A recent real-world clinical trial from Spain has found that clozapine, a well-established medication for treatment-resistant psychosis, appears to yield even greater benefits in patients with schizoaffective disorder (SZD) than in those with treatment-resistant schizophrenia (TRS). The findings not only reaffirm clozapine’s role in managing severe psychosis but also expand its potential therapeutic value for individuals struggling with the dual challenges of psychotic and mood symptoms.
Between 2021 and 2024, researchers conducted a prospective, pragmatic clinical trial at the Consorci Hospitalari Provincial de Castelló in Castellón de la Plana, Spain. The study included 127 adults with refractory psychosis, with a mean age of 38.5 years; nearly three-quarters of the participants were male.
Participants were grouped into three cohorts:
- TRS-clozapine group: 43 individuals with treatment-resistant schizophrenia treated with clozapine.
- TRS-control group: 42 individuals with TRS receiving optimised standard antipsychotic therapy.
- SZD-clozapine group: 42 individuals with schizoaffective disorder treated with clozapine. This arm was non-randomised due to the lower prevalence of SZD.
Over a 3-month period, participants underwent monthly evaluations using a comprehensive battery of psychiatric rating scales, including the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale (MADRS), Calgary Depression Scale for Schizophrenia (CDSS), Clinical Global Impression (CGI) scale, and the Udvalg für Kliniske Undersogelser (UKU) scale for side effects.
The trial aimed to assess clozapine’s efficacy in TRS, its real-world effectiveness for both psychotic and affective symptoms in SZD, and differences in treatment response and tolerability between TRS and SZD patients on clozapine.
Results
The results painted a clear picture: clozapine outperformed standard treatment in TRS, but its benefits were even more pronounced in SZD.
- TRS findings: Compared with the TRS-control group, the TRS-clozapine group showed significantly greater 3-month reductions in PANSS positive, negative, and total scores (all P < 0.001). Improvements were also noted in depression measures (CDSS, P < 0.001; MADRS, P = 0.003) and overall clinical impression (CGI, P < 0.001).
- SZD findings: Patients with schizoaffective disorder receiving clozapine experienced rapid and substantial improvements across all domains from the first month onward. Significant reductions were seen in psychotic symptoms (PANSS-P, P = 0.027; PANSS-N, P = 0.002; PANSS-T, P = 0.005) and in affective symptom scores (YMRS, MADRS, CDSS — all P < 0.001).
When directly compared to TRS patients on clozapine, the SZD group achieved larger decreases in several key measures at 3 months:
- PANSS-P: –23.4 vs –19.3
- PANSS-T: –68.7 vs –63.0
- YMRS: –15.3 vs –4.9
- MADRS: –8.4 vs –6.0
- CDSS: –5.4 vs –4.1
Additionally, SZD patients on clozapine required fewer adjunct antipsychotics and sedatives and reported a better overall treatment perception (P < 0.01). Clozapine use also emerged as the sole independent predictor of superior symptom and substance use outcomes.
Clozapine was generally well tolerated in both TRS and SZD groups, with no serious treatment-related adverse events reported. Mild side effects, such as drowsiness or asthenia, were managed by reducing doses of co-administered medications. Interestingly, UKU side effect scores decreased from the second month onward, suggesting improved tolerability over time.
These results support expanding clozapine use to more patients with schizoaffective disorder, where both mood and psychotic symptoms are present.
Study Limitations
The study faced certain limitations, including incomplete patient histories, the omission of measures for clozapine’s potential antisuicidal properties, no direct comparison between dual-disorder and pure psychosis groups, potential diagnostic instability, gender imbalance among participants, its single-site setting, possible overfitting in regression analyses, and a relatively short three-month follow-up.
Reference:
Peraire M et al. Journal of Psychopharmacology. 2025;0(0). Abstract
