Double trouble: mixed bipolar episodes.

By DSM-IV standards, mixed episodes must satisfy criteria for both manic and depressive episodes and are relatively rare in bipolar disorder, but not everyone goes by this definition.

"There's a general feeling that the DSM-IV notion is overly conservative," said Dr. Roger S. McIntyre, head of the mood disorders psychopharmacology unit at the University of Toronto. "It's not the way patients commonly present."

A more clinically useful conceptualization, many think, is broader: a full-blown manic episode with significant depressive symptoms or a major depressive episode with elements of mania.

These "depressive mixed states" or "dysphoric manias" are quite common. According to Dr. Joseph F. Goldberg of the Mount Sinai School of Medicine, New York, about two-thirds of depressed enrollees in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study demonstrated manic features. The prevalence of depressive symptoms during manic episodes, on the other hand, has been reported at 25%-40% (Am. J. Psychiatry 1992;149:1633-44).

Mixed symptomatology often implies heightened urgency. The hopeless thoughts of depression and the impulsivity and psychomotor acceleration of mania are "an especially volatile combination"; these patients are ill longer and more often than those who are simply depressed, and their lifetime risk of suicide is higher, Dr. Goldberg said.

"At the heart of treating a mixed state is making a diagnosis based on formal criteria," said Dr. Gary S. Sachs, director of the bipolar clinic and research program at Massachusetts General Hospital, Boston. All too often, he said, "manic symptoms are ignored in the face of a presumptive clinical diagnosis of bipolar depression. ... With a standard assessment, you [identify] patients who have periods of impulse control problems, racing thoughts, grandiosity, considerably more often than might be expected."

A brief self-rating instrument such as the one developed in his clinic (available at www.manicdepressive.org/tools_clinical.html) can help identify many of these patients, he said.

Regardless of predominant polarity, mixed states should be addressed "pretty much like mania," Dr. Sachs said. "If you treat the depression first, it's likely to worsen manic symptoms, but if you treat the mania, depression often resolves."

Food and Drug Administration-approved agents for treatment of manic symptoms of bipolar mixed episodes include most atypical antipsychotics (paliperidone [Invega], quetiapine [Seroquel], and clozapine excepted) and long-acting formulations of the anticonvulsants divalproex sodium (Depakote) and carbamazepine.

Dr. McIntyre generally chooses an atypical antipsychotic first. "They're head and shoulders above the rest," he said. They often work quickly, producing "a meaningful clinical benefit" within 24-48 hours.

More often than not, he opts for agents with histamine receptor affinity--quetiapine, olanzapine (Zyprexa), or risperidone (Risperdal)--for their sedating effects. Concerns about weight gain or metabolic effects, however, might incline him toward one of the others.

Most important, Dr. Goldberg said, is avoiding antidepressants. "They may have some value when added to mood-stabilizing agents for some depressed patients without manic symptoms or a history of antidepressant-associated mania or hypomania, but there's no place for them here. They don't help bipolar depressive symptoms but aggravate concomitant manic symptoms."

He led a study of STEP-BD patients that found a poor outcome of antidepressant treatment in bipolar depression patients with manic symptoms (Am. J. Psychiatry 2007;164:1348-55).

"I'd focus on antimanic mood-stabilizing agents that also have antidepressant properties," Dr. Goldberg said. "Divalproex, olanzapine, quetiapine, or possibly one of the other atypicals--these are appropriate foundational drugs to consider."

Prior response should be weighed in deciding which drug to use first, as well as comorbidity. Substance use disorders are highly prevalent in mixed-episode patients, he pointed out, and divalproex has been shown to reduce drinking in hepatically stable alcoholic bipolar patients (Arch. Gen. Psychiatry 2005;62:37-45).

Lithium might be somewhat less effective than divalproex for mixed presentations, but it "nevertheless should still be considered for dysphoric mania," Dr. Goldberg said. "The more mania and less depression is in the picture, the better choice lithium becomes."

In urgent situations, the possibility of rapid titration is a key factor; divalproex and olanzapine can be titrated quickly, Dr. Goldberg said, whereas concerns about akathisia with risperidone make rapid dosage escalation less feasible. Aggressive dosing is not appropriate for lithium and carbamazepine, either, Dr. Sachs observed.

Drugs that have not been approved for mixed states might nonetheless have a role in their treatment. Dr. McIntyre considers lamotrigine (Lamictal) after unsuccessful trials of several atypical antipsychotics, although the need for slow titration limits its applicability.

Intermediate-half-life benzodiazepines also have some short-term utility, he said, particularly for patients who have responded reasonably well to atypicals but continue to experience irritability and racing thoughts.

Benzodiazepines also should be considered for comorbid anxiety, which is common among patients who are subject to mixed states. "If an antimanic drug isn't enough, I'm not reluctant to add a benzodiazepine or gabapentin, along with cognitive-behavioral therapy," Dr. Sachs said.

Dr. Goldberg considers anxiety when choosing a primary drug. "The same way it is useful to think about the antidepressant properties of mood stabilizers, one should also consider their antianxiety properties," he said. No drugs have been thoroughly studied to treat comorbid anxiety in bipolar patients, but quetiapine has the most extensive data among atypical antipsychotics for certain anxiety disorders, suggesting its possible utility, he noted.

For those who have breakthrough episodes while on maintenance, adherence issues, comorbidity (particularly substance abuse), and other complicating factors should be considered before modifying the regimen. Such changes might mean subtraction rather than addition.

After acute symptoms have resolved, "you're more likely to see relapses when discontinuing medication after mixed than after pure manic or depressive episodes." Dr. Sachs said. "The median duration of mixed episodes might be close to a year, compared to 20-25 weeks for pure depressive and 10 weeks for pure manic episodes."

Prevention should be a priority. Dr. McIntyre observed that one mixed episode is likely to be followed by others, and that the risk of depression is also heightened. "You need to anticipate problems down-stream," he said. "Be vigilant. Symptoms of depression are often subsyndromal and insidious, such as sedation and fatigue that are easily misattributed to side effects."

Dr. McIntyre has been on the speakers bureau or advisory board of, or received research support from, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Co., the France Foundation, GlaxoSmithKline, Janssen-Ortho Inc., Solvay/Wyeth, Eli Lilly & Co., Organon Inc., H. Lundbeck A/S, Biovail Corp., Pfizer Inc., and Shire PLC.

Dr. Goldberg has been on the speakers bureau or scientific advisory board of Eli Lilly, GlaxoSmithKline, Abbott Laboratories, AstraZeneca, and Pfizer.

Dr. Sachs has been on the speakers bureau or advisory board of, or received research support from, Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon Inc., Elan Pharmaceuticals, Eli Lilly, GalxoSmithKline, Janssen, Memory Pharmaceuticals Inc., Merck & Co., Novartis, Organon, Pfizer, Repligen Corp., Sanofi-Aventis, Sepracor Inc., Shire, Sigma-Tau Pharmaceuticals Inc., Solvay Pharmaceuticals Inc., and Wyeth. He is a stockholder of Concordant Rater Systems Inc.

By Carl Sherman, contributing writer