Objectives: We reviewed the treatment of bipolar mixed states using efficacy data of licensed and non-licensed physical or pharmacological treatments.
Methods: We conducted a literature search to identify published studies reporting data on mixed states. Grading was done using an in-house level of evidence and we compared the efficacy with treatment recommendations of mixed states in current bipolar disorder guidelines.
Results: A total of 133 studies reported data on mixed states, and seven guidelines differentiate the acute treatment of mixed states from pure states. The strongest evidence in treating co-occurring manic and depressive symptoms was for monotherapy with aripiprazole, asenapine, extended release carbamazepine, valproate, olanzapine, and ziprasidone. Aripiprazole was recommended in three guidelines, asenapine in one, and carbamazepine and ziprasidone in two. As adjunctive treatment, the strongest evidence of efficacy was for olanzapine plus lithium or valproate. For maintenance, there is evidence for the efficacy of monotherapy with valproate, olanzapine, and quetiapine. In the six guidelines valproate or olanzapine are first line monotherapy options; one recommends quetiapine. Recommended add-on treatments are lithium or valproate plus quetiapine.
Conclusions: There is a lack of studies designed to address the efficacy of medications in mixed affective symptoms. Guidelines do not fully reflect the current evidences.
Keywords: bipolar disorder; clinical guidelines; clinical management; mixed states; pharmacotherapy.