Speech Latency Biomarker Improves Schizophrenia Trial Outcomes; Clozapine Shows Efficacy

Researchers have identified speech latency as a promising biomarker that could significantly enrich clinical trials by reducing sample size requirements and enhancing statistical outcomes. By using speech latency, participants who are likely to show a high placebo response can be identified and excluded. The study in Biological Psychiatry showed that when these participants were removed from the main analysis, the treatment-placebo effect increased dramatically, by as much as two to three times the original results.

Speech latency is an objective measure of verbal response time derived from standard clinical assessments. It is sensitive to cognitive, social, and motivational factors and can be measured using recordings of psychiatric interviews. The single, interpretable speech biomarker identified in this study was extracted from screening interviews with 406 participants with schizophrenia from three countries representing eight languages in a Phase III study of the antipsychotic drug brilaroxazine (RP5063).

Among the many potential speech biomarkers related to schizophrenia, speech latency was chosen because it is tied to social communication, motivation, and cognition. It is conceptually and empirically tied to psychomotor slowing, whereby a longer pause suggests a disruption in the neural circuits responsible for translating thought into speech.

By enriching the sample using the speech-latency ratio, statistical significance was achieved with approximately half the sample size, with much larger effects on key symptom and functional domains. These effects were particularly notable in total, positive, and negative symptoms, of which 80%, 73%, and 57% of patients, respectively, showed a statistically significant improvement. Improved treatment-placebo separation was observed for negative symptoms, the primary endpoint and nearly every secondary endpoint.

Enrichment strategies to decrease heterogeneity, reduce confounding psychiatric conditions, and identify participants likely to demonstrate a true pharmacological response rather than a placebo effect can successfully improve clinical trial outcomes, reduce associated costs, and help bring effective treatments to patients faster.

Beyond its clinical accuracy, the study highlights a shift toward interpretable AI. While modern digital phenotyping often relies on "black box" algorithms, the researchers found that the most striking aspect of speech latency is the transparency and simplicity of the measure itself. The study demonstrates that speech latency analysis is useful for evaluating clinical trial results. Given that speech latencies can be automatically and quickly computed, they could help inform participant screening. However, the authors caution that speech latencies should not be used as an endpoint.

In a separate randomized clinical trial including 654 participants, clozapine was found to be more efficacious than olanzapine or amisulpride in patients who fail to respond to an initial antipsychotic drug trial. The sequential, assessor-blind trial with 2 randomizations was conducted across 7 centers in China from February 2019 to October 2022. Included were individuals aged 16 to 45 years with first-episode psychosis (schizophrenia, schizophreniform disorder, or schizoaffective disorder).

In phase 1, patients with first-episode psychosis were randomized to receive oral olanzapine, risperidone, amisulpride, aripiprazole, or perphenazine for 8 weeks. In phase 2, nonresponders were rerandomized to receive olanzapine, amisulpride, or clozapine for another 8 weeks. Of the eligible participants, 556 (85.4%) completed phase 1, and 359 (55.1%) responded to treatment. Response rates were 60.5% (78 of 129) for olanzapine, 63.4% (83 of 131) for risperidone, 61.8% (81 of 131) for amisulpride, 44.3% (58 of 131) for aripiprazole, and 45.7% (59 of 129) for perphenazine.

In phase 2, 111 nonresponders were rerandomized (41 taking olanzapine, 38 taking amisulpride, and 32 taking clozapine). A total of 92 patients (82.9%) completed phase 2, and the following achieved a response: 13 (31.7%) taking olanzapine vs 17 (44.7%) taking amisulpride and 20 (62.5%) taking clozapine. The majority of patients with first-episode psychosis responded to an initial antipsychotic drug trial, with risperidone and amisulpride being superior to aripiprazole and perphenazine. In those who initially did not respond to antipsychotic treatment, clozapine was more efficacious than olanzapine and amisulpride based on the Positive and Negative Syndrome Scale ratings criteria outcome.