Imaging Dopamine Release in Depression

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