estratregias para prescripcion de medicamentos con blackbox
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Review Article
Strategies for the Prescription of Psychotropic Drugs
with Black Box Warnings
Jonathan R. Stevens, M.D., M.P.H., Tiana Jarrahzadeh, D.O.,
Rebecca Weintraub Brendel, M.D., J.D., Theodore A. Stern, M.D.
Background: The Black Box Warning (BBW) is the
Food and Drug Administration’s highest level of drug warning. It signi es that a medication has serious (or
potentially life-threatening) side effects and is prom-
inently displayed on a medication’s package insert. It
literally consists of the medication warning and is
surrounded by a bold black border. Objective: This
article aims to review data related to BBWs on
psychotropic medications currently used in clinical
practice, with special attention to clinical situations and
questions relevant to consultation-liaison psychiatrists.
Results: We review 3 clinical advisories or BBWs for
psychotropic medications (i.e., antidepressant medi-cation and suicidality in the pediatric population,
stimulant medication and sudden death in the pediatric
population, and antipsychotic medication and increased mortality in the elderly) and discuss the effect they have
had on prescribing practices. We provide a table of
current BBWs relevant to psychotropic medications.
Conclusions: BBWs can have unintended and far-
reaching consequences, albeit with a limited ability to
target speci c populations and practice patterns.
Although it is critical for clinicians to be aware of these
serious potential side effects and to inform patients
about these warnings, medications with boxed warnings
remain Food and Drug Administration-approved and
may have critically important therapeutic roles.(Psychosomatics 2014; 55:123 – 133)
The Black Box Warning (BBW) is the most seriouslabeling change that the Food and Drug Admin-istration (FDA) can issue. BBWs are intended to be a
safety tool, created to communicate potentially serious
safety information about a particular medicine. Usu-
ally, the BBW is located at the beginning of the labeling
with a rectangle surrounding its boldface text, so that it
stands out and is readily seen by a prescriber. To put itsimply, it is a way to urge physicians to carefully
consider the risks and benets before prescribing a drug
that has a potentially disabling or fatal reaction.
Most psychotropics in current use carry a boxed
warning (Table); several psychotropics have more than
1 BBW (e.g., clozapine has 5 and valproic acid has 3).
As the FDA has reached out beyond providers to the
general public to publicize BBWs, it is increasingly
common for physicians to encounter questions from
patients about serious medication risks before
denitive information is available.1 The psychiatrist
who tries to prescribe“around” boxed warnings would
work from a vastly reduced pharmacopeia (e.g.,
buspirone, gabapentin, oxcarbazepine, and benzodia-
zepines), which could hamper effective care. Therefore,
consultants who practice psychosomatic medicine are
mindful of, but not paralyzed by, these warnings.
Received July 8, 2013; revised August 21, 2013; accepted August 26,
2013. From Henry Ford Health Systems, Dearborn, MI; Wayne State
University, Detroit, MI; Michigan State University, East Lansing, MI;
Red Sox Foundation and Massachusetts General Hospital (MGH),
Home Base Program, Boston, MA; Harvard Medical School (HMS),
Boston, MA; Avery D. Weisman Psychiatry Consultation Service
at MGH, Boston, MA. Send correspondence and reprint requests
to Jonathan Stevens, M.D., M.P.H., Henry Ford Health Systems,
5111 Auto Club Road, Suite 112, Dearborn, MI 48126; e-mail:
jsteven8@hfhs.org
& 2014 The Academy of Psychosomatic Medicine. Published by
Elsevier Inc. All rights reserved.
Psychosomatics 2014:55:123 – 133 & 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Psychosomatics 55:2, March/April 2014 www.psychosomaticsjournal.org 123
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Psychiatrists today face the conundrum of how to
responsibly prescribe FDA-approved medicines that areneeded by often vulnerable patient populations in the
face of FDA warnings about drug safety. What does a
clinician have to do when he/she learns that a medication
he/she prescribes has received a BBW? Specically, what
does a clinician have to discuss with a patient about a
drug with a BBW? How should one respond when an
adverse event occurs after prescribing a drug with a
BBW? And, in such a case, what liability might there be?
These questions frame our discussion of an attempt to
generate a strategy for the prescription of drugs with
BBWs in general, and psychotropics in particular. Tothis end, we review 3 BBWs for psychotropic medica-
tions and discuss the effect they have had on prescribing
practices. We also provide a reference table of BBWs
relevant to psychotropic medications.
WHAT DOES IT TAKE FOR THE FDA TO
LABEL A DRUG WITH A BBW?
Imposing a BBW has signicant ramications
for product liability. Within the section dealing
with warnings, the Code of Federal regulations2
states:
Labeling shall describe serious adverse reactions and potential
safetyhazards, limitations in useimposed by them, andsteps that
should be taken if they occur. The labeling shall be revised to
include a warning as soon as there is reasonable evidence of an
association of a serious hazard with a drug; a causal relationship
need nothave been proved…Special problems, particularlythose
that may lead to death or serious injury, may be required by the
Food and Drug Administration to be placed in a prominently
displayed box. The boxed warning ordinarily shall be based on
clinical data, butserious animaltoxicitymay alsobe thebasisof a
boxed warning in the absence of clinical data.
After a drug is approved, and so as to monitor itssafety, the FDA seeks a commitment from the
pharmaceutical company to conduct specic postmar-
keting clinical trials (phase 4 studies). Established in
1969 as a postmarketing surveillance tool, the Adverse
Event Reporting System (AERS) detects previously
unidentied adverse drug events that often occur.3 The
AERS is a computerized database that combines the
voluntary adverse drug reaction reports submitted to
the FDA by health care professionals to the Med-
Watch program with the mandatory reports from
TABLE. Black Box Warnings on Available* Psychotropic Medications
FDA boxed warnings Drug classes or medications included
Suicidal thinking and behavior in children and
adolescents
All selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants
(TCAs), monoamine oxidase inhibitors (MAOIs), atomoxetine,
quetiapine, and aripiprazole
Subject to misuse, abuse, addiction, or diversion All methylphenidates and amphetaminesMisuse may cause serious cardiovascular adverse
events and sudden death All amphetamines
Increased risk of death in elderly patients with
dementia-related psychosis
All rst-generation (typical) and second-generation (atypical)
antipsychotics
Aplastic anemia Carbamazepine
Agranulocytosis Clozapine and carbamazepine
Myocarditis Clozapine
Orthostatic hypotension Clozapine
Seizures Clozapine and umazenil
Stevens-Johnson Syndrome Lamotrigine
Lithium toxicity Lithium
Pancreatitis Valproic acid
Teratogenicity Valproic acid
Hepatotoxicity Naltrexone, dantrolene, and valproic acid
QTc prolongation; Torsades de Pointes Thioridazine, mesoridazine, and droperidol
Life-threatening thyroid toxicity; ineffective for
weight reduction Levothyroxine
Certied programs only Methadone
Contraindicated during alcohol intoxication; needs
patient's full knowledge Disulram
Respiratory depression Midazolam
n Does not include psychotropics already withdrawn from the market because of safety concerns (e.g., pemoline, nefazodone, or
propoxyphene).
Strategies for the Prescription of Psychotropic Drugs
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pharmaceutical companies on adverse events. Those
events serve as early warning signals for possible
serious adverse reactions that may lead to a BBW.
The FDA may convene a public advisory committee
to determine the signicance of a safety signal. If a
safety concern emerges from clinical trial data or
consistent reports made to the AERS, an interdisci-
plinary team convenes with representatives from the
Of ce of Surveillance and Epidemiology and the
Of ce of New Drugs.1 This collaborative team then
decides whether to continue monitoring, require a
boxed warning, or withdrawthe drug from the market.
Despite this monitoring system, the FDA has not
articulated clearly its rationale and basis for issuing a
BBW.
In the absence of such guidance, Beach et al.4
devised a classication scheme to analyze what it takesfor the FDA to create a BBW. Based on their analysis
of the wordings of 375 BBWs of 206 drugs, they
identied the following 6 criteria that seem to inuence
the FDA’s decision to have BBWs added to the
labeling of drug products: (1) identication of an
adverse event that can be prevented through early
detection and intervention; (2) a clearly categorized
patient cohort for whom the treatment is particularly
dangerous; (3) a situation in which the risk of treat-
ment likely outweighs its benets (in certain circum-
stances); (4) identied issues of dosing or druginteraction, or both, that are critical to the risk;
(5) situations involving special settings or training of
physicians that are critical to the safe administration of
a drug; and (6) situations in which the method of drug
administration requires exceptional care. In addition,
they4 classied the type of evidence for supporting a
boxed warning into 4 categories: patterns of post-
marketing reports (52.4%); clinical trials that were part
of the new drug application (28.7%); epidemiologic
surveys (9.4%); and, occasionally, miscellaneous bases
(9.4%).According to their report, the most frequent
warning (25%) was for the identication and avoid-
ance of high-risk patients. Dosing considerations or
harmful drug interactions were the next most common
purpose of the warnings (20%).
HOW EFFECTIVE IS THE BBW SYSTEM?
The results of the study by Beach et al.4 indicated that
more than half of the BBWs were discovered after the
approved drugs were already on the market, being
advertised, and prescribed to patients who were
exposed to possibly unknown toxic effects. In fact, it
is estimated that less than 10% of all adverse drug
reactions are reported to MedWatch, which makes the
potential risks even more alarming. Many adverse
effects were brought to light only after receiving
approval for a drug because the premarketing drug
trials were often underpowered to detect serious
adverse events and had limited follow-up.5
Lasser et al.6 traced the discovery course of new
BBWs by analyzing their incidence in the Physician
Desk Reference from 1975 to 2000 and calculating the
frequency and timing of drug withdrawals during that
period. They found that 10% of the 584 drugs initially
approved by the FDA over that 25-year span had been
pulled from the market by 2000 or required a newBBW for safety reasons. A probability analysis
showed that each new drug had a 20% chance of
being withdrawn from the market or acquiring a BBW
during the study period. Half of these changes occur-
red within 7 years of drug production, and half of the
withdrawals occurred within 2 years of their approval.
Their data showed that the most frequent reasons for
BBWs or withdrawals fell into the categories of
hepatotoxicity, cardiotoxicity, blood dyscrasias, drug
interactions, and safety concerns during pregnancy.6
The prediction that 1 in 5 new drugs would, within 25years, acquire a new BBW or be withdrawn from the
U.S. market led many physicians to suggest careful
consideration of the reasons for prescribing a new
drug, particularly when an equally effective alternative
was available, as there is always some risk of an
undiscovered adverse event. It is probably fair to say
that the safety of new agents cannot be established
with reasonable certainty until the drug has been used
widely in the market for several years.
HAVE CLINICIANS BEEN ADHERENT WITH
THE BBW REQUIREMENTS?
Physician adherence to boxed warnings is voluntary
and research suggests that physicians often fail to
comply with FDA BBWs. Wagner et al.7 looked at the
use of 216 BBWs and found a substantial number of
inconsistent adherences. Analyzing the automated
claims data of nearly 930,000 enrollees in health care
plans revealed that 42% of enrollees received at least
1 drug carrying a BBW.7 In nearly half of all cases
Stevens et al.
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where the BBW included recommendations for base-
line laboratory monitoring, those recommendations
were not followed. These data raised concerns about
the power of BBWs in changing physicians’ prescrib-
ing practices.
Lasser et al’s.8 study found similar results. They
reviewed the electronic health records of patients
receiving care from Partners Health Care outpatient
clinics in the Boston area to determine how often
physicians prescribed a drug labeled with a BBW, and
how frequently that prescribing them resulted in harm.
They found that 33,778 (10.4%) of 324,548 outpatients
in 2002 received a medication that contained a BBW.
However, of those 33,778 patients, only 2354 patients
(7% or 0.7% of all outpatients) received prescriptions
in violation of the BBW. Most of those patients, 1744
of 2354 (74%), did not receive adequate monitoring,17% were already taking a contraindicated drug that
may have resulted in a serious drug-drug interaction,
and 9% had a disease that was contraindicated for its
use. Fortunately, less than 1% of patients who received
a drug despite its BBW had an adverse event as a
result. This study was completed in early 2004, before
the imposition of a BBW on antidepressants (October
2004) and antipsychotics (April 2005). However, with
regard to other psychotropic medications, Lasser
et al.8 found that many BBWs involving mood
stabilizers and anticonvulsants were frequently dis-regarded. Nearly 25% of patients (129 of 526) on
carbamazepine had no documented evidence of CBC-
platelet count monitoring at baseline and of once per
year monitoring during therapy. Furthermore, nearly
69% of patients taking lithium did not have a serum
lithium level checked every 2 months as advised in the
lithium BBW, and nearly 30% of patients receiving
valproate did not undergo baseline liver function tests
and monitoring once per year. These results were quite
similar to those of Marcus et al’s.9 study on Medicaid
patients with bipolar disorder, in which 36% of thepatients who were prescribed lithium, 42% of the
patients who were prescribed carbamazepine, and 42%
of the patients who were prescribed valproate received
inadequate laboratory monitoring, as dened in prac-
tice guidelines that were based upon expert consensus.
Current clinical practice lacks a formal system to
document appropriate patient selection for medica-
tions, risk counseling, or drug safety monitoring.1 To
improve physician adherence to BBWs, researchers7,8
suggested more precise wording on the magnitude of
risks inherent in prescribing despite BBWs, stated in
clear language that can be easily understood by both
physicians and patients. Moreover, they7,8 recom-
mended the implementation of automated alerts at
the point of prescribing and dispensing. Some10 have
argued that the FDA may be dispensing BBWs more
quickly in response to recent criticism that it has not
been doing enough to ensure drug safety and warned
that the public’s health might suffer if the FDA-
mandated warnings were not justied. For instance,
the American Psychiatric Association (APA) and
American Academy of Child and Adolescent Psychia-
try issued a joint statement expressing deep concerns
that a BBW on antidepressants may negatively affect
treatment rates and hoped that the FDA would set in
place a system to track the effect of BBWs on
prescribing patterns and overall patients’ quality of life.11
WHAT IS THE EFFECT OF FDA ADVISORIES
AND BBWS? 3 CASE STUDIES OF FDA
ADVISORIES AND BBWS IN PRACTICE
Case Study #1 — Antidepressant Medications and
Suicidality in the Pediatric Population
Major depressive disorder is a common mentalhealth problem in adolescents worldwide, with an
estimated 1-year prevalence of 4% – 5% in midadoles-
cence to late adolescence.12,13
Depression in adoles-
cents is a major risk factor for suicide, the second or
third leading cause of death in this age group (depend-
ing on the year),14 with more than half of adolescent
suicide victims reported to have a depressive disorder
at the time of their death.15 Unfortunately, the
pharmacotherapy for youth with depression is less
straightforward than it is with adults. Unlike in adults,
tricyclic antidepressants are not an effective treatmentfor adolescents with depression.16 Fluoxetine, a selec-
tive serotonin reuptake inhibitor (SSRI), seems effec-
tive in meta-analyses (http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC3488279/-R137)17 and randomized
controlled trials,18 – 20 but evidence is more inconsistent
for other antidepressants. Even in the best circum-
stances, antidepressants are only moderately effective
in adolescents with depression.21
Against this backdrop, the FDA warning of
potentially increased suicidal thinking and behavior
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in children and adolescents taking SSRI antidepres-
sants added complexity to an already challenging
treatment situation. The FDA action both reected
and fueled public suspicion of pediatric psychophar-
macology. It is perhaps one of the best-known and
most controversial examples of a BBW on a psycho-
tropic medication.
To detail how the pediatric antidepressant advi-
sories affected prescribing practices, the chronologic
development of this BBW has been reviewed. In 2003,
the United Kingdom’s Medicines and Healthcare
Regulatory Agency, a regulatory agency analogous
to the FDA initiated an investigation into the safety of
antidepressant medications. This investigation was
triggered by anecdotal reports regarding withdrawal
reactions, suicidal ideation, and suicidal behavior
from adult and pediatric patients taking paroxe-tine.22,23 Within the year, the Medicines and Health-
care Regulatory Agency, FDA, and European
Medicines Agency all issued advisories regarding
reports of suicidality in young patients given anti-
depressants. They advised against using paroxetine to
treat depression in children and adolescents. Those
advisories were a consequence of post hoc analyses
that found a statistically signicant increase in suicidal
behavior with paroxetine treatment.22,23 Further (in
2003), the UK’s Committee on the Safety of Medicines
conducted a review of antidepressants and concludedthat clinicians should prescribe uoxetine for
depressed children and adolescents.22,24 In 2004, after
the FDA held a public hearing and issued a public
health advisory, they advised that “Health care
providers should carefully monitor patients receiving
antidepressants for possible worsening of depression
or suicidality, especially at the beginning of therapy or
when the dose either increases or decreases.”25 The
FDA also determined that uoxetine was the only
SSRI noted to be helpful in treating depression in the
pediatric population.
26
In October 2004, the FDAissued a BBW describing the probable risk of increased
suicidality in children and adolescents and suggested
close monitoring for side effects and response in youth.
The following year (2005), antidepressant manufac-
turers were required to include a BBW on antidepres-
sant product labels.25 Then, in May 2007, the FDA
updated the BBW on antidepressants to include young
adults (aged 18 – 24 years) during initial antidepressant
treatment. The warning stated that patients of all ages
who were started on antidepressant therapy should be
monitored appropriately and observed closely for
clinical worsening, suicidality, or unusual changes in
behavior.27 The FDA based this extension on a second
meta-analysis that found a study’s results that
approached signicance for young adults (aged 18 – 24
years) and a decreased risk in adults (aged 25 – 64
years).28
The FDA’s black box labeling of antidepressant
medications for the pediatric population has had far-
reaching consequences. In the United States, before
2005, the rate of diagnosed new episodes of pediatric
depression increased consistently between 1999 and
2004. In 2005, however, the rate decreased sharply and
returned to 1999 rates.22,29,30 Strikingly, as depression
diagnoses decreased, overall estimates of depressive
symptomatology actually increased, suggesting clini-
cian resistance to providing a new depression diag-nosis to clinically depressed youth.32 Busch et al.32
reported a 47% reduction in the use of antidepressants
in the United States from 2002 to 2006 among patients
aged 5 – 21 years who had not previously been exposed
to antidepressants. Interestingly, antidepressant rates
remained the same in this age group for those who had
been previously exposed to treatment.32
Perhaps the most notable change in prescribing
practice was noted in nonpsychiatrists. Amongst pro-
viders, 3.9% of family medicine practitioners and 11.5%
of pediatricians reported that they no longer treatedyoung patients with antidepressants, whereas only 0.8%
of psychiatrists did so.33 Pamer et al.34 found a decrease
in the use of all SSRIs in the pediatric population after
the FDA issued its 2004 advisory. Others35 showed that
uoxetine prescriptions increased for those newly
prescribed an antidepressant following the regulatory
action. Moreover, after the FDA’s warnings, prescrib-
ing clinicians reported that 14% – 22% of guardians and
9% of pediatric patients refused treatment with anti-
depressants.33,36 The FDA recommended that patients
meet with a physician weekly for the
rst 4 weeks of medication initiation, biweekly for a month, and after
12 weeks of treatment.37 Despite this recommendation,
a study showed that the frequency of follow-up
appointments showed little to no change following
the FDA’s guidelines.38
The most serious and unintended effect of FDA
advisories was on pediatric suicides. Gibbons et al.28
provided a comparative study of suicide prevalence
rates in the pediatric populations in the United States
and the Netherlands before and after regulatory agency
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warnings. This study showed that, after 2003, anti-
depressant prescription rates in the United States
decreased for all groups less than 60 years of age.
The magnitude of the decrease in prescription rates was
inversely proportional to age; the decrease in the
2 youngest age groups (up to age 14) was approx-
imately 20% and 30% overall for new prescriptions.28
The decrease in SSRI prescription rates in youth
occurred at a time when the suicide rate increased by
14% from 2003 to 2004 among children and adoles-
cents.28 They found that declines in SSRI prescription
rates in the Netherlands were comparable to those in
the United States, with the largest decreases observed in
the population younger than 20 years. More striking,
however, was the 49% increase of suicides among
people younger than 20 years in the Netherlands.28
Others31 (e.g., Wolitzky-Taylor et al.39) did notnd a change in suicidal ideation post regulatory
action. Brent40 pointed out that the concerns regarding
the risk of suicidality in youth occurred at a time when
the adolescent suicide rate had been dropping. He
advised that the risk of not treating depression was a
greater risk than the risk of suicidality.
Suicidal risk in relation to antidepressant use
remains controversial.17,41 Several studies, including
a meta-analysis, suggest a signicant association with
such risk,17 especially in young people. Thoughts
about suicide were more likely to develop in individ-uals younger than 25 years who were treated with
antidepressants than in older adults. However, a large
meta-analysis (http://www.ncbi.nlm.nih.gov/pmc/articles/
PMC3488279/-R141)41 showed that the benets of
such treatments still outweighed the risks (numbers
needed to treat 10 vs numbers needed to harm 143).
With the mixed evidence and because untreated
depression in adolescents is itself so strongly associ-
ated with risk of suicide, suicidal risk should be
monitored in this clinical group, irrespective of treat-
ment choice.
Case Study #2 — Stimulant Medication and Sudden
Death in the Pediatric Population
Attention-decit/hyperactivity disorder (ADHD) is
one of the most common neurobehavioral disorders in
the United States, affecting approximately 8% of
children and adolescents.42,43 Pharmacotherapy with
stimulants is the mainstay treatment for ADHD.41 – 45
With a stimulant (i.e., methylphenidate) being the
most commonly prescribed medication for US chil-
dren and adolescents,46,47 conicting data regarding
potentially serious side effects of ADHD and subse-
quent FDA public health advisories have been a
source of controversy and consternation.48
In February 2005, the FDA issued a public health
advisory about the potential for serious cardiovascular
events with the use of amphetamine and dextroam-
phetamine.46,47 Later that same year, in September,
the FDA issued a public health advisory for atom-
oxetine (a nonstimulant FDA-approved medication
for ADHD), which warned of the potential for sudden
death and suicidal ideation and includes a boxed
warning for the medication.45,47 In 2007, the FDA
issued an advisory for all ADHD medications and
warned of “possible cardiovascular risks and risks of adverse psychiatric symptoms.” Subsequently, in
2008, the American Heart Association and the Amer-
ican Academy of Pediatrics issued statements advising
that children receiving pharmacotherapy for ADHD
should be assessed for heart conditions.45,49
Since the 2007 FDA advisory, Wilens et al.50
reviewed more than 300 controlled trials of stimulant
medication involving more than 5000 subjects; no
cases of sudden death were detected. More recently,
Hammerness et al.51 reviewed relevant clinical liter-
ature through 2011 and found that stimulants wereassociated with small elevations of blood pressure
(r5 mm Hg) and heart rate (r10 beats/min) without
electrocardiographic changes (e.g., QTc prolonga-
tion). However, it was extremely rare for a child or
adolescent receiving stimulants to have a serious
cardiovascular event during treatment; in fact, the
overall cardiovascular risk was the same as that of
groups of youth not receiving stimulant medication.51
This last nding was further supported by a large
retrospective cohort study52 involving more than
1 million children and young adults analyzed forpotential serious cardiovascular events (e.g., sudden
death, acute myocardial infarction, or stroke). Users
of medication for ADHD were not at increased risk for
serious cardiovascular events compared with nonusers
or former users of stimulants.52
At this stage, it appears that sudden death is a rare
event in youth with ADHD, and there are insuf cient
data to establish a causal link with stimulant medi-
cation used to treat this condition.52 With regard to
stimulant treatment for ADHD, regulatory agency
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warnings do not appear to have changed the prescrib-
ing practices. Korneld et al.46 analyzed a nationally
representative audit of of ce-based providers between
2000 and 2008 and noted that FDA advisories for
stimulants and atomoxetine had little effect on
prescribing use.
Case Study #3 — Antipsychotic Medication and
Increased Mortality in the Elderly
In addition to children and adolescents, the elderly
are another potentially vulnerable population that
may be disproportionately affected by regulatory
agency advisories and warnings. One recent example
is the BBW on antipsychotics in elderly patients with
dementia. Dementia results in progressive and irre-versible loss of cognitive abilities. Alzheimer’s disease
is the most common dementia, currently estimated to
affect 5.2 million Americans of all ages.53 Patients with
dementia may have associated behavioral dysregula-
tion, agitation, and assaultiveness, all behaviors that
pose a clinical dilemma (as there are no FDA-
approved medicines to treat these symptoms). Atyp-
ical antipsychotics became a commonly used class to
treat the elderly with behavioral and psychologic
symptoms of dementia (albeit on an off-label basis)
after several clinical trials showed benets in thispopulation.54,55 However, safety concerns were quick
to follow, rst about an increased risk of stroke (linked
to risperidone) after a MedWatch warning in 2003. In
2004, emerging links with hyperglycemia and new-
onset diabetes compounded concerns about the safety
of atypical antipsychotics.56,57
In 2005, the FDA issued a warning based on a
meta-analysis of 17 randomized controlled trials stat-
ing that second-generation antipsychotic treatment of
the behavioral disturbances resulting from dementia
was associated with an increased mortality as com-pared with placebo.56 The mortality rate owing to heart
failure or sudden death was about 1.6 – 1.7 times higher
with atypical antipsychotics than it was with placebo.57
In 2008, the FDA extended the BBW to rst-gener-
ation, or typical, antipsychotic medications.58
Gill et al.57 found that atypical antipsychotic use
was associated with a small but signicant increase in
mortality among older adults with dementia. The risk
became apparent within a month and lasted up to
6 months. They also noted that conventional
antipsychotics posed a greater risk of mortality than
atypical antipsychotics.57
After the FDA warning on antipsychotics, the use
of atypical antipsychotics in elderly people with
dementia decreased within a month after the advisory
and continued at least through 2008.58 Their monthly
use dropped by an estimated 50% during this period.56
Dorsey et al.59 used data obtained from 2 large
national surveys from 2003 to 2008 and concluded
that after the FDA warnings, there was a small decline
in the use of atypical antipsychotics in the elderly
population. They did not note any substitution of an
atypical antipsychotic for another class of psycho-
tropic medication.59 The 2005 advisory was also
associated with a statistically signicant decline in
the use of atypical antipsychotics in elderly patients
without dementia. The use of atypical medicationsdeclined overall, even for FDA-approved indica-
tions.58 Nevertheless, atypical antipsychotics continue
to be used for elderly patients with dementia. A survey
after the BBW on antipsychotics found that 39.1% of
nursing home facilities reported reduced use of atyp-
ical antipsychotics; half the facilities tried nonphar-
macologic interventions or alternate agents.60
WHAT DOES A CLINICIAN HAVE TO DISCUSS
WITH A PATIENT ABOUT A DRUG WITH A
BBW?
Physicians have a duty to disclose to patients the
information necessary for them to make informed
decisions about treatment recommendations. The
3 preceding case studies highlight the often dif cult
task of identifying effective treatments for psychiatric
disorders in youth or the elderly and educating patients
(or their guardians) about potentially serious
treatment-related risks. Some physicians have mixed
feelings about the disclosure of BBW information to
patients. They argue that providing such informationmay result in unnecessary anxiety and perhaps non-
adherence to the medication. The consequence of such
an approach carries a violation to patients’ civil rights
and bears serious liability and responsibility if an
adverse effect occurs and the patient has not been
informed. Downplaying the adverse events inherent in
the BBW to mislead patients to give consent may set
the ground for a malpractice lawsuit.
Physicians have an obligation to inform the patient
of the relevant information and engage in a collaborative
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decision-making process. An informed decision about a
medication with a BBW, like any other informed
consent, cannot be made unless the provider has
communicated the necessary information in a clear,
concise, and comprehensive manner. The basic content
of the BBW informed consent should include61 the
nature of the proposed treatment; the risks and benets
of the proposed treatment; the alternatives to the
proposed treatment; the risks and benets of the alter-
native treatments; and, the risks and benets of doing
nothing (those interested in the process and documenta-
tion of informed consent are directed to reviews by
Glezer et al.62 or Brendel et al.63).
Physicians can use professional judgment to
decide whether to recommend or prescribe a drug
with a boxed warning. The basis of this professional
judgment is usually established by the “reasonable-ness” standard, which applies the standard of care
exercised by other physicians practicing in similar
situation. Sources that may be utilized to determine the
standard of care include, but are not limited to, FDA
regulations, APA guidelines, professional journal
articles and books, JACHO standards, and a facility’s
policies.64 Furthermore, it is crucial that physicians
appropriately document the informed consent process
with the patient, the basis for clinical decisions,and the
ongoing monitoring and response to treatment.
Knowing what is inside the black box is quiteimportant to the physician and to the patient, but
“thinking outside the box” is often necessary for
optimal outcome.
HOW SHOULD A CLINICIAN RESPOND
WHEN A BBW ADVERSE EFFECT OCCURS?
Health care is not as safe as we hope it should be. The
magnitude of harm that results from medical errors is
quite striking. At least 44,000 Americans die each year
as a result of medical errors. This number is greaterthan the number attributable to the eighth leading
cause of death: suicide.65 The rst step in management
of a patient with BBW adverse effect is prevention.
Rothschild et al.66 found that adverse drug events
associated with malpractice claims were often severe,
costly, and preventable. Psychiatrists, like other med-
ical professionals, bear the responsibility to do the
right thing in the right manner. “First, do no harm”
continues to be an essential value in the protection of
patient welfare. Nevertheless, it is imperative to know
that adverse effects happen, including those cautioned
in the BBW, with or without medical errors, and
despite the prevention programs available at a given
time. Appreciating this limitation in our current
medical practice can actually stimulate initiatives
for a more effective system.
When a BBW adverse event happens and a
medical error is detected, the provider should take
the responsibility and acknowledge it, correct it, and
truthfully inform the patient about the course of
treatment that led to the BBW adverse event. Many
physicians train in a culture of silence that stigmatizes
making mistakes or exposing them. Relying heavily on
their commitment to condentiality, some psychia-
trists may argue that the nature of the psychiatric care
does not lend itself to error reporting and analysis. In
contrast, the APA task force on patient safety andpsychiatry emphasized that “the most compelling
lesson in patient safety is that sharing information
about practices is essential if preventable adverse
medical events are to be reduced.”67
CONCLUSION
As safety concerns related to prescription medications
are often discovered only after a medicine has been
approved and on the market, FDA advisories are an
important means of communicating potential riskinformation to providers and the general public. BBWs
are reserved for those medication risks deemed to be of
the highest public importance. Physicians need to
continuously weighthe risksand benets corresponding
to the medicines they prescribe or recommend as
consultants. In practice, some prescribers and patients
may interpret BBWs as indicating a poisonous sub-
stance and danger, akin to a skull-and-crossbones
warning; others may dismiss these warnings altogether.
Almost all psychotropics recommended by psychiatric
consultants carry a BBW. In recent years, our
eld hasbeen roiled by advisories and boxed warnings about
increased suicidal thinking in depressed youth taking
antidepressants, rare but serious cardiac events for
those treated with stimulants for ADHD, and increased
mortality in elderly with dementia receiving antipsy-
chotics. Despite these highly publicized warnings, all of
these medications remain viable — and necessary —
treatment options with appropriate patient selection.
Ultimately, physicians must decide how (not if) to
recommend and prescribe medications with BBWs.
Strategies for the Prescription of Psychotropic Drugs
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