SchizophreniaPhase 4APICNCT02435095
Antipsychotic Induced Structural and Functional Brain Changes
A Phase 4 study testing Maintenance treatment and Intermittent treatment in people with Schizophrenia, run by RWTH Aachen University at 11 sites in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Schizophrenia
- What is being tested?
- Maintenance treatment and Intermittent treatment
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 174 participants
- Where
- 11 sitesGermany
- Study dates
- May 2015to Aug 2020
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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)
Trial locations and contacts
11 sites in 1 country.
11 sites in 1 country
Germany11 sites
RWTH University Hospital Aachen
Aachen, North Rhine-Westphalia, 52074
Alexianer Aachen GmbH
Aachen, 52062
Zentrum für Neurologie und Seelische Gesundheit im Kapuziner Karree Aachen
Aachen, 52062
LVR Klinik Bonn
Bonn, 53111
LVR Klinik Düren
Düren, 52353
Klinik und Poliklinik für Psychiatrie und Psychotherapie der Heinrich-Heine-Universität Düsseldorf
Düsseldorf, 40629
LVR Klinik Essen
Essen, 45147
ViaNobis Gangelt
Gangelt, 52538
Klinik Königshof (Abteilung für Allgemeine Psychiatrie)
Krefeld, 47807
LVR Klinik Langenfeld
Langenfeld, 40764
LVR Klinik Viersen
Viersen, 41749
About this study
Official title: 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.
Read the 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.
- Conditions
- Schizophrenia
- Being tested
- Maintenance treatment, Intermittent treatment
- Keywords
- Schizophrenia, Maintenance treatment, Intermittent treatment, Brain volume, Antipsychotics
- Medical subject headings
- Schizophrenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Maintenance treatmentDrug
Also called Antipsychotics
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).
Intermittent treatmentDrug
Also called Antipsychotics
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).
| Study group | Role | What they receive |
|---|---|---|
| Maintenance treatment (Control) | Active comparator | 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). Receives: Drug: Maintenance treatment |
| Intermittent Treatment (Experimental) | 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). Receives: Drug: Intermittent treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Total grey matter volume
change in total grey matter volume
Measured: over 12 months
Secondary outcomes (9)
Grey matter volume (hippocampus, prefrontal cortex)
change of volume
Measured: after 6 and 24 months
Assessment of safety as assessed with the following instrument: EPS
Extrapyramidal symptom scale (EPS)
Measured: after 6 and 12 months
Assessment of safety as assessed with the following instrument: BARS
Barnes Akathisia Rating Scale (BARS)
Measured: after 6 and 12 months
Assessment of safety as assessed with the following instrument: Arizona Scale
Sexual function (Arizona Scale)
Measured: after 6 and 12 months
Global assessment of safety as assessed with laboratory values
Metabolic side effects (Body mass index, HbA1c, Glucose, Cholesterol, Triglycerides)
Measured: after 6 and 12 months
Cognition
Brief Assessment of Cognition in Schizophrenia (BACS)
Measured: after 6 and 12 months
Quality of life
Short Form-36 Health Survey (SF-36), Global Assessment of Functioning Scale (GAF), visual analogue scales
Measured: after 6 and 12 months
Psychopathology as assessed with the PANSS
Positive and Negative Syndrome Scale (PANSS)
Measured: after 6 and 12 months
Psychopathology as assessed with the CGI
Clinical Global Impression (CGI)
Measured: after 6 and 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 May 2015 (estimated)
- Study startMay 2015
- Primary completionAug 2020
- Study completionAug 2020
Why it stopped: slow patient recruitment, low patient-commpliance, high dropout rates,
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 174 participants (actual)
Sponsor and investigators
- Lead sponsor
- RWTH Aachen University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Klaus Mathiak, Univ.-Prof. Dr. Dr., Principal investigator, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital RWTH Aachen, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02435095
- Sponsor's protocol ID
- 13-082
- Acronym
- APIC
- Status last verified
- Nov 2020
- First submitted
- 14 Apr 2015
- Last updated
- 25 Nov 2020
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 25 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Are Antipsychotics Neurotoxic or Neuroprotective? A Long-term Comparison of Two Treatment Strategies
- ClinicalTrials.gov ID
- NCT02435095
- Acronym / sponsor ID
- APIC / 13-082
- Conditions
- Schizophrenia
- Keywords
- Schizophrenia, Maintenance treatment, Intermittent treatment, Brain volume, Antipsychotics
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: slow patient recruitment, low patient-commpliance, high dropout rates,
- Enrolment
- 174 participants (actual)
- Lead sponsor
- RWTH Aachen UniversityUniversity, hospital or other
- Study start
- May 2015
- Primary completion
- Aug 2020 (actual)
- Study completion
- Aug 2020 (actual)
- First posted
- 6 May 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Maintenance treatment (Control) | Active comparator | Drug: Maintenance treatment287 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). |
| Intermittent Treatment (Experimental) | Experimental | Drug: Intermittent treatment287 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). |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Maintenance treatmentAlso: AntipsychoticsTreatment 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). | Drug | Maintenance treatment (Control) |
| Intermittent treatmentAlso: AntipsychoticsTreatment 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). | Drug | Intermittent Treatment (Experimental) |
Primary outcome
Total grey matter volume
Time frame: over 12 months
change in total grey matter volume
9 secondary outcomes
Grey matter volume (hippocampus, prefrontal cortex)
Time frame: after 6 and 24 months
Assessment of safety as assessed with the following instrument: EPS
Time frame: after 6 and 12 months
Assessment of safety as assessed with the following instrument: BARS
Time frame: after 6 and 12 months
Assessment of safety as assessed with the following instrument: Arizona Scale
Time frame: after 6 and 12 months
Global assessment of safety as assessed with laboratory values
Time frame: after 6 and 12 months
Cognition
Time frame: after 6 and 12 months
Quality of life
Time frame: after 6 and 12 months
Psychopathology as assessed with the PANSS
Time frame: after 6 and 12 months
Psychopathology as assessed with the CGI
Time frame: after 6 and 12 months
Results and safety
The study was stopped early (reason given: slow patient recruitment, low patient-commpliance, high dropout rates,). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Nov 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Klaus Mathiak, Univ.-Prof. Dr. Dr. principal investigator
Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital RWTH Aachen, Germany
11 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Maintenance treatment and Intermittent treatment in people with Schizophrenia, run by RWTH Aachen University at 11 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 25 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: slow patient recruitment, low patient-commpliance, high dropout rates,). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Total grey matter volume (time frame: over 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Nov 2020.