APIC: Antipsychotic Induced Structural and Functional Brain Changes

Sponsor

RWTH Aachen University (Other)

Overall Status

Terminated

CT.gov ID

NCT02435095

Collaborator

(none)

174

Enrollment

Locations

Arms

Duration (Months)

15.8

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Maintenance treatment Drug: Intermittent treatment	Phase 4

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 Design

Study Type:

Interventional

Actual Enrollment :

174 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

May 1, 2015

Actual Primary Completion Date :

Aug 1, 2020

Actual Study Completion Date :

Aug 1, 2020

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Total grey matter volume [over 12 months]
change in total grey matter volume

Secondary Outcome Measures

Grey matter volume (hippocampus, prefrontal cortex) [after 6 and 24 months]
change of volume
Assessment of safety as assessed with the following instrument: EPS [after 6 and 12 months]
Extrapyramidal symptom scale (EPS)
Assessment of safety as assessed with the following instrument: BARS [after 6 and 12 months]
Barnes Akathisia Rating Scale (BARS)
Assessment of safety as assessed with the following instrument: Arizona Scale [after 6 and 12 months]
Sexual function (Arizona Scale)
Global assessment of safety as assessed with laboratory values [after 6 and 12 months]
Metabolic side effects (Body mass index, HbA1c, Glucose, Cholesterol, Triglycerides)
Cognition [after 6 and 12 months]
Brief Assessment of Cognition in Schizophrenia (BACS)
Quality of life [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 [after 6 and 12 months]
Positive and Negative Syndrome Scale (PANSS)
Psychopathology as assessed with the CGI [after 6 and 12 months]
Clinical Global Impression (CGI)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	RWTH University Hospital Aachen	Aachen	NRW	Germany	52074
2	Alexianer Aachen GmbH	Aachen		Germany	52062
3	Zentrum für Neurologie und Seelische Gesundheit im Kapuziner Karree Aachen	Aachen		Germany	52062
4	LVR Klinik Bonn	Bonn		Germany	53111
5	LVR Klinik Düren	Düren		Germany	52353
6	Klinik und Poliklinik für Psychiatrie und Psychotherapie der Heinrich-Heine-Universität Düsseldorf	Düsseldorf		Germany	40629
7	LVR Klinik Essen	Essen		Germany	45147
8	ViaNobis Gangelt	Gangelt		Germany	52538
9	Klinik Königshof (Abteilung für Allgemeine Psychiatrie)	Krefeld		Germany	47807
10	LVR Klinik Langenfeld	Langenfeld		Germany	40764
11	LVR Klinik Viersen	Viersen		Germany	41749

Sponsors and Collaborators

RWTH Aachen University

Investigators

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