Antipsychotic Induced Structural and Functional Brain Changes (APIC)

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

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.

Study Overview

• Status: Terminated
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Maintenance treatment; Drug: Intermittent treatment

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.

• Study Type: Interventional
• Enrollment (Actual): 174
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52062
    • Alexianer Aachen GmbH
  • Aachen, Germany, 52062
    • Zentrum für Neurologie und Seelische Gesundheit im Kapuziner Karree Aachen
  • Bonn, Germany, 53111
    • LVR Klinik Bonn
  • Düren, Germany, 52353
    • LVR Klinik Düren
  • Düsseldorf, Germany, 40629
    • Klinik und Poliklinik für Psychiatrie und Psychotherapie der Heinrich-Heine-Universität Düsseldorf
  • Essen, Germany, 45147
    • LVR Klinik Essen
  • Gangelt, Germany, 52538
    • ViaNobis Gangelt
  • Krefeld, Germany, 47807
    • Klinik Königshof (Abteilung für Allgemeine Psychiatrie)
  • Langenfeld, Germany, 40764
    • LVR Klinik Langenfeld
  • Viersen, Germany, 41749
    • LVR Klinik Viersen
  • NRW
    • Aachen, NRW, Germany, 52074
      • RWTH University Hospital Aachen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Maintenance treatment (Control); 287 female and male patients with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V) will be directed randomly to the maintenance treatment group (control). Patients will be treated according to the current clinical standard of long-term maintenance antipsychotic treatment. Study related procedures include safety assessments (physical examination, questionaires), laboratory assessments (blood sampling, urine analysis), efficacy assessments (questionaires) and volumetric Magnetic Resonance Imaging (structural MRI incl. volumetry). Study procedures are the same for both study groups (control/experimental).	Drug: Maintenance treatment; Treatment with antipsychotic drug (either second-generation antipsychotics or low-dose first generation antipsychotics) for at least 12 months. All antipsychotics approved in Germany are permitted (amisulpride, aripiprazole, benperidol, bromperidol, chlorprothixene, clozapine, flupentixole, fluphenazine, fluspirilene, haloperidol, levomepromazine, loxapine, lurasidone, melperone, olanzapine, paliperidone, perazine, perphenazine, pimozide, pipamperone, prothipendyl, quetiapine, risperidone, sertindole, sulpiride, thioridazine, ziprasidone, zuclopenthixole).; Other Names: Antipsychotics
Experimental: Intermittent Treatment (Experimental); 287 female and male patients with schizophrenia according to DSM-V will be directed randomly to the intermittent treatment group (experimental). Patients directed to this group will be tapered off medication. Study related procedures include safety assessments (physical examination, questionaires), laboratory assessments (blood sampling, urine analysis), efficacy assessments (questionaires) and volumetric Magnetic Resonance Imaging (structural MRI incl. volumetry). Study procedures are the same for both study groups (control/experimental).	Drug: Intermittent treatment; Treatment with antipsychotic drug (either second-generation antipsychotics or low-dose first generation antipsychotics) only for first episode of schizophrenia, tapering-off medication after remission of positive symptoms, reinstatement of treatment only in case of recurrence of positive symptoms. All antipsychotics approved in Germany are permitted (amisulpride, aripiprazole, benperidol, bromperidol, chlorprothixene, clozapine, flupentixole, fluphenazine, fluspirilene, haloperidol, levomepromazine, loxapine, lurasidone, melperone, olanzapine, paliperidone, perazine, perphenazine, pimozide, pipamperone, prothipendyl, quetiapine, risperidone, sertindole, sulpiride, thioridazine, ziprasidone, zuclopenthixole).; Other Names: Antipsychotics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total grey matter volume	change in total grey matter volume	over 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grey matter volume (hippocampus, prefrontal cortex)	change of volume	after 6 and 24 months
Assessment of safety as assessed with the following instrument: EPS	Extrapyramidal symptom scale (EPS)	after 6 and 12 months
Assessment of safety as assessed with the following instrument: BARS	Barnes Akathisia Rating Scale (BARS)	after 6 and 12 months
Assessment of safety as assessed with the following instrument: Arizona Scale	Sexual function (Arizona Scale)	after 6 and 12 months
Global assessment of safety as assessed with laboratory values	Metabolic side effects (Body mass index, HbA1c, Glucose, Cholesterol, Triglycerides)	after 6 and 12 months
Cognition	Brief Assessment of Cognition in Schizophrenia (BACS)	after 6 and 12 months
Quality of life	Short Form-36 Health Survey (SF-36), Global Assessment of Functioning Scale (GAF), visual analogue scales	after 6 and 12 months
Psychopathology as assessed with the PANSS	Positive and Negative Syndrome Scale (PANSS)	after 6 and 12 months
Psychopathology as assessed with the CGI	Clinical Global Impression (CGI)	after 6 and 12 months

Collaborators and Investigators

• Sponsor: RWTH Aachen University
• Investigators: Principal Investigator: Klaus Mathiak, Univ.-Prof. Dr. Dr., Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital RWTH Aachen, Germany

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): August 1, 2020
• Study Completion (Actual): August 1, 2020

Study Registration Dates

• First Submitted: April 14, 2015
• First Submitted That Met QC Criteria: April 30, 2015
• First Posted (Estimate): May 6, 2015

Study Record Updates

• Last Update Posted (Actual): November 25, 2020
• Last Update Submitted That Met QC Criteria: November 23, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Schizophrenia; Antipsychotics; Maintenance treatment, Intermittent treatment; Brain volume
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Antipsychotic Agents
• Other Study ID Numbers: 13-082