Clozapine may be more effective when used earlier in first-episode psychosis (FEP), challenging current guidelines that endorse the drug’s use in patients who fail two trials of other antipsychotics.

Investigators found that among individuals with FEP who did not respond to an initial antipsychotic, 62.5% responded to second-line treatment with clozapine compared with 31.7% for olanzapine and 44.7% for amisulpride.

“If it is imperative to obtain an early treatment response, this study provides some evidence for clinicians to consider using clozapine as the next sequential treatment after patients have failed an adequate trial with one of the more traditional antipsychotics,” the researchers, led by Dengtang Liu, MD, PhD, at Shanghai Jiao Tong University in Shanghai, China, wrote.

The study was published online on March 11 in JAMA Psychiatry.

A Lack of Evidence-Based Guidelines

Clozapine is currently the only FDA-approved drug for treatment-resistant schizophrenia. An estimated 30% of people with schizophrenia are considered treatment-resistant, yet estimates suggest only 4% ever receive the drug.

Clozapine is typically prescribed after a patient has not responded to at least two antipsychotic trials. However, response rates tend to decline with each successive treatment, and a substantial proportion of patients go on to develop treatment-resistant illness, the researchers noted.

Clozapine is underprescribed primarily due to concerns of potential adverse side effects. The most serious of these is agranulocytosis which requires regular blood monitoring. Further, the investigators noted there is a lack of evidence-based guidelines for treating patients with FEP who fail to respond to an initial antipsychotic.

To determine whether clozapine might be more effective than traditional agents when used earlier as a second-line treatment the investigators conducted the first randomized controlled trial of its kind. It included 654 participants aged 16-45 years (mean age, 27 years; 50.2% men) with a diagnosis of schizophrenia, schizophreniform, or schizoaffective disorder who were randomized to receive oral olanzapine (5-20 mg), risperidone (2-6 mg), amisulpride (400-1200 mg), aripiprazole (10-30 mg) or perphenazine (6-36 mg) daily for 8 weeks in phase 1 of the trial.

Those who did not respond to treatment in phase 1 were rerandomized to receive daily doses of olanzapine, amisulpride, or clozapine (200-400 mg) for another 8 weeks.

Randomization was done by a computer system, and patients did not receive the same medication as they did in phase 1. Participants responded were enrolled in a 1-year follow-up. Outcome assessors were blinded to treatment assignments.

The primary outcomes were the proportion of patients who had a 40% or more decrease in Positive and Negative Syndrome Scale (PANSS) total score and the time taken to discontinue antipsychotic drugs for any reason. The secondary outcome was the mean percentage change in PANSS total score from baseline.

At baseline and weeks 2, 4, 8, 12, and 16, participants were assessed using the PANSS, the Calgary Depression Scale for Schizophrenia (CDSS) and Clinical Global Impression Scale-Severity (CGI-S).

Blood, vitals, and weight were assessed from baseline until the end of the trial and patients taking clozapine had weekly blood tests.

The primary endpoint was analyzed using a χ² test to compare the number of participants achieving a response between treatment groups. The log-rank test was used to compare time to all-cause treatment discontinuation between groups in both trial phases.

An Earlier Role for Clozapine?

Of the 651 patients randomized in phase 1 of the trial, 556 completed it and just over half responded to the initial treatment.

Among responders, 60.5% responded to olanzapine, 63.4% for risperidone, 61.8% for amisulpride, 44.3% for aripiprazole, and 45.7% for perphenazine (χ² = 18.3; P = .001). There was no significant difference between groups in PANSS reduction rate.

During the 1-year follow-up, 66.4% of phase 1 patients discontinued treatment, mainly due to lack of efficacy.

Of the 197 nonresponders, 86 did not progress to phase 2 of the study for reasons that included consent withdrawal, clinical judgement by their physician and risk for aggression or impulsivity. The remaining participants (n = 111) were re-randomized and 41 received olanzapine, 38 given amisulpride and 32 clozapine.

Of the 92 patients that completed this second phase of treatment, clozapine yielded the highest response rate (62.5%), followed by amisulpride (44.7%) and olanzapine (31.7%).

By the end of phase 2, clozapine showed a higher PANSS reduction rate than olanzapine and amisulpride (P = .005). All treatment groups showed progressive decreases in CGI-S scores and CDSS scores from baseline to week 8.

Among patients in phase 2, 64% discontinued treatment during the 1-year follow-up, most commonly due to lack of efficacy. There was no significant difference in all-cause discontinuation between treatment groups, and no serious adverse events were reported.

Given that the results showed that clozapine was more effective than other second-line options in patients with FEP who did not respond to an initial antipsychotic, the investigators suggest it could have a role earlier in treatment.

However, they noted that the findings are limited by the study’s small sample size and the lack of improvement in all-cause discontinuation and so they need to be confirmed in larger studies.

This study was funded by Key Program of SMHC Clinical Research Center, National Natural Science Foundation of China, medical innovation research project and the science and technology innovation action of Shanghai Science and Technology Commission and the Shanghai Municipal Health Commission. See study for author disclosures.