"Multimodal Prevention of Psychosis - Investigating Efficacy of N-Acetylcysteine and Psychotherapy in CHR-Patients" (ESPRIT-B1)

Multimodal Prevention of First Psychotic Episode - a 2x2-Factorial Randomized Trial Investigating the Efficacy of Acetylcysteine and Integrated Preventive Psychological Intervention in Subjects Clinically at High Risk for Psychosis

Schizophrenia is a severe mental disorder associated with significant impairments in affective, cognitive and social functioning. Consequently, a special interest in the prevention of schizophrenia and psychotic disorders has emerged. Pharmacological as well as psychological interventions show promising preventive effects. The purpose of this multicentric study is the investigation of possible preventive effects of a treatment combination containing a psychotherapy form and medication (N-Acetylcytein - NAC) in individuals with an enhanced risk for developing schizophrenia. Both treatment forms may reduce the risk in this population due to their specific properties: The psychotherapy can improve social skills, whereas NAC is supposed to develop its protective effects on neuronal level due to its antiinflammatory properties. The investigators will examine the preventive effects by measuring transition rates to psychosis after treatment as well as improvements in social, affective and cognitive functioning.

Study Overview

• Status: Terminated
• Conditions: Prodromal Schizophrenia
• Intervention / Treatment: Drug: N-Acetylcysteine; Behavioral: IPPI (Integrated Preventive Psychological Intervention); Behavioral: PSM (Psychological stress management); Drug: Placebo

Detailed Description

Psychotic disorders are among the most expensive brain-related disorders in Europe. This is mainly due to their onset early in life and their long-term disabling courses. Current treatments fail to improve most influential factors such as social-cognitive deficits. Prevention is recognized as one of the key strategies to fight these deteriorating outcomes and is expected to significantly reduce both, the societal costs as well as the immense burden for the patients and for their families. Recent meta-analyses indicate promising preventive effects of both pharmacological and cognitive-behavioural interventions. Yet, reported transition rates are still too high. Clinical evidence suggests that disturbances of social functioning predict conversion to psychosis. Neurobiological evidence implicates glutamatergic dysfunction and redox imbalance in the pathophysiology of schizophrenia. The investigators hypothesize that interventions targeting (i) social functioning and (ii) glutamatergic / oxidative pathways already in at-risk states would significantly reduce transition rates. To test these hypotheses, our study is designed as a randomized, placebo-controlled, 18-month trial (six months of intervention plus 12 months of follow-up), involving 200 subjects at-risk for psychosis. Specifically, the investigators will compare the preventive effects of a cognitive-behavioural and social-cognitive intervention to a pharmacological intervention (IPPI) with Acetylcysteine, a drug with a proglutamatergic, neuroprotective and anti-inflammatory profile in a 2x2 factorial design. The results of our planned study are expected to provide new and well tolerated interventions, thus hopefully helping to achieve the major goal of individualized prevention, and, consequently, lower the individual and societal burden of psychosis.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Charite Berlin
  • Berlin, Germany, 10967
    • Berlin Vivantes
  • Baden-Württemberg
    • Mannheim, Baden-Württemberg, Germany, 68159
      • Zentralinstitut für Gesundheit Mannheim
    • Tübingen, Baden-Württemberg, Germany, 72076
      • Universitatsklinik Tubingen
  • Bayern
    • München, Bayern, Germany, 80336
      • LMU Klinikum München
  • Nordrhein-Westfalen
    • Aachen, Nordrhein-Westfalen, Germany, 52074
      • Uniklinik Aachen
    • Bonn, Nordrhein-Westfalen, Germany, 53127
      • Uniklinikum Bonn
    • Düsseldorf, Nordrhein-Westfalen, Germany, 40225
      • LVR Klinik Düsseldorf
    • Köln, Nordrhein-Westfalen, Germany, 50937
      • Uniklinik Köln
  • Rheinland-Pfalz
    • Alzey, Rheinland-Pfalz, Germany, 55232
      • Rheinhessen Fachklinik Alzey

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 38 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 - 40 years;
2. Subjects with the ability to follow study instructions and likely to attend and complete all required visits;
3. Written informed consent of the subject;

4. Subjects are able to speak, write and understand the German language sufficiently well (at the investigators discretion) to complete all required study procedures;

   Specific inclusion criterion:

5. Clinical High Risk Criteria : ESPRIT Ultra-high risk criteria (Attenuated Positive Symptoms and/or Brief Llimited Intermittend Psychotic Symptoms and/or a combination of familial risk or schizotypal disorder with a significant loss of functioning; severity assessed by the Structured Interview for Prodromal Syndromes, SIPS 5.0) and/or The Basic Symptom Criterion 'Cognitive Disturbances, COGDIS' (2/9 cognitive-perceptive basic symptoms; assessed by the Schizophrenia Proneness Instrument - Adult Version, SPI-A)

Exclusion Criteria:

1. Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure;
2. Simultaneously participation in another clinical trial involving administration of an investigational medicinal product within 30 days prior to clinical trial beginning. The simultaneous participation in a noninterventional clinical trial is permitted in case the subject is nevertheless able and willing to attend and complete all required visits and in case there are no other contraindications;
3. Subjects with a physical or psychiatric condition which at the investigator's discretion may put the subject at other clinically significant risks than those that are defined as outcome of this study (development of a first psychotic episode, functional deterioration), may confound the trial results, or may interfere with the subject's per protocol participation in this clinical trial;
4. Acute Suicidality;
5. Known substance abuse or dependence according to DSM-IV-TR;
6. Patients with hepatic or renal failure, or with known problems of galactose intolerance, clinically significant lactase deficiency or glucose-galactose malabsorption or histamine-intolerance;
7. Subjects with known asthma bronchiale;
8. Subjects with a history of gastrointestinal ulcer;
9. Intake of antitussives (cough-relieving agents);
10. Intake of nitroglycerin
11. Exclusion criteria regarding special restrictions for females: Current pregnancy or pregnancy planned within 9 months after start of medication or nursing women and

12. Females of childbearing potential, who are not using and not willing to use medically reliable methods of contraception for the entire study duration (such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices) unless they are surgically sterilized / hysterectomized or there are any other criteria considered sufficiently reliable by the investigator in individual cases.

    Indication specific exclusion criteria:

13. Having had a psychotic episode for > 1 week (according to SIPS 5.0);
14. Having symptoms relevant for inclusion potentially arising from a known general medical disorder;
15. Life time antipsychotic medication for more than 30 days (cumulative number of days) at or above minimum dosage of the '1st episode psychosis' range of DGPPN S3 Guidelines (Exception: maximum dosage for aripiprazole 5 mg/d) (Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde, 2006);
16. Any intake of antipsychotic medication (i.e., independent of duration of intake) within the past 3 months before psychopathological baseline assessments (including self-ratings and screening assessments) at or above minimum dosage of the '1st episode psychosis' range of DGPPN S3 Guidelines (Exception: maximum dosage for aripiprazole 5 mg/d) (Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde, 2006);
17. Any intake of mood stabilizers (lithium, valproate, carbamazepine, oxcabazepine, lamotrigine) > 30 days (cumulative number of days) during the past three months or any intake during the month before psychopathological baseline assessments;
18. Intake of antidepressants during the past 30 days before psychopathological baseline assessments;
19. Intake of benzodiazepines for more than 2 consecutive days during the past 5 days before psychopathological baseline assessments;
20. Psychotherapeutic intervention during the past 30 days before psychopathological baseline assessments;
21. Any past psychotherapeutic treatment targeting specifically psychotic symptoms or its prevention.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IPPI + NAC; IPPI (Integrated Preventive Psychological Intervention): 21 sessions, the first 20 sessions are scheduled weekly, the last session two weeks after session 20. Single blinded (statistician & rater). N-Acetylcysteine (2000 mg/d, 1000 mg in the morning/evening, oral intake). Will be applied continously over 26 weeks parallel to the psychological intervention. Double-blinded.	Drug: N-Acetylcysteine; N-Acetylcysteine (2000 mg/d, 1000 mg in the morning/evening, oral intake). Will be applied continously over 26 weeks parallel to the psychological intervention (IPPI or PSM).; Other Names: NAC; Behavioral: IPPI (Integrated Preventive Psychological Intervention); IPPI (Integrated Preventive Psychological Intervention): 21 sessions, the first 20 sessions are scheduled weekly, the last session two weeks after session 20. Single blinded (statistician & rater)
Experimental: PSM + NAC; PSM (Psychological stress management): 11 sessions; the first 10 sessions will be offered biweekly, the last one 2 weeks after session 10. Single blinded (statistician & rater). N-Acetylcysteine (2000 mg/d, 1000 mg in the morning/evening, oral intake). Will be applied continously over 26 weeks parallel to the psychological intervention. Double-blinded.	Drug: N-Acetylcysteine; N-Acetylcysteine (2000 mg/d, 1000 mg in the morning/evening, oral intake). Will be applied continously over 26 weeks parallel to the psychological intervention (IPPI or PSM).; Other Names: NAC; Behavioral: PSM (Psychological stress management); PSM (Psychological stress management): 11 sessions; the first 10 sessions will be offered biweekly, the last one 2 weeks after session 10. Single blinded (statistician & rater).
Experimental: IPPI + Placebo; IPPI (Integrated Preventive Psychological Intervention): 21 sessions, the first 20 sessions are scheduled weekly, the last session two weeks after session 20. Single blinded (statistician & rater). Placebo will be applied continously over 26 weeks (oral intake of capsules) parallel to the psychological intervention (IPPI or PSM).	Behavioral: IPPI (Integrated Preventive Psychological Intervention); IPPI (Integrated Preventive Psychological Intervention): 21 sessions, the first 20 sessions are scheduled weekly, the last session two weeks after session 20. Single blinded (statistician & rater); Drug: Placebo; Will be applied continously over 26 weeks (oral intake of capsules) parallel to the psychological intervention (IPPI or PSM).
Active Comparator: PSM + Placebo; PSM (Psychological stress management): 11 sessions; the first 10 sessions will be offered biweekly, the last one 2 weeks after session 10. Single blinded (statistician & rater). N-Acetylcysteine (2000 mg/d, 1000 mg in the morning/evening, oral intake). Placebo will be applied continously over 26 weeks (oral intake of capsules) parallel to the psychological intervention (IPPI or PSM).	Behavioral: PSM (Psychological stress management); PSM (Psychological stress management): 11 sessions; the first 10 sessions will be offered biweekly, the last one 2 weeks after session 10. Single blinded (statistician & rater).; Drug: Placebo; Will be applied continously over 26 weeks (oral intake of capsules) parallel to the psychological intervention (IPPI or PSM).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transition to psychosis	Transition to psychosis within 18 months, defined (according to EPOS1) as the presence of at least one psychotic symptom for at least one week (assessed by the SIPS).	I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)
Psychosocial functioning	Psychosocial functioning assessed by the SOFAS and the FROGS	I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptom remission	1. Remission of symptomatic clinical high risk (CHR) criteria (APS/BLIPS and/or COGIDS); decrease of positive, negative and disorganization symptoms (assessed by the SIPS, BNSS score); conceptual disorganization and cognitive basic symptoms (COGDIS, SPI-A); as well as at-risk symptoms according to UHR (SPI-A);	I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)
Depression remission	Remission of depressive symptoms (measured by CDSS)	I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)
Improvement of social cognition	Improvement of social cognition (measured by SAT-MC I & II, PoFA)	I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)
Assessment of safety and tolerability	Neurologic and general examination (medical history, weight, - adverse events (assessed by UKU SYMPTOM-LIST), Laboratory assessments	I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)

Collaborators and Investigators

• Sponsor: University Hospital, Bonn
• Collaborators: Charite University, Berlin, Germany; Heinrich-Heine University, Duesseldorf; University of Cologne; RWTH Aachen University; Ludwig-Maximilians - University of Munich; University Hospital Tuebingen; Central Institute of Mental Health, Mannheim

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2016
• Primary Completion (Actual): January 1, 2021
• Study Completion (Actual): January 1, 2021

Study Registration Dates

• First Submitted: May 8, 2017
• First Submitted That Met QC Criteria: May 8, 2017
• First Posted (Actual): May 11, 2017

Study Record Updates

• Last Update Posted (Actual): May 9, 2022
• Last Update Submitted That Met QC Criteria: May 3, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Prodrome, CHR, Schizophrenia, prevention, N-acetylcysteine
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: University Hospital, Bonn

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided