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Randomized Controlled Trial
. 2025 Nov;39(11):1284-1298.
doi: 10.1177/02698811251355602. Epub 2025 Aug 1.

Randomised controlled trial of clozapine in resistant schizophrenia and schizoaffective disorder

Marc Peraire  1   2 , Francisco Arnau-Peiró  1   2   3 , Mariano Villar-García  2 , Ana Benito  1   4 , Iván Echeverria  1   2 , Gonzalo Haro  1   2
Affiliations
Randomized Controlled Trial

Randomised controlled trial of clozapine in resistant schizophrenia and schizoaffective disorder

Marc Peraire et al. J Psychopharmacol. 2025 Nov.

Abstract

Background: Clozapine (CLZ) stands out for its unique receptor profile, making it more effective than other antipsychotics, especially in treatment-resistant schizophrenia (TRS). There is growing evidence supporting its use in schizoaffective disorder (SZD), although diagnostic challenges and drug characteristics have complicated the implementation of specific clinical trials.

Aim: Compare efficacy and tolerability of CLZ in real-world patients with TRS and SZD.

Methods: Prospective, pragmatic, three-month, evaluator-blinded clinical trial with two randomised controlled arms (TRS groups) and a third fixed arm (SZD group). The clinical response was assessed by monthly visits during which the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale (MADRS), Calgary Depression Scale for Schizophrenia (CDSS), Clinical Global Impression (CGI) and Udvalg für Kliniske Undersogelser were administered. One hundred twenty-seven participants (74.8% men, 25.2% women; 84 TRS, 42 SZD; mean age of 38.53) completed the follow-up.

Results: Patients treated with CLZ showed a greater reduction in all the PANSS subscales, MADRS and CDSS. In cases of SZD, there was a significant decrease in positive (F: 3.72, p < 0.05) and negative (F: 6.58, p < 0.01) symptoms, the overall score of PANSS (F: 5.64, p < 0.01) and YMRS (F: 12.01, p < 0.01). Patients using CLZ had a better subjective perception of their treatment (χ2: 17.29, p < 0.01). CLZ prescription was the only predictor of better outcomes across all the scales and improved substance use (dual disorders).

Conclusions: CLZ was effective in reducing psychotic and affective symptoms in patients with dual psychosis, with better outcomes in SZD compared with TRS.EudraCT protocol trial:2021-001278-44 (Comparative analysis of the effectiveness of clozapine in resistant schizophrenia and schizoaffective disorder; clinicaltrialsregister.eu/ctr-search/trial/2021-001278-44/ES).

Keywords: Clozapine; dual disorders; refractory psychosis; schizoaffective disorder; schizophrenia.

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Conflict of interest statement

Declaration of conflicting interestThe authors declare that doctoral student Marc Peraire is the lead author of the present research and that all authors agree to its inclusion in his PhD thesis by compendium of articles. Non-doctoral authors waive any claim to use this article in future doctoral theses. The authors report no conflicts of interest.

Figures

Clinical trial process (according to CONSORT 2010).
Figure 1.
Clinical trial flowchart (according to CONSORT 2010).
See this image and copyright information in PMC

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