Mixed states address the relationships between episodes and the course of an illness, presenting significant clinical challenges. Recurrent affective disorders were described thousands of years ago as dimensional disturbances of the basic elements of behavior, combining the characteristics of what we would now consider manic and depressive episodes. It was recognized from the beginning that combinations of depressive and manic features are associated with a severe illness course, including increased suicide risk. Early descriptions of affective disorders formulated them as systemic illnesses, a concept supported by more recent data. Descriptions of affective disorders and their course, including mixed states, became more systematic during the 19th century. Structured criteria achieved importance with evidence that, in addition to early onset, frequent recurrence, and comorbid problems, mixed states had worse treatment outcomes than other episodes. In contrast to 2000 years of literature on recurrent affective episodes and mixed states, the unipolar–bipolar disorder distinction was formalized in the mid-20th century. Mixed-state criteria, initially developed for bipolar disorder, ranged from fully combined depression and mania to the DSM–5 criteria, no longer limited to bipolar disorder, of a primary depressive or manic episode with at least three symptoms of the other episode type. The challenges involved in understanding and identifying mixed states center largely on what drives them, including (1) their formulation as either categorical or dimensional constructs, (2) the specificity of their relationships to depressive or manic episodes, and (3) specificity for bipolar versus major depressive disorder. Their existence challenges the distinction between bipolar and major depressive disorders. The challenges involved in identifying the underlying physiological mechanisms go to the heart of these questions.

Various terms have been used to describe mania when it is accompanied by depressive symptoms. In this article, we attempt to define and discuss 3 of these terms: dysphoric mania, mixed state, and mania with mixed features specifier. We conclude that whatever term is used, it is important to be aware that mania is more often unpleasant than pleasant, and that the unpleasantness is not limited to depression.

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.

Mixed states in bipolar disorder have been neglected, and the data concerning treatment of these conditions have been relatively obscure. To address this, we systematically reviewed published pharmacological treatment data for “mixed states/episodes” in mood disorders, including “with mixed features” in DSM–5. We searched PubMed, MEDLINE, The Cochrane Library, clinicaltrials.gov, and controlled-trials.com (with different combinations of the following keywords: “mixed states/features,” “bipolar,” “depressive symptoms/bipolar depression,” “manic symptoms,” “treatment,” “DSM–5”) through to October 2016. We applied a quality-of-evidence approach: first-degree evidence=randomized placebo-controlled studies of pharmacological interventions used as monotherapy; second-degree evidence=a similar design in the absence of a placebo or of a combination therapy as a comparative group; third-degree evidence=case reports, case series, and reviews of published studies. We found very few primary double-blind, placebo-controlled studies on the treatment of mixed states: the preponderance of available data derives from subgroup analysis performed on studies that originally involved manic patients. Future research should study the effects of treatments in mixed states defined using current criteria.

During the past two decades, a number of studies have found that depressed patients frequently have manic symptoms intermixed with depressive symptoms. While the frequency of mixed syndromes are more common in bipolar than in unipolar depressives, mixed states are also common in patients with major depressive disorder. The admixture of symptoms may be evident when depressed patients present for treatment, or they may emerge during ongoing treatment. In some patients, treatment with antidepressant medication might precipitate the emergence of mixed states. It would therefore be useful to systematically inquire into the presence of manic/hypomanic symptoms in depressed patients. We can anticipate that increased attention will likely be given to mixed depression because of changes in the DSM–5. In the present article, I review instruments that have been utilized to assess the presence and severity of manic symptoms and therefore could be potentially used to identify the DSM–5 mixed-features specifier in depressed patients and to evaluate the course and outcome of treatment. In choosing which measure to use, clinicians and researchers should consider whether the measure assesses both depression and mania/hypomania, assesses all or only some of the DSM–5 criteria for the mixed-features specifier, or assesses manic/hypomanic symptoms that are not part of the DSM–5 definition. Feasibility, more so than reliability and validity, will likely determine whether these measures are incorporated into routine clinical practice.

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM–5 codified a new nosological entity, the “mixed features specifier,” referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM–IV definition of “mixed states” wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.