Sleep in depressed patients resembles sleep in normal subjects whose circadian rhythms of temperature and rapid-eye-movement sleep are phase-advanced (shifted earlier) relative to their sleep schedules. If this analogy is relevant to the pathophysiology of depressive illness, advancing the time of sleep and awakening should temporarily compensate for the abnormal timing of depressed patients' circadian rhythms. Four of seven manic-depressive patients studied longitudinally spontaneously advanced their times of awakening (activity onset) as they emerged from the depressive phase of their illness. In a phase-shift experiment, a depressed manic-depressive woman was twice brought out of depression for 2 weeks by advancing her sleep period so that she went to sleep and arose 6 hours earlier than usual. The antidepressant effect of the procedure was temporary and similar in duration to circadian desynchronization induced by jet lag in healthy subjects. This result supports the hypothesis that abnormalities of sleep patterns in some types of depression are due to abnormal internal phase relationships of circadian rhythms.

Twenty-four hour urinary excretion of 3-methoxy-4-hydroxphaeylglycol (MHPG), the metabolite thought best to reflect brain norepinephrine metabolism, was studied longitudinally in ten depressed patients before and during the acute and chronic phases of lithium treatment. Five of the patients were identified as bipolar I (prior history of mania), 3 as bipolar II (history of hypomania) and 2 as unipolar (history of depression). During acute lithium administration (first week) there was no consistent pattern of change in MHPG. Comparing the predrug period with the third and fourth week of treatment, all of the responders showed an increase in MHPG, while the non-responders showed no change or a decrease. It is concluded that the change in clinical state is the most important variable contributing to MHPG changes in these patients. There was a tendency for the pretreatment MHPG excretion to be low in the patients who went on to show a clear-cut antidepressant response to lithium compared to those who were unequivocal non-responders. The predrug MHPG for the bipolar patients (prior history of mania) was significantly lower than the unipolar patients, a difference which apparently contributes to the lower MHPG in the lithium responders, all of whom were in the bipolar group.

In order to test the efficacy of the pineal neurohumor melatonin on depression, the hormone was administered in varying doses to six moderately to severely depressed patients and two patients with Huntington's chorea in double-blind crossover study. Melatonin exacerbated symptoms of dysphoria in these patients, as well as causing a loss of sleep and weight and a drop in oral temperature. Melatonin increased cerebrospinal fluid 5-hydroxyindoleacetic acid and calcium in three of four patients studied. The authors discuss the implications of this finding.

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