Antipsychotic Induced Structural and Functional Brain Changes

Condition(s) targeted: Schizophrenia

Intervention: Maintenance treatment (Drug); Intermittent treatment (Drug)

Phase: Phase 4

Status: Not yet recruiting

Sponsored by: RWTH Aachen University

Official(s) and/or principal investigator(s):
Gerhard Gründer, Prof., MD, Principal Investigator, Affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital RWTH Aachen, Germany

Overall contact:
Sabrina Schaffrath, Phone: 0049 241 80, Ext: 89821, Email: saschaffrath@ukaachen.de

Continuation of antipsychotic drug treatment for at least 12 months after remission of the first psychotic episode represents the gold clinical standard, and it is recommended by all international treatment guidelines. Numerous studies have shown that the risk of relapse is significantly increased, if drug treatment is terminated prematurely. However, only a minority of patients achieve functional remission, even if they fully comply with treatment. Long-term adverse effects of the currently available drugs, specifically brain grey matter loss and development of supersensitivity psychosis, might outweigh their benefits. Thus, the current standard of long-term maintenance antipsychotic treatment, which has the primary goal of relapse prevention, has to be questioned. Here the investigators hypothesise that intermittent antipsychotic treatment (targeted exclusively at positive symptoms) initiated after the first psychotic episode is associated with less regional and global brain (grey matter) volume loss over a period of twelve months than continuous antipsychotic treatment. Furthermore, the investigators hypothesise that this targeted treatment approach is associated with better functional outcome (fewer negative symptoms, better cognitive performance, better quality of life) than continuous antipsychotic treatment,although the latter is initially associated with fewer relapses.

Official title: Are Antipsychotics Neurotoxic or Neuroprotective? A Long-term Comparison of Two Treatment Strategies

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Total grey matter volume

Secondary outcome:

Grey matter volume (hippocampus, prefrontal cortex)

Assessment of safety as assessed with the following instrument: EPS

Assessment of safety as assessed with the following instrument: BARS

Assessment of safety as assessed with the following instrument: Arizona Scale

Global assessment of safety as assessed with laboratory values

Cognition

Quality of life

Psychopathology as assessed with the PANSS

Psychopathology as assessed with the CGI

Detailed description: All patients with the first episode of schizophrenia admitted to a hospital participating in the consortium will undergo magnetic resonance imaging (MRI) as soon as possible after admission. Ideally, this procedure is performed before initiation of antipsychotic treatment (benzodiazepines are allowed). If not possible for clinical reasons, antipsychotic treatment will be started and the MRI will be acquired within three days of initiation of drug treatment. The choice of the antipsychotic will be made by the treating physician. All approved antipsychotics are permitted, including first-generation antipsychotics such as haloperidol or flupenthixol. This is based on the recommendation of the British NICE guidelines: "In nine randomized controlled trials (RCTs) with a total of 1,801 participants with first-episode or early schizophrenia (including people with a recent onset of schizophrenia and people who have never been treated with antipsychotic medication), the evidence suggested there were no clinically significant differences in efficacy between the antipsychotic drugs examined." (NICE 2009, p. 105). However, since second-generation antipsychotics (SGA) are now considered first-line treatment for schizophrenia according to the German S3 guideline, it can be assumed that more than 80% of all patients will be treated with an SGA. As soon as positive symptoms are sufficiently controlled, medication will be completely tapered off within four weeks. Sufficient control of positive symptoms will defined as follows: "delusions" (Positive and Negative Syndrome Scale (PANSS) item 1), "hallucinatory behaviour" (PANSS item 3), and "suspiciousness/persecution" (PANSS item 6) have to be "absent" or "mild" (scores 1 or 2). The PANSS Positive score (7 items) must not be above 18. Patients in the experimental group who will not reach remission according to this definition will be switched to another antipsychotic according to clinical standards. Tapering of medication might be considered at a later time-point. Patients who cannot be tapered off medication will be treated with the lowest possible dose. Treatment of subsequent exacerbations / psychotic relapses will follow the same rules.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients with first-episode of schizophrenia according to DSM-V

- aged between18 and 65 years

- written informed consent prior to study participation

- Subjects who are contractually capable and mentally able to understand and follow the

instructions of the study personnel

- Subjects eligible for MRI

Exclusion Criteria:

- The subject has a history of any other illness, which, in the opinion of the

investigator, might have an effect on the study performance (e. g. malignant disease, epilepsia)

- previous treatment with antipsychotics prior to study participation

- magnetizable metal parts in or at the body, pacemakers, piercings

- pregnant and lactating females

- subject has been committed to an institution by legal or regulatory order

- dependency or working relationship with the investigator

- participation in a parallel interventional clinical study

Sabrina Schaffrath, Phone: 0049 241 80, Ext: 89821, Email: saschaffrath@ukaachen.de

Alexianer Aachen GmbH, Aachen 52062, Germany; Not yet recruiting

Neurologisch-Psychiatrische Gemeinschaftspraxis am Marienhospital, Aachen 52066, Germany; Not yet recruiting
Yavuz Kara, Dr. med.

Praxis für Psychiatrie und Psychotherapie, Aachen 52070, Germany; Not yet recruiting
Beraat Mersuh-Böcker, Dr. med.

Zentrum für Neurologie und Seelische Gesundheit im Kapuziner Karree Aachen, Aachen 52062, Germany; Not yet recruiting
Frank Bergmann, Dr. med.

LVR Klinik Bonn, Bonn 53111, Germany; Not yet recruiting

Klinik und Poliklinik für Psychiatrie und Psychotherapie der Heinrich-Heine-Universität Düsseldorf, Düsseldorf 40629, Germany; Not yet recruiting

Gangelter Einrichtungen Maria Hilf, Gangelt 52538, Germany; Not yet recruiting

Klinik für Psychiatrie und Psychotherapie der Uniklinik Köln, Köln 50937, Germany; Not yet recruiting

LVR Klinik Langenfeld, Langenfeld 40764, Germany; Not yet recruiting

Starting date: May 2015
Last updated: May 5, 2015