The overall aim of this study is to utilize an integrative research model in order to dynamically assess reward-related dopamine (DA) transmission in major depressive disorder (MDD) and test the role of dysfunctional DA release in depression and anhedonia.

The first arm of this line of research (PET scan) aims to investigate phasic DA release in MDD during incentive motivation. The investigators will utilize an established molecular imaging technique to measure striatal DA release dynamically during performance of testing and control versions of a monetary incentive delay task, which involves anticipation and receipt of monetary rewards. In doing so, this experiment will link together independent lines of research that have associated depression with decreased hedonic responsiveness, impaired reinforcement learning and dysfunctional DA transmission. We hypothesize that, relative to matched controls, unmedicated MDD subjects will show reduced reward-related ligand (11C-raclopride) displacement. Reduced ligand displacement will be interpreted as indicating reduced task-induced release of endogenous striatal DA in response to reward-predicting cues and unpredictable reward in MDD subjects.

In the second arm of this research (EEG recording), the investigators aim to probe the spatio-temporal dynamics of brain mechanisms underlying positive and negative reinforcement learning in MDD and their relations to phasic DA. Participants will perform the probabilistic stimulus selection task (PSST) while event-related potentials (ERPs) are collected. The investigators expect that, relative to matched controls, unmedicated MDD subjects will show reduced positive reinforcement learning, potentiated negative reinforcement learning, and larger (i.e., more negative) feedback-related negativity (FRN) in response to positive reinforcement (indicative of reduced DA transmission). Moreover, the investigators hypothesize that a more negative FRN in response to positive reinforcement will be associated with decreased striatal raclopride displacement (i.e., lower release of endogenous DA) as measured by PET in the first part of the study. This experiment will investigate the effects of blunted DA transmission on behavioral and ERP markers of both positive and negative reinforcement learning.

Inclusion Criteria:

• Both genders and all ethnic origins, age between 18 and 45;
• Written informed consent;
• Right-handed (Chapman and Chapman 1987);
• Absence of serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease;
• Absence of history of seizure disorder;
• Absence of history of 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 cocaine or stimulant abuse; which will lead to exclusion), as assessed by subject history and a structured clinical interview (SCID-I/NP);
• Absence of history of cocaine or stimulant use (e.g., amphetamine, cocaine, methamphetamine);
• Absence of history of use of dopaminergic drugs (including methylphenidate);
• Absence of current use of other psychotropic drugs
• Absence of substance dependence or substance abuse in the last 12 months;
• Absence of history or current diagnosis of dementia, or a score greater than 26 on the Mini Mental Status Examination (Folstein, 1975) at the screening visit;
• Absence of clinical or laboratory evidence of hypothyroidism;
• Absence of neurological illness

Specific exclusion criteria for PET scan are as follows:

• Pregnant women, women trying to get pregnant, or women of childbearing potential who are not using a medically accepted means of contraception (defined as implant, condom, diaphragm, spermicide, IUD, s/p tubal ligation, partner with vasectomy).
• Failure to meet standard PET safety requirements.

Specific inclusion criteria for depressed participants are as follows:

• DSM-IV diagnostic criteria for MDD melancholia subtype (diagnosed with the use of the SCID) or MDD with anhedonia (score of 3 or greater on the Snaith-Hamilton Pleasure Scale (SHPS));
• A baseline HRSD score (Hamilton 1960) greater than or equal to 16 (17-item version);
• Absence of suicidal ideation where outpatient treatment is determined unsafe by the study clinician. These patients will be immediately referred to appropriate clinical treatment;
• Absence of past or current mood congruent or incongruent psychotic features;
• Absence of lifetime history of electroconvulsive therapy (ECT)
• Subjects taking antidepressants at the time of their screening visit will be enrolled only if they are willing (after discussing with their prescribing clinician), and the study clinician determines that it is clinically appropriate for them to discontinue their current antidepressant for a period greater than five half-lives of their current medication (but no longer than 7 days). For these subjects, the baseline visit and the first physiology session will only occur after the 7 day interval has passed.

Specific inclusion criteria for control participants are as follows:

• Absence of any psychiatric illness (including alcohol and substance abuse), as assessed by subject history and a structured clinical interview (SCID-I/NP).
• Absence of any medication for at least three weeks.

Individuals with Major Depressive Disorder and Healthy Controls