bdi12098

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Review Article

Impact of psychotropic drugs on suicide andsuicidal behaviors

Yerevanian BI, Choi YM. Impact of psychotropic drugs on suicide andsuicidal behaviors.Bipolar Disord 2013: 15: 594–621. 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 andsuicidal behaviors in bipolar disorders.

Methods: A Medline search of articles published from January 1960 toJanuary 2013 was performed using relevant keywords to identify studiesexamining the relationship of psychotropic drugs to suicidal behaviors.The publications were further reviewed for relevant references andinformation. Additionally, the US Food and Drug AdministrationCenter for Drug Evaluation Research website was searched.

Results: The available studies used differing methodologies, makinginterpretation of the findings difficult. Studies suggest thatantidepressants may increase suicidal risk in bipolar disorder, thispossibly being related to the induction of broadly defined mixed states.There is no evidence that antiepileptic drugs as a class increase suicidalrisk in patients with bipolar disorder. Only lithium provides convincingdata that it reduces the risk of suicide over the long term. There is littleknown regarding the effects of antipsychotics, as well as anti-anxiety and

hypnotic drugs, on suicidal behavior.

Conclusions: The available evidence for the impact of psychotropics onsuicidal risk in patients with bipolar disorder is largely methodologicallyflawed and, except for a few instances, clinically not useful at this point.Adequately powered, prospective randomized controlled studies areneeded to assess the impact of each class of psychotropic and eachpsychotropic as well as common combination therapies. Until suchstudies have been carried out, clinicians are urged to exercise caution inusing these drugs and rely on the traditional means of carefully assessingand monitoring patients with bipolar disorder who are at high risk forsuicide.

Boghos I Yerevaniana,b and YoungMee Choia,b

aDepartment 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: [email protected]

Bipolar disorder ranks highest in terms of suicidalrisk among all psychiatric disorders, with a relativerisk ratio (RR) of completed suicide of about 25compared to the general population (1) and a life-time risk of suicide of between 6 and 15% (1 – 8).Twenty-five to fifty per cent of patients with bipo-lar disorder attempt suicide during their lifetime (9,10). Furthermore, suicide attempts in this group of patients are more lethal, as one in three attemptsends 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-

order tend to be more lethal than those by patientswith major depressive disorder (MDD) (11). Thisincrease in suicidality may be related to the highlevel of impulsivity and irritability in bipolar disor-der (12) as well as factors such as cyclothymic orhyperthymic temperaments (13 – 15).

Untreated bipolar disorder is associated withexcess mortality, including death by suicide as wellas accidents, violence, and medical illness (3).Duration of untreated bipolar illness is associatedwith a higher frequency of suicide attempts and a

higher number of suicide attempters (16). A recent594

Bipolar Disorders 2013: 15: 594–621 Published 2013. This article is a U.S. Governmentwork and is in the public domain in the USA

BIPOLAR DISORDERS

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report from the Systematic Treatment Enhance-ment Program for Bipolar Disorder (STEP-BD)(17) found a suicide rate of 0.014 per 100 person-years among 4360 closely followed patients withbipolar disorder, suggesting that treatment had animportant 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 406hospitalized mood disorder patients, of whommore than half had bipolar disorder, that all treat-ment modalities, including lithium, antidepres-sants, and neuroleptics, were associated withdecreased suicide rates over the long term.

Being suicidal at baseline may predict poordepression treatment outcomes in both bipolardepression and unipolar depression, even whensuicidality rating scores improve (19). Ahrens and

Muller-Oerlinghausen (20) found a reduction insuicide attempts by both responders and non-responders to lithium and suggested that lithiummay decrease suicidal risk independent of its effectson affective episodes. Furthermore, suicidal idea-tion, suicide attempts and suicide completion maybe independent clinical conditions and may onlyhave an indirect relationship to the major affectivedisorders. If that is the case, these suicidal statesmay have distinct treatment responses (21).

The number of psychotropic drugs with regula-tory approval to treat the various phases of bipolardisorder is increasing. Off-label use of psychotropicmedications in bipolar disorder has led to the wide-spread use of medications in all phases of bipolardisorder, often without adequate data regardingsuicide in this high-risk population.

Suicide prevention and avoidance of increasingsuicidal risk should be of primary concern. It can-not be assumed that drugs that are effective in par-ticular phases of bipolar disorders are also effectivein reducing suicidal risk. Medications can poten-tially worsen outcomes, including suicidality. Ear-lier reports that antidepressants were linked tosuicide (22, 23), especially among children and

adolescents (24), have raised concerns about otherpsychotropic medications in adult and pediatricpopulations. All antidepressants currently carryFood and Drug Administration (FDA) black boxwarnings of suicidality as a potential adverse out-come. These warnings were initially for childrenand adolescents, but in 2004 they were extended toadults up to age 25 years. The FDA also requiredmanufacturers of antiepileptic drugs (AEDs) toinclude a warning about increased risk of suicidali-ty in their labeling. Despite approval of clozapineas a drug for reducing suicidal risk among patients

with schizophrenia, the status of all antipsychotic

drugs with respect to suicidal risk in patients withbipolar disorder is currently unclear.

When analyzing the available data pertaining tosuicide risk associated with pharmacological treat-ments used in bipolar disorder, it is important torecognize the different presentations of suicidality,

which include completed suicide, attempted suicideof high and low lethality, hospitalization for sui-cidal ideation with serious intent, and suicidal idea-tion. Different neurobiological processes maymediate these different phenomena. Therefore,psychotropic medications may have different sui-cide risk modifying effects on these presentations.

Improved risk assessment instruments for assess-ing and grading suicidal risk with demonstratedpsychometric and clinical utility are needed. Arecent expert consensus statement (25) on the issueagreed with the FDA’s endorsement of the termi-

nology of the Columbia Classification Algorithmof Suicide Assessment (C-CASA) with the hopethat industry and clinical researchers will useC-CASA compatible instruments in monitoringtreatment-emergent suicidal behaviors. The FDAincreasingly requires such instruments to monitortreatment-associated changes in suicidal ideationand behavior in pre-licensing clinical trials of newdrugs with central nervous system activity. Suchefforts may contribute to the growing understand-ing of the link between biological systems and sui-cidal behavior (26 – 29).

In this paper, we review evidence pertaining towhether a particular class of drug used in the treat-ment of bipolar disorder has a suicide-promoting, asuicide-preventing, or a neutral effect on suicidality.Whenever data are available, we will examine indi-vidual drugs. Data for suicide completers, attemp-ters and ideators will be examined whenever thisdistinction has been made. The implications of thefindings for research and clinical practice will thenbe discussed. Although many other drugs, includ-ing those of abuse, may affect suicidality inpatients with bipolar disorder, this review willfocus only on therapeutic agents typically used in

mood disorders.The studies reviewed were identified by perform-

ing Medline searches for the timeframe January1960 to January 2013 using the keywords antiepi-leptic, anticonvulsant, antidepressant, antipsychotic,benzodiazepine, bipolar disorder, lithium, mood dis-order, psychotropic drugs, sedatives, hypnotics, andsuicide. We further refined our search using indi-vidual drug names and also identified additionalstudies from the citations of the reviewed papers.We also searched the US Food and Drug Adminis-tration Center for Drug Evaluation and Research

website.595

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Antidepressants

A major controversy in the treatment of bipolardisorder concerns the use of antidepressants(Table 1). This controversy arises from observa-tions and an accumulating body of evidence that

antidepressant use in bipolar disorders is associ-ated with the emergence of clinical states thatincrease suicidal risk, particularly in type Ipatients. These higher risk states include mixedstates (30), broadly defined mixed states (31), emo-tional instability, or rapid cycling (32 – 34), andswitching into mania, hypomania, mixed states, orpsychosis (35). It is possible that antidepressantsincrease suicidal risk via mechanisms, such asworsening of depression, behavioral activation andagitation, that do not satisfy diagnostic criteria formania or a mixed state, sometimes termed an acti-

vation syndrome (36). There also may be otherunknown mechanisms.

The use of antidepressants in bipolar disorder isvery common. Sometimes they are used prior to theemergence of manic or hypomanic symptoms inpatients, when clinicians believe they are treatingunipolar depression (37, 38). Antidepressants arealso used in diagnosed bipolar disorders becauseclinicians feel compelled to alleviate the symptomsof bipolar depression. Data from the Stanley Net-work as well as the National Institute of MentalHealth (NIMH) STEP-BD project indicate that 35to 55% of patients with bipolar disorder receiveantidepressants at some point in their illness andeven more frequently than mood stabilizers. Bal-dessarini et al. (39) reported that in a large groupof 7760 bipolar disorder patients, regardless of their clinical state, 50% were given an antidepres-sant as a first treatment, and only 25% a mood sta-bilizer. Baldessarini et al. (40) reported in anotherstudy of 7406 patients with bipolar disorder thatantidepressants were the most often first-prescribedtreatment and were second only to lithium in beingsustained 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 rela-tively pure mania at baseline, 36% were treatedwith an antidepressant (41). This proportionremained high throughout follow-up. As expected,the rate of antidepressant use was twice as highduring dysphoric mixed states as during mania(55% versus 27%, respectively, p < 0.001). Inter-estingly, the authors noted that, while antidepres-sants are not recommended in mixed states, morethan half of the mixed state patients were main-tained on them for the 24 months of follow-up.

Mood stabilizers have limited efficacy in acute

bipolar depression and probably also in unipolar

depression, with small or moderate effect sizes (42).The addition of antidepressants may not have asignificant impact in the treatment of bipolardepression (43). Several reviews, as well as experttreatment guidelines for bipolar disorder, havebeen published (42, 44 – 47). Most have recom-

mended extreme caution in the use of antidepres-sants. It is an interesting phenomenon that theclass of medications least recommended by expertsfor bipolar disorder is the most widely used by cli-nicians.

Mood stabilizers are also not very effective inpreventing relapses into mania or bipolar depres-sion, despite their demonstrated superiority overplacebo in numerous controlled studies (44).Relapse rates are still high for lithium and divalp-roex (48). Mood stabilizers from the antipsychoticgroup, including quetiapine, aripiprazole, olanza-

pine, and the olanzapine/fluoxetine combination,are also limited by inconsistent and low rates of relapse prevention.

Therefore, the clinician is under pressure to con-sider antidepressant medications. Many cliniciansdo notice benefits for their patients after addingantidepressants. They also notice that adverseevents, including suicidal behavior, occur withantidepressant treatment of bipolar disorderpatients. Thus there is a clinical dilemma (45, 49 – 51) that is also a major public health concern, sincethe estimated 50 million patients with bipolar dis-order in the world spend the majority of their illtime in depression rather than mania and are thus‘vulnerable’ to antidepressant treatment (52, 53).

Antidepressants are not very effective in bipolardepression (54, 55). The logical expectation there-fore would be that they are not effective agents forreducing suicidal risk. In contrast, lithium is alsonot a particularly good antidepressant in bipolardepression, with response rates rarely exceeding50%, but it is effective in preventing suicide andsuicide attempts with long-term use. Lithium isalso somewhat effective against mixed states whichcarry very high suicidal risk (31). Unlike lithium,

antidepressants have a propensity to induce mixedstates (14). Therefore, they are not expected to bevery protective against suicidality in patients withbipolar disorder.

But what do the data show?

In a case – control prospective study, Marangellet al. (56) reported on the suicidal events in a largegroup of patients with bipolar disorder from theSTEP-BD. Of the 4360 participants in the study,182 exhibited suicidal behavior. In this group,

there were 270 suicide events (eight completed596

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T a b l e

1 .

A n t i d e p r e s s a n t s

S t u d y

D e s i g n

P o p

u l a t i o n

s t u d i e d

D i a g n o s i s / s u b t y p e

N

T r e a t m e n t

S t u

d y /

t r e a t m e n t

d u r a t i o n

S u i c i d e

t y p e

R e s u l t s

C o m m e n t s

M a r a n g e l l

e t a l .

2 0 0 8 ( 5 6 )

C a s e – c o n t r o l ,

p r o s p e c t i v e

s t u d y

S T E P - B D

p o p u

l a t i o n

D S M - I V B D - I ,

B D - I I ,

B D - N O S ,

c y c l o t h y m i c d / o ,

S Z A B D s u b t y p e

1 8 2 p a t i e n t s

w i t h s u i c i d e

e v e n t s

S y s t e m a t i c

a l g o r i t h m

w i t h

v a r i o u s A D s

6 y e a r s

S C ,

S A

L i n o t p r o t e c t i v e

a g a i n s t s u i c i d e

I n c r e a s e d

s u i c i d a l r i s k

w i t h S S R I s

S t u d y w a s n o t

d e s i g n e d t o

a s s e s s

a s s o c i a t i o n o f

S S R I s w i t h

s u i c i d e r i s k

F e w p a t i e n t s

t a k i n g L i

B a u e r

e t a l .

2 0 0 6 ( 7 2 )

P r o s p e c t i v e

s t u d y

A d u l t S

T E P -

B D

o u t p a

t i e n t s

D S M - I V B D - I ,

B D - I I ,

B D - N O S ,



4 2 5 a

A D v e r s u s n o

A D u s e

3 0 m o n t h s

S u i c i d a l i t y

b r o a d l y

d e fi n e d

i n c l u d i n g

S I , s e l f -

h a r m

e v e n t s ,

S A ,

S C

I n c r e a s e d A D

e x p o s u r e w a s

n o t a s s o c i a t e d

w i t h i n c r e a s e d

e m e r g e n t

s u i c i d a l i t y

S m a l l n u m b e r s

i n s u b g r o u p s

N u m b e r s w e r e

i n s u f fi c i e n t t o

t e s t f o r

d i f f e r e n c e s

a m o n g

s p e c i fi c A D s

T o h e n

e t a l .

2 0 0 3 ( 7 3 )

P B O - c o n t r o l l e d

R C T

A d u l t

o u t p a

t i e n t s

B D - I d e p r e s s e d

T o t a l N

=

8 3 3

P B O =

3 7 7

O L Z =

3 7 0

O F C =

8 6

P B O v e r s u s

O L Z o r O F C

8 w e e k s

A n y s u i c i d a l

e v e n t

N o s u i c i d a l

e v e n t s i n

e i t h e r g r o u p

S h o r t - t e r m

s t u d y

n o t d e s i g n e d

w i t h s u i c i d a l i t y

a s a p r i m a r y

o u t c o m e

T o n d o

e t a l .

2 0 0 8 ( 5 8 )

S y s t e m a t i c

f o l l o w - u p

O u t p a t i e n t

c l i n i c

‘ A f f e c t i v e l y i l l ’ ,

M D D ,

B D - I ,

B D - I I

T o t a l N

=

7 8 9

M D D =

6 0 5

B D - I ,

B D - I I =

1 8 4

V a r i o u s A D s

a s c l i n i c a l l y

i n d i c a t e d

M e a n =

3 . 5

9

m o n t h s

S I

W i t h s u s t a i n e d

A D t r e a t m e n t ,

8 1 . 5

%

i n i t i a l l y

s u i c i d a l p a t i e n t s

b e c a m e ‘ n o n -

s u i c i d a l ’ o n

H D R S i t e m # 3

N a t u r a l i s t i c

s t u d y

G o l d b e r g

e t a l .

2 0 0 5 ( 6 1 )

C r o s s - s e c t i o n a l

a n a l y s i s o f S T E P -

B D c o h o r t

A d u l t S

T E P - B D

c o h o r t

D S M - I V B D - I ,

B D - I I ,

B D - N O S ,



1 0 0 0

A D v e r s u s

n o A D

1 7 m o n t h s

S I

A D g r o u p h a d

h i g h e r r a t e o f

S I t h a n n o - A D

g r o u p ( 2 5 %

v e r s u s 1 4 % )

C o n f o u n d i n g b y

i n d i c a t i o n n o t

r e s o l v e d

597


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T a b l e

1 .

( C o n t i n u e d )

S t u d y

D e s i g n

P o p

u l a t i o n

s t u d i e d


N

T r e a t m e n t

S t u

d y /

t r e a t m e n t

d u r a t i o n

S u i c i d e

t y p e

R e s u l t s

C o m m e n t s

G o l d b e r g

e t a l .

1 9 9 9 ( 6 2 )

C r o s s - s e c t i o n a l

s t u d y

A d u l t S

t e p - B D

c o h o r t

M a n i a / m i x e d m a n i a

1 0 0

A D v e r s u s n o

A D i n w e e k

p r i o r t o

h o s p i t a l

a d m i s s i o n

1 w e e k

S I

P a t i e n t s w i t h

d y s p h o r i c

m a n i a w h o h a d

t a k e n A D s i n t h e

w e e k p r i o r t o

a d m i s s i o n h a d

s i g n i fi c a n t l y m o r e

S I t h a n t h o s e

w i t h o u t A D s

S u g g e s t s a n

a c u t e e f f e c t o f

A D s o n S I

Y e r e v a n i a n

e t a l .

2 0 0 7 ( 5 9 )

R e t r o s p e c t i v e

r e v i e w

V e t e r a n

i n p a t i e n t s

a n d

o u t p a

t i e n t s

B D - I ,

B D - I I ,

B D - N O S ,

S Z A

4 0 5

A D M O N

A D +

M S

M S o n l y

( M S =

L i ,

V A L ,

C B Z )

3 y e a r s

S A ,

S C ,

h o s p i t a l i -

z a t i o n

f o r S I

A l l s u i c i d a l e v e n t s :

M S M O N O

3 . 4

8 / 1 0 0

p a t i e n t - y e a r s ;

M S +

A D 9 . 7 5 / 1 0 0

p a t i e n t - y e a r s ;

A D M O N O

2 5 . 9

2 / 1 0 0 p a t i e n t

-

y e a r s


i n d i c a t i o n n o t

r e s o l v e d

M S m i t i g a t e s

A D -

a s s o c i a t e d


P a c c h i a r o t t i

e t a l .

2 0 1 1 ( 6 0 )


r e v i e w w i t h


f o l l o w - u p

I n p a t i e

n t s a n d

o u t p a

t i e n t s

B D - I ,

B D - I I

T o t a l N

=

9 5

A D M O

N O

=

6 1

A D + M

S =

3 4

A D M O N O

A D +

M S

1 0 y e a

r s

S A

M e a n n o . o f S A s f o

r

A D M O N O

=

0 . 5

( S D =

1 . 2

) w a s

s i g n i fi c a n t l y

h i g h e r t h a n f o r

A D +

M S =

0 . 2

( S D =

0 . 4

)

( p =

0 . 0

0 1 )

S t r e n g t h s w e r e

l o n g - t e r m

f o l l o w - u p a n d

M O N O v e r s u s

p o l y t h e r a p y

T i i h o n e n

e t a l .

2 0 0 6 ( 6 9 )

C o h o r t s t u d y w i t h

f o l l o w - u p i n a

n a t i o n w i d e

d a t a b a s e

P a t i e n t s

h o s p i t a l i z e d

a f t e r S A

I C D - 1 0 S A

1 5 3 9 0

V a r i o u s T C A s

S S R I

S N A s

O t h e r A D s

v e r s u s

n o A D s

M e a n f o l l o w -

u p =

3 . 4

y e a r s

S A ,

S C

F L X w a s

a s s o c i a t e d w i t h

t h e l o w e s t r i s k o f

s u i c i d e

( R R =

0 . 5

2 ; 9 5 %

C I : 0 . 3

0 – 0 . 9

3 )

V F X w a s


t h e h i g h e s t r i s k

( R R =

1 . 6

1 ; 9 5 %

1 . 0

1 – 2 . 5 7 )

O n e o f o n l y f e w

s t u d i e s w i t h

s i n g l e d r u g

c o m p a r i s o n s

598

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T a b l e

1 .


S t u d y

D e s i g n

P o p

u l a t i o n

s t u d i e d


N

T r e a t m e n t

S t u

d y /

t r e a t m e n t

d u r a t i o n

S u i c i d e

t y p e

R e s u l t s

C o m m e n t s

R a j a

e t a l .

2 0 0 9 ( 5 7 )


c h a r t r e v i e w

A c u t e

a d m i s s i o n s

t o i n p

a t i e n t

p s y c h i a t r i c

u n i t s

M i x e d a f f e c t i v e

g r o u p , s u b -

a n a l y s i s f o r B D s

S A = 1

2 9

N o S A

=

1 2 3 3

V a r i o u s A D s ,

B Z D s

3 m o n t h s

p r i o r

t o a c u t e

h o s p i t a l i -

z a t i o n

S A

T h o s e a d m i t t e d

w i t h S A s w e r e

m o r e l i k e l y t o

h a v e t a k e n

S S R I s t h a n

B D Z s c o m p a r e d

t o t h o s e w i t h o u t

S A s ( 4 1 . 3

%

v e r s u s 2 4 . 9

% ,

v 2

=

1 1 . 1

9 ,

p =

0 . 0

0 0 1 )

T h e y d i d n o t

r e s o l v e

c o n f o u n d i n g

i s s u e s

A k i s k a l

e t a l .

2 0 0 3 ( 6 3 )


r e v i e w a n d

f o l l o w - u p

I n p a t i e

n t s

B D - I I w i t h A D -

i n d u c e d v e r s u s

s p o n t a n e o u s

m a n i a

A D - i n d u c e d =

5 2

S p o n t a n e o u s

m a n i a =

1 4 4

A D v e r s u s

n o A D

6 m o n t h

r e t r o s

p e c t i v e

r e v i e w a n d

f o l l o w

- u p a t

1 m o n t h

S I

4 2 %

o f t h e

h o s p i t a l i z e d

s p o n t a n e o u s

g r o u p w e r e

a d m i t t e d f o r

s u i c i d a l r i s k

v e r s u s 8 0 %

o f

t h e h o s p i t a l i z e d

A D - i n d u c e d

g r o u p ( p =

0 . 0

0 2 )


t r e a t m e n t

C o n f o u n d i n g

i s s u e s n o t

r e s o l v e d

S t o l l

e t a l .

1 9 9 4 ( 6 4 )

B l i n d ,

r e t r o s p e c t i v e

r e v i e w

I n p a t i e

n t s

B D - I m a n i c

T o t a l N

=

9 8

A D - a s s

o c i a t e d

m a n i a

=

4 9

S p o n t a

n e o u s

m a n i a

=

4 9

V a r i o u s A D s

v e r s u s

n o A D

1 2 m o n t h s

S I s e v e r i t y

o n a

s c a l e o f

1 – 7

A D - a s s o c i a t e d

g r o u p ( 2 . 0 ,

S D =

1 . 5

) a n d

t h e s p o n t a n e o u s

g r o u p

( 1 . 9 ,

S D =

1 . 4

)

h a d s i m i l a r


s c o r e s , p =

n s

T r e a t m e n t

g r o u p s t o o

s m a l l t o

a s s e s s

e f f e c t s o f

i n d i v i d u a l A D s

K e s s i n g

e t a l .

2 0 0 5 ( 6 5 )

P h a r m a c o -

e p i d e m i o l o g i c ,

r e t r o s p e c t i v e

d e s i g n

L a r g e a d u l t

c o h o r t

o f L i

u s e r s

b a s e d

o n p h

a r m a c y

p u r c h

a s e d a t a

P u r c h a s e r s o f L i ,

n o c l i n i c a l d a t a

L i p u r c h a s e r s =

1 3 1 8 6

C o n t r o l g e n e r a l

p o p u l a t i o n =

1 . 2 m i l l i o n

L i v e r s u s

L i +

A D

5 y e a r s

S C

T h o s e

p u r c h a s i n g

A D h a d a h i g h e r

r i s k o f S C ,

R R =

6 . 0 7 ,

9 5 % C I : 5 . 1

0 – 7 . 2

1

P h a r m a c y d a t a

m a y n o t r e fl e c t

c l i n i c a l

T h e

p e r c e n t a g e o f

B D i s u n c l e a r


i s s u e s n o t

r e s o l v e d

599


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suicides and 262 attempts). When the group withsuicidal events was compared to a matched controlgroup without suicidal events, exposure to lithiumin the six-month period prior to an event was simi-lar in the two groups. The findings were somewhatsurprising in that no suicide-protective effect was

noted in the lithium cohort. Exposure to selectiveserotonin reuptake inhibitor (SSRI) antidepres-sants was associated with increased suicidal events.Confounding by indication was not resolved.

In an analysis of a group of affectively illpatients with various diagnoses, admitted to a psy-chiatric intensive care unit, Raja et al. (57) foundthat those who were admitted following a suicideattempt were more likely than those without a sui-cide attempt to have taken antidepressants andbenzodiazepines in the three months prior toadmission. Suicidal patients were also less likely to

have taken antipsychotics, AEDs or lithium. Thesefindings held true when the bipolar and mixed sub-groups were analyzed separately. The study didnot control for confounding factors, including con-founding by indication. In a Sardinian group of 785 affectively ill patients (605 with MDD and 184with bipolar I and II), systematically followed foran average of 3.59 months, Tondo et al. (58)reported that, with sustained antidepressant treat-ment, 81.5% of initially suicidal patients becamenon-suicidal as measured by Item #3 of the Hamil-ton Depression Rating Scale (HDRS). This con-version to non-suicidal status occurredindependent of diagnosis, treatment type, or dos-age of medication. The subgroup of patients withbipolar disorder in this group does not appear tohave shown increased suicidal risk.

A group of 1582 unrecognized patients withbipolar disorder in a community sample of 25460depressed patients, who were given antidepressantsfor depressive-phase illness, were significantly morelikely to attempt suicide (0.9%) than recognizedpatients with bipolar disorder (0.3%) or non-bipo-lar-disorder patients (0.2%) (p < 0.0001) (37). Thestudy 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, suicidalevent rates (suicide attempts and hospitalizationsfor suicidal intent) were 7.4 times higher duringtreatment with antidepressant monotherapy (25.92events/100 patient-years) than during treatmentwith mood stabilizer monotherapy (3.48 events/100 patient-years) and 2.7 times higher than duringtreatment with mood stabilizer and antidepressantcombination therapy (9.75 events/100 patient-years) (59). For suicide events: (i) mood stabilizer

and antidepressant versus mood stabilizer T a b l e

1 .


S t u d y

D e s i g n

P o p

u l a t i o n

s t u d i e d


N

T r e a t m e n t

S t u

d y /

t r e a t m e n t

d u r a t i o n

S u i c i d e

t y p e

R e s u l t s

C o m m e n t s

S h i e t a l .

2 0 0 4 ( 3 7 )


a n a l y s i s

M e d i - C

a l p a i d

c l a i m

d a t a b a s e

R e c o g n i z e d B D ,

u n r e c o g n i z e d B D ,

n o n - B D b u t

a f f e c t i v e l y i l l

R e c o g n i z e d B D =

3 7 9 7

U n r e c o

g n i z e d

B D = 1

5 8 2

N o n B D

, b u t

a f f e c t i v

e l y i l l =

2 0 0 8 1

V a r i o u s A D s

6 y e a r s

A D

t r e a t m

e n t

p e r i o d =

m i n i m

u m

1 2 m o n t h s

S A

U n r e c o g n i z e d

B D s g i v e n A D s

w e r e m o r e l i k e l y

t o a t t e m p t

s u i c i d e t h a n

r e c o g n i z e d

B D s o r n o n - B D s

N o r e v i e w o f

c l i n i c a l c h a r t s


i s s u e s n o t

r e s o l v e d

A D =

a n t i d e p r e s s a n t ; B D =

b i p o l a r d i s o r d

e r ; B D - I =

b i p o l a r I d i s o r d e r ; B D - I I =

b i p o l a r I I d i s o r d e r ; B D - N O S =

b i p o l a r d i s o r d e r

; n o t o t h e r w i s e s p e c i fi e d ; B Z D =

b e n z o d i a

z e p i n e ; C B Z =

c a r -

b a m a z e p i n e ; C I =

c o n fi d e n c e i n t e r v a l ; d / o =

d i s o r d e r ; F L X =

fl u o x e t i n e ; H D R S = H a m i l t o n D e p r e s s i o n R a t i n g S c a l e ; I C D = I n t e r n a t i o n a l S t a t i s t i c a l C l a s s i fi c a t i o n o f D i s e a s e s a n d R e l a t e d

H e a l t h P r o b l e m s ; L i =

l i t h i u m ; M D D =

m a j o r d e p r e s s i v e d i s o r d e r ; M O N O

=

m o n o t h e

r a p y ; M S =

m o o d s t a b i l i z e r ; n s =

n o n - s i g n

i fi c a n t ; O F C =

o l a n z a p i n e – fl u o x e t i n e c o m b i n a t i o n ; O L Z =

o l a -

n z a p i n e ; P B O

=

p l a c e b o ; R C T =

r a n d o m i z e d c o n t r o l l e d t r i a l ; R R =

r i s k r a t i o ; S A = s u

i c i d e a t t e m p t ; S C =

s u i c i d e c o m p l e t e d ; S D =

s t a n d a r d d e v i a t i o n ; S I =

s u i c i d a l i d e a t i o n ; S N A s =

s e r o t o -

n e r g i c - n o r a d r e n e r g i c a n t i d e p r e s s a n t s ; S S

R I =

s e l e c t i v e s e r o t o n i n r e u p t a k e i n h i b i t o r

; S T E P - B D =

S y s t e m a t i c T r e a t m e n t E n h a n

c e m e n t P r o g r a m

f o r B i p o l a r D i s o r d e r ; S Z A =

s c h i z o a f f e c t i v e ;

T C A s =

t r i c y c l i c a n t i d e p r e s s a n t s ; V A L = v

a l p r o a t e ; V F X =

v e n l a f a x i n e .

a O f t h e fi r s t 2 0 0 0 S T E P - B D p a r t i c i p a n t s w i t h n e w o n s e t m a j o r d e p r e s s i v e e p i s o d e w i t h o u t i n i t i a l S I .

600

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monotherapy, p = 0.003; (ii) mood stabilizer andantidepressant versus antidepressant monotherapy,p = 0.0005; and (iii) mood stabilizer monotherapyversus antidepressant monotherapy, p < 0.0001.

Pacchiarotti et al. (60) studied 95 patients withbipolar disorder initially given either antidepres-

sant monotherapy or antidepressant and moodstabilizer combination therapy. These patientswere followed up for up to 10 years. Includingretrospective data, they found that patients withbipolar depression maintained on antidepressantmonotherapy had a higher mean number of sui-cide attempts than those maintained on combi-nation 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-BDstudy (61) found that suicidal ideation was more

prevalent in patients taking antidepressants versusthose not taking antidepressants (25% versus14%). Confounding issues were not resolved.

In a study of 100 manic patients, dysphoricmanic patients who had taken antidepressants inthe week prior to admission had significantlyhigher rates of suicidal ideation compared tothose who were not taking antidepressants: 54%versus 34%, respectively (p < 0.05). (62). Inother words, although all patients were at higherrisk by virtue of being in mixed states, the pres-ence of antidepressants increased the risk of sui-cidal ideation even more. In another study,antidepressant-associated hypomanic patientswere about twice as likely to have been admittedwith suicidal ideation than patients with bipolarII disorder with spontaneous hypomania (80%versus 43%, respectively) (63). In a retrospectivechart review, Stoll et al. (64) found that antide-pressant-associated manic patients, although clin-ically assessed as having less severe illnesscompared to a group of spontaneously manicpatients, nevertheless had similar scores on aseven-item suicidal ideation rating scale. Theresults raise the possibility that antidepressants

may have a role in increasing suicidal ideationindependent of episode. In a large cohort studyfrom Denmark (65), patients treated with lith-ium, presumably mostly patients with bipolardisorder, who also purchased an antidepressanthad a higher risk of completed suicide, with anRR of 6.07 [95% confidence interval (CI): 5.10 – 7.21]. None of the studies resolved the issues of confounding by indication or other confounds.

Among antidepressants, venlafaxine may beinvolved in increased suicidality due to itspropensity to induce more switches and mixed

states (66 –

68), which carry a higher risk for

suicidality (14). The RR of suicidal behavior/idea-tion based on the FDA analysis (24) of controlledtrial data in pediatric patients was 1.58 with mirt-azapine (95% CI: 0.06 – 38.37) and 8.84 with venla-faxine (95% CI: 1.12 – 69.51).

In a cohort study of 15390 subjects hospitalized

after a suicide attempt, Tiihonen et al. (69)reported that, among various antidepressants, fluo-xetine was associated with the lowest risk of suicidecompared to placebo (RR = 0.52; 95% CI: 0.30 – 0.93). Venlafaxine was associated with the highestrisk of suicide (RR = 1.61; 95% CI: 1.01 – 2.57).Furthermore, in a recent comparison of differentantidepressant subtypes, an increased risk of sui-cide attempts with venlafaxine versus other antide-pressants was observed in a heterogeneous groupof patients, most of whom had depression oranxiety (70).

We found no studies specific to bupropion andsuicidal risk in patients with bipolar disorder. Atthis time, bupropion should be considered similarto other antidepressants pending reliable data inbipolar disorder. The impression that bupropionmay cause less switching or fewer mixed stateswhen used in bipolar depression may be a potentialadvantage in this regard (66, 71).

In a prospective study of a large group of patients in the STEP-BD, Bauer et al. (72) foundno evidence that an increase in antidepressantexposure was associated with increased suicidality.However, in that report, the numbers of patientsexposed to each antidepressant subtype were toosmall to permit an adequate statistical assessmentof differential effects.

In the randomized placebo-controlled study of Tohen et al. (73) comparing olanzapine, olanza-pine – fluoxetine combination and placebo in bipo-lar I depression, there were no serious suicidalevents in any of the three groups during the eight-week study period. There was a modest reductionon the Montgomery – Asberg Depression RatingScale (MADRS) suicidal thought item in all threegroups. In this eight-week study, which excluded

patients with a history of suicidal behavior withinthe past three months, it is difficult to interpret theeffect on suicidality of fluoxetine alone or in com-bination with an antipsychotic.

Few studies have examined suicidal outcome asa result of the use of tricyclic antidepressants(TCAs) in bipolar depression. Data for patientswith unipolar depression suggest that in unipolardepression TCAs may be protective against suicide(74), whereas in bipolar disorder the situation maybe the reverse. TCAs, via a contribution to theswitch process, may increase the risk of suicidal

behaviors (59, 68).601


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In the large meta-analysis by Fergusson et al.(22), the odds ratio (OR) comparing TCAs toSSRIs for suicide attempts was 0.88 (95% CI:0.54 – 1.42) and for suicides was 1.08 (95% CI:0.28 – 4.09), indicating that there may not be a sig-nificant difference between TCAs and SSRIs. The

study population was composed of patients regis-tered in a large number of clinical trials for depres-sion and anxiety disorders but not for bipolardisorders. Given the large number of patients,however, one may assume that a certain propor-tion of subjects were unrecognized patients withbipolar disorder.

Leon et al. (75) longitudinally followed a cohortof 757 patients for up to 27 years in naturalistictreatment settings and compared times whenpatients were exposed to antidepressants to whenthey were not on antidepressants. Treatment was

associated with a 20% risk reduction for suicideattempts and death by suicide. The populationunder study, however, consisted primarily of patients with unipolar depression (77.7%), and theissue of bipolarity was not addressed.

Suicide and suicidal behaviors are complex phe-nomena and have multiple determinants: somegenetic, some environmental and some related tothe nature of the illness and its different phases.Severity, which is often difficult to define, isanother factor. Suicidality is also impacted by co-morbid conditions including alcoholism, drugaddiction, anxiety disorders, and psychotic disor-ders, all of which are independent risks factors forsuicidality. Under those conditions, it is a chal-lenge to figure out if antidepressant use in patientswith bipolar disorder increases, decreases, or hasno effects on suicidal behavior. The methodologi-cal hurdles do not appear to have been resolved.As McElroy et al. (68) indicated, in four out of fivestudies that demonstrated increased suicidalitywith antidepressants, the findings could potentiallybe explained by the fact that higher suicidal riskmay actually have led to the choice of an antide-pressant rather than the reverse. Similar conclu-

sions have recently been reached in studies of unipolar patients (76).

Most of the available data thus point to the pos-sibility of heightened risk of suicidal behavior inantidepressant-exposed patients with bipolar disor-der. The discrepancies between the suicide-promot-ing and suicide-preventing data in bipolar disorderhighlight the complexity of the issue. Finer suicidemonitoring tools and predictors of treatment-emergent suicidality are needed. Some patientswith bipolar disorder need antidepressants, do wellon them, and never become suicidal. Other patients

with bipolar disorder may be activated by the use

of antidepressants and become suicidal within ashort period of treatment. Such increased risk maybe mediated by mixed states, agitated dysphoria orincreased aggressivity presumably induced by theantidepressants. How does one distinguish betweenthose that do well and those that become more sui-

cidal? General suicide risk considerations are notvery useful for the individual patient. Therefore, itis difficult to predict which patients, especiallywhich newly diagnosed patients, should not begiven antidepressants. Although caution should beexercised with antidepressants in this patientgroup, at this time, with adequate safeguardsincluding thoughtful assessments, careful monitor-ing and follow-up, there may be a place for antide-pressants in the treatment of bipolar disorder,particularly bipolar depression.

Lithium

To date, lithium is the only medication convinc-ingly shown to reduce suicidal risk in bipolar disor-der (Table 2). Earlier randomized controlledstudies (77 – 83) provided support for the conclu-sion that lithium is effective in reducing suicideattempts and completed suicides. A recent ran-domized placebo-controlled study by Lauterbachet al. (84) indicated that adjunctive lithium treat-ment, although not associated with a reduction insuicide attempts, may be effective in reducing com-pleted suicides in adult affectively ill patients. Pre-vious reviews have shown a dramatic reduction of suicide risk with long-term lithium use (1, 85 – 87),with the most recent meta-analysis (10) indicatingthat lithium reduces suicide risk by a factor of about five compared to no treatment. Anotherreview of 32 controlled trials also found a 4- to5-fold reduction in the risk of both completed sui-cide and deliberate non-fatal self harm events inpatients receiving lithium, compared to thosereceiving either placebo or other active treatment(88).

Not all studies, however, have found lithium to

have anti-suicidal properties. The established roleof lithium in suicide prevention is probably appli-cable only in chronic lithium treatment (89). Ashorter term treatment effect is a possibility thatdeserves study. In the first year of lithium treat-ment, mortality rates are still 12 times that of thegeneral population. By about two years of treatment, the rates of suicide attempts, althoughstill higher, are no longer statistically differentfrom that of the general population. Cliniciansmust be cautious in using lithium for acute anti-suicidal effect. In a recent analysis of completed

suicide in a large group of former psychiatric inpa-602

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T a b l e

2 .

L i t h i u m

a n d o t h e r m o o d s t a b i l i z e r s

S t u d y

D e s i g n

P o p u l a t i o n

s t u d i e

d

D i a g n o s i s /

s u b t y p e

N

T r e a t m e n t

S t u d y /

t r e a t m e n t

d u r a t i o n

S u

i c i d e

t y p e

R e s u l t s

C o m m e n t s

O q u e n d o

e t a l .

2 0 1 1 ( 1 0 6 )

D o u b l e - b l i n d ,

r a n d o m i z e d ,

p a r a l l e l -

g r o u p s t u d y

A d u l t

i n p a t i e n t s

a n d

o u t p a t i e n t s

B D - I ,

B D - I I ,

B D - N O S i n

a d e p r e s s i v e

o r m i x e d

e p i s o d e w i t h

a t l e a s t o n e

p a s t S A

9 8

V A L v e r s u s

L i

2 . 5 y e a r s

S C , t

i m e

t o S A ,

t i m e

t o

s u i c

i d e

e v e n t ,

i . e . ,

S I

w i t h

a

p l a n

r e q u i r i n g

a c h

a n g e

i n t r e a t m e n t

N o S C i n e i t h e r g r o u p

N o d i f f e r e n c e s

b e t w e e n V A L a n d

L i g r o u p s i n t i m e

t o S A o r s u i c i d e

e v e n t

C u r r e n

t l y , t h e b e s t

p o s s i b l e s t u d y d e s i g n

b u t s m a l l s i z e p r e c l u d e s

d e t e c

t i o n o f s m a l l

d i f f e r e n c e s

T h i e s -

F l e c h t n e r

e t a l .

1 9 9 6 ( 9 3 )

R a n d o m i z e d


t r i a l

A d u l t


M a j o r a f f e c t i v e

d i s o r d e r s

i n c l u d i n g B D

a n d S Z A

3 7 8

L i v e r s u s

C B Z

v e r s u s

a m i t r i p t y l i n e

2 . 5 y e a r s

S A , S

C

A l l s u i c i d a l e v e n t s :

9 S C a n d 5 S A

o c c u r r e d i n t h e

C B Z g r o u p ; n o n e

i n t h e L i g r o u p

S t u d y d e s i g n i s a s t r e n g t h

B o w d e n

e t a l .

2 0 0 0 ( 4 8 )

R C T

A d u l t

o u t p a t i e n t

r e c e n t l y

r e c o v e r e

d

f r o m m a n i a

B D - I

3 7 2

D V P X v e r s u s

L i v e r s u s

P B O

1 2 m o n t h s

S A

N o d i f f e r e n c e i n L i

v e r s u s D V P X S A

r a t e s

S t u d y n o t d e s i g n e d w i t h

s u i c i d

a l i t y a s a n

e n d p

o i n t

L a u t e r b a c h

e t a l .

2 0 0 8 ( 8 4 )

R C T

A d u l t s w i t h

r e c e n t S A

D e p r e s s i v e

s p e c t r u m

T o t a l N =

1 6 7

L i =

8 4

P B O

=

8 3

M D D =

7 6 %

L i v e r s u s P B O

a s a d j u n c t

1 y e a r

S A , S

C

A l l s u i c i d e e v e n t s ’

i n c i d e n c e r a t e /

p a t i e n t - y e a r :

L i : 1 2 . 7

% ,

P B O : 2 1 . 7

%

A d j u s t e d H R : 0 . 5

1 7

( C I : 0 . 1

8 6 – 1 . 4

3 8 )

p =

0 . 2

0 6

P o s t - h o c a n a l y s i s

r e v e a l e d a

s i g n i fi c a n t

p r o t e c t i v e e f f e c t o f

a d j u n c t i v e L i

a g a i n s t c o m p l e t e d

s u i c i d e

F e w B D p a t i e n t s i n t h i s

c o h o r t

H i g h d

r o p o u t r a t e

603


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T a b l e

2 .


S t u d y

D e s i g n

P o p u l a t i o n

s t u d i e

d

D i a g n o s i s /

s u b t y p e

N

T r e a t m e n t

S t u d y /

t r e a t m e n t

d u r a t i o n

S u

i c i d e

t y p e

R e s u l t s

C o m m e n t s

F D A 2 0 0 8

( 9 7 )

M e t a - a n a l y s i s

o f 1 9 9 R C T

o f 1 1 A E D s

V a r i e d

p o p u l a t i o n

2 5 %

e p i l e p s y ,

2 7 %

p s y c h i a t r i c ,

a n d t h e

r e m a i n d e r

‘ o t h e r ’

g r o u p s

T o t a l N =

4 3 8 9 2

D r u g =

2 7 8 6 3

P B O

=

1 6 0 2 9

C o m p a r i n g

a l l A E D s

v e r s u s P B O

S h o r t - t e r m

c l i n i c a l

t r i a l s

S I , S A

, S C ,

p r e p a r a t o r y

a c t s

A d j u s t e d r i s k

e s t i m a t e f o r

s u i c i d a l w a s 0 . 4

3 %

f o r d r u g g r o u p

v e r s u s 0 . 2 4 %

o f

P B O

N o B D

g r o u p

I n t h e

p s y c h i a t r i c g r o u p ,

t h e O

R w a s 0 . 6 5 f o r

C B Z a n d 0 . 7

2 f o r D V P X ,

w i t h v

e r y w i d e C I s

c o n t a

i n i n g 1

R e d d e n

e t a l .

2 0 1 1 ( 1 0 5 )

M e t a - a n a l y s i s

o f 1 3 P B O -

c o n t r o l l e d

R C T s

9 / 1 3 s t u d i e s

w e r e

p s y c h i a t

r i c a

E p i l e p s y ,

B D ,

m i g r a i n e

p r o p h y l a x i s ,

i m p u l s i v e

a g g r e s s i o n

a n d d e m e n t i a

T o t a l N =

2 3 1 9

D V P X =

1 3 2 7

P B O

=

9 9 2

D V P X

v e r s u s P B O

3 – 5 2 w e e k s ,

m e a n

d u r a t i o n

=

1 3 w e e k s

6 8 d a y s

f o r D V P X

S u i c i d e

e v e n t s

u s i n

g

C - C

A S A

A c r o s s d i a g n o s t i c

c a t e g o r i e s ,

D V P X

d o e s n o t a p p e a r

t o i n c r e a s e r i s k o f

s u i c i d e - r e l a t e d

e v e n t s r e l a t i v e t o

P B O

O v e r a l l e s t i m a t e d

O R o f s u i c i d a l

b e h a v i o r o r S I w a s

0 . 7

2 %

( 9 5 %

C I : 0 . 2

9 – 1 . 8 4 )

O n l y 6

o f 1 3 s t u d i e s

p e r t a i n e d t o B D

p o p u l a t i o n s

N o n e

o f t h e D V P X

s t u d i e s w e r e d e s i g n e d

w i t h s

u i c i d a l i t y a s a n

o u t c o

m e m e a s u r e

Y e r e v a n i a n

e t a l . 2 0 0 7

( 5 9 )


c h a r t

a n a l y s i s

A d u l t v e t e

r a n s

B D - I ,

B D - I I ,

B D - N O S ,

S Z A

4 0 5

L i v e r s u s

D V P X

v e r s u s C B Z

3 y e a r s w i t h

m i n i m u m

6 - m o n t h

t r e a t m e n t

d u r a t i o n

S A , h o s p i t a l i -

z a t i o n f o r

s u i c

i d a l i t y

N o d i f f e r e n c e i n

n o n - f a t a l s u i c i d e

e v e n t s a m o n g L i ,

D V P X , a n d C B Z

g r o u p s

B e i n g o f f a n y o f t h e t h r e e

M S s w a s a s s o c i a t e d w i t h

a n i n c r e a s e i n s u i c i d a l

r i s k

A h e a r n

e t a l .

2 0 1 3 ( 9 6 )



I n p a t i e n t a n d

o u t p a t i e n t

V e t e r a n s

B D - I ,

B D - I I

1 3 0 7

L i L i +

D V P X

D V P X

D V P X +

A P

C B Z

C B Z +

A P

M S M S +

A P

6 - y e a r r e v i e w

A v e r a g e

t i m e t a k i n g :

L i : 2 9 . 6

m o n t h s

D V P X :

2 4 m o n t h s

A P : 1 8 . 7

m o n t h s

S A

L o w e s t S A r a t e w a s

f o r L i +

D V P X

( 6 . 3 a t t e m p t s p e r

1 0 0 0 0 m o n t h s o f

e x p o s u r e ) ,

f o l l o w e d b y

D V P X ( 7 . 0

/ 1 0 0 0 0 ) ,

t h e n L i ( 7 . 7

/ 1 0 0 0 0 )

C o n f o u

n d i n g b y i n d i c a t i o n

n o t r e

s o l v e d

I n a 6

y e a r s t u d y , m o s t

S A s o

c c u r r e d d u r i n g

o f f m e d i c a t i o n p e r i o d s

( m e a n d u r a t i o n

4 5 m o n t h s )

Y e r e v a n i a n

e t a l . 2 0 0 3

( 9 4 )



A d u l t


B D - I ,

B D - I I ,

B D - N O S ,

S Z A

1 4 0

L i v e r s u s

D V P X

v e r s u s C B Z

2 3 y e a r s ,

m i n i m u m

t r e a t m e n t

d u r a t i o n

=

6 m o n t h s

S A , h

o s p i t a l i -

z a t i o n f o r

s u i c

i d a l i t y

N o s i g n i fi c a n t

d i f f e r e n c e s a m o n g

t h e t h r e e g r o u p s

D i s c o n

t i n u a t i o n o f a l l

t h r e e

M S s l e d t o

i n c r e a s e i n s u i c i d a l r i s k

604

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T a b l e

2 .


S t u d y

D e s i g n

P o p u l a t i o n

s t u d i e

d

D i a g n o s i s /

s u b t y p e

N

T r e a t m e n t

S t u d y /

t r e a t m e n t

d u r a t i o n

S u

i c i d e

t y p e

R e s u l t s

C o m m e n t s

A r a n a e t a l .

2 0 1 0 ( 1 0 3 )

O b s e r v a t i o n a l

c o h o r t s t u d y

w i t h c a s e –

c o n t r o l

T h e H e a l t h

I m p r o v e m e n t

N e t w o r k

d a t a b a s e

r e p r e s e n

t a t i v e

o f U K g e

n e r a l

p o p u l a t i o n

W i t h o r

w i t h o u t

e p i l e p s y o r

d e p r e s s i o n

o r B D , w i t h

a n d w i t h o u t

A E D s

T o t a l

N =

5 1 3 0 7 9 5

p a t i e n t s w i t h

3 1 5 2 7 5 8 5

p a t i e n t -

y e a r s o f

f o l l o w - u p

B D w i t h o u t

A E D s =

3 8 1 4

B D o n

A E D s =

1 8 0 9

C B Z G B P N

L a m o t r i g i n e

L e v e t i r a c e t a m

O x c a r b a z e p i n e

P r e g a b a l i n

T i a g a b i n e

T o p i r a m a t e

P a l p r o a t e

Z o n i s a m i d e

~ 2 0 y e a r s

S u i c i d e -

r e l a t e d

e v e n t s

I n t h e a d j u s t e d

a n a l y s e s ,

A E D s

w e r e n o t


i n c r e a s e d r i s k o f

s u i c i d e - r e l a t e d

e v e n t s i n t h e B D

g r o u p ( 1 . 1

3 ; 9 5 %

C I : 0 . 3 5 – 3 . 6

1 )

S t u d y p a r t i a l l y c o n t r o l l e d

c o n f o

u n d i n g f a c t o r s

b u t e x c l u d e d p a t i e n t s

w i t h p

a s t s u i c i d e - r e l a t e d

e v e n t s

S ø n d e r g a r d

e t a l . 2 0 0 8

( 1 0 4 )

P h a r m a c y

p u r c h a s e

d a t a a n d

l i n k a g e d a t a

f r o m D a n i s h

N a t i o n a l

R e g i s t e r

B D i n p a t i e n t s

a n d


d i s c h a r g

e d

f r o m

p s y c h i a t

r i c

h o s p i t a l

B D

5 9 2 6

L i , A E D s

5 y e a r s ,

t r e a t m e n t

d u r a t i o n

a s s e s s e d

b y p h a r m a c y

p u r c h a s e s

S C

S C r a t e w a s h i g h e r

d u r i n g A E D

p e r i o d s t h a n L i

p e r i o d s

R a t e o f S C

d e c r e a s e d w i t h n o .

o f a d d i t i o n a l

p r e s c r i p t i o n s

S w i t c h o r

a u g m e n t a t i o n s

s i g n i fi c a n t l y

r e d u c e d s u i c i d e

r a t e ( r a t e r a t i o =

0 . 2

8 ,

9 5 %

C I : 0 . 2

0 – 0 . 4

0 )

N o . o f

p r e s c r i p t i o n s m a y

n o t r e

fl e c t a c t u a l

t r e a t m

e n t

C o n f o u n d i n g v a r i a b l e s

n o t r e

s o l v e d

G o o d w i n

e t a l .

2 0 0 3 ( 9 1 )


c o h o r t s t u d y

H M O h e a l t h

p l a n

m e m b e r s

≥ 1 4 y e a r s o f

a g e

B D w i t h a t

l e a s t 2

p r e s c r i p t i o n s

f o r L i , D V P X ,

o r C B Z

2 0 6 3 8

h e a l t h

p l a n

m e m b e r s

D V P X

v e r s u s L i

v e r s u s C B Z

7 y e a r s

S A , S

C

S C a d j u s t e d r i s k w a s

2 . 7 t i m e s h i g h e r a n d

S A a d j u s t e d r i s k w a s

1 . 7 t i m e s h i g h e r f o r

D V P X t h a n L i

L a r g e s t u d y b u t

c o n f o

u n d i n g i s s u e s

n o t r e

s o l v e d

605


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T a b l e

2 .


S t u d y

D e s i g n

P o p u l a t i o n

s t u d i e

d

D i a g n o s i s /

s u b t y p e

N

T r e a t m e n t

S t u d y /

t r e a t m e n t

d u r a t i o n

S u

i c i d e

t y p e

R e s u l t s

C o m m e n t s

C o l l i n s a n d

M c F a r l a n d

2 0 0 8 ( 1 0 0 )


a n a l y s i s

M e d i c a i d

c l a i m

d a t a b a s e o f

a d u l t s

B D u

n s p e c i fi e d ,

o n m e d i c a t i o n

1 2 6 6 2

D V P X : 3 3 %

G B P N : 3 2 %

L i : 2 5 %

C B Z : 3 %

5 y e a r s

E R v i s i t s

f o r S

A

a n d

S C

A d j u s t e d H R v e r s u s

L i u s e r s f o r S A w e r e :

2 . 7

f o r D V P X

( p <

0 . 0

0 1 )

1 . 6

f o r G B P N ( n s )

2 . 8

f o r C B Z ( n s )

F o r S C , t h e a d j u s t e d

H R s w e r e :

1 . 5

f o r D V P X ( n s )

2 . 6

f o r G B P N

( p <

0 . 0

0 1 )

C B Z : n o t a v a i l a b l e

T h e d i f f e r e n t i a l e f f e c t o f

A E D s

o n S A a n d S C ,

i f

c o n fi r m e d ,

i s

h e u r i s t i c a l l y i m p o r t a n t

G i b b o n s

e t a l .

2 0 0 9 ( 1 0 1 )


p h a r m a c o -

e p i d e m i o l o g i c

s t u d y

M e d i c a l c

l a i m s

d a t a b a s e

B D

4 7 9 1 8

L i M O N O

A E D M O N O

A t l e a s t

1 y e a r

i n f o r m a t i o n

b e f o r e a n d

a f t e r i n d e x

e p i s o d e o f

i l l n e s s

S A

S A r a t e s w e r e t h e

s a m e f o r L i a n d

A E D s

B e f o r e a n d a f t e r

A E D s ,

S A r a t e s

d r o p p e d f r o m 7 2

t o 1 3 p e r 1 0 0 0

p a t i e n t - y e a r s

S t u d y s t r e n g t h s w e r e

M O N O g r o u p s w i t h

b e f o r e a n d a f t e r i n d e x

e p i s o

d e d a t a

C o n f o u n d i n g i s s u e s

w e r e

n o t r e s o l v e d

G i b b o n s

e t a l .

2 0 1 0 ( 1 0 2 )


p h a r m a c o -

e p i d e m i o l o g i c

s t u d y

M e d i c a l c

l a i m s

d a t a b a s e

B D ,

M D D ,

S Z ,

o t h e r


g r o u p s ,

e p i l e p s y ,

p a i n

d i s o r d e r s

1 3 1 , 1 7 8

G B P N b e f o r e

a n d a f t e r

i n d e x e p i s o d e

A t l e a s t

1 y e a r


b e f o r e a n d

w h i l e

t a k i n g

G B P N

S A


d i f f e r e n c e i n o v e r a l l

S A r a t e s b e f o r e

v e r s u s a f t e r G B P N

b u t t h e r e w e r e

s i g n i fi c a n t

r e d u c t i o n s i n S A

r a t e s s e e n f o r B D s

( 4 7 . 8 5 / 1 0 0 0 p e r s o n -

y e a r s v e r s u s 3 1 . 4

6 /

1 0 0 0 p e r s o n - y e a r s )

a s w e l l a s i n t h e

M D D a n d o t h e r

p s y c h i a t r i c g r o u p s

L i m i t a t

i o n s i n c l u d e d u s e

o f m e

d i c a l c l a i m s d a t a

n o t c l i n i c a l i n t e r v i e w s ,

p o s s i b l e u n d e r -

r e p o r

t i n g o f S A s a n d

n o S C


A E D =

a n t i e p i l e p t i c ; A P =

a n t i p s y c h o t i c ; B

D =

b i p o l a r d i s o r d e r ; B D - I =

b i p o l a r I d i s o

r d e r ; B D - I I =

b i p o l a r I I d i s o r d e r ; B D - N O S

=

b i p o l a r d i s o r d e r ; n o t o t h e r w i s e s p e c i fi e d

; C B Z =

c a r b a m a z -

e p i n e ; C - C A S A =

C o l u m b i a C l a s s i fi c a t i o n

A l g o r i t h m o f S u i c i d e A s s e s s m e n t ; C I =

c o n fi d e n c e i n t e r v a l ; D V P X =

d i v a l p r o e x ; E R =

e m e r g e n c y r o o m ; G B P N =

g a b a p e n t i n ; H

M O

=

h e a l t h m a i n -

t e n a n c e

o r g a n i z a t i o n ; H R =

h a z a r d

r a t i o ; L i =

l i t h i u m ; M D D =

m a j o r d e p r e s s i v

e

d i s o r d e r ; M O N O

=

m o n o t h e r a p y ; M S

=

m o o d

s t a b i l i z e r ; n s =

n o n - s i g n i fi c a n t ; O R =

o d d s

r a t i o ;

P B O

=

p l a c e b o ; R C T =

r a n d o m i z e d c o n t r o l l e d t r i a l ; S A =

s u i c i d e a t t e m p t ; S C =

s u i c

i d e c o m p l e t e d ; S I =

s u i c i d a l i d e a t i o n ; S Z =

s c h i z o p h r e n i a ; S Z A =

s c h i z o a f f e c t i v e ; V A L =

v a l p r o a t e .

a A c u t e m a n i a , m a n i a m a i n t e n a n c e ,

b i p o l a r d e p r e s s i o n ,

d e m e n t i a , a n d i m p u l s i v e a g g

r e s s i o n .

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tients (96 suicides in 4441 hospitalized patients),Sani et al. (90) found that longer term treatmentswith lithium and anticonvulsants were associatedwith decreased risk of completed suicide comparedto shorter term treatments which they assessed aspositively predicting completed suicide. This find-

ing should alert clinicians not to rely on lithium oranticonvulsants in the short-term management andprevention of suicidal behavior, particularly in abipolar population.

Anticonvulsants

Over the past decade, the use of lithium in thetreatment of bipolar disorder has declined and theuse of anticonvulsants (Table 2), particularlydivalproex, has steadily increased and they havebecome more commonly prescribed than lithium

(91, 92).Among the many AEDs, only five have FDA

approval for psychiatric conditions. Yet manymore are used off-label, sometimes despite credibledata with negative results. The use of gabapentinand topiramate for bipolar disorder may be twosuch examples. One randomized prospective study(93) of 378 patients with major affective disordersfound that carbamazepine was associated withmore suicidal events than lithium.

In another 12-month controlled clinical trialcomparing lithium, divalproex, and placebo in 372patients meeting criteria for recovery from a recentmanic episode, no significant difference was foundin the rate of suicide attempts between lithium anddivalproex (48). The study was not designed withsuicidal risk as a variable of study.

The first formal study to address the questionof the role of anticonvulsants in suicide preven-tion in bipolar disorder did not find a significantdifference among lithium, divalproex and carba-mazepine in suicide attempts and hospitalizationsfor suicidal intent (94). Furthermore, a potentialprotective role was implied for all three moodstabilizers by the fact that discontinuation of any

of them resulted in significantly heightened riskfor suicidal behavior. The study was retrospectiveand the results were limited to non-fatal suicidalbehaviors. In a subsequent retrospective month-by-month analysis of the records of 405 veterans(95), Yerevanian et al. compared the rates of non-lethal suicide behavior on and off lithium,divalproex and carbamazepine. For all threemood stabilizers and for the total group of moodstabilizers versus no treatment, there were highlysignificant differences in the rates of non-lethalsuicidal 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 stabiliz-ers as a group [v2 = 13.95 (df = 1), p < 0.0002].These results suggest that all three mood stabiliz-ers have a protective effect against non-lethal sui-cide attempts.

In a retrospective chart review analysis of 1306veterans with bipolar disorder from five VA Medi-cal Centers, Ahearn et al. (96) found that the low-est suicide attempt rate occurred with lithium anddivalproex combination (6.3 attempts per10000 months of exposure), followed by divalp-roex alone (7/10000), then lithium alone (7.7/10000). The authors interpreted their findings assuggesting that lithium and divalproex protectedagainst suicide attempts. Most of the suicideattempts occurred during periods off medications.

In a large retrospective study of patients with

bipolar disorder from two Health MaintenanceOrganization (HMO) databases, Goodwin et al.(91) found that the adjusted risk of death by sui-cide was 2.7 times higher in the divalproex groupcompared to the lithium group. The correspondingRR for non-fatal suicide attempts was 1.7. Fur-thermore, suicide risk without treatment was0.116% per year, about nine times the base rate forthat population of 0.012% per year. This studyalso suggests that lithium has protective effectssuperior to divalproex.

In 2005, the FDA requested suicidality datafrom randomized placebo-controlled clinical trialsof 11 AEDs from their sponsors and conducted ameta-analysis of 199 such studies. Published in2008 (97), the results were as follows: the adjustedrisk estimate for suicidal behavior or ideation was0.43% for drug patients and 0.24% for placebopatients. Of the total 104 events in this meta-analy-sis, 67 were suicidal ideation, 30 were attempts,three were preparatory acts, and four were com-pleted suicides. The FDA analyzed the data usingthree indication categories: Epilepsy (25%), Psychi-atric (27%), and a Large Group of Other Condi-tions. This report, however, did not specifically

identify a bipolar disorder group. Although themajority of reported events were suicidal ideation,it is noteworthy that the more serious events weremore likely in the AED group compared with pla-cebo, with an OR of 2.92 (95% CI: 1.47 – 6.47). Sui-cidal ideation events had an OR of 1.45 (95% CI:0.93 – 2.30), suggesting no significant differencebetween treatment and placebo groups. In assess-ing the overall risk in the psychiatric group, theOR was 1.51 but the CI was 0.95 – 2.45. Interest-ingly, among the 11 drugs studied, only carbamaz-epine and divalproex, the most commonly used

antiepileptics for bipolar disorder, had ORs below607


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1, 0.65 and 0.72, respectively, with very wide CIscontaining 1.

In January 2008, the FDA issued a warning tohealth care professionals regarding an increasedrisk of suicidality with AEDs. In the epileptic pop-ulation, the risks associated with not using or stop-

ping AEDs may outweigh the risk of suicide giventhe potential deaths due to and associated with epi-lepsy (98). Conclusions about the effects of AEDsin psychiatric, especially bipolar, populations werenot possible from the FDA study data. In 2013, anad hoc task force of the Commission on Neuropsy-chobiology of the International League AgainstEpilepsy (99) issued an expert consensus statementregarding AEDs and suicidality in light of theFDA alert. Noting the subsequent number of stud-ies with contradictory results, the group found itimpossible to determine whether AEDs are associ-

ated with suicidal behavior. They concluded thatsome AEDs can be associated with psychiatricproblems that can lead to suicidal ideation andbehavior but the actual suicidal risk was not estab-lished 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 comple-tions and suicide attempts. Divalproex was themost common mood stabilizer (used by 33% of subjects) followed by gabapentin (32%), lithium(25%), and carbamazepine (3%). There were 11suicide deaths and 79 attempts. Adjusted hazardratios versus lithium users for suicide attemptswere 2.7 for divalproex users (p < 0.001), 1.6 forgabapentin users (not significant), and 2.8 for car-bamazepine users (not significant). For suicidedeaths, the adjusted hazard ratios were 1.5 fordivalproex users (not significant), 2.6 for gabapen-tin users (p < 0.001), and not available for carba-mazepine users. For suicide completion,divalproex fared about as well as lithium but lith-ium appeared to be more protective against suicideattempts. Despite the large number of patients

with bipolar disorder, the study had its limitations,including reliance on automated pharmacy recorddata and possibly a brief duration of mood stabi-lizer use. Short-term comparisons are a major issuein such studies, since even lithium, the gold stan-dard of pharmacologic suicide prevention, requiresat least a year or two of treatment before its fullbenefits in suicide prevention become clear (89).

Gibbons et al. (101), in a pharmaco-epidemio-logical study of bipolar disorder patients in a largemedical claims database, compared the rates of sui-cide attempts associated with AEDs versus lithium

monotherapy. Suicide attempt rates were com-

pared before and after treatment and with a medi-cation-free control group. The study included47918 patients with bipolar disorder, for whomthere was a minimum of one year of informationboth prior to and after the index episode of illness.There was no difference in the rate of suicide

attempts between those treated with AEDs andlithium. Those, however, who were currently onAEDs had a significantly higher rate of suicideattempts prior to the initiation of the AEDs (72versus 13 per 1000 patient-years before and aftertreatment initiation, respectively). Under mono-therapy conditions, AEDs were protective againstsuicide attempts when compared to the no-treat-ment group, with a suicide attempt rate of 3 versus15 per 1000 patient-years, respectively. The majorstrengths of this study were its large number of patients with bipolar disorder, the discrimination,

importantly between monotherapy and treatmentwith concomitant medications, and the before andafter treatment design. The study, however, wasretrospective and non-randomized, and did notaddress the perennial problem of confounding byindication. It also suffered from the limitations of medical claims-based diagnoses and data.

In a subsequent report, using the same PharMet-rics medical claims database, Gibbons et al. (102)found that gabapentin use in non-psychiatric pop-ulations did not increase suicide attempts. Therewas, however, a significant reduction in suicideattempt rates in patients with bipolar disorder trea-ted with gabapentin as compared to rates beforetreatment. Similar reductions were noted in otherpsychiatric groups, including those with MDD.

In a large observational cohort study withn = 5130795, Arana et al. (103) found that amongthe bipolar disorder group (n = 5623) AEDs werenot associated with an increased risk for suicide-related events (1.13; 95% CI: 0.35 – 3.61) whencompared to the group without AEDs.

Søndergard et al. (104), using linkage data fromDanish national registers, examined the associa-tion between continued use of lithium and anticon-

vulsants and the risk of suicide. The treatment andcontinued use were assessed using pharmacy pur-chase data as an indicator of continued use.Although the rates of completed suicide werehigher during continued purchase of anticonvul-sants compared to continued purchase of lithium,for both groups over time the risk of suicide dimin-ished compared to the group that purchased a pre-scription only once (rate ratio for lithium = 0.20,95% CI: 0.10 – 0.38 and for AEDs = 0.25, 95% CI:0.19 – 0.41). Their conclusion was that, althoughlithium may be somewhat superior to AEDs in pre-

venting completed suicide, both groups benefit608

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from continuous treatment. The explanations forthis are complex, including the possibility that thetreatment process itself, rather than the specifictreatment agent, is important in preventing suici-dality. One could also argue that, in the longerterm, the less sick survive and hence the suicidality

rates diminish by virtue of that factor, independentof treatment modality. In addition, the assumptionof treatment use from pharmacy purchase data hasits own limitations.

A recent meta-analysis of the relationshipbetween divalproex treatment and suicidality (105)examined 13 placebo-controlled studies and onelow-dose controlled study of divalproex in a mixedpopulation including those with bipolar disorders,epilepsy, migraine, impulsive aggression, anddementia. No increased risk for suicide attempt orsuicidal ideation compared to the placebo controls

was found in AED-treated subjects; the overall ORwas 0.72 (95% CI: 0.29 – 1.84) and not significant.There were no completed suicides in the analyzedstudies.

In the first randomized clinical trial comparinglithium and valproate explicitly designed to test forthe prevention of suicidal behavior, Oquendo et al.(106) followed 98 patients with bipolar disorderwith past suicide attempts for 2.5 years. Patientswere randomized to lithium or valproate. Therewere no suicides in either group. Other suicideevents were not different between the groups,although the small sample size did not allow detec-tion of small differences between the two groups.The study highlights the feasibility of conductingprospective randomized controlled trials with sui-cide as the study outcome when the treatment armsconsist of medications with similar efficacies.

We found no studies specifically examining therole of lamotrigine and topiramate in patients withbipolar disorder. The role of lamotrigine is particu-larly important since it has gained wide usage inbipolar disorder. In a recent review of five random-ized trials of lamotrigine for bipolar depression, su-icidality was not addressed (107).

Antipsychotics

Antipsychotics are commonly used in bipolar dis-orders (Table 3). In recent years, second-genera-tion (atypical) antipsychotics are becomingfavored over first-generation, conventional (typi-cal) agents (108). These agents are also replacingtraditional mood stabilizers such as lithium,divalproex and carbamazepine. One recent studyin a Medicaid population showed a trend towardless frequent use of mood stabilizer monotherapy

and more frequent use of antipsychotic monother-

apy in patients with bipolar disorder during theperiod 2001 – 2004 (109).

The FDA has approved several atypical antipsy-chotics for the treatment of bipolar disorder in var-ious phases. More recently, this class of drugs hasbeen used for the treatment of bipolar depression

(110). Quetiapine and olanzapine –

fluoxetine com-bination have been approved for the treatment of acute bipolar depression. Aripiprazole and olanza-pine have been approved for maintenance treat-ment. There is, however, little known about theimpact of this group of medications on suicidalbehavior.

Clozapine reduces suicide attempts and hospital-izations for suicidality in schizophrenia and schizo-affective disorder and it outperforms olanzapine inthis regard (111). Meltzer et al. (112) conducted amulticenter randomized control trial comparing

olanzapine to clozapine in a group of schizo-phrenic and schizoaffective patients at risk for sui-cide. In this two-year study with 980 patients,clozapine was more helpful than olanzapine inreducing suicidal behavior (hazard ratio = 0.76,95% CI: 0.58 – 0.97, p = 0.03). There were five com-pleted suicides in the clozapine group and three inthe olanzapine group (p = 0.73). There was nobipolar group in this study. The Hennen andBaldessarini meta-analysis found that, with long-term treatment with clozapine, the overall RR of clozapine compared to other treatments was 3.3times lower. The six studies reviewed, however, didnot include patients with bipolar disorder.

In a Swiss retrospective study (113), 94 inpa-tients continuously maintained on clozapine for amean duration of 15 months were compared witha similar number in the pre-clozapine period. Thegroup maintained on clozapine had a significantlylower rate of suicidal behavior, including serioussuicidal behavior, compared to the pre-clozapinegroup in a follow-up period of equal duration (3%versus 28%, respectively). The ORs were 11.6(95% CI: 3.4 – 39.9) and 12.3 (95% CI: 1.6 – 97.5)for suicidal and serious suicidal behaviors, respec-

tively. Clozapine is the first treatment, with FDAapproval in 2003, for reduction of recurrent sui-cidal behavior in schizophrenia or schizoaffectivedisorders.

Two cohort studies using national data sourcesin Finland reported the risk of suicide while takingatypical antipsychotics (114, 115). The results of the first study (114) support a role for clozapine insuicide prevention in schizophrenia but not for ris-peridone, quetiapine, or olanzapine, which did nothave suicide-preventive effects. The second study(115), in a smaller cohort, could not demonstrate a

beneficial effect of clozapine.609


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T a b l e

3 .

A n t i p s y c h o t i c s

S t u d y

D e s i g n

P o p u l a t i o n

s t u

d i e d

D i a g n o s i s /

s u b t y p e

N

T r e a t m e n t

S t u d y /

t r e a t m e n t

d u r a t i o n

S u i c i d e

t y p e

R e s u l t s

C o m m e n t s

C a l a b r e s e

e t a l . 2 0 0 5

( 1 1 7 )

F i x e d d o s e ,

D B ,

P B O -

c o n t r o l l e d

R C T

O u t p a t i e n t s

a t 3 9

U S

c e n t e

r s

B D - I o r

B D - I I

e x p e r i e n c i n g

M D E b y

D S M - I V

c r i t e r i a

T o t a l N =

5 4 2

B D - I =

3 6 0

B D - I I =

1 8 2

Q U E T

3 0 0 m g

o r 6 0 0 m g

v e r s u s

P B O

8 w e e k s

S

I m e a s u r e d

b y M A D R A S

s u b s c a l e

S I d e c r e a s e d w i t h

b o t h d o s e s

P a t i e n t s w h o

‘ p o s e d a c u r r e n t

s e r i o u s s u i c i d a l

o r h o m i c i d a l r i s k

w e r e a l s o

e x c l u d e d ’

M e l t z e r e t a l .

2 0 0 3 ( 1 1 2 )

M u l t i c e n t e r ,

R C T

M e n a n

d

w o m e

n

c o n s i d e r e d

h i g h r i s k f o r

c o m m

i t t i n g

s u i c i d

e a t 6 7

m e d i c a l

c e n t e

r s i n

1 1 c o

u n t r i e s

S Z ,

S Z A

9 8 0

O L Z C L Z

2 y e a r s

S

A , r e q u i r e d

h o s p i t a l i z a t i o n ,

o r r e s c u e

i n t e r v e n t i o n

t o p r e v e n t

s u i c i d e

S u i c i d a l b e h a v i o r

o f C L Z l e s s t h a n

o f O L Z ( H R =

0 . 7

6 ,

9 5 %

C I : 0 . 5

8 - 0 . 9 7 ,

p =

0 . 0

3 )

C L Z g r o u p

r e q u i r e d f e w e r

h o s p i t a l i z a t i o n s ,

r e s c u e

i n t e r v e n t i o n s

N o B D g r o u p

H o u s t o n e t a l .

2 0 0 6 ( 1 1 8 )

P o s t h o c

a n a l y s i s

o f d a t a

f r o m a

D B R C T

I n p a t i e

n t s

D S M - I V B D - I

m a n i c o r

m i x e d

e p i s o d e

p a t i e n t s w h o

w e r e p a r t i a l l y

r e s p o n s i v e

t o a t l e a s t

2 w e e k s o f

L i M O N O o r

D V P X M O N O

5 8

P B O o r

O L Z

a d d e d t o

L i o r

D V P X

8 w e e k s

H

D R S - 3

S I r a t i n g

N o O L Z e f f e c t o n

s u i c i d a l i t y s c o r e

P o s t h o c a n d s m a l l

s t u d y

N o a c t u a l s u i c i d a l

e v e n t s

S u i c i d a l i t y w a s n o t

a n e n d p o i n t o f t h e

s t u d y

H e n n e n a n d

B a l d e s s a r i n i

2 0 0 5 ( 1 1 1 )

M e t a -

a n a l y s i s

P s y c h o

t i c

p a t i e n t s

t r e a t e

d w i t h

C L Z

c o n s i s t e n t l y

f o r 1 2

m o n t h s

v e r s u

s o t h e r

a g e n t s

S Z o r S Z A

( D S M - I I I - R

o r - I V )

2 4 0 5 6 4

c a s e s i n

6 s t u d i e s

O L Z v e r s u s

C L Z ,

B e f o r e

a n d o n

C L Z ,

C L Z

v e r s u s

o t h e r A P

a g e n t s

1 0 4 7 9 6

p e r s o n -

y e a r s o f

e x p o s u r e t o

C L Z a n d

4 4 7 2 8 1

p e r s o n -

y e a r s w i t h

o t h e r

t r e a t m e n t s

1

s t u d y : S A

4 s t u d i e s : S C

1 s t u d y :

S A / S C

p o o l e d d a t a

L o w e r o v e r a l l r i s k

o f s u i c i d a l

b e h a v i o r s w i t h

C L Z v e r s u s o t h e r

t r e a t m e n t s

( R R =

3 . 3 ,

9 5 %

C I : 1 . 7 – 6 . 3 ,

p <

0 . 0

0 0 1 )

S C : R R =

2 . 9 ,

9 5 %

C I : 1 . 5 – 5 . 7 ,

p =

0 . 0

0 2

N o B D g r o u p

T h e o n l y R C T d i d

n o t fi n d r e d u c e d

r i s k o f c o m p l e t e d

s u i c i d e

610

Yerevanian and Choi

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T a b l e

3 .


S t u d y

D e s i g n

P o p u l a t i o n

s t u

d i e d

D i a g n o s i s /

s u b t y p e

N

T r e a t m e n t

S t u d y /

t r e a t m e n t

d u r a t i o n

S u i c i d e

t y p e

R e s u l t s

C o m m e n t s

F o u n t o u l a k i s

e t a l . 2 0 1 1

( 1 2 3 )

M e t a -

a n a l y s i s

o f a l l

a v a i l a b l e

D B R C T s

w i t h

p l a c e b o

o r a

c o m p a r a t o r

o n t h e

e f fi c a c y o f

A R I i n B D

M u l t i - c e n t e r ,

i n p a t i e n t s

a n d

o u t p a

t i e n t s

M a n i c / m i x e d

e p i s o d e s

A c u t e b i p o l a r

d e p r e s s i o n

2 3 0 3

A R I v e r s u s

P B O

3 – 1 2 w e e k s

f o r a c u t e

s t u d i e s

2 6 – 7 4

w e e k s f o r

m a i n t e n a n c e

s t u d y

S

A ,

S C

N o S C

1 s t u d y h a d 1 S A

1 u n p u b l i s h e d

s t u d y h a d a t

l e a s t 1 ,

m a x i m u m 3

S A s o n A R I a n d

n o n e o n P B O

S u i c i d e r a t e s w e r e

n o t r e p o r t e d i n

a c u t e d e p r e s s i o n ,

a n d w e r e

n e g l i g i b l e f o r a l l

g r o u p s i n m a n i a

S t u d y n o t

d e s i g n e d w i t h

s u i c i d e r i s k

o u t c o m e

G o l d b e r g

e t a l . 2 0 0 5

( 6 1 )

C r o s s -

s e c t i o n a l

r e v i e w

F i r s t 1 0

0 0

p a t i e n t s

e n r o l l e d i n

S T E P - B D

B D - I ,

B D - I I ,

B D - N O S

T o t a l N =

1 0 0 0

B D - I =

7 1 0

B D - I I =

2 3 9

B D -

N O S =

4 1

S Z A =

7

C y c l o t h y m i c

=

3

8 5 %

t a k i n g

p s y c h o t r o p i c s

i n v a r i o u s

c o m b i n a t i o n s

C r o s s -

s e c t i o n a l

( m e d i c a t i o n s

a t t i m e o f

i n t a k e )

S

I u s i n g

t h e A D E

S I s i m i l a r t o t h o s e

t a k i n g o r n o t

t a k i n g e i t h e r L i o r

D V P X

S I w a s

s i g n i fi c a n t l y m o r e

p r e v a l e n t f o r

t h o s e t a k i n g S G A

t h a n t h o s e w h o

w e r e n o t ( 2 6 %

v e r s u s 1 7 % )


i n d i c a t i o n a n d

d e s i g n i s s u e

V i e t a e t a l .

2 0 0 8 ( 1 2 2 )

P r o s p e c t i v e ,

m i r r o r

d e s i g n

o b s e r v a t i o n a l

s t u d y

I n p a t i e

n t s

a n d

o u t p a

t i e n t s

D S M - I V

‘ a c u t e l y m a n i c

B D i n p a t i e n t s

w i t h a h i s t o r y

o f p o o r o r

p a r t i a l

a d h e r e n c e t o

m e d i c a t i o n ’

2 9


t r e a t m e n t f o r

a m a n i c

e p i s o d e a n d

l o n g - a c t i n g ,

i n j e c t a b l e R I S

M e a n p e r i o d

o f 2 y e a r s

S

A


r e d u c t i o n i n S A

f o u n d i n R I S

g r o u p

S m a l l

u n d e r p o w e r e d

s t u d y

Y e r e v a n i a n

e t a l . 2 0 0 7

( 1 2 0 )



w i t h m o n t h l y

a n a l y s i s o f

t h e r e c o r d

V e t e r a n s ,

i n p a t i e n t

a n d

o u t p a

t i e n t

B D - I ,

B D - I I ,

B D - N O S ,

S Z A

4 0 5

L i L i +

A P

D V P X

D V P X +

A P

C B Z

C B Z +

A P

M S M S +

A P

U p t o 8 y e a r s

S

C ,

S A ,

h o s p i t a l i z a t i o n

f o r s u i c i d a l

i n t e n t

N o n - l e t h a l s u i c i d e

e v e n t r a t e s w e r e

9 . 4 t i m e s h i g h e r

d u r i n g A P M O N O ;

3 . 5 t i m e s g r e a t e r

d u r i n g M S +

A P t h a n d u r i n g

M S M O N O


s t u d y w i t h

c o n f o u n d i n g b y

i n d i c a t i o n

611


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T a b l e

3 .


S t u d y

D e s i g n

P o p u l a t i o n

s t u

d i e d

D i a g n o s i s /

s u b t y p e

N

T r e a t m e n t

S t u d y /

t r e a t m e n t

d u r a t i o n

S u i c i d e

t y p e

R e s u l t s

C o m m e n t s

A h e a r n s e t a l .

2 0 1 3 ( 9 6 )



V e t e r a n s ,

i n p a t i e n t

a n d

o u t p a

t i e n t

B D - I ,

B D - I I

1 3 0 7

L i L i +

D V P X

D V P X

D V P X +

A P

C B Z

C B Z +

A P

M S M S +

A P

6 - y e a r r e v i e w

A v e r a g e

t i m e t a k i n g :

L i =

2 9 . 6

m o n t h s

D V P X =

2 4

m o n t h s

A P =

1 8 . 7

m o n t h s

S

A

A t y p i c a l A P h a d

h i g h e s t S A r a t e

M o s t S A s o n n o m e d s

O R s o f d r u g

e x p o s u r e v e r s u s

n o d r u g e x p o s u r e :

L i =

1 . 0

3 ,

9 5 %

C I : 0 . 6

1 – 1 . 7

3 ,

p =

0 . 9

3 4

D V P X =

1 . 0

8 ,

9 5 %

C I : 0 . 6

6 – 1 . 6

8 ,

p =

0 . 7 4 6

A P =

2 . 4 5 ,

9 5 %

C I : 1 . 5 5 – 3 . 8

6 ,

p =

0 . 0

0 1 )


i n d i c a t i o n

9 0 %

o f s u b j e c t s

a v e r a g e d

4 5 m o n t h s i n

6 y e a r s o f f m e d s

a n d m o s t o f t h e

S A s w e r e d u r i n g

o f f - m e d i c a t i o n

p e r i o d s

M o d e s t i n e t a l .

2 0 0 5 ( 1 1 3 )



w i t h m i r r o r

d e s i g n

I n p a t i e

n t s

t r e a t e

d

c o n t i n

u o u s l y

w i t h C

L Z f o r

a t l e a s t

6 w e e

k s

b e t w e

e n

1 9 6 2

a n d

1 9 9 4

S Z ,

S Z A , a n d

a f f e c t i v e

d i s o r d e r

u s i n g I C D -

1 0 c r i t e r i a

T o t a l

N =

9 4

S Z =

7 5

S Z A =

1 4

A f f e c t i v e

d i s o r d e r = 5

P r e - a n d p o s t -

C L Z p e r i o d s

w i t h a n d

w i t h o u t

a n t i d e p r e s s a n t s

a n d t y p i c a l

n e u r o l e p t i c s

A t l e a s t

6 w e e k s w i t h

m e a n

d u r a t i o n =

1 5

m o n t h s o f

b o t h p r e -

C L Z a n d

C L A p e r i o d s

S

A , s u i c i d a l

t h r e a t , S I

( M o t t o ’ s

g r a d e s 2 – 4 )

R a t e s o f s u i c i d a l

b e h a v i o r :

P r e - C L Z

p e r i o d =

2 8 %

( 2 6 / 9 4 )

C L Z p e r i o d =

3 %

( 3 / 9 4 )

P o s t - C L Z

p e r i o d =

1 8 %

( 3 / 1 7 )

C L Z p e r i o d

c o m p a r e d w i t h

t h e p r e - C L Z

p e r i o d :

S u i c i d a l

b e h a v i o r :

O R =

1 1 . 6 ,

9 5 %

C I : 3 . 4 – 3 9 . 9

S e r i o u s s u i c i d a l

b e h a v i o r :

O R =

1 2 . 3 ,

9 5 %

C I : 1 . 6 – 9 7 . 5

N o B D g r o u p

D u r i n g C L Z

p e r i o d , a l l p a t i e n t s

w e r e c o n t i n u o u s l y

h o s p i t a l i z e d u n l i k e

t h e p r e - C L Z

p e r i o d

612

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T a b l e

3 .


S t u d y

D e s i g n

P o p u l a t i o n

s t u

d i e d

D i a g n o s i s /

s u b t y p e

N

T r e a t m e n t

S t u d y /

t r e a t m e n t

d u r a t i o n

S u i c i d e

t y p e

R e s u l t s

C o m m e n t s

B a r a k e t a l .

2 0 0 4 ( 1 1 6 )


c a s e – c o n t r o l

s t u d y

I s r a e l i

u n i v e r s i t y

a f fi l i a t e d w i t h

a t e r t i a r y c a r e


h o s p i t a l

S Z o r S Z A

u s i n g I C D - 1 0

c r i t e r i a w i t h

S A p r i o r t o

h o s p i t a l i z a t i o n

T o t a l N =

7 5 6

S Z =

8 4 . 7

%

S Z A =

1 5 . 3 %

C L Z O L Z

R I S

5 y e a r s

S

A

O f t h e 3 7 8 w h o h a d

S A ,

1 6 . 1

%

w e r e

e x p o s e d t o S G A ,

3 7 %

i n c o n t r o l

g r o u p ( p =

0 . 0

0 0 0 1 )

P r o t e c t i v e O R :

S G A =

3 . 5 4 ,

9 5 %

C I : 2 . 4 – 5 . 3

)

R I S =

3 . 1

6 ,

9 5 %

C I : 1 . 9 – 5 . 3 ,

p =

0 . 0

0 1

O L Z =

1 . 7

6 ,

9 5 %

C I : 1 . 2 – 3 . 3 ,

p =

0 . 0

2

N o B D g r o u p

F e w t a k i n g C L Z

U l c i c k a s Y o o d

e t a l . 2 0 1 0

( 1 2 4 )


r e v i e w o f

a d m i n i s t r a t i v e

d a t a

A d u l t s

w i t h a t

l e a s t o n e

p r e s c

r i p t i o n

f o r o l d e r

a n t i p s y c h o t i c s

o r S G

A f r o m

1 1 - 1 - 0 2

t h r o u g h

1 2 - 3 1

- 0 5

B D ,

S Z , o r b o t h

u s i n g I C D - 9 /

I C D - 1 0 c o d e s

2 0 4 8 9 A P

u s e r s ,

8 9 8 5

p a t i e n t - y e a r s

B D =

1 7 , 4 2

2

S Z =

2 , 9

2 5

B o t h =

1 4 2

Z I P P B O

3 y e a r s

S

A ,

S C

C o m p a r e d t o o t h e r

S G A s ,

A R I d i d n o t

h a v e a n i n c r e a s e d

r i s k o f s u i c i d e e v e n t s

( c r u d e H R =

0 . 7

9 ,

9 5 %

C I : 0 . 4

8 – 1 . 3

0 ;

a d j u s t e d H R =

0 . 6

9 ,

9 5 %

C I : 0 . 4

2 – 1 . 1 4 )

H i g h c o m o r b i d i t y ,

h i g h c o n c u r r e n t

u s e o f o t h e r

m e d i c a t i o n s

K a r a y a l e t a l .

2 0 1 1 ( 1 2 5 )

P o o l e d a n a l y s i s

o f P B O -

c o n t r o l l e d

D B R C T s

2 2 t r i a l s

i n c l u d

e d

m i x t u r e o f

a d u l t

a n d

p e d i a

t r i c t r i a l s

i n S Z ,

B D ,

a n d S

Z A

B D - I ,

S Z ,

S Z A ,

v a r i o u s

d e m e n t i a ,

a c u t e b i p o l a r

m a n i a , t i c

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5 , 1

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1 7 / 2 2 s t u d i e s

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S

C ,

S A ,

S I ,

p r e p a r a t o r y

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A d u l t t r i a l s ( 1 9 / 2 2 )

T h e R R f o r


i n t h e B D t r i a l s

w a s 0 . 7

0 ,

9 5 %

C I : 0 . 0

3 3 1 – 1 . 4

8 7

c o m p a r e d t o P B O

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p e d i a t r i c c o m b i n e d

t r i a l s ,

R R =

0 . 5

6 ,

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C I : 0 . 0

3 5 –

9 . 0

1 3 c o m p a r e d

t o P B O

L a r g e l y s h o r t -

t e r m s t u d i e s

A D E =

A f f e c t i v e D i s o r d e r s E v a l u a t i o n ; A P =

a n

t i p s y c h o t i c ; A R I =

a r i p i p r a z o l e ; B D =

b i p o l a r d

i s o r d e r ; B D - I =

b i p o l a r I d i s o r d e r ; B D - I I =

b i p o

l a r I I d i s o r d e r ; B D - N O S =

b i p o l a r d i s o r d e r ; n o

t o t h e r w i s e s p e c i fi e d ;

C B Z =

c a r b a m a z e p i n e ; C - C A S A =

C o l u m b i a C l a s s i fi c a t i o n A l g o r i t h m o f S u i c i d e A s s e s s m e n t ; C I =

c o n fi d e n c e i n t e r v a l ; C L Z =

c l o z a p i n e ; D B =

d o u b l e b l i n d ; D V P X =

d i v a l p r o e x ; H D R S =

H a m i l t o n D e p r e s s i o n R a t i n g

S c a l e ; H R =

h a z a r d r a t i o ; I C D =

I n t e r n a t i o n a l S t a t i s t i c a l C l a s s i fi c a t i o n o f D i s e a s e s a n d R e l a t e d H e a l t h P r o b l e m s ; L i =

l i t h i u m ; M A D R S =

M o n t g o

m e r y –

A s b e r g D e p r e s s i o n R a t i n g S c a l e ; M D E =

m a j o r d e p r e s s i v e e p i -

s o d e ; M O N O

=

m o n o t h e r a p y ; M S =

m o o d s t a b

i l i z e r ; O L Z =

o l a n z a p i n e ; O R =

o d d s r a t i o ; P B O

=

p l a c e b o ; Q U E T =

q u e t i a p i n e ; R C T =

r a n d o m i z e d c o n t r o l l e d t r i a l ; R I S =

r i s p e r i d o n e ; R R =

r i s k r a t i o ; S A =

s u i c i d e

a t t e m p t ; S C =

s u i c i d e c o m p l e t e d ; S G A =

s e c o n

d - g e n e r a t i o n a n t i p s y c h o t i c ; S I =

s u i c i d a l i d e a t i o

n ; S T E P - B D =

S y s t e m a t i c T r e a t m e n t E n h a n c e m e n t P r o g r a m f o r B i p o l a r D i s o r d e r ; S Z =

s c h i z o p h

r e n i a ; S Z A =

s c h i z o a f -

f e c t i v e ; Z I P =

z i p r a s i d o n e .

613


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In a case – control study of a large group of schizo-phrenic and schizoaffective patients admitted to ahospital, Barak et al. (116) reported that patientswho had attempted suicide (n = 378) had a lowerrate of exposure to atypical antipsychotics than acontrol group of patients who had not attempted

suicide (16.1% exposure to SGA versus 37% in thecontrol group, p = 0.0001). This finding suggeststhe possibility of a suicide-protective effect, butdoes not rule out confounding by indication.

In a short-term randomized controlled trial of bipolar depression, patients on quetiapine hadgreater reductions in suicidal ideation ratings com-pared to patients on placebo (117).

Among 58 mixed-state patients with bipolar Idisorder, Houston et al. (118) found a greaterreduction in the mean HDRS Item #3 score (119),1 – 2 weeks after the addition of olanzapine to

mood stabilizer compared to placebo added to themood stabilizer. In contrast to the above findings,Goldberg et al. (61) reported from the STEP-BDstudy that, at baseline, suicidal ideation was moreprevalent among patients who were taking a sec-ond-generation antipsychotic than among thosewho 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 non-lethal suicidal behavior (attempts and hospitaliza-tions for impending suicidal behavior) was lowestduring mood stabilizer monotherapy (lithium, val-proate/divalproex, or carbamazepine), intermedi-ate during therapy with a mood stabilizer incombination with an antipsychotic, and highestduring antipsychotic monotherapy. There were3.48 suicide events/100 patient-years on mood sta-bilizer monotherapy versus 12.29 on a mood stabi-lizer and an antipsychotic versus 32.8 forantipsychotic monotherapy. For mood stabilizersversus mood stabilizers and antipsychotics, for allsuicide events, v2

= 15.13 (p = 0.0001). Comparingmood stabilizer monotherapy to antipsychoticmonotherapy, there was a more than 9-fold higher

rate of suicide events in the antipsychotic mono-therapy group (v2 = 28.29, p < 0.0001). The find-ings suggest that antipsychotic monotherapy inbipolar disorder is associated with a high suiciderisk which may be mitigated by the use of moodstabilizers, but this study did not resolve confound-ing by indication. In a subsequent study of a sub-group comprised of 161 patients with bipolardisorder in the same population who were givenantipsychotics, Koek et al. (121) found that non-lethal suicide events were more common with first-generation antipsychotic monotherapy compared

to second-generation antipsychotic monotherapy

(9 events/110 months of exposure versus 6 events/381 months of exposure, v2 = 9.65, p = 0.002).These differences between first- and second-genera-tion antipsychotics disappeared when antipsy-chotic medications were used in conjunction with amood stabilizer. There were no differences among

risperidone, olanzapine and quetiapine monothera-pies with respect to suicidal events. In the Ahearnet al. study (96) there was a significantly higherrate of suicide attempts in bipolar veterans main-tained on antipsychotics alone compared to notherapy (OR = 2.45, 95% CI: 1.55 – 3.86,p = 0.001).

In a long-term prospective study on outcomes forpatients with bipolar disorder maintained on long-acting risperidone, Vieta et al. (122) found that ris-peridone did not significantly affect the occurrenceof suicide attempts. The number of patients was

small (n = 28) and the study was underpoweredand not designed with specific suicide outcome mea-sures. In a recent meta-analysis of all available ran-domized controlled trials on the efficacy of aripiprazole monotherapy in the treatment of bipo-lar disorder, Fountoulakis et al. (123) found thesuicide rates to be negligible in mania groups trea-ted with aripiprazole, but results in bipolar depres-sion were not reported in the studies reviewed.

In a large post marketing study of aripiprazole,Ulcickas et al. (124) found that aripiprazole usedfor schizophrenia and bipolar disorder was notassociated with increased suicidality compared to acombined group of other antipsychotics. Theunadjusted rate of suicide attempts plus comple-tion was 2.069 events per 100 patient-years as com-pared to 2.399 for olanzapine, 3.233 forquetiapine, 1.969 for risperidone, and 4.852 forziprasidone (95).

In a pooled analysis of suicidality in double-blind placebo randomized controlled trials of ziprasidone, Karayal et al. (125) did not find statis-tically significant differences in treatment-emergentsuicidality between ziprasidone and placebo in 22clinical trials involving 5123 subjects treated either

with placebo or ziprasidone. These were short-termtrials with no pediatric trial (n = 3) longer thaneight weeks and only five of 19 studies in the adultpopulations exceeding five weeks.

To our knowledge, the published data on theeffects of typical, first-generation antipsychotics onsuicidal behavior in patients with bipolar disorderare limited to a single study (121).

Benzodiazepine and hypnotics

An increasing body of literature suggests that

anxiety is an independent risk factor for suicidal614

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behavior in patients with major affective disorders.In a cross-sectional chart review study of 2778 out-patients with various diagnoses, Diefenbach et al.(126) found that self-reported anxiety symptomswere associated with a 2-fold increase in the likeli-hood 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 foundthat, in a group of 1356 patients with bipolar disor-der in remission, those given benzodiazepines wereat higher risk for relapse of mood episodes com-pared to those without benzodiazepine therapy.The authors also tried to address whether this asso-ciation was confounded by indication by perform-ing a parallel analysis of gabapentin thatprescribers may have used as an anxiolytic. Gaba-pentin was not associated with poorer outcomes.

The issue of suicidal risk with benzodiazepines,however, was not addressed. It may be possible toextrapolate that a higher relapse rate may increasesuicidal risk.

In a Swedish study of autopsies of suicide vic-tims (128), toxic serum concentrations of zolpidemwere found in a high proportion of cases. Whetherzolpidem contributed to the suicides or was simplyused as an overdose method is not clear. In anotherstudy, high levels of eszopiclone were found amongsuicide attempters (129). These studies, while notproving causation, should sensitize clinicians to thepossibility of an association.

In a cohort of 120 patients with bipolar disorderfrom the STEP-BD study, Simon et al. (130) foundthat the presence of a lifetime history of a comor-bid anxiety disorder more than doubled the oddsof having a past suicide attempt. Furthermore,patients with current anxiety disorders had morethan double the odds of current suicidal ideationcompared to patients with bipolar disorder withoutsuch comorbidity. Patients with bipolar disorderwith current anxiety disorders had more severe sui-cidal ideation and a higher expectancy of futuresuicidal behaviors. The authors did caution, how-

ever, that some of this increase might reflectgreater severity of the bipolar disorder.

One difficulty in assessing the contribution of these drugs to increased suicidality is that insomniacan be an independent risk factor for suicidality inbipolar disorder (131). Brower et al. (132) per-formed a secondary analysis of the National Com-orbidity Survey Replication Data for 5692respondents and found that users of zolpidem orzaleplon were 5.7, 7.6, and 9.3 times more likelythan non-users to report suicidal thoughts, plansand attempts, respectively. After adjusting for sex,

age, race/ethnicity, marital and poverty status, 11

lifetime physical conditions, mental health disor-ders in the past 12 months and insomnia, theyfound the adjusted ratios to be 2.2, 1.9, and 3.4 forsuicidal 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 psy-chotropic drugs, however, there are insufficientdata to make informed clinical judgments.

(ii) The effect of these psychotropic drugs may beobserved in the short term or may be observedonly after long-term use. In general, increasingsuicidality occurs rather early in treatment,

such as with antidepressants, while preventionof suicidality usually requires long-term treat-ment, such as with lithium.

(iii) There are some predictors of treatment-emer-gent suicidality, including treatment-emergentagitation, anger, insomnia, prolonged dyspho-ria, and mixed states. It is important to recog-nize that these predictors of treatment-emergent suicidal risk may be different fromthe general suicide risk factors for patientswith bipolar disorder, e.g., race, family his-tory, or cocaine abuse, and therefore need tobe anticipated and monitored closely (133).

(iv) Lithium is the best-studied psychotropic drugwith respect to suicide prevention in bipolardisorders. The mechanism of this anti-suicidaleffect is unclear, but the frequent visits andmonitoring of patients on lithium with associ-ated psychosocial support and attention mayexplain some of the benefits. Since not all stud-ies have found anti-suicidal effects for lithium,it is important to investigate the characteristicsof responders versus non-responders.

(v) Available evidence suggests that antidepressantuse in bipolar disorder contributes to rather

than prevents suicidal behavior. With respect toiatrogenic suicidality, unipolar and bipolar disor-ders may be very different disorders. The effectsof antidepressants on suicidality in unipolardisorders should not be extrapolated to bipolardisorders. Antidepressants may be protective inunipolar disorder and may have the oppositeeffect in bipolar disorder. In fact, the de novodevelopment of suicidality after the introduc-tion of an antidepressant should raise one’sindex of suspicion of a bipolar diathesis andfuture bipolar course. There is some evidence

for this assertion in children and adolescents615


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(134), but whether this is true in at least a sub-group of adult patients with bipolar disorder isinteresting heuristically and practically. Onemay posit that antidepressant-induced suicidal-ity may be an external validator and eventuallyan endophenotype of bipolar disorder. Despite

the aforementioned cautionary findings, ouropinion is that there is a place for judicious useof antidepressants for shorter periods of time inpatients with treatment-resistant bipolardepression. Perhaps antidepressants can evenbe used as maintenance treatment in bipolar dis-order with careful follow-up conditions. Akis-kal et al. (14) and Rihmer and Gonda (135)have proposed that the suicide-inducing poten-tial of antidepressants is related to occult bipo-larity. If this is the case, clinicians must have ahigh 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, mostresearch literature does not support that asso-ciation in bipolar populations. In the FDAmeta-analysis, the most commonly usedAEDs in bipolar disorder, namely divalproexand carbamazepine, did not show a statisti-cally significant association with suicidalbehavior in the psychiatric group. Divalproexappears to have some protective effect againstsuicidality when compared to no treatmentover the long term. Divalproex does notappear to acutely induce suicidality. Thesefindings are somewhat reassuring, becausemany patients with bipolar disorder who donot take lithium for various reasons are main-tained on divalproex. Among patients withbipolar disorder, the status of other anticon-vulsants with respect to suicidal risk is cur-rently unknown.

(vii) The effect of second-generation antipsychoticswith respect to suicidal risk in patients withbipolar disorder is not clear. There are no ran-domized controlled trials addressing this issue.

The few available studies have used differentmethodologies that are not comparable. If weextrapolate from schizophrenia studies, cloza-pine appears to have the most promise amongantipsychotics. Clozapine studies are neededin bipolar disorder. The studies that examinedantipsychotics in pure bipolar populations(61, 96, 117, 118, 120, 122, 123) had variousfindings: increasing, decreasing and unchang-ing suicidality associated with antipsychoticuse. These studies, however, had various limi-tations, including unresolved confounding by

indication.

(viii) Vigilance is required when using benzodiaze-pines and the newer hypnotics since the dataregarding their effects on suicidality in bipo-lar disorder populations are very limited.

(ix) During polytherapy, a common practice, lith-ium and some AEDs appear to mitigate the

suicide-promoting effects of antidepressants.Similarly, they also may mitigate any antipsy-chotic suicide-associated effects. Few studieshave examined the effects of specific psycho-tropic drug combinations on suicidality inbipolar disorder.

Discussion

This broad review of the impact of psychotropicmedications on suicidality in patients with bipolardisorder highlights the significant gaps in our

understanding of the complicated relationshipbetween psychotropic drugs and suicidal behavior.

Suicide is multifactorial. Suicidal ideation mayhave a different pathogenesis from either suicideattempt or suicide completion and may respond todifferent drugs and different psychosocial interven-tions. Understanding the differential contributionsof biological, social and psychological factors inthe genesis of the various presentations of suicidal-ity is of importance. No studies have adequatelyaddressed these contextual issues when reportingthe connection between psychotropic drug use andsuicide. Studies of large national and insurancedatabases are particularly vulnerable to this limita-tion, since they rarely address the psychosocialaspects of suicide in a reliable and meaningful way,particularly in the absence of clinical information.

Another important limitation in evaluating therelationship between psychotropic drug use andsuicidal behavior is the lack of adequately poweredrandomized controlled trials to assess the relation-ship of any drug to suicidality. Such studies wouldideally involve explicit standardized and validatedoutcome measures determined a priori . Currentstudy approaches have been multiple: pharmaco-

epidemiologic studies, clinical case series,case – control studies, and meta-analyses of avail-able literature. Most are retrospective. Few studiesare prospective with suicide as the end point.Although prospective in nature, industry-spon-sored trials are of short duration and not designedto assess suicide-promoting or suicide-protectiveproperties of the drugs studied. The most seriousoutcomes, completed suicides and seriousattempts, in those studies have been rare events.Therefore, they have been unhelpful in clarifyingthe psychotropic drug and suicidal risk connection.

Designing prospective randomized controlled trials616

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with suicide as the primary outcome of the study isdifficult because of practical and ethical con-straints.

Another serious limitation in most of the studiesreviewed is confounding by indication. When stud-ies are retrospective, it is difficult to assess whether

a particular psychotropic was prescribed becausethe patient was suicidal or decompensating, or thepatient became suicidal after being prescribed thatmedication. There is a gap between finding anassociation and establishing causation. The avail-able literature is far from closing this gap. Theideal remedy for this limitation is to conduct largeprospective randomized controlled trials withmonotherapy or specified combinations withclearly defined suicidal outcome parameters as theoutcome measures.

Complicating matters further is the issue of

polytherapy which appears to be a common treat-ment choice in all phases of bipolar disorder. By2007, more than 70% of patients with bipolar dis-order were taking two or more psychotropics (40,136). In 2008, Baldessarini et al. (40) found that,within one year of initiating treatment for bipolardisorders, the rate of monotherapy decreased from67% to 31%. A total of 32% of patients receivedpolytherapy treatment and 37% of patientsreceived no psychotropic medications. There arefew polytherapy and fixed combination studies inbipolar disorder populations. Polytherapy createsdifficulties in many ways. First, it makes the issueof confounding by indication more problematicbecause typically more medications are prescribedto sicker patients who may be more prone to sui-cide. Secondly, in polytherapy the various medica-tions may interact in unpredictable ways withrespect to suicidality. Even if we understand indi-vidual drug effects, complex combination effectsare virtually impossible to assess unless such com-binations are specifically studied.

Although not examined in detail, it is importantto consider two other related issues. One is thattreatment non-adherence is notoriously prevalent

in bipolar disorder (137). The other is the very sig-nificant effect of psychotropic withdrawal, particu-larly rapid withdrawal, on suicidal risk. Both of these issues may be missed in research reports thatrely on non-clinical databases. Even in clinicalpopulations, systematic assessment of treatmentadherence is often not reported. Future studiesmust pay careful attention to these issues, espe-cially in smaller studies with infrequent eventswhere one or two misclassified events can drasti-cally change the statistics.

Prospective, randomized, controlled trials are

necessary to clarify the relationship of suicide risk

and psychotropic drugs, as monotherapy or incombinations. Studies need to be designed withspecific suicidal behaviors as outcomes. The ethicaland practical hurdles of such potential studies needto be resolved. It is clinically unwise and scientifi-cally untenable to extrapolate from the available

but limited literature of psychotropic drug classeffects to individual or combination drug treat-ments. Addressing these concerns will be a longprocess. In the meantime, clinical vigilance, judi-cious use of psychotropic drugs, consideration of all relevant and contextual suicide risk factors,adequate duration of follow-up and patientinvolvement in treatment decision-making shouldguide clinical practice.

Disclosures

The authors, or any of their immediate family members, donot have any potential conflicts of interest to report.

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