FROM THE CLINICAL KNOWLEDGE CENTER
Improvement in Bipolar Depression with an Adjunctive Wake-Promoting Agent

by Michelle Ostrander, PhD

Bipolar disorder (BP) is a clinically complex mood disorder characterized by a pattern of alternating manic and depressive episodes. BP has an estimated prevalence in the U.S. population of 1.5%,(1) but estimates are increased 5-fold if bipolar spectrum disorders are included.(2,3)

BP causes significant morbidity and mortality, particularly suicide. Suicide risk in patients with BP is estimated to range from 8% to 20%, and is 10 to 20 times that of the general population.(4) Completed suicide occurs most frequently during depressive episodes of BP.(5) Depressive symptoms are 3 to 4 times more likely than manic symptoms in patients with BP I disorder(6,7) and 39 times more likely in patients with BP II disorder.(8)

The pharmacotherapeutic management of BP depression is complex given its multiple presentations and variable course, the common use of combination therapy (mood stabilizers and antidepressants), and the possibility of switching into manic, hypomanic, or rapid-cycling states.(9) Furthermore, while an array of medications are Food and Drug Administration (FDA) approved for the treatment of acute mania in BP, the options for the acute treatment of BP depression are limited. There are currently only two agents with FDA indications for the management of BP depression—an olanzapine-fluoxetine combination and quetiapine. Although several randomized, controlled studies of adjunctive antidepressants and pramipexole have been conducted, as well as placebo-controlled trials of lithium, lamotrigine, and divalproex sodium, these studies have had mixed results. Thus, an urgent need remains for effective therapeutic options for the treatment of BP depression.

A recent study by Frye and colleagues evaluated the efficacy and safety of modafinil as an adjunctive treatment for BP depression,(10) which is often characterized by excessive sleepiness and fatigue. Modafinil is currently approved by the FDA for the management of excessive sleepiness in shift work disorder and narcolepsy, as well as residual sleepiness in patients receiving standard treatment for obstructive sleep apnea.

In this 6-week double-blind, placebo-controlled study, 85 patients with a diagnosis of BP I (n = 64) or BP II (n = 21), and an inadequate response to mood stabilizer therapy (with or without adjunctive antidepressants), were randomized to either placebo or modafinil (100-200 mg/day). Ratings performed at baseline, and every week thereafter during the study, included the Inventory of Depressive Symptoms—Clinician Rated (IDS), the Young Mania Rating Scale (YMRS), the Clinical Global Impression—Bipolar Version scale (CGI-BP), the Epworth Sleepiness Scale (ESS), and the Fatigue Severity Scale (FSS).

The primary outcome measure was change from baseline to endpoint on the IDS. Several secondary outcome measures were also examined including 1) clinical response, or a 50% reduction in overall IDS score at trial endpoint; 2) remission, or a final IDS score < 12; 3) change from baseline to endpoint on the CGI-BP depression severity score; 4) change from baseline to endpoint on a subset of IDS questions specifically assessing fatigue and energy-related symptoms.

The completion rate for this 6-week trial was 68.2% (58 participants) and the mean drug dose was 174.2 mg for modafinil and 177.27 mg for placebo. There was no significant difference in baseline demographic or clinical characteristics between the modafinil and placebo groups. The only group difference observed in medication regimen was that a greater number of patients in the modafinil group received sedative-hypnotics than in the placebo group. No other significant differences in number of medications or percentage of patients taking a particular class of medication (lithium, divalproex sodium, lamotrigine, carbamazepine, atypical antipsychotics, or adjunctive antidepressants) were noted.

Administration of modafinil significantly decreased scores on the IDS (p = .04), the four-item fatigue and energy subset of the IDS (p = .01), and the CGI-BP depression severity scale (p = .005) using an ANCOVA that controlled for baseline scores. Rates of response (50% reduction in overall IDS score) and remission (a final IDS score < 12) were significantly higher in the modafinil group than the placebo group (response: 44% versus 23%, p = .038; remission: 39% versus 18%, p = .01). Furthermore, the response rate on the four-item IDS subset was significantly greater for the modafinil than the placebo group (59% versus 31%, p = .01). Across the 6-week trial, the modafinil group exhibited greater improvements in IDS scores (from baseline) than the placebo group at week 2 (p = .029), week 5 (p = .005), and week 6 (p = .04).

There were no significant differences between the modafinil and placebo groups at endpoint in the YMRS score, the ESS score, the FSS score. Treatment-emergent mania/hypomania (TEM) did not differ between modafinil and placebo groups and TEM in the modafinil versus placebo groups was not affected by whether patients did or did not receive adjunctive antidepressant treatment.

Although this study did not randomize according to BP I versus BP II subtypes, the endpoint IDS score was significantly improved in BP I patients relative to BP II patients, after controlling for baseline scores (p = .012). In addition, patients with BP I exhibited a higher response rate (modafinil versus placebo, 68% and 42%, respectively, p = .05) on the four-item IDS than BP II patients (modafinil versus placebo, 14% and 7%, respectively, p = .6).

The results of this 6-week trial suggest that modafinil may be an effective adjunctive treatment for the improvement of symptoms of fatigue and low energy in bipolar depression. The researchers note several limitations of this study. First, participants received antidepressant therapy that was not standardized by dose, drug class, or duration of treatment. Second, mood stabilizer treatment was also not standardized by dose or treatment duration. Third, a greater percentage of patients in the modafinil group were on sedative-hypnotics than the placebo group. Fourth, dosing of modafinil in this study was fixed at a relatively low dose (100-200 mg/day). The researchers suggest that future studies should examine the effects of low versus high doses of modafinil on outcome measures.

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