Journal of Affective Disorders 166 (2014) 258–263
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Review
Treatment of comorbid bipolar disorder and obsessive–compulsive 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 obsessive–compulsive disorder (OCD), but treatment of BD–OCD is a clinical challenge. Although serotonin reuptake inhibitors (SRIs) are the first line treatment for OCD, they can induce mood instability in BD. An optimal treatment approach remains to be defined. Methods: We systematically reviewed MEDLINE, Embase, PsychINFO and the Cochrane Library and retrieved data on clinical management of comorbid BD–OCD patients. Pharmacologic, psychotherapeutic and others alternative approaches were included. Results: Fourteen studies were selected. In all selected studies BD–OCD 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 BD–OCD patients on mood stabilizer therapy benefitted 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 BD–OCD 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 Obsessive–compulsive 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.: þ 39 0521 903594; fax: þ 39 0521 347047. E-mail address: [email protected] (A. Amerio).
http://dx.doi.org/10.1016/j.jad.2014.05.026 0165-0327/& 2014 Elsevier B.V. All rights reserved.
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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 Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Appendix A. Supporting information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
1. Introduction Apparent comorbidity between bipolar disorder (BD) and obsessive–compulsive 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 clarified yet. More importantly—from a clinical perspective—the treatment of BD–OCD is a great challenge. Though serotonin reuptake inhibitors (SRIs) are the first 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 specific pharmacologic or psychotherapeutic approaches to patients with BD–OCD comorbidity is limited (Schaffer et al., 2012). No systematic review of this topic has been performed. The present paper is the first systematic review of pharmacologic and non-pharmacologic treatment of BD–OCD 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 identified 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, obsessive–compulsive 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 ((((“Obsessive–Compulsive Disorder”[Mesh]) OR OCD) OR Obsessive–compulsive) OR Obsessive–compulsive disorder))). The strategy was first 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 field. 2.2. Inclusion criteria 2.2.1. Study population and study design We considered studies that focused on the management of comorbid BD–OCD subjects. Studies were included if diagnostic
criteria for BD and OCD were specified. Among BD study populations, studies that only focused on BD-I, BD-II or BD Non Otherwise Specified (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 Identified studies were independently reviewed for eligibility by two authors (AA, SNG) in a two-step based process; a first 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 modified 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 identified 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 identified 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
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* 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 Yale–Brown Obsessive Compulsive Scale (Y–BOCS).
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 BD–OCD 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 BD–OCD where mood and obsessive–compulsive 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 BD–OCD patients to olanzapine (Joshi et al., 2010; Marazziti et al., 2005; Petrikis et al., 2004). In one analysis, antimanic response in BD–OCD was significantly 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 obsessive–compulsive 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 Y–BOCS, while at the end of the study, unipolar depressed patients showed a lower reduction in the Y–BOCS total score than in BD (Pfanner et al., 2000). A few case reports suggested benefit with neuroleptic augmentation of standard mood stabilizers for treating OC symptoms in BD, specifically 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 BD–OCD (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 BD–OCD vs. non-comorbid patients. This manic
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Table 1 Included studies. References
Study design
Country Study population
Focus
Outcomes
Assessment tools
Diagnosis assessment
Disorder appeared first
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
Efficacy of behavior therapy on OCD symptoms Efficacy of divalproex and lamotrigine on BD and OCD symptoms Efficacy of deep brain stimulation on refractory OCD pt. Efficacy of escitalopram on OCD symptoms in BD–OCD 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 BD–OCD (n¼ 2, mean age¼ 41) Pt. with BD–OCD (n¼ 2, mean age¼ 33.5) Pt. with refractory OCD (n¼ 1, age¼ 28) Pt. with BD–OCD (n¼ 1, age ¼43)
Efficacy of the combination of olanzapine and SRIs on resistant OCD pt. Clinical and treatment implications of BD–OCD comorbidity Pt. with BD–OCD (n¼ 1, Efficacy of olanzapine on OCD age ¼30) symptoms in BD pt. Pt. with resistant OCD Efficacy of risperidone (n¼ 20, mean age¼ 32.6) augmentation in refractory OCD
Pt. with resistant OCD (n¼ 26, mean age ¼33.87 9.9) Pt. with BD–OCD (n¼ 68, mean age¼ 35.97 12.2)
Case report
Italy
Pt. with BD–OCD (n¼ 7, mean age¼ 33.6)
Clinical management of BD–OCD comorbidity
Case report
Italy
Pt. with BD–OCD (n¼ 1, age ¼53)
Efficacy of quetiapine on BD and OCD symptoms
Case report Clinical trial Crosssectional study Crosssectional study
Turkey
Pt. with BD–OCD (n¼ 3, mean age¼ 25.3) Pt. with BD (n¼ 52, mean age ¼8.4 7 3.1) Pt. with OCD (n¼ 120, mean age¼ 13.7 7 2.8)
Efficacy of aripiprazole on OCD symptoms in BD–OCD pt. Antimanic response to olanzapine Clinical and treatment implications of BD–OCD comorbidity Treatment response in pediatric OCD
USA Italy
Italy
Pt. with OCD (n¼ 257, mean age¼ 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: obsessive–compulsive 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: Yale–Brown Obsessive–Compulsive 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 specified; Pt.: patients. a
Checklist for measuring study quality developed by Downs and Black.
induction was worse in BD–OCD patients who did not concomitantly receive mood stabilizers (Perugi et al., 2002). We identified only a single case report showing SRI benefit: a BD patient responded well to high doses of escitalopram (40 mg/ die) added to divalproex (serum level 76 μg/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 BD–OCD received bilateral anterior limb stimulation of the internal capsules. Refractory obsessive–compulsive symptoms improved, but manic symptoms worsened, with talkativeness, grandiosity, euphoria and flight 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 insufficiently studied. Scant and heterogeneous data are available on treatment strategies, but, given the available scientific evidence, some observations can be made. In all selected studies BD–OCD patients received mood stabilizers. In the study with the largest sample size, 42.1% of BD–OCD 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 BD–OCD than in either noncomorbid patients. BD–OCD patients on mood stabilizer therapy appear to benefit from complementary psychotherapy.
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Table 2 Study results. References
Results
Adults Baer et al., 1985
Improvement of obsessive–compulsive symptoms in BD–OCD 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 BD–OCD pt. Herstowska and Cubala, Remission for both BD and OCD after six-months treatment with escitalopram (40 mg/die), divalproex (serum level, 76 μg/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 Y–BOCS score and sub-scales (Y–BOCS: 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 significant (p ¼ 0.07), response to augmentation with olanzapine vs. resistant OCD pt. without comorbid lifetime BD. Perugi et al., 2002 In BD–OCD pt., compared to non-BD–OCD 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%). BD–OCD pt. that did not concomitantly receive mood stabilizers presented more frequent pharmacologic mania/hypomania as compared to non-BD–OCD 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 BD–OCD pt. Petrikis et al., 2004 The addition of Olanzapine 15 mg pro die to the therapeutic regimen in a BD–OCD pt. led to clear improvement in the obsessive–compulsive symptoms over a period of 6 weeks (Y–BOCS: 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 Y–BOCS 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 Y–BOCS 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 BD–OCD pt. (87%) presented improvement of obsessive–compulsive 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 obsessive–compulsive symptoms after pharmacologic treatment with aripiprazole (15–25 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 OCD–BD pt. significantly lower as compared to non-OCD–BD 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 significant differences reported in the rate of dropouts or adverse effects. BD–OCD pt. received more mood stabilizers as compared to non-BD–OCD pt. (86.0% vs. 10.4%); 69.8% of BD–OCD pt. were treated with SRIs; the rate of non responders to pharmacological treatment compared to responders was higher in BD–OCD pt. than in non-BD–OCD pt. (54.7% vs. 25.6%). BD–OCD pt. more frequently received polypharmacy than taking SRIs alone (51.1% vs. 5.6%).
BD: bipolar disorder; OCD: obsessive–compulsive disorder; Y–BOCS: Yale–Brown Obsessive Compulsive Scale; SRIs: Serotonin Reuptake Inhibitors; YMRS: Young Mania Rating Scale; CGI: Clinical Global Impression; Pt.: patients. Differences statistically significant (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 50–75% 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 often—and sometimes exclusively—during 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 BD–OCD 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 BD–OCD, which finds that there is more evidence of benefit with using BD treatments primarily, whereas OCD-specific 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 definitive conclusions cannot be drawn. However, the basic principle of evidence-based medicine is not that we should draw no conclusions until evidence is definitive, 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. Benefit 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 BD–OCD 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 BD–OCD. To allow more definitive 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 first systematic review of this topic, and thus includes the entire available scientific evidence. Further, all included original studies used methodologically similar and psychometrically-validated diagnostic and outcome measures: DSM-based criteria and the Y–BOCS 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
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outpatient units; this might have introduced selection bias and limited the generalizability of findings to the community, where such patients tend to be less refractory. Role of funding source No funding sources.
Conflict 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. References Alevizos, B., Papageorgiou, C., Christodoulou, G.N., 2004. Obsessive–compulsive symptoms with olanzapine. Int. J. Neuropsychopharmacol. 7, 375–377. Amerio, A., Odone, A., Liapis, C.C., Ghaemi, S.N., 2014a. Diagnostic validity of comorbid bipolar disorder and obsessive–compulsive disorder: a systematic review. Acta Psychiatr. Scand. 129, 343–358. Amerio, A., Odone, A., Marchesi, C., Ghaemi, S.N., 2014b. Do antidepressant-induced manic episodes in obsessive–compulsive disorder patients represent the clinical expression of an underlying bipolarity? Aust. N. Z. J. Psychiatry, [Epub ahead of print], PubMed PMID: 24711576. Baer, L., Minichiello, W.E., Jenike, M.A., 1985. Behavioral treatment in two cases of obsessive–compulsive disorder with concomitant bipolar affective disorder. Am. J. Psychiatry 142, 358–360. Bisol, L.W., Lara, D.R., 2009. Improvement of obsessive–compulsive disorder with divalproex and lamotrigine in two patients with bipolar II disorder. Pharmacopsychiatry 42, 37–39. Chang, C.H., Chen, S.Y., Hsiao, Y.L., Chen, S.J., Tsai, S.T., Chang, C.H., Yeh, Y.Y., Tsai, H.C., 2009. Hypomania-like syndrome induced by deep brain stimulation of bilateral anterior limbs of the internal capsules. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 33, 906–907. Chen, Y.W., Dilsaver, S.C., 1995. Comorbidity for obsessive–compulsive disorder in bipolar and unipolar disorders. Psychiatry Res. 59, 57–64. Downs, S.H., Black, N., 1998. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J. Epidemiol. Community Health 52, 377–384. Herstowska, M., Cubala, W.J., 2013. Escitalopram efficacy in obsessive–compulsive disorder comorbid with bipolar disorder. Dusunen Adam 26, 115–116. Joshi, G., Mick, E., Wozniak, J., Geller, D., Park, J., Strauss, S., Biederman, J., 2010. Impact of obsessive–compulsive disorder on the antimanic response to olanzapine therapy in youth with bipolar disorder. Bipolar Disord. 12, 196–204.
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Liberati, A., Altman, D.G., Tetzlaff, J., Mulrow, C., Gotzsche, P.C., Ioannidis, J.P., Clarke, M., Devereaux, P.J., Kleijnen, J., Moher, D., 2009. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Br. J. Med. 339, b2700. Marazziti, D., Pfanner, C., Dell’osso, B., Ciapparelli, A., Presta, S., Corretti, G., Di Nasso, E., Mungai, F., Dell’osso, L., 2005. Augmentation strategy with olanzapine in resistant obsessive compulsive disorder: an Italian long-term open-label study. J. Psychopharmacol. 19, 392–394. Masi, G., Millepiedi, S., Perugi, G., Pfanner, C., Berloffa, S., Pari, C., Mucci, M., 2009. Pharmacotherapy in paediatric obsessive–compulsive disorder: a naturalistic, retrospective study. CNS Drugs 23, 241–252. Masi, G., Perugi, G., Millepiedi, S., Toni, C., Mucci, M., Pfanner, C., Berloffa, S., Pari, C., Akiskal, H.S., 2007. Bipolar co-morbidity in pediatric obsessive–compulsive disorder: clinical and treatment implications. J. Child Adolesc. Psychopharmacol. 17, 475–486. Math, S.B., Janardhan Reddy, Y.C., 2007. Issues in the pharmacological treatment of obsessive–compulsive disorder. Int. J. Clin. Pract. 61, 1188–1197. Merikangas, K.R., Akiskal, H.S., Angst, J., Greenberg, P.E., Hirschfeld, R.M., Petukhova, M., Kessler, R.C., 2007. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch. Gen. Psychiatry 64, 543–552. Morel, B.A., 1860. Traité des maladies mentales. Masson, Paris. Pacchiarotti, I., Bond, D.J., Baldessarini, R.J., Nolen, W.A., Grunze, H., Licht, R.W., Post, R.M., Berk, M., Goodwin, G.M., Sachs, G.S., Tondo, L., Findling, R.L., Youngstrom, E.A., Tohen, M., Undurraga, J., Gonzalez-pinto, A., Goldberg, J.F., Yildiz, A., Altshuler, L.L., Calabrese, J.R., Mitchell, P.B., Thase, M.E., Koukopoulos, A., Colom, F., Frye, M.A., Malhi, G.S., Fountoulakis, K.N., Vazquez, G., Perlis, R.H., Ketter, T.A., Cassidy, F., Akiskal, H., Azorin, J.M., Valenti, M., Mazzei, D.H., Lafer, B., Kato, T., Mazzarini, L., Martinez-aran, A., Parker, G., Souery, D., Ozerdem, A., Mcelroy, S.L., Girardi, P., Bauer, M., Yatham, L.N., Zarate, C.A., Nierenberg, A.A., Birmaher, B., Kanba, S., El-mallakh, R.S., Serretti, A., Rihmer, Z., Young, A.H., Kotzalidis, G.D., Macqueen, G.M., Bowden, C.L., Ghaemi, S.N., Lopez-jaramillo, C., Rybakowski, J., Ha, K., Perugi, G., Kasper, S., Amsterdam, J. D., Hirschfeld, R.M., Kapczinski, F., Vieta, E., 2013. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am. J. Psychiatry 170, 1249–1262. Perugi, G., Toni, C., Frare, F., Travierso, M.C., Hantouche, E., Akiskal, H.S., 2002. Obsessive–compulsive–bipolar comorbidity: a systematic exploration of clinical features and treatment outcome. J. Clin. Psychiatry 63, 1129–1134. Petrikis, P., Andreou, C., Bozikas, V.P., Karavatos, A., 2004. Effective use of olanzapine for obsessive–compulsive symptoms in a patient with bipolar disorder. Can. J. Psychiatry 49, 572–573. Pfanner, C., Marazziti, D., Dell’osso, L., Presta, S., Gemignani, A., Milanfranchi, A., Cassano, G.B., 2000. Risperidone augmentation in refractory obsessive–compulsive disorder: an open-label study. Int. Clin. Psychopharmacol. 15, 297–301. Raja, M., Azzoni, A., 2004. Clinical management of obsessive–compulsive–bipolar comorbidity: a case series. Bipolar Disord. 6, 264–270. Remington, G., Adams, M., 1994. Risperidone and obsessive–compulsive symptoms. J. Clin. Psychopharmacol. 14, 358–359. Schaffer, A., Mcintosh, D., Goldstein, B.I., Rector, N.A., Mcintyre, R.S., Beaulieu, S., Swinson, R., Yatham, L.N., 2012. The CANMAT task force recommendations for the management of patients with mood disorders and comorbid anxiety disorders. Ann. Clin. Psychiatry 24, 6–22. Stamouli, S., Lykouras, L., 2006. Quetiapine-induced obsessive–compulsive symptoms: a series of five cases. J. Clin. Psychopharmacol. 26, 396–400. Stratta, P., De Cataldo, S., Mancini, G., Gianfelice, D., Rinaldi, O., Rossi, A., 2003. Quetiapine as adjunctive treatment of a case of rapid-cycling bipolar disorder with comorbidity. Hum. Psychopharmacol. 18, 559–560. Uguz, F., 2010. Successful treatment of comorbid obsessive–compulsive disorder with aripiprazole in three patients with bipolar disorder. Gen. Hosp. Psychiatry 32, 556–558.
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Review
Treatment of comorbid bipolar disorder and obsessive–compulsive 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 obsessive–compulsive disorder (OCD), but treatment of BD–OCD is a clinical challenge. Although serotonin reuptake inhibitors (SRIs) are the first line treatment for OCD, they can induce mood instability in BD. An optimal treatment approach remains to be defined. Methods: We systematically reviewed MEDLINE, Embase, PsychINFO and the Cochrane Library and retrieved data on clinical management of comorbid BD–OCD patients. Pharmacologic, psychotherapeutic and others alternative approaches were included. Results: Fourteen studies were selected. In all selected studies BD–OCD 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 BD–OCD patients on mood stabilizer therapy benefitted 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 BD–OCD 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 Obsessive–compulsive 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.: þ 39 0521 903594; fax: þ 39 0521 347047. E-mail address: [email protected] (A. Amerio).
http://dx.doi.org/10.1016/j.jad.2014.05.026 0165-0327/& 2014 Elsevier B.V. All rights reserved.
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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 Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Appendix A. Supporting information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
1. Introduction Apparent comorbidity between bipolar disorder (BD) and obsessive–compulsive 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 clarified yet. More importantly—from a clinical perspective—the treatment of BD–OCD is a great challenge. Though serotonin reuptake inhibitors (SRIs) are the first 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 specific pharmacologic or psychotherapeutic approaches to patients with BD–OCD comorbidity is limited (Schaffer et al., 2012). No systematic review of this topic has been performed. The present paper is the first systematic review of pharmacologic and non-pharmacologic treatment of BD–OCD 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 identified 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, obsessive–compulsive 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 ((((“Obsessive–Compulsive Disorder”[Mesh]) OR OCD) OR Obsessive–compulsive) OR Obsessive–compulsive disorder))). The strategy was first 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 field. 2.2. Inclusion criteria 2.2.1. Study population and study design We considered studies that focused on the management of comorbid BD–OCD subjects. Studies were included if diagnostic
criteria for BD and OCD were specified. Among BD study populations, studies that only focused on BD-I, BD-II or BD Non Otherwise Specified (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 Identified studies were independently reviewed for eligibility by two authors (AA, SNG) in a two-step based process; a first 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 modified 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 identified 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 identified 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
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* 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 Yale–Brown Obsessive Compulsive Scale (Y–BOCS).
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 BD–OCD 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 BD–OCD where mood and obsessive–compulsive 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 BD–OCD patients to olanzapine (Joshi et al., 2010; Marazziti et al., 2005; Petrikis et al., 2004). In one analysis, antimanic response in BD–OCD was significantly 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 obsessive–compulsive 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 Y–BOCS, while at the end of the study, unipolar depressed patients showed a lower reduction in the Y–BOCS total score than in BD (Pfanner et al., 2000). A few case reports suggested benefit with neuroleptic augmentation of standard mood stabilizers for treating OC symptoms in BD, specifically 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 BD–OCD (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 BD–OCD vs. non-comorbid patients. This manic
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Table 1 Included studies. References
Study design
Country Study population
Focus
Outcomes
Assessment tools
Diagnosis assessment
Disorder appeared first
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
Efficacy of behavior therapy on OCD symptoms Efficacy of divalproex and lamotrigine on BD and OCD symptoms Efficacy of deep brain stimulation on refractory OCD pt. Efficacy of escitalopram on OCD symptoms in BD–OCD 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 BD–OCD (n¼ 2, mean age¼ 41) Pt. with BD–OCD (n¼ 2, mean age¼ 33.5) Pt. with refractory OCD (n¼ 1, age¼ 28) Pt. with BD–OCD (n¼ 1, age ¼43)
Efficacy of the combination of olanzapine and SRIs on resistant OCD pt. Clinical and treatment implications of BD–OCD comorbidity Pt. with BD–OCD (n¼ 1, Efficacy of olanzapine on OCD age ¼30) symptoms in BD pt. Pt. with resistant OCD Efficacy of risperidone (n¼ 20, mean age¼ 32.6) augmentation in refractory OCD
Pt. with resistant OCD (n¼ 26, mean age ¼33.87 9.9) Pt. with BD–OCD (n¼ 68, mean age¼ 35.97 12.2)
Case report
Italy
Pt. with BD–OCD (n¼ 7, mean age¼ 33.6)
Clinical management of BD–OCD comorbidity
Case report
Italy
Pt. with BD–OCD (n¼ 1, age ¼53)
Efficacy of quetiapine on BD and OCD symptoms
Case report Clinical trial Crosssectional study Crosssectional study
Turkey
Pt. with BD–OCD (n¼ 3, mean age¼ 25.3) Pt. with BD (n¼ 52, mean age ¼8.4 7 3.1) Pt. with OCD (n¼ 120, mean age¼ 13.7 7 2.8)
Efficacy of aripiprazole on OCD symptoms in BD–OCD pt. Antimanic response to olanzapine Clinical and treatment implications of BD–OCD comorbidity Treatment response in pediatric OCD
USA Italy
Italy
Pt. with OCD (n¼ 257, mean age¼ 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: obsessive–compulsive 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: Yale–Brown Obsessive–Compulsive 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 specified; Pt.: patients. a
Checklist for measuring study quality developed by Downs and Black.
induction was worse in BD–OCD patients who did not concomitantly receive mood stabilizers (Perugi et al., 2002). We identified only a single case report showing SRI benefit: a BD patient responded well to high doses of escitalopram (40 mg/ die) added to divalproex (serum level 76 μg/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 BD–OCD received bilateral anterior limb stimulation of the internal capsules. Refractory obsessive–compulsive symptoms improved, but manic symptoms worsened, with talkativeness, grandiosity, euphoria and flight 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 insufficiently studied. Scant and heterogeneous data are available on treatment strategies, but, given the available scientific evidence, some observations can be made. In all selected studies BD–OCD patients received mood stabilizers. In the study with the largest sample size, 42.1% of BD–OCD 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 BD–OCD than in either noncomorbid patients. BD–OCD patients on mood stabilizer therapy appear to benefit from complementary psychotherapy.
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Table 2 Study results. References
Results
Adults Baer et al., 1985
Improvement of obsessive–compulsive symptoms in BD–OCD 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 BD–OCD pt. Herstowska and Cubala, Remission for both BD and OCD after six-months treatment with escitalopram (40 mg/die), divalproex (serum level, 76 μg/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 Y–BOCS score and sub-scales (Y–BOCS: 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 significant (p ¼ 0.07), response to augmentation with olanzapine vs. resistant OCD pt. without comorbid lifetime BD. Perugi et al., 2002 In BD–OCD pt., compared to non-BD–OCD 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%). BD–OCD pt. that did not concomitantly receive mood stabilizers presented more frequent pharmacologic mania/hypomania as compared to non-BD–OCD 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 BD–OCD pt. Petrikis et al., 2004 The addition of Olanzapine 15 mg pro die to the therapeutic regimen in a BD–OCD pt. led to clear improvement in the obsessive–compulsive symptoms over a period of 6 weeks (Y–BOCS: 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 Y–BOCS 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 Y–BOCS 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 BD–OCD pt. (87%) presented improvement of obsessive–compulsive 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 obsessive–compulsive symptoms after pharmacologic treatment with aripiprazole (15–25 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 OCD–BD pt. significantly lower as compared to non-OCD–BD 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 significant differences reported in the rate of dropouts or adverse effects. BD–OCD pt. received more mood stabilizers as compared to non-BD–OCD pt. (86.0% vs. 10.4%); 69.8% of BD–OCD pt. were treated with SRIs; the rate of non responders to pharmacological treatment compared to responders was higher in BD–OCD pt. than in non-BD–OCD pt. (54.7% vs. 25.6%). BD–OCD pt. more frequently received polypharmacy than taking SRIs alone (51.1% vs. 5.6%).
BD: bipolar disorder; OCD: obsessive–compulsive disorder; Y–BOCS: Yale–Brown Obsessive Compulsive Scale; SRIs: Serotonin Reuptake Inhibitors; YMRS: Young Mania Rating Scale; CGI: Clinical Global Impression; Pt.: patients. Differences statistically significant (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 50–75% 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 often—and sometimes exclusively—during 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 BD–OCD 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 BD–OCD, which finds that there is more evidence of benefit with using BD treatments primarily, whereas OCD-specific 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 definitive conclusions cannot be drawn. However, the basic principle of evidence-based medicine is not that we should draw no conclusions until evidence is definitive, 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. Benefit 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 BD–OCD 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 BD–OCD. To allow more definitive 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 first systematic review of this topic, and thus includes the entire available scientific evidence. Further, all included original studies used methodologically similar and psychometrically-validated diagnostic and outcome measures: DSM-based criteria and the Y–BOCS 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
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outpatient units; this might have introduced selection bias and limited the generalizability of findings to the community, where such patients tend to be less refractory. Role of funding source No funding sources.
Conflict 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. References Alevizos, B., Papageorgiou, C., Christodoulou, G.N., 2004. Obsessive–compulsive symptoms with olanzapine. Int. J. Neuropsychopharmacol. 7, 375–377. Amerio, A., Odone, A., Liapis, C.C., Ghaemi, S.N., 2014a. Diagnostic validity of comorbid bipolar disorder and obsessive–compulsive disorder: a systematic review. Acta Psychiatr. Scand. 129, 343–358. Amerio, A., Odone, A., Marchesi, C., Ghaemi, S.N., 2014b. Do antidepressant-induced manic episodes in obsessive–compulsive disorder patients represent the clinical expression of an underlying bipolarity? Aust. N. Z. J. Psychiatry, [Epub ahead of print], PubMed PMID: 24711576. Baer, L., Minichiello, W.E., Jenike, M.A., 1985. Behavioral treatment in two cases of obsessive–compulsive disorder with concomitant bipolar affective disorder. Am. J. Psychiatry 142, 358–360. Bisol, L.W., Lara, D.R., 2009. Improvement of obsessive–compulsive disorder with divalproex and lamotrigine in two patients with bipolar II disorder. Pharmacopsychiatry 42, 37–39. Chang, C.H., Chen, S.Y., Hsiao, Y.L., Chen, S.J., Tsai, S.T., Chang, C.H., Yeh, Y.Y., Tsai, H.C., 2009. Hypomania-like syndrome induced by deep brain stimulation of bilateral anterior limbs of the internal capsules. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 33, 906–907. Chen, Y.W., Dilsaver, S.C., 1995. Comorbidity for obsessive–compulsive disorder in bipolar and unipolar disorders. Psychiatry Res. 59, 57–64. Downs, S.H., Black, N., 1998. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J. Epidemiol. Community Health 52, 377–384. Herstowska, M., Cubala, W.J., 2013. Escitalopram efficacy in obsessive–compulsive disorder comorbid with bipolar disorder. Dusunen Adam 26, 115–116. Joshi, G., Mick, E., Wozniak, J., Geller, D., Park, J., Strauss, S., Biederman, J., 2010. Impact of obsessive–compulsive disorder on the antimanic response to olanzapine therapy in youth with bipolar disorder. Bipolar Disord. 12, 196–204.
263
Liberati, A., Altman, D.G., Tetzlaff, J., Mulrow, C., Gotzsche, P.C., Ioannidis, J.P., Clarke, M., Devereaux, P.J., Kleijnen, J., Moher, D., 2009. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Br. J. Med. 339, b2700. Marazziti, D., Pfanner, C., Dell’osso, B., Ciapparelli, A., Presta, S., Corretti, G., Di Nasso, E., Mungai, F., Dell’osso, L., 2005. Augmentation strategy with olanzapine in resistant obsessive compulsive disorder: an Italian long-term open-label study. J. Psychopharmacol. 19, 392–394. Masi, G., Millepiedi, S., Perugi, G., Pfanner, C., Berloffa, S., Pari, C., Mucci, M., 2009. Pharmacotherapy in paediatric obsessive–compulsive disorder: a naturalistic, retrospective study. CNS Drugs 23, 241–252. Masi, G., Perugi, G., Millepiedi, S., Toni, C., Mucci, M., Pfanner, C., Berloffa, S., Pari, C., Akiskal, H.S., 2007. Bipolar co-morbidity in pediatric obsessive–compulsive disorder: clinical and treatment implications. J. Child Adolesc. Psychopharmacol. 17, 475–486. Math, S.B., Janardhan Reddy, Y.C., 2007. Issues in the pharmacological treatment of obsessive–compulsive disorder. Int. J. Clin. Pract. 61, 1188–1197. Merikangas, K.R., Akiskal, H.S., Angst, J., Greenberg, P.E., Hirschfeld, R.M., Petukhova, M., Kessler, R.C., 2007. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch. Gen. Psychiatry 64, 543–552. Morel, B.A., 1860. Traité des maladies mentales. Masson, Paris. Pacchiarotti, I., Bond, D.J., Baldessarini, R.J., Nolen, W.A., Grunze, H., Licht, R.W., Post, R.M., Berk, M., Goodwin, G.M., Sachs, G.S., Tondo, L., Findling, R.L., Youngstrom, E.A., Tohen, M., Undurraga, J., Gonzalez-pinto, A., Goldberg, J.F., Yildiz, A., Altshuler, L.L., Calabrese, J.R., Mitchell, P.B., Thase, M.E., Koukopoulos, A., Colom, F., Frye, M.A., Malhi, G.S., Fountoulakis, K.N., Vazquez, G., Perlis, R.H., Ketter, T.A., Cassidy, F., Akiskal, H., Azorin, J.M., Valenti, M., Mazzei, D.H., Lafer, B., Kato, T., Mazzarini, L., Martinez-aran, A., Parker, G., Souery, D., Ozerdem, A., Mcelroy, S.L., Girardi, P., Bauer, M., Yatham, L.N., Zarate, C.A., Nierenberg, A.A., Birmaher, B., Kanba, S., El-mallakh, R.S., Serretti, A., Rihmer, Z., Young, A.H., Kotzalidis, G.D., Macqueen, G.M., Bowden, C.L., Ghaemi, S.N., Lopez-jaramillo, C., Rybakowski, J., Ha, K., Perugi, G., Kasper, S., Amsterdam, J. D., Hirschfeld, R.M., Kapczinski, F., Vieta, E., 2013. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am. J. Psychiatry 170, 1249–1262. Perugi, G., Toni, C., Frare, F., Travierso, M.C., Hantouche, E., Akiskal, H.S., 2002. Obsessive–compulsive–bipolar comorbidity: a systematic exploration of clinical features and treatment outcome. J. Clin. Psychiatry 63, 1129–1134. Petrikis, P., Andreou, C., Bozikas, V.P., Karavatos, A., 2004. Effective use of olanzapine for obsessive–compulsive symptoms in a patient with bipolar disorder. Can. J. Psychiatry 49, 572–573. Pfanner, C., Marazziti, D., Dell’osso, L., Presta, S., Gemignani, A., Milanfranchi, A., Cassano, G.B., 2000. Risperidone augmentation in refractory obsessive–compulsive disorder: an open-label study. Int. Clin. Psychopharmacol. 15, 297–301. Raja, M., Azzoni, A., 2004. Clinical management of obsessive–compulsive–bipolar comorbidity: a case series. Bipolar Disord. 6, 264–270. Remington, G., Adams, M., 1994. Risperidone and obsessive–compulsive symptoms. J. Clin. Psychopharmacol. 14, 358–359. Schaffer, A., Mcintosh, D., Goldstein, B.I., Rector, N.A., Mcintyre, R.S., Beaulieu, S., Swinson, R., Yatham, L.N., 2012. The CANMAT task force recommendations for the management of patients with mood disorders and comorbid anxiety disorders. Ann. Clin. Psychiatry 24, 6–22. Stamouli, S., Lykouras, L., 2006. Quetiapine-induced obsessive–compulsive symptoms: a series of five cases. J. Clin. Psychopharmacol. 26, 396–400. Stratta, P., De Cataldo, S., Mancini, G., Gianfelice, D., Rinaldi, O., Rossi, A., 2003. Quetiapine as adjunctive treatment of a case of rapid-cycling bipolar disorder with comorbidity. Hum. Psychopharmacol. 18, 559–560. Uguz, F., 2010. Successful treatment of comorbid obsessive–compulsive disorder with aripiprazole in three patients with bipolar disorder. Gen. Hosp. Psychiatry 32, 556–558.
