Bipolar mixed states: evolution of the concept and implications for the treatment and research

Gli stati misti bipolari: evoluzione del concetto e implicazioni per la cura e la ricerca

C. Vampini, F. Nifosì

2° Servizio di Psichiatria, Ospedale Civile Maggiore, Verona, Dipartimento per la Salute Mentale, Verona



Bipolar mixed states remain a nosologic dilemma, diagnostic challenge and neglected area of therapeutic research. Mixed episodes are reported to occur in up to 40% of acute bipolar admissions and are associated with more severe manic and general psychopathology, more catatonic symptoms, more comorbidity, a higher risk of suicide and a poorer outcome than pure manic episodes. Kraepelin was the first to emphasize the clinical relevance of mixed states. In recent years, several authors have contributed to promove a greater awareness of this issue, considering the (DSM-IV-TR) definition of mixed states extremely narrow and inadequate. The nomenclature for the cooccurrence of manic and depressive symptoms has been revised in the new DSM-5 version to accommodate a mixed categorical– dimensional concept. The new classification will capture subthreshold non-overlapping symptoms of the opposite pole using a “with mixed features” specifier to be applied to manic episodes in bipolar disorder I, hypomanic, and major depressive episodes experienced in bipolar disorder I, bipolar disorder II, bipolar disorder not otherwise specified, and major depressive disorder. The revision will have a substantial impact in several fields: epidemiology, diagnosis, treatment, research, education, and regulations.


Findings are based upon review of the current literature. We searched the Medline and Pubmed databases using combinations of the keywords: “mixed states”, “with mixed features”, “bipolar”, “manic”, “depressive, “hypomanic”, “manic depression”, “bipolar depression”, “DSM-5” and all the medications we described.


Overall, there were very few double-blind, placebo-controlled studies specifically designed to treat manic-depressive mixed states. Rather, patients with mixed states comprised a sub-group of the examined patient cohorts. Nevertheless, the data show that acute mixed states do not respond favourably to lithium. Instead, valproate and olanzapine are drugs of first choice. Carbamazepine may play a role in the prevention of mixed states. Antidepressants should be avoided, because they may worsen intraepisodic mood lability. Lamotrigine may be useful in treating mixed states with predominantly depressive symptoms. With the emergence of second-generation antipsychotics, which in some cases have both antimanic and antidepressant effects, monotherapy options in the treatment of mixed states may increase.


However, assessing their comparative effectiveness in the treatment of the newly defined mixed states will require specific and prospectively designed clinical trials. The medications that are effective in treating mixed episodes per the DSM-IV-TR definition may also be effective in treating mixed features per the DSM-5, but new studies are needed to demonstrate it.

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