Abstract
Background: Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and has minimal risk for extrapyramidal symptoms. Therapeutic benefits, however, are accompanied by a myriad of cardiometabolic side-effects. The specific reasons for clozapine's high propensity to cause adverse cardiometabolic events remain unknown, but it is believed that autonomic dysfunction may play a role in many of these.Objective: This systematic review summarizes the literature on autonomic dysfunction and related cardiovascular side effects associated with clozapine treatment.Method: A search of the EMBASE, MEDLINE, and EBM Cochrane databases was conducted using the search terms antipsychotic agents, antipsychotic drug*, antipsychotic*, schizophrenia, schizophren*, psychos*, psychotic*, mental ill*, mental disorder*, neuroleptic*, cardiovascular*, cardiovascular diseases, clozapine*, clozaril*, autonomic*, sympathetic*, catecholamine*, norepinephrine, noradrenaline, epinephrine, adrenaline.Results: The search yielded 37 studies that were reviewed, of which only 16 studies have used interventions to manage cardiovascular side effects. Side effects reported in the studies include myocarditis, orthostatic hypotension and tachycardia. These were attributed to sympathetic hyperactivity, decreased vagal contribution, blockade of cholinergic and adrenergic receptors, reduced heart rate variability and elevated catecholamines with clozapine use. Autonomic neuropathy was identified by monitoring blood pressure and heart rate changes in response to stimuli and by spectral analysis of heart rate variability. Metoprolol, lorazepam, atenolol, propranolol, amlodipine, vasopressin and norepinephrine infusion were used to treat tachycardia and fluctuations in blood pressure, yet results were limited to case reports.Conclusion: The results indicate there is a lack of clinical studies investigating autonomic dysfunction and a limited use of interventions to manage cardiovascular side effects associated with clozapine. As there is often no alternative treatment for refractory schizophrenia, the current review highlights the need for better designed studies, use of autonomic tests for prevention of cardiovascular disease and development of novel interventions for clozapine-induced side effects.
Highlights
Clozapine (CLZ) is the antipsychotic drug of choice for treatment-resistant schizophrenia, displaying superior efficacy in an estimated 30% of patients who are persistently unresponsive to other antipsychotic drugs (Kane et al, 1988; Meltzer, 1997; Honer et al, 2015)
The remaining 66 full-text articles were assessed and 29 full-text articles were excluded with reasons (i.e. CLZ was not administered, the study did not involve patients with schizophrenia, autonomic function was not discussed, human subjects were under 18 years of age and/or the article is a review)
The final 37 articles comprised of case reports and studies evaluating the effects of CLZ on autonomic function
Summary
Clozapine (CLZ) is the antipsychotic drug of choice for treatment-resistant schizophrenia, displaying superior efficacy in an estimated 30% of patients who are persistently unresponsive to other antipsychotic drugs (Kane et al, 1988; Meltzer, 1997; Honer et al, 2015). CLZ has been shown to effectively reduce suicidality in patients with treatment-resistant schizophrenia (Meltzer and Okayli, 1995; Reinstein et al, 2002) and is the sole agent approved by the U.S Food and Drug administration to manage suicidal behavior in persons with schizophrenia or schizoaffective disorder (Citrome et al, 2016). Compared to most first generation antipsychotics (FGAs) and many second generation antipsychotics (SGAs), CLZ has minimal risk for extrapyramidal symptoms (EPS) (Lindström, 1988; Casey, 1989) and does not induce hyperprolactinemia (Kane et al, 1981; Melkersson, 2005). The specific reasons for clozapine’s high propensity to cause adverse cardiometabolic events remain unknown, but it is believed that autonomic dysfunction may play a role in many of these
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