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.

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.

Eligibility Criteria:
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