Thirty-five patients, all with major depressive illness, bipolar disorder, or schizoaffective disorder, were retrospectively identified as having received valproate either alone or in combination with lithium, after having failed to adequately respond to previous lithium and/or carbamazepine treatment. Clinical evaluation and Global Assessment Scale (GAS) scores indicated that at baseline all but 3 of the patients experienced serious psychiatric symptoms, serious impairment in social or professional functioning, or significant impairment in reality testing. Mean GAS scores after a mean duration of at least 1 year of valproate administration improved in 7 of 9 depressed patients, 12 of 12 patients with bipolar disorder, and 11 of 14 patients with schizoaffective states. Mean increases in GAS scores were 27.7 points for depressive disorder patients, 34.5 points for mixed bipolar disorder patients, and 17.1 points for patients with schizoaffective states. For patients with either depressive disorders or mixed bipolar disorders, that mean change represented a level of improvement sufficient to elevate the majority of the patients into the mild symptom range or the virtually asymptomatic state. That improvement was confirmed by the investigator's global evaluation of patient response with regard to affect: valproate administration produced significant affective responses in 7 of 9 depressed patients, 12 of 12 patients with mixed bipolar disorders, and 11 of 14 patients with schizoaffective states. The responses of patients with bipolar and schizoaffective disorders to valproate treatment compared with valproate plus lithium treatment were also evaluated. Patients in both diagnostic categories demonstrated very similar and quite substantial improvement in mean change in GAS ratings and global evaluations, regardless of whether valproate was administered alone or in combination with lithium.