Ask the Expert: Bipolar Disorder
In meetings and presentations, I am increasingly hearing the term “mixed depression”—what is it and how best should I be treating it?
There is no consensus or operationalized criteria for mixed depression. There are however, several definitions that generally define the concept as a syndromal episode of major depression plus several symptoms (i.e., nonsyndromal) of mania/hypomania (1–4). Review, for example, the following case report.
A 30-year-old businesswoman sought consultation for persistent depressive symptoms and increased irritability despite ongoing antidepressant (venlafaxine 300 mg) and mood stabilization (divalproex sodium 1000 mg) cotherapy. She had been treated with divalproex since her first and only admission 10 years ago for nonpsychotic mixed mania complicated by alcohol abuse and migraine. Her current symptoms include depressed mood, anhedonia, guilty ruminations, early morning awakening with reduced appetite, and weight loss. In addition, she reports irritability, racing thoughts, distractibility, and an uncomfortable energy that she describes as “pushed, hyperactive, wired and tired.” All these symptoms were present despite a therapeutic level of valproate (60 mcg/dl). The addition of venlafaxine has reduced the symptom severity of depression and anhedonia by 50% but the irritability, racing thoughts, and agitation have increased.
This presentation (i.e., episode of major depression with concurrent minimal hypomanic symptoms and a history of mania) is consistent with mixed depression. It is increasingly recognized that mixed depression is not uncommon as more than 50% of depressed patients with bipolar disorder followed in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) program study reported subsyndromal symptoms of mania/hypomania; most commonly, the symptoms were distractibility, racing thought/flight of ideas, increased activity, and increased speech (5).
This distinction between mixed depression and traditional or DSM-IV-TR mixed mania [major depression plus three manic (euphoric)/or four (mixed) symptoms)] or mixed hypomania (6) is unclear. It is unlikely that one symptom would distinguish distinct categorical disease states. More likely is a spectrum of mixed presentations with original Kraepelinian descriptions (i.e., depressive or anxious mania, excited depression, and depression with flight of ideas) that remain timelessly rich (7). It is clear that DSM-5 is focusing on this categorical versus dimensional aspect of mixed presentations in mood disorder (8). The proposed revision is to have a “mixed features specifier,” which would apply “in episodes where subthreshold symptoms from the opposing pole are present during a full mood episode”; these symptoms may be “relatively simultaneous,” or “they may also occur closely juxtaposed in time as a waxing and waning of individual symptoms of the opposite pole.”
What remains is how best to treat mixed depression. There are few data other than studies that show, in comparison to nonmixed depression, reduced response to antidepressant therapy and antidepressant-induced mania (9, 10). A recent 6-week randomized, double-blind, placebo-controlled study, which reported efficacy of ziprasidone in mixed depression (n = 44 bipolar II and 30 major depressive disorder), is the first study to look at mood stabilization therapy (11). Further study for diagnostic clarification in bipolar and unipolar disorders as well as treatment guidelines is warranted.
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11. Patkar A, Gilmer W, Pae C, Filkowski MM, Holtzman NS, Vöhringer P, Whitham EA, Thommi SB, Loebel A, Masand P, Ghaemi NS: A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state. PLoS (in press).Google Scholar
