Treating bipolar depression: newly diagnosed patients may resist taking a mood stabilizer, but the cycling—not just the depression—requires treatment

Journal of Family Practice, March, 2003 by Richard C. Shelton

Bipolar depression can be difficult to recognize, especially early in the course of illness. In the outpatient setting, patients are more likely to present for treatment in a depressed rather than manic phase. (1) When the history is gathered, the patient may not recall manic or hypomanic periods, may not recognize hypomania as pathologic, or may have a diathesis for bipolar disorder without having experienced a manic episode.

Because accurate diagnosis is critical to effective pharmacologic treatment of bipolar disorder, it is important to query depressed patients fur evidence of mania, hypomania, or mixed states. Questioning a family member also can be helpful. Other findings that may suggest bipolar disorder include a family history of bipolar illness, early age of onset, and frequent mood episodes. (2)

Clinical hallmarks--although not absolute--can provide clues to the diagnosis. Bipolar depression (or mixed states) may be more likely than unipolar depression to present with severe fatigue, hypersomnia, marked irritability, severe anxiety, or racing thoughts. (1)

Even though you may decide the patient meets criteria for bipolar depression, the patient may resist the diagnosis or treatment with a mood stabilizer. Patients often identify depression as their principal problem and may experience mania or hypomania as pleasant, not abnormal. They may fear that treating hypomania may reduce their productivity on the job or at home. It is important, therefore, to recognize the illness and to inform the patient that the cycling--not just the depression--is the problem. Mood-stabilizing medications are the mainstay of treatment.

Mood stabilizers

The three medications considered foundational mood stabilizers in treating bipolar disorder are lithium, valproate (divalproex), and olanzapine. Other anticonvulsants and antipsychotics are being investigated as potential bipolar treatments, although much of the evidence is mixed.

Lithium. Lithium is effective as maintenance therapy for preventing mania and depression, and it has also shown benefit as monotherapy for bipolar depression in at least eight controlled trials. (3) However, lithium monotherapy is not an ideal treatment for bipolar depression. One direct comparison suggested that lithium may be somewhat less effective than antidepressants in depression. (4) Lithium also may produce an incomplete and delayed response relative to other therapies. This distinguishes lithium's effects in mania and maintenance therapy from its acute effects in depression.

Divalproex. Considerable evidence supports divalproex's effect in acute mania, and it may be an effective maintenance treatment. Open case reports and series have suggested a direct benefit of divalproex in bipolar depression. (3) However, a recent study by Sachs et al. (5) indicated that divalproex was not more effective than placebo in treating bipolar depression during an 8-week trial. This study was limited by a relatively small sample size, and more research is needed.

At this time, divalproex monotherapy cannot be considered a primary treatment for bipolar depression.

Olanzapine. The effects of olanzapine in treating mania and as maintenance therapy are reviewed elsewhere in this monograph. I will review its effects as a foundational agent in treating bipolar depression in the following section.

Atypical antipsychotics

Evidence ranging from case reports to double-blind, controlled clinical trials suggests that atypical antipsychotics are effective in bipolar disorder. Using evidence-based medicine's gold standard--the double-blind, randomized trial--olanzapine has a strong data set in bipolar illness, and risperidone also has some support. (6)

Unipolar depression. The effects of atypical antipsychotics in patients with unipolar depression support a potential benefit in bipolar depression as well. Two open case series suggest that risperidone may have an effect in resistant depression and may promote response in nonresistant depression.

Ostroff and Nelson (7) studied eight patients with unipolar depression unresponsive to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine or paroxetine. When a modest (0.5 or 1.0 mg/d) open-label dosage of risperidone was added, all eight patients responded rapidly and profoundly. This outcome supported risperidone's effectiveness as combination therapy in SSRI-resistant depression.

In another series of 36 patients with unipolar depression, risperidone was combined with fluvoxamine as initial therapy. (8) Among 30 patients who completed the study, 76% achieved remission and 7% did not respond. This response rate is higher than would be expected with fluvoxamine alone.

My colleagues and I conducted a controlled trial of olanzapine and fluoxetine in 28 patients with treatment-resistant, unipolar, nonpsychotic depression. (9) They had not responded to trials with an SSRI and a norepinephrine-serotonin reuptake inhibitor or to a 6-week run-in period with fluoxetine, up to 60 mg/d. Patients then were randomly assigned to 8 weeks of treatment with: