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Do Antipsychotic Agents Induce Supersensitivity in Humans: A Combined PET/MRI Study in Patients With Schizophrenia

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ClinicalTrials.gov Identifier: NCT03911726
Recruitment Status : Recruiting
First Posted : April 11, 2019
Last Update Posted : February 24, 2021
Sponsor:
Information provided by (Responsible Party):
Xenia Hart, Central Institute of Mental Health, Mannheim

Study Description
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Brief Summary:
The aim of the present study is to detect changes in the dopamine system in the brain of patients with schizophrenia, especially when pretreated with antipsychotic medication. Here, the investigators want to find out whether the treatment with these drugs can cause permanent changes in docking points (receptors) of dopamine in the brain. It will be examined whether number and response of dopamine receptors is altered, which are associated with the onset of psychotic symptoms. For this purpose, a single PET/MR measurement will be performed in all participants. In total 140 volunteers, consisting of 30 healthy volunteers, 20 first-episode, drug-naive patients with schizophrenia and 90 pretreated patients with schizophrenia will be included over a time period of three years. In addition, the influence of nicotine consumption on dopamine receptors will be invesitgated by comparing data from smoking and non-smoking patients. In clinical practice, an elevation of dopamine action caused by alterations in receptors in the brain is of most importance. This may be the reason why the treatment with antipsychotic agents does not work in some patients. In addition, a permanent elevation of dopamine action is associated with permanent brain alterations by these drugs. The result can contribute to work out valuable indications, whether it makes sense to continue a long term therapy with antipsychotic drugs in a patient. But also the in-depth understanding of the impact of nicotine on the course of therapy can help to open up possibilities for improved drug treatment.

Condition or disease Intervention/treatment Phase
Schizophrenia Radiation: Single PET/MR-measurement Not Applicable

Detailed Description:
This project will study for the first time in humans, whether long-term treatment with antipsychotic agents, representing nowadays gold standard for patients with schizophrenia, may lead to an up regulation of dopamine D2-like receptors and associated, a supersensitivity of these receptors. The detection of such changes and the study of influencing factors (in particular smoking and type of medication) are most important for the understanding of relapse risks, development of treatment resistance and the risks for motor complications of antipsychotic pharmacotherapy. This monocentric, controlled study will include 140 participants over a time period of three years. 30 healthy volunteers, 20 first-episode, drug-naive patients with schizophrenia and 90 pretreated patients with schizophrenia will undergo a single PET/MR measurement.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: All study participants will undergo a single PET/MR-measurement.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Do Antipsychotic Agents Induce Supersensitivity in Humans: A Combined PET/MRI Study in Patients With Schizophrenia
Actual Study Start Date : August 1, 2020
Estimated Primary Completion Date : July 1, 2022
Estimated Study Completion Date : July 1, 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Healthy subjects
30 healthy subjects will undergo a single PET/MR-measurement.
 Radiation: Single PET/MR-measurement
A single PET/MR-measurement using [18F]Fallypride with a duration of 180min. Within this measurement, the dopamine receptor agonist apomorphine is applicated.
Experimental: First-episode, drug-naive patients with schizophrenia
20 first-episode, drug-naive patients with schizophrenia will undergo a single PET/MR-measurement.
 Radiation: Single PET/MR-measurement
A single PET/MR-measurement using [18F]Fallypride with a duration of 180min. Within this measurement, the dopamine receptor agonist apomorphine is applicated.
Experimental: Pretreated chronically ill patients with schizophrenia
90 pretreated chronically ill patients with schizophrenia will undergo a single PET/MR-measurement.
 Radiation: Single PET/MR-measurement
A single PET/MR-measurement using [18F]Fallypride with a duration of 180min. Within this measurement, the dopamine receptor agonist apomorphine is applicated.


Outcome Measures
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Primary Outcome Measures :
  1. Dopamine D2/D3-receptor availability [ Time Frame: 180 minutes ]
    Dopamine D2/D3-receptor availability measured as binding potential (BP) using PET and blood-oxygen-level-dependant (BOLD)-response measured with fMRI.


Secondary Outcome Measures :
  1. D2/D3-receptor availability in first-episode, drug-naive patients with schizophrenia [ Time Frame: 180 minutes ]
    In first-episode, drug-naive patients with schizophrenia expressions of NSS and AIMS correlate significantly with striatal D2/D3-receptor availability.

  2. D2/D3-receptor availability in patients with TD [ Time Frame: 180 minutes ]
    In pretreated, chronically ill patients with schizophrenia, patients with TD show a significantly higher D2/D3-receptor availability than patients without TD.

  3. Follow-up of pretreated, chronically ill patients with schizophrenia [ Time Frame: two years ]
    In pretreated, chronically ill patients with schizophrenia, the D2/D3-receptor availability correlates with the relapse risk and the risk for the development of TD over the course of two years.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria for healthy subjects:

  • Age: 18-65
  • The subject is capable to understand scope and individual consequences of the clinical study.
  • An informed consent is signed and personally dated by the subject. • No psychiatric disorder (DSM-5) currently, or in the medical history (ensured by a standardized psychiatric interview (DIAX: composite international diagnostic interview)).

Inclusion Criteria for patients:

  • Age: 18-65
  • The criteria for schizophrenia after DSM-5 are met.
  • The subject is capable to understand scope and individual consequences of the clinical study.
  • For first-episode patients, no application of antipsychotic drugs in history. Other psychoactive substances (in particular antidepressants) are allowed if last application is at least three months ago and total Duration did not exceed three months. Benzodiazepines are allowed.
  • For medically pretreated patients: at least one year pharmacotherapy with one of the following three substances: aripiprazole or quetiapine or risperidone. A medication break of - depending on the plasma level - two days (quetiapine) up to two weeks (aripiprazole) should be clinically defensible.
  • An informed consent is signed and personally dated by the patient. For patients with legal support in addition: signature of the legal supervisor.

Exclusion criteria for patients and subjects:

  • Hypersensitivity against apomorphine or a chemically similar substance or one of the components of the applied medication.
  • Participation in other clinical trials during or within six months prior to this clinical study.
  • Medical or psychological conditions which may endanger a proper performance of the clinical trial.
  • Physical disorders which interfere according to type and severity with the planned examinations, which could influence the parameter to be investigated or could compromise the subject during the examination procedure.
  • Inability to comply with the study protocol.
  • Limited or completely repealed legal capacity.
  • For female participants: positive pregnancy test on the day of the study inclusion or on the day of the PET/MR-measurement.
  • Acute suicidality or endangerment
  • Poor general condition.
  • Participation in a study using ionising Radiation within the last five years.
  • Alcohol abuse, alcohol dependence or addiction disease / abuse of dependence-inducing substances (excluding nicotine) in the history, additional exclusion criterion for healthy subjects: regular medication intake; within the last two weeks before PET/MR-measurement no drugs at all must be taken.

Additional exclusion criterion for patients: other than the approved axis I diagnosis according to DSM-5. An axis II diagnosis is not a criterion for exclusion

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03911726


Contacts
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Contact: Gerhard Gründer, Prof. Dr. +49621 1703-1900 gerhard.gruender@zi-mannheim.de
Contact: Xenia Hart +49621 1703-6061 xenia.hart@zi-mannheim.de

Locations
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Germany
Central Institute of Mental Health Recruiting
Mannheim, Baden-Württemberg, Germany, 68159
Contact: Gerhard Gründer, Prof. Dr.    +49621 1703-1900    gerhard.gruender@zi-mannheim.de   
Contact: Xenia Hart    +49621 1703-6061    xenia.hart@zi-mannheim.de   
Sponsors and Collaborators
Central Institute of Mental Health, Mannheim
Investigators
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Principal Investigator: Gerhard Gründer, Prof. Dr. Central Institute of Mental Health, Mannheim
More Information
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Responsible Party: Xenia Hart, Prof. Dr. Gerhard Gründer, Central Institute of Mental Health, Mannheim
ClinicalTrials.gov Identifier: NCT03911726    
Other Study ID Numbers: 2018-09-18
First Posted: April 11, 2019    Key Record Dates
Last Update Posted: February 24, 2021
Last Verified: February 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Xenia Hart, Central Institute of Mental Health, Mannheim:
PET/MR
Dopaminergic supersensitivity
D2/3 receptor availability
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders