Multimodal prevention of first psychotic episode through N-acetyl-L-cysteine and integrated preventive psychological intervention in individuals clinically at high risk for psychosis - Protocol of a randomized, placebo-controlled, parallel-group trial

Aug 24, 2026

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Indicated prevention is being tested for people clinically at high risk (CHR) for psychosis, targeting both transition to psychotic disorders and social functioning. The protocol addresses limitations of prior antipsychotic and cognitive-behavioural approaches by combining a pharmacological neuroprotective agent (N-acetyl-L-cysteine) with an integrated preventive psychological intervention (stress-/symptom-management plus social-cognitive remediation). A 2×2 factorial, multi-centre double-/single-blind randomized design will assign 200 CHR participants across four conditions, delivering interventions over 26 weeks with 12-month follow-up.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Need for integrated preventive psychological interventions

Methods

Interventions and factorial design

Randomization, sample size, and follow-up

Results

Trial design and outcomes

Conclusion

DOI: 10.1111/eip.12781 OR IGINAL ARTI CLE Multimodal prevention of first psychotic episode through N-acetyl-L-cysteine and integrated preventive psychological intervention in individuals clinically at high risk for psychosis: Protocol of a randomized, placebo-controlled, parallel-group trial Stefanie J. Schmidt1,2,3 | René Hurlemann4,5 | Johannes Schultz4,5 | Sven Wasserthal4,5 | Christian Kloss4,5 | Wolfgang Maier4,6 | Andreas Meyer-Lindenberg7 | Martin Hellmich8 | Ana Muthesius-Digón3 | Tanja Pantel3 | Pia-Sophie Wiesner3 | Joachim Klosterkötter3 | Stephan Ruhrmann3 | the ESPRIT-B1 Group 1Department of Clinical Psychology and Psychotherapy, University of Bern, Bern, Switzerland 2University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland 3Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany 4Department of Psychiatry, University Hospital Bonn, Bonn, Germany 5Division of Medical Psychology, University Hospital Bonn, Bonn, Germany 6German Center for Neurodegenerative Diseases, Bonn, Germany 7Central Institute of Mental Health, Mannheim, Germany 8Institute of Medical Statistics and Computational Biology, University of Cologne, Cologne, Germany Correspondence Stefanie J. Schmidt, Department of Clinical Psychology and Psychotherapy, University of Bern, Fabrikstrasse 8, 3012 Bern, Switzerland. Email: [stefanie.schmidt@psy.unibe.ch](stefanie.schmidt@psy.unibe.ch)[ ](stefanie.schmidt@psy.unibe.ch)Funding information Bundesministerium für Bildung und Forschung, Grant/Award Number: 01EE1407C, 01EE14071 Aim: Meta-analyses indicate positive effects of both antipsychotic and cognitive-behavioural interventions in subjects clinically at high risk (CHR) for psychosis in terms of a delay or prevention of psychotic disorders. However, these effects have been limited regarding social functioning and the relative efficacy of both types of interventions remains unclear. Furthermore, neuroprotective substances seem to be a promising alternative agent in psychosis-prevention as they are associated with few and weak side-effects. Methods: In this multi-centre randomized controlled trial (RCT), we investigate the effects of two interventions on transition to psychosis and social functioning: (a) an integrated preventive psychological intervention (IPPI) including stress-/symptom-management and social-cognitive remediation; (b) N-acetyl-L-cysteine (NAC) as a pharmacological intervention with glutamatergic, neuroprotective and anti-inflammatory capabilities. Results: This is a double-blind, placebo-controlled RCT with regard to NAC and a single-blind RCT with regard to IPPI using a 2 × 2-factorial design to investigate the individual and combined preventive effects of both interventions. To this aim, a total of 200 CHR subjects will be randomized stratified by site to one of four conditions: (a) IPPI and NAC; (b) IPPI and Placebo;(c) NAC and psychological stress management; (d) Placebo and psychological stress management. Interventions are delivered over 26 weeks with a follow-up period of 12 months. Conclusion: This paper reports on the rationale and protocol of an indicated prevention trial to detect the most effective and tolerable interventions with regard to transition to psychosis as well as improvements in social functioning, and to evaluate the synergistic effects of these interventions. KEYWORDS clinical high risk, cognitive remediation, N-acetyl-L-cysteine, prevention, psychosis, social cognition 1 | INTRODUCTION Psychotic disorders are associated with huge individual and societal burden. Therefore, they are among the most expensive brain-related disorders in Europe (Vigo, Thornicroft, & Atun, 2016; Wittchen et al., 2011). To fight these detrimental outcomes, indicated prevention approaches have been developed to target individuals at clinical high risk (CHR) for psychosis (Fusar-Poli et al., 2013; Schultze-Lutter

FAQs

What interventions are evaluated in the trial?

The study tests an integrated preventive psychological intervention (stress-/symptom-management and social-cognitive remediation) and N-acetyl-L-cysteine as a pharmacological neuroprotective and anti-inflammatory agent.

How are participants assigned to study conditions?

A total of 200 CHR subjects are randomized in a 2×2 factorial design into four groups, stratified by site, to evaluate individual and combined effects.

What is the trial duration and follow-up period?

Interventions are delivered over 26 weeks, followed by a 12-month follow-up period to assess outcomes related to transition to psychosis and social functioning.

Aug 24, 2026

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