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Antipsychotics for obsessive-compulsive disorder: Weighing risks vs benefits

Taylor Modesitt, PharmD, Traci Turner, PharmD, BCPP, Lindsay Honaker, DO, Todd Jamrose, DO, Elizabeth Cunningham, DO, and Christopher Thomas, PharmD, BCPS, BCPP

r. E, age 37, has a 20-year history uncontrollable, recurrent thoughts or urges of obsessive-compulsive disorder (obsessions) as well as actions (compulsions) M (OCD), with comorbid generalized in response to those thoughts and/or urges. and hypertension. His medica- OCD symptom severity is commonly mea- tion regimen consists of lisinopril, 40 mg/d, to sured using the Y-BOCS, a 10-item clinician- control his pressure, and , rated scale. The Y-BOCS score ranges from 0 40 mg/d, for OCD and anxiety symptoms, which to 40, with higher scores indicating greater Vicki L. Ellingrod, he started taking 12 weeks ago. Mr. E also has severity of symptoms. First-line treatment for PharmD, FCCP completed cognitive-behavioral therapy (CBT) OCD includes selective reuptake Department Editor with Exposure Response Prevention (ERP) inhibitors (SSRIs) and CBT. The use of anti- therapy for his OCD symptoms. Although esci- psychotics for treating OCD is indicated in and CBT have reduced Mr. E’s OCD treatment guidelines (Box,1-3 page 48) and has symptoms, he still exhibits obsessions, such as been the subject of multiple studies.1-4 fear of contamination, and compulsions, includ- ing handwashing, that are time-consuming Efficacy and cause significant social and occupational The 2013 National Institute for Health distress. His Yale-Brown Obsessive Compulsive Care and Excellence Evidence Update Scale (Y-BOCS) score is 24. Mr. E asks his psychia- included a 2010 Cochrane Review of 11 trist if there is anything else that may provide randomized controlled trials (RCTs) of benefit. He is started on , 0.5 mg at bedtime, in addition to his existing . Practice Points After 8 weeks of treatment with risperidone, • In patients with a partial response to Mr. E’s Y-BOCS score decreases to 21. selective serotonin reuptake inhibitors (SSRIs) and/or cognitive-behavioral therapy (CBT), American Psychiatric OCD, a chronic illness with a prevalence of Association guidelines recommend that approximately 1% to 2%, is characterized by augmentation may be preferable to Dr. Modesitt is PGY-2 Psychiatric Pharmacy Resident, Dr. Turner switching treatments. is Clinical Pharmacy Specialist, and Dr. Honaker is Staff Psychiatrist, Chillicothe VA Medical Center, Chillicothe, Ohio. Dr. Jamrose is Staff • Assessing the potential harms related Psychiatrist, Appalachian Behavioral Healthcare, Athens, Ohio. to the use of in treating Savvy Psychopharmacology Dr. Cunningham is Associate Program Director, Community Health obsessive-compulsive disorder (OCD) is is produced in partnership Network Psychiatry Residency Program, Indianapolis, Indiana. complicated, because this information is with the College Dr. Thomas is Director, PGY-1 and PGY-2 Residency Programs, Clinical of Psychiatric Pharmacy Specialist in Psychiatry, Chillicothe VA Medical Center, not always assessed in trials. and Neurologic Chillicothe, Ohio, and is Clinical Associate Professor of , Pharmacists Ohio University College of Osteopathic Medicine, Athens, Ohio. • Although most evidence supports using cpnp.org Exposure Response Prevention (ERP) over mhc.cpnp.org (journal) Disclosures The contents of this article do not represent the views of the U.S. antipsychotics for treating OCD symptoms Department of Veterans Affairs or the United States Government. that have not responded to SSRIs, ERP This material is the result of work supported with resources and poses its own challenges that may limit the use of facilities at the Chillicothe Veterans Affairs Medical clinical utility. Current Psychiatry Center in Chillicothe, Ohio. Vol. 17, No. 2 47 Savvy Psychopharmacology

Box Antipsychotics for OCD: What the guidelines recommend

he 2013 American Psychiatric Association is discontinued. If the patient has T(APA) obsessive-compulsive disorder a partial response to ERP, intensification of (OCD) treatment guidelines include therapy also can be considered based on recommendations regarding the use of patient-specific factors. In non-responders, antipsychotics in patients who do not switching therapies may be necessary. respond to first-line treatment with selective Alternative treatments including a different serotonin reuptake inhibitors (SSRIs) and/or SSRI; an from a difference cognitive-behavioral therapy (CBT). The APA class, such as or ; recommends evaluating contributing factors, an ; or CBT. including comorbidities, family support, and The 2006 National Institute for Health ability to tolerate or maximum and Clinical Excellence guidelines for OCD recommended doses, before augmenting recommend additional high-intensity CBT, Clinical Point or switching therapies.1 adding an antipsychotic to an SSRI or In patients with a partial response to clomipramine, or combining clomipramine In patients with a SSRIs and/or CBT, the APA suggests that with in non-responders. There is no augmentation may be preferable to switching guidance regarding the order in which these partial response to treatments. Augmentation strategies for treatments should be trialed. Antipsychotics SSRIs and/or CBT, SSRIs include antipsychotics or CBT with are recommended as an entire class, and there Exposure Response Prevention (ERP); are no recommendations regarding dosing or the APA suggests augmentation strategies for CBT include long-term risks. These guidelines are based that augmentation SSRIs. Combining SSRIs and CBT may on limited evidence, including only 1 trial of decrease the chance of relapse when and 1 trial of .2,3 may be preferable to switching treatments

antipsychotics as adjunctive treatment to there was a significant difference between SSRIs.5 All trials were <6 months, and most groups (n = 80, 2 RCTs, OR 0.27; 95% CI 0.09 were limited regarding quality aspects. to 0.87; effect size d = 0.27 [0.09, 0.87]). Two trials found no statistically signifi- Adjunctive treatment with risperidone cant difference with olanzapine in efficacy was superior to antidepressant mono­ measures (Y-BOCS mean difference [MD] therapy for participants without a signifi- −2.96; 95% confidence interval [CI] −7.41 cant response in OCD symptom severity of to 1.22; effect size d = −2.96 [−7.14, 1.22]). at least 25% with validated measures (OR Among patients with no clinically signifi- 0.17; 95% CI 0.04 to 0.66; effect size d = 0.17 cant change (defined as ≤35% reduction in [0.04, 0.66]), and in depressive and anxi- Y-BOCS), there was no significant difference ety symptoms. Mean reduction in Y-BOCS between groups (n = 44, 1 RCT, scores was not statistically significant with [OR] 0.76; 95% CI 0.17 to 3.29; effect size risperidone (MD −3.35; 95% CI −8.25 to d = 0.76 [0.17, 3.29]). Studies found increased 1.55; effect size d = −3.35 [−8.25, 1.55]).5 with olanzapine compared with antidepressant monotherapy. A 2014 meta-analysis by Veale et al3 Statistically significant differences were included double-blind, randomized trials demonstrated with the addition of que- that examined atypical antipsychotics com- Discuss this article at tiapine to antidepressant monotherapy as pared with for adults with OCD www.facebook.com/ shown in Y-BOCS score at endpoint (Y-BOCS that used an intention-to-treat analysis. CurrentPsychiatry MD −2.28; 95% CI −4.05 to −0.52; effect Unlike the Cochrane Review, these stud- size d −2.28 [−4.05, −0.52]). Quetiapine ies used the Y-BOCS as a primary outcome also demonstrated benefit for depressive measure. Participants had a Y-BOCS score and anxiety symptoms. Among patients of ≥16; had at least 1 appropriate trial of an with no clinically significant change SSRI or clomipramine (defined as the maxi- Current Psychiatry 48 February 2018 (defined as ≤35% reduction in Y-BOCS), mum dose tolerated for at least 8 weeks); Savvy Psychopharmacology

and had to continue taking the SSRI or OCD severity (16 to 23). Those with higher clomipramine throughout the trial, which baseline Y-BOCS scores had a larger effect was a duration of at least 4 weeks. Of 46 size for risperidone and quetiapine.3 published antipsychotic papers that were Two studies included in the meta- identified, 20 were excluded and 12 were analysis classified OCD symptoms by sub- duplicates. The primary reason for trial type, such as by dimensions of checking; exclusion was open-label study design. symmetry, ordering, counting, and repeat- Fourteen articles were included in the ing; contamination and cleaning; and meta-analysis, but all had small sample hoarding. Currently, no clinically signifi- sizes and no long-term follow-up data.3 cant predictor of outcome of antipsychotic Antipsychotics in the meta-analysis included therapy has been identified. Two studies risperidone (4 studies), quetiapine (5 stud- included in the meta-analysis assessed ies), olanzapine (2 studies), (2 patients with comorbid tic disorders and Clinical Point studies), and (1 study). found no difference by treatment. One A 2015 study found no The overall difference in Y-BOCS score study demonstrated benefit of haloperi- change between drug and placebo groups dol in patients with comorbid tic disorders association between was 2.34 points, which had an overall effect compared with those without comorbid antipsychotic dose and size of d = 0.40. Those taking antipsychot- tic disorders. Of note, none of the stud- treatment response, ics had approximately a 10% reduction in ies included in the meta-analysis excluded suggesting higher Y-BOCS score over time. The overall differ- patients with hoarding characteristics, doses may not be ence was statistically significant with ris- which generally indicate a worse prognosis peridone (overall mean reduction of 3.89 with treatment.3 more effective points on the Y-BOCS; 95% CI 1.43 to 5.48; effect size of d = 0.53) and aripiprazole (dif- In 2015, Dold et al6 provided an update to ference in Y-BOCS outcome 0.1 scores of 6.29 a 2013 meta-analysis7 assessing antipsychotic points; effect size of d = 1.11). One trial of ris- augmentation of SSRIs in treatment-resistant peridone used a low dose (0.5 mg) and had OCD. This update included 2 new RCTs. a larger effect size than the studies that used The 2013 analysis7 concluded that risperi- moderate doses. The overall difference was done should be considered first-line and is not statistically significant for quetiapine preferred over olanzapine and quetiapine. (difference of Y-BOCS outcome scores of 0.81 However, the update found the highest points) or olanzapine (difference in Y-BOCS effect size for aripiprazole (d = −1.35), fol- outcome scores of −0.19; indicating <1 point lowed by haloperidol (d = −0.82), risperidone difference on the Y-BOCS).3 (d = −0.59), quetiapine (d = −0.50), olanzapine Studies included in the meta-analysis (d = −0.49), and paliperidone (d = −0.21).6,7 ranged in durations from 6 to 16 weeks; The 2015 update6 concluded that the anti- duration of ≥4 weeks did not make a differ- psychotic doses used in trials were moderate ence in response. One study demonstrated and that there was no association between a worsening of symptoms in the quetiap- dose and treatment response, indicating ine group between weeks 4 and 12. Only that high doses of antipsychotics may not 4 studies included most patients that had be more effective. Dold et al6 postulated that a previous trial of CBT. One study with an the antipsychotic doses required for treat- additional treatment arm evaluating CBT ing OCD are similar to those used in treat- found that adding CBT was superior to ing major depressive disorder and lower adjunctive risperidone or placebo. Another than doses used in treating . study found that adding clomipramine or The 2013 meta-analysis demonstrated that placebo to was superior to treat- moderate doses of antipsychotics resulted in ment with quetiapine. All study participants statistically significant efficacy (relative risk Current Psychiatry had Y-BOCS scores that indicated moderate [RR] = 3.99, 95% CI 1.92 to 8.27), while low Vol. 17, No. 2 49 Savvy Psychopharmacology

doses did not demonstrate statistical signifi- One study that was not included in cance (RR = 1.06, 95% CI 0.45 to 2.53).6,7 the meta-analysis by Veale et al3 evalu- The 2015 subgroup analysis update ated individuals who did not respond evaluated the duration of SSRI treatment to a SSRI, and randomly assigned them prior to the antipsychotic augmentation to quetiapine, olanzapine, or risperidone phase, but did not demonstrate statisti- plus CBT. At 1-year follow-up, 50% of par- cally significant efficacy for studies with ticipants receiving an antipsychotic had an <8 weeks’ duration of SSRI treatment, fur- increase of >10% in body mass index (BMI) ther highlighting the need for extended and had higher fasting blood sugars com- duration of treatment with an SSRI prior to pared with only 15.2% of participants with augmentation.6 increased BMI in the comparison group The 2013 meta-analysis discussed popula- (SSRI responders).3 Clinical Point tions with comorbid tic disorders, including Foa et al8 investigated long-term out- Consider the a study that found that patients with OCD comes (ie, 6 months) of SSRI augmentation and comorbid tic disorders benefit more with ERP or risperidone in patients with potential physical from adjunctive antipsychotic therapy than OCD. Forty patients were randomized to risks of long-term those without the comorbidity. The 2015 receive risperidone, and 9 were considered antipsychotic use, update excluded trials that included patients responders. Only 8 chose to enter the main- such as weight gain with comorbid tic disorders to reduce bias, tenance phase, and of those participants, 5 which did not affect the overall effect sizes did not complete the study. Two withdrew and extrapyramidal of the data.6,7 due to worsening , 2 withdrew side effects In summary, efficacy has been demon- due to intolerable adverse effects, and 1 was strated for risperidone and aripiprazole. lost to follow-up. Unfortunately, there was There has been no benefit demonstrated no further discussion of what the intoler- with olanzapine and limited benefit with able adverse effects were.8 quetiapine. One study suggested worsening Patients with comorbid schizophrenia of symptoms with quetiapine the longer that and OCD face additional risks. Lifetime treatment persisted.3,5-7 prevalence rates of OCD are greater in per- sons with schizophrenia compared with Safety the general population (26% vs 8%, respec- Assessing potential harms related to the use tively). Most studies have demonstrated of antipsychotics in treating OCD is compli- poor prognosis and medication adherence cated, because this information is not always among patients with comorbid schizophre- assessed in trials. Instead, researchers often nia and OCD. Fonseka et al9 assessed the risk focus on exploring potential benefits because of antipsychotic induction and exacerbation long-term effects of antipsychotics, includ- of OCD symptoms in patients with schizo- ing sedation, weight gain, metabolic syn- phrenia. Induction and exacerbation of OCD drome, and extrapyramidal side effects, are symptoms with was evident in well documented.3 several case reports, series, and retrospec- Trials included in the meta-analysis by tive reviews. A dose-dependent relationship Veale et al3 had a maximum duration of is demonstrated in the literature as well. It 16 weeks, so it is likely that many of the is thought that this risk is related to clozap- potential harms of antipsychotic use would ine’s action at the 5-HT2 receptor. Although not yet have been measurable. The authors evidence is limited, it appears that compared cautioned that, although aripiprazole and with other antipsychotics, clozapine is asso- risperidone demonstrated benefit, their ciated with the greatest risk of induction and benefit must be weighed against the poten- exacerbation of OCD symptoms, with 20% tial physical risks of long-term antipsy- to 28% of clozapine-treated patients exhibit- Current Psychiatry 50 February 2018 chotic use.3 ing induction of OCD symptoms and 10% to Savvy Psychopharmacology

18% exhibiting an exacerbation of existing Related Resource OCD symptoms. • Schatzberg AF, Nemeroff CB. The American Psychiatric Evidence of olanzapine induction and Association Publishing textbook of psychopharmacology. exacerbation of OCD symptoms is also lim- 5th ed. Arlington, VA: American Psychiatric Association Publishing; 2017. ited to case reports and retrospective stud- ies. However, some studies have estimated Drug Brand Names induction of OCD symptoms with olan- Aripiprazole • Abilify Lisinopril • Prinivil, Zestril Citalopram • Celexa Mirtazapine • Remeron zapine in 11% to 20% of patients.9 There is Clomipramine • Anafranil Olanzapine • Zyprexa insufficient evidence to form conclusions Clozapine • Clozaril Paliperidone • Invega Escitalopram • Lexapro Quetiapine • Seroquel 9 regarding other antipsychotics. Fonseka et al Fluoxetine • Prozac Risperidone • Risperdal recommends switching to an antipsychotic • Haldol with lower 5HT-2 binding affinity or adding an SSRI, such as , if induction or Clinical Point exacerbation of OCD symptoms occurs. Compared with trials; however, high doses of risperidone are Consider long-term risks unlikely to provide additional benefit and other antipsychotics, The evidence for benefits with antipsy­ increase the risk of adverse effects. If risperi- clozapine is associated chotics in treatment-resistant OCD is limited done does not provide a clinically favorable with the greatest by different populations recruited, small risk–benefit ratio for Mr. E, aripiprazole is a risk of induction sample sizes, and lack of long-term follow- potential alternative. and exacerbation up. Most evidence supports using ERP over antipsychotics for treating OCD symptoms References of OCD symptoms 1. American Psychiatric Association. Practice guideline for the that have not responded to SSRIs. However, treatment of patients with obsessive-compulsive disorder. https://psychiatryonline.org/pb/assets/raw/sitewide/ ERP poses its own challenges that may limit practice_guidelines/guidelines/ocd.pdf. Published July 2007. clinical utility, such as economic and time Accessed December 11, 2017. restraints. Therefore, benefits with antipsy- 2. National Institute for Health and Care Excellence (NICE). Obsessive compulsive disorder. http://arms.evidence.nhs.uk/ chotics, such as risperidone and aripipra- resources/hub/1028833/attachment. Updated September 18, zole, must be weighed against potential 2013. Accessed December 11, 2017. 3. Veale D, Miles S, Smallcombe N, et al. long-term risks of treatment, including seda- augmentation in SSRI treatment refractory obsessive- compulsive disorder: a systematic review and meta-analysis. tion, weight gain, , and BMC Psychiatry. 2014;14:317. extrapyramidal side effects. 4. Diagnostic and statistical manual of mental disorders, 5th ed. Regarding Mr. E’s case, because he had Washington, DC: American Psychiatric Publishing; 2013. 5. Komossa K, Depping AM, Meyer M, et al. Second-generation been maximized on SSRI therapy for an antipsychotics for obsessive compulsive disorder. Cochrane adequate duration (escitalopram, 40 mg/d, Database Syst Rev. 2010;12:1-44. 6. Dold M, Aigner M, Lanzenberger R, et al. Antipsychotic for 12 weeks) and completed CBT with augmentation of serotonin reuptake inhibitors in treatment- ERP with a partial response, adding risperi- resistant obsessive-compulsive disorder: an update meta- analysis of double-blind, randomized, placebo-controlled trials. done, 0.5 mg at bedtime, was an appropri- Int J Neuropsychopharmacol. 2015;18(9). doi: 10.1093/ijnp/ ate treatment option that is supported by pyv047. 7. Dold M, Aigner M, Lanzenberger R, et al. Antipsychotic the available guidelines and evidence. The augmentation of serotonin reuptake inhibitors in treatment- risperidone dose is reflective of the initial resistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials. Int J dosing strategies used in clinical trials. It is Neuropsychopharmacol. 2013;16(3):557-574. recommended to assess efficacy of treatment 8. Foa EB, Simpson HB, Rosenfield D, et al. Six-month outcomes from a randomized trial augmenting serotonin reuptake at 8 weeks with a validated measure, such as inhibitors with exposure and response prevention or risperidone in adults with obsessive-compulsive disorder. J the Y-BOCS. A dose increase may be needed Clin Psychiatry. 2015;76(4):440-446. to achieve clinically significant symptom 9. Fonseka TM, Richter MA, Muller DJ. Second generation improvement, because moderate doses of antipsychotic-induced obsessive-compulsive symptoms in schizophrenia: a review of the experimental literature. Curr risperidone have demonstrated efficacy in Psychiatry Rep. 2014;16(11):510.

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