• INCLUSION CRITERIA:

Healthy Volunteers (n=80)

Right-handed subjects (ages 18-50) will be selected who have not met criteria for any major psychiatric disorder, have no known first-degree relatives with mood disorders, and have a current score on the Hamilton Depression Rating Scale (HDRS; 17 item) in the not depressed range (<= 7). Control subjects will be matched to depressed subjects and their relatives for age, gender, and education.

MDD Samples (n = 80)

Right-handed subjects (ages 18-50) will be selected with a past history of MDD by DSM-IV criteria.

Healthy Relatives (n=40)

Healthy, right-handed, first-degree relatives of patients with MDD will be recruited.

EXCLUSION CRITERIA:

Subjects must not have taken antidepressant drugs for at least 3 months (4 months for fluoxetine) prior to the fMRI studies or other medications likely to alter monoamine neurochemistry or cerebrovascular and cardiovascular function for at least 3 weeks prior to imaging. However, effective medications will not be discontinued for the purposes of this study. Subjects will also be excluded if they have:

1. Psychosis
2. Medical or neurological illnesses likely to affect physiology or anatomy, i.e. hypertension, cardiovascular disorders
3. A history of drug (including benzodiazepines (BZD)) or alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM IV criteria)
4. Current pregnancy (as documented by pregnancy testing at screening or at days of the challenge studies)
5. Current breast feeding
6. Are smokers
7. Serious suicidal ideation or behavior. In this study, there is a small risk of transient depressive symptoms occurring after ingesting the amino acid mixture. Therefore, if volunteers manifest evidence of serious suicidal ideation or behavior, they will be excluded from participating. Criteria for meeting suicidal ideation include but are not limited to: 1) thoughts of suicide within the past 3 months which are accompanied by intent to harm oneself, serious consideration of means or plan to attempt suicide, evidence of arranging for a suicide attempt (e.g. giving away prized possessions or updating a will), or clear desire to commit suicide, 2) severity of past suicide events, if applicable or 3) a current plan for harming themselves. All assessments will be conducted by an experienced, NIMH credentialed health professional, such as a psychiatrist or psychiatric nurse who will use their expert knowledge and experiences in determining the authenticity of a participant's information and handle the situation accordingly.

GENERAL MRI EXCLUSION CRITERIA:

Subjects must exhibit no or only moderate alcohol use. Subjects with current or previous regular use (greater than 4 weeks) of BZDs and excessive use of alcohol (greater than 8 ounces/day for men and greater than 6 ounces/day for women) in the past or present are ineligible for participation, as such drug use may confound the results (Primus and Gallager 1992; Ulrichsen et al. 1996). Smokers (regular use within the last 3 months) are ineligible because of the evidence for interactions between nicotine and depression (Ong and Walsh 2001), and the possibility of withdrawal symptoms that may affect behavioral and neural responses to TD.

Subjects beyond age 50 are excluded to address the biological heterogeneity encompassed by the MDD criteria, since depressives whose age-at-onset is later than 50 have a far greater likelihood of having MRI correlates of cerebrovascular disease than age-matched healthy controls or age-matched early-onset depressives (Krishnan et al. 1993). Subjects whose first major depressive episodes arose temporally after other medical or psychiatric conditions will also be excluded, since their functional imaging results generally differ from those reported in primary MDD (Drevets 2000).