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Psychosomatics 2014:55:123133

& 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

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 Administrations highest level of drug
warning. It signies that a medication has serious (or
potentially life-threatening) side effects and is prominently displayed on a medications 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 medication 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 farreaching consequences, albeit with a limited ability to
target specic 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; 55:123133)

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 benzodiazepines), which could hamper effective care. Therefore,
consultants who practice psychosomatic medicine are
mindful of, but not paralyzed by, these warnings.

he Black Box Warning (BBW) is the most serious


labeling change that the Food and Drug Administration (FDA) can issue. BBWs are intended to be a
safety tool, created to communicate potentially serious
safety information about a particular medicine. Usually, 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 it
simply, 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
Psychosomatics 55:2, March/April 2014

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.

www.psychosomaticsjournal.org

123

Strategies for the Prescription of Psychotropic Drugs


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
All methylphenidates and amphetamines

Subject to misuse, abuse, addiction, or diversion


Misuse may cause serious cardiovascular adverse
events and sudden death
Increased risk of death in elderly patients with
dementia-related psychosis
Aplastic anemia
Agranulocytosis
Myocarditis
Orthostatic hypotension
Seizures
Stevens-Johnson Syndrome
Lithium toxicity
Pancreatitis
Teratogenicity
Hepatotoxicity
QTc prolongation; Torsades de Pointes
Life-threatening thyroid toxicity; ineffective for
weight reduction
Certied programs only
Contraindicated during alcohol intoxication; needs
patient's full knowledge
Respiratory depression

All amphetamines
All rst-generation (typical) and second-generation (atypical)
antipsychotics
Carbamazepine
Clozapine and carbamazepine
Clozapine
Clozapine
Clozapine and umazenil
Lamotrigine
Lithium
Valproic acid
Valproic acid
Naltrexone, dantrolene, and valproic acid
Thioridazine, mesoridazine, and droperidol
Levothyroxine
Methadone
Disulram
Midazolam

n
Does not include psychotropics already withdrawn from the market because of safety concerns (e.g., pemoline, nefazodone, or
propoxyphene).

Psychiatrists today face the conundrum of how to


responsibly prescribe FDA-approved medicines that are
needed 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. To
this end, we review 3 BBWs for psychotropic medications 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
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with warnings, the Code of Federal regulations2


states:
Labeling shall describe serious adverse reactions and potential
safety hazards, limitations in use imposed by them, and steps 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 not have been provedSpecial problems, particularly those
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, but serious animal toxicity may also be the basis of a
boxed warning in the absence of clinical data.

After a drug is approved, and so as to monitor its


safety, the FDA seeks a commitment from the
pharmaceutical company to conduct specic postmarketing 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 MedWatch program with the mandatory reports from
Psychosomatics 55:2, March/April 2014

Stevens et al.
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 interdisciplinary team convenes with representatives from the
Ofce of Surveillance and Epidemiology and the
Ofce of New Drugs.1 This collaborative team then
decides whether to continue monitoring, require a
boxed warning, or withdraw the 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 takes
for 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 FDAs 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 treatment likely outweighs its benets (in certain circumstances); (4) identied issues of dosing or drug
interaction, 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 postmarketing 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 avoidance 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
Psychosomatics 55:2, March/April 2014

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 new
BBW 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 occurred 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 25
years, 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
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Strategies for the Prescription of Psychotropic Drugs


where the BBW included recommendations for baseline laboratory monitoring, those recommendations
were not followed. These data raised concerns about
the power of BBWs in changing physicians prescribing practices.
Lasser et als.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 disregarded. Nearly 25% of patients (129 of 526) on
carbamazepine had no documented evidence of CBCplatelet 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 als.9 study on Medicaid
patients with bipolar disorder, in which 36% of the
patients 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 practice guidelines that were based upon expert consensus.
Current clinical practice lacks a formal system to
document appropriate patient selection for medications, risk counseling, or drug safety monitoring.1 To
improve physician adherence to BBWs, researchers7,8
suggested more precise wording on the magnitude of
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risks inherent in prescribing despite BBWs, stated in


clear language that can be easily understood by both
physicians and patients. Moreover, they7,8 recommended 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 publics health might suffer if the FDAmandated warnings were not justied. For instance,
the American Psychiatric Association (APA) and
American Academy of Child and Adolescent Psychiatry 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 #1Antidepressant Medications and
Suicidality in the Pediatric Population
Major depressive disorder is a common mental
health problem in adolescents worldwide, with an
estimated 1-year prevalence of 4%5% in midadolescence to late adolescence.12,13 Depression in adolescents is a major risk factor for suicide, the second or
third leading cause of death in this age group (depending 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 treatment
for adolescents with depression.16 Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), seems effective in meta-analyses (http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC3488279/-R137)17 and randomized
controlled trials,1820 but evidence is more inconsistent
for other antidepressants. Even in the best circumstances, antidepressants are only moderately effective
in adolescents with depression.21
Against this backdrop, the FDA warning of
potentially increased suicidal thinking and behavior
Psychosomatics 55:2, March/April 2014

Stevens et al.
in children and adolescents taking SSRI antidepressants added complexity to an already challenging
treatment situation. The FDA action both reected
and fueled public suspicion of pediatric psychopharmacology. It is perhaps one of the best-known and
most controversial examples of a BBW on a psychotropic medication.
To detail how the pediatric antidepressant advisories affected prescribing practices, the chronologic
development of this BBW has been reviewed. In 2003,
the United Kingdoms 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 paroxetine.22,23 Within the year, the Medicines and Healthcare Regulatory Agency, FDA, and European
Medicines Agency all issued advisories regarding
reports of suicidality in young patients given antidepressants. 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 UKs Committee on the Safety of Medicines
conducted a review of antidepressants and concluded
that 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 FDA
issued 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 manufacturers were required to include a BBW on antidepressant product labels.25 Then, in May 2007, the FDA
updated the BBW on antidepressants to include young
adults (aged 1824 years) during initial antidepressant
treatment. The warning stated that patients of all ages
who were started on antidepressant therapy should be
Psychosomatics 55:2, March/April 2014

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 studys results that
approached signicance for young adults (aged 1824
years) and a decreased risk in adults (aged 2564
years).28
The FDAs black box labeling of antidepressant
medications for the pediatric population has had farreaching 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 clinician resistance to providing a new depression diagnosis 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 521 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 providers, 3.9% of family medicine practitioners and 11.5%
of pediatricians reported that they no longer treated
young 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 FDAs warnings, prescribing clinicians reported that 14%22% of guardians and
9% of pediatric patients refused treatment with antidepressants.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 FDAs 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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Strategies for the Prescription of Psychotropic Drugs


warnings. This study showed that, after 2003, antidepressant 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 approximately 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 adolescents.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 not
nd 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 individuals 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 associated with risk of suicide, suicidal risk should be
monitored in this clinical group, irrespective of treatment choice.
Case Study #2Stimulant 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.4145
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With a stimulant (i.e., methylphenidate) being the


most commonly prescribed medication for US children and adolescents,46,47 conicting data regarding
potentially serious side effects of ADHD and subsequent 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 dextroamphetamine.46,47 Later that same year, in September,
the FDA issued a public health advisory for atomoxetine (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 American 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 literature through 2011 and found that stimulants were
associated with small elevations of blood pressure
(r5 mm Hg) and heart rate (r10 beats/min) without
electrocardiographic changes (e.g., QTc prolongation). 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 for
potential 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 insufcient
data to establish a causal link with stimulant medication used to treat this condition.52 With regard to
stimulant treatment for ADHD, regulatory agency
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Stevens et al.
warnings do not appear to have changed the prescribing practices. Korneld et al.46 analyzed a nationally
representative audit of ofce-based providers between
2000 and 2008 and noted that FDA advisories for
stimulants and atomoxetine had little effect on
prescribing use.
Case Study #3Antipsychotic 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 irreversible loss of cognitive abilities. Alzheimers 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 dysregulation, agitation, and assaultiveness, all behaviors that
pose a clinical dilemma (as there are no FDAapproved medicines to treat these symptoms). Atypical 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 this
population.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 newonset 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 stating that second-generation antipsychotic treatment of
the behavioral disturbances resulting from dementia
was associated with an increased mortality as compared with placebo.56 The mortality rate owing to heart
failure or sudden death was about 1.61.7 times higher
with atypical antipsychotics than it was with placebo.57
In 2008, the FDA extended the BBW to rst-generation, 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
Psychosomatics 55:2, March/April 2014

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 psychotropic 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 medications
declined overall, even for FDA-approved indications.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 atypical antipsychotics; half the facilities tried nonpharmacologic 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 difcult
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 information
may result in unnecessary anxiety and perhaps nonadherence 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 alternative treatments; and, the risks and benets of doing
nothing (those interested in the process and documentation 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 reasonableness 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 facilitys
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 quite
important 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 greater
than 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 medical 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
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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 psychiatrists 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 and
psychiatry 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 risk
information 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 weigh the risks and benets corresponding
to the medicines they prescribe or recommend as
consultants. In practice, some prescribers and patients
may interpret BBWs as indicating a poisonous substance 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 has
been 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 antipsychotics. Despite these highly publicized warnings, all of
these medications remain viableand necessary
treatment options with appropriate patient selection.
Ultimately, physicians must decide how (not if) to
recommend and prescribe medications with BBWs.
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