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Published 2013. This article is a U.S.

Government
work and is in the public domain in the USA

Bipolar Disorders 2013: 15: 594621

BIPOLAR DISORDERS

Review Article

Impact of psychotropic drugs on suicide and


suicidal behaviors
Yerevanian BI, Choi YM. Impact of psychotropic drugs on suicide and
suicidal behaviors.
Bipolar Disord 2013: 15: 594621. Published 2013. This article is a U.S.
Government work and is in the public domain in the USA.
Objective: To examine the impact of psychotropic drugs on suicide and
suicidal behaviors in bipolar disorders.
Methods: A Medline search of articles published from January 1960 to
January 2013 was performed using relevant keywords to identify studies
examining the relationship of psychotropic drugs to suicidal behaviors.
The publications were further reviewed for relevant references and
information. Additionally, the US Food and Drug Administration
Center for Drug Evaluation Research website was searched.
Results: The available studies used diering methodologies, making
interpretation of the ndings dicult. Studies suggest that
antidepressants may increase suicidal risk in bipolar disorder, this
possibly being related to the induction of broadly dened mixed states.
There is no evidence that antiepileptic drugs as a class increase suicidal
risk in patients with bipolar disorder. Only lithium provides convincing
data that it reduces the risk of suicide over the long term. There is little
known regarding the eects of antipsychotics, as well as anti-anxiety and
hypnotic drugs, on suicidal behavior.
Conclusions: The available evidence for the impact of psychotropics on
suicidal risk in patients with bipolar disorder is largely methodologically
awed and, except for a few instances, clinically not useful at this point.
Adequately powered, prospective randomized controlled studies are
needed to assess the impact of each class of psychotropic and each
psychotropic as well as common combination therapies. Until such
studies have been carried out, clinicians are urged to exercise caution in
using these drugs and rely on the traditional means of carefully assessing
and monitoring patients with bipolar disorder who are at high risk for
suicide.

Bipolar disorder ranks highest in terms of suicidal


risk among all psychiatric disorders, with a relative
risk ratio (RR) of completed suicide of about 25
compared to the general population (1) and a lifetime risk of suicide of between 6 and 15% (18).
Twenty-ve to fty per cent of patients with bipolar disorder attempt suicide during their lifetime (9,
10). Furthermore, suicide attempts in this group of
patients are more lethal, as one in three attempts
ends in completed suicide compared to a ratio of
one in 30 attempts in the general population (9,
10). Suicide attempts by patients with bipolar dis-

594

Boghos I Yerevaniana,b and Young


Mee Choia,b
a

Department of Psychiatry, Greater Los Angeles


VA Healthcare System, Sepulveda Ambulatory
Care Center, North Hills, bDepartment of
Psychiatry and Biobehavioral Sciences, David
Geffen School of Medicine, University of
California at Los Angeles, Los Angeles, CA, USA

doi: 10.1111/bdi.12098
Key words: anticonvulsants
antidepressants antipsychotics bipolar
disorder lithium mood disorder
psychotropic drugs sedatives and
hypnotics suicide
Received 3 October 2011, revised and
accepted for publication 25 March 2013
Corresponding author:
Boghos I. Yerevanian, M.D.
Department of Psychiatry
Greater Los Angeles VA Healthcare System
Sepulveda Ambulatory Care Center
16111 Plummer Street
Building 10, MC 116A3
North Hills, CA 91343
USA
Fax: 818-876-0546
E-mail: byerevan@ucla.edu

order tend to be more lethal than those by patients


with major depressive disorder (MDD) (11). This
increase in suicidality may be related to the high
level of impulsivity and irritability in bipolar disorder (12) as well as factors such as cyclothymic or
hyperthymic temperaments (1315).
Untreated bipolar disorder is associated with
excess mortality, including death by suicide as well
as accidents, violence, and medical illness (3).
Duration of untreated bipolar illness is associated
with a higher frequency of suicide attempts and a
higher number of suicide attempters (16). A recent

Psychotropic drugs and suicidal risk in bipolar disorders


report from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)
(17) found a suicide rate of 0.014 per 100 personyears among 4360 closely followed patients with
bipolar disorder, suggesting that treatment had an
important impact on suicide outcome, bringing the
rate close to the general population base rate of
0.015 per 100 person-years. Angst et al. (18)
reported in a long-term follow-up study of 406
hospitalized mood disorder patients, of whom
more than half had bipolar disorder, that all treatment modalities, including lithium, antidepressants, and neuroleptics, were associated with
decreased suicide rates over the long term.
Being suicidal at baseline may predict poor
depression treatment outcomes in both bipolar
depression and unipolar depression, even when
suicidality rating scores improve (19). Ahrens and
Muller-Oerlinghausen (20) found a reduction in
suicide attempts by both responders and nonresponders to lithium and suggested that lithium
may decrease suicidal risk independent of its eects
on aective episodes. Furthermore, suicidal ideation, suicide attempts and suicide completion may
be independent clinical conditions and may only
have an indirect relationship to the major aective
disorders. If that is the case, these suicidal states
may have distinct treatment responses (21).
The number of psychotropic drugs with regulatory approval to treat the various phases of bipolar
disorder is increasing. O-label use of psychotropic
medications in bipolar disorder has led to the widespread use of medications in all phases of bipolar
disorder, often without adequate data regarding
suicide in this high-risk population.
Suicide prevention and avoidance of increasing
suicidal risk should be of primary concern. It cannot be assumed that drugs that are eective in particular phases of bipolar disorders are also eective
in reducing suicidal risk. Medications can potentially worsen outcomes, including suicidality. Earlier reports that antidepressants were linked to
suicide (22, 23), especially among children and
adolescents (24), have raised concerns about other
psychotropic medications in adult and pediatric
populations. All antidepressants currently carry
Food and Drug Administration (FDA) black box
warnings of suicidality as a potential adverse outcome. These warnings were initially for children
and adolescents, but in 2004 they were extended to
adults up to age 25 years. The FDA also required
manufacturers of antiepileptic drugs (AEDs) to
include a warning about increased risk of suicidality in their labeling. Despite approval of clozapine
as a drug for reducing suicidal risk among patients
with schizophrenia, the status of all antipsychotic

drugs with respect to suicidal risk in patients with


bipolar disorder is currently unclear.
When analyzing the available data pertaining to
suicide risk associated with pharmacological treatments used in bipolar disorder, it is important to
recognize the dierent presentations of suicidality,
which include completed suicide, attempted suicide
of high and low lethality, hospitalization for suicidal ideation with serious intent, and suicidal ideation. Dierent neurobiological processes may
mediate these dierent phenomena. Therefore,
psychotropic medications may have dierent suicide risk modifying eects on these presentations.
Improved risk assessment instruments for assessing and grading suicidal risk with demonstrated
psychometric and clinical utility are needed. A
recent expert consensus statement (25) on the issue
agreed with the FDAs endorsement of the terminology of the Columbia Classication Algorithm
of Suicide Assessment (C-CASA) with the hope
that industry and clinical researchers will use
C-CASA compatible instruments in monitoring
treatment-emergent suicidal behaviors. The FDA
increasingly requires such instruments to monitor
treatment-associated changes in suicidal ideation
and behavior in pre-licensing clinical trials of new
drugs with central nervous system activity. Such
eorts may contribute to the growing understanding of the link between biological systems and suicidal behavior (2629).
In this paper, we review evidence pertaining to
whether a particular class of drug used in the treatment of bipolar disorder has a suicide-promoting, a
suicide-preventing, or a neutral eect on suicidality.
Whenever data are available, we will examine individual drugs. Data for suicide completers, attempters and ideators will be examined whenever this
distinction has been made. The implications of the
ndings for research and clinical practice will then
be discussed. Although many other drugs, including those of abuse, may aect suicidality in
patients with bipolar disorder, this review will
focus only on therapeutic agents typically used in
mood disorders.
The studies reviewed were identied by performing Medline searches for the timeframe January
1960 to January 2013 using the keywords antiepileptic, anticonvulsant, antidepressant, antipsychotic,
benzodiazepine, bipolar disorder, lithium, mood disorder, psychotropic drugs, sedatives, hypnotics, and
suicide. We further rened our search using individual drug names and also identied additional
studies from the citations of the reviewed papers.
We also searched the US Food and Drug Administration Center for Drug Evaluation and Research
website.

595

Yerevanian and Choi


Antidepressants

A major controversy in the treatment of bipolar


disorder concerns the use of antidepressants
(Table 1). This controversy arises from observations and an accumulating body of evidence that
antidepressant use in bipolar disorders is associated with the emergence of clinical states that
increase suicidal risk, particularly in type I
patients. These higher risk states include mixed
states (30), broadly dened mixed states (31), emotional instability, or rapid cycling (3234), and
switching into mania, hypomania, mixed states, or
psychosis (35). It is possible that antidepressants
increase suicidal risk via mechanisms, such as
worsening of depression, behavioral activation and
agitation, that do not satisfy diagnostic criteria for
mania or a mixed state, sometimes termed an activation syndrome (36). There also may be other
unknown mechanisms.
The use of antidepressants in bipolar disorder is
very common. Sometimes they are used prior to the
emergence of manic or hypomanic symptoms in
patients, when clinicians believe they are treating
unipolar depression (37, 38). Antidepressants are
also used in diagnosed bipolar disorders because
clinicians feel compelled to alleviate the symptoms
of bipolar depression. Data from the Stanley Network as well as the National Institute of Mental
Health (NIMH) STEP-BD project indicate that 35
to 55% of patients with bipolar disorder receive
antidepressants at some point in their illness and
even more frequently than mood stabilizers. Baldessarini et al. (39) reported that in a large group
of 7760 bipolar disorder patients, regardless of
their clinical state, 50% were given an antidepressant as a rst treatment, and only 25% a mood stabilizer. Baldessarini et al. (40) reported in another
study of 7406 patients with bipolar disorder that
antidepressants were the most often rst-prescribed
treatment and were second only to lithium in being
sustained as monotherapy in up to a year of follow-up.
In a French prospective study of patients with
bipolar disorder with either mixed states or relatively pure mania at baseline, 36% were treated
with an antidepressant (41). This proportion
remained high throughout follow-up. As expected,
the rate of antidepressant use was twice as high
during dysphoric mixed states as during mania
(55% versus 27%, respectively, p < 0.001). Interestingly, the authors noted that, while antidepressants are not recommended in mixed states, more
than half of the mixed state patients were maintained on them for the 24 months of follow-up.
Mood stabilizers have limited ecacy in acute
bipolar depression and probably also in unipolar

596

depression, with small or moderate eect sizes (42).


The addition of antidepressants may not have a
signicant impact in the treatment of bipolar
depression (43). Several reviews, as well as expert
treatment guidelines for bipolar disorder, have
been published (42, 4447). Most have recommended extreme caution in the use of antidepressants. It is an interesting phenomenon that the
class of medications least recommended by experts
for bipolar disorder is the most widely used by clinicians.
Mood stabilizers are also not very eective in
preventing relapses into mania or bipolar depression, despite their demonstrated superiority over
placebo in numerous controlled studies (44).
Relapse rates are still high for lithium and divalproex (48). Mood stabilizers from the antipsychotic
group, including quetiapine, aripiprazole, olanzapine, and the olanzapine/uoxetine combination,
are also limited by inconsistent and low rates of
relapse prevention.
Therefore, the clinician is under pressure to consider antidepressant medications. Many clinicians
do notice benets for their patients after adding
antidepressants. They also notice that adverse
events, including suicidal behavior, occur with
antidepressant treatment of bipolar disorder
patients. Thus there is a clinical dilemma (45, 49
51) that is also a major public health concern, since
the estimated 50 million patients with bipolar disorder in the world spend the majority of their ill
time in depression rather than mania and are thus
vulnerable to antidepressant treatment (52, 53).
Antidepressants are not very eective in bipolar
depression (54, 55). The logical expectation therefore would be that they are not eective agents for
reducing suicidal risk. In contrast, lithium is also
not a particularly good antidepressant in bipolar
depression, with response rates rarely exceeding
50%, but it is eective in preventing suicide and
suicide attempts with long-term use. Lithium is
also somewhat eective against mixed states which
carry very high suicidal risk (31). Unlike lithium,
antidepressants have a propensity to induce mixed
states (14). Therefore, they are not expected to be
very protective against suicidality in patients with
bipolar disorder.
But what do the data show?

In a casecontrol prospective study, Marangell


et al. (56) reported on the suicidal events in a large
group of patients with bipolar disorder from the
STEP-BD. Of the 4360 participants in the study,
182 exhibited suicidal behavior. In this group,
there were 270 suicide events (eight completed

Casecontrol,
prospective
study

Prospective
study

PBO-controlled
RCT

Systematic
follow-up

Cross-sectional
analysis of STEPBD cohort

Bauer
et al.
2006 (72)

Tohen
et al.
2003 (73)

Tondo
et al.
2008 (58)

Goldberg
et al.
2005 (61)

Design

Marangell
et al.
2008 (56)

Study

Table 1. Antidepressants

Adult STEP-BD
cohort

Outpatient
clinic

Adult
outpatients

Adult STEPBD
outpatients

STEP-BD
population

Population
studied

DSM-IV BD-I, BD-II,


BD-NOS,
cyclothymic d/o,
SZA BD subtype

Affectively ill,
MDD, BD-I, BD-II

BD-I depressed

DSM-IV BD-I, BD-II,


BD-NOS,
cyclothymic d/o,
SZA BD subtype

DSM-IV BD-I, BD-II,


BD-NOS,
cyclothymic d/o,
SZA BD subtype

Diagnosis/subtype

PBO versus
OLZ or OFC

Total N = 833

1000

MDD = 605
BD-I,
BD-II = 184

Total N = 789

AD versus
no AD

Various ADs
as clinically
indicated

AD versus no
AD use

425a

PBO = 377
OLZ = 370
OFC = 86

Systematic
algorithm
with
various ADs

Treatment

182 patients
with suicide
events

17 months

Mean = 3.59
months

8 weeks

30 months

6 years

Study/
treatment
duration

SI

SI

Any
suicidal
event

Suicidality
broadly
defined
including
SI, selfharm
events,
SA, SC

SC, SA

Suicide
type

With sustained
AD treatment,
81.5% initially
suicidal patients
became nonsuicidal on
HDRS item #3
AD group had
higher rate of
SI than no-AD
group (25%
versus 14%)

No suicidal
events in
either group

Increased AD
exposure was
not associated
with increased
emergent
suicidality

Increased
suicidal risk
with SSRIs

Li not protective
against suicide

Results

Confounding by
indication not
resolved

Numbers were
insufficient to
test for
differences
among
specific ADs
Short-term
study
not designed
with suicidality
as a primary
outcome
Naturalistic
study

Few patients
taking Li
Small numbers
in subgroups

Study was not


designed to
assess
association of
SSRIs with
suicide risk

Comments

Psychotropic drugs and suicidal risk in bipolar disorders

597

598

Cross-sectional
study

Retrospective
review

Retrospective
review with
prospective
follow-up

Cohort study with


follow-up in a
nationwide
database

Yerevanian
et al.
2007 (59)

Pacchiarotti
et al.
2011 (60)

Tiihonen
et al.
2006 (69)

Design

Goldberg
et al.
1999 (62)

Study

Table 1. (Continued)

Patients
hospitalized
after SA

Inpatients and
outpatients

Veteran
inpatients
and
outpatients

Adult Step-BD
cohort

Population
studied

ICD-10 SA

BD-I, BD-II

BD-I, BD-II,
BD-NOS, SZA

Mania/mixed mania

Diagnosis/subtype

15390

AD MONO = 61
AD + MS = 34

Total N = 95

405

100

Various TCAs
SSRI
SNAs
Other ADs
versus
no ADs

AD MONO
AD + MS

AD MON
AD + MS
MS only
(MS = Li,
VAL, CBZ)

AD versus no
AD in week
prior to
hospital
admission

Treatment

Mean followup = 3.4


years

10 years

3 years

1 week

Study/
treatment
duration

SA, SC

SA

SA, SC,
hospitalization
for SI

SI

Suicide
type

VFX was
associated with
the highest risk
(RR = 1.61; 95%
1.012.57)

Patients with
dysphoric
mania who had
taken ADs in the
week prior to
admission had
significantly more
SI than those
without ADs
All suicidal events:
MS MONO
3.48/100
patient-years;
MS + AD 9.75/100
patient-years;
AD MONO
25.92/100 patientyears
Mean no. of SAs for
AD MONO = 0.5
(SD = 1.2) was
significantly
higher than for
AD + MS = 0.2
(SD = 0.4)
(p = 0.001)
FLX was
associated with
the lowest risk of
suicide
(RR = 0.52; 95%
CI: 0.300.93)

Results

One of only few


studies with
single drug
comparisons

Strengths were
long-term
follow-up and
MONO versus
polytherapy

Confounding by
indication not
resolved
MS mitigates
ADassociated
suicidality

Suggests an
acute effect of
ADs on SI

Comments

Yerevanian and Choi

Retrospective
chart review

Retrospective
review and
follow-up

Blind,
retrospective
review

Pharmacoepidemiologic,
retrospective
design

Akiskal
et al.
2003 (63)

Stoll
et al.
1994 (64)

Kessing
et al.
2005 (65)

Design

Raja
et al.
2009 (57)

Study

Table 1. (Continued)

Large adult
cohort of Li
users based
on pharmacy
purchase data

Inpatients

Inpatients

Acute
admissions
to inpatient
psychiatric
units

Population
studied

Purchasers of Li,
no clinical data

BD-I manic

BD-II with ADinduced versus


spontaneous
mania

Mixed affective
group, subanalysis for BDs

Diagnosis/subtype

Various ADs
versus
no AD

Total N = 98

Li purchasers = 13186
Control general
population = 1.2 million

Li versus
Li + AD

AD versus
no AD

AD-induced = 52
Spontaneous
mania = 144

AD-associated
mania = 49
Spontaneous
mania = 49

Various ADs,
BZDs

Treatment

SA = 129
No SA = 1233

5 years

12 months

6 month
retrospective
review and
follow-up at
1 month

3 months
prior
to acute
hospitalization

Study/
treatment
duration

SC

SI severity
on a
scale of
17

SI

SA

Suicide
type
Those admitted
with SAs were
more likely to
have taken
SSRIs than
BDZs compared
to those without
SAs (41.3%
versus 24.9%,
v2 = 11.19,
p = 0.0001)
42% of the
hospitalized
spontaneous
group were
admitted for
suicidal risk
versus 80% of
the hospitalized
AD-induced
group (p =
0.002)
AD-associated
group (2.0,
SD = 1.5) and
the spontaneous
group
(1.9, SD = 1.4)
had similar
suicidality
scores, p = ns
Those
purchasing
AD had a higher
risk of SC,
RR = 6.07,
95%
CI: 5.107.21

Results

Confounding
issues not
resolved

The
percentage of
BD is unclear

Pharmacy data
may not reflect
clinical

Treatment
groups too
small to
assess
effects of
individual ADs

Confounding
issues not
resolved

Naturalistic
treatment

They did not


resolve
confounding
issues

Comments

Psychotropic drugs and suicidal risk in bipolar disorders

599

600

AD
treatment
period =
minimum
12 months

AD = antidepressant; BD = bipolar disorder; BD-I = bipolar I disorder; BD-II = bipolar II disorder; BD-NOS = bipolar disorder; not otherwise specified; BZD = benzodiazepine; CBZ = carbamazepine; CI = confidence interval; d/o = disorder; FLX = fluoxetine; HDRS = Hamilton Depression Rating Scale; ICD = International Statistical Classification of Diseases and Related
Health Problems; Li = lithium; MDD = major depressive disorder; MONO = monotherapy; MS = mood stabilizer; ns = non-significant; OFC = olanzapinefluoxetine combination; OLZ = olanzapine; PBO = placebo; RCT = randomized controlled trial; RR = risk ratio; SA = suicide attempt; SC = suicide completed; SD = standard deviation; SI = suicidal ideation; SNAs = serotonergic-noradrenergic antidepressants; SSRI = selective serotonin reuptake inhibitor; STEP-BD = Systematic Treatment Enhancement Program for Bipolar Disorder; SZA = schizoaffective;
TCAs = tricyclic antidepressants; VAL = valproate; VFX = venlafaxine.
a
Of the first 2000 STEP-BD participants with new onset major depressive episode without initial SI.

Confounding
issues not
resolved

No review of
clinical charts

Unrecognized
BDs given ADs
were more likely
to attempt
suicide than
recognized
BDs or non-BDs
SA
6 years
Various ADs
Recognized BD = 3797
Unrecognized
BD = 1582
Non BD, but
affectively ill = 20081
Shi et al.
2004 (37)

Retrospective
analysis

Medi-Cal paid
claim database

Recognized BD,
unrecognized BD,
non-BD but
affectively ill

Treatment
Study

Table 1. (Continued)

Design

Population
studied

Diagnosis/subtype

Study/
treatment
duration

Suicide
type

Results

Comments

Yerevanian and Choi


suicides and 262 attempts). When the group with
suicidal events was compared to a matched control
group without suicidal events, exposure to lithium
in the six-month period prior to an event was similar in the two groups. The ndings were somewhat
surprising in that no suicide-protective eect was
noted in the lithium cohort. Exposure to selective
serotonin reuptake inhibitor (SSRI) antidepressants was associated with increased suicidal events.
Confounding by indication was not resolved.
In an analysis of a group of aectively ill
patients with various diagnoses, admitted to a psychiatric intensive care unit, Raja et al. (57) found
that those who were admitted following a suicide
attempt were more likely than those without a suicide attempt to have taken antidepressants and
benzodiazepines in the three months prior to
admission. Suicidal patients were also less likely to
have taken antipsychotics, AEDs or lithium. These
ndings held true when the bipolar and mixed subgroups were analyzed separately. The study did
not control for confounding factors, including confounding by indication. In a Sardinian group of
785 aectively ill patients (605 with MDD and 184
with bipolar I and II), systematically followed for
an average of 3.59 months, Tondo et al. (58)
reported that, with sustained antidepressant treatment, 81.5% of initially suicidal patients became
non-suicidal as measured by Item #3 of the Hamilton Depression Rating Scale (HDRS). This conversion
to
non-suicidal
status
occurred
independent of diagnosis, treatment type, or dosage of medication. The subgroup of patients with
bipolar disorder in this group does not appear to
have shown increased suicidal risk.
A group of 1582 unrecognized patients with
bipolar disorder in a community sample of 25460
depressed patients, who were given antidepressants
for depressive-phase illness, were signicantly more
likely to attempt suicide (0.9%) than recognized
patients with bipolar disorder (0.3%) or non-bipolar-disorder patients (0.2%) (p < 0.0001) (37). The
study was based on an analysis of Medicaid paid
claim data without review of clinical charts.
In a group of 405 veterans with bipolar disorder
followed for an average of three years, suicidal
event rates (suicide attempts and hospitalizations
for suicidal intent) were 7.4 times higher during
treatment with antidepressant monotherapy (25.92
events/100 patient-years) than during treatment
with mood stabilizer monotherapy (3.48 events/
100 patient-years) and 2.7 times higher than during
treatment with mood stabilizer and antidepressant
combination therapy (9.75 events/100 patientyears) (59). For suicide events: (i) mood stabilizer
and antidepressant versus mood stabilizer

Psychotropic drugs and suicidal risk in bipolar disorders


monotherapy, p = 0.003; (ii) mood stabilizer and
antidepressant versus antidepressant monotherapy,
p = 0.0005; and (iii) mood stabilizer monotherapy
versus antidepressant monotherapy, p < 0.0001.
Pacchiarotti et al. (60) studied 95 patients with
bipolar disorder initially given either antidepressant monotherapy or antidepressant and mood
stabilizer combination therapy. These patients
were followed up for up to 10 years. Including
retrospective data, they found that patients with
bipolar depression maintained on antidepressant
monotherapy had a higher mean number of suicide attempts than those maintained on combination
therapy:
0.5
[standard
deviation
(SD) = 1.2] versus 0.2 (SD = 0.4), respectively
(p = 0.001).
A cross-sectional analysis from the STEP-BD
study (61) found that suicidal ideation was more
prevalent in patients taking antidepressants versus
those not taking antidepressants (25% versus
14%). Confounding issues were not resolved.
In a study of 100 manic patients, dysphoric
manic patients who had taken antidepressants in
the week prior to admission had signicantly
higher rates of suicidal ideation compared to
those who were not taking antidepressants: 54%
versus 34%, respectively (p < 0.05). (62). In
other words, although all patients were at higher
risk by virtue of being in mixed states, the presence of antidepressants increased the risk of suicidal ideation even more. In another study,
antidepressant-associated hypomanic patients
were about twice as likely to have been admitted
with suicidal ideation than patients with bipolar
II disorder with spontaneous hypomania (80%
versus 43%, respectively) (63). In a retrospective
chart review, Stoll et al. (64) found that antidepressant-associated manic patients, although clinically assessed as having less severe illness
compared to a group of spontaneously manic
patients, nevertheless had similar scores on a
seven-item suicidal ideation rating scale. The
results raise the possibility that antidepressants
may have a role in increasing suicidal ideation
independent of episode. In a large cohort study
from Denmark (65), patients treated with lithium, presumably mostly patients with bipolar
disorder, who also purchased an antidepressant
had a higher risk of completed suicide, with an
RR of 6.07 [95% condence interval (CI): 5.10
7.21]. None of the studies resolved the issues of
confounding by indication or other confounds.
Among antidepressants, venlafaxine may be
involved in increased suicidality due to its
propensity to induce more switches and mixed
states (6668), which carry a higher risk for

suicidality (14). The RR of suicidal behavior/ideation based on the FDA analysis (24) of controlled
trial data in pediatric patients was 1.58 with mirtazapine (95% CI: 0.0638.37) and 8.84 with venlafaxine (95% CI: 1.1269.51).
In a cohort study of 15390 subjects hospitalized
after a suicide attempt, Tiihonen et al. (69)
reported that, among various antidepressants, uoxetine was associated with the lowest risk of suicide
compared to placebo (RR = 0.52; 95% CI: 0.30
0.93). Venlafaxine was associated with the highest
risk of suicide (RR = 1.61; 95% CI: 1.012.57).
Furthermore, in a recent comparison of dierent
antidepressant subtypes, an increased risk of suicide attempts with venlafaxine versus other antidepressants was observed in a heterogeneous group
of patients, most of whom had depression or
anxiety (70).
We found no studies specic to bupropion and
suicidal risk in patients with bipolar disorder. At
this time, bupropion should be considered similar
to other antidepressants pending reliable data in
bipolar disorder. The impression that bupropion
may cause less switching or fewer mixed states
when used in bipolar depression may be a potential
advantage in this regard (66, 71).
In a prospective study of a large group of
patients in the STEP-BD, Bauer et al. (72) found
no evidence that an increase in antidepressant
exposure was associated with increased suicidality.
However, in that report, the numbers of patients
exposed to each antidepressant subtype were too
small to permit an adequate statistical assessment
of dierential eects.
In the randomized placebo-controlled study of
Tohen et al. (73) comparing olanzapine, olanzapineuoxetine combination and placebo in bipolar I depression, there were no serious suicidal
events in any of the three groups during the eightweek study period. There was a modest reduction
on the Montgomery
Asberg Depression Rating
Scale (MADRS) suicidal thought item in all three
groups. In this eight-week study, which excluded
patients with a history of suicidal behavior within
the past three months, it is dicult to interpret the
eect on suicidality of uoxetine alone or in combination with an antipsychotic.
Few studies have examined suicidal outcome as
a result of the use of tricyclic antidepressants
(TCAs) in bipolar depression. Data for patients
with unipolar depression suggest that in unipolar
depression TCAs may be protective against suicide
(74), whereas in bipolar disorder the situation may
be the reverse. TCAs, via a contribution to the
switch process, may increase the risk of suicidal
behaviors (59, 68).

601

Yerevanian and Choi


In the large meta-analysis by Fergusson et al.
(22), the odds ratio (OR) comparing TCAs to
SSRIs for suicide attempts was 0.88 (95% CI:
0.541.42) and for suicides was 1.08 (95% CI:
0.284.09), indicating that there may not be a signicant dierence between TCAs and SSRIs. The
study population was composed of patients registered in a large number of clinical trials for depression and anxiety disorders but not for bipolar
disorders. Given the large number of patients,
however, one may assume that a certain proportion of subjects were unrecognized patients with
bipolar disorder.
Leon et al. (75) longitudinally followed a cohort
of 757 patients for up to 27 years in naturalistic
treatment settings and compared times when
patients were exposed to antidepressants to when
they were not on antidepressants. Treatment was
associated with a 20% risk reduction for suicide
attempts and death by suicide. The population
under study, however, consisted primarily of
patients with unipolar depression (77.7%), and the
issue of bipolarity was not addressed.
Suicide and suicidal behaviors are complex phenomena and have multiple determinants: some
genetic, some environmental and some related to
the nature of the illness and its dierent phases.
Severity, which is often dicult to dene, is
another factor. Suicidality is also impacted by comorbid conditions including alcoholism, drug
addiction, anxiety disorders, and psychotic disorders, all of which are independent risks factors for
suicidality. Under those conditions, it is a challenge to gure out if antidepressant use in patients
with bipolar disorder increases, decreases, or has
no eects on suicidal behavior. The methodological hurdles do not appear to have been resolved.
As McElroy et al. (68) indicated, in four out of ve
studies that demonstrated increased suicidality
with antidepressants, the ndings could potentially
be explained by the fact that higher suicidal risk
may actually have led to the choice of an antidepressant rather than the reverse. Similar conclusions have recently been reached in studies of
unipolar patients (76).
Most of the available data thus point to the possibility of heightened risk of suicidal behavior in
antidepressant-exposed patients with bipolar disorder. The discrepancies between the suicide-promoting and suicide-preventing data in bipolar disorder
highlight the complexity of the issue. Finer suicide
monitoring tools and predictors of treatmentemergent suicidality are needed. Some patients
with bipolar disorder need antidepressants, do well
on them, and never become suicidal. Other patients
with bipolar disorder may be activated by the use

602

of antidepressants and become suicidal within a


short period of treatment. Such increased risk may
be mediated by mixed states, agitated dysphoria or
increased aggressivity presumably induced by the
antidepressants. How does one distinguish between
those that do well and those that become more suicidal? General suicide risk considerations are not
very useful for the individual patient. Therefore, it
is dicult to predict which patients, especially
which newly diagnosed patients, should not be
given antidepressants. Although caution should be
exercised with antidepressants in this patient
group, at this time, with adequate safeguards
including thoughtful assessments, careful monitoring and follow-up, there may be a place for antidepressants in the treatment of bipolar disorder,
particularly bipolar depression.
Lithium

To date, lithium is the only medication convincingly shown to reduce suicidal risk in bipolar disorder (Table 2). Earlier randomized controlled
studies (7783) provided support for the conclusion that lithium is eective in reducing suicide
attempts and completed suicides. A recent randomized placebo-controlled study by Lauterbach
et al. (84) indicated that adjunctive lithium treatment, although not associated with a reduction in
suicide attempts, may be eective in reducing completed suicides in adult aectively ill patients. Previous reviews have shown a dramatic reduction of
suicide risk with long-term lithium use (1, 8587),
with the most recent meta-analysis (10) indicating
that lithium reduces suicide risk by a factor of
about ve compared to no treatment. Another
review of 32 controlled trials also found a 4- to
5-fold reduction in the risk of both completed suicide and deliberate non-fatal self harm events in
patients receiving lithium, compared to those
receiving either placebo or other active treatment
(88).
Not all studies, however, have found lithium to
have anti-suicidal properties. The established role
of lithium in suicide prevention is probably applicable only in chronic lithium treatment (89). A
shorter term treatment eect is a possibility that
deserves study. In the rst year of lithium treatment, mortality rates are still 12 times that of the
general population. By about two years of
treatment, the rates of suicide attempts, although
still higher, are no longer statistically dierent
from that of the general population. Clinicians
must be cautious in using lithium for acute antisuicidal eect. In a recent analysis of completed
suicide in a large group of former psychiatric inpa-

Double-blind,
randomized,
parallelgroup study

Randomized
prospective
trial

RCT

RCT

ThiesFlechtner
et al.
1996 (93)

Bowden
et al.
2000 (48)

Lauterbach
et al.
2008 (84)

Design

Oquendo
et al.
2011 (106)

Study

Adult
outpatient
recently
recovered
from mania
Adults with
recent SA

Adult
outpatients

Adult
inpatients
and
outpatients

Population
studied

Table 2. Lithium and other mood stabilizers

Depressive
spectrum

BD-I

Major affective
disorders
including BD
and SZA

BD-I, BD-II,
BD-NOS in
a depressive
or mixed
episode with
at least one
past SA

Diagnosis/
subtype

Li versus PBO
as adjunct

Total N = 167
Li = 84
PBO = 83
MDD = 76%

DVPX versus
Li versus
PBO

Li versus
CBZ
versus
amitriptyline

VAL versus
Li

Treatment

372

378

98

1 year

12 months

2.5 years

2.5 years

Study/
treatment
duration

SA, SC

SA

SC, time
to SA,
time to
suicide
event,
i.e., SI
with a
plan
requiring
a change
in
treatment
SA, SC

Suicide
type

Post-hoc analysis
revealed a
significant
protective effect of
adjunctive Li
against completed
suicide

Adjusted HR: 0.517


(CI: 0.1861.438)
p = 0.206

All suicide events


incidence rate/
patient-year:
Li: 12.7%,
PBO: 21.7%

No difference in Li
versus DVPX SA
rates

All suicidal events:


9 SC and 5 SA
occurred in the
CBZ group; none
in the Li group

Few BD patients in this


cohort
High dropout rate

Study not designed with


suicidality as an
end point

Study design is a strength

Currently, the best


possible study design
but small size precludes
detection of small
differences

No SC in either group
No differences
between VAL and
Li groups in time
to SA or suicide
event

Comments

Results

Psychotropic drugs and suicidal risk in bipolar disorders

603

604

Meta-analysis
of 199 RCT
of 11 AEDs

Meta-analysis
of 13 PBOcontrolled
RCTs

Retrospective
chart
analysis

Retrospective
chart review

Retrospective
chart review

Redden
et al.
2011 (105)

Yerevanian
et al. 2007
(59)

Ahearn
et al.
2013 (96)

Yerevanian
et al. 2003
(94)

Design

FDA 2008
(97)

Study

Table 2. (Continued)

Adult
outpatients

Inpatient and
outpatient
Veterans

Adult veterans

9/13 studies
were
psychiatrica

Varied
population

Population
studied

BD-I, BD-II,
BD-NOS,
SZA

BD-I, BD-II

BD-I, BD-II,
BD-NOS,
SZA

25% epilepsy,
27%
psychiatric,
and the
remainder
other
groups
Epilepsy, BD,
migraine
prophylaxis,
impulsive
aggression
and
dementia

Diagnosis/
subtype

140

1307

405

DVPX = 1327
PBO = 992

Li versus
DVPX
versus CBZ

Li
Li + DVPX
DVPX
DVPX + AP
CBZ
CBZ + AP
MS
MS + AP

Li versus
DVPX
versus CBZ

DVPX
versus PBO

Total N = 2319

Drug = 27863
PBO = 16029

Comparing
all AEDs
versus PBO

Treatment

Total N = 43892

Average
time taking:
Li: 29.6
months
DVPX:
24 months
AP: 18.7
months
23 years,
minimum
treatment
duration
= 6 months

3 years with
minimum
6-month
treatment
duration
6-year review

68 days
for DVPX

352 weeks,
mean
duration
= 13 weeks

Short-term
clinical
trials

Study/
treatment
duration

SA, hospitalization for


suicidality

SA

SA,
hospitalization for
suicidality

Suicide
events
using
C-CASA

SI, SA, SC,


preparatory
acts

Suicide
type

No significant
differences among
the three groups

Overall estimated
OR of suicidal
behavior or SI was
0.72% (95%
CI: 0.291.84)
No difference in
non-fatal suicide
events among Li,
DVPX, and CBZ
groups
Lowest SA rate was
for Li + DVPX
(6.3 attempts per
10000 months of
exposure),
followed by
DVPX (7.0/10000),
then Li (7.7/10000)

Across diagnostic
categories, DVPX
does not appear
to increase risk of
suicide-related
events relative to
PBO

Adjusted risk
estimate for
suicidal was 0.43%
for drug group
versus 0.24% of
PBO

Results

Discontinuation of all
three MSs led to
increase in suicidal risk

In a 6 year study, most


SAs occurred during
off medication periods
(mean duration
45 months)

Confounding by indication
not resolved

Being off any of the three


MSs was associated with
an increase in suicidal
risk

None of the DVPX


studies were designed
with suicidality as an
outcome measure

In the psychiatric group,


the OR was 0.65 for
CBZ and 0.72 for DVPX,
with very wide CIs
containing 1
Only 6 of 13 studies
pertained to BD
populations

No BD group

Comments

Yerevanian and Choi

Goodwin
et al.
2003 (91)

Snderg
ard
et al. 2008
(104)

Arana et al.
2010 (103)

Study

Retrospective
cohort study

Pharmacy
purchase
data and
linkage data
from Danish
National
Register

Observational
cohort study
with case
control

Design

Table 2. (Continued)

HMO health
plan
members
14 years of
age

BD inpatients
and
outpatients
discharged
from
psychiatric
hospital

The Health
Improvement
Network
database
representative
of UK general
population

Population
studied

BD with at
least 2
prescriptions
for Li, DVPX,
or CBZ

BD

With or
without
epilepsy or
depression
or BD, with
and without
AEDs

Diagnosis/
subtype

20638
health
plan
members

BD without
AEDs = 3814
BD on
AEDs = 1809
5926

CBZ
GBPN
Lamotrigine
Levetiracetam
Oxcarbazepine

Total
N = 5130795
patients with
31527585
patientyears of
follow-up

DVPX
versus Li
versus CBZ

Li, AEDs

Pregabalin
Tiagabine
Topiramate
Palproate
Zonisamide

Treatment

7 years

5 years,
treatment
duration
assessed
by
pharmacy
purchases

~20 years

Study/
treatment
duration

SA, SC

SC

Suiciderelated
events

Suicide
type

SC rate was higher


during AED
periods than Li
periods
Rate of SC
decreased with no.
of additional
prescriptions
Switch or
augmentations
significantly
reduced suicide
rate (rate ratio = 0.28,
95% CI: 0.200.40)
SC adjusted risk was
2.7 times higher and
SA adjusted risk was
1.7 times higher for
DVPX than Li

In the adjusted
analyses, AEDs
were not
associated with
increased risk of
suicide-related
events in the BD
group (1.13; 95%
CI: 0.353.61)

Results

Large study but


confounding issues
not resolved

No. of prescriptions may


not reflect actual
treatment
Confounding variables
not resolved

Study partially controlled


confounding factors
but excluded patients
with past suicide-related
events

Comments

Psychotropic drugs and suicidal risk in bipolar disorders

605

606

Medical claims
database

Retrospective
pharmacoepidemiologic
study

Gibbons
et al.
2010 (102)

BD, MDD, SZ,


other
psychiatric
groups,
epilepsy,
pain
disorders

BD

BD
unspecified,
on
medication

Diagnosis/
subtype

Li MONO
AED MONO

GBPN before
and after
index episode

131,178

DVPX: 33%
GBPN: 32%
Li: 25%
CBZ: 3%

Treatment

47918

12662

At least
1 year
information
before and
while
taking
GBPN

At least
1 year
information
before and
after index
episode of
illness

5 years

Study/
treatment
duration

SA

SA

ER visits
for SA
and SC

Suicide
type

For SC, the adjusted


HRs were:
1.5 for DVPX (ns)
2.6 for GBPN
(p < 0.001)
CBZ: not available
SA rates were the
same for Li and
AEDs
Before and after
AEDs, SA rates
dropped from 72
to 13 per 1000
patient-years
No significant
difference in overall
SA rates before
versus after GBPN
but there were
significant
reductions in SA
rates seen for BDs
(47.85/1000 personyears versus 31.46/
1000 person-years)
as well as in the
MDD and other
psychiatric groups

Adjusted HR versus
Li users for SA were:
2.7 for DVPX
(p < 0.001)
1.6 for GBPN (ns)
2.8 for CBZ (ns)

Results

Limitations included use


of medical claims data
not clinical interviews,
possible underreporting of SAs and
no SC information

Study strengths were


MONO groups with
before and after index
episode data
Confounding issues
were not resolved

The differential effect of


AEDs on SA and SC, if
confirmed, is
heuristically important

Comments

AED = antiepileptic; AP = antipsychotic; BD = bipolar disorder; BD-I = bipolar I disorder; BD-II = bipolar II disorder; BD-NOS = bipolar disorder; not otherwise specified; CBZ = carbamazepine; C-CASA = Columbia Classification Algorithm of Suicide Assessment; CI = confidence interval; DVPX = divalproex; ER = emergency room; GBPN = gabapentin; HMO = health maintenance organization; HR = hazard ratio; Li = lithium; MDD = major depressive disorder; MONO = monotherapy; MS = mood stabilizer; ns = non-significant; OR = odds ratio;
PBO = placebo; RCT = randomized controlled trial; SA = suicide attempt; SC = suicide completed; SI = suicidal ideation; SZ = schizophrenia; SZA = schizoaffective; VAL = valproate.
a
Acute mania, mania maintenance, bipolar depression, dementia, and impulsive aggression.

Medical claims
database

Retrospective
pharmacoepidemiologic
study

Gibbons
et al.
2009 (101)

Medicaid claim
database of
adults

Retrospective
analysis

Design

Population
studied

Collins and
McFarland
2008 (100)

Study

Table 2. (Continued)

Yerevanian and Choi

Psychotropic drugs and suicidal risk in bipolar disorders


tients (96 suicides in 4441 hospitalized patients),
Sani et al. (90) found that longer term treatments
with lithium and anticonvulsants were associated
with decreased risk of completed suicide compared
to shorter term treatments which they assessed as
positively predicting completed suicide. This nding should alert clinicians not to rely on lithium or
anticonvulsants in the short-term management and
prevention of suicidal behavior, particularly in a
bipolar population.
Anticonvulsants

Over the past decade, the use of lithium in the


treatment of bipolar disorder has declined and the
use of anticonvulsants (Table 2), particularly
divalproex, has steadily increased and they have
become more commonly prescribed than lithium
(91, 92).
Among the many AEDs, only ve have FDA
approval for psychiatric conditions. Yet many
more are used o-label, sometimes despite credible
data with negative results. The use of gabapentin
and topiramate for bipolar disorder may be two
such examples. One randomized prospective study
(93) of 378 patients with major aective disorders
found that carbamazepine was associated with
more suicidal events than lithium.
In another 12-month controlled clinical trial
comparing lithium, divalproex, and placebo in 372
patients meeting criteria for recovery from a recent
manic episode, no signicant dierence was found
in the rate of suicide attempts between lithium and
divalproex (48). The study was not designed with
suicidal risk as a variable of study.
The rst formal study to address the question
of the role of anticonvulsants in suicide prevention in bipolar disorder did not nd a signicant
dierence among lithium, divalproex and carbamazepine in suicide attempts and hospitalizations
for suicidal intent (94). Furthermore, a potential
protective role was implied for all three mood
stabilizers by the fact that discontinuation of any
of them resulted in signicantly heightened risk
for suicidal behavior. The study was retrospective
and the results were limited to non-fatal suicidal
behaviors. In a subsequent retrospective monthby-month analysis of the records of 405 veterans
(95), Yerevanian et al. compared the rates of
non-lethal suicide behavior on and o lithium,
divalproex and carbamazepine. For all three
mood stabilizers and for the total group of mood
stabilizers versus no treatment, there were highly
signicant dierences in the rates of non-lethal
suicidal behavior, favoring lithium [v2 = 20.90
(df = 1), p < 0.001], divalproex [v2 = 21.38

(df = 1), p < 0.0001], and carbamazepine (v2 =


3.63 (df = 1), p = 0.057] as well as mood stabilizers as a group [v2 = 13.95 (df = 1), p < 0.0002].
These results suggest that all three mood stabilizers have a protective eect against non-lethal suicide attempts.
In a retrospective chart review analysis of 1306
veterans with bipolar disorder from ve VA Medical Centers, Ahearn et al. (96) found that the lowest suicide attempt rate occurred with lithium and
divalproex combination (6.3 attempts per
10000 months of exposure), followed by divalproex alone (7/10000), then lithium alone (7.7/
10000). The authors interpreted their ndings as
suggesting that lithium and divalproex protected
against suicide attempts. Most of the suicide
attempts occurred during periods o medications.
In a large retrospective study of patients with
bipolar disorder from two Health Maintenance
Organization (HMO) databases, Goodwin et al.
(91) found that the adjusted risk of death by suicide was 2.7 times higher in the divalproex group
compared to the lithium group. The corresponding
RR for non-fatal suicide attempts was 1.7. Furthermore, suicide risk without treatment was
0.116% per year, about nine times the base rate for
that population of 0.012% per year. This study
also suggests that lithium has protective eects
superior to divalproex.
In 2005, the FDA requested suicidality data
from randomized placebo-controlled clinical trials
of 11 AEDs from their sponsors and conducted a
meta-analysis of 199 such studies. Published in
2008 (97), the results were as follows: the adjusted
risk estimate for suicidal behavior or ideation was
0.43% for drug patients and 0.24% for placebo
patients. Of the total 104 events in this meta-analysis, 67 were suicidal ideation, 30 were attempts,
three were preparatory acts, and four were completed suicides. The FDA analyzed the data using
three indication categories: Epilepsy (25%), Psychiatric (27%), and a Large Group of Other Conditions. This report, however, did not specically
identify a bipolar disorder group. Although the
majority of reported events were suicidal ideation,
it is noteworthy that the more serious events were
more likely in the AED group compared with placebo, with an OR of 2.92 (95% CI: 1.476.47). Suicidal ideation events had an OR of 1.45 (95% CI:
0.932.30), suggesting no signicant dierence
between treatment and placebo groups. In assessing the overall risk in the psychiatric group, the
OR was 1.51 but the CI was 0.952.45. Interestingly, among the 11 drugs studied, only carbamazepine and divalproex, the most commonly used
antiepileptics for bipolar disorder, had ORs below

607

Yerevanian and Choi


1, 0.65 and 0.72, respectively, with very wide CIs
containing 1.
In January 2008, the FDA issued a warning to
health care professionals regarding an increased
risk of suicidality with AEDs. In the epileptic population, the risks associated with not using or stopping AEDs may outweigh the risk of suicide given
the potential deaths due to and associated with epilepsy (98). Conclusions about the eects of AEDs
in psychiatric, especially bipolar, populations were
not possible from the FDA study data. In 2013, an
ad hoc task force of the Commission on Neuropsychobiology of the International League Against
Epilepsy (99) issued an expert consensus statement
regarding AEDs and suicidality in light of the
FDA alert. Noting the subsequent number of studies with contradictory results, the group found it
impossible to determine whether AEDs are associated with suicidal behavior. They concluded that
some AEDs can be associated with psychiatric
problems that can lead to suicidal ideation and
behavior but the actual suicidal risk was not established and seemed very low.
In a large Oregon Medicaid claim database of
12662 patients with bipolar disorder, Collins et al.
(100) compared lithium to gabapentin, divalproex,
and carbamazepine with respect to suicide completions and suicide attempts. Divalproex was the
most common mood stabilizer (used by 33% of
subjects) followed by gabapentin (32%), lithium
(25%), and carbamazepine (3%). There were 11
suicide deaths and 79 attempts. Adjusted hazard
ratios versus lithium users for suicide attempts
were 2.7 for divalproex users (p < 0.001), 1.6 for
gabapentin users (not signicant), and 2.8 for carbamazepine users (not signicant). For suicide
deaths, the adjusted hazard ratios were 1.5 for
divalproex users (not signicant), 2.6 for gabapentin users (p < 0.001), and not available for carbamazepine users. For suicide completion,
divalproex fared about as well as lithium but lithium appeared to be more protective against suicide
attempts. Despite the large number of patients
with bipolar disorder, the study had its limitations,
including reliance on automated pharmacy record
data and possibly a brief duration of mood stabilizer use. Short-term comparisons are a major issue
in such studies, since even lithium, the gold standard of pharmacologic suicide prevention, requires
at least a year or two of treatment before its full
benets in suicide prevention become clear (89).
Gibbons et al. (101), in a pharmaco-epidemiological study of bipolar disorder patients in a large
medical claims database, compared the rates of suicide attempts associated with AEDs versus lithium
monotherapy. Suicide attempt rates were com-

608

pared before and after treatment and with a medication-free control group. The study included
47918 patients with bipolar disorder, for whom
there was a minimum of one year of information
both prior to and after the index episode of illness.
There was no dierence in the rate of suicide
attempts between those treated with AEDs and
lithium. Those, however, who were currently on
AEDs had a signicantly higher rate of suicide
attempts prior to the initiation of the AEDs (72
versus 13 per 1000 patient-years before and after
treatment initiation, respectively). Under monotherapy conditions, AEDs were protective against
suicide attempts when compared to the no-treatment group, with a suicide attempt rate of 3 versus
15 per 1000 patient-years, respectively. The major
strengths of this study were its large number of
patients with bipolar disorder, the discrimination,
importantly between monotherapy and treatment
with concomitant medications, and the before and
after treatment design. The study, however, was
retrospective and non-randomized, and did not
address the perennial problem of confounding by
indication. It also suered from the limitations of
medical claims-based diagnoses and data.
In a subsequent report, using the same PharMetrics medical claims database, Gibbons et al. (102)
found that gabapentin use in non-psychiatric populations did not increase suicide attempts. There
was, however, a signicant reduction in suicide
attempt rates in patients with bipolar disorder treated with gabapentin as compared to rates before
treatment. Similar reductions were noted in other
psychiatric groups, including those with MDD.
In a large observational cohort study with
n = 5130795, Arana et al. (103) found that among
the bipolar disorder group (n = 5623) AEDs were
not associated with an increased risk for suiciderelated events (1.13; 95% CI: 0.353.61) when
compared to the group without AEDs.
Snderg
ard et al. (104), using linkage data from
Danish national registers, examined the association between continued use of lithium and anticonvulsants and the risk of suicide. The treatment and
continued use were assessed using pharmacy purchase data as an indicator of continued use.
Although the rates of completed suicide were
higher during continued purchase of anticonvulsants compared to continued purchase of lithium,
for both groups over time the risk of suicide diminished compared to the group that purchased a prescription only once (rate ratio for lithium = 0.20,
95% CI: 0.100.38 and for AEDs = 0.25, 95% CI:
0.190.41). Their conclusion was that, although
lithium may be somewhat superior to AEDs in preventing completed suicide, both groups benet

Psychotropic drugs and suicidal risk in bipolar disorders


from continuous treatment. The explanations for
this are complex, including the possibility that the
treatment process itself, rather than the specic
treatment agent, is important in preventing suicidality. One could also argue that, in the longer
term, the less sick survive and hence the suicidality
rates diminish by virtue of that factor, independent
of treatment modality. In addition, the assumption
of treatment use from pharmacy purchase data has
its own limitations.
A recent meta-analysis of the relationship
between divalproex treatment and suicidality (105)
examined 13 placebo-controlled studies and one
low-dose controlled study of divalproex in a mixed
population including those with bipolar disorders,
epilepsy, migraine, impulsive aggression, and
dementia. No increased risk for suicide attempt or
suicidal ideation compared to the placebo controls
was found in AED-treated subjects; the overall OR
was 0.72 (95% CI: 0.291.84) and not signicant.
There were no completed suicides in the analyzed
studies.
In the rst randomized clinical trial comparing
lithium and valproate explicitly designed to test for
the prevention of suicidal behavior, Oquendo et al.
(106) followed 98 patients with bipolar disorder
with past suicide attempts for 2.5 years. Patients
were randomized to lithium or valproate. There
were no suicides in either group. Other suicide
events were not dierent between the groups,
although the small sample size did not allow detection of small dierences between the two groups.
The study highlights the feasibility of conducting
prospective randomized controlled trials with suicide as the study outcome when the treatment arms
consist of medications with similar ecacies.
We found no studies specically examining the
role of lamotrigine and topiramate in patients with
bipolar disorder. The role of lamotrigine is particularly important since it has gained wide usage in
bipolar disorder. In a recent review of ve randomized trials of lamotrigine for bipolar depression, suicidality was not addressed (107).
Antipsychotics

Antipsychotics are commonly used in bipolar disorders (Table 3). In recent years, second-generation (atypical) antipsychotics are becoming
favored over rst-generation, conventional (typical) agents (108). These agents are also replacing
traditional mood stabilizers such as lithium,
divalproex and carbamazepine. One recent study
in a Medicaid population showed a trend toward
less frequent use of mood stabilizer monotherapy
and more frequent use of antipsychotic monother-

apy in patients with bipolar disorder during the


period 20012004 (109).
The FDA has approved several atypical antipsychotics for the treatment of bipolar disorder in various phases. More recently, this class of drugs has
been used for the treatment of bipolar depression
(110). Quetiapine and olanzapineuoxetine combination have been approved for the treatment of
acute bipolar depression. Aripiprazole and olanzapine have been approved for maintenance treatment. There is, however, little known about the
impact of this group of medications on suicidal
behavior.
Clozapine reduces suicide attempts and hospitalizations for suicidality in schizophrenia and schizoaective disorder and it outperforms olanzapine in
this regard (111). Meltzer et al. (112) conducted a
multicenter randomized control trial comparing
olanzapine to clozapine in a group of schizophrenic and schizoaective patients at risk for suicide. In this two-year study with 980 patients,
clozapine was more helpful than olanzapine in
reducing suicidal behavior (hazard ratio = 0.76,
95% CI: 0.580.97, p = 0.03). There were ve completed suicides in the clozapine group and three in
the olanzapine group (p = 0.73). There was no
bipolar group in this study. The Hennen and
Baldessarini meta-analysis found that, with longterm treatment with clozapine, the overall RR of
clozapine compared to other treatments was 3.3
times lower. The six studies reviewed, however, did
not include patients with bipolar disorder.
In a Swiss retrospective study (113), 94 inpatients continuously maintained on clozapine for a
mean duration of 15 months were compared with
a similar number in the pre-clozapine period. The
group maintained on clozapine had a signicantly
lower rate of suicidal behavior, including serious
suicidal behavior, compared to the pre-clozapine
group in a follow-up period of equal duration (3%
versus 28%, respectively). The ORs were 11.6
(95% CI: 3.439.9) and 12.3 (95% CI: 1.697.5)
for suicidal and serious suicidal behaviors, respectively. Clozapine is the rst treatment, with FDA
approval in 2003, for reduction of recurrent suicidal behavior in schizophrenia or schizoaective
disorders.
Two cohort studies using national data sources
in Finland reported the risk of suicide while taking
atypical antipsychotics (114, 115). The results of
the rst study (114) support a role for clozapine in
suicide prevention in schizophrenia but not for risperidone, quetiapine, or olanzapine, which did not
have suicide-preventive eects. The second study
(115), in a smaller cohort, could not demonstrate a
benecial eect of clozapine.

609

610

Fixed dose,
DB, PBOcontrolled
RCT

Multicenter,
RCT

Post hoc
analysis
of data
from a
DB RCT

Metaanalysis

Meltzer et al.
2003 (112)

Houston et al.
2006 (118)

Hennen and
Baldessarini
2005 (111)

Design

Calabrese
et al. 2005
(117)

Study

Table 3. Antipsychotics

Psychotic
patients
treated with
CLZ
consistently
for 12 months
versus other
agents

Inpatients

Men and
women
considered
high risk for
committing
suicide at 67
medical
centers in
11 countries

Outpatients
at 39 US
centers

Population
studied

DSM-IV BD-I
manic or
mixed
episode
patients who
were partially
responsive
to at least
2 weeks of
Li MONO or
DVPX MONO
SZ or SZA
(DSM-III-R
or -IV)

BD-I or
BD-II
experiencing
MDE by
DSM-IV
criteria
SZ, SZA

Diagnosis/
subtype

240564
cases in
6 studies

58

980

BD-I = 360
BD-II = 182

Total N = 542

OLZ versus
CLZ,
Before
and on
CLZ,
CLZ
versus
other AP
agents

PBO or
OLZ
added to
Li or
DVPX

QUET
300 mg
or
600 mg
versus
PBO
OLZ
CLZ

Treatment

104796
personyears of
exposure to
CLZ and
447281
personyears with
other
treatments

8 weeks

2 years

8 weeks

Study/
treatment
duration

1 study: SA
4 studies: SC
1 study:
SA/SC
pooled data

HDRS-3
SI rating

SA, required
hospitalization,
or rescue
intervention
to prevent
suicide

SI measured
by MADRAS
subscale

Suicide
type

SC: RR = 2.9, 95%


CI: 1.55.7,
p = 0.002

Lower overall risk


of suicidal
behaviors with
CLZ versus other
treatments
(RR = 3.3,
95% CI: 1.76.3,
p < 0.0001)

CLZ group
required fewer
hospitalizations,
rescue
interventions
No OLZ effect on
suicidality score

Suicidal behavior
of CLZ less than
of OLZ (HR = 0.76,
95% CI: 0.58-0.97,
p = 0.03)

SI decreased with
both doses

Results

The only RCT did


not find reduced
risk of completed
suicide

No BD group

Post hoc and small


study
No actual suicidal
events
Suicidality was not
an end point of the
study

Patients who
posed a current
serious suicidal
or homicidal risk
were also
excluded
No BD group

Comments

Yerevanian and Choi

Veterans,
inpatient
and
outpatient

Retrospective
chart review
with monthly
analysis of
the record

Yerevanian
et al. 2007
(120)

DSM-IV
acutely manic
BD inpatients
with a history
of poor or
partial
adherence to
medication
BD-I, BD-II,
BD-NOS,
SZA

Inpatients
and
outpatients

Prospective,
mirror
design
observational
study

Acute bipolar
depression

Manic/mixed
episodes

Diagnosis/
subtype

BD-I, BD-II,
BD-NOS

Multi-center,
inpatients
and
outpatients

Population
studied

First 1000
patients
enrolled in
STEP-BD

Vieta et al.
2008 (122)

Goldberg
et al. 2005
(61)

Metaanalysis
of all
available
DB RCTs
with
placebo
or a
comparator
on the
efficacy of
ARI in BD
Crosssectional
review

Design

Fountoulakis
et al. 2011
(123)

Study

Table 3. (Continued)

405

Li
Li + AP
DVPX
DVPX + AP
CBZ
CBZ + AP
MS
MS + AP

Naturalistic
treatment for
a manic
episode and
long-acting,
injectable RIS

29

BD-I = 710
BD-II = 239
BDNOS = 41
SZA = 7
Cyclothymic
=3

85% taking
psychotropics
in various
combinations

ARI versus
PBO

Treatment

Total N = 1000

2303

Up to 8 years

Mean period
of 2 years

Crosssectional
(medications
at time of
intake)

2674
weeks for
maintenance
study

312 weeks
for acute
studies

Study/
treatment
duration

SC, SA,
hospitalization
for suicidal
intent

SA

SI using
the ADE

SA, SC

Suicide
type

Non-lethal suicide
event rates were
9.4 times higher
during AP MONO;
3.5 times greater
during MS +
AP than during
MS MONO

SI was
significantly more
prevalent for
those taking SGA
than those who
were not (26%
versus 17%)
No significant
reduction in SA
found in RIS
group

SI similar to those
taking or not
taking either Li or
DVPX

1 unpublished
study had at
least 1,
maximum 3
SAs on ARI and
none on PBO

1 study had 1 SA

No SC

Results

Retrospective
study with
confounding by
indication

Small
underpowered
study

Confounding by
indication and
design issue

Study not
designed with
suicide risk
outcome

Suicide rates were


not reported in
acute depression,
and were
negligible for all
groups in mania

Comments

Psychotropic drugs and suicidal risk in bipolar disorders

611

612

Retrospective
chart review

Retrospective
chart review
with mirror
design

Modestin et al.
2005 (113)

Design

Ahearns et al.
2013 (96)

Study

Table 3. (Continued)

BD-I, BD-II

SZ, SZA, and


affective
disorder
using ICD10 criteria

Inpatients
treated
continuously
with CLZ for
at least
6 weeks
between
1962 and
1994

Diagnosis/
subtype

Veterans,
inpatient
and
outpatient

Population
studied

Total
N = 94
SZ = 75
SZA = 14
Affective
disorder = 5

1307

Pre- and postCLZ periods


with and
without
antidepressants
and typical
neuroleptics

Li
Li + DVPX
DVPX
DVPX + AP
CBZ
CBZ + AP
MS
MS + AP

Treatment

At least
6 weeks with
mean
duration = 15
months of
both preCLZ and
CLA periods

Average
time taking:
Li = 29.6
months
DVPX = 24
months
AP = 18.7
months

6-year review

Study/
treatment
duration

SA, suicidal
threat, SI
(Mottos
grades 24)

SA

Suicide
type

Serious suicidal
behavior:
OR = 12.3,
95% CI: 1.697.5

Suicidal
behavior:
OR = 11.6,
95% CI: 3.439.9

CLZ period
compared with
the pre-CLZ
period:

CLZ period = 3%
(3/94)
Post-CLZ
period = 18%
(3/17)

ORs of drug
exposure versus
no drug exposure:
Li = 1.03, 95%
CI: 0.611.73,
p = 0.934
DVPX = 1.08, 95%
CI: 0.661.68,
p = 0.746
AP = 2.45, 95%
CI: 1.553.86,
p = 0.001)
Rates of suicidal
behavior:
Pre-CLZ
period = 28%
(26/94)

Most SAs on no meds

Atypical AP had
highest SA rate

Results

During CLZ
period, all patients
were continuously
hospitalized unlike
the pre-CLZ
period

No BD group

90% of subjects
averaged
45 months in
6 years off meds
and most of the
SAs were during
off-medication
periods

Confounding by
indication

Comments

Yerevanian and Choi

Retrospective
review of
administrative
data

Pooled analysis
of PBOcontrolled
DB RCTs

Ulcickas Yood
et al. 2010
(124)

Karayal et al.
2011 (125)

Adults with at
least one
prescription
for older
antipsychotics
or SGA from
11-1-02
through
12-31-05
22 trials
included
mixture of
adult and
pediatric trials
in SZ, BD,
and SZA

Israeli
university
affiliated with
a tertiary care
psychiatric
hospital

Population
studied

BD-I, SZ, SZA,


various
dementia,
acute bipolar
mania, tic
disorder

BD, SZ, or both


using ICD-9 /
ICD-10 codes

SZ or SZA
using ICD-10
criteria with
SA prior to
hospitalization

Diagnosis/
subtype

5,123

BD = 17,422
SZ = 2,925
Both = 142

20489 AP
users, 8985
patient-years

SZ = 84.7%
SZA = 15.3%

Total N = 756

ZIP
PBO

ZIP
PBO

CLZ
OLZ
RIS

Treatment

17/22 studies
<6 weeks
5 studies
>40 weeks

3 years

5 years

Study/
treatment
duration

SC, SA, SI,


preparatory
acts (C-CASA)

SA, SC

SA

Suicide
type

In the adult/
pediatric combined
trials, RR = 0.56,
95% CI: 0.035
9.013 compared
to PBO

Adult trials (19/22)


The RR for
suicidality
in the BD trials
was 0.70, 95%
CI: 0.03311.487
compared to PBO

Protective OR:
SGA = 3.54,
95% CI: 2.45.3)
RIS = 3.16,
95% CI: 1.95.3,
p = 0.001
OLZ = 1.76,
95% CI: 1.23.3,
p = 0.02
Compared to other
SGAs, ARI did not
have an increased
risk of suicide events
(crude HR = 0.79,
95% CI: 0.481.30;
adjusted HR = 0.69,
95% CI: 0.421.14)

Of the 378 who had


SA, 16.1% were
exposed to SGA,
37% in control
group (p = 0.00001)

Results

Largely shortterm studies

High comorbidity,
high concurrent
use of other
medications

Few taking CLZ

No BD group

Comments

ADE = Affective Disorders Evaluation; AP = antipsychotic; ARI = aripiprazole; BD = bipolar disorder; BD-I = bipolar I disorder; BD-II = bipolar II disorder; BD-NOS = bipolar disorder; not otherwise specified;
CBZ = carbamazepine; C-CASA = Columbia Classification Algorithm of Suicide Assessment; CI = confidence interval; CLZ = clozapine; DB = double blind; DVPX = divalproex; HDRS = Hamilton Depression Rating
Scale; HR = hazard ratio; ICD = International Statistical Classification of Diseases and Related Health Problems; Li = lithium; MADRS = Montgomery
Asberg Depression Rating Scale; MDE = major depressive episode; MONO = monotherapy; MS = mood stabilizer; OLZ = olanzapine; OR = odds ratio; PBO = placebo; QUET = quetiapine; RCT = randomized controlled trial; RIS = risperidone; RR = risk ratio; SA = suicide
attempt; SC = suicide completed; SGA = second-generation antipsychotic; SI = suicidal ideation; STEP-BD = Systematic Treatment Enhancement Program for Bipolar Disorder; SZ = schizophrenia; SZA = schizoaffective; ZIP = ziprasidone.

Retrospective
casecontrol
study

Design

Barak et al.
2004 (116)

Study

Table 3. (Continued)

Psychotropic drugs and suicidal risk in bipolar disorders

613

Yerevanian and Choi


In a casecontrol study of a large group of schizophrenic and schizoaective patients admitted to a
hospital, Barak et al. (116) reported that patients
who had attempted suicide (n = 378) had a lower
rate of exposure to atypical antipsychotics than a
control group of patients who had not attempted
suicide (16.1% exposure to SGA versus 37% in the
control group, p = 0.0001). This nding suggests
the possibility of a suicide-protective eect, but
does not rule out confounding by indication.
In a short-term randomized controlled trial of
bipolar depression, patients on quetiapine had
greater reductions in suicidal ideation ratings compared to patients on placebo (117).
Among 58 mixed-state patients with bipolar I
disorder, Houston et al. (118) found a greater
reduction in the mean HDRS Item #3 score (119),
12 weeks after the addition of olanzapine to
mood stabilizer compared to placebo added to the
mood stabilizer. In contrast to the above ndings,
Goldberg et al. (61) reported from the STEP-BD
study that, at baseline, suicidal ideation was more
prevalent among patients who were taking a second-generation antipsychotic than among those
who were not (26% versus 17%, respectively).
In a report based on a retrospective review of
records of 405 longitudinally treated veterans,
Yerevanian et al. (120) found that the rate of nonlethal suicidal behavior (attempts and hospitalizations for impending suicidal behavior) was lowest
during mood stabilizer monotherapy (lithium, valproate/divalproex, or carbamazepine), intermediate during therapy with a mood stabilizer in
combination with an antipsychotic, and highest
during antipsychotic monotherapy. There were
3.48 suicide events/100 patient-years on mood stabilizer monotherapy versus 12.29 on a mood stabilizer and an antipsychotic versus 32.8 for
antipsychotic monotherapy. For mood stabilizers
versus mood stabilizers and antipsychotics, for all
suicide events, v2 = 15.13 (p = 0.0001). Comparing
mood stabilizer monotherapy to antipsychotic
monotherapy, there was a more than 9-fold higher
rate of suicide events in the antipsychotic monotherapy group (v2 = 28.29, p < 0.0001). The ndings suggest that antipsychotic monotherapy in
bipolar disorder is associated with a high suicide
risk which may be mitigated by the use of mood
stabilizers, but this study did not resolve confounding by indication. In a subsequent study of a subgroup comprised of 161 patients with bipolar
disorder in the same population who were given
antipsychotics, Koek et al. (121) found that nonlethal suicide events were more common with rstgeneration antipsychotic monotherapy compared
to second-generation antipsychotic monotherapy

614

(9 events/110 months of exposure versus 6 events/


381 months of exposure, v2 = 9.65, p = 0.002).
These dierences between rst- and second-generation antipsychotics disappeared when antipsychotic medications were used in conjunction with a
mood stabilizer. There were no dierences among
risperidone, olanzapine and quetiapine monotherapies with respect to suicidal events. In the Ahearn
et al. study (96) there was a signicantly higher
rate of suicide attempts in bipolar veterans maintained on antipsychotics alone compared to no
therapy (OR = 2.45, 95% CI: 1.553.86,
p = 0.001).
In a long-term prospective study on outcomes for
patients with bipolar disorder maintained on longacting risperidone, Vieta et al. (122) found that risperidone did not signicantly aect the occurrence
of suicide attempts. The number of patients was
small (n = 28) and the study was underpowered
and not designed with specic suicide outcome measures. In a recent meta-analysis of all available randomized controlled trials on the ecacy of
aripiprazole monotherapy in the treatment of bipolar disorder, Fountoulakis et al. (123) found the
suicide rates to be negligible in mania groups treated with aripiprazole, but results in bipolar depression were not reported in the studies reviewed.
In a large post marketing study of aripiprazole,
Ulcickas et al. (124) found that aripiprazole used
for schizophrenia and bipolar disorder was not
associated with increased suicidality compared to a
combined group of other antipsychotics. The
unadjusted rate of suicide attempts plus completion was 2.069 events per 100 patient-years as compared to 2.399 for olanzapine, 3.233 for
quetiapine, 1.969 for risperidone, and 4.852 for
ziprasidone (95).
In a pooled analysis of suicidality in doubleblind placebo randomized controlled trials of
ziprasidone, Karayal et al. (125) did not nd statistically signicant dierences in treatment-emergent
suicidality between ziprasidone and placebo in 22
clinical trials involving 5123 subjects treated either
with placebo or ziprasidone. These were short-term
trials with no pediatric trial (n = 3) longer than
eight weeks and only ve of 19 studies in the adult
populations exceeding ve weeks.
To our knowledge, the published data on the
eects of typical, rst-generation antipsychotics on
suicidal behavior in patients with bipolar disorder
are limited to a single study (121).
Benzodiazepine and hypnotics

An increasing body of literature suggests that


anxiety is an independent risk factor for suicidal

Psychotropic drugs and suicidal risk in bipolar disorders


behavior in patients with major aective disorders.
In a cross-sectional chart review study of 2778 outpatients with various diagnoses, Diefenbach et al.
(126) found that self-reported anxiety symptoms
were associated with a 2-fold increase in the likelihood of reporting suicidality after controlling for
confounding variables such as demographics,
depressive symptoms, and diagnoses. Perlis et al.
(127) in a report from the STEP-BD trials found
that, in a group of 1356 patients with bipolar disorder in remission, those given benzodiazepines were
at higher risk for relapse of mood episodes compared to those without benzodiazepine therapy.
The authors also tried to address whether this association was confounded by indication by performing a parallel analysis of gabapentin that
prescribers may have used as an anxiolytic. Gabapentin was not associated with poorer outcomes.
The issue of suicidal risk with benzodiazepines,
however, was not addressed. It may be possible to
extrapolate that a higher relapse rate may increase
suicidal risk.
In a Swedish study of autopsies of suicide victims (128), toxic serum concentrations of zolpidem
were found in a high proportion of cases. Whether
zolpidem contributed to the suicides or was simply
used as an overdose method is not clear. In another
study, high levels of eszopiclone were found among
suicide attempters (129). These studies, while not
proving causation, should sensitize clinicians to the
possibility of an association.
In a cohort of 120 patients with bipolar disorder
from the STEP-BD study, Simon et al. (130) found
that the presence of a lifetime history of a comorbid anxiety disorder more than doubled the odds
of having a past suicide attempt. Furthermore,
patients with current anxiety disorders had more
than double the odds of current suicidal ideation
compared to patients with bipolar disorder without
such comorbidity. Patients with bipolar disorder
with current anxiety disorders had more severe suicidal ideation and a higher expectancy of future
suicidal behaviors. The authors did caution, however, that some of this increase might reect
greater severity of the bipolar disorder.
One diculty in assessing the contribution of
these drugs to increased suicidality is that insomnia
can be an independent risk factor for suicidality in
bipolar disorder (131). Brower et al. (132) performed a secondary analysis of the National Comorbidity Survey Replication Data for 5692
respondents and found that users of zolpidem or
zaleplon were 5.7, 7.6, and 9.3 times more likely
than non-users to report suicidal thoughts, plans
and attempts, respectively. After adjusting for sex,
age, race/ethnicity, marital and poverty status, 11

lifetime physical conditions, mental health disorders in the past 12 months and insomnia, they
found the adjusted ratios to be 2.2, 1.9, and 3.4 for
suicidal thoughts, plans and attempts, respectively
(all p-values <0.01).
Conclusions

(i) Some psychotropic drugs (notably lithium)


appear to protect against suicidal behavior,
some (probably antidepressants) promote it,
and others appear to do neither. For most psychotropic drugs, however, there are insucient
data to make informed clinical judgments.
(ii) The eect of these psychotropic drugs may be
observed in the short term or may be observed
only after long-term use. In general, increasing
suicidality occurs rather early in treatment,
such as with antidepressants, while prevention
of suicidality usually requires long-term treatment, such as with lithium.
(iii) There are some predictors of treatment-emergent suicidality, including treatment-emergent
agitation, anger, insomnia, prolonged dysphoria, and mixed states. It is important to recognize that these predictors of treatmentemergent suicidal risk may be dierent from
the general suicide risk factors for patients
with bipolar disorder, e.g., race, family history, or cocaine abuse, and therefore need to
be anticipated and monitored closely (133).
(iv) Lithium is the best-studied psychotropic drug
with respect to suicide prevention in bipolar
disorders. The mechanism of this anti-suicidal
eect is unclear, but the frequent visits and
monitoring of patients on lithium with associated psychosocial support and attention may
explain some of the benets. Since not all studies have found anti-suicidal eects for lithium,
it is important to investigate the characteristics
of responders versus non-responders.
(v) Available evidence suggests that antidepressant
use in bipolar disorder contributes to rather
than prevents suicidal behavior. With respect to
iatrogenic suicidality, unipolar and bipolar disorders may be very dierent disorders. The eects
of antidepressants on suicidality in unipolar
disorders should not be extrapolated to bipolar
disorders. Antidepressants may be protective in
unipolar disorder and may have the opposite
eect in bipolar disorder. In fact, the de novo
development of suicidality after the introduction of an antidepressant should raise ones
index of suspicion of a bipolar diathesis and
future bipolar course. There is some evidence
for this assertion in children and adolescents

615

Yerevanian and Choi


(134), but whether this is true in at least a subgroup of adult patients with bipolar disorder is
interesting heuristically and practically. One
may posit that antidepressant-induced suicidality may be an external validator and eventually
an endophenotype of bipolar disorder. Despite
the aforementioned cautionary ndings, our
opinion is that there is a place for judicious use
of antidepressants for shorter periods of time in
patients with treatment-resistant bipolar
depression. Perhaps antidepressants can even
be used as maintenance treatment in bipolar disorder with careful follow-up conditions. Akiskal et al. (14) and Rihmer and Gonda (135)
have proposed that the suicide-inducing potential of antidepressants is related to occult bipolarity. If this is the case, clinicians must have a
high index of suspicion for occult bipolarity in
patients presumed to have unipolar depression.
(vi) Despite recent FDA warnings about the
increased suicidal risk with AEDs, most
research literature does not support that association in bipolar populations. In the FDA
meta-analysis, the most commonly used
AEDs in bipolar disorder, namely divalproex
and carbamazepine, did not show a statistically signicant association with suicidal
behavior in the psychiatric group. Divalproex
appears to have some protective eect against
suicidality when compared to no treatment
over the long term. Divalproex does not
appear to acutely induce suicidality. These
ndings are somewhat reassuring, because
many patients with bipolar disorder who do
not take lithium for various reasons are maintained on divalproex. Among patients with
bipolar disorder, the status of other anticonvulsants with respect to suicidal risk is currently unknown.
(vii) The eect of second-generation antipsychotics
with respect to suicidal risk in patients with
bipolar disorder is not clear. There are no randomized controlled trials addressing this issue.
The few available studies have used dierent
methodologies that are not comparable. If we
extrapolate from schizophrenia studies, clozapine appears to have the most promise among
antipsychotics. Clozapine studies are needed
in bipolar disorder. The studies that examined
antipsychotics in pure bipolar populations
(61, 96, 117, 118, 120, 122, 123) had various
ndings: increasing, decreasing and unchanging suicidality associated with antipsychotic
use. These studies, however, had various limitations, including unresolved confounding by
indication.

616

(viii) Vigilance is required when using benzodiazepines and the newer hypnotics since the data
regarding their eects on suicidality in bipolar disorder populations are very limited.
(ix) During polytherapy, a common practice, lithium and some AEDs appear to mitigate the
suicide-promoting eects of antidepressants.
Similarly, they also may mitigate any antipsychotic suicide-associated eects. Few studies
have examined the eects of specic psychotropic drug combinations on suicidality in
bipolar disorder.
Discussion

This broad review of the impact of psychotropic


medications on suicidality in patients with bipolar
disorder highlights the signicant gaps in our
understanding of the complicated relationship
between psychotropic drugs and suicidal behavior.
Suicide is multifactorial. Suicidal ideation may
have a dierent pathogenesis from either suicide
attempt or suicide completion and may respond to
dierent drugs and dierent psychosocial interventions. Understanding the dierential contributions
of biological, social and psychological factors in
the genesis of the various presentations of suicidality is of importance. No studies have adequately
addressed these contextual issues when reporting
the connection between psychotropic drug use and
suicide. Studies of large national and insurance
databases are particularly vulnerable to this limitation, since they rarely address the psychosocial
aspects of suicide in a reliable and meaningful way,
particularly in the absence of clinical information.
Another important limitation in evaluating the
relationship between psychotropic drug use and
suicidal behavior is the lack of adequately powered
randomized controlled trials to assess the relationship of any drug to suicidality. Such studies would
ideally involve explicit standardized and validated
outcome measures determined a priori. Current
study approaches have been multiple: pharmacoepidemiologic studies, clinical case series,
casecontrol studies, and meta-analyses of available literature. Most are retrospective. Few studies
are prospective with suicide as the end point.
Although prospective in nature, industry-sponsored trials are of short duration and not designed
to assess suicide-promoting or suicide-protective
properties of the drugs studied. The most serious
outcomes, completed suicides and serious
attempts, in those studies have been rare events.
Therefore, they have been unhelpful in clarifying
the psychotropic drug and suicidal risk connection.
Designing prospective randomized controlled trials

Psychotropic drugs and suicidal risk in bipolar disorders


with suicide as the primary outcome of the study is
dicult because of practical and ethical constraints.
Another serious limitation in most of the studies
reviewed is confounding by indication. When studies are retrospective, it is dicult to assess whether
a particular psychotropic was prescribed because
the patient was suicidal or decompensating, or the
patient became suicidal after being prescribed that
medication. There is a gap between nding an
association and establishing causation. The available literature is far from closing this gap. The
ideal remedy for this limitation is to conduct large
prospective randomized controlled trials with
monotherapy or specied combinations with
clearly dened suicidal outcome parameters as the
outcome measures.
Complicating matters further is the issue of
polytherapy which appears to be a common treatment choice in all phases of bipolar disorder. By
2007, more than 70% of patients with bipolar disorder were taking two or more psychotropics (40,
136). In 2008, Baldessarini et al. (40) found that,
within one year of initiating treatment for bipolar
disorders, the rate of monotherapy decreased from
67% to 31%. A total of 32% of patients received
polytherapy treatment and 37% of patients
received no psychotropic medications. There are
few polytherapy and xed combination studies in
bipolar disorder populations. Polytherapy creates
diculties in many ways. First, it makes the issue
of confounding by indication more problematic
because typically more medications are prescribed
to sicker patients who may be more prone to suicide. Secondly, in polytherapy the various medications may interact in unpredictable ways with
respect to suicidality. Even if we understand individual drug eects, complex combination eects
are virtually impossible to assess unless such combinations are specically studied.
Although not examined in detail, it is important
to consider two other related issues. One is that
treatment non-adherence is notoriously prevalent
in bipolar disorder (137). The other is the very signicant eect of psychotropic withdrawal, particularly rapid withdrawal, on suicidal risk. Both of
these issues may be missed in research reports that
rely on non-clinical databases. Even in clinical
populations, systematic assessment of treatment
adherence is often not reported. Future studies
must pay careful attention to these issues, especially in smaller studies with infrequent events
where one or two misclassied events can drastically change the statistics.
Prospective, randomized, controlled trials are
necessary to clarify the relationship of suicide risk

and psychotropic drugs, as monotherapy or in


combinations. Studies need to be designed with
specic suicidal behaviors as outcomes. The ethical
and practical hurdles of such potential studies need
to be resolved. It is clinically unwise and scientically untenable to extrapolate from the available
but limited literature of psychotropic drug class
eects to individual or combination drug treatments. Addressing these concerns will be a long
process. In the meantime, clinical vigilance, judicious use of psychotropic drugs, consideration of
all relevant and contextual suicide risk factors,
adequate duration of follow-up and patient
involvement in treatment decision-making should
guide clinical practice.
Disclosures
The authors, or any of their immediate family members, do
not have any potential conicts of interest to report.

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