The Effects of Dopamine on Reward Processing

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.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder (MDD)
• Intervention / Treatment: Drug: amisulpride; Drug: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 159
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Belmont, Massachusetts, United States, 02478
      • McLean Hospital

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: MDD-amisulpride; Subjects experiencing a current episode of major depression who are randomized to receive amisulpride	Drug: amisulpride; single low-dose pharmacological challenge, 50 mg amisulpride; Other Names: Solian
Placebo Comparator: MDD-placebo; Subjects experiencing a current episode of major depression who are randomized to receive placebo	Drug: placebo; single-dose placebo capsule
Active Comparator: HC-amisulpride; Subjects having no history of mental disorder (healthy controls, HC) who are randomized to receive amisulpride	Drug: amisulpride; single low-dose pharmacological challenge, 50 mg amisulpride; Other Names: Solian
Placebo Comparator: HC-placebo; Subjects having no history of mental disorder who are randomized to receive placebo	Drug: placebo; single-dose placebo capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	administered after scan
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.	administered after scan
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.	Scan session
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.	Scan session
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.	Scan session
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.	During scan session
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.	During scan session
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.	During scan session

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	During scan session
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.	During scan session

Collaborators and Investigators

• Sponsor: Mclean Hospital
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Diego A Pizzagalli, PhD, McLean Hospital, Harvard University

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): May 1, 2016
• Study Completion (Actual): May 1, 2016

Study Registration Dates

• First Submitted: December 1, 2010
• First Submitted That Met QC Criteria: December 1, 2010
• First Posted (Estimate): December 3, 2010

Study Record Updates

• Last Update Posted (Actual): April 27, 2018
• Last Update Submitted That Met QC Criteria: April 25, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: MDD; Major Depressive Disorder; Amisulpride
• 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: 2010-P001568; R01MH068376 (U.S. NIH Grant/Contract)

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