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Antipsychotic Induced Structural and Functional Brain Changes (APIC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02435095
Recruitment Status : Terminated (slow patient recruitment, low patient-commpliance, high dropout rates,)
First Posted : May 6, 2015
Last Update Posted : November 25, 2020
Sponsor:
Information provided by (Responsible Party):
RWTH Aachen University

Tracking Information
First Submitted Date  ICMJE April 14, 2015
First Posted Date  ICMJE May 6, 2015
Last Update Posted Date November 25, 2020
Study Start Date  ICMJE May 2015
Actual Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 3, 2016)
Total grey matter volume [ Time Frame: over 12 months ]
change in total grey matter volume
Original Primary Outcome Measures  ICMJE
 (submitted: April 30, 2015)
Total grey matter volume [ Time Frame: after 12 months ]
change in total grey matter volume
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 5, 2015)
  • Grey matter volume (hippocampus, prefrontal cortex) [ Time Frame: after 6 and 24 months ]
    change of volume
  • Assessment of safety as assessed with the following instrument: EPS [ Time Frame: after 6 and 12 months ]
    Extrapyramidal symptom scale (EPS)
  • Assessment of safety as assessed with the following instrument: BARS [ Time Frame: after 6 and 12 months ]
    Barnes Akathisia Rating Scale (BARS)
  • Assessment of safety as assessed with the following instrument: Arizona Scale [ Time Frame: after 6 and 12 months ]
    Sexual function (Arizona Scale)
  • Global assessment of safety as assessed with laboratory values [ Time Frame: after 6 and 12 months ]
    Metabolic side effects (Body mass index, HbA1c, Glucose, Cholesterol, Triglycerides)
  • Cognition [ Time Frame: after 6 and 12 months ]
    Brief Assessment of Cognition in Schizophrenia (BACS)
  • Quality of life [ Time Frame: after 6 and 12 months ]
    Short Form-36 Health Survey (SF-36), Global Assessment of Functioning Scale (GAF), visual analogue scales
  • Psychopathology as assessed with the PANSS [ Time Frame: after 6 and 12 months ]
    Positive and Negative Syndrome Scale (PANSS)
  • Psychopathology as assessed with the CGI [ Time Frame: after 6 and 12 months ]
    Clinical Global Impression (CGI)
Original Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2015)
  • Grey matter volume (hippocampus, prefrontal cortex) [ Time Frame: after 6 and 24 months ]
    change of volume
  • Global assessment of safety as assessed with the following instruments: EPS, BARS, Arizone Scale, laboratory values [ Time Frame: after 6 and 12 months ]
    Drop-out rates, extrapyramidal side effects (Extrapyramidal symptom scale (EPS),Barnes Akathisia Rating Scale (BARS); sexual function (Arizona Scale); metabolic side effects (Body mass index, HbA1c, Glucose, Cholesterol, Triglycerides)
  • Cognition [ Time Frame: after 6 and 12 months ]
    Brief Assessment of Cognition in Schizophrenia (BACS)
  • Quality of life [ Time Frame: after 6 and 12 months ]
    Short Form-36 Health Survey (SF-36), Global Assessment of Functioning Scale (GAF), visual analogue scales
  • Psychopathology as assessed with the PANSS and the CGI [ Time Frame: after 6 and 12 months ]
    Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Antipsychotic Induced Structural and Functional Brain Changes
Official Title  ICMJE Are Antipsychotics Neurotoxic or Neuroprotective? A Long-term Comparison of Two Treatment Strategies
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Schizophrenia
Intervention  ICMJE
  • 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 Name: Antipsychotics
  • 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 Name: Antipsychotics
Study Arms  ICMJE
  • 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).
    Intervention: Drug: Maintenance treatment
  • 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).

    Intervention: Drug: Intermittent treatment
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: November 23, 2020)
174
Original Estimated Enrollment  ICMJE
 (submitted: April 30, 2015)
666
Actual Study Completion Date  ICMJE August 2020
Actual Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02435095
Other Study ID Numbers  ICMJE 13-082
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party RWTH Aachen University
Study Sponsor  ICMJE RWTH Aachen University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Klaus Mathiak, Univ.-Prof. Dr. Dr. Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital RWTH Aachen, Germany
PRS Account RWTH Aachen University
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP