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The Effects of Dopamine on Reward Processing

Primary Purpose

Major Depressive Disorder (MDD)

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
amisulpride
placebo
Sponsored by
Mclean Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Major Depressive Disorder (MDD) focused on measuring MDD, Major Depressive Disorder, Amisulpride

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Inclusion Criteria for subjects with Major Depressive Disorder (MDD):

    1. Diagnostic and Statistical Manual of Mental Disorders (DSM IV) diagnostic criteria for MDD, diagnosed with the use of the Structured Clinical Interview for DSM Disorders (SCID);
    2. Written informed consent;
    3. Both genders and all ethnic origins, age between 18 and 45;
    4. A baseline score > 16 on the Hamilton Rating Scale for Depression (HRSD) 17-item version;
    5. Right-handed.
    6. Absence of any psychotropic medications for at least 2 weeks:

      • 6 weeks for fluoxetine,
      • 6 months for neuroleptics,
      • 2 weeks for benzodiazepines,
      • 2 weeks for any other antidepressants.

Inclusion Criteria for Control Subjects:

  1. Absence of medical, neurological, and psychiatric illness (including alcohol and substance abuse), as assessed by subject history and a structured clinical interview (SCID-I/NP);
  2. Written informed consent;
  3. Both genders and all ethnic origins, age between 18 and 45;
  4. Right-handed;
  5. Absence of any medications for at least 3 weeks;
  6. Absence of pregnancy.

Exclusion Criteria:

  • Exclusion Criteria for All Subjects:

    1. Subjects with suicidal ideation where outpatient treatment is determined unsafe by the study clinician. These patients will be immediately referred to appropriate clinical treatment;
    2. Pregnant women or women of childbearing potential who are not using a medically accepted means of contraception (defined as oral contraceptive pill or implant, condom, diaphragm, spermicide, intrauterine device, s/p tubal ligation, or partner with vasectomy);
    3. Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurological or hematologic disease;
    4. Lifetime history of seizure disorder;
    5. Lifetime history or current diagnosis of any of the following DSM-IV psychiatric illnesses: organic mental disorder, schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, bipolar disorder, patients with mood congruent or mood incongruent psychotic features, substance dependence, substance abuse within the last 12 months (with the exception of alcohol abuse within the last 12 months, which is permissible for MDD subjects); eating disorders, post-traumatic stress disorder (lifetime PTSD is exclusionary for control subjects, PTSD within the last 24 months is exclusionary for MDD subjects); simple phobia, social anxiety disorder and generalized anxiety disorders will be allowed only if secondary to MDD;
    6. More than five instances of lifetime cocaine or stimulant use (e.g., amphetamine, cocaine, methamphetamine);
    7. Use of dopaminergic drugs (including methylphenidate) within the last 6 months;
    8. Lifetime history or current diagnosis of dementia, or a score of < 26 on the Mini Mental Status Examination at the screening visit;
    9. Lifetime history of adverse drug reactions or allergy to the study drug (amisulpride);
    10. Patients with mood congruent or mood incongruent psychotic features;
    11. Current use of other psychotropic drugs;
    12. Clinical or laboratory evidence of hypothyroidism;
    13. Patients with a lifetime history of electroconvulsive therapy (ECT);
    14. Patients with renal insufficiency;
    15. Failure to meet standard MRI safety requirements
    16. Electrolytes, blood urea nitrogen, creatinine: outside the normal range (also ruling out renal insufficiency);
    17. Liver function tests above 1.5 times the upper normal;
    18. Corrected QT interval (QTc) interval in EKG above 450 ms or EKG indicative of arrhythmia or cardiac conduction abnormalities;
    19. Diabetes with poor glucose control;
    20. Cardiac disease, bradycardia less than 55 bpm, hypokalemia, congenital prolongation of QT interval or on-going treatment with a medication likely to induce one of these conditions.
    21. Currently in cognitive-behavioral therapy

Sites / Locations

  • McLean Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Arm Label

MDD-amisulpride

MDD-placebo

HC-amisulpride

HC-placebo

Arm Description

Subjects experiencing a current episode of major depression who are randomized to receive amisulpride

Subjects experiencing a current episode of major depression who are randomized to receive placebo

Subjects having no history of mental disorder (healthy controls, HC) who are randomized to receive amisulpride

Subjects having no history of mental disorder who are randomized to receive placebo

Outcomes

Primary Outcome Measures

Effect on PST Reward Learning
This statistic shows the effect (beta) that the combination of diagnosis and drug has on the ability to learn from rewards during a Probabilistic Selection Task (PST). A higher effect size indicates greater ability to learn from reward trials.
Effect on PST Penalty Learning
This statistic shows the effect (beta) that the combination of diagnosis and drug has on the ability to learn from penalties during a Probabilistic Selection Task (PST). A higher effect size indicates greater ability to learn from penalty trials.
Effect on Caudate Response to Cues
This statistic shows the effect (beta) that the combination of diagnosis and drug has on caudate activation after presentation of a cue. Positive values indicate an increase in activation relative to baseline.
Effect on NAcc Response to Cues
This statistic shows the effect (beta) that the combination of diagnosis and drug has on nucleus accumbens (NAcc) activation after presentation of a cue. Positive values indicate an increase in activation relative to baseline.
Putamen Response to Cues
This statistic shows the effect (beta) that the combination of diagnosis and drug has on putamen activation after presentation of a cue. Positive values indicate an increase in activation relative to baseline.
Effect on Caudate Response to Reward
This statistic shows the effect (beta) that the combination of diagnosis and drug has on caudate activation after Reward outcomes. Positive values indicate an increase in activation relative to baseline.
Effect on NAcc Response to Reward
This statistic shows the effect (beta) that the combination of diagnosis and drug has on nucleus accumbens (NAcc) activation after reward outcomes. Positive values indicate an increase in activation relative to baseline.
Effect on Putamen Response to Reward
This statistic shows the effect (beta) that the combination of diagnosis and drug has on putamen activation (beta) after reward outcomes. Positive values indicate an increase in activation relative to baseline.

Secondary Outcome Measures

Effect on Caudate-dACC Connectivity After Reward
This statistic shows the effect (beta) that the combination of diagnosis and drug has on functional connectivity between caudate and dorsal anterior cingulate cortex (dACC) in response to reward outcomes
Effect on NAcc-MCC Connectivity After Reward
This statistic shows the effect (beta) that the combination of diagnosis and drug has on functional connectivity between nucleus accumbens (NAcc) and mid-cingulate cortex (MCC) in response to reward outcomes.

Full Information

First Posted
December 1, 2010
Last Updated
April 25, 2018
Sponsor
Mclean Hospital
Collaborators
National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT01253421
Brief Title
The Effects of Dopamine on Reward Processing
Official Title
The Effects of Dopamine on Reward Processing
Study Type
Interventional

2. Study Status

Record Verification Date
April 2018
Overall Recruitment Status
Completed
Study Start Date
February 2012 (undefined)
Primary Completion Date
May 2016 (Actual)
Study Completion Date
May 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Mclean Hospital
Collaborators
National Institute of Mental Health (NIMH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to evaluate the effects of a single low dose of the D2/D3 antagonist amisulpride on reward processing. More generally, this study will test the role of dopamine (a naturally occurring brain chemical) in depression. Hypotheses: Administration of a single low dose of the D2/D3 antagonist amisulpride will (1) improve performance in a behavioral task assessing learning from feedback and (2) boost activation in reward-related brain regions.
Detailed Description
Through an integration of a functional magnetic resonance imaging (fMRI) approach coupled with a pharmacological challenge, the goal of the current study will be to investigate the role of dopamine in MDD. Participants in this research will include 36 MDD subjects and 36 demographically matched healthy participants recruited from the community by Dr. Pizzagalli's laboratory at McLean Hospital's Center for Depression, Anxiety and Stress Research. This study will include two sessions: The first session will involve a diagnostic interview, and a series of questionnaires and assessments. The second session will take place at the McLean Hospital's Neuroimaging Center, and include the administration of a low-dose of amisulpride (50 mg capsule) or placebo, followed by an fMRI brain scan and administration of two behavioral tasks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder (MDD)
Keywords
MDD, Major Depressive Disorder, Amisulpride

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
There were two groups of subjects: currently experiencing a major depressive episode, or normal health controls. The groups were matched for age, gender, and race. Within each group, half of the subjects were assigned to receive the study drug (amisulpride) and half to receive a placebo.
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
159 (Actual)

8. Arms, Groups, and Interventions

Arm Title
MDD-amisulpride
Arm Type
Active Comparator
Arm Description
Subjects experiencing a current episode of major depression who are randomized to receive amisulpride
Arm Title
MDD-placebo
Arm Type
Placebo Comparator
Arm Description
Subjects experiencing a current episode of major depression who are randomized to receive placebo
Arm Title
HC-amisulpride
Arm Type
Active Comparator
Arm Description
Subjects having no history of mental disorder (healthy controls, HC) who are randomized to receive amisulpride
Arm Title
HC-placebo
Arm Type
Placebo Comparator
Arm Description
Subjects having no history of mental disorder who are randomized to receive placebo
Intervention Type
Drug
Intervention Name(s)
amisulpride
Other Intervention Name(s)
Solian
Intervention Description
single low-dose pharmacological challenge, 50 mg amisulpride
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
single-dose placebo capsule
Primary Outcome Measure Information:
Title
Effect on PST Reward Learning
Description
This statistic shows the effect (beta) that the combination of diagnosis and drug has on the ability to learn from rewards during a Probabilistic Selection Task (PST). A higher effect size indicates greater ability to learn from reward trials.
Time Frame
administered after scan
Title
Effect on PST Penalty Learning
Description
This statistic shows the effect (beta) that the combination of diagnosis and drug has on the ability to learn from penalties during a Probabilistic Selection Task (PST). A higher effect size indicates greater ability to learn from penalty trials.
Time Frame
administered after scan
Title
Effect on Caudate Response to Cues
Description
This statistic shows the effect (beta) that the combination of diagnosis and drug has on caudate activation after presentation of a cue. Positive values indicate an increase in activation relative to baseline.
Time Frame
Scan session
Title
Effect on NAcc Response to Cues
Description
This statistic shows the effect (beta) that the combination of diagnosis and drug has on nucleus accumbens (NAcc) activation after presentation of a cue. Positive values indicate an increase in activation relative to baseline.
Time Frame
Scan session
Title
Putamen Response to Cues
Description
This statistic shows the effect (beta) that the combination of diagnosis and drug has on putamen activation after presentation of a cue. Positive values indicate an increase in activation relative to baseline.
Time Frame
Scan session
Title
Effect on Caudate Response to Reward
Description
This statistic shows the effect (beta) that the combination of diagnosis and drug has on caudate activation after Reward outcomes. Positive values indicate an increase in activation relative to baseline.
Time Frame
During scan session
Title
Effect on NAcc Response to Reward
Description
This statistic shows the effect (beta) that the combination of diagnosis and drug has on nucleus accumbens (NAcc) activation after reward outcomes. Positive values indicate an increase in activation relative to baseline.
Time Frame
During scan session
Title
Effect on Putamen Response to Reward
Description
This statistic shows the effect (beta) that the combination of diagnosis and drug has on putamen activation (beta) after reward outcomes. Positive values indicate an increase in activation relative to baseline.
Time Frame
During scan session
Secondary Outcome Measure Information:
Title
Effect on Caudate-dACC Connectivity After Reward
Description
This statistic shows the effect (beta) that the combination of diagnosis and drug has on functional connectivity between caudate and dorsal anterior cingulate cortex (dACC) in response to reward outcomes
Time Frame
During scan session
Title
Effect on NAcc-MCC Connectivity After Reward
Description
This statistic shows the effect (beta) that the combination of diagnosis and drug has on functional connectivity between nucleus accumbens (NAcc) and mid-cingulate cortex (MCC) in response to reward outcomes.
Time Frame
During scan session

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Inclusion Criteria for subjects with Major Depressive Disorder (MDD): Diagnostic and Statistical Manual of Mental Disorders (DSM IV) diagnostic criteria for MDD, diagnosed with the use of the Structured Clinical Interview for DSM Disorders (SCID); Written informed consent; Both genders and all ethnic origins, age between 18 and 45; A baseline score > 16 on the Hamilton Rating Scale for Depression (HRSD) 17-item version; Right-handed. Absence of any psychotropic medications for at least 2 weeks: 6 weeks for fluoxetine, 6 months for neuroleptics, 2 weeks for benzodiazepines, 2 weeks for any other antidepressants. Inclusion Criteria for Control Subjects: Absence of medical, neurological, and psychiatric illness (including alcohol and substance abuse), as assessed by subject history and a structured clinical interview (SCID-I/NP); Written informed consent; Both genders and all ethnic origins, age between 18 and 45; Right-handed; Absence of any medications for at least 3 weeks; Absence of pregnancy. Exclusion Criteria: Exclusion Criteria for All Subjects: Subjects with suicidal ideation where outpatient treatment is determined unsafe by the study clinician. These patients will be immediately referred to appropriate clinical treatment; Pregnant women or women of childbearing potential who are not using a medically accepted means of contraception (defined as oral contraceptive pill or implant, condom, diaphragm, spermicide, intrauterine device, s/p tubal ligation, or partner with vasectomy); Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurological or hematologic disease; Lifetime history of seizure disorder; Lifetime history or current diagnosis of any of the following DSM-IV psychiatric illnesses: organic mental disorder, schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, bipolar disorder, patients with mood congruent or mood incongruent psychotic features, substance dependence, substance abuse within the last 12 months (with the exception of alcohol abuse within the last 12 months, which is permissible for MDD subjects); eating disorders, post-traumatic stress disorder (lifetime PTSD is exclusionary for control subjects, PTSD within the last 24 months is exclusionary for MDD subjects); simple phobia, social anxiety disorder and generalized anxiety disorders will be allowed only if secondary to MDD; More than five instances of lifetime cocaine or stimulant use (e.g., amphetamine, cocaine, methamphetamine); Use of dopaminergic drugs (including methylphenidate) within the last 6 months; Lifetime history or current diagnosis of dementia, or a score of < 26 on the Mini Mental Status Examination at the screening visit; Lifetime history of adverse drug reactions or allergy to the study drug (amisulpride); Patients with mood congruent or mood incongruent psychotic features; Current use of other psychotropic drugs; Clinical or laboratory evidence of hypothyroidism; Patients with a lifetime history of electroconvulsive therapy (ECT); Patients with renal insufficiency; Failure to meet standard MRI safety requirements Electrolytes, blood urea nitrogen, creatinine: outside the normal range (also ruling out renal insufficiency); Liver function tests above 1.5 times the upper normal; Corrected QT interval (QTc) interval in EKG above 450 ms or EKG indicative of arrhythmia or cardiac conduction abnormalities; Diabetes with poor glucose control; Cardiac disease, bradycardia less than 55 bpm, hypokalemia, congenital prolongation of QT interval or on-going treatment with a medication likely to induce one of these conditions. Currently in cognitive-behavioral therapy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Diego A Pizzagalli, PhD
Organizational Affiliation
McLean Hospital, Harvard University
Official's Role
Principal Investigator
Facility Information:
Facility Name
McLean Hospital
City
Belmont
State/Province
Massachusetts
ZIP/Postal Code
02478
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
27771973
Citation
Admon R, Kaiser RH, Dillon DG, Beltzer M, Goer F, Olson DP, Vitaliano G, Pizzagalli DA. Dopaminergic Enhancement of Striatal Response to Reward in Major Depression. Am J Psychiatry. 2017 Apr 1;174(4):378-386. doi: 10.1176/appi.ajp.2016.16010111. Epub 2016 Oct 24.
Results Reference
background
PubMed Identifier
31784354
Citation
Liu Y, Admon R, Mellem MS, Belleau EL, Kaiser RH, Clegg R, Beltzer M, Goer F, Vitaliano G, Ahammad P, Pizzagalli DA. Machine Learning Identifies Large-Scale Reward-Related Activity Modulated by Dopaminergic Enhancement in Major Depression. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Feb;5(2):163-172. doi: 10.1016/j.bpsc.2019.10.002. Epub 2019 Oct 22.
Results Reference
derived

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The Effects of Dopamine on Reward Processing

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