DEPRESSION AND ANXIETY 31:196–206 (2014)

Review
CO-OCCURRENCE OF ANXIETY AND BIPOLAR
DISORDERS: CLINICAL AND THERAPEUTIC OVERVIEW
Gustavo H. Vázquez, M.D., Ph.D.,1,2 ∗ Ross J. Baldessarini, M.D.,1,3 and Leonardo Tondo, M.D., M.S.1,3,4,5

Background: Anxiety commonly co-occurs with bipolar disorders (BDs), but

the significance of such “co-morbidity” remains to be clarified and its optimal
treatment adequately defined. Methods: We reviewed epidemiological, clinical,
and treatment studies of the co-occurrence of BD and anxiety disorder through
electronic searching of Pubmed/MEDLINE and EMBASE databases. Results:
Nearly half of BD patients meet diagnostic criteria for an anxiety disorder at some
time, and anxiety is associated with poor treatment responses, substance abuse,
and disability. Reported rates of specific anxiety disorders with BD rank: panic
≥ phobias ≥ generalized anxiety ≥ posttraumatic stress ≥ obsessive-compulsive
disorders. Their prevalence appears to be greater among women than men, but
similar in types I and II BD. Anxiety may be more likely in depressive phases
of BD, but relationships of anxiety phenomena to particular phases of BD, and
their temporal distributions require clarification. Adequate treatment trials for
anxiety syndromes in BD patients remain rare, and the impact on anxiety of
treatments aimed at mood stabilization is not clear. Benzodiazepines are some-
times given empirically; antidepressants are employed cautiously to limit risks
of mood switching and emotional destabilization; lamotrigine, valproate, and
second-generation antipsychotics may be useful and relatively safe. Conclusions:
Anxiety symptoms and syndromes co-occur commonly in patients with BD, but
“co-morbid” phenomena may be part of the BD phenotype rather than separate
illnesses. Depression and Anxiety 31:196–206, 2014. 
C 2014 Wiley Periodicals,

Inc.

Key words: anxiety disorders; bipolar disorders; comorbidity; prevalence;

treatment

INTRODUCTION
Bipolar disorders (BDs; types I and II), cyclothymic
disorder, and proposed “bipolar spectrum” disorders
with recurrent depression and relatively mild hypo-
1 InternationalConsortium for Bipolar and Psychotic Disor- manic symptoms are episodic illnesses with high lev-
ders Research, Mailman Research Center, McLean Hospital, els of morbidity and disability, despite use of available
Belmont, Massachusetts treatments.[1,2] Bipolar I and II disorders also carry sim-
2 Department of Neuroscience, Palermo University, Buenos
ilar, very high risks for suicide.[3] The broad range of pu-
Aires, Argentina tative bipolar-like disorders occurs internationally at an
3 Department of Psychiatry, Harvard Medical School, Boston,
estimated lifetime prevalence of up to 10% of the general
Massachusetts
4 Lucio Bini Mood Disorder Centers, Cagliari, Italy
population.[1, 4, 5] BDs of types I and II are among leading
5 Lucio Bini Mood Disorder Centers, Rome, Italy

Contract grant sponsor: Bruce J. Anderson Foundation. Received for publication 16 October 2013; Revised 12 January
∗ Correspondence 2014; Accepted 18 January 2014
to: Gustavo Vázquez, Department of Neu-
roscience, Palermo University, Sanchez de Bustamante DOI 10.1002/da.22248
2167, 7mo “D”. CP 1425 Buenos Aires, Argentina. E-mail: Published online in Wiley Online Library
[email protected] (wileyonlinelibrary.com).


C 2014 Wiley Periodicals, Inc.
 Review: Anxiety in Bipolar Disorder 197

causes of disability from any illness.[6] They commonly METHODS

co-occur with features of other psychiatric, substance We performed computerized literature searching for reports ad-
abuse, or personality disorders.[1] In addition, though dressing relationships between anxiety symptoms or syndromes with
not addressed in this report, cardiovascular and other BD through September 2013, using the Pubmed/MEDLINE (from
general medical disorders occur at higher rates in BDs 1955) and EMBASE (from 1988) research literature databases. Search
than in the general population and can lead to an excess terms were various combinations of “agoraphobia, anxiety, bipolar,
of premature mortality from medical causes that is simi- epidemiology, generalized anxiety, obsessive-compulsive, panic, pho-
lar to suicide and other forms of violent deaths in terms bia, post-traumatic stress, prevalence, social anxiety, and treatment.”
of total deaths/year.[7–11] We also considered studies cited in identified reports and in reviews
The term “co-morbidity” is widely used to indicate reported during the past decade.
Inclusion criteria were deliberately broad, and considered abstracts,
co-occurrence in the same patient of symptoms meet-
peer-reviewed, epidemiological, clinical, prospective, or retrospec-
ing standard diagnostic criteria for more than one clin- tive studies, as well as randomized or open-label trials involving psy-
ical condition.[12] However, this term can be confusing, chopharmacological or other treatment, of patients with co-occurring
particularly when applied to psychiatric disorders, due BD and anxiety symptoms, syndromes, or disorders identified by stan-
to symptomatic overlap among syndromes.[13–15] Such dardized international diagnostic criteria (DSM-IV or ICD-10), and
overlap is especially likely between anxiety and mood reported in English. When reported, we considered subjects diagnosed
disorders.[13, 16–20] Moreover, fundamental reliance by with “any anxiety disorder” to avoid exaggerating prevalences by repet-
the major international nosological systems on categor- itive counting of subjects meeting diagnostic criteria for more than one
ical diagnostic schemes virtually guarantees prolifera- anxiety disorder.
tion of clinical entities and high likelihood of meeting Findings obtained were tabulated in summaries pertaining to preva-
lence of particular anxiety disorder diagnoses and their relationships
diagnostic criteria for multiple disorders in the same
to BD diagnostic type (I or II) and sex, using standard analytical meth-
person.[13, 21, 22] ods and commercial statistical programs (Stata.12, StataCorp, College
In addition to its theoretical challenges, the concept Station, TX; Statview-5, STS Institute, Cary, NC). Data are reported
of comorbidity also presents practical problems for both as means ± standard deviation SD) or with computed 95% confidence
diagnosis and treatment. For example, it is not uncom- intervals (CIs).
mon to overlook the presence of BD, especially at times
when the disorder is not fully or typically expressed and
among persons presenting with depression, anxiety, sub- RESULTS
stance abuse, or medical illnesses that command clini- We preliminarily identified 128 reports that appeared
cal attention.[2, 9, 23] For example, identification of a his- to meet our broad inclusion criteria. We discarded overly
tory of hypomania is especially challenging since mod- general reviews, commentaries, and single case reports,
erate elation and high energy are often considered by and selected 46 studies for analyses. Reports included re-
persons diagnosed with a BD as part of their optimal ported lifetime or point-prevalence estimates of anxiety
mood and performance. In addition, when recognized, disorders in patients diagnosed with type I or II BD—
it is typically unclear how to treat complex clinical pre- all meeting standard diagnostic criteria—or information
sentations including anxiety syndromes associated with about treatment responses, or about long-term illness
specific phases of BD. It is especially uncertain when to course and outcome. Most findings are sufficiently ten-
rely primarily on mood-stabilizing treatments in hopes tative, that detailed, critical, methodological assessments
of ameliorating a range of psychopathological phenom- were considered unwarranted, although characteristics
ena in BD patients, and when to consider alternative of treatment trials are summarized below.
treatments or polytherapy directed at symptoms consid-
ered to represent discrete illnesses in need of separate
treatments.[2, 9, 24] Additional complications arise when PREVALENCE OF ANXIETY SYNDROMES IN BD
effects of treatments, themselves, produce symptoms PATIENTS
that can resemble or add to those of the conditions being Anxiety disorders are far more prevalent among BD
treated. Examples include the mania-inducing or mood- patients than in the general population, at rates similar
destabilizing actions of antidepressants, and depression- to those found among patients diagnosed with unipo-
like or restless agitation responses to some antipsychotic lar, recurrent major depressive disorders.[30–35] Find-
agents.[25–28] ings pertaining to prevalence of anxiety syndromes in
Aside from controversies regarding the concept of BD patients derive from both epidemiological[4, 30, 36–43]
psychiatric comorbidity itself, studies reporting research and clinical studies.[5, 31, 44–52] Nearly half of BD patients
data on the prevalence, prognosis, outcome, and effects studied have met standard diagnostic criteria for at least
of treatments in patients meeting standard diagnostic one anxiety disorder at some time[35, 42, 47, 48] ; we found
criteria for BD and anxiety disorders remain notably an average risk of 46.8% [95% CI: 39.2–54.5] across
infrequent.[29] These circumstances led us to undertake 25 studies (Table 1). The reported prevalence of par-
a brief overview on what is known currently about the ticular anxiety syndromes in BD patients ranged from
nature, epidemiology, and treatment of anxiety phenom- 13.0 to 22.3%, and ranked: panic disorder ≥ social and
ena co-occurring with BD. specific phobias ≥ generalized anxiety ≥ posttraumatic

Depression and Anxiety

198 Vázquez et al.

TABLE 1. Lifetime risks of anxiety disorders among

patients with bipolar disorders

Study Cases (n) Prevalence (%)

Young et al.[54] 81 32.0

Kessler et al.[38] 29 80.3
Chen and Dilsaver[37] 167 41.9
Keck et al.[55] 71 29.0
Krüger et al.[56] 149 35.0
Dilsaver et al.[57] 129 62.3
Pini et al.[31] 24 89.0
Szádóczky et al.[58] 149 48.9
McElroy et al.[44] 288 42.4
Rihmer et al.[32] 195 37.9
Henry et al.[45] 318 24.0
Simon et al.[48] 475 51.2
Baldassano et al.[59] 500 40.9
Grant et al.[60] 883 48.5
Faravelli et al.[61] 2,363 40.0 Figure 1. Lifetime prevalence (%) of anxiety disorders among
Mantere et al.[62] 191 44.5 bipolar disorder patients (data from Tables 1 and 2) versus the
Benedetti et al.[63] 72 68.5 general population[50, 53] based on two to eight epidemiological
Brieger et al.[64] 121 16.0 studies per disorder, with 95% confidence intervals (CI). The
Merikangas et al.[4] 184 88.1 ratios of risk in bipolar disorder to the general population ranked:
Albert et al.[65] 105 41.0 any anxiety disorder (16.0) ≥ panic disorder (14.0) > obsessive-
Altshuler et al.[66] 711 48.4 compulsive disorder (OCD; 6.28) ≥ phobias (6.18) > generalized
Saunders et al.[67] 736 46.1 anxiety disorder (GAD; 3.78) > PTSD (2.16).
Das[68] 102 46.4
Hawke et al.[43] 808 25.9
Baldessarini et al.[69] 321 42.6
stress syndrome ≥ obsessive-compulsive syndrome
Mean (25 reports) [95% CI] Total N 9,172 46.8 [39.2–54.5]
(Table 2 and Fig. 1.). These risks are 3.8–16 times greater
Risks were similar in men and women [RR = 0.96–1.02; 55; 137], than reported lifetime prevalence for anxiety disorders
but much higher in depressive than manic episodes [RR = 1.95; 136]. in the general population[53] (Fig. 1).
Studies are cited in order of the publication year. Reported rates of anxiety syndromes have been
higher among women than men diagnosed with BD
in several[42, 59, 66] but not all studies.[69] Data pooled

TABLE 2. Anxiety disorders co-occurring with bipolar disorders

Study Panic Phobias GAD PTSD OCD

Fogarty et al.[70] —— 18.4 —— —— ——

Chen and Dilsaver[37] 20.8 —— —— —— 21.0
Kessler et al.[38] 32.9 58.6 42.4 38.8 ——
Angst[36] 35.6 12.6 —— —— 5.19
McElroy et al.[44] 20.1 12.5 3.13 3.13 4.86
Rihmer et al.[32] 8.43 14.0 12.6 —— ——
Goodwin and Hoven[39] 35.0 —— —— —— ——
Simon et al.[48] 17.5 30.3 18.3 17.1 9.89
Baldassano et al.[59] 0.83 20.3 —— 15.4 9.54
Grant et al.[60] 19.0 21.8 21.8 —— ——
Faravelli et al.[61] 16.0 —— 24.0 —— ——
Mantere et al.[62] 24.1 27.8 15.2 10.5 2.09
Benedetti et al.[63] 40.0 —— —— —— 48.0
Merikangas et al.[4] 28.0 36.5 37.8 32.8 22.8
Albert et al.[65] 10.5 6.67 16.2 —— 13.3
Altshuler et al.[66] 18.8 19.7 —— 8.02 8.30
Das[68] 15.5 28.6 21.4 —— 7.10
Saunders et al.[67] 25.1 15.4 —— —— ——
Baldessarini et al.[69] 33.4 1.66 7.41 0.39 4.87
Mean [95% CI] 22.3 [17.1–27.5] 21.7 [14.0–29.3] 20.0 [12.1–27.9] 15.8 [4.35–27.2] 13.0 [4.95–21.1]

GAD, generalized anxiety disorder; OCD, obsessive-compulsive disorder; PTSD, posttraumatic stress disorder. Anxiety syndromes are in order of
reported mean prevalence. Studies are cited in order of the publication year.

Depression and Anxiety

 Review: Anxiety in Bipolar Disorder 199

TABLE 3. Lifetime risks of all co-occurring anxiety disorders with bipolar disorders, type I versus type II

Prevalence (cases/subjects [%])

Study or syndrome Bipolar I Bipolar II I/II risk ratio

Kessler et al.[38] 27/29 [92.9] —— ——

Angst[36] —— 34/59 [57.6] ——
McElroy et al.[44] 100/239 [41.8] 22/49 [44.9] 0.93
Doughty et al.[61] 28/100 [28.0] 25/65 [38.5] 0.73
Simon et al.[48] 190/360 [52.8] 53/115 [46.1] 1.15
Mantere et al.[62] 32/90 [35.6] 53/101 [52.5] 0.68
Merikangas et al.[4] 71/82 [86.7] 91/102 [89.2] 0.97
Albert et al.[65] 18/44 [40.9] 25/61 [41.0] 1.00
Zimmermann et al.[34] 36/65 [55.4] 20/33 [60.6] 0.91
Sala et al.[42] 566/1,183 [47.8] 159/417 [38.1] 1.25
Das[68] 47/102 [46.1] —— ——
Baldessarini et al.[69] 116/259 [44.8] 85/213 [39.9] 1.13
Pooled risk [%] [95% CI] 1,231/2,553 [48.2%] [43.3–50.2] 557/1,215 [45.8%] [43.0–48.7] 1.05 [0.89–1.21]

Doughty et al.[61] is for recurrent panic only. Random effects meta-analysis also indicated no significant difference by diagnostic subtype (RR =
1.00; 95% CI: 0.88–1.14). Studies are cited in order of the publication year.

from these reports indicate that prevalences in women of anxiety as well as of depression or mania/hypomania
(467/946; 49.4% [CI: 46.1–52.6%]) have averaged 1.42 recur episodically among patients with BDs.[7] Indeed,
times higher than in men (242/694; 34.9% [CI: 31.3– when followed longitudinally, patients with BD may ex-
38.5]; χ 2 = 34.3; P < .0001). perience anxiety syndromes even more frequently and
We identified 12 reports on rates of anxiety disor- for longer time than depressive, manic/hypomanic, or
ders in patients diagnosed with BD subtypes (Table 3). mixed mood states.[74–76]
The reported prevalences in type I (48.2%) and type Anxiety symptoms may be more prevalent during
II cases (45.8%) did not differ significantly (risk ra- depressive or mixed than in manic or hypomanic
tio = 1.05). However, when particular anxiety disor- episodes of BDs, but such associations have rarely
ders were considered, phobias were identified 3.35 times been studied systematically. A recent prospective study
more often among type I than type II BD patients supported an association of anxiety syndromes with
(Table 4). depressive phases of BD,[77] and anxiety symptoms
Anxiety symptoms or syndromes also are prevalent an- (not disorders) were associated with greater long-term
tecedents of BD, sometimes years before syndromal pre- depressive morbidity among BD patients.[78] There was
sentations of BD, including in youth.[71] Moreover, rates also a strong association of excesses of later anxiety and
of treatment-associated mania or hypomania in placebo- depression with first lifetime illness episodes of anxiety
controlled trials of antidepressant treatment for juvenile or depression among patients eventually diagnosed with
anxiety disorders are at least as high as in trials for ju- BD.[69] These findings also point to an important defi-
venile depression.[72] This finding suggests that anxiety ciency in understanding anxiety features in BD patients
as well as depression can sometimes precede clinical ex- and their poorly defined natural course, despite the
pression of typical BD. In addition, first and subsequent clinically important implications of such knowledge for
episodes of BD often include admixtures of anxiety, de- planning long-term treatment and clinical management
pression, and sleep disturbances,[24, 44, 73] and episodes of anxiety and mood morbidity in BD patients.

TABLE 4. Prevalence of specific anxiety syndromes in bipolar I and bipolar II patients

Prevalence (%) [95% CI]

Anxiety disorder Bipolar I (n = 2,106) Bipolar II (n = 726) I/II risk ratio t-Score P-value

Phobias 28.5 [16.3–40.6] 8.50 [5.53–11.5] 3.35 3.54 .002

GAD 20.3 [9.09–20.2] 15.4 [4.53–26.4] 1.32 0.71 .24
PTSD 20.2 [2.17–38.3] 16.4 [4.52–28.2] 1.23 0.42 .34
OCD 10.3 [3.86–16.8] 8.99 [2.21–15.8] 1.15 0.35 .37
Panic 21.7 [15.0–28.5] 24.5 [16.1–32.9] 0.89 0.61 .72
Any type 50.7 [34.6–66.8] 53.7 [40.6–66.7] 0.94 0.31 .62

GAD, generalized anxiety disorder; PTSD, posttraumatic stress disorder; OCD, obsessive-compulsive disorder. Prevalences are for lifetime risk
except that Mantere et al.[62] reported point prevalence. Data are from Kessler et al. [38] ; Angst[36] ; McElroy et al.[44] ; Rihmer et al.[32] ; Simon
et al.[48] ; Grant et al.[60] ; Mantere et al.[62] ; Merikangas et al.[4] ; Albert et al.[65] ; Baldessarini et al.[69] ; Das[68] .

Depression and Anxiety

200 Vázquez et al.

TABLE 5. Potential treatments for comorbid anxiety symptoms or disorders in bipolar disorders

Treatments Evidence types Main findings References

Pharmacotherapies
Antidepressants No trials for BD with anxiety; anecdotal comments, Used empirically for BD with [48, 92–94]

case series: OCD in BD-I or BD-II (n = 28) prominent anxiety; risks mood
destabilization
Aripiprazole No trials; anecdotal use for OCD in BD (N = 3) Appeared to be effective [95]

Benzodiazepines No trials; common empirical use Appear to be helpful [92, 96, 97]

Divalproex No RCTs; case series: BD-II with panic (n = 5); Appeared to be effective for panic [98, 99]

3 year add-on to ADs in BD-II (n = 35)

Gabapentin Case series: add GPN (1.3 g/day) to mood stabilizers Appeared to reduce anxiety [100]

in treatment-resistant BD (n = 43) symptoms

Lamotrigine Open trial: LTG vs. Li panic with BD (n = 164) LTG may be more effective than Li [101]

Lithium salts 1 RCT (12 weeks), single blind, euthymic BD-I or Li+ONZ more effective than Li + [102]

BD-II with anxiety symptoms; add to OLZ LTG (ONZ effect?)

(8 mg/day) vs. LTG 97 (mg/day) (n = 47)
Olanzapine 1 RCT vs. PBO (8 weeks) in BD-I depression: ONZ more effective than PBO [103]

secondary analysis of HAM-A scores (n = 168)

Olanzapine + 1 RCT vs. PBO (8 weeks) in BD-I depression: OFC more effective than PBO (or [103]

fluoxetine secondary analysis of HAM-A scores (n = 31) ONZ)

Pregabalin No trials; expert recommendations Recommended for BD with anxiety [92]

Quetiapine 4 RCTs in BD-I or BD-II depression, 300 or Reduced anxiety symptoms in [92, 104, 105]

600 mg/day vs. PBO, secondary HAM-A scores (n BD-I and BD-II depression;
= 3,168); 1 RCT (8 weeks) vs. DVP-XR vs. PBO QTP more effective than DVP
in BD depression with anxiety symptoms (n = 149) or PBO but not dose dependent
Risperidone 1 monotherapy (2.5 mg/day) RCT vs. PBO for panic Ineffective [106]

or OCD in BD-I and BD-II and BD-NOS

Psychotherapies
Psychosocial 3 trials in BD-I or BD-II: CBT vs. IPT; CBT vs. CBT most effective [87, 107, 108]

treatments family psychotherapy; CBT vs. psychoeducation

(n = 204)

AD, antidepressant; CBT, cognitive-behavioral therapy; DVP-XR, divalproex extended release; GAD, generalized anxiety disorder; GPN,
gabapentin; IPT, interpersonal psychotherapy; Li, lithium carbonate; LTG, lamotrigine; NOS, not otherwise specified; OFC, olanzapine-fluoxetine
combined; ONZ, olanzapine; PBO, placebo; QTP, quetiapine; RTC, randomized controlled trial.

Overall, the various findings just reviewed, support the particular clinical and public health significance, several
clinical impression that there is a strong association of studies have found that anxiety symptoms in BD patients
anxiety disorders with BD, and perhaps particularly with were associated with substantially increased risks of sui-
depressive phases of BD. These associations may suggest cidal ideation, attempts, and suicides,[35, 88–90] often in
that anxiety symptoms are within the range of symp- association with a more severe symptomatic course of
tomatic expression of BD, but do not clarify whether illness.[40, 42, 43, 91]
two distinct disorders are present or not. Findings that
might support the presence of separate, “co-morbid” dis- TREATMENTS FOR ANXIETY SYNDROMES IN BD
orders include observations that nearly half of patients PATIENTS
diagnosed with BD never meet diagnostic criteria for Therapeutics research for anxiety syndromes occur-
an anxiety disorder, and that most patients with a pri- ring in BD patients remains extraordinarily underdevel-
mary anxiety disorder do not show clinical features of oped (Table 5). Recent reviews have identified very few
BD.[48, 49, 79, 80] randomized, controlled trials of either pharmacothera-
pies or psychotherapies directed at any type of anxiety
EFFECTS OF ANXIETY ON COURSE AND morbidity in BD, and virtually none directed at specific
OUTCOME IN BD anxiety syndromes, or at anxiety in particular phases (de-
It has been noted consistently that co-occurring anx- pression, mixed states, mania/hypomania, euthymia) or
iety symptoms and disorders in BD patients are associ- types (I vs. II) of BD.[23, 24, 80, 92]
ated with younger onset age, greater overall morbidity Despite widespread clinical use of benzodiazepines to
reflected in more hospitalizations and a worse overall treat anxiety symptoms, recent expert task force rec-
prognosis, with slower or inferior treatment responses, ommendations have positioned this class of medica-
more substance abuse, and greater economic costs (re- tions at the lowest level of evidence (anecdotal data)
lated to clinical care and disability) than among BD pa- for treatment of anxiety syndromes in adults diagnosed
tients without anxiety disorders.[24, 35, 48, 55, 65, 77, 80–87] Of with BD.[92, 96] However, several other reviews support
Depression and Anxiety
 Review: Anxiety in Bipolar Disorder 201

their use (especially clonazepam) for improving a range overall treatment responses in BD,[23, 24, 108] at least one
of acute affective symptoms and the long-term course study found that BD patients with versus without anx-
among patients with major affective disorders, without iety features given supplemental CBT or psychoeduca-
specific evidence of their value for anxiety syndromes in tion, showed more improvement of anxiety symptoms as
BD.[96, 97, 109] Benzodiazepines appear not to be inferior well as in mood, functional status, and adherence to rec-
to antidepressants for the short-term treatment of pa- ommended treatment.[86] A study of acutely depressed
tients with primary anxiety disorders.[110] However, we BD patients found that those with versus with a history
found no reported studies that specifically evaluated the of an anxiety disorder were less likely to recover (49 vs.
efficacy and safety of benzodiazepines themselves, or in 66% over 1 year) with a variety of types of intensive psy-
comparison to alternatives, to treat anxiety symptoms or chotherapy, but that effects of psychotherapy exceeded
syndromes in BD patients. those of routine care overall.[114] Several other studies
We also found no trials testing potential effects of the also have provided evidence that psychotherapies can
standard mood stabilizer lithium for effects in anxiety contribute to reducing anxiety symptoms in BD patients,
disorders associated with BD. Some second-generation long term.[115–117]
antipsychotic medications may have beneficial effects for
anxiety symptoms in BD patients.[24] Added to lithium,
olanzapine was more effective than lamotrigine against TREATMENT OF PRIMARY ANXIETY DISORDERS
anxiety symptoms in BD patients, and olanzapine as a WITH MEDICATIONS USED FOR BD
monotherapy or add-on treatment also was effective in Despite the paucity of therapeutic studies of anxiety
depressed BD patients with anxiety symptoms.[102, 103] in BDs,[24, 80, 92] some investigations have evaluated
Quetiapine, which has beneficial effects in mania also medicines commonly used in the treatment of BDs for
was effective in depressed bipolar I or II disorder their effects on primary anxiety disorders not associated
patients.[104] In a recent meta-analytic review, we found with BD.[23, 118] Even considering such studies assumes
that quetiapine was 36% more effective for bipolar de- that treatment effects in primary anxiety disorders and
pression than placebo, compared to 25% for olanzap- those associated with BD can be compared validly.
ine, in five trials of each antipsychotic.[111] In a recent Treatments tested include lithium, antimanic or
controlled trial, quetiapine was more effective than val- mood-stabilizing anticonvulsants, antipsychotic med-
proate or placebo against generalized anxiety or panic ications, antidepressants, and rare consideration of
in BD patients.[105] In contrast, risperidone was ineffec- benzodiazepines or other sedatives. However,
tive against panic or obsessive-compulsive disorder as- such studies have yielded limited information
sociated with BD.[24, 106] A small case series suggested and very few are based on randomized, controlled
that aripiprazole had beneficial effects against obsessive- trials.
compulsive features in BD patients.[95] Antidepressants, including tricyclics, monoamine
Mood-stabilizing anticonvulsants have rarely been oxidase inhibitors, serotonin-reuptake inhibitors,
studied in the treatment of anxiety disorders co- and serotonin–norepinephrine-reuptake inhibitors,
occurring with BD. However, at least one trial found and some atypical agents (notably, mirtazapine) are
valproate to be effective for panic disorder in BD pa- standard treatments for a range of anxiety disorders,
tients, even after poor responses to antidepressants.[98] as are benzodiazepines. However, their application
In one report, anxiety disorder morbidity was greater for anxiety syndromes in BD remains unstudied.
among BD patients who had received relatively less This deficiency probably reflects concern for po-
mood-stabilizer treatment, although cause-effect rela- tential mood- and behavior-destabilizing actions of
tionships in this association are not clear.[112] Studies antidepressants in BD patients, particularly in type I
of potential short- or long-term value of lamotrigine in BD.[25–27]
treating anxiety symptoms in BD patients are notably Lithium appears to lack important therapeutic effects
lacking, although we identified one trial suggesting ben- in primary anxiety disorders. However, it has been stud-
efits in panic associated with BD.[101] Although its ef- ied only rarely and in few types of anxiety disorder,
ficacy for anxiety in BD in general is not proved,[113] with indications of possible benefits in reducing depres-
there is anecdotal evidence that gabapentin may have sive and episodic obsessive-compulsive symptoms as an
some value for anxiety symptoms in BD patients.[100] adjunct to other treatments for obsessive-compulsive
Studies of psychosocial treatments for coexisting anxi- disorder.[118–120] In addition, subtle anxiolytic ef-
ety disorders and BD also are rare. In line with a broad fects of lithium have been noted in mood disorder
clinical and research consensus on the relevant role of patients.[101]
cognitive-behavioral psychotherapy (CBT) for depres- Among anticonvulsants with antimanic or mood-
sive and primary anxiety disorders, some recent studies stabilizing effects, carbamazepine was ineffective in pri-
have found that CBT may be effective, and possibly su- mary panic disorder[121] ; lamotrigine has some evidence
perior to interpersonal psychotherapy, family therapy, of benefit for posttraumatic stress disorder and perhaps
or psychoeducational programs for BD patients with in obsessive-compulsive disorder[122, 123] ; gabapentin
anxiety disorders.[107] Although some reports suggest may have some benefits in primary social phobia but
that co-occurring anxiety disorders can interfere with perhaps not in panic disorder[123–127] ; and pregabalin
Depression and Anxiety
202 Vázquez et al.

may be effective in social phobia and is probably effec- CONCLUSIONS

tive in generalized anxiety disorder.[123–125, 128] Valproate
is not extensively studied as a treatment for primary The present, brief overview supports the clinical
anxiety disorders[23, 118, 123, 129] but may have beneficial impression that anxiety symptoms and syndromes are
effects in generalized anxiety disorder and possibly in highly prevalent among patients diagnosed with BDs,
panic disorder,[92, 124, 130] and has been recommended for affecting approximately half of types I and II BD pa-
treating anxiety in BD.[24] There are suggestions that rel- tients at some time. Accordingly, anxiety symptoms and
atively nonspecific anxiety symptoms associated with re- syndromes require thoughtful consideration in the com-
currences of major episodes of affective illness in BD pa- prehensive assessment and treatment of BD patients over
tients may improve as other aspects of the illness respond time. In addition, mood disorders should be considered
to mood-stabilizing treatments.[23, 24, 80, 92] Nevertheless, in assessing patients considered to have a primary anxiety
it is important to reiterate that systematic assessments of disorder. Reported evidence concerning prevalence of
lithium or mood-stabilizing anticonvulsants specifically specific anxiety disorders in BD patients suggests a sub-
for effects on anxiety features in BD patients remain to stantially (but not statistically significantly) higher preva-
be carried out. lence of panic disorder than obsessive-compulsive dis-
There are a few studies of antipsychotic medications order. We found that reported prevalence ranked: panic
for primary anxiety disorders. Trials involving mod- disorder ≥ phobias ≥ generalized anxiety ≥ posttrau-
ern, second-generation agents have yielded inconsis- matic stress disorder ≥ obsessive-compulsive disorder
tent effects on particular types of primary anxiety (Table 2; Fig. 1). Co-occurring anxiety disorders in BD
disorders.[23, 24, 118, 131] For example, risperidone was probably are more prevalent among women: we found a
found to be useful in several controlled trials for pri- significant, 1.42-fold female/male excess. Overall risk of
mary obsessive-compulsive disorder and posttraumatic anxiety disorders appears to be similar in types I and II
stress disorder.[132–134] Olanzapine has shown inconsis- BD (Table 4; Fig. 1), but BD-I may have a higher risk of
tent effects in obsessive-compulsive disorder[135, 136] but phobias than BD-II (Table 5).
has some evidence of efficacy in posttraumatic stress There is some consensus that anxiety features are asso-
disorder.[137, 138] Aripiprazole appeared to be effective ciated with generally poorer prognosis in BDs, including
for some forms of anxiety in open trials, including for less responsiveness to standard mood-stabilizing agents,
patients with anxiety syndromes associated with major greater disability, more substance abuse, and possibly
depression.[139] This finding is consistent with the strong greater risk of suicidal behaviors. However, details of
epidemiological and clinical overlap of symptoms of anx- the course and temporal distribution of anxiety phenom-
iety disorders and depressive disorders.[140] Quetiapine ena in BD patients, and of their association with partic-
has shown inconsistent or weak effects in obsessive- ular components of BD require clarification, although
compulsive disorder,[141–143] but has been promising selective association with depression and perhaps mixed
in generalized anxiety disorder.[144] Of note, most of states is suspected. Associations of anxiety features with
these applications have been for otherwise treatment- adverse clinical outcomes in BD call for therapeutic stud-
unresponsive cases or as adjunctive treatments with ies specifically directed at anxiety of particular types as-
other, more standard, anxiolytic treatments. Studies of sociated with subtypes (I vs. II) and phases (depressive,
treatments for anxiety syndromes associated with BD are mixed, manic/hypomanic, dysthymic, euthymic) of BD.
summarized in Table 5. Some suggestive therapeutic findings pertaining to
anxiety in BD patients are emerging, including probable
benefits of olanzapine, quetiapine, divalproex, as well as
EXPERIMENTAL TREATMENTS FOR ANXIETY psychotherapy (Table 5). Although prescription of ben-
DISORDERS zodiazepines or antidepressants to treat anxiety symp-
toms in BP patients appears not to be uncommon clini-
Another potential source of treatments for anxiety dis-
cally, their use requires critical assessment in individual
orders associated with BD is a growing number of exper-
patients over time, with due concern about the poten-
imental treatments for various primary anxiety disorders.
tial for intoxication, abuse and dependence with seda-
Promising preliminary findings have been reported for
tives, and emotionally behaviorally destabilizing risks of
such diverse treatments as various antiglutamate agents:
antidepressants. A fundamental conceptual riddle that
riluzole,[145, 146] the NMDA-glutamate receptor antago-
remains is whether anxiety syndromes co-occurring in
nist memantine developed to treat dementia,[147] and in-
BD reflect the range of symptomatic-phenotypic expres-
tranasal ketamine in juvenile BD with prominent fears
sion of BD, represent separate illnesses (disorders), or are
of harm.[148] Among nonpharmacological methods, re-
largely an artifact of contemporary categorical diagnostic
peated transcranial magnetic stimulation (rTMS), re-
methods.
cently FDA-approved for treatment of major depression,
has been considered for treatment of anxiety disorders,
so far with very limited success.[149–151] However, it is
important to underscore that none of these experimental Acknowledgments. Supported in part by a research
approaches has been tested in anxiety syndromes associ- award from the Aretæus Foundation of Rome and by the
ated with BD. Lucio Bini Private Donors Research Fund (L.T.), and by
Depression and Anxiety
 Review: Anxiety in Bipolar Disorder 203

a grant from the Bruce J. Anderson Foundation and the 17. van Praag HM. Comorbidity (psycho)analysed. Br J Psychiatry
McLean Private Donors Research Fund (R.J.B.). 1996;168(30 Suppl):129s–134s.
18. Wittchen HU. Critical issues in the evaluation of comorbidity of
Financial disclosures: The topic of this study is also ad-
psychiatric disorders. Br J Psychiatry 1996;168(30 Suppl):9s–16s.
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tients: focus on anxiety syndromes. In Bipolar Disorder, cal practice: is comorbidity being missed? Compr Psychiatry
1999;40:182–191.
edited by Yildiz A., Nemeroff C., and Ruiz P. New York:
21. American Psychiatric Association (APA). Diagnostic and Sta-
Oxford University Press, 2014). tistical Manual of Mental Disorders, editions 3 to 5 (DSM-
No author or immediate family member has relation- III, DSM-III-R, DSM-IV, DSM-IV-TR, DSM-5). Washing-
ships with corporate or other commercial entities that ton, DC: American Psychiatric Publishing Co; 1980, 1987, 1994,
might represent potential conflicts of interest with the 2000, 2013.
22. World Health Organization (WHO). International Statistical
material reported.
Classification of Diseases and Related Health Problems, eleventh
edition (ICD-11). Geneva: WHO; 2014, in press.
23. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network
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