The relationships between lithium dosage, affective morbidity, side-effects, thyroid and renal function and biological markers for depression were examined in the context of a prospective double-blind lithium reduction study in patients receiving prophylactic lithium. Unipolar and bipolar patients on such treatment were randomly allocated to two groups over a period of one year, either continuing with their usual dosage of lithium or reducing their lithium dosage by up to 50%. Biological markers investigated included dexamethasone suppression test (DST) and 5-hydroxytryptamine (5-HT) transport into platelets (Vmax). Results showed no association between affective morbidity and lithium dosage/level. There was, however, an association between lower dosage/level of lithium and lower side-effects, including tremor and weight gain, lower TSH levels and lower 24 h urinary volume in these patients. Elderly patients, however, experienced significantly greater morbidity upon reduction of their lithium dosage. There was an association between increased Vmax of 5-HT transport and a reduction in morbidity. DST non-suppression was associated with lower mean weight for the whole year of the study.