Abstract
Growing evidence indicates that historical descriptions of mixed depression-broadly defined as major depressive episodes with subthreshold manic or hypomanic (hypo/manic) symptoms-are incredibly clinically relevant in this day-and-age. However, the first operational definition of mixed depression did not occur in the modern nomenclature until 2013 with publication of Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), and there has not been enough time to evaluate these criteria empirically. Thus, the most valid operational definition of a mixed depressive episode is still unknown, widely accepted treatment guidelines are not available, and no treatment has regulatory approval for mixed depression-whether associated with bipolar I disorder, bipolar II disorder, or major depressive disorder. This is despite seven drugs having regulatory indications for mixed episodes, defined as the co-occurrence of syndromal depression and syndromal mania, and now recognized as mania with mixed features by DSM-5. Indeed, we found only two randomized, placebo-controlled trials in patients with protocol defined mixed depression, one with ziprasidone and one with lurasidone. Both studies were positive, suggesting treatment with second-generation antipsychotics may be helpful for mixed depressive episodes associated with bipolar II or unipolar disorder. We found no randomized control trial of antidepressant monotherapy in mixed depression and many clinical reports that such treatment may worsen mixed depression Randomized, placebo-controlled trials of antidepressants, antipsychotics, and mood stabilizers-alone and in combination-in individuals with carefully defined mixed depression are needed before firm treatment guidelines can be produced.
Highlights
IntroductionThe term bipolar disorder is a misnomer as manic and depressive symptoms often co-occur, perhaps in an infinite number of combinations.[1,2,3] Often called mixed states, the Diagnostic and Statistical Manual, 5th Edition (DSM-5)[4] recognizes two broad types of these combinations: (1) mania or hypomania (hypo/mania) with depressive symptoms (called hypo/mania with mixed features or mixed hypo/mania) and (2) depression with subsyndromal hypo/manic symptoms (called depression with mixed features or mixed depression).[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22] While both types of mixed states have been recognized since ancient times,[1] modern research has given far more attention to the diagnosis and treatment of mixed mania than to mixed depression.[14]
Defined conceptually as prominent depressive symptoms accompanied by subthreshold hypo/manic symptoms, it is important to realize that the precise operational definition of mixed depression is as yet unclear
DSM-5 requires the presence of syndromal depression with three or more specific or polar opposite hypo/manic symptoms, other data suggest mixed depression may be defined with fewer hypo/ manic symptoms, including so-called nonspecific symptoms
Summary
The term bipolar disorder is a misnomer as manic and depressive symptoms often co-occur, perhaps in an infinite number of combinations.[1,2,3] Often called mixed states, the Diagnostic and Statistical Manual, 5th Edition (DSM-5)[4] recognizes two broad types of these combinations: (1) mania or hypomania (hypo/mania) with depressive symptoms (called hypo/mania with mixed features or mixed hypo/mania) and (2) depression with subsyndromal hypo/manic symptoms (called depression with mixed features or mixed depression).[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22] While both types of mixed states have been recognized since ancient times,[1] modern research has given far more attention to the diagnosis and treatment of mixed mania than to mixed depression.[14]. Though seven drugs (six second-generation antipsychotics and carbamazepine) have regulatory approval for treatment of mixed mania, no drug has regulatory approval for treatment of mixed depression
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