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

Primary Purpose

Schizophrenia

Status
Recruiting
Phase
Not Applicable
Locations
Germany
Study Type
Interventional
Intervention
Single PET/MR-measurement
Sponsored by
Central Institute of Mental Health, Mannheim
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Schizophrenia focused on measuring PET/MR, Dopaminergic supersensitivity, D2/3 receptor availability

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Central Institute of Mental HealthRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Experimental

Experimental

Arm Label

Healthy subjects

First-episode, drug-naive patients with schizophrenia

Pretreated chronically ill patients with schizophrenia

Arm Description

30 healthy subjects will undergo a single PET/MR-measurement.

20 first-episode, drug-naive patients with schizophrenia will undergo a single PET/MR-measurement.

90 pretreated chronically ill patients with schizophrenia will undergo a single PET/MR-measurement.

Outcomes

Primary Outcome Measures

Dopamine D2/D3-receptor availability
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

D2/D3-receptor availability in first-episode, drug-naive patients with schizophrenia
In first-episode, drug-naive patients with schizophrenia expressions of NSS and AIMS correlate significantly with striatal D2/D3-receptor availability.
D2/D3-receptor availability in patients with TD
In pretreated, chronically ill patients with schizophrenia, patients with TD show a significantly higher D2/D3-receptor availability than patients without TD.
Follow-up of pretreated, chronically ill patients with schizophrenia
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.

Full Information

First Posted
April 9, 2019
Last Updated
July 12, 2022
Sponsor
Central Institute of Mental Health, Mannheim
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1. Study Identification

Unique Protocol Identification Number
NCT03911726
Brief Title
Do Antipsychotic Agents Induce Supersensitivity in Humans: A Combined PET/MRI Study in Patients With Schizophrenia
Official Title
Do Antipsychotic Agents Induce Supersensitivity in Humans: A Combined PET/MRI Study in Patients With Schizophrenia
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 1, 2020 (Actual)
Primary Completion Date
July 1, 2023 (Anticipated)
Study Completion Date
July 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Central Institute of Mental Health, Mannheim

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Schizophrenia
Keywords
PET/MR, Dopaminergic supersensitivity, D2/3 receptor availability

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
All study participants will undergo a single PET/MR-measurement.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
140 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Healthy subjects
Arm Type
Other
Arm Description
30 healthy subjects will undergo a single PET/MR-measurement.
Arm Title
First-episode, drug-naive patients with schizophrenia
Arm Type
Experimental
Arm Description
20 first-episode, drug-naive patients with schizophrenia will undergo a single PET/MR-measurement.
Arm Title
Pretreated chronically ill patients with schizophrenia
Arm Type
Experimental
Arm Description
90 pretreated chronically ill patients with schizophrenia will undergo a single PET/MR-measurement.
Intervention Type
Radiation
Intervention Name(s)
Single PET/MR-measurement
Intervention Description
A single PET/MR-measurement using [18F]Fallypride with a duration of 180min. Within this measurement, the dopamine receptor agonist apomorphine is applicated.
Primary Outcome Measure Information:
Title
Dopamine D2/D3-receptor availability
Description
Dopamine D2/D3-receptor availability measured as binding potential (BP) using PET and blood-oxygen-level-dependant (BOLD)-response measured with fMRI.
Time Frame
180 minutes
Secondary Outcome Measure Information:
Title
D2/D3-receptor availability in first-episode, drug-naive patients with schizophrenia
Description
In first-episode, drug-naive patients with schizophrenia expressions of NSS and AIMS correlate significantly with striatal D2/D3-receptor availability.
Time Frame
180 minutes
Title
D2/D3-receptor availability in patients with TD
Description
In pretreated, chronically ill patients with schizophrenia, patients with TD show a significantly higher D2/D3-receptor availability than patients without TD.
Time Frame
180 minutes
Title
Follow-up of pretreated, chronically ill patients with schizophrenia
Description
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.
Time Frame
two years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gerhard Gründer, Prof. Dr.
Phone
+49621 1703-1900
Email
gerhard.gruender@zi-mannheim.de
First Name & Middle Initial & Last Name or Official Title & Degree
Xenia Hart
Phone
+49621 1703-6061
Email
xenia.hart@zi-mannheim.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gerhard Gründer, Prof. Dr.
Organizational Affiliation
Central Institute of Mental Health, Mannheim
Official's Role
Principal Investigator
Facility Information:
Facility Name
Central Institute of Mental Health
City
Mannheim
State/Province
Baden-Württemberg
ZIP/Postal Code
68159
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gerhard Gründer, Prof. Dr.
Phone
+49621 1703-1900
Email
gerhard.gruender@zi-mannheim.de
First Name & Middle Initial & Last Name & Degree
Xenia Hart
Phone
+49621 1703-6061
Email
xenia.hart@zi-mannheim.de

12. IPD Sharing Statement

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

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