% or better earns the participant 1.5 AMA PRA Category 1 Credits™. A fee of $15 will be charged. Participants are allowed 2 attempts to successfully complete the activity.

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To earn credit online, go to www.PsychiatricTimes.com/cme.

Understanding QTc Interval Prolongation,

Polymorphic Ventricular Tachycardia, and Its

Subtype Torsade de Pointes

by W. Victor R. Vieweg, MD, Mehrul Hasnain, MD,

Mark A. Wood, MD, Antony Fernandez, MD,

Edward J. Lesnefsky, MD, and

Ananda K. Pandurangi, MD

Depression will soon join coronary ar-tery disease (CAD) to become 1 of the 2 leading causes of disability in devel-oped countries.1 In the United States,

morbidity and mortality from CAD is decreasing while the prevalence and burden of depression are increasing. In contrast, both the prevalence of and mortality associated with schizophrenia have remained stable over the past several decades.2 Thus, psychiatrists continue to face the daunting task of improving the mental health of the many persons suffering from depression or schizophre-nia. Although the literature is somewhat mixed,

they must do this in the face of emerging evi-dence that suggests that cardiometabolic toxicity is associated with the use of antidepressant and antipsychotic drugs.

In this first of 2 articles on the cardiometabol-ic risks of antidepressant and antipsychotic drugs, we address their proarrhythmic adverse effects and focus on the role of the corrected QT interval (QTc) prolongation as a marker of such effects. In the next article, to be published in the May 2011 issue of Psychiatric Times, we will discuss the metabolic risks associated with these psycho-tropic agents.

CATEGORY151PSYCHIATRIC TIMES APRIL 2011

Brugada syndrome, sudden cardiac death, and psychotropic medicationsWhat is the connection between Brugada syn-drome and antidepressant and antipsychotic drug-induced sudden cardiac death (SCD)?3 Brugada syndrome was first described in 1992 as a distinct ECG and clinical syndrome charac-terized by right bundle-branch block and per-sistent ST-segment elevation in the right precor-dial leads, as well as by SCD.4 Drug-induced Brugada syndrome is of intense interest (www.brugadadrugs.org).5,6 Drugs to be avoided or pref-erably avoided in patients with Brugada syn-drome include, for example, antiarrhythmic drugs, psycho tropic drugs, and antianginal drugs. Psychotropic medications specifically to be avoided include amitriptyline, clomipramine, desipramine, lithium, loxapine, nortriptyline, and trifluoperazine. Drugs that are preferably avoided include carbamazepine, cyamemazine, doxepin, fluoxetine, imipramine, maprotiline, perphen-azine, phenytoin, and thioridazine.5

ECG manifestations of this syndrome may be intermittent. Therefore, normal findings on an ECG do not rule it out. Fever and low heart rates may allow this syndrome to become manifest, and provocative testing with infusions of sodium channel (fast channel) blocking drugs (flecainide, ajmaline, and procainamide) may uncover the diagnostic ECG pattern. Drugs (eg, quinidine) that block the myocardial cell action potential transient outward potassium current appear to re-duce arrhythmias.7(Figure 4)

The diagnosis of Brugada syndrome is based on the ECG pattern described above, with at least 1 clinical feature that includes syncope, prior cardiac arrest, polymorphic ventricular tachycardia (PVT) or ventricular fibrillation, and/or a family member who had SCD before 45 years of age.6 This syndrome is familial (more common among men than women contrasted with torsade de pointes [TdP], which is more com mon among women) and displays an autoso-mal dominant transmission mode, with incom-

plete penetrance and an incidence of 5 to 66 cases per 10,000.

The Brugada syndrome is one of the ion chan-nel disorders, the so-called channelopathies, usu-ally found in structurally normal hearts. Early interest was in the congenital long QT syndrome, with subsequent attention paid to the Brugada syndrome.8 A short QT syndrome has now been recognized, but it has not been linked to psycho-tropic drug administration.9

Risk factors for coronary artery diseaseRisk factors for CAD have largely remained sta-ble over the past several decades. Risk factors that can be altered include:• Elevated levels of low-density lipoprotein

cholesterol and fasting triglycerides• Hypertension• Diabetes and prediabetes• Overweight and obesity• Smoking• Lack of physical activity (sedentary lifestyle)• Unhealthy diet• Stress (variously defined and understood)

Risk factors that cannot be altered include:• Age• Sex• Family history

A discussion of these risk factors and emerg-ing risk factors is beyond the scope of this article, with the single exception of stress.10 However, there is a growing awareness that the nonspecific stress (distress) of depression or schizophrenia may contribute to the origin and deteriorating clinical course of CAD.11

The cardiac conduction system and the ECGThe tangent method is the most popular way to calculate or measure the QT interval (Figure 1).12 The length of the QT interval varies inversely with heart rate: the slower the heart rate, the lon-ger the QT interval. Several group-derived for-mulas are used to correct (normalize) the QT in-

terval (QTc interval) for heart rate.13 The Bazett formula (QTc interval = QT interval in seconds divided by the square root of the R-R interval in seconds) is the most popular method used to cal-culate the QTc interval.14

The recommended Bazett-corrected QTc in-terval measurements in adults are presented in Table 1.13 While seemingly beyond the expertise of the psychiatrist, accurately measuring the QTc interval may even be challenging for the internist or cardiologist.15 Therefore, it behooves the psy-chiatrist to be familiar with the issues and lan-guage surrounding QTc interval calculation so as to best engage the assistance of the interested car-diac electrophysiologist as necessary.

For readers interested in a more detailed de-scription of the action potential of a single ven-tricular muscle, including sodium, calcium, and potassium ion movements, please refer to the 2009 article “Proarrhythmic risk with antipsy-chotic and antidepressant drugs: implications in the elderly.”7 The article discusses sequential ECG and action potential changes that lead to PVT of the TdP type and to FDA regulatory con-cerns about some newer atypical antipsychotic drugs and their association with QTc interval pro-longation in premarketing studies.

Figure 2 shows the typical ECG features of TdP. The ventricular complexes appear wide apart, consistent with their origin in ventricular myocytes, and ventricular beats appear close to-gether, consistent with tachycardia. Cyclic altera-tions of the QRS electrical axis (caused by mi-grating electrical foci) best explain the varying QRS morphology—torsade (ie, twisting of the points) in TdP. Both the QT and QTc intervals commonly exceed 500 ms in TdP.16

The link between coronary heart disease and depressionThe evidence that links depression and coronary heart disease (CHD) has reached a point of con-sensus sufficient for the American Heart Associa-tion Science Advisory to publish recommenda-tions for screening, referral, and treatment of patients with comorbid depression and CHD.17 This publication was endorsed by the American Psychiatric Association. In brief, the authors pointed out that:• Depression is about 3 times more common in

patients after acute myocardial infarction (MI) than in the general population.

• Fifteen percent to 20% of patients after MI meet DSM-IV-TR criteria for major depres-sive disorder and even a larger percentage manifest depressive symptoms.

• Women are at particularly high risk for depres-sion following acute MI.

• Major depressive disorder and depressive symptoms are more common among persons with CHD than in the general population.

• Major depressive disorder and elevated de-pressive symptoms are associated with a worse prognosis in patients with CHD, and this phenomenon is likely symptom-severity– dependent.

• Some researchers assert that the link between depression and CHD is best explained by CHD-induced depression. Others argue that

(Please see Proarrhythmic Risks, page 52)

Tangent method of calculating the QT interval using the ECG lead II32

Tangent

RR-R interval

P

Q

S

T

U

Baseline

QT

Note: Draw a tangent to the steepest slope of the downward limb of the T wave. The intersection of the tangent and baseline defines the end of the QT interval.

Figure 1

after correcting for disease-induced depres-sive symptoms, the link between depression and comorbid CHD persists. Still others be-lieve that the nebulous boundaries of depres-sion and the mismatch between the precision and reliability of instruments used to assess depression and those used to assess CHD pre-clude elucidating any link at this time.18

• Both biological and behavioral mechanisms have been offered to explain the link between depression and comorbid CHD.

• Depressed patients with comorbid CHD have reduced medication compliance.

• Screening for depression in patients with CHD is recommended (although we have argued for additional evidence before implementing such screening).19

• The Patient Health Questionnaire (PHQ)-2 provides 2 screening questions and may be followed by the PHQ-9 if either answer is positive.20,21

• If the PHQ-9 is consistent with a high proba-bility of depression, refer the patient to a men-tal health professional.

• Cardiologists should take depression into ac-count when managing patients with CHD.

• Only about half of cardiologists report that they treat depression in their patients.

• There is no current evidence that screening for depression improves outcomes in CHD patients.

• Treatment options include antidepressant drugs, cognitive-behavioral therapy, and phys-ical activity.

The link between coronary heart disease and schizophreniaPatients with schizophrenia have a life expec-tancy that is reduced by 20 to 25 years compared with the general population. Most of this reduc-tion is the result of CHD. This differential mortal-ity gap is widening.22,23 Risk factors for CHD morbidity and mortality that appear more com-monly among those with schizophrenia include smoking, diabetes mellitus, dyslipidemia, hyper-tension, and obesity. Many of these risk factors appear as part of the metabolic syndrome, the prevalence of which is increased in persons with schizophrenia.24

Cardiac risks of antidepressant drugsCase-control studies have produced conflicting evidence that tricyclic antidepressants (TCAs) and SSRIs lead to an increased risk of cardiovas-cular disease (CVD). A recent article by Hamer and colleagues25 described a prospective cohort study of 14,784 middle-aged adults free of CVD drawn from the Scottish Health Surveys. About 5% had used antidepressant drugs. Over an 8-year follow-up, TCAs were linked to an in-creased risk of new-onset CVD (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.03 - 1.77). The link between TCAs and CHD events did not reach statistical significance (HR, 1.24; 95% CI, 0.87 - 1.75). SSRI use was not linked to CVD. While recommending replication of this important prospective study that showed a link between TCAs and CVD, the researchers con-cluded that existing mental illness did not explain this link. Rather, the excess disease burden was best explained by the use of TCAs.

Several years ago, we reviewed the cardiovas-cular adverse effects of newer antidepressant drugs (primarily SSRIs) and pointed out their su-perior cardiovascular safety relative to older an-tidepressant drugs, particularly TCAs.26 Potential complications of SSRI administration that in-clude the serotonin syndrome, tachycardia, ar-rhythmias, and other cardiovascular findings were described in the review.

In 1996, we reviewed antidepressant drug–induced blood pressure changes and their man-agement.27,28 TCAs have the most significant car-diovascular adverse effects of any of the anti-depressant drugs currently available in the United States. These adverse effects are most prevalent in patients with preexisting cardiovascular dis-ease. Orthostatic hypotension is the most com-mon cardiovascular adverse effect; conduction disturbances and ventricular arrhythmias are the most life-threatening adverse effects. The quini-dine-like action of TCAs accounts for conduction and rhythm disturbances.

Monoamine oxidase inhibitors (MAOIs) com-monly induce orthostatic hypotension. Hyperten-sive crises and the serotonin syndrome are the most serious cardiac adverse effects associated with MAOI administration. Patients who use these agents require dietary and concomitant drug restrictions to minimize adverse effects. Oc-casionally, spontaneous severe hypertension may occur without dietary or drug-drug interactions.

Bupropion may increase blood pressure, par-ticularly in patients with preexisting hyperten-sion. Trazodone may be associated with ventricu-lar arrhythmias. Nefazodone (no longer used much in the United States because of adverse liver effects) and SSRIs may contribute to ad-verse cardiac drug-drug interactions. Coadminis-tration of SSRIs and MAOIs may produce the serotonin syndrome and vasomotor instability. Venlafaxine may increase supine diastolic blood pressure, and according to the manufacturer, pa-tients who are receiving this drug require blood pressure monitoring.

Periodic blood pressure assessment should probably be a routine part of patient care among those taking antidepressant drugs—particularly elderly patients. Recently, Mark and colleagues29

52 PSYCHIATRIC TIMES APRIL 2011

CATEGORY1Proarrhythmic RisksContinued from page 51

Typical ECG features of torsade de pointes

AxisAxis

Torsade de pointes321 4

PVCPPVCP

Note: Typical ECG pattern found in torsade de pointes (TdP). A sinus beat with a normal QRS interval (1) is followed by premature ventricular contraction (PVC) (2) with a short coupling interval. After a compensatory pause, another

sinus beat (3) with a normal QRS interval is followed by PVC (4) with short coupling interval. The second PVC (4) is the first beat in the TdP ventricular tachyarrhythmia. In summary, we see the typical ECG features of short-long-

short R-R intervals followed by TdP.

Figure 2

Recommended Bazett-corrected QTc measurements to diagnose QT interval prolongation

according to Goldenberg and colleagues13

Rating Adult men Adult women

Normal < 430 ms < 450 ms

Borderline 430 - 450 ms 450 - 470 ms

Prolonged > 450 ms > 470 ms

Table 1

53PSYCHIATRIC TIMES APRIL 2011

CATEGORY1documented that about half of geriatric patients who receive antidepressant drugs may have drug-drug interactions.

Antipsychotic drugs and cardiac toxicityEvidence that links antipsychotic drugs to SCD is compelling. Ray and colleagues30 looked at 481,744 Tennessee Medicaid recipients who had been enrolled from January 1, 1988, through De-cember 31, 1993 (before the introduction of ris-peridone and other atypical antipsychotics), that included 26,749 person-years for current moder-ate-dose antipsychotic drug use (more than 100 mg of thioridazine equivalents); 31,864 person-years for current low-dose antipsychotic drug use (less than 100 mg of thioridazine equivalents); 37,881 person-years for use in the past year only; and 1,186,501 person-years for no antipsychotic drug use. They found 1487 confirmed SCDs. Current moderate-dose users compared with non-users yielded a risk ratio of 2.39 (95% CI, 1.77 - 3.22; P < .001). This risk ratio was greater than for current low-dose users (risk ratio, 1.30; 95% CI, 0.98 - 1.72; P = .003) and former users (risk ratio, 1.20; 95% CI, 0.91 - 1.58; P < .001). How-ever, among current moderate-dose users with severe CVD, the risk ratio was 3.53 (95% CI, 1.66 - 7.51), which yielded an additional 367 SCDs per 10,000 person-years of follow-up.

In an accompanying editorial, Zarate and Patel31 pointed out that:• Newer antipsychotic drugs are no less cardio-

toxic than older ones• Antipsychotic drug cardiotoxicity may be

missed in phase 2 and phase 3 clinical trials because of the small number of patients and short trial duration

• Psychotropic drugs, including TCAs and some antipsychotic drugs (particularly thiorida-zine), are known to prolong the QTc interval and may produce PVT, including TdP

• QTc interval prolongation may be found in up to 8% of psychiatric patients, with women and older patients at the greatest risk

• Antipsychotic drug–induced ventricular fibril-lation is thought to be the main contributor to SCD among patients taking TCAs and anti-psychotic drugs

• Risk factors for cardiotoxicity include hypo-kalemia, hypomagnesemia, hypocalcemia, bradycardia, preexisting cardiovascular dis-ease, congenital QTc interval prolongation, female sex, advancing age, baseline QTc inter-val prolongation, and coadministration of non-psychotropic drugs associated with QTc inter-

val prolongation• Patients with chronic psychosis have reduced

life expectancy independent of any drug ad-ministration

• Depression may accompany psychosis and not be recognized, or depression may itself be a cardiovascular risk factor independent of anti-psychotic drug treatment and contributor to cardiac toxicityStrikingly absent from the editorial is mention

of weight gain commonly associated with antide-pressant and antipsychotic drug administration. In our experience, malpractice litigation is more likely to arise from psychotropic drug–induced metabolic problems than from psychotropic drug–induced cardiac arrhythmias.

In a follow-up to their earlier work, Ray and colleagues32 looked at patients treated with atypi-cal antipsychotics. They conducted a primary analysis in a retrospective cohort study of Ten-nessee Medicaid enrollees that included 44,218 and 46,089 baseline users of single typical and atypical antipsychotic drugs, respectively, and 186,600 matched nonusers. The researchers per-formed a secondary analysis of users of antipsy-chotic drugs free of a baseline diagnosis of schizophrenia or related psychoses and with whom nonusers were matched according to pro-pensity score to assess residual confounding because of factors linked to antipsychotic drug use.

Study results showed that typical and atypical antipsychotic drug use was associated with high-er rates of SCD (adjusted incidence-rate ratio of 1.99; 95% CI, 1.68 - 2.34, and adjusted inci-dence-rate ratio of 2.26; 95% CI, 1.88 - 2.72, re-spectively). The incidence-rate ratio for users of atypical antipsychotic drugs compared with users of typical antipsychotic drugs was 1.14 (95% CI, 0.94 - 1.39). There was no significantly increased risk of SCD for former antipsychotic drug users (1.13; 95% CI, 0.98 - 1.30). For both typical and atypical antipsychotic drug users, the risk of SCD increased significantly with increasing dose. The incidence-rate ratios increased (P < .001) from 1.31 (95% CI, 0.97 - 1.77) for those taking low doses to 2.42 (95% CI, 1.91 - 3.06) for those tak-ing high doses of typical antipsychotic drugs. The incidence-rate ratios increased (P = .01) from 1.59 (95% CI, 1.03 - 2.46) with low doses to 2.86 (95% CI, 2.25 - 3.65) with high doses of atypical antipsychotic drugs. In the cohort matched for propensity score, findings were similar. The re-searchers concluded that both users of typical and users of atypical antipsychotics had similar, dose-related increased risk of SCD.

Cardiac arrhythmiasWith rare exception, those in whom ventricular cardiac arrhythmias develop coincident with an-tipsychotic or antidepressant drug administration have 1 or more risk factors for QT interval pro-longation.7 Table 2 lists the more important risk factors.

Su and colleagues33 assessed QT interval aging trends in healthy older adults in Taiwan. These authors manually measured the QT interval from the beginning of the QRS complex to the end of the T wave. The study was made up of 115 per-sons (90 men and 25 women). Serial QTc interval measurements at baseline, 2 years, and 4 years were 422 ± 20, 425 ± 21, and 429 ± 27 millisec-onds, respectively. The QTc interval increased significantly during the 4-year follow-up (P = .001). The authors concluded that the QTc inter-val increases progressively with age.

However, conclusions and regulatory guide-lines about drug-induced QTc interval prolonga-tion in studies and clinical practice are based on durations of weeks and months rather than years. Although the FDA requires drug-induced group mean QTc interval lengthening no longer than 5 milliseconds to approve a medication for market-ing, individual patient/drug changes of less than 20 milliseconds may not be clinically significant because of differences in individual measure-ments.34,35 Thus, changes in the QTc interval over 4 years as documented by Su and colleagues33 may have limited clinical utility.

The QTc interval varies throughout the day and night. Nighttime values are about 20 milli-seconds longer than daytime measurements be-cause of differences in sympathetic and parasym-pathetic tone.36,37 In 20 normal subjects, daily QTc interval variation was 76 ± 19 milliseconds (range, 35 to 108 milliseconds). However, this range may be increased in patients with cardio-vascular disease.37

Before puberty, the QTc interval is the same for both sexes.38 Compared with the QTc interval in adolescent girls, the QTc interval in boys short-ens by about 20 milliseconds at puberty, and this shortening appears to be androgen-driven. These sex differences remain until age 50 to 55 years, when declining male testosterone values narrow these differences; however, differences may con-tinue even into old age. On the basis of the usual cardiovascular risk factors, we expect about 45% of cases of TdP to occur in women but, in fact, about 70% of cases of TdP occur in women, par-ticularly older women.8 In a recent review of pa-tients aged 60 years or older, almost four-fifths of those in whom QTc interval prolongation, PVT/TdP, and/or SCD developed while they were tak-ing antidepressant or antipsychotic drugs or a combination of these agents were women.7

Elderly men and women tend to have longer QTc intervals than their younger counterparts—even when both groups are free of CVD.39 Age-matched patients with CVD tend to have longer QTc intervals than those patient free of CVD.39

Electrolyte abnormalities, especially hypoka-lemia and hypomagnesemia, may cause or wors-en QTc interval prolongation.40-42 Hypokalemia prolongs the cardiac action potential and may cause early afterdepolarizations leading to TdP.

Risk factors for QT interval prolongation

• Age: elderly at greatest risk

• Circadian variation: nighttime period of greatest risk

• Sex: women more vulnerable than men

• Cardiovascular disease: presence considerably increases risk

• Electrolyte abnormalities: particularly hypokalemia and hypomagnesemia

• Pharmacodynamic/pharmacokinetic factors: poor metabolizers at greatest risk

Table 2

(Please see Proarrhythmic Risks, page 54)

CATEGORY154 PSYCHIATRIC TIMES APRIL 2011

CATEGORY1

Diuretics, especially the thiazides, are the most common cause of hypokalemia. Other causes in-clude vomiting, diarrhea, postprandial states, ex-ercise, and agitation.

Recently, the American Heart Association and the American College of Cardiology Foundation jointly published a scientific statement that fo-cused on the prevention of TdP in hospital set-tings.43 Table 3 provides a list of drugs that have a risk of causing TdP. (For readers interested in a more detailed list, visit www.qtdrugs.org pro-vided by the Arizona CERT World Web site.)

Hypertrophic cardiomyopathyAlthough not traditionally considered a risk fac-tor for QTc interval prolongation in patients who take antipsychotics or antidepressants, cardiac hypertrophy and left ventricular outflow tract ob-struction may delay ventricular depolarization and repolarization and thereby prolong the QT and QTc intervals.44 Johnson and colleagues44 found QTc interval prolongation (more than 480 milliseconds) in 1 of 8 patients with hypertrophic cardiomyopathy. Therefore, when considering

administration of psychotropic drugs with the potential to prolong the QTc interval to patients with hypertrophic cardiomyopathy, obtain a baseline ECG.

Reflections, conclusions, and recommendationsWe recommend that noncardiologists who pre-scribe antipsychotics and antidepressants that may prolong the QTc interval in the elderly ob-tain a baseline ECG for women who have addi-tional risk factors, such as a personal or a family history of presyncope or syncope, electrolyte dis-turbance, and cardiovascular disease. Elderly men with similar risk factors are also at increased risk for QTc interval prolongation and TdP. In-spect the ECG yourself using the Phoon45 short-hand rule (as long as the heart rate is 70 beats per minute or more, the QTc interval will be normal if the QT interval is less than half of the R-R interval).

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16. Bednar MM, Harrigan EP, Anziano RJ, et al. The QT interval. Prog

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19. Hasnain M, Vieweg WVR, Lesnefsky EJ, et al. Depression screening

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20. Whooley MA, Simon GE. Managing depression in medical out-

patients. N Engl J Med. 2000;343:1942-1950.

21. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief

depression severity measure. J Gen Intern Med. 2001;16:606-613.

22. Newcomer JW, Hennekens CH. Severe mental illness and risk of

cardiovascular disease. JAMA. 2007;298:1794-1796.

23. Saha S, Chant D, McGrath J. A systematic review of mortality in

schizophrenia: is the differential mortality gap worsening over time?

Arch Gen Psychiatry. 2007;64:1123-1131.

24. Meyer JM, Stahl SM. The metabolic syndrome and schizophrenia.

Acta Psychiatr Scand. 2009;119:4-14.

25. Hamer M, David Batty G, Seldenrijk A, Kivimaki M. Antidepressant

medication use and future risk of cardiovascular disease: the Scottish

Proarrhythmic RisksContinued from page 53

Drugs that have a risk of causing torsade de pointes43

Generic name Brand name(s) Clinical use

Arsenic trioxide Trisenox Cancer/leukemia

Bepridil Vascor Antianginal

Chloroquine Aralen Antimalarial

Chlorpromazine Thorazine Antipsychotic, antischizophrenic, antiemetic

Cisapride Propulsid GI stimulant

Clarithromycin Biaxin Antibiotic

Disopyramide Norpace Antiarrhythmic

Dofetilide Tikosyn Antiarrhythmic

Droperidol Inapsine Sedative, antiemetic

Erythromycin E.E.S., Erythrocin Antibiotic, increase GI motility

Halofantrine Halfan Antimalarial

Haloperidol Haldol Antipsychotic, antischizophrenic, agitation

Ibutilide Corvert Antiarrhythmic

Levomethadyl Orlaam Opiate agonist, pain control, narcotic dependence

Mesoridazine Serentil Antipsychotic, antischizophrenic

Methadone Dolophine, Methadose Opiate agonist, pain control, narcotic dependence

Pentamidine NebuPent, Pentam Anti-infective, Pneumocystis pneumonia

Pimozide Orap Antipsychotic, Tourette tics

Procainamide Pronestyl, Procan Antiarrhythmic

Quinidine Quinaglute, Cardioquin Antiarrhythmic

Sotalol Betapace Antiarrhythmic

Sparfloxacin Zagam Antibiotic

Thioridazine Mellaril Antipsychotic, antischizophrenic

Table 3

Health Survey. Eur Heart J. 2011;32:437-442.

26. Fernandez A, Bang SE, Srivathsan K, Vieweg WV. Cardiovascular

side effects of newer antidepressants. Anadolu Kardiyol Derg. 2007;

7:305-309.

27. Vieweg WVR, Nicholson CS. Antidepressant drugs and the cardio-

vascular system. Med Update Psychiatrists. 1996;1:154-160.

28. Vieweg WVR. Antidepressant drug-induced blood pressure chang-

es and their management. Med Update Psychiatrists. 1996;1:161-

164.

29. Mark TL, Joish VN, Hay JW, et al. Antidepressant use in geriatric

populations: the burden of side effects and interactions and their im-

pact on adherence and costs. Am J Geriatr Psychiatry. 2011;19:211-

215.

30. Ray WA, Meredith S, Thapa PB, et al. Antipsychotics and the risk of

sudden cardiac death. Arch Gen Psychiatry. 2001;58:1161-1167.

31. Zarate CA Jr, Patel J. Sudden cardiac death and antipsychotic

drugs: do we know enough? Arch Gen Psychiatry. 2001;58:1168-

1171.

32. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs

and the risk of sudden cardiac death [published correction appears in

N Engl J Med. 2009;361:1814]. N Engl J Med. 2009;360:225-235.

33. Su HM, Chiu HC, Lin TH, et al. Longitudinal study of the ageing

trends in QT interval and dispersion in healthy elderly subjects. Age

Ageing. 2006;35:636-638.

34. Darpo B, Nebout T, Sager PT. Clinical evaluation of QT/QTc prolon-

gation and proarrhythmic potential for nonantiarrhythmic drugs: the

International Conference on Harmonization of Technical Requiremnts

for Registration of Pharmaceuticals for Human Use E14 guidelines.

J Clin Pharmacol. 2006;46:498-507.

35. Camm AJ, Malik M, Yap YG. Acquired Long QT Syndrome. London:

Blackwell Futura; 2004.

36. Browne KF, Prystowsky E, Heger JJ, et al. Prolongation of the Q-T

interval in man during sleep. Am J Cardiol. 1983;52:55-59.

37. Morganroth J, Brozovich FV, McDonald JT, Jacobs RA. Variability

of the QT measurement in healthy men, with implications for selection

of an abnormal QT value to predict drug toxicity and proarrhythmia.

Am J Cardiol. 1991;67:774-776.

38. Tutar HE, Ocal B, Imamoglu A, Atalay S. Dispersion of QT and QTc

interval in healthy children, and effects of sinus arrhythmia on QT dis-

persion. Heart. 1998;80:77-79.

39. Khan SP, Dahlvani S, Vieweg WVR, et al. Electrocardiographic QT

interval in a geropsychiatric inpatient population: a preliminary study.

Med Psychiatr. 1998;1:71-74.

40. Compton SJ, Lux RL, Ramsey MR, et al. Genetically defined ther -

apy of inherited long-QT syndrome. Correction of abnormal repolariza-

tion by potassium. Circulation. 1996;94:1018-1022.

41. Hatta K, Takahashi T, Nakamura H, et al. Hypokalemia and agitation

in acute psychotic patients. Psychiatry Res. 1999;86:85-88.

42. Hatta K, Takahashi T, Nakamura H, et al. Prolonged QT interval in

acute psychotic patients. Psychiatry Res. 2000;94:279-285.

43. Drew BJ, Ackerman MJ, Funk M, et al; American Heart Association

Acute Cardiac Care Committee of the Council on Clinical Cardiology,

Council on Cardiovascular Nursing, and the American College of Car-

diology Foundation. Prevention of torsade de pointes in hospital set-

tings: a scientific statement from the American Heart Association and

the American College of Cardiology Foundation [published correction

appears in Circulation. 2010;122:e440]. Circulation. 2010;121:1047-

1060.

44. Johnson JN, Grifoni C, Bos JM, et al. Prevalence and clinical cor-

relates of QT prolongation in patients with hypertrophic cardiomyopa-

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ing QTc. Am J Cardiol. 1998;82:400-402. ❒

CATEGORY155PSYCHIATRIC TIMES APRIL 2011

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Available online the 20th of the month.To speak to a customer service representative, call (800) 447-4474 or (201) 984-6278 (M - F, 9 AM to 6 PM Eastern Time).

1. Which of the following medications needs to be avoided in

patients with Brugada syndrome or those in whom Brugada

syndrome is suspected?

A. Amitriptyline

B. Lithium

C. Desipramine

D. All of the above

E. None of the above

2. Which of the following is the Bazett formula, used to correct

the QT interval for heart rate?

A. QTc interval = QT interval in seconds divided by the

square root of the RR interval in seconds

B. QTc interval = RR interval in seconds divided by the

square root of the QT interval in seconds

C. QTc interval = QT interval in seconds divided by the

square root of the RR interval in minutes

D. None of the above

3. Which of the following Bazett-corrected QT interval

measurements is normal for adult men?

A. < 430

B. < 450

C. > 450

4. Women are at particularly high risk for depression following

acute myocardial infarction.

A. True

B. False

5. Risk factors for coronary heart disease morbidity and mortal-

ity that appear more commonly among patients with schizo-

phrenia include which of the following?

A. Smoking

B. Diabetes mellitus

C. Dyslipidemia

D. All of the above


6. SSRIs have been linked to an increased risk of new-onset

cardiovascular disease.

A. True

B. False

7. SSRIs have been linked to serotonin syndrome, tachycardia,

and arrhythmias.

A. True

B. False

8. Tricyclic antidepressants may induce which of the

following?

A. Orthostatic hypotension

B. Serotonin syndrome

C. Conduction and rhythm disturbances

D. All of the above


9. Atypical antipsychotics have been found to have less

cardiotoxicity than typical antipsychotics.

A. True

B. False

10. Which of the following may be risk factors for QTc interval

prolongation?

A. Male sex

B. Younger age

C. Electrolyte abnormalities

D. All of the above


A11001041

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