Clozapine-Associated Obsessive-Compulsive Symptoms and Their Management: A Systematic Review and Analysis of 107 Reported Cases

Abstract

Background: It is not uncommon to find obsessive-compulsive symptoms (OCS) in patients treated with clozapine. These symptoms are attributed to anti-serotonergic effects of clozapine. The objective of this study was to conduct a systematic review of reported cases of clozapine-associated OCS to better understand the nature and management of these symptoms. Methods: MEDLINE, Embase, and PsycIN-FO databases were searched with no publication year or language restrictions. Studies reporting cases of clozapine-associated OCS, either de novo or exacerbation of preexisting OCS, were included. The final search date was July 11, 2019. Results: Fifty-seven studies, involving 107 cases (75 de novo, 32 exacerbated OCS), were included. Clozapine triggered moderate-severe OCS at varying doses (100-900 mg/day) and treatment durations (median 6 months, interquartile range 2-24 months). Higher severity was significantly associated with preexisting OCS, poorer insight into OCS, and active psychosis at the time of OCS. Common strategies to treat clozapine-associated OCS included adding selective serotonin reuptake inhibitors, clomipramine, or aripiprazole, often accompanied by clozapine dose reduction. The rate of response to antidepressants was 49% (29/59), where younger age, shorter duration of underlying illness, shorter clozapine treatment duration, better insight into OCS, and presence of taboo thoughts were significantly associated with antidepressant response. Subsequent clozapine dose reduction was effective in many non-responders, where aripiprazole was simultaneously added in 50% (8/16). Conclusions: Clozapine can trigger severe OCS. Adding aripiprazole with/ without clozapine dose reduction may be a good alternative to antidepressants for managing clozapine-associated OCS. Clinicians should be more vigilant about these adverse effects and administer appropriate treatments.

Efficacy and tolerability of aripiprazole versus D2 antagonists in the early course of schizophrenia: a systematic review and meta-analysis

“…Aripiprazole’s D 2 partial agonistic properties have prolactin-sparing effects 34 , 35 . Its partial agonistic activity at postsynaptic 5-HT 1A and 5-HT 2C receptors, coupled with desensitization of presynaptic 5-HT 1A receptors, would lead to an increased serotonergic tone, which may play a role in improving depressive and anxiety disorders 38 , 39 . Aripiprazole’s relatively lower affinity for H 1 receptors compared with other second-generation antipsychotics may explain its lower propensity to induce sedation 35 , 36 .…”

A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology

“…Due to its complexity and lack of good studies, there is no agreement in the literature on its management. In this journal issue, Kim et al [210] reviewed the limited available literature and provided the very helpful conclusion that adding aripiprazole with/without clozapine dose reduction may be a good alternative to antidepressants for managing clozapine-associated OCS. Future controlled studies will need to clarify whether this conclusion is correct or not.…”

Clozapine‐induced gastroesophageal rumination in 22q11.2 Deletion Syndrome. A case report on gastroesophageal side effects management without renouncing clozapine's effectiveness

“…Psychosis in 22q11.2DS is treated in the same way as idiopathic schizophrenia, and clozapine results the most effective tool in pharmacological treatment of treatment‐resistant schizophrenia (TRS) in 22q11.2DS even if entailing more severe side effects, as seizures, hematological problems, and myocarditis, compared to individuals with nongenetic determined psychotic disorders 6‐8 . The correlation between the employment of clozapine and the onset or worsening of obsessive‐compulsive symptoms has been deeply investigated in literature 9,10 . The present work is aimed to further describe the set of side effects associated with the employment of clozapine in people with 22q11.2DS and schizophrenia.…”

“…[6][7][8] The correlation between the employment of clozapine and the onset or worsening of obsessive-compulsive symptoms has been deeply investigated in literature. 9,10 The present work is aimed to further describe the set of side effects associated with the employment of clozapine in people with 22q11.2DS and schizophrenia. Our aim is to emphasize the efficacy of clozapine in TRS, encouraging its rechallenge with a tight monitoring after the resolution of potential severe side effects in order to manage such a critical clinical condition, as it has already been described in certain cases.…”