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BIPOLAR DISORDERS
Review Article
594
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
595
596
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
Affectively ill,
MDD, BD-I, BD-II
BD-I depressed
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
Comments
597
598
Cross-sectional
study
Retrospective
review
Retrospective
review with
prospective
follow-up
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
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
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
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
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
Comments
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
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
602
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
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
No difference in Li
versus DVPX SA
rates
No SC in either group
No differences
between VAL and
Li groups in time
to SA or suicide
event
Comments
Results
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
SA,
hospitalization for
suicidality
Suicide
events
using
C-CASA
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
Confounding by indication
not resolved
No BD group
Comments
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
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
Comments
605
606
Medical claims
database
Retrospective
pharmacoepidemiologic
study
Gibbons
et al.
2010 (102)
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
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
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)
607
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
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-
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
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
No BD group
Patients who
posed a current
serious suicidal
or homicidal risk
were also
excluded
No BD group
Comments
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
Comments
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
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
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)
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
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
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
SA, SC
SA
Suicide
type
In the adult/
pediatric combined
trials, RR = 0.56,
95% CI: 0.035
9.013 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)
Results
High comorbidity,
high concurrent
use of other
medications
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)
613
614
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
615
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
References
1. Baldessarini RJ, Tondo L, Hennen J. Lithium treatment
and suicide risk in major aective disorders: update and
new ndings. J Clin Psychiatry 2003; 64 (Suppl. 5): 44
52.
2. Guze SB, Robins E. Suicide and primary aective disorders. Br J Psychiatry 1970; 117: 437438.
3. Sharma R, Markar HR. Mortality in aective disorder. J
Aect Disord 1994; 31: 9196.
4. Amaddeo F, Biso G, Bonizzato P, Micciolo R, Tansella M. Mortality among patients with psychiatric illness.
A ten-year case register study in an area with a community-based system of care. Br J Psychiatry 1995; 166:
783788.
5. Harris EC, Barraclough B. Suicide as an outcome for
mental disorders. A meta-analysis. Br J Psychiatry 1997;
170: 205228.
6. Inskip HM, Harris EC, Barraclough B. Lifetime risk of
suicide for aective disorder, alcoholism and schizophrenia. Br J Psychiatry 1998; 172: 3537.
7. OLeary D, Paykel E, Todd C, Vardulaki K. Suicide in
primary aective disorders revisited: a systematic review
by treatment era. J Clin Psychiatry 2001; 62: 804811.
8. Ilgen MA, Bohnert AS, Ignacio RV et al. Psychiatric
diagnoses and risk of suicide in veterans. Arch Gen Psychiatry 2010; 67: 11521158.
9. Baldessarini RJ, Pompili M, Tondo L. Suicide in bipolar
disorder: risks and management. CNS Spectr 2006; 11:
465471.
10. Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J. Decreased risk of suicides and
attempts during long-term lithium treatment: a metaanalytic review. Bipolar Disord 2006; 8: 625639.
11. Zalsman G, Braun M, Arendt M et al. A comparison of
the medical lethality of suicide attempts in bipolar and
major depressive disorders. Bipolar Disord 2006; 8: 558
565.
12. Rihmer Z, Benazzi F. Impact on suicidality of the borderline personality traits impulsivity and aective instability. Ann Clin Psychiatry 2010; 22: 121128.
617
618
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65. Kessing LV, Sondergard L, Kvist K, Andersen PK. Suicide risk in patients treated with lithium. Arch Gen Psychiatry 2005; 62: 860866.
66. Post RM, Altshuler LL, Leverich GS et al. Mood switch
in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry 2006;
189: 124131.
67. Vieta E, Martinez-Aran A, Goikolea JM et al. A randomized trial comparing paroxetine and venlafaxine in
the treatment of bipolar depressed patients taking mood
stabilizers. J Clin Psychiatry 2002; 63: 508512.
68. McElroy SL, Kotwal R, Kaneria R, Keck PE Jr. Antidepressants and suicidal behavior in bipolar disorder. Bipolar Disord 2006; 8: 596617.
69. Tiihonen J, Lonnqvist J, Wahlbeck K, Klaukka T, Tanskanen A, Haukka J. Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a
nationwide cohort. Arch Gen Psychiatry 2006; 63: 1358
1367.
70. Rubino A, Roskell N, Tennis P, Mines D, Weich S,
Andrews E. Risk of suicide during treatment with venlafaxine, citalopram, uoxetine, and dothiepin: retrospective cohort study. BMJ 2007; 334: 242.
71. Haykal RF, Akiskal HS. Bupropion as a promising
approach to rapid cycling bipolar II patients. J Clin Psychiatry 1990; 51: 450455.
72. Bauer MS, Wisniewski SR, Marangell LB et al. Are antidepressants associated with new-onset suicidality in
bipolar disorder? A prospective study of participants in
the Systematic Treatment Enhancement Program for
Bipolar Disorder (STEP-BD). J Clin Psychiatry 2006; 67:
4855.
73. Tohen M, Vieta E, Calabrese J et al. Ecacy of olanzapine and olanzapine-uoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;
60: 10791088.
74. Yerevanian BI, Koek RJ, Feusner JD, Hwang S, Mintz
J. Antidepressants and suicidal behaviour in unipolar
depression. Acta Psychiatr Scand 2004; 110: 452458.
75. Leon AC, Solomon DA, Li C et al. Antidepressants and
risks of suicide and suicide attempts: a 27-year observational study. J Clin Psychiatry 2011; 72: 580586.
76. Brent D. Antidepressants and suicidal behavior: cause or
cure? Am J Psychiatry 2007; 164: 989991.
77. Prien RF, Caey EM Jr, Klett CJ. Factors associated
with treatment success in lithium carbonate prophylaxis.
Report of the Veterans Administration and National
Institute of Mental Health collaborative study group.
Arch Gen Psychiatry 1974; 31: 189192.
78. Prien RF, Klett CJ, Caey EM Jr. Lithium prophylaxis
in recurrent aective illness. Am J Psychiatry 1974; 131:
198203.
79. Greil W, Ludwig-Mayerhofer W, Erazo N et al. Comparative ecacy of lithium and amitriptyline in the maintenance treatment of recurrent unipolar depression: a
randomised study. J Aect Disord 1996; 40: 179190.
80. Greil W, Ludwig-Mayerhofer W, Erazo N et al. Lithium
versus carbamazepine in the maintenance treatment of
bipolar disordersa randomised study. J Aect Disord
1997; 43: 151161.
81. Bauer M, Bschor T, Kunz D, Berghofer A, Strohle A,
Muller-Oerlinghausen B. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar
major depression. Am J Psychiatry 2000; 157: 1429
1435.
619
620
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
127. Perlis RH, Ostacher MJ, Miklowitz DJ et al. Benzodiazepine use and risk of recurrence in bipolar disorder: a
STEP-BD report. J Clin Psychiatry 2010; 71: 194200.
128. Jonsson A, Holmgren P, Ahlner J. Fatal intoxications in
a Swedish forensic autopsy material during 19922002.
Forensic Sci Int 2004; 143: 5359.
129. Forrester MB. Eszopiclone ingestions reported to Texas
poison control centers, 2005 2006. Hum Exp Toxicol
2007; 26: 795800.
130. Simon NM, Zalta AK, Otto MW et al. The association
of comorbid anxiety disorders with suicide attempts and
suicidal ideation in outpatients with bipolar disorder. J
Psychiatr Res 2007; 41: 255264.
131. Plante DT, Winkelman JW. Sleep disturbance in bipolar
disorder: therapeutic implications. Am J Psychiatry
2008; 165: 830843.
132. Brower KJ, McCammon RJ, Wojnar M, Ilgen MA,
Wojnar J, Valenstein M. Prescription sleeping pills,
insomnia, and suicidality in the National Comorbidity
Survey Replication. J Clin Psychiatry 2011; 72: 515521.
133. Cassidy F. Risk factors of attempted suicide in bipolar
disorder. Suicide Life Threat Behav 2011; 41: 611.
134. Akiskal HS. Developmental pathways to bipolarity: are
juvenile-onset depressions pre-bipolar? J Am Acad Child
Adolesc Psychiatry 1995; 34: 754763.
135. Rihmer Z, Gonda X. Antidepressant-resistant depression and antidepressant-associated suicidal behaviour:
the role of underlying bipolarity. Depress Res Treat
2011; 2011: 906462.
136. Frye MA, Ketter TA, Leverich GS et al. The increasing
use of polypharmacotherapy for refractory mood disorders: 22 years of study. J Clin Psychiatry 2000; 61: 915.
137. Perlis RH, Ostacher MJ, Miklowitz DJ et al. Clinical
features associated with poor pharmacologic adherence
in bipolar disorder: results from the STEP-BD study. J
Clin Psychiatry 2010; 71: 296303.
621