This study aims to determine whether ventral striatal dopamine release is a mechanism of reward motivation in major depression, whether dopamine release is low in depression, and whether DA release and reward motivation predict response to dopamine-targeted treatment with pramipexole.

Better understanding of the basic neurobiology of mood dysfunction appears necessary to enable further progress in the treatment of depression. Reward motivation (and the closely related construct of "reward learning") is a core neurobehavioral domain.(1,2) In major depressive disorder (MDD), low reward motivation is a key aspect of anhedonia, a cardinal symptom of MDD, and is related to resistance to treatment.(2,3) Although much has been learned about reward motivation's neurobiology and relevance to psychopathology, important gaps in our knowledge have impeded the application of basic science findings to improving treatment of MDD. Reward motivation in healthy subjects involves ventrostriatal (VST) dopamine (DA)(4,5), and reduced reward motivation is linked to MDD and anhedonia.(3,6) These data suggest that VST DA dysfunction might be present in MDD and manifested clinically by anhedonia. While DA neuroreceptor imaging studies have failed to verify this, they have been methodologically compromised. Limitations include imaging methods with poor resolution of functional striatal subregions, MDD samples heterogeneous for antidepressant use, and use of self-report measures of anhedonia, rather than objective behavioral testing of the specific domain of reward motivation. This will be the first study of both VST DA release (by PET imaging) and reward motivation, and will include patients with MDD and healthy volunteers. Reward motivation will be captured and operationalized as reward learning in a probabilistic reward task (prior to imaging). This will clarify if VST DA dysfunction is linked to impaired motivation in MDD. To test clinical implications in MDD patients, we will assess the relationship of VST DA release, reward motivation, and anhedonia to outcome of subsequent open label treatment with the DA D2 receptor agonist pramipexole.

Inclusion Criteria:

• Weight between 44 kg and 115 kg
• Meets DSM-IV criteria for principal diagnosis of MDD, current major depressive episode, without psychotic features
• Score of >16 and <29 on 17-item Hamilton Rating Scale for Depression
• Psychotropic-naïve, as defined by lifetime <2 weeks treatment with antidepressants, anxiolytics or antipsychotics
• Able to tolerate a treatment-free period during study participation
• Able to provide informed consent

Exclusion Criteria:

• A principal diagnosis of any current Axis I psychiatric disorder other than the MDD
• Lifetime diagnosis of any psychotic disorder, bipolar disorder, mental retardation, attention deficit/hyperactivity disorder, or substance use disorders (including nicotine use disorders)
• Serious suicidal risk or history of violent behavior which would make participation in the protocol unsafe
• Any tobacco use in the prior three months (if not already excluded for abuse/dependence by #1)
• Illicit drug use in the prior three months, as evidenced by history or urine toxicology screen
• Women who are pregnant, nursing, postmenopausal, or using hormonal methods of birth control
• Women who are not using an effective birth control method or sexual abstinence during the ten days before the scan
• Any medical or neurological problem that might affect interpretation of findings or safety of participation (e.g., blood dyscrasias, lymphomas, hypersplenism, endocrinopathies, renal failure or chronic obstructive lung disease, malignancy, neurological diseases of the brain, history of seizures or head trauma), low hemoglobin (Hb < 12 gm/dL in males, Hb < 10.5 gm/dL in females))
• Blood donation within 4 weeks of study
• Metal implants or paramagnetic objects in the body that might affect safety of undergoing MRI (e.g., heart pacemaker, shrapnel, bullets, surgical prostheses or surgical clips), as determined in consultation with a neuroradiologist and according to the guidelines set forth in the reference: "Guide to MR procedures and metallic objects" Shellock; Lippincott Williams and Wilkins, NY, 2001
• More than one major risk factor for coronary artery disease (e.g. hyperlipidemia, sedentary lifestyle). Smokers are already excluded by #4 above, and diabetics by #8 above
• Systolic blood pressure > 140 or diastolic blood pressure > 90 based on at least two readings at rest
• History of untoward reaction to amphetamine or other stimulant medication, or pramipexole
• Any psychotropic treatment in the past 3 weeks (or depot medication in the past 6 months), except for lorazepam,which may be administered as needed prior to imaging day
• Current, past or anticipated exposure to radiation in the workplace, or participation in nuclear medicine procedures, including research protocols (In case of previous exposure to activity due to research studies, subjects will be eligible if all conditions listed below are fulfilled: 1) The injected dose and dosimetry of the radiotracer are known; 2) Except for research studies, the subject has not been exposed to radiation (workplace and medical); 3) Adding prior exposure to the exposure due to the study will result in a yearly cumulative exposure lower than the FDA limit for research studies
• Family history of schizophrenia in parents, siblings, or children
• Ongoing cognitive-behavioral or interpersonal psychotherapy for depression (Supportive therapy is not an exclusion)
• Ongoing treatment with cimetidine

Baseline information was collected for 26 patients with MDD and 25 HC control subjects. One HC subject signed consent but was withdrawn from the study before completing any assessments due to not matching well.

6 weeks

Information was collected on a side effect checklist, with each adverse event rated from 0 (absent) to 3 (severe). A subject was considered to have experienced a side effect during the study if the rating for that adverse event increased in severity at any point during the treatment.

Adverse events were not assessed for Healthy Controls, because by study design they did not receive any therapeutic intervention.