update in clinical psychopharmacology peter a. demaria, jr., m.d., fasam tuttleman counseling...
TRANSCRIPT
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Update in Clinical Psychopharmacology
Peter A. DeMaria, Jr., M.D., FASAMTuttleman Counseling Services
Temple UniversityClinical Associate Professor of Psychiatry
Temple University School of MedicinePhiladelphia, PA
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Disclosures
• I have no actual or potential conflict of interest in relation to this educational activity or presentation.
• Use of trade versus generic drug names
• Off-label use of drugs.
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Treatment Planning
1. Medication
2. Psychotherapy
3. Combined medication and psychotherapy
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Referral for Psychopharmacologic Evaluation/Treatment
1. When to refer
2. Preparing the patient
3. What to expect
4. The challenge of split treatment– Communication– Dynamics– Ethics– Legal issues
5. What to expect
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Neurotransmission
Taken from: Bloom FE, Neurotransmission in the Central Nervous System inGoodman & Gilman’s Pharmacological Basis of Therapeutics, 9th Ed, p. 270
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Pharmacokinetics
Taken from: Julien, R. A Primer of Drug Action. WH Freeman Co., New York, 1998. p. 25.
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Drug Interactions Synergism (e.g. alcohol + sedative) Induction of enzymes and increased metabolism Inhibition of enzymes and delayed metabolism In vitro versus clinical significance
FDA approval vs. clinical use
(“Off-label use”)
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Selecting a Psychotropic Agent• Diagnosis/symptom complex
• Patient’s prior response
• Family member’s experience
• FDA approved indication
• Pharmacologic actions
• Documented efficacy
• Side effect profile
• Insurance coverage/finances
• Patient preference
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DSM-IV Classification of Depressive Disorders
• Adjustment disorder with depressed mood
• Dysthymia
• Major depression (MDD)
• Premenstrual Dysphoric disorder (PMDD)
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Pharmacotherapy options• Monoamine oxidase inhibitors (MAOI)
• Tricyclic antidepressants (TCA)– Amitriptyline (Elavil) Imipramine (Tofranil)– Nortriptyline (Pamelor) Desipramine (Norpramin)
• Selective Serotonin Reuptake Inhibitors (SSRI)
• Serotonin and Norepinephrine Reuptake inhibitors (SNRI)
• Atypical antidepressants– Bupropion (Wellbutrin) Nefazodone (Serzone)
• On the horizon
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Selective Serotonin Reuptake Inhibitors (SSRI)
1. ExamplesSertraline (Zoloft) Fluoxetine(Prozac) Citalopram (Celexa) Escitalopram
(Lexapro)Paroxetine (Paxil) Fluvoxamine
(Luvox)
2. Mechanism of ActionBlocks re-uptake of serotonin thereby
increasing serotonin in the synapse
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SSRI - FDA Approved Indications
MD PMDD OCD PD PTSD GAD SP BN
Sertraline (Zoloft) X X X X X X Paroxetine (Paxil) X X X X X X X Fluoxetine (Prozac) X X X X X Citalopram (Celexa) X Escitalopram (Lexapro) X X Fluvoxamine (Luvox) X
Therapeutic Response• Can take between 2 and 8 weeks• Response is gradual• Others may notice the response before the patient does
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SSRI/SNRI Side Effects• Gastrointestinal
• Anxiety/insomnia
• Flushing/night sweats
• Vivid dreams
• Weight change
• Sexual dysfunction
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Antidepressant-Induced Sexual Dysfunction
Desire Decreased libido
Arousal Difficulties w/ erection/lubrication
Orgasm Delayed orgasm/anorgasmia
Management– Spontaneous resolution– Decrease dose– Change agent– Adjunctive medication
Selective PDE5 Inhibitor Bupropion (Wellbutrin)
Cyproheptadine (Periactin)
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“Poop-out” Effect1. Definition
2. Explanation– Placebo response– Inadequate dose– Potential changes in receptors
3. Management– Drug holiday– Increase dose– Change antidepressant– Add agent with NE or DA properties
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Discontinuation Syndrome• Develops after abrupt cessation of SSRI/SNRI• Symptoms = washed-out, flu-like,
lightheaded, H/A, emotional liability, diarrhea• Can occur with all SSRIs/SNRIs• May be related to half-life• Worse with paroxetine (Paxil) and venlafaxine
(Effexor)• Abates with re-challenge of SSRI/SNRI• Slow taper of SSRI/SNRI or change to longer
acting agent.
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Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
MDD GAD PD SAD FM
Desvenlafaxine (Pristiq) X
Duloxetine (Cymbalta) X X X
Mirtazapine (Remeron) X
Venlafaxine (Effexor-XR) X X X X
• Mechanism of Action
• Examples and Indications
• Side Effects
MDD = Major depressive disorder, GAD = Generalized anxiety disorder, PD = Panic disorder, SAD = Social anxiety disorder, FM = Fibromyalgia.
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Treatment Resistant Depression1. Is the patient medication compliant?
2. Is the diagnosis correct?
3. Change agents-Within/between classes
4. Antidepressant combinations -Complementary mechanisms of action
5. Add psychotherapy
6. Augmentation strategies– Lithium Thyroid hormone– Antipsychotic Estrogen
7. ECT/Focal Brain Stimulation
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Focal Brain Stimulation• Vagal Nerve Stimulation
(VNS)– Pulse generator implanted
in the left chest wall– Electrode wrapped around
the left vagus nerve– Pulse on for 30 seconds and
off for 5 minutes– Efficacy = ?
• Transcranial magnetic stimulation (TMS)– Uses an electromagnetic
coil placed against the scalp to create a rapidly changing magnetic field that depolarizes neurons.
– Outpatient procedure– Safe and well tolerated– Efficacy =?
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How long to Treat?• 6-12 months• Longer if,
– Return of symptoms on discontinuation of AD– Recurrent episodes of depression– Severe depression (suicide attempt, psychosis)
Number of Prior Episodes of Depression Recurrence Rate
1 < 50%
2 50-90%
3 or more >90%
Taken from: Stahl S. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd Ed., Cambridge University Press. 2000, p. 150.)
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FDA Suicide Warning
• Black Box Warning
• All antidepressants
• Increased risk of suicidal thinking and behaviors
• Affects 18-24 y/o
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On the Horizon
• Corticotropin releasing factor-1 (CRF1) antagonists
• Glucocorticoid receptor antagonists• Substance P receptor antagonists• NMDA receptor antagonists• Melanocyte inhibiting factor (nemifitide)• Omega -3 fatty acids• Melatonin receptor antagonists• Focal and deep brain stimulation therapies
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STAR*D• Largest (n=4041, age 18-75 y/o) study of treatment
of non-psychotic MDD• Multiple real-world psychiatric and primary care
settings• Conducted between July 2001 and April 2004• Funded by National Institute of Mental Health
(NIMH)• Goal was remission (< 5 on the QIDS-C16)• Treatment involved 6 levels with patient ability to
choose options• Available at www.star-d.org
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STAR*D Results N RemissionRate
Response Rate
Step 1 Citalopram 3,671 36.8% 48.6%Step 2 Switch to bupropion, sertraline, venlafaxine, or CBT, OR augment with bupropion, buspirone, or CBT
1,439 30.6% 28.5%
Step 3 Switch to Mirtazapine, nortriptyline OR augment with lithium or T3
390 13.7% 16.8%
Step 4 Switch to tranylcypromine or venlafaxine plus mirtazapine
123 13% 16.3%
(Rush AJ et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psych 163:1905-1917, 2006.)
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STAR*D• MDD is a chronic and recurrent illness.• Using objective measurements of symptoms and side
effects a can help with treatment decisions.• Remission can take time (at least 8, but up to 14
weeks).• Many steps may be needed to reach remission.
– Remission rate of 50% was reached after 2 steps.– Remission rate of 70% was reached after 4 steps
• Remission results in better log-term outcomes.• Participant attrition is high.
(Warden D et al. The STAR*D project results: a comprehensive review of findings. Current Psychiatry Reports 9:449-459, 2007.)
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DSM-IV Anxiety Disorders
1.Adjustment disorder
2.Generalized anxiety disorder (GAD)
3.Panic disorder
4.Obsessive-compulsive disorder (OCD)
5.Social anxiety disorder (social phobia)
6.Acute stress disorder
7.Post traumatic stress disorder (PTSD)
8.Specific phobia
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Benzodiazepines
Benzodiazepine Half-life(hr)
Activemetabolites
Anxiolytic doserange (mg/day)
Approximate doseequivalency (mg)
Alprazolam (Xanax) 12 Yes 0.5-4 0.25
Chlordiazepoxide (Librium) 100 Yes 15-100 10
Clonazepam (Klonopin) 34 No 0.5-10 0.5
Clorazepate (Tranxene) 100 Yes 7.5-60 7.5
Diazepam (Valium) 100 Yes 2-40 5
Lorazepam (Ativan) 15 No 2-4 1
Oxazepam (Serax) 8 No 30-120 15
Taken from: Kaplan SI, Sadock BJ. Kaplan & Sadock’s Synopsis of Psychiatry, 8 th ed., Lippincott, Williams & Wilkins, Philadelphia, 1998, p. 996.
Advantages Disadvantages-Rapid onset of action -Physiologic dependence-Highly effective -Addicting
-Impaired cognitionAnterograde amnesia
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J of Clin. Psychiatry, 60(5), 252, May 1999
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FDA Approved Indications MDD PD OCD SP PTSD GAD PMDD BN ND FM
SSRI Citalopram (Celexa) X Escitalopram (Lexapro) X X Fluoxetine (Prozac) X X X X X Paroxetine (Paxil/CR) X X X X X X X Sertraline (Zoloft) X X X X X X SNRI Duloxetine (Cymbalta) X X X Venlafaxine (Effexor/XL) X X X X Tricyclic Antidepressant Fluvoxamine (Luvox) X Other Bupropion (Wellbutrin) X X Buspirone (BuSpar) X Mirtazapine (Remeron) X
MDD=major depressive disorder, PMDD=peri-menstrual dysphoric disorder, PD = panic disorder, PTSD=post-traumatic stress disorder, GAD=generalized anxiety disorder, OCD=obsessive-compulsive disorder, SP=social phobia, BN = bulimia nervosa, ND = nicotine dependence, FM = fibromyalgia
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SSRI/SNRIs in Anxiety Disorders
Advantages• High efficacy• Non-addicting• Effective for a number
of conditions
Disadvantages• Can take 2-8 weeks or
longer to be effective• Side effects• Drug interactions• Discontinuation
syndrome
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Other Options for Anxiety Disorders
• Buspirone (BuSpar)
• Beta blockers
• Combinations– SSRI/SNRI + Benzodiazepine
• Antipsychotics– Trifluoperazine (Stelazine)– Quetiapine (?)
• Pregabalin (?)
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Psychotropic Choices for Specific Conditions
Condition Pharmacotherapy Option
Obsessive compulsive disorder SSRIClomipramine
Social anxiety disorder SSRI/SNRI
Panic disorder SSRI/SNRITCABenzodiazepine
PTSD SSRI
Generalized anxiety disorder SSRI/SNRIBenzodiazepineBuspirone
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DSM-IV Psychotic Disorders
1.Schizophreniform disorder
2.Schizophrenia
3.Schizoaffective disorder
4. Brief psychotic disorder
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The Disease Process
Positive Symptoms• Hallucinations• Delusions• Disorganization• Agitation
Negative symptoms• Blunted affect• Emotional withdrawal• Social withdrawal• Anhedonia
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FDA Approved Indications for Atypical Antipsychotics
Indication OLA RIS ILO QUE ZIP ARI ASEN
Schizophrenia X X X X X X X
Schizoaffective Disorder
X
Bipolar Mania/Mixed
X X X X X X
Bipolar Depression
X X
Adjunct in MDD
X X X
OLA = Olanzapine, RIS = Risperidone, ILO = Iloperidone, QUE = Quetiapine, ZIP = Ziprasidone, ARI = Aripiprazole, ASEN = Asenapine
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Atypical (2nd Generation) AntipsychoticsSide Effect HL CPZ CLZ RIS OLZ QTP ZIP
Anticholinergic - +++ ++++ - +++ - -
EPS +++++ +++ + ++ + + ++
Sedation + ++++ +++++ + +++ +++ ++
Orthostasis + +++ ++++ + + + +
Weight gain + +++ ++++ ++ +++ + -
Lipid increase - ?? +++ ?? ++ ?? -
Prolactin elevation +++ ++ - +++ + - +
HL=haloperidol (Haldol), CPZ=chlorpromazine (Thorazine), CLZ=clozapine (Clozaril), RIS=risperidone (Risperdal), OLZ=olanzapine (Zyprexa), QTP=quetiapine (Seroquel), ZIP=ziprasidone (Geodon)
(Taken from: Jam, MW. Advances in the treatment of psychosis: a multidisciplinary continuing education program. Power-Pak CE, New York, NY 2001, p. 8.)
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Metabolic Syndrome & Atypical Antipsychotics
Medication Weight Gain ↑FBS ↑ Lipids
Clozapine +++ +++ +++
Olanzapine +++ +++ +++
Quetiapine ++ ++ ++
Risperidone ++ ++ ++
Aripiprazole 0 0 0
Ziprasidone 0 0 0
Risk of adverse effects at therapeutic doses: 0 = None, ++ = Sometimes, +++ = FrequentlyJ. Clin. Psych 2004: 66; 267-272
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CATIE• 1460 “real-world” schizophrenics (no first-break
schizophrenics)• NIMH funded• Comparison of second generation antipsychotics to a
representative first generation antipsychotic (perphenazine).
Agent Time to Discontinuation (months)
All Cause Discontinuation Rate
Olanzapine 9.2 64%
Perphenazine 5.6 75%
Quetiapine 4.6 82%
Risperidone 4.8 74%
Ziprasidone 3.5 79%
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CATIE• Overall findings:
– Discontinuation rates for all agents were high.– Olanzapine was the most efficacious
medication, however, it was associated with the greatest weight gain, and the worst metabolic profiles.
– For those patients changing drugs due to tolerability, olanzapine and risperidone were more efficacious second choice drugs.
– Ziprasidone had a better metabolic profile.
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DSM-IV Mood Disorders
Bipolar disorder (manic-depressive disorder) Bipolar I
(recurrent major depression and mania)
Bipolar II (recurrent major depression with hypomania)
Specifiers Rapid cycling (more than 4 episodes in a 12 month period) Seasonal pattern
Cyclothymia
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The Heterogeneity of Bipolar Disorder
Taken from:http://www.psychosis-bipolar.com/information-about-psychoses-57.htmlTaken
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Pharmacotherapy for Mood Disorders1. Mood stabilizers
Lithium2. Anticonvulsant Mood Stabilizers
Valproic acid (Depakote) Carbamazepine (Tegretol) Oxcarbazepine (Trileptal) Lamotrigine (Lamictal) Topiramate (Topamax)-?
3. Atypical Antipsychotics Olanzapine (Zyprexa) Risperidone (Risperdal) Quetiapine (Seroquel) Aripiprazole (Abilify) Ziprasidone (Geodon)
4. Combination Olanzapine/fluoxetine (Symbyax)
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Treating Bipolar Disorder• Use mood charting.
• Combination pharmacotherapy is the rule rather than the exception.
• Mood stabilizers are the cornerstone of therapy.
• Optimize therapeutic effect and tolerability while minimizing side effects.
• Antidepressants mat worsen the disease course.
• Anticonvulsants & FDA suicide warning
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Pharmacotherapy for Bipolar Disorder
Phase Treatment Options
Mania Lithium (Li)Valproate (VP)Atypical antipsychoticCarbamazepine/oxcarbamazepineLi/VP + atypical antipsychoticElectroconvulsive therapy (ECT)
Depression Optimize mood stabilizerLamotrigineQuetiapineOlanzapine/fluoxetineMood stabilizer + antidepressant
Maintenance In general, continue regimen that is working, however, simplify as clinically indicated.
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Insomnia• A symptom, not a diagnosis• Evaluate for underlying cause• Promote good sleep hygiene• Use a sleep log• Pharmacotherapy
– 10 days or less– Options
• Non-benzodiazepine hypnotics
• Benzodiazepine hypnotics
• Sedating antihistamines
• Sedating antidepressants
• Sedating antipsychotics
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Attention Deficit Hyperactivity Disorder
1. Stimulants– Amphetamine salts (Adderall)– Methylphenidate (Ritalin, Concerta, Focalin)– Dextroamphetamine (Dexedrine)– Pemoline (Cylert)
2. Non-stimulants– Atomoxetine (Strattera)– Guanfacine extended release (Intuniv)– Others
• Bupropion(Wellbutrin)• Tricyclic antidepressants• Venlafaxine (Effexor)
3. New Delivery Systems– Methylphenidate patch (Daytrana)– Pro-drug: lisdexamfetamine (Vyvanse)
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Pharmacotherapy for Eating Disorders
1. Classification
Anorexia nervosa
Bulimia nervosa
Eating disorder NOS
2. Pharmacotherapy options
SSRIs for bingeing/purging
Topiramate for binging/purging - ?
Treatment for co-morbid disorders
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Pharmacotherapy for Personality DisordersSymptom targeted
Symptom Spectrum Pharmacotherapy Option
Affective symptoms SSRI/SNRIAtypical antidepressantMood stabilizer
Mood dysregulation/impulsivity
Mood stabilizerAnticonvulsant mood stabilizerAtypical antipsychotic
Psychotic/para-psychotic symptoms
Atypical antipsychoticAntipsychotic
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Pharmacotherapy in Severe Personality DisordersMeta-analysis of 21 retrieved studies-Borderline & Schizotypal P.D.
AP AD MSCognitive perceptual symptoms
S (++) NS NS
Impulsive behavioral dyscontrol
NS NS S (++++)
Affective dysregulation Depressed mood Anxiety Anger
NSNS
S (++/+++)
NSS (+/++)S (+/++)
S (++)HS (+++)S (++++)
Global functioning S (+/++) NS S (+++)
NS = Not significant, S = Significant, HS = Highly significant(+) = Small, (++) = Moderate, (+++) = Large, (++++) = Very largeIngehoven T et al. J. Clinical Psychiatry 71(1):14-25, 2010
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Pharmacotherapy for Substance Use Disorders• Drugs for intoxication/withdrawal• Aversive agents
– Disulfiram (Antabuse)• Maintenance agents
– Methadone– Buprenorphine (Suboxone/Subutex)
• Anticraving agents– Nicotine replacement therapy (NRT)– Naltrexone (ReVia. Vivitrol)– Acamprosate (Campral)– Varenicline (Chantix)– Topiramate (Topamax) - ?
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