Clozapine the Best Option For Treatment-Resistant Schizophrenia

T. Scott Stroup, MD, MPH

A new review of existing studies shows that clozapine is the best medication for treatment-resistant schizophrenia (TRS).

A research team led by T. Scott Stroup, MD, MPH, Department of Psychiatry, Columbia University, recently conducted a review of 63 cohort studies to determine whether clozapine or oral nonclozapine second-generation antipsychotics (NC-SGAs) are best to treat schizophrenia.

In the study, the investigators reviewed 68 articles from the studies with 109,341 patients of which 60.3% were male with a median age of 38.8 years old, 11 years of illness, and 19.1 months of study duration.

Of the 63 studies, 33 had a prospective design and 30 had a retrospective design.

Clozapine was significantly linked with lower hospitalization risks despite greater illness severity, as well as better outcomes for overall symptoms and the Clinical Global Impressions scale severity. However, clozapine was also tied to significant body weight and body mass index increases, as well as a greater risk for type 2 diabetes.

“In cohort studies, despite more severely ill patients being treated with clozapine, use of clozapine was associated with better key efficacy outcomes and higher cardiometabolic-related risk outcomes vs NC-SGAs,” the authors wrote. “We found that clozapine was associated with a significant reduction in hospitalization risk by 18% and all-cause discontinuation by 27%, despite greater illness severity and/or chronicity in patients treated with clozapine.”

A recent meta-analyses of masked randomized clinical trials compared clozapine with other NC-SGAs and found inconsistent results, where one network meta-analysis found clozapine superior in TRS compared with antipsychotics but not individual or pooled NC-SGAs.

The methodology of these results has been challenged for a number of reasons, including lower clozapine dosages than in clinical care and the possibility of sampling bias of patients selected for trials.

In the study, the investigators calculated the risk ratio using dichotomous data, the number needed to treat/number needed to harm from an assumed control group risk, estimated the mean occurrence of the respective outcome in the NC-SGA group.

They also calculated the standardized mean difference and the mean difference for cardiometabolic-related outcomes using continuous data.

They analyzed baseline illness severity using 4 data types, conducted subgroup and meta-regression analyses of the coprimary outcomes to explore potential moderators and sources of biases.

Other studies focusing on long-acting injectable (LAI) antipsychotics have produced conflicting results as well where the LAI antipsychotics were not superior to oral antipsychotics in a meta-analysis of RCTs, where meta-analyses of mirror-image studies and cohort studies expect to better reflect real-world patients and practice than RCTs.

In an accompanying editorial published in JAMA Psychiatry, authors said it is common practice to use antipsychotic drugs to reduce both symptoms and the risk of relapse and hospitalization. Clozapine in particularly is considered the “last resort” drug for people with treatment-resistant schizophrenia and patients with persistent suicidality or hostility, despite being linked to serious adverse effects and requires blood monitoring.

Approximately 30% of patients do not respond to 2 or more antipsychotic trials of adequate dosage and duration.

The evidence-based guidelines also include more granular recommendations on how and when to use antipsychotic drugs, but are unclear on issues like the use of other types of psychotropic medications, combinations of antipsychotic agents, and the role of long-acting, injectable antipsychotic drugs.

“It may be time to accept that there is an important role for combinations of psychotropic medications for schizophrenia,” the authors wrote. “In routine practice, people diagnosed with schizophrenia are rarely prescribed just a single antipsychotic drug.”