The outpatient clinic provides a "well state" patient population for genetic and pharmacologic studies of persons with Unipolar (major depressive) and Bipolar (manic-depressive) disorders. Such a "well state" population is crucial in identifying biochemical, pharmacologic, or physiologic abnormalities which are present in persons vulnerable to affective disorder, and which may serve as genetic markers to affective illness. Studies of cholinergic sensitivity in Bipolar patients and relatives are continuing. We have confirmed increased susceptibility to arecoline rapid-eye movement sleep (REM) induction in patients never medicated or off medications for months or years. Pupillometry studies show increased sensitivity to pilocarpine in euthymic patients off medications as compared with controls. Our study of amphetamine response in patients is complete and the data are being analyzed. Lithium accumulation in platelets is being studied in collaboration with the Clinical Neuropharmacology Branch of NIMH. Preliminary results indicate that lithium attaches to the dense bodies in the platelet. A study of the phenomenology of affective illness has focused on seizure-like phenomena during mania and depression. Thirty-five clinic patients have been interviewed in conjunction with this study. Their histories are being compared with groups of epileptics and hypertensives.