The Benefits of Clozapine Beyond Its Antipsychotic Properties in Treatment-Resistant Schizophrenia

Abstract Background Compared to the general population, persons with schizophrenia are five times more likely to have a substance use disorder (SUD). A causal hypothesis of shared origin of substance use and schizophrenia, where one reinforces the other, is observed in clinical practice and correlates with the prevalence of substance use in more 50% of those with schizophrenia. The relative risk of suicide in schizophrenia is about 10 times greater than in the general population and is attributed to a loss of decade in lifespan. To make matters worse, a meta-analysis of 50 studies found that one third of patients with schizophrenia had treatment-resistance. Management of treatment-resistant schizophrenia (TRS) with substance use and suicidal behavior is fraught with challenges. Clozapine is the only drug approved for TRS. Beyond its antipsychotic effect, clozapine is indicated to reduce recurrent suicidal behaviour. However, the drug is often under-prescribed and poorly utilized. Aims & Objectives Review the evidence for clozapine in reducing the risk for SUD in those with TRS and suggest ways to overcome the barriers to its timely use. Method A scoping review of recent scientific literature was conducted to understand the impact of clozapine on substance use comorbid with TRS. Results Clozapine has been repeatedly shown to be effective for comorbid substance use with TRS. Its unique pharmacological profile of weak D2 receptor blockade, potent noradrenergic alpha2 receptor blockade, and significant increase of norepinephrine, is likely to contribute to this effect. Clozapine treatment is linked to reduced substance use, diminished craving, and higher abstinence rates across several SUDs. In TRS, clozapine was found to be equally effective for those with and without a history of substance use. Discussion & Conclusions Not infrequently, clinicians view the use of clozapine burdensome because of excessive caution over the uncommon and manageable incidence of neutropenia along with other side-effects, and the complexity of patient-monitoring. A lack of appropriate training for physicians was observed to be a key barrier and the need to develop professional education programs to train clinicians, both practicing and those in training, on the relevance and efficacy of clozapine in TRS treatment and management of potential adverse events was deemed essential.