The DSM–5 incorporates a broad concept of mixed states and captured ≥3 nonoverlapping symptoms of the opposite polarity using a “with mixed features” specifier to be applied to manic/hypomanic and major depressive episodes. Pharmacotherapy of mixed states is challenging because of the necessity to treat both manic/hypomanic and depressive symptoms concurrently. High-potency antipsychotics used to treat manic symptoms and antidepressants can potentially deteriorate symptoms of the opposite polarity. This review aimed to provide a synthesis of the current evidence for pharmacotherapy of mixed states with an emphasis on mixed mania/hypomania. A PubMed search was conducted for randomized controlled trials (RCTs) that were at least moderately sized, included a placebo arm, and contained information on acute-phase and maintenance treatments of adult patients with mixed episodes or mania/hypomania with significant depressive symptoms. Most studies were post-hoc subgroup and pooled analyses of the data from RCTs for acute manic and mixed episodes of bipolar I disorder; only two prospectively examined efficacy for mixed mania/hypomania specifically. Aripiprazole, asenapine, carbamazepine, olanzapine, and ziprasidone showed the strongest evidence of efficacy in acute-phase treatment. Quetiapine and divalproex/valproate were also efficacious. Combination therapies with these atypical antipsychotics and mood stabilizers can be considered in severe cases. Olanzapine and quetiapine (alone or in combination with lithium/divalproex) showed the strongest evidence of efficacy in maintenance treatment. Lithium and lamotrigine may be beneficial given their preventive effects on suicide and depressive relapse. Further prospective studies primarily focusing on mixed states are needed.

This article focuses on the controversial decision to exclude the overlapping symptoms of distractibility, irritability, and psychomotor agitation (DIP) with the introduction of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) mixed features specifier. In order to understand the placement of mixed states within the current classification system, we first review the evolution of mixed states. Then, using Kraepelin’s original classification of mixed states, we compare and contrast his conceptualization with modern day definitions. The DSM-5 workgroup excluded DIP symptoms, arguing that they lack the ability to differentiate between manic and depressive states; however, accumulating evidence suggests that DIP symptoms may be core features of mixed states. We suggest a return to a Kraepelinian approach to classification—with mood, ideation, and activity as key axes—and reintegration of DIP symptoms as features that are expressed across presentations. An inclusive definition of mixed states is urgently needed to resolve confusion in clinical practice and to redirect future research efforts.