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:

[email protected]

& 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).


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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



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488279/-R137http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488279/-R137http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488279/-R137http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488279/-R137


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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

Stevens et al.



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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



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488279/-R141http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488279/-R141http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488279/-R141http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488279/-R141


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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

Stevens et al.



8/11

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.




9/11

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