Modafinil: Not just for sleep disorders?

• decreased adverse CNS effects
  
• fewer drug-drug interactions
  
• minimal risk for dependence or abuse.
  

Two double-blind, placebo-controlled studies evaluated adjunctive modafinil treatment for patients whose MDD did not remit or partially responded to selective serotonin reuptake inhibitor therapy. In one, modafinil, 100 to 400 mg/d, produced significant decreases in Epworth Sleepiness Scale scores at 1 week and Fatigue Severity Scale scores at 2 weeks, but modafinil’s overall effects were not significantly greater than those of placebo in either study (Table 3).^14,15

A 6-week open-label study of 25 depressed patients with residual fatigue and sleepiness showed that adjunctive modafinil, 100 to 200 mg/d, significantly improved these symptoms, as well as Hamilton Rating Scale for Depression (HAM-D) score, as early as week 2. Seventy-six percent of patients responded to treatment, defined as a >50% reduction in HAM-D scores.¹⁶

Several open-label studies and case re-ports have evaluated adjunctive modafinil use in patients with:

• depression characterized by ongoing lethargy or apathy¹⁷
  
• depression with atypical features¹⁸
  
• seasonal affective disorder¹⁹
  
• partial response to antidepressants.^20,21
  

Modafinil improved depressive symptoms, overall clinical condition, fatigue, and excessive sleepiness, but these findings need to be confirmed by larger, randomized controlled trials.

Bipolar depression. A 6-week, double-blind, placebo-controlled trial randomly assigned 85 patients with bipolar depression to adjunctive modafinil, 100 to 200 mg/d, or placebo for 6 weeks (Table 3).²² The number of patients receiving an antidepressant or mood stabilizer was not significantly different between the modafinil and placebo groups.

The primary outcome measure was change in the Inventory for Depressive Symptoms (IDS) score from baseline to endpoint. Forty-four percent of patients receiving modafinil achieved a ≥50% reduction in IDS score, compared with 23% of the placebo group; this difference was statistically significant (P=0.03).

In this study, modafinil was well tolerated and did not induce mania or hypomania. Cases of modafinil-induced mania have been reported elsewhere.^23,24

The mechanisms of modafinil’s antidepressant effects are unclear. The drug does not cause release of norepinephrine or dopamine. One study proposed that modafinil acts by releasing histamine and activating noradrenaline receptors.²⁵ Activation of these receptors increases dopamine and norepinephrine in these areas, and excites histaminergic tuberomammillary neurons, increasing histamine levels. Another trial suggested that modafinil may improve mood by mechanisms similar to the antidepressant effects induced by sleep deprivation.²⁶

Summary. Modafinil may have a role in managing residual fatigue and excessive sleepiness associated with MDD and bipolar depression. Evidence for a mood-elevating effect is minimal; additional studies are needed. Adjunctive modafinil and conventional stimulants have not been compared head-to-head in patients with mood disorders. Modafinil’s tolerability profile and lack of euphorigenic and reinforcing properties make it a potentially attractive alternative, however.

ADHD. Approximately 30% of ADHD patients do not respond to or are unable to tolerate conventional stimulant medications such as methylphenidate and dextroamphetamine.²⁷ Several studies have evaluated modafinil as a potential treatment for ADHD based on the drug’s action on arousal and attention systems. Although modafinil’s precise mechanism of action in ADHD is unknown, proposed mechanisms include:

• hypothalamic and cerebral cortex neuronal activation
  
• action on histamine that results in internal vigilance.²⁸
  

Table 3

Can modafinil help patients with mood disorders?

Author	Study design	Modafinil dose	Conclusion
Major depressive disorder
Fava et al, 200514	8-week, double-blind, placebo-controlled; 331 subjects with partial or no response to SSRI monotherapy	200 mg/d	No significant difference between modafinil and placebo at final visit
DeBattista et al, 200315	6-week, double-blind, placebo-controlled; 136 subjects with partial response to antidepressant therapy	100 to 400 mg/d	Significant improvement in sleepiness by week 1 and fatigue by week 2, but differences between modafinil and placebo were not statistically significant by end of study
Konuk et al, 200616	6-week, open-label; 25 subjects with residual sleepiness or fatigue after SSRI therapy	100 to 200 mg/d	All patients showed significant improvement in sleepiness, fatigue, and HAM-D scores
Bipolar depression
Frye et al, 200722	6-week, double-blind, placebo-controlled trial; 85 subjects who did not respond to a mood stabilizer with or without concomitant antidepressant therapy	100 to 200 mg/d (mean 177 mg/d)	44% of modafinil patients achieved ≥50% reduction in IDS score compared with 23% in placebo group (P=0.03)
HAM-D: Hamilton Rating Scale for Depression; IDS: Inventory for Depressive Symptoms; SSRI: selective serotonin reuptake inhibitor

CASE 2: Another Tx for ADHD

Matt, age 8, is referred to our outpatient child psychiatric clinic after his parents noted declining school performance associated with increased aggression and irritability. Our assessment strongly supports a diagnosis of ADHD without comorbid conditions. We start Matt on methylphenidate, 5 mg twice daily, which quickly improves his ADHD symptoms. However, the medication causes GI side effects and profound sleep and weight changes.