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Affective disorders are a major cause of morbidity and disability among middleaged and older people. Thus, the prophylaxis of both unipolar depression and bipolar disorder in this patient subpopulation is an important task of psychiatrists and other physicians. Although lithium remains an effective prophylactic and treatment agent in younger individuals with bipolar disorder, its prophylactic efficacy and tolerability has not been thoroughly investigated among middle aged and older people with unipolar depression and bipolar disorder. Our study is based on a mirror-image design that compared the clinical course with lithium treatment and the clinical course prior to lithium treatment based on a retrospective chart review. We examined the results obtained with long-term lithium maintenance in a group of 60 middle-aged and older adult patients (age > 60 years) with unipolar depression and bipolar disorder. More specifically, we analyzed changes of frequency, severity, and duration of depressive or manic relapses, rate and duration of hospitalizations and suicidal behavior (thoughts or attempts), and various assessments of outcome. A significant reduction was found on all indices during lithium therapy compared to before lithium treatment, attesting to the prophylactic efficacy of long-term lithium in unipolar depression and bipolar disorder. The range of side effects in our sample was similar to that found in other reports in this age group. The probability of relapse and recurrence in patients with bipolar disorder and with unipolar depression can be significantly decreased by lithium prophylaxis. Further investigation is mandated to confirm these findings under double-blind conditions.