Patient description: A 20 yo female college student with no significant past medical history presents with a chief complaint of fatigue. She reports increased sleep and appetite over the past few months as well as difficulty concentrating on her schoolwork. She no longer enjoys spending time with her friends and feels guilty for not spending more time with her family. Her physical exam and laboratory tests, including hemoglobin, hematocrit and thyroid stimulating hormone, are within normal limits.

Clinical trial eligibility criteria: eligible ages (years): 18.0-60.0,  Mood Disorder Bipolar Disorder Depression MDD Seventy subjects (ages 18 to 60) with MDD will be selected who additionally meet for one of 3 subgroups A) MDD, Currently depressed with FPDD, as defined by DSM-IV for recurrent MDD, currently in a major depressive episode, who have a first degree relative with MDD but no first degree relatives with mania, alcoholism, or antisocial personality disorder B) MDD, Currently in remission with a history of FPDD, defined as a period of at least six months with no more than one clinically significant symptom, and during which time subjects were not taking an AD agent. Subjects will thus meet the historical for recurrent MDD (DSM-IV). We will also require that subjects previously had a least one antidepressant drug trial, to ensure that the severity of previous episodes warranted treatment C) MDD, Currently depressed, non-FPDD. To assess the specificity of the findings in MDD to FPDD, a sample meeting for MDD, currently in a depressive episode, but not FPDD will also be imaged Forty five subjects (ages 18 to 60) who meet DSM-IV for bipolar disorder and are currently in a major depressive episode. Subjects may be inpatients or outpatients. Because effective treatment will not be discontinued for the purposes of this protocol, subjects will be identified who have never been treated or who have discontinued medication due to lack of efficacy, noncompliance, physician order or other reasons prior to study entry LOW RISK One hundred and four subjects (ages 18 to 60) who have not met for any major psychiatric disorder. The control subjects will have no known first or second degree relatives with mood disorders Ten subjects (ages 18 to 60) with probable Cushing's Disease will be recruited who have both clinical and biochemical evidence of hypercortisolism (including urinary free cortisol excretion higher than the upper limit of normal (greater than 248) nmole/day, and marked central adiposity, cutaneous atrophy, proximal myopathy, and large purple striae). The diagnosis of probable Cushing's Disease will also have been established prior to referral via CRH and ACTH (n equals 12; ages 18-50). These females are recruited, screened and diagnosed by collaboration under protocol number 81-M-0126, previously approved by IRB, entitled 'The Phenomenology and Biophysiology of Menstrually Regulated Mood and Behavioral Disorders', principal investigator, David Rubinow, M.D. As described in that protocol these subjects must have a regular menstrual cycle lasting 21  Subjects must not have taken antidepressant or other medications likely to alter monoamine neurochemistry or cerebrovascular function for at least 3 weeks (8 weeks for fluoxetine) prior to scanning. Subjects being scanned at two points or the same point twice in their menstrual cycle must not have taken birth control pills for at least 6 months prior to scanning. However, effective medications will not be discontinued for the purposes of this study. Instead, subjects will be recruited who are not currently receiving psychotropic drugs. Subjects will also be excluded if they have serious suicidal ideation or behavior psychosis to the extent that the ability to provide informed consent is in doubt medical or neurological illnesses likely to affect physiology or anatomy a history of drug or alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM IV criteria) current pregnancy current breast feeding general MRI previous exposure to ecstasy (i.e. MDMA) which has neurotoxic effects on 5-HTT expressing neurons Subjects beyond age 50 are excluded from the MRMD sample due to peri-menopausal status and subjects beyond age 60 are excluded to reduce the biological heterogeneity encompassed by the MDD since depressives whose age-at MDD-onset is later than 60 have a far greater likelihood of having MRI correlates of cerebrovascular disease than age-matched, healthy controls or age-matched, early-onset depressives