Clozapine-Induced Obsessive-Compulsive Symptoms in Schizophrenia: A Critical Review

Abstract

Obsessive-compulsive disorder (OCD) is rarely associated with schizophrenia, whereas 20 to 30% of schizophrenic patients, suffer from comorbid obsessive-compulsive symptoms (OCS). So far no single pathogenetic theory convincingly explained this fact suggesting heterogeneous subgroups. Based on long-term case observations, one hypothesis assumes that second-onset OCS in the course of schizophrenia might be a side effect of second generation antipsychotics (SGA), most importantly clozapine (CLZ). This review summarizes the supporting epidemiological and pharmacological evidence: Estimations on prevalence of OCS increase in more recent cross-sectional studies and in later disease stages. Longitudinal observations report the de novo-onset of OCS under clozapine treatment. This association has not been reported with first generation antipsychotics (FGA) or SGAs with mainly dopaminergic mode of action. Finally, significant correlations of OCS-severity with duration of treatment, dose and serum levels suggest clozapine-induced OCS. However, supposed causal interactions need further verifications. It is also unclear, which neurobiological mechanisms might underlie the pathogenetic process. Detailed genotypic and phenotypic characterizations of schizophrenics with comorbid OCS regarding neurocognitive functioning and activation in sensitive tasks of functional magnetic imaging are needed. Multimodal large-scaled prospective studies are necessary to define patients at risk for second-onset OCS and to improve early detection and therapeutic interventions.

Obsessive‐compulsive symptoms: a side‐effect of antipsychotic treatment

“…5,6 This comorbidity has been attributed to several causes in the literature, one being the use of antipsychotics that exhibit a high level of antiserotonergic 5-HT 2a antagonism (clozapine, olanzapine, risperidone). 2,4,5,7 This is in line with the theory that the pathophysiology of obsessive compulsive disorder (OCD) is underpinned by serotonin depletion in the orbitofrontal cortex (OFC) and associated circuits. 8 Those atypical antipsychotics that work primarily on the D2/D3 receptor subtypes as opposed to 5-HT 2a (such as aripiprazole, amisulpride) are not associated with OCS.…”

“…1 The prevalence of the presentation has been estimated in the range of 7-64%. [2][3][4] It is postulated that comorbid OCS and schizophrenia has a worse prognosis. 5,6 This comorbidity has been attributed to several causes in the literature, one being the use of antipsychotics that exhibit a high level of antiserotonergic 5-HT 2a antagonism (clozapine, olanzapine, risperidone).…”

“…6,9 Clozapine is the antipsychotic most associated with OCS. 2,3 One study showed that use of clozapine had twice the risk of being associated with OCS compared with haloperidol, and although the result was found to be statistically insignificant, the severity of the OCS was significant with clozapine. 10 However, there is a question mark as to whether this is because patients on clozapine are more likely to have more resistant and complex psychopathology.…”

“…10 There is also evidence to show a correlation between the dose of clozapine and severity of symptoms. 2,7,11 There have been studies implying that the presence of OCS might be related to the severity of the schizophrenia, higher dose of clozapine administered and longer duration of cloza pine use. 3 It has been suggested that OCS presents more with obsessions rather than compulsions compared with primary OCD.…”

“…Some studies have suggested that OCS often resolve spontaneously, while others have suggested that symptoms reduce when the dose of clozapine is reduced. 3,7 Some studies report an improvement when SSRIs are used. 13,14 We looked at three cases where an antipsychotic with high affinity for 5-HT 2a antagonism was used with the patient later developing new obsessive symptoms.…”