Antipsychotics. Quetiapine16 and a combination of olanzapine and fluoxetine17 are approved for treating bipolar depression. The studies supporting this indication lasted only 8 weeks, however, and excluded patients with the kinds of complicated and comorbid mood disorders commonly seen in clinical practice.
Many patients dropped out before the studies were completed, and “screen fails” (patients with the diagnosis who were not enrolled in the study) were not reported. In addition, “remitted” patients remained symptomatic.
Therefore, FDA approval of this indication does not guarantee these medications’ long-term efficacy or safety for bipolar depression or that they are useful in patients with complex forms of bipolar depression.
Recommended approach. Treatment resistance of bipolar depression to multiple mood stabilizers—with or without an antidepressant—or to an antipsychotic may manifest as lack of response, partial response, or initial good response followed by relapse or recurrence. Sometimes depression improves but irritability or mood lability worsen.
No reliable controlled studies have addressed complex refractory bipolar depression, but clinical experience suggests 1 approach for all of these responses:
Reconsider possible hypothyroidism. A low-normal T4—especially if decreased over time—and a mid-range or high-normal TSH—especially if increased—may indicate that subclinical hypothyroidism is inhibiting a response to mood stabilizers and antidepressants.18
Stop the antidepressant. If your patient is taking an antidepressant, it may be ineffective, creating mixed dysphoric hypomania, and/or driving another recurrence of depression. This is especially likely if the patient shows an initial prompt antidepressant response, but depression returns with irritability, insomnia, restlessness, or other subtle symptoms of dysphoric hypomania.
Withdraw the antidepressant gradually; for example, you might reduce the dose by 10% every few weeks so that the agent is discontinued across several months. Discontinuing an antidepressant too rapidly—even if it does not seem to be having any effect—can cause rebound depression that creates the mistaken impression that the antidepressant is needed.
Combine mood stabilizers. If a single mood stabilizer does not at least eliminate mood lability and other symptoms of activation, add a second agent. The combination of lithium and carbamazepine helps some depressed patients.20 Patients with considerable mood instability or psychotic symptoms may benefit from an adjunct antipsychotic.
Introduce mood stabilizers gradually. These medications may work more rapidly against mixed manic symptoms than they do against depression, especially when the dose is raised too quickly. The result is rapid control of irritability, hyperactivity, agitation, and related symptoms but an apparent increase in depression as mixed elements of elevated mood and energy are filtered out.
Add an antidepressant? If gradual adjustment of mood stabilizers eliminates mixed symptoms and mood fluctuations but the patient is still depressed, cautiously add an antidepressant. Antidepressants may be less likely to destabilize mood after all mixed elements have been treated completely.
Rapid and ultradian cycling: Complex disorders, complex treatment
No empiric data support the choice of one antidepressant over another. Published experience suggests that lamotrigine, 25 to 200 mg/d, may be less likely to destabilize mood, especially in combination with an established mood-stabilizing regimen. Approximately 20% of bipolar patients are thought to experience rapid cycling, defined as ≥4 affective episodes/year separated by at least 2 weeks of euthymia between poles or with an immediate switch from one pole to the other.32 The prevalence of ultradian cycling—in which multiple brief affective episodes (usually subsyndromal or mixed) occur each day—is unclear.
Both cycling types probably represent stages in the evolution of bipolar mood disorders rather than distinct diagnoses. In many cases, mood cycling abates after months to years, but morbidity can be high and the wrong treatment may perpetuate mood cycling.
Complex mood cycling rarely responds to a single treatment, probably because its pathophysiology is complex. The need for polypharmacy may create the impression of treatment failure, but no one would expect a single medication to be sufficient for other complex illnesses such as cancer or AIDS.