Mixed Symptoms in Mood Disorders: A Historical, Clinical, and Therapeutic Review

Mixed symptoms, combining manic or hypomanic elements with depressive features, are a core and frequent dimension of mood disorders. From Kraepelin and Weygandt’s early descriptions to contemporary formulations, diagnostic definitions have shifted between highly restrictive and broader dimensional approaches. The DSM-5 “with mixed features” specifier represented progress, yet limitations remain, notably the exclusion of overlapping symptoms (irritability, distractibility, psychomotor agitation). Recent systematic reviews estimate prevalence at 18% of major depressive episodes, 33% of bipolar depressive episodes, and 35% of manic or hypomanic episodes. Mixed presentations are linked to higher suicide risk, greater illness burden, and poorer treatment response. In recent years, the most robust pharmacological evidence comes from trials with second-generation antipsychotics, particularly lumateperone (with prespecified data across MDD and BD-I/II), lurasidone, ziprasidone, cariprazine, and olanzapine/fluoxetine. In contrast, lithium, valproate, and lamotrigine lack specific studies in depressive episodes with mixed features, and antidepressant monotherapy remains insufficiently supported. This review integrates historical foundations, epidemiological data, and updated therapeutic evidence, highlighting the need for more sensitive diagnostic consensus and longer-term controlled trials to guide clinical practice.