Two methods for the measurement of cyclic AMP, enzymic radioisotopic displacement and protein binding (saturation) assay, were established. Vitamins B12 and C were found, in in vitro studies, to be more effective inhibitors of cyclic AMP phosphodiesterase than theophylline. Plasma and urinary levels of cyclic AMP were found to exhibit a diurnal variation in normal volunteers. The majority gave a plasma pattern with a maximum at 24.00h and a minimum at 16.00h. The minority plasma pattern showed a peak at 12.00h. The urinary excretion gave a pattern in the majority with a maximum between 04.00 -08.00h and a minimum between 12.00 - 16.00h. The minority showed a peak urine value between 12.00 - 16.00h and a trough between 24.00 - 04.00h. A further pattern was noted in menstrual cycle with a mid-cycle peak. This was absent in males, and was lost in secondary amenorrhoea, pregnancy and after prolonged ingestion of oral contraceptives. The amplitude was more pronounced in pre-menstrual tension syndrome, suggesting the possibility of overswing. Muscular activity produced a transient increase in plasma cyclic AMP, but this was not reflected in the urinary level. Limited studies on dietary change showed no significant influence. Patients suffering from endogenous depression showed low plasma and urinary levels of cyclic AMP. On clinical improvement urinary levels returned to the normal range. The urinary excretion of cyclic AMP in endogenous depression showed a peak between 08.00 - 12.00 h. On clinical improvement the pattern became bimodal with peaks between 04.00 - 08.00h and 16.00 - 20.00h. The reactive depression group showed a bimodal pattern (peaks between 24.00 - 04.00h and 12.00 - 16.00h) both before and after clinical improvement. Electroconvulsive therapy caused a marked rise in both plasma and urinary levels of cyclic AMP on the day of treatment. The plasma concentration doubled and remained elevated for up to 90 min after electrical stimulation. Patients who did not respond to E. C. T. in terms of cyclic AMP increase also showed no clinical improvement
