Effects of a Single Dose of Amisulpride on Functional Brain Changes

Sponsor

Simone Grimm (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05347199

Collaborator

Charité Research Organisation GmbH (Other), Boehringer Ingelheim (Industry)

120

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Amisulpride Pill Drug: Placebo	Phase 1

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 Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

May 1, 2022

Anticipated Primary Completion Date :

Oct 1, 2023

Anticipated Study Completion Date :

Oct 1, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

BOLD fMRI parameter estimates [during MID task at treatment day 1]
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)

Other Outcome Measures

Exploratory endpoint: average %BOLD signal change and 90th percentile thereof within ROIs during SID [during SID task at treatment day 2]
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
Exploratory endpoint: average %BOLD signal change and 90th percentile thereof within ROIs during intstrumental learning task [during instrumental learning task at treatment day 1]
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
Exploratory endpoint: average %BOLD signal change and 90th percentile thereof within ROIs during effort-based decision making task [during effort-based decision making task at treatment day 2]
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
Exploratory endpoint: reaction times in ms [during all tasks at treatment day 1 and day 2]
Reaction times in ms extracted from the in- scanner protocol log files
Exploratory endpoint: response accuracy in percent [during all tasks at treatment day 1 and day 2]
Estimates of response accuracy extracted from the in- scanner protocol log files
Exploratory endpoint:average %BOLD signal change and 90th percentile thereof within ROIs during resting state [during resting state at treatment day 1]
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)
Exploratory endpoint: Arterial Spin Labeling (ASL) [during asl at treatment day 1]
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
Exploratory endpoint (Correlation between BOLD signal and self-reported anhedonia ) [treatment day 1 and treatment day 2]
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
Exploratory endpoint (Correlation between BOLD signal and behavioral measures) [treatment day 1 and treatment day 2]
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
Exploratory endpoint (Correlation between functional connectivity and self-reported anhedonia) [treatment day 1 and treatment day 2]
Correlation between resting state functional connectivity and self- reported anhedonia after amisulpride administration as compared to placebo in MDD patients relative to HV
Exploratory endpoint (Correlation between functional connectivity and behavioral measures) [treatment day 1 and treatment day 2]
Correlation between resting state functional connectivity and behavioral measures after amisulpride administration as compared to placebo in MDD patients relative to HV
Exploratory endpoint (Change in plasma levels of amisulpride) [treatment day 1 and treatment day 2]
Changes in plasma levels of amisulpride including correlation to changes in BOLD signal in MDD patients relative to HV
Exploratory endpoint (Change in whole brain BOLD signal) [treatment day 1 and treatment day 2]
Changes in whole brain BOLD signal after amisulpride administration as compared to placebo in MDD patients relative to HV

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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.