Clinical trial NCT02435095: Antipsychotic Induced Structural and Functional Brain Changes
Official title: Are Antipsychotics Neurotoxic or Neuroprotective? A Long-term Comparison of Two Treatment Strategies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Schizophrenia
Keywords: Schizophrenia
Maintenance treatment, Intermittent treatment
Brain volume
Antipsychotics
Lead sponsor: RWTH Aachen University
Sponsor class: OTHER
First posted: 2015-05-06
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 hypothesize that intermittent treatment (experimental) with antipsychotics, which is directed exclusively against the positive symptoms of Schizophrenia, is associated with less loss in total grey matter volume than maintenance treatment (control). 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.The aim of the present study is to compare two different drug therapies -maintenance therapy versus on-demand, intermittent therapy- in terms of their treatment's success and the structural changes in the brain.

Detailed description: Patients with diagnosis of schizophrenia according to DSM-5 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.

Eligibility criteria: Inclusion Criteria:

* Patients with diagnosis of schizophrenia according to DSM-5
* Age 18-65 years
* Written declaration of consent
* Subjects being contractually and mentally capable to attend the medical staffs' orders.
* MRI capability

Exclusion Criteria:

* Relevant somatic diseases, which could have an impact on the conduct of the study based on clinical judgement of the treating physician (e.g. epilepsy, cancer)
* Prior insufficiently documented drug therapy with antipsychotics
* Magnetic metals in and on the body, cardiac pacemakers and body piercings.
* Pregnancy or lactation
* Hospitalization of the patient ordered by the court or public authorities
* Relationship of dependence or employment to sponsor or investigator
* Simultaneous participation in another clinical trial (participation in an APIC subproject excluded)

Primary outcomes:
measure: Total grey matter volume
timeFrame: over 12 months
Secondary outcomes:
measure: Grey matter volume (hippocampus, prefrontal cortex)
timeFrame: after 6 and 24 months
measure: Assessment of safety as assessed with the following instrument: EPS
timeFrame: after 6 and 12 months
measure: Assessment of safety as assessed with the following instrument: BARS
timeFrame: after 6 and 12 months
measure: Assessment of safety as assessed with the following instrument: Arizona Scale
timeFrame: after 6 and 12 months
measure: Global assessment of safety as assessed with laboratory values
timeFrame: after 6 and 12 months
measure: Cognition
timeFrame: after 6 and 12 months
measure: Quality of life
timeFrame: after 6 and 12 months
measure: Psychopathology as assessed with the PANSS
timeFrame: after 6 and 12 months
measure: Psychopathology as assessed with the CGI
timeFrame: after 6 and 12 months
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: RWTH University Hospital Aachen
state: NRW
city: Aachen
country: Germany
facility: Alexianer Aachen GmbH
city: Aachen
country: Germany
facility: Zentrum für Neurologie und Seelische Gesundheit im Kapuziner Karree Aachen
city: Bonn
country: Germany
facility: LVR Klinik Bonn
city: Düren
country: Germany
facility: LVR Klinik Düren
city: Düsseldorf
country: Germany
facility: Klinik und Poliklinik für Psychiatrie und Psychotherapie der Heinrich-Heine-Universität Düsseldorf
city: Essen
country: Germany
facility: LVR Klinik Essen
city: Gangelt
country: Germany
facility: ViaNobis Gangelt
city: Krefeld
country: Germany
facility: Klinik Königshof (Abteilung für Allgemeine Psychiatrie)
city: Langenfeld
country: Germany
facility: LVR Klinik Langenfeld
city: Viersen
country: Germany
facility: LVR Klinik Viersen
Study officials:
affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital RWTH Aachen, Germany
name: Klaus Mathiak, Univ.-Prof. Dr. Dr.
role: PRINCIPAL_INVESTIGATOR
References: