The Effects of Dopamine on Reward Processing

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.

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