Efficacy and safety of clozapine in psychotic disorders—a systematic quantitative meta-review

Abstract

A recent increase in the literature regarding the evidence base for clozapine has made it increasingly difficult for clinicians to judge “best evidence” for clozapine use. As such, we aimed at elucidating the state-of-the-art for clozapine with regard to efficacy, effectiveness, tolerability, and management of clozapine and clozapine-related adverse events in neuropsychiatric disorders. We conducted a systematic PRISMA-conforming quantitative meta-review of available meta-analytic evidence regarding clozapine use. Primary outcome effect sizes were extracted and transformed into relative risk ratios (RR) and standardized mean differences (SMD). The methodological quality of meta-analyses was assessed using the AMSTAR-2 checklist. Of the 112 meta-analyses included in our review, 61 (54.5%) had an overall high methodological quality according to AMSTAR-2. Clozapine appears to have superior effects on positive, negative, and overall symptoms and relapse rates in schizophrenia (treatment-resistant and non-treatment-resistant subpopulations) compared to first-generation antipsychotics (FGAs) and to pooled FGAs/second-generation antipsychotics (SGAs) in treatment-resistant schizophrenia (TRS). Despite an unfavorable metabolic and hematological adverse-event profile compared to other antipsychotics, hospitalization, mortality and all-cause discontinuation (ACD) rates of clozapine surprisingly show a pattern of superiority. Our meta-review outlines the superior overall efficacy of clozapine compared to FGAs and most other SGAs in schizophrenia and suggests beneficial efficacy outcomes in bipolar disorder and Parkinson’s disease psychosis (PDP). More clinical studies and subsequent meta-analyses are needed beyond the application of clozapine in schizophrenia-spectrum disorders and future studies should be directed into multidimensional clozapine side-effect management to foster evidence and to inform future guidelines.

Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores

“…In secondary analyses, we merged the two CLOZUK cohorts and then stratified these individuals by their highest daily clozapine dose into three categories: (1) those taking a low dose (<300 mg/day), (2) those taking standard maintenance doses (300-600 mg/day), and (3) those individuals taking a higher dose than the usual maintenance dose (>600 mg/day)(28). For these analyses, we also included extra curation procedures ( Figure 1 ): First, we selected only those individuals with at least three assays in the clozapine monitoring system, spanning a period of 6 months or more.…”

“…Approximately one-third of individuals with schizophrenia experience symptoms that do not meaningfully improve after two courses of standard antipsychotics, a presentation often called treatment-resistant schizophrenia (TRS) (1). Clozapine, a second-generation antipsychotic, is the evidence-based treatment of choice for TRS, given its proven efficacy to treat symptoms that have not responded to other antipsychotics (2). However, despite its clear benefits in TRS, clozapine also has the potential to cause a range of adverse effects, and these are major contributors to treatment discontinuation (3).…”

MDMA for the Treatment of Negative Symptoms in Schizophrenia

“…For example, clozapine, an SGA, requires a risk–benefit analysis and weekly monitoring for months to years in order to assess for abnormal white blood cell counts due to the risk of agranulocytosis [ 163 ]. It also carries significant risks of seizure and cardiotoxicity [ 164 , 165 ]. Despite these known risks, it is considered a standard pharmacologic intervention for treatment-resistant schizophrenia, targeting mostly positive symptoms [ 164 ].…”

“…It also carries significant risks of seizure and cardiotoxicity [ 164 , 165 ]. Despite these known risks, it is considered a standard pharmacologic intervention for treatment-resistant schizophrenia, targeting mostly positive symptoms [ 164 ]. Both positive and negative symptoms, when untreated, bear significant functional burden [ 1 , 2 , 7 , 44 ].…”

Clozapine-Encapsulated Binary Mixed Micelles in Thermosensitive Sol–Gels for Intranasal Administration

“…Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia [ 1 ]. It is, however, associated with many peripheral adverse drug reactions (ADRs), including cardiac (myocarditis, cardiomyopathy and postural hypotension), metabolic (metabolic syndrome, obesity and diabetes), hypersalivation and gastrointestinal (constipation and ileus) [ 2 , 3 ]. Nose-to-brain (N2B) drug delivery offers a promising approach to the delivery of antipsychotics to the central nervous system (CNS) in the management of schizophrenia.…”