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Journal of Affective Disorders 166 (2014) 258263

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Journal of Affective Disorders


journal homepage: www.elsevier.com/locate/jad

Review

Treatment of comorbid bipolar disorder and obsessivecompulsive


disorder: A systematic review
A. Amerio a,b,n, A. Odone c,d, C. Marchesi a, S.N. Ghaemi b,e
a

Section of Psychiatry, Department of Neuroscience, University of Parma, 43126 Parma, Italy


Mood Disorders Program, Tufts Medical Center, Boston, MA, USA
c
School of Medicine - Public Health Unit, University of Parma, Parma, Italy
d
Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA
e
Tufts University Medical School, Department of Psychiatry and Pharmacology, Boston, MA, USA
b

art ic l e i nf o

a b s t r a c t

Article history:
Received 30 October 2013
Received in revised form
17 May 2014
Accepted 19 May 2014
Available online 28 May 2014

Background: More than 20% of patients with bipolar disorder (BD) show lifetime comorbidity for
obsessivecompulsive disorder (OCD), but treatment of BDOCD is a clinical challenge. Although
serotonin reuptake inhibitors (SRIs) are the rst line treatment for OCD, they can induce mood instability
in BD. An optimal treatment approach remains to be dened.
Methods: We systematically reviewed MEDLINE, Embase, PsychINFO and the Cochrane Library and
retrieved data on clinical management of comorbid BDOCD patients. Pharmacologic, psychotherapeutic
and others alternative approaches were included.
Results: Fourteen studies were selected. In all selected studies BDOCD patients received mood
stabilizers. In the largest study, 42.1% of comorbid patients required a combination of multiple mood
stabilizers and 10.5% a combination of mood stabilizers with atypical antipsychotics. Addition of
antidepressants to mood stabilizers led to clinical remission of both conditions in only one study. Some
BDOCD patients on mood stabilizer therapy benetted from adjunctive psychotherapy.
Limitations: Most studies are case reports or cross-sectional studies based on retrospective assessments.
Enrollment of subjects mainly from outpatient specialty units might have introduced selection bias and
limited community-wide generalizability.
Conclusions: Keeping in mind scantiness and heterogeneity of the available literature, the best
interpretation of the available evidence appears to be that mood stabilization should be the primary
goal in treating BDOCD patients. Addition of SRI agents seems unnecessary in most cases, although it
may be needed in a minority of BD patients with refractory OCD.
& 2014 Elsevier B.V. All rights reserved.

Keywords:
Bipolar disorder
Obsessivecompulsive disorder
Comorbidity
Treatment

Contents
1.
2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
2.1.
Information sources and search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
2.2.
Inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
2.2.1.
Study population and study design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
2.2.2.
Outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
2.2.3.
Study selection and data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
2.2.4.
Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
3.1.
Included studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
3.2.
Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

n
Corresponding author at: Section of Psychiatry, Department of Neuroscience, University of Parma, c/o Ospedale Maggiore, Pad. 21 - Braga, Viale A. Gramsci 14, 43126
Parma, Italy. Tel.: 39 0521 903594; fax: 39 0521 347047.
E-mail address: andrea.amerio@studenti.unipr.it (A. Amerio).

http://dx.doi.org/10.1016/j.jad.2014.05.026
0165-0327/& 2014 Elsevier B.V. All rights reserved.

A. Amerio et al. / Journal of Affective Disorders 166 (2014) 258263

259

3.2.1.
Mood-stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
3.2.2.
Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
3.2.3.
Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
3.2.4.
Behavioral treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
3.2.5.
Alternative therapeutic approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
5. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Conict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Appendix A.
Supporting information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

1. Introduction
Apparent comorbidity between bipolar disorder (BD) and
obsessivecompulsive disorder (OCD) is a common condition in
psychiatry. According to the Epidemiologic Catchment Area study
(ECA) and the National Comorbidity Survey Replication (NCS-R),
21% and 25% of patients with BD showed a lifetime comorbidity
for OCD (Chen and Dilsaver, 1995; Merikangas et al., 2007).
The meaning of this comorbidity has not been claried yet.
More importantlyfrom a clinical perspectivethe treatment of
BDOCD is a great challenge. Though serotonin reuptake inhibitors
(SRIs) are the rst line treatment for OCD, they can induce mood
instability in BD, especially if administered at high doses and
maintained for a long time (Math and Janardhan Reddy, 2007;
Pacchiarotti et al., 2013). The literature on specic pharmacologic
or psychotherapeutic approaches to patients with BDOCD comorbidity is limited (Schaffer et al., 2012). No systematic review of this
topic has been performed.
The present paper is the rst systematic review of pharmacologic and non-pharmacologic treatment of BDOCD comorbidity.

2. Methods
The systematic review was conducted following the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines (Liberati et al., 2009).
2.1. Information sources and search strategy
Studies were identied by searching the electronic databases
MEDLINE, Embase, PsycINFO and Cochrane. We combined the search
strategy of free text terms and exploded MESH headings for the topics
of bipolar disorder, obsessivecompulsive disorder and treatment
combined as following: ((((((Therapeutics[Mesh]) OR treatmentn)
OR therapn) OR pharmacotherapn) OR psychotherapn)) AND
(((((((((Bipolar Disorder[Mesh]) OR Bipolar disorder) OR BD) OR
Bipolar) OR Manic depressive disorder) OR Manic depressive) OR
Manic)) AND ((((ObsessiveCompulsive Disorder[Mesh]) OR OCD)
OR Obsessivecompulsive) OR Obsessivecompulsive disorder))).
The strategy was rst developed in MEDLINE and then adapted for
use in the other databases (Appendix). Studies published in English
from June 30th, 2013 were included. In addition, further studies were
retrieved from reference listing of relevant articles and consultation
with experts in the eld.
2.2. Inclusion criteria
2.2.1. Study population and study design
We considered studies that focused on the management of
comorbid BDOCD subjects. Studies were included if diagnostic

criteria for BD and OCD were specied. Among BD study populations, studies that only focused on BD-I, BD-II or BD Non Otherwise
Specied (NOS) were included. Participants of both sexes older
than 6 years of age were considered.
Both population-based and hospital-based studies were included.
Among hospital-based studies, inpatients, day-hospital and outpatient subjects were included. All experimental and observational study
designs were included. Narrative and systematic reviews and book
chapters were excluded.
2.2.2. Outcome measures
Either pharmacologic, psychotherapeutic and others alternative
approaches were considered.
2.2.3. Study selection and data extraction
Identied studies were independently reviewed for eligibility by
two authors (AA, SNG) in a two-step based process; a rst screening
was performed based on title and abstract while full texts were
retrieved for the second screening. At both stages disagreements by
reviewers were resolved by consensus. Data were extracted by one
author (AA) and supervised by a second author (SNG) using an
ad-hoc developed data extraction spreadsheet. The data extraction
spreadsheet was piloted on 10 randomly selected papers and
modied accordingly.
2.2.4. Quality assessment
The same authors who performed data extraction (AA, SNG)
independently assessed the quality of selected studies using the
checklist developed by Downs and Black both for randomized and
non-randomized studies (Downs and Black, 1998). Disagreements
by reviewers were resolved by consensus.

3. Results
Eight hundred and one potential studies were identied from
searching the selected databases and listing references of relevant
articles. After removing duplicates, 590 articles were retrieved.
Studies were screened and selected as described in Fig. 1. The
search identied 14 articles that were included in the systematic
review.
3.1. Included studies
The characteristics of the included studies are reported in
Table 1. Eight of the 14 studies were case reports, three crosssectional studies and three clinical trials. All the included studies
were hospital-based. Three studies assessed child and adolescent
populations. The largest sample size in a study was 257 subjects.
The majority of the studies were conducted in Europe. In all
cases, diagnoses were based on standard Diagnostic and Statistical

260

A. Amerio et al. / Journal of Affective Disorders 166 (2014) 258263

* Search strategy limited to June 2013, English language and human subjects older than 6 years old.
Fig. 1. Flow diagram of papers selected.

Manual (DSM) criteria and were established using validated


assessment scales (Table 1). OC symptoms were assessed using
the YaleBrown Obsessive Compulsive Scale (YBOCS).

3.2. Outcomes
Studies included in the review reported: a high rate of nonresponse
to pharmacological treatments (Joshi et al., 2010; Masi et al., 2007),
polypharmacy (Masi et al., 2009; Perugi et al., 2002), and pharmacologic manic/hypomanic switches (Perugi et al., 2002) (Table 2).
The following therapeutic approaches were used: mood stabilizers, antipsychotics, antidepressants, behavioral treatment, and
alternative therapeutic approaches.

3.2.1. Mood-stabilizers
In the largest clinical sample to date, 42.1% of BDOCD patients
required a combination of multiple mood stabilizers (lithium plus
antiepileptics); 10.5% were treated with mood stabilizers plus
neuroleptic agents (clozapine, olanzapine, risperidone) (Perugi
et al., 2002).
One study reported two cases of comorbid BDOCD where mood
and obsessivecompulsive symptoms improved after treatment with,
respectively, divalproex alone, and lamotrigine (100 mg/d) added to
divalproex. Patients remained stable for almost two years (Bisol and
Lara, 2009).

3.2.2. Antipsychotics
Three studies examined the treatment response of BDOCD
patients to olanzapine (Joshi et al., 2010; Marazziti et al., 2005;
Petrikis et al., 2004). In one analysis, antimanic response in
BDOCD was signicantly lower than in non-comorbid patients
(Joshi et al., 2010). In the other two studies, addition of olanzapine
to mood stabilizers or SRIs led to an improvement in the
obsessivecompulsive symptoms (Marazziti et al., 2005; Petrikis
et al., 2004).
One study evaluated augmentation with risperidone in OCD
mood disorder comorbidity in outpatients refractory to SRIs.
At baseline, OCD patients with unipolar or bipolar depression
presented similar values of YBOCS, while at the end of the study,
unipolar depressed patients showed a lower reduction in the
YBOCS total score than in BD (Pfanner et al., 2000).
A few case reports suggested benet with neuroleptic augmentation of standard mood stabilizers for treating OC symptoms in
BD, specically for risperidone (Raja and Azzoni, 2004), and for
quetiapine and aripiprazole (Stratta et al., 2003; Uguz, 2010).

3.2.3. Antidepressants
Only a few reports evaluated the effects of antidepressants in
BDOCD (Herstowska and Cubala, 2013; Perugi et al., 2002). One
hospital-based study found that clomipramine (39%) and, to a
lesser extent, SRIs (14%) were associated with more manic/hypomanic switches in BDOCD vs. non-comorbid patients. This manic

A. Amerio et al. / Journal of Affective Disorders 166 (2014) 258263

261

Table 1
Included studies.
References

Study
design

Country Study population

Focus

Outcomes

Assessment
tools

Diagnosis
assessment

Disorder
appeared
rst

Qualitya

Baer et al.,
1985
Bisol and
Lara, 2009

Case
report
Case
report

USA

NS; DSM-III

OCD

18/31

YBOCS

NS; DSM-IV

BD (1 Pt.)/ 18/31
OCD (1 Pt.)

Case
report
Case
report

Reduction of
OCD symptoms
Reduction of BD
and OCD
symptoms
Reduction of
OCD symptoms
Reduction of
OCD symptoms

NS

Chang et al.,
2009
Herstowska
and
Cubala,
2013
Marazziti et
al., 2005

Efcacy of behavior therapy on


OCD symptoms
Efcacy of divalproex and
lamotrigine on BD and OCD
symptoms
Efcacy of deep brain stimulation
on refractory OCD pt.
Efcacy of escitalopram on OCD
symptoms in BDOCD pt.

NS

NS; DSM-IV

OCD

18/31

YBOCS

NS; DSM

OCD

18/31

Reduction of
OCD symptoms

YBOCS

SCID; DSMIV

OCD

25/31

Reduction of BD
and OCD
symptoms
Reduction of
OCD symptoms
Reduction of
OCD symptoms

GAF, OCD
interview

SCID; DSMIV

OCD

20/31

YBOCS

NS; DSM-IV

BD

18/31

YBOCS, CGI,
HRSD,
DOTES
NS

NS; DSM-IV

OCD

25/31

NS; DSM-IV- OCD


TR

18/31

NS

NS; DSM

OCD

18/31

YBOCS

SCID; DSMIV
K-SADS-E;
DSM-IV
K-SADS-PL,
DICA-R;
DSM-IV
K-SADS-PL;
DSM-IV

BD (1 Pt.)/ 18/31
OCD (2 Pt.)
BD
20/31

Clinical
trial

Perugi et al., Cross2002


sectional
study
Petrikis et
Case
al., 2004
report
Pfanner et
Clinical
al., 2000
trial
Raja and
Azzoni,
2004
Stratta et al.,
2003
Uguz , 2010
Joshi et al.,
2010
Masi et al.,
2007
Masi et al.,
2009

Brazil

Taiwan
Poland

Italy

Italy

Greece
Italy

Pt. with BDOCD (n 2,


mean age 41)
Pt. with BDOCD (n 2,
mean age 33.5)
Pt. with refractory OCD
(n 1, age 28)
Pt. with BDOCD (n 1,
age 43)

Efcacy of the combination of


olanzapine and SRIs on resistant
OCD pt.
Clinical and treatment
implications of BDOCD
comorbidity
Pt. with BDOCD (n 1, Efcacy of olanzapine on OCD
age 30)
symptoms in BD pt.
Pt. with resistant OCD
Efcacy of risperidone
(n 20, mean age 32.6) augmentation in refractory OCD

Pt. with resistant OCD


(n 26, mean
age 33.87 9.9)
Pt. with BDOCD (n 68,
mean age 35.97 12.2)

Case
report

Italy

Pt. with BDOCD (n 7,


mean age 33.6)

Clinical management of BDOCD


comorbidity

Case
report

Italy

Pt. with BDOCD (n 1,


age 53)

Efcacy of quetiapine on BD and


OCD symptoms

Case
report
Clinical
trial
Crosssectional
study
Crosssectional
study

Turkey

Pt. with BDOCD (n 3,


mean age 25.3)
Pt. with BD (n 52, mean
age 8.4 7 3.1)
Pt. with OCD (n 120,
mean age 13.7 7 2.8)

Efcacy of aripiprazole on OCD


symptoms in BDOCD pt.
Antimanic response to
olanzapine
Clinical and treatment
implications of BDOCD
comorbidity
Treatment response in pediatric
OCD

USA
Italy

Italy

Pt. with OCD (n 257,


mean age 13.6 7 2.7)

Reduction of BD
and OCD
symptoms
Reduction of BD
and OCD
symptoms
Reduction of
OCD symptoms
Reduction of
manic symptoms
Reduction of BD
and OCD
symptoms
Reduction of
OCD symptoms

YMRS, CGI
YBOCS, CGI,
C-GAS
YBOCS, CGI,
C-GAS

OCD

21/31

OCD

22/31

BD: bipolar disorder; OCD: obsessivecompulsive disorder; DSM: Diagnostic and Statistical Manual of Mental Disorders; SCID: Structured Clinical Interview; K-SADS-E:
Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version; K-SADS-PL: Schedule for Affective Disorders and Schizophrenia
for School Age Children-Present and Lifetime Version; DICA-R: Diagnostic Interview for Children and Adolescents-Revised; YBOCS: YaleBrown ObsessiveCompulsive Scale;
YMRS: Young Mania Rating Scale; CGI: Clinical Global Impression; C-GAS: Children's Global Assessment Scale; HRSD: Hamilton Depression Rating Scale; DOTES: Dosage
Record and Treatment Emergent Symptom; GAF: Global Assessment of Functioning; SRIs: serotonin reuptake inhibitors; NS: not specied; Pt.: patients.
a

Checklist for measuring study quality developed by Downs and Black.

induction was worse in BDOCD patients who did not concomitantly receive mood stabilizers (Perugi et al., 2002).
We identied only a single case report showing SRI benet: a
BD patient responded well to high doses of escitalopram (40 mg/
die) added to divalproex (serum level 76 g/ml) along with
psychoeducation with behavioral intervention (Herstowska and
Cubala, 2013).

3.2.4. Behavioral treatments


Two cases of well controlled BD (lithium and neuroleptics)
showed long-lasting improvement (about one year) for treatment
of comorbid OCD with biweekly behavioral therapy (in vivo
exposure plus response prevention in 51 and 30 sessions, respectively) (Baer et al., 1985).

3.2.5. Alternative therapeutic approaches


A Chinese patient with BDOCD received bilateral anterior limb
stimulation of the internal capsules. Refractory obsessivecompulsive symptoms improved, but manic symptoms worsened, with
talkativeness, grandiosity, euphoria and ight of ideas. Manic

symptoms were especially prominent at the ventral contacts and


worsened with higher voltage ( Z4 V) (Chang et al., 2009).

4. Discussion
The co-occurrence of symptoms of BD and OCD was noted 150
years ago by Morel (1860), but the topic remains insufciently
studied. Scant and heterogeneous data are available on treatment
strategies, but, given the available scientic evidence, some
observations can be made.
In all selected studies BDOCD patients received mood stabilizers. In the study with the largest sample size, 42.1% of BDOCD
patients required a combination of multiple mood stabilizers
(lithium, antiepileptics), and 10.5% required a combination of
mood stabilizers with atypical antipsychotics (clozapine, olanzapine, risperidone). In only one study, addition of SRI (escitalopram)
to mood stabilizers led to clinical remission of both conditions. In
other cases, antidepressants seemed especially prone to cause
more manic/hypomanic episodes in BDOCD than in either noncomorbid patients. BDOCD patients on mood stabilizer therapy
appear to benet from complementary psychotherapy.

262

A. Amerio et al. / Journal of Affective Disorders 166 (2014) 258263

Table 2
Study results.
References

Results

Adults
Baer et al., 1985

Improvement of obsessivecompulsive symptoms in BDOCD pt. with behavioral therapy (in vivo exposure plus response prevention) after the
affective illness was well controlled by pharmacotherapy (case 1: lithium, aloperidol; case 2: lithium, haloperidol, desipramine).
Bisol and Lara, 2009
Relevant improvements for both BD and OCD after pharmacologic treatment with divalproex alone and lamotrigina (100 mg/die) added to
divalproex (YBOCS: from 46 to 4, after 6 months; from 23 to 4, after 6 weeks).
Chang et al., 2009
DBS of bilateral anterior limbs of the internal capsules induced hypomania-like syndrome in BDOCD pt.
Herstowska and Cubala, Remission for both BD and OCD after six-months treatment with escitalopram (40 mg/die), divalproex (serum level, 76 g/ml) and lithium
2013
(serum level, 0.30 mmol/l) along with psychoeducation with behavioral intervention (YBOCS: from 31 to 16, on discharge).
Marazziti et al., 2005
68% of pt. showed a reduction of at least 35% in the total baseline YBOCS score and sub-scales (YBOCS: from 29.3 7 6.1 to 187 3.3, after 12
months). The 15 resistant OCD pt. with comorbid lifetime BD showed a more marked, although not signicant (p 0.07), response to
augmentation with olanzapine vs. resistant OCD pt. without comorbid lifetime BD.
Perugi et al., 2002
In BDOCD pt., compared to non-BDOCD pt., clomipramine and, to a lesser extent, SRIs were related to a higher rate of manic/hypomanic
switches (clomipramine: 39.1% vs. 4.1%; SRIs: 13.9% vs. 0.0%). BDOCD pt. that did not concomitantly receive mood stabilizers presented more
frequent pharmacologic mania/hypomania as compared to non-BDOCD pt. (38.7% vs. 8.8%). Polypharmacologic treatments were required in
42.1% (a combination of multiple mood stabilizers) and 10.5% (a combination of mood stabilizers with atypical antipsychotics, clozapine,
olanzapine, risperidone) of the BDOCD pt.
Petrikis et al., 2004
The addition of Olanzapine 15 mg pro die to the therapeutic regimen in a BDOCD pt. led to clear improvement in the obsessivecompulsive
symptoms over a period of 6 weeks (YBOCS: from 20 to 6, after 6 weeks).
Pfanner et al., 2000
In refractory OCD outpatients, risperidone was added to SRI and the dosage titrated up to the mean dose of 3 mg/die over 8 weeks. At baseline,
unipolar OCD and bipolar OCD pt. showed similar values of YBOCS total scores (35.87 2.8 and 36.5 73.6, respectively), while at the end of the
study, the unipolar pt. showed a lower reduction in the YBOCS total score than the bipolar pt. (27.9 7 4.4, 20% vs. 22.6 7 3.5, 33%).
Raja and Azzoni, 2004
Almost all BDOCD pt. (87%) presented improvement of obsessivecompulsive symptoms with mood stabilizers (valproate, lithium) and/or
atypical antipsychotics (quetiapine, risperidone).
Stratta et al., 2003
Improvements for both BD and OCD after pharmacologic treatment with lithium (plasma level, 0.65 mEq/l) and quetiapine (600 mg/die).
Uguz, 2010
Relevant improvements for obsessivecompulsive symptoms after pharmacologic treatment with aripiprazole (1525 mg/die) and mood
stabilizers (lithium or valproate) (YBOCS: from 21 to 12, after 8 weeks; from 28 to 16, after 8 weeks; from 34 to 12, after 8 weeks).
Children/adolescents
Joshi et al., 2010

Masi et al., 2007

Masi et al., 2009

Antimanic response in OCDBD pt. signicantly lower as compared to non-OCDBD pt. (YMRS mean reduction:  5.9 7 13.1 vs.  13.7 7 18.8;
Z 30% reduction: 25% vs. 63%; CGI-S improvement score r 2: 25% vs. 68%). No statistically signicant differences reported in the rate of
dropouts or adverse effects.
BDOCD pt. received more mood stabilizers as compared to non-BDOCD pt. (86.0% vs. 10.4%); 69.8% of BDOCD pt. were treated with SRIs; the
rate of non responders to pharmacological treatment compared to responders was higher in BDOCD pt. than in non-BDOCD pt. (54.7% vs.
25.6%).
BDOCD pt. more frequently received polypharmacy than taking SRIs alone (51.1% vs. 5.6%).

BD: bipolar disorder; OCD: obsessivecompulsive disorder; YBOCS: YaleBrown Obsessive Compulsive Scale; SRIs: Serotonin Reuptake Inhibitors; YMRS: Young Mania
Rating Scale; CGI: Clinical Global Impression; Pt.: patients. Differences statistically signicant (po 0.05).

The entire question of comorbidity deserves attention, which


we have provided separately (Amerio et al., 2014a, 2014b). In our
review of diagnostic studies, we found that 5075% of OCD cases
are limited to mood episodes in BD. In other words, the majority of
comorbid OCD cases appear to be secondary to mood episodes,
while a substantial minority of comorbid OCD cases are not
episodic and may represent true OCD independent of BD. Overall, OC symptoms in comorbid patients appear more oftenand
sometimes exclusivelyduring depressive episodes, and comorbid
BD and OCD cycle together, with OC symptoms often remitting
during manic/hypomanic episodes (Amerio et al., 2014a).
In short, in a systematic review that examines course as a key
diagnostic validator, most cases of apparently comorbid BDOCD
are instead cases of BD alone, with OC symptoms as secondary
manifestations of depressive or manic episodes.
This diagnostic conclusion is consistent with this systematic
review of treatment of BDOCD, which nds that there is more
evidence of benet with using BD treatments primarily, whereas
OCD-specic treatments like SRIs tend to be less effective and
more harmful. This judgment is made based on the available
evidence, which is limited. And thus denitive conclusions
cannot be drawn. However, the basic principle of evidence-based
medicine is not that we should draw no conclusions until evidence
is denitive, but rather that we should draw our best conclusions
given the evidence we possess.
BD treatments used in this systematic review were mainly
lithium and anticonvulsants. Benet with neuroleptics was also
seen, although a few reports also exist of exacerbation of
OC symptoms with neuroleptic agents (Alevizos et al., 2004;
Remington and Adams, 1994; Stamouli and Lykouras, 2006).

This systematic review found that SRIs and other antidepressants were less effective and more harmful in BDOCD than in
non-comorbid patients. Nonetheless, in a minority of BD patients
with refractory OCD, addition of low doses of antidepressants
might also be considered while strictly monitoring emerging
symptoms of mania and hypomania. Deep brain stimulation also
seems to carry risks of manic worsening, and thus may not be
a useful intervention in BDOCD.
To allow more denitive conclusions, prospective controlled
studies are needed in this important diagnostic and clinical topic.

5. Limitations
The main strength of this study is that it is the rst systematic
review of this topic, and thus includes the entire available scientic evidence. Further, all included original studies used methodologically similar and psychometrically-validated diagnostic and
outcome measures: DSM-based criteria and the YBOCS scale.
The main limitation of included studies is sample size, as
documented by the quality assessment scores. Six (43%) studies
were assigned a score equal or greater than 20/31 on the Downs
and Black quality scale (Downs and Black, 1998) (Table 1). The
majority of the selected studies are case reports (57%) or crosssectional studies based on retrospective assessments (21%). The
use of retrospective assessment scales with low sensitivity in
discriminating true ego-dystonic obsessions from depressive
ruminations may have biased results towards an overestimation
of obsessive symptom prevalence. In addition, patients included in
the review were mainly recruited from specialized BD and OCD

A. Amerio et al. / Journal of Affective Disorders 166 (2014) 258263

outpatient units; this might have introduced selection bias and


limited the generalizability of ndings to the community, where
such patients tend to be less refractory.
Role of funding source
No funding sources.

Conict of interest
Dr. Amerio, Dr. Odone, Dr. Marchesi: no competing interests.
Dr. Ghaemi: in the past 12 months has received a research grant from Takeda
Pharmaceuticals and has made a one-time research consultation to Sunovion
Pharmaceuticals. Neither he nor his family hold equity positions in pharmaceutical
corporations.

Acknowledgments
The authors thank Matteo Tonna MD for his careful critique and his helpful
comments.

Appendix A. Supporting information


Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.jad.2014.05.026.
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