Effects of a Single Dose of Amisulpride on Functional Brain Changes

Effects of a Single Dose of Amisulpride on Functional Brain Changes During Reward- and Motivation-related Processing

This study is designed to investigate effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing and at rest in healthy volunteers (HV) and in patients with Major Depressive Disorder (MDD).

Study Overview

• Status: Not yet recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Placebo; Drug: Amisulpride Pill

Detailed Description

Double blind, placebo-controlled, randomized, single dose, parallel-group design The study is designed to investigate effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing and at rest. Measurement of functional brain changes will occur after a single dose of amisulpride or placebo in HV and patients with MDD. It is hypothesized that functional brain changes previously linked to reward- and motivation-related processing require dopaminergic signaling and are diminished in MDD compared to HV. In MDD, but not in HV, treatment with a single low dose (100 mg) amisulpride should increase brain activation associated with reward- and motivation-related processing. To test these hypotheses, we will implement a randomized, placebo-controlled, parallel- group design with 4 treatment arms (MDD/placebo, MDD/amisulpride, HV/placebo and HV/ amisulpride). All subjects will undergo MRI scanning sessions at Visit 3 and Visit 4. Treatment with amisulpride or matching placebo will occur 3.5 to 4 hours before the start of each scanning session. Time of treatment will be standardized across subjects.

At Visit 3 and Visit 4, blood samples will be taken 30 minutes pre-dose, and 1 hour, 3.5 to 4 hours, and 4.5 to 5 hours after oral drug administration to determine target plasma levels of amisulpride.

The study is composed of 4 outpatient visits: Screening, baseline and 2 scanning sessions.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Simone Grimm, Prof. Dr. PhD; Phone Number: +49 30 7668375 814; Email: simone.grimm@medicalschool-berlin.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

MDD Patients:

Inclusion:

• Male and female patients with MDD; aged 18 to 45 years
• Montgomery-Åsberg Depression Rating Scale (MADRS) score > 7 and <26 at screening.

Exclusion:

• Meeting diagnostic criteria for any major psychiatric disorder (other than MDD), as determined by DSM-5 at screening.
• Having received prescribed medication (including antidepressants (AD)) within 14 days or fluoxetine within 90 days prior to Visit 3 (apart from the contraceptive pill).
• Having received psychotherapy within 14 days prior to Visit 3.
• Positive severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) test.

Healthy Volunteers:

Inclusion:

• Healthy
• aged 18 to 45 years

Exclusion:

• Meeting diagnostic criteria for any major psychiatric disorder.
• A history of psychiatric or neurologic disorders.
• Having received prescribed medication within 14 days prior to Visit 3 (apart from the contraceptive pill).
• Positive SARS-CoV-2 test.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Healthy Volunteers Placebo; placebo pill at two time points	Drug: Placebo; two doses, orally
Active Comparator: Healthy Volunteers Amisulpride; amisulpride pill at two time points	Drug: Amisulpride Pill; Two single low doses amisulpride (100 mg); orally
Active Comparator: MDD Patients Placebo; placebo pill at two time points	Drug: Placebo; two doses, orally
Experimental: MDD Patients Amisulpride; amisulpride pill at two time points	Drug: Amisulpride Pill; Two single low doses amisulpride (100 mg); orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BOLD fMRI parameter estimates	Blood oxygen level dependent (BOLD) fMRI parameter estimates (ß-weights within the GLM analysis) will be extracted from task-related regions of interest (average %BOLD signal change and 90th percentile thereof within ROIs) under the following task-specific contrasts: Monetary Incentive Delay (MID) task: Contrast of 'High-gain'vs. 'No-gain' condition during the task CUE period ROIs ventral striatum (including nucleus accumbens)	during MID task at treatment day 1

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory endpoint: average %BOLD signal change and 90th percentile thereof within ROIs during SID	Blood oxygen level dependent (BOLD) fMRI parameter estimates (ß-weights within the GLM analysis) will be extracted from task-related regions of interest (average %BOLD signal change and 90th percentile thereof within ROIs) under the following task-specific contrasts: Social Incentive Delay (SID) task: Contrast of 'High-gain' vs. 'No-gain' condition during the task CUE period ROIs: ventral striatum (including nucelues accumbens), ventral tegmental area, dorsal anterior cingulate cortex, insula, ventromedial prefrontal cortex/ orbitofrontal cortex and ventral pallidum	during SID task at treatment day 2
Exploratory endpoint: average %BOLD signal change and 90th percentile thereof within ROIs during intstrumental learning task	Blood oxygen level dependent (BOLD) fMRI parameter estimates (ß-weights within the GLM analysis) will be extracted from task-related regions of interest (average %BOLD signal change and 90th percentile thereof within ROIs) under the following task-specific contrasts: Instrumental Learning task: Contrast of the Gain-cue vs. neutral cue conditions during the task cue and feedback periods ROIs: ventral striatum (including nucelues accumbens), ventral tegmental area, dorsal anterior cingulate cortex, insula, ventromedial prefrontal cortex/ orbitofrontal cortex and ventral pallidum	during instrumental learning task at treatment day 1
Exploratory endpoint: average %BOLD signal change and 90th percentile thereof within ROIs during effort-based decision making task	Blood oxygen level dependent (BOLD) fMRI parameter estimates (ß-weights within the GLM analysis) will be extracted from task-related regions of interest (average %BOLD signal change and 90th percentile thereof within ROIs) under the following task-specific contrasts: Effort-based Decision Making task: Contrast of the High reward vs. Low reward conditions during the task CUE2 period Contrast of the High effort vs. Low effort conditions during the task CUE2 period ROIs: ventral striatum (including nucelues accumbens), ventral tegmental area, dorsal anterior cingulate cortex, insula, ventromedial prefrontal cortex/ orbitofrontal cortex and ventral pallidum	during effort-based decision making task at treatment day 2
Exploratory endpoint: reaction times in ms	Reaction times in ms extracted from the in- scanner protocol log files	during all tasks at treatment day 1 and day 2
Exploratory endpoint: response accuracy in percent	Estimates of response accuracy extracted from the in- scanner protocol log files	during all tasks at treatment day 1 and day 2
Exploratory endpoint:average %BOLD signal change and 90th percentile thereof within ROIs during resting state	Blood oxygen level dependent (BOLD) fMRI signal magnitude and BOLD signal standard deviation during Resting State within the following a-priori defined regions: Default Mode Network (posterior cingulate, vmPFC and medial temporal lobe), Central Executive Network (dorsolateral prefrontal cortex, premotor cortex, precuneus), and Salience Network Network (amygdala, insula and dorsal anterior cingulate)	during resting state at treatment day 1
Exploratory endpoint: Arterial Spin Labeling (ASL)	Changes in relative and absolute cerebral blood flow measured through Arterial Spin Labelling MR in whole brain and in the following brain regions: (bilateral): ventral striatum, ventromedial prefrontal cortex/ orbitofrontal cortex, ventral tegmental area, dorsal anterior cingulate cortex, insula, and ventral pallidum after amisulpride administration	during asl at treatment day 1
Exploratory endpoint (Correlation between BOLD signal and self-reported anhedonia )	Correlation between magnitude of BOLD signal during reward-and motivation-related processing and self-reported anhedonia after amisulpride administration as compared to placebo in MDD patients relative to HV	treatment day 1 and treatment day 2
Exploratory endpoint (Correlation between BOLD signal and behavioral measures)	Correlation between magnitude of BOLD signal during reward-and motivation-related processing and behavioral measures after amisulpride administration as compared to placebo in MDD patients relative to HV	treatment day 1 and treatment day 2
Exploratory endpoint (Correlation between functional connectivity and self-reported anhedonia)	Correlation between resting state functional connectivity and self- reported anhedonia after amisulpride administration as compared to placebo in MDD patients relative to HV	treatment day 1 and treatment day 2
Exploratory endpoint (Correlation between functional connectivity and behavioral measures)	Correlation between resting state functional connectivity and behavioral measures after amisulpride administration as compared to placebo in MDD patients relative to HV	treatment day 1 and treatment day 2
Exploratory endpoint (Change in plasma levels of amisulpride)	Changes in plasma levels of amisulpride including correlation to changes in BOLD signal in MDD patients relative to HV	treatment day 1 and treatment day 2
Exploratory endpoint (Change in whole brain BOLD signal)	Changes in whole brain BOLD signal after amisulpride administration as compared to placebo in MDD patients relative to HV	treatment day 1 and treatment day 2

Collaborators and Investigators

• Sponsor: Simone Grimm
• Collaborators: Boehringer Ingelheim; Charité Research Organisation GmbH
• Investigators: Principal Investigator: Christian Keicher, Dr. med., Charite University, Berlin, Germany

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2022
• Primary Completion (Anticipated): October 1, 2023
• Study Completion (Anticipated): October 1, 2023

Study Registration Dates

• First Submitted: April 12, 2022
• First Submitted That Met QC Criteria: April 20, 2022
• First Posted (Actual): April 26, 2022

Study Record Updates

• Last Update Posted (Actual): May 2, 2022
• Last Update Submitted That Met QC Criteria: April 26, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Major Depressive Disorder; Amisulpride; Functional Brain Changes; BOLD responses
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Dopamine Agents; Dopamine Antagonists; Antidepressive Agents, Second-Generation; Amisulpride
• Other Study ID Numbers: MSB-C002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No