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Journal of Affective Disorders 115 (2009) 1 – 10

www.elsevier.com/locate/jad

Review

A review of panic and suicide in bipolar disorder:

Does comorbidity increase risk?

Edward J. Kilbane , N. Simay Gokbayrak, Igor Galynker, Lisa Cohen, Susan Tross

Beth Israel Medical Center, Department of Psychiatry, NYC, NY, United States

Received 7 April 2008; received in revised form 13 September 2008; accepted 14 September 2008

Available online 8 November 2008

Abstract

Introduction: Bipolar mood disorder carries a serious suicide risk. Panic disorder, which also confers an independent risk of
suicide and psychiatric comorbidity, in general has been found to amplify suicidality in mood-disordered patients. This article
assesses the available literature on how panic and suicide relate to each other in bipolar mood-disordered patients.
Methods: We conducted a search on Medline and PsycINFO using the keywords “anxiety”, “attempted suicide”, “completed
suicide”, “mortality”, “self-harm” in combination with “bipolar”, “manic depression” and “panic”. Twenty-four articles were
included in the evaluation.

Results: 14 papers support increased risk, 9 papers do not support increased risk, and 3 papers are inconclusive.

Conclusions: The presence of comorbid panic disorder in individuals with bipolar disorder may confer an increased risk of
suicide risk. Some papers' reviewed have conflicting conclusions but the majority of papers support an increased risk. This is
consistent with a recent (2008) literature review supporting increased risk of suicide in bipolar patients with comorbid anxiety
disorders. Future research should study specific bipolar subgroups, focus on anxiety and panic symptoms rather than diagnosis,
and look at the role of specific pharmacological treatment in patients with comorbid mood and anxiety disorders.

© 2008 Elsevier B.V. All rights reserved.

Keywords: Anxiety; Attempted suicide; Completed suicide; Mortality; Self-harm; Bipolar; Manic depression; Panic

Contents

1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
3.
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2

3.1.
Bipolar NOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
3.2.
Bipolar I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4

3.3.
Bipolar mixed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4

3.4.
Bipolar rapid cycling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4

3.5.
Bipolar NOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5

3.6.
Bipolar I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6

Corresponding author. Tel.: +1 212 844 1946; fax: +1 212 420 4397. E-mail address: ekilbane@chpnet.org (E.J. Kilbane). X

0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi: 10.1016/j.jad.2008.09.014X
2 E.J. Kilbane et al. / Journal of Affective Disorders 115 (2009) 1–10

3.7. Bipolar rapid cycling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

3.8. Bipolar psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

3.9. Bipolar NOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

3.10. Bipolar I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

4. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

found to amplify suicidality in mood-disordered patients (


Goodwin and Hoven, 2002; Nemeroff 2002; MacK-
innon et al., 1998; Frank et al., 2002; Freeman et al.,
2002; Savino et al., 1993; Chen and Dilsaver, 1995) and
comorbidity of mood and anxiety disorders is consid-ered
to be the rule rather than the exception ( Nemeroff,
1. Introduction 2002). However, few investigations have looked
specifically at the role of panic in this regard. Given the
possibility that patients who meet criteria for bipolar
disorder and panic disorder may represent a clinical
Bipolar and panic disorders are common and serious subgroup presenting a particularly high suicide risk (
psychiatric conditions, each of which confers increased MacKinnon et al., 2005), we have reviewed available
risk of suicide attempt or completion. According to one literature that present data relating to this issue.X
study, bipolar mood disorder (BD) carries an 18.9% risk
of suicide attempt with numerous factors proposed as
contributors ( Goodwin and Jameson, 1990). Panic
disorder (PD) also has been reported to pose an 2. Methods
independent risk of suicide ( Weissman et al., 1989,
Sareen et al., 2005). Psychiatric comorbidity has been
Our review evaluates suicide in bipolar disorder
populations across all age groups who present with
comorbid panic symptoms. We conducted a literature 3. Results
search on Medline and PsycINFO dating between 1950
and August 2007 employing the following keywords:
comorbidity, completed suicide, attempted suicide,
mortality, and self-harm in combination with bipolar The following papers support an increased risk of
disorder, manic depression and panic disorder. We suicide in people with comorbid bipolar and panic
excluded all articles whose primary focus was on: disorders. Study information is listed in Table 1.X
alcohol/substance abuse, schizophrenia, schizoaffective
disorder, personality disorders, unipolar depression,
trauma, physical/sexual abuse, medical disorders,
insomnia, primary care, insight, and pharmacology. 3.1. Bipolar NOS
Twenty-four original research articles were included in

The bipolar NOS group consists of bipolar illness that


does not fit into the other subtypes of bipolar disorder.
One large (N =229) prospective study ( Clay- ton, 1993)
of patients with bipolar disorder concluded that anxiety
symptoms (psychic anxiety, worry, and panic attacks) are
the evaluation and are summarized as follows: support an predictive of short term or “early” (within one year of
increased risk of suicide, do not support an increased risk initial assessment) suicide risk in patients with major
of suicide, or are inconclusive. Subtypes of bipolar affective disorders (including “manic-depressive illness”).
disorder evaluated include: bipolar disorder NOS, Clayton comments that most subjects did not meet
bipolar-I depression and mania, bipolar-II depression and criteria for panic disorder, but does not comment on the
hypomania, bipolar disorder with mixed states, bipolar number that did. Furthermore, she emphasizes that
disorder with rapid mood switching, and bipolar disorder anxiety symptoms, rather than diagnosis, are predictive of
with psychosis. Some papers are included in more than suicidal behavior.X
one section as they use bipolar samples from more than
one subgroup. In addition, all papers specify rates of
panic disorder within the bipolar subgroup, but in some
papers only anxiety symptoms are measured in relation to Several retrospective studies have specifically exam-ined
suicide. As anxiety and panic symptoms can serve as a the effect of panic disorder on suicide in patients with
proxy for panic disorder, these papers are also included in bipolar disorder NOS. Two studies ( Simon et al., 2004,
the review.
2007) used 475 and 120 subjects, respectively,X

E.J. Kilbane et al. / Journal of Affective Disorders 115 (2009) 1–10


3
Table 1

Panic increases risk of suicide in bipolar disorder.


Study author/year
Study design
Sample (N)
Study population
Measurement
Outcome

Clayton (1993)X
Prospective
299
NIMH Collaborative Program
N/A
Mean psychic anxiety rating

on Psychobiology of Depression

N4.5 predict suicide risk


Simon et al. (2007)X
Retrospective
120
STEP-BD
MINI, BSI, SBQ
Suicide attempts OR=2.1;

suicide ideation OR=4.3


Young et al. (1993)X
Retrospective
81
University of Toronto
SADS-LV
High anxiety group (including PD)=

Bipolar Clinic

increased suicide attempts


Simon et al. (2004)X
Retrospective
475
STEP-BD
DSM-IV, QLES,
Suicide attempts OR=2.45

RIFT

Chen and Dilsaver (1996)X


Retrospective
168
ECA
DSM-III, DIS
Lifetime suicide rate 31.4%
Goodwin andX
Retrospective
421
NCS
WHO-CIDI
BP correlates with early onset
Hamilton (2001)X

fearful panic, AOR=7.9


Goodwin andX
Retrospective
1689
ECA
DIS
BP correlates with early onset
Hamilton (2002)X

fearful panic, AOR=7.9


Dilsaver et al. (2006)X
Retrospective
115
Starr County, Texas
SCID-CV
Suicidal ideation OR=2.6

outpatient psychiatric clinic

Goldstein et al. (2005)X


Retrospective
405
COBY
DSM-IV, SADS
Suicide attempts OR=4.0
Frank et al. (2002)X
Retrospective
66
WPIC, Pittsburgh, PA
DSM-IV, SCID,
Suicidal ideation OR=4.2

HDRS, BMRS

Dilsaver et al. (1997)X


Retrospective
129
HCPC
DSM-III-R, DSM-
Suicide risk OR=21.5

IV, RDC, SADS

Dilsaver andX
Retrospective
44
HCPC
DSM-III-R, SCID,
Suicide risk OR=21.5
Chen (2003)X

SADS, RDC

Balazs et al. (2006)X


Retrospective
100
Budapest, Hungary hospital
MINI
Higher rate of suicidal ideation

and PD in mixed depression


MacKinnon et al.X
Retrospective
603
NIMH Bipolar Disorder
DSM-III-R, RDC,
Rapid switching associated with
(2003)X

Genetics Initiative
DIGS
increased PD and suicide attempts

NIMH=National Institute of Mental Health. STEP-BD=Systematic Treatment Enhancement Program fro Bipolar Disorder.
ECA=Epidemiological Catchment Area. NCS=National Comorbidity Study. COBY=Course and Outcome of Bipolar Youth. WPIC=Western
Psychiatric Institute and Clinic. HCPC=Harris County Psychiatric Center, Texas.

group; subjects with comorbid panic disorder were more


than twice as likely to attempt suicide. The earlier study
from the Systematic Treatment Enhancement Program for cites rates of comorbid panic and bipolar disorder ranging
Bipolar Disorder (STEP-BD). The more recent study from 10.6–62.5%. It reports a prevalence of current panic
demonstrates that lifetime anxiety disorders, including disorder of 8% and lifetime panic disorder of 17.3%.
panic disorder, are associated with current and lifetime Moreover, subjects with comorbid panic disorder +
suicidal ideation as measure by the Beck Scale for agoraphobia (current and lifetime) had statistically
Suicidal Ideation and the Suicide Behaviors Question- significant shorter durations of euthymic mood compared
naire. It also reports increased suicide attempts in this to subjects without panic disorder. Bipolar subjects with
comorbid panic disorder-agora-phobia (current only) also SADS-LV, patients were divided into High and Low
had statistically significant shorter durations of euthymic Anxiety Groups. Those in the High Anxiety Group were
mood compared to subjects without panic disorder. In this more likely to have suicide attempts. Furthermore,
sample, panic disorder with and without agoraphobia was patients were divided on the presence or absence of
significantly related to increased suicide attempt rate generalized anxiety disorder and panic disorder; 32% met
compared to subjects with no anxiety disorder. The criteria for one or both of these disorders and 56% of the
authors suggest High Anxiety Group met criteria for one or both of these
disorders. They conclude, like Clayton, that anxiety
symptoms, rather than diagnosis, are related to morbidity
and outcome measures such as suicidal behavior.X
that early anxiety may be a precursor or prodrome to
bipolar disorder and that they may share a genetic /
biological commonality.
Chen and Dilsaver (1996) report the comorbidity of
panic disorder among bipolar and unipolar subjects (N
=168) as 20.8% and 10%, respectively. They com-
A study ( Young et al., 1993) of 81 patients with bipolar
pared lifetime rates of suicide attempts between indivi-
disorder I and II (combined for analysis) examined
duals with bipolar disorder, unipolar disorder, and
whether anxiety symptoms in bipolar disorder have an
controls. Of their bipolar sample, 29.2% had a
impact on suicidal behavior. Using six items from the
lifetimeX
4 E.J. Kilbane et al. / Journal of Affective Disorders 115 (2009) 1–10

suicide attempts but was associated with


an increased report of suicidal ideation.
suicide attempt; 29% of the sample Goldstein et al. (2005) used a pediatric
without panic disorder had a lifetime sample (N =405) drawn from the Course
suicide attempt and 31.4% of the sample and Outcome of Bipolar Youth (COBY)
with panic disorder had a lifetime suicide database and found that 32% had a least
attempt. They conclude that comorbidity one lifetime suicide attempt. Of suicide
of panic disorder may contribute to attempters in this sample, 23% were
increased suicidality in bipolar patients. diagnosed with bipolar NOS, 67% with
bipolar I, and 10% with bipolar II;
diagnoses were not delineated for
analysis. Of bipolar patients who
Two studies by Goodwin and Hamilton attempted suicide, 12% were diagnosed
(2001, 2002) use data from the National with panic disorder (statistically
Comorbidity Survey and significant from non-attempters, p b
Epidemiological Catchment Area Survey 0.001). Their findings suggest that the
with sample sizes of 421 and 1,689 strongest predictors of suicide attempt in
respectively. They evaluated panic patients with bipolar disorder are
attacks as a predictor for subsequent clinical/illness history variables
psychopathol-ogy and described four (psychiatric hospitalization, self injurious
subtypes of panic (early onset without behavior, mixed episodes, psychosis) and
fear, early onset with fear, late onset comorbid conditions (substance use
without fear, late onset with fear). Early disorder, panic disorder).X
onset includes age ≤20 years and late
onset includes age N 20 years; fear
following first panic attack was assessed
by asking the question “After the first 3.2. Bipolar I
attack, were you immediately afraid of
having another attack?” The four groups
were compared across a number of
variables including mental disorders, Two retrospective studies ( Frank et al.,
suicidal ideation, and suicide attempts. 2002; Goodwin and Hamilton, 2001)
They conclude that early onset fearful support increased risk of suicidal ideation
panic is associated with increased and behavior. The former assessed 66
incidence and earlier onset of subjects with bipolar disorder I using Panic-
psychopathology as well as increased Agoraphobic Spec-X
suicidal behavior. Of note, bipolar
disorder is an independent correlate of
early onset fearful panic, with an adjusted
odd ratio=7.9 (p b 0.05).X trum-Self Report (PAS-SR) in order to
quantify typical and atypical symptoms of
panic. These include somatic symptoms,
anticipatory anxiety symptoms, and agora-
phobia. Subjects were divided into High
Two retrospective studies assessed
(≥35) and Low (≤35) groups depending on
adolescents with bipolar disorder NOS.
their PAS-SR score. Forty-eight and a half
Dilsaver et al. (2006) studied Latino
percent of subjects with High scores had
adolescents (N =115), 47.8% of whom
suicidal ideation and 18.2% of subjects with
had comorbid panic disorder. The Low scores had suicidal ideation. The
presence of panic disorder was not former group was four times more likely to
associated with an increased number of report suicidal ideation (odds ratio=4.2).
The second study used data from the IEPD, and 57.9% had both. IEPD is 20
National Comorbid-ity Survey and was times more common (odds ratio=21.5, p
described previously. As previously stated b 0.0001) in depressive-mania than in
early onset fearful panic is associated with pure-mania. The third study ( Balazs et
increased suicidal behavior. The risk of al., 2006) defined mixed depression as
mania as a psychiatric comorbidity in early major depressive disorder or dysthymic
onset panic with fear and late onset panic disorder plus ≥3 co-occurring hypomanic
with fear was statistically significant (p b
symptoms. Mixed depression subjects (N
0.05) with adjusted odds ratios of 43.4 and
=63) had significantly higher rates of
17.1 respectively.
thinking about death, thinking about self-
harm, thinking about suicide, thinking
about suicide plans, and panic disorder
3.3. Bipolar mixed compared to those without mixed
depression. Almost half of the suicide
attempters with mixed depression had
comorbid panic disorder; none of the
Three retrospective studies using subjects suicide attempters without mixed
with a mixed bipolar state support depression had comorbid panic disorder. X
increased risk of suicide when comorbid
panic disorder is present. Two studies (
Dilsaver et al., 1997; Dilsaver and Chen,
2003) assessed social phobia, panic 3.4. Bipolar rapid cycling
disorder, and suicidality during the
“manic” state of subjects with pure and
depressive-mania; subjects with
depressive-mania are reviewed now and One retrospective study ( MacKinnon
subjects with pure euphoric mania are et al., 2003) assessed families with a
described later in this paper. Intra- pro-band of bipolar disorder. Subjects
episodic panic disorder (IEPD) is (N =1574) with rapid switching were
discussed as panic disorder concurrent more than twice as likely to have panic
with the manic state ( Dilsaver et al., disorder as those without rapid
1997). Of 19 patients with depressive- switching. The authors comment thatX
mania, 63.2% were suicidal, 84.4% had

E.J. Kilbane et al. / Journal of Affective Disorders 115 (2009) 1–10


5

The following papers do not support an


increased risk of suicide in people with
heretofore suicide and rapid switching comorbid bipolar and panic disorders.
have not been linked, but their data Study information is listed in Table 2.X
supports an association and this may be
similar to the association observed in
bipolar mixed states. The authors
conclude that rapid switching in familial 3.5. Bipolar NOS
bipolar disorder is common and
associated with both increased panic
disorder and suicide attempts.
Six papers, two using adolescent
samples, do not support increased risk of
suicide in subjects with bipolar disorder
and comorbid panic disorder. One
prospective study ( Warshaw et al., 2000) behavior (p =0.032). This finding
examined suicidal behavior in 498 was not replicated
subjects with a current or past diagnosis (p = 0.097, odds ratio = 0.42) in
of panic disorder in order to determine a second logistic
the effect of several variables including
psychiatric comborbidity. Several
variables (i.e. past suicidal behavior, regression analysis that only included
current major depressive episode, variables that were significant in the
borderline personality disorder etc.) were
first regression analysis.
predictive of suicidal behavior; bipolar or
schizoaffective disorder (grouped
together) was not a predictor of suicidal
behavior (p =0.47); being married and Grunebaum et al. (2006) describe a
having children were protective factors. stress-diathesis model of suicidal
The other prospective study ( Slama et behavior in bipolar patients [i.e. inter-
al., 2004) of bipolar subjects (N =307) action of stress (mood disorder) and
with and without a history of suicidal diathesis (aggres-sive traits and suicidal
behavior included univariate analysis for ideation)]. In their retrospective study of
all clinical and demo-X 96 subjects, suicide attempters and non-
attempters did not differ in manic
symptom severity, general
psychopathology, and frequency of panic
Table 2 attacks, amongst other variables.
Attempter did have higher scores of
aggression, impulsivity, and recent
suicidal ideation. Of 64 suicide
Panic does not increase risk of suicide in bipolar
disorder. attempters, 1.5% had panic attacks during
the current mood episode and of 32 non-
attempters, 1.3% had panic attack during
the current mood episode (p =0.64
graphic variables. The authors found that between groups).X
10.9% without a history of suicide
attempt had panic disorder, whereas 4.7%
with a history of suicide attempt had
panic disorder (p =0.06). A multivariate A retrospective study ( Schurhoff et al.,
analysis that controlled for the duration 2000) of 210 subjects with bipolar
of disease, total number of mood disorder delineates early onset bipolar
episodes, and early age of onset of mood disorder (onset b18 years) from late onset
disorder demonstrated that absence of bipolar disorder (onset N40 years) and
panic disorder was associated with notes clinical differencesX
suicidal

Study author/year
Study design
Sample (N)
Study population
Measurement
Outcome
Warshaw et al.X
Prospective
11
HARP
DSM-III-R, SCID-P,
Comorbid BD not a predictor of suicidal
(2000)X

SADS-L
behavior in current or past PD
Slama et al.X
Prospective
307
French university
DSM-IV, DIGS, FIGS
Absence of PD was associated with suicidal
(2004)X

hospitals

behavior
GrunebaumX
Retrospective
96
NY State
HAM-17, BDI,
No difference manic or panic symptoms
et al. (2006)X

Psychiatric Institute
BPRS, GAS, SPRS
between suicide attempters/non-attempters
Schurhoff et al.X
Retrospective
210
Two Parisian
DSM-IV, RDC, DIGS
No difference in rates of suicide attempts
(2000)X

hospitals

between early and late onset panic


Lewinsohn et al.X
Retrospective
18
OADP
DSM-III-R, K-SADS
No differences when compared bipolar subjects
(1995)X

with and without lifetime non-affective disorders

with suicide attempts


Birmaher et al.X
Retrospective
8
USA child and
DSM-III-R, K-SADS-P
No difference in prevalance of suicide attempts
(2002)X

adolescents clinic
between PD comorbid with BD, non-panic anxiety

disorders comorbid with BD, non-anxious

psychiatric controls comorbid with BD


Dilsaver et al.X
Retrospective
129
HCPC
DSM-III-R, DSM-IV,
No increased suicide risk in comorbid PD and
(1997)X

RDC, SADS
euphoric mania
Dilsaver andX
Retrospective
25
HCPC
DSM-III-R, SCID,
No increased suicide risk in comorbid PD and
Chen (2003)X

SADS, RDC
euphoric mania
Wu & DunnerX
Retrospective
100
UW Center for
DSM-III-R, HAMD-18
Rapid cycling subjects without higher suicide
(1993)X

Anxiety and Depression

rates but with more panic attacks

HARP=Harvard/Brown Anxiety Disorders Research project. OADP=Oregon Adolescent Depression


Project. HCPC=Harris County Psychiatric Center, Texas. UW=University of Washington.
6 E.J. Kilbane et al. / Journal of Affective Disorders 115 (2009) 1–10

other than panic disorder (N =22), and


subjects with bipolar disorder and non-
between the two. These include anxiety comor-bidity (N =112). They
increased psychotic symptoms ( expected that youths with panic disorder
McGlashan, 1988), manic symptoms ( have higher rates of bipolar disorder and
Angst et al., 1987) and comorbid that this comorbidity results in increased
conduct, substance, and eating severity of symptoms and suicidality. The
disorders ( Bashir et al., 1987) in the authors note that panic attacks are
frequent in children and adolescents (5.4–
early onset group. There was no
10.2%) while panic disorder is much less
significant difference in the rates of
common (0.5– 0.8%). There was no
suicide attempts or violent suicide
significant difference in the prevalence of
attempts between early and late onset
suicide attempts between the three
samples even though the two groups groups; however, there was a trend for
differed significantly in rates of panic the subjects with comorbid panic disorder
disorder (21% and 2.6% respectively, p and bipolar disorder to have higher rates
=0.01).X of suicidal ideation than either group
alone.X

Two retrospective studies of youths using


very small sample sizes ( Lewinsohn et
al., 1995; Birmaher et al., 2002) do not
support increased suicidal risk. The first 3.6. Bipolar I
study identified 18 adolescents aged 14–
18 years with bipolar disorder NOS.
They compared subjects with bipolar
disorder, subjects without diagnosis of Two retrospective studies ( Dilsaver et
bipolar disorder but with significant al., 1997; Dilsaver and Chen, 2003)
symptoms including elevated, expansive, assessed social phobia, panic disorder,
or irritable mood (“Core positive” group, and suicidality during the “manic” state of
5.7% of sample), and subjects without subjects with pure and depressive-mania;
diagnosis of bipolar disorder or subjects with pure-mania are considered
significant “manic” symptoms (“Core currently. The second studyX
negative” group). They note high rates of
comorbidity in patients with bipolar
disorder, and 11.1% of their bipolar
sample had comorbid panic disorder (p b had 25 patients with pure-mania: one
0.001 compared to “Core Negative” and patient was suicidal, one patient had
“Core Positive” samples). However, when IEPD, and no patients had both. This
they com-pared bipolar subjects with and differs significantly (p b 0.0001) from
without lifetime non-affective disorders rates for the depressive-mania group in
on variables including treatment, suicide the same study. They conclude that
attempts, and current/past year Global anxiety disorders are associated with
Assess-ment Function (GAF), they found depressive symptoms of mania rather
no significant differences. The second than pure-manic symptoms.
study of youths aged 5– 19 years
compared subjects with bipolar disorder
and panic disorder (N =8), subjects with
bipolar disorder and anxiety disorder 3.7. Bipolar rapid cycling
(50%) had significantly more psychotic
symptoms than subjects without an
One retrospective study ( Wu and anxiety disorder (12.5%, p =0.02).
Dunner, 1993) compared 100 rapid However, there was no significant
cycling subjects with 120 non-rapid difference in suicide attempts or
cycling patients. They stress that
ideation between the groups.X
although rapid cycling is defined as at
least four episodes per year, many
individuals have more episodes and they
propose that the number of depressive The following papers are inconclusive
episodes is associated with increased
as to whether there is an increased risk
suicidality. As panic disorder is
of suicide in people with comorbid
associated with increased suicide risk,
bipolar and panic disorders. Study
they assessed panic attacks as well.
Rapid cycling subjects did not have informa-tion is listed in Table 3.X
signifi-cantly higher suicide rates but did
have more panic attacks. This does not
support an association between panic
3.9. Bipolar NOS
attacks and suicide attempts.X

A prospective study ( Warshaw et al.,


3.8. Bipolar psychosis 1995) of 527 subjects with panic disorder
(current or past, with or without
agoraphobia) assessed comorbidity with
schi-zoaffective / bipolar disorder; 27
One retrospective study ( Birmaher et
subjects had comor-bidity. In their
al., 2002) discussed previously also
sample, subjects with schizoaffective/
assessed bipolar disorder with bipolar disorders have the highest rates of
psychosis. They looked at three groups: suicide attempts or gestures (40.7%),
bipolar disorder with panic disorder, there is no evidence of increased risk of
bipolar disorder with (non-panic suicidal behavior in uncomplicated panic
disorder) anxiety, and bipolar disorder disorder, and they state “our study cannot
without anxiety disorder. Subjects with address the question of whether the
comorbid bipolar and panic disorder presence of panic disorderX

E.J. Kilbane et al. / Journal of Affective Disorders 115 (2009) 1–10


7
Table 3
Inconclusive whether panic affects suicide risk in bipolar disorder.

Study author/year
Study design
Sample (N)
Study population
Measurement
Outcome

Warshaw et al.X
Prospective
27
HARP
DSM-III-R, PHDD,
Inconclusive whether the presence of PD increases rates
(1995)X
SCIP-P, RDS, SADS-L
of suicide in comorbid disorders

Perlis et al.X
Retrospective
983
STEP-BD
MINI, ADE, GAF,
Analysis of suicide attempts within panic subgroups not
(2004)X

QlESQ, LIFE-RIFT
shown

Vickers andX
Retrospective
272
NCS
DSM-III-R, CIDI, DIS
No effect of PD on suicidality in mania; subjects with PD
McNally (2004)X

and suicide attempts had significantly (p =0.02) higher

rates of mania than those without suicide attempts


HARP=Harvard / Brown Anxiety Research Program. STEP-BD=Systematic Treatment Enhancement
Program for Bipolar Disorder. NCS=National Comorbidity Study.

risk when comorbidity is controlled.


The authors describe an opposing view
increases the chance of suicide on panic disorder and suicidality.
attempts in patients with depression or Individuals with panic disorder
other disorders”. commonly appear as hypochondriacs
with fears of dying and, thus a
decreased suicide risk. In the survey,
subjects with panic disorder and
One retrospective study using subjects
suicide attempts had significantly
with bipolar NOS is inconclusive. Perlis
higher rates of mania than those
et al. (2004) divided 983 subjects into
without suicide attempts. Although this
three groups: b13 years old, 13–18 years
old, N18 years old. Rates of panic with
paper uses subjects with PD rather than
agoraphobia were 18.5%, 11.8%, and BD, it does conclude that an interaction
8.2%, respectively. Rates of panic between the two may increase
without agoraphobia were 8.9%, 9.6%, likelihood of suicide attempt.X
and 6.0%, respectively. For panic with
agoraphobia, there was statistical
significance (p =0.002) between the pre-
pub-ertal and adolescent groups as well 4. Discussion
as between the pre-pubertal and adult
groups. Suicide attempts were 49.8%,
37%, and 24.6% respectively. Further
analysis of suicide attempts within panic This review is intended to clarify
subgroups was not performed.X
whether bipolar disorder with comorbid
panic disorder imparts a higher risk for
suicide than bipolar disorder without
comorbid panic disorder. 24 original
3.10. Bipolar I research papers were reviewed and
assessed with regards to the samples'
bipolar diagnosis, panic comorbidity,
and measures of
Vickers and McNally (2004)
completed a retro-spective study using
data from the National Comorbid-ity
Survey (N =272) to determine that suicidality (ideation, attempt,
panic disorder does not affect suicide completion); as some papers assessed
more than one clinical subgroup of BD,
there are 26 reviews; 14 papers support least, early onset bipolar comorbidity
increased risk, 9 papers do not support (panic attacks and panic disorder)
increased risk, and 3 papers are predicts increased suicidal behavior.
inconclusive. Specific relationships between panic
symptom variables (i.e., early onset and
PAS-SR score) and affective symptom
variables (i.e., mixed state) may increase
According to the recent review by Hawton risk of suicide. Recent research ( Lee and
et al. (2005), completed suicide and Dunner, 2007; Kauer-Sant'Anna et al.,
suicidality measures in people with BD are 2007; Rihmer, 2007) assessing anxiety
associated with single marital status, family comorbidity, but not panic specifically, in
history of suicide and affective disorders, bipolar disorder concludes that comorbid
early physical or sexual abuse, early onset anxiety is associated with suicidal
of psychiatric illness, alcohol and other
ideation, behavior, and attempts.X
substance use disorders, expressed
hopelessness, and comorbid anxiety
disorder. Prior suicide attempt is the single
best predictor of suicide.X
In this review there are also several
papers that do not support an increased
risk of suicidality in this popula-tion. A
recent study ( Nakagawa et al., 2008)
Several papers reviewed here support
found that anxiety associated with cluster
increased incidence of panic disorder in
b personality disorders increased the risk
individuals with BD and an increased risk
of suicide in bipolar patients while Axis I
for suicide attempt and completion in this
anxiety disorders did not. A review (
group. Some research on BD in youths
Hagwood and De Leo, 2008) of the
also supports these findings. Early onset
literature from January 2006 to May 2007
and comorbidity specifically worsen the
on anxiety and suicidal behavior
outcome and it may be that early onset
highlights the methodological issues that
panic disorder predisposes to subsequent
psychopathology, particularly BD. At the limit the interpretation ofX
8 E.J. Kilbane et al. / Journal of Affective Disorders 115 (2009) 1–10

that allow computation of odd ratios, and


diverse samples drawn from larger
data between studies. Some of these studies (STEP-BD, NCS, ECA). In
limitations are differences in sample size addition, when assessing youths, the two
and demographic, assessment and papers that support increased risk were
diagnosis, study design, follow-up conducted amongst distinct ethnic groups
duration, and variables controlled for. and included large samples sizes. Two
These methodological issues affect this prospective papers ( Warshaw et al.,
review and the findings here are not 2000; Slama et al., 2004) with adequate
conclusive. However, as stated by sample sizes that do not support
Hagwood and De Leo: increased suicide risk are difficult to
interpret. As stated earlier, Warshaw et al.
use subjects with PD and there may be a
qualitative difference from the subjects
“Globally speaking, anxiety disorders used in other studies. Also, in the analysis
have an influence on suicidal behaviour, they combine bipolar and schizoaffective
especially when they occur co-morbid patients. Slama et al.'s finding that
with other mental disorders. Evidence absence of PD contributed to suicide
regarding the independent influence of attempt was not replicated in their own
any single anxiety disorder is less further analysis.X
consistent in literature and, overall, is less
convincing. In any case, the available
knowledge is sufficient to inform us that
efforts to prevent suicide must not There are several limitations within the
neglect the identification and treatment of studies reviewed; many use a
anxiety disorders.” retrospective design, the sample numbers
differ greatly between studies and some
studies have small sample sizes,
assessment scales differ between studies,
A significant proportion of the age of samples differs between studies,
literature examined in this review and while some studies separate out panic
supports such a relationship for panic disorder in relation to suicide, others only
disorder specifically and underscores assess panic disorder within a general
the importance of diagnosis and comorbidity group (specifically
treatment.

“anxiety comorbidity”). In addition,


In reviewing these articles, more some studies specifically assess a
consideration must be given to those subset of bipolar patients but others
which use a prospective study design as combine subsets (i.e. bipolar I and II)
retrospective designs are inherently for analysis. One particular limitation is
biased by recall and cross-sectional data
the variability and inconsistency
collection is limited to a particular point
present in the use of terms relating to
in time. Based on the articles reviewed, it
suicidal ideation, behavior, attempt,
appears that comorbid affective and
and completion. This limitation is
anxiety symptoms increase the likelihood
highlighted in the work of Posner et al.
of suicidal ideation and attempts. Those
papers supporting increased risk of (2007), and future use of a standardized
suicide include one prospective study, assessment tool such as the Columbia
large sample sizes, statistical techniques Classification Algorithm of Suicide
Assess-ment (C-CASA) will allow for anatomical and neurochemical
valid and reliable comparisons between dysfunction. These include the amygdala
studies.X and hippocampus, mono-amines,
catechol-O-methyltransferase, and the
serotonin transporter gene to name but a
few. These shared biological substrates
Some investigations allude to convergent may be amenable to the same treatment
biological substrates linking BD, panic, strategies. Furthermore, medications
and suicidality. In describ-ing the “manic- indicated for stabilizing depressive and
panic” connection, MacKinnon and manic/hypomanic mood symptoms in
Zamoiski (2006) propose that mood and bipolar patients may also ameliorate
anxiety disorders are linked in one of panic symptoms and reduce suicidality.
three ways: expression of the same One might hypothe-size that the
genotype, mediation via the same causal combination of panic symptoms with
risk factors and cellular mechanisms, or specific bipolar symptoms affects
distinct etiologies with common suicidality, and as Chen and Dilsaver
pathophysiology. Panic disorder cosegre- report it is the individual with depressive-
gates with BD ( MacKinnon et al., 1997) mania that is more at risk than the
suggesting both disorders are linked to individual with euphoric manic. The
the same chromosome. One study importance of recognizing and treating
examining bipolar linkage to comorbid panic in patients with BD is
chromosome 18q demon-strated five under-scored by the association with
families (of 28) in which the pro-band increased suicidal risk. While it is
had panic disorder ( Stine et al., 1995). common for psychiatrists to screen for
Both disorders occur in episodes and comorbid disorders, there are no
previous episodes predict increased rate treatment guidelines available. Future
of recurrence. Similar to the kindling research should study specific bipolar
phenomenon in epilepsy, both bipolar and subgroups, focus on anxiety and panic
panic disorders may exhibit tendencies symptoms rather than diagnosis, evaluate
for long term potentiation at the synaptic the exacerbation/ amelioration of panic
level resulting in a predisposition for symptoms in treated bipolar patients (and
recurrence. Another possibility is that viceX
there are distinct etiologies with common

E.J. Kilbane et al. / Journal of Affective Disorders 115 (2009) 1–10


9

There was no funding given for this review.

versa), and look at the role of specific


pharmacological treatment in patients
Conflict of interest
with comorbid mood and anxiety
disorders.

None of the authors reports any conflict of


interests.

Role of funding source

Acknowledgments
Clayton, P., 1993. Suicide in panic disorder
and depression. Current Therapeutic Research
54 (6), 825–831.
The authors would like to thank
Cynthia Schtupak for her assistance in
collecting articles.
Dilsaver, S.C., Chen, Y.W., 2003. Social
phobia, panic disorder and suicidality in
subjects with pure and depressive mania.
Journal of Affective Disorders 77, 173–177.

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