Clinical trial NCT03149107: "Multimodal Prevention of Psychosis - Investigating Efficacy of N-Acetylcysteine and Psychotherapy in CHR-Patients"
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Prodromal Schizophrenia
Keywords: Prodrome, CHR, Schizophrenia, prevention, N-acetylcysteine
Lead sponsor: University Hospital, Bonn
Sponsor class: OTHER
Collaborators: name: University of Cologne
name: Central Institute of Mental Health, Mannheim
name: Ludwig-Maximilians - University of Munich
name: University Hospital Tuebingen
name: Heinrich-Heine University, Duesseldorf
name: Charite University, Berlin, Germany
name: RWTH Aachen University
First posted: 2017-05-11
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Transition to psychosis
timeFrame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)
measure: Psychosocial functioning
timeFrame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)
Secondary outcomes:
measure: Symptom remission
timeFrame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)
measure: Depression remission
timeFrame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)
measure: Improvement of social cognition
timeFrame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)
measure: Assessment of safety and tolerability
timeFrame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start)
Other outcomes:
Locations:
city: Mannheim
country: Germany
facility: Zentralinstitut für Gesundheit Mannheim
state: Baden-Württemberg
city: Tübingen
country: Germany
facility: Universitätsklinik Tübingen
state: Baden-Württemberg
city: München
country: Germany
facility: LMU Klinikum München
state: Bayern
city: Aachen
country: Germany
facility: Uniklinik Aachen
state: Nordrhein-Westfalen
city: Bonn
country: Germany
facility: Uniklinikum Bonn
state: Nordrhein-Westfalen
city: Düsseldorf
country: Germany
facility: LVR Klinik Düsseldorf
state: Nordrhein-Westfalen
city: Köln
country: Germany
facility: Uniklinik Köln
state: Nordrhein-Westfalen
city: Alzey
country: Germany
facility: Rheinhessen Fachklinik Alzey
state: Rheinland-Pfalz
city: Berlin
country: Germany
facility: Charité Berlin
city: Berlin
country: Germany
facility: Berlin Vivantes
Study officials:
References: