The depressive and anhedonic response precipitated by CD raises the possibility that dysfunction of the dopamine system is a stable, sometimes latent characteristic of MDD. Following this line of reasoning, central catecholamine dysfunction as evinced by CD may be equally salient in a subset of unaffected relatives who are at genetic risk for developing the disorder. We plan to extend the phase I project to unaffected relatives of BD and MDD patients in order to evaluate sensitivity to CD as an endophenotype of MDD and BD. In order to maximize our statistical power, we will be recruiting equal numbers healthy low and high-risk relatives. Here, risk is defined on the basis of chronological age (see below for more detail). Furthermore, it has recently become feasible to conduct genome-wide association studies and quantify the burden of risk alleles carried by an individual. Certainly, the identity of these risk alleles remains unknown or unproven. Nevertheless, Francis McMahon's group, with whom we are collaborating, have identified upwards of 20 common risk variants in two independent samples. Individuals carrying 19 or more of these risk alleles were found to be 4 times more likely to be cases than controls. This approach may provide us with another method of quantifying genetic risk. The endophenotypic status of sensitivity to CD will be evaluated with psychometric instruments, FDG PET, and an fMRI-coupled appetitive learning task. We now have access to a high resolution PET scanner (High Resolution Research Tomograph) that will enable us to study hitherto irresolvable structures of importance such as the habenula and peri-aqueductal gray matter (PAG) in addition to previously implicated regions such as the ventral striatum and OFC. Analysis of the metabolic activity of these regions under sham and CD conditions in both remitted MDD and relatives of BD and MDD patients is of great theoretical import. So to is identifying regions of the brain involved in reward response that are selectively impacted by CD, a question that we hope to answer through the use of the fMRI-coupled appetitive learning task.
* INCLUSION CRITERIA: MDD Sample: 40 subjects (ages 18-45) with remitted MDD will be selected. MDD is defined by the DSM-IV criteria, and one of the following additional criteria: 1. history of two or more major depressive episodes, or 2. history of one major depressive episode and a family history for major depression. Remission is defined as a period of at least three months during which the subject has not taken any antidepressant agents, with the Hamilton Depression Rating Scale (HDRS; 21-item) scores in the non-depressed range (less than 8), and with no more than one clinically significant depressive symptom. Unaffected MDD Relative Sample: 40 healthy relatives of MDD probands (ages 18-45) will be recruited. Subjects will be screened to ensure that they have no history of psychiatric illness. Unaffected BD Relative Sample: Healthy relatives of BD probands (ages 18-45) will be recruited. Subjects will be screened to ensure that they have no history of psychiatric illness. Healthy Control Samples: -Healthy subjects (ages 18-45) without a known personal or first-degree family history of psychiatric disorders in first-degree relatives will be selected. EXCLUSION CRITERIA: * Any subject who appears incapable of providing informed consent will be excluded from the study. * Subjects who take effective antidepressant medication * Subjects must not have taken antidepressant or other medications likely to alter monoamine neurochemistry or cerebrovascular and cardiovascular function for at least 3 months prior to the studies. * Subjects who have: 1. psychosis to the extent that the ability to provide informed consent is in doubt 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) longer than 2 years 4. current pregnancy (as documented by pregnancy testing at screening or at days of the challenge studies) 5. current breast feeding 6. smokers 7. serious suicidal ideation or behavior 8. general MRI exclusion criteria (e.g., subjects with metallic implants that are ferromagnetic will be excluded from the fMRI scanning). Subjects must exhibit no or only moderate alcohol use. Subjects with current excessive use of alcohol (greater than 4 ounces/day for men and greater than 3 ounces/day for women) are ineligible for participation, as such drug use confounds the results 9. smokers are ineligible because of the evidence for interactions between nicotine and depression, and the possibility of withdrawal symptoms that may affect behavioral and neural responses to CD 10. history of suicidality and other axis I diagnoses beside major depressive disorder 11. lactose intolerance 12. women not using a reliable contraception method. Finally subjects who have had an upper respiratory tract infection in the last week will be excluded as this may impact sense of smell. * Subjects beyond age 45 * Individuals whose first major depressive episodes arose after other medical or psychiatric conditions * Subjects showing significant side effects during AMPT depletion such as dystonic reactions will receive adequate treatment and will be excluded from the study