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Evidence-Based Reviews


Modafinil: Not just for sleep disorders?

Off-label use of this stimulant might improve mood disorders, ADHD, and other conditions.

Vol. 6, No. 11 / November 2007

Ms. B, a middle-aged mother of 3, is being monitored for bipolar disorder. She has a history of stimulant abuse but has been in remission for 5 years. She complains of excessive daytime sleepiness. Most days she wakes at 7 AM, but sleeps on several occasions during the day. She also complains of fatigue and lack of motivation.

She is being treated with lithium, venlafaxine, and zolpidem and reports good adherence. Basic laboratory work and serum lithium levels are within acceptable ranges. Her symptoms do not improve when venlafaxine is titrated from 225 mg/d to 300 mg/d. She also reports previously failed trials with bupropion and fluoxetine.

We decide to try a psychostimulant as an augmenting agent. Because of her past stimulant abuse, we add modafinil, 100 mg/d and increase to 200 mg/d. Ms. B reports improvement in her daytime sleepiness and fatigue and—except for a mild headache—tolerates the medication well.

Modafinil is being investigated for potential roles in managing inattention, excess sleepiness, fatigue, and cognitive dysfunction associated with:

  • mood disorders (major depression and bipolar depression)
  • attention-deficit/hyperactivity disorder (ADHD)
  • schizophrenia
  • cocaine dependence.

This article discusses how the drug promotes wakefulness, how it might improve cognitive function, and what the evidence reveals about off-label indications.

How it works

Although modafinil’s precise mechanism of action is unknown, it is believed to promote wakefulness more selectively than conventional stimulants such as amphetamine and methylphenidate. Modafinil does not bind to norepinephrine, serotonin, dopamine, or benzodiazepine receptors.1,2 It might target specific hypothalamic regions such as the tuberomammillary nucleus and orexin neurons, which are peptide neurotransmitters that promote wakefulness.3,4

Preclinical studies found that modafinil increases neuronal activation in the hypothalamus.2,3 Because several cell groups in the hypothalamus project diffusely to the cerebral cortex and mediate arousal and attention, it has been suggested that modafinil might improve cognitive function.

Clinical trials found that modafinil has beneficial effects on:

  • working memory, recognition memory, and sustained attention in healthy humans
  • prefrontal-dependent cognitive functions in schizophrenia, major depression, and adult ADHD.5

Evidence for approved indications

Modafinil is indicated to improve wakefulness in patients who have excessive sleepiness associated with narcolepsy, obstructive sleep apnea, or shift work sleep disorder. It was approved for reducing excessive sleepiness in narcoleptic patients after two 9-week placebo-controlled clinical trials. The drug significantly reduced sleepiness and improved overall disease status as measured by the Clinical Global Impression of Change (CGI-C) scale.6,7

Modafinil also significantly improved sleep latency and CGI-C scores in 2 clinical trials of patients with obstructive sleep apnea/hypopnea.8,9 Approximately 80% of patients in these studies were using their continuous positive airway pressure devices.

In patients with shift work sleep disorder, a 12-week placebo-controlled clinical trial found that modafinil significantly improved sleep latency and CGI-C scores.10

Dosage and side effects. For patients with narcolepsy or obstructive sleep apnea, the recommended dose is 200 mg given in the morning.11 For patients prescribed modafinil for work-time wakefulness, the dose is 200 mg 1 hour before their work shift. Lower doses are recommended for patients who are elderly or have hepatic impairment. Those with severe hepatic impairment typically are prescribed 100 mg/d.11 Modafinil is rapidly absorbed and is metabolized primarily by the liver (Table 1). A summary of potential drug-drug interactions appears in Table 2.11

In pivotal trials, adverse events that occurred more frequently with modafinil than with placebo and in >5% of the study population included headache, nausea, nervousness, rhinitis, diarrhea, back pain, insomnia, dizziness, and dyspepsia. Headache was most commonly reported; in most patients, it resolved soon after they started taking modafinil. Post-marketing reports have included cases of psychosis, mania, and suspected serious skin reactions, including Stevens-Johnson syndrome.11 Modafinil lacks euphorigenic properties and has minimal potential for abuse.12

Table 1

Modafinil’s pharmacokinetics

Absorbed rapidly, with peak plasma concentrations at 2 to 4 hours

Apparent steady states reached after 2 to 4 days of dosing

Half-life: 15 hours

Major route of elimination (~90%) is metabolism, primarily by the liver

Table 2

Selected drug-drug interactions with modafinil

Action of modafinil

Potential drug interactions

Increases elimination of CYP 3A4 substrates

Carbamazepine, phenytoin may decrease modafinil levels
Azole antifungals, protease inhibitors, and erythromycin may increase modafinil levels

Inhibits CYP 2C19 enzyme

Modafinil may increase levels of citalopram, diazepam, and sertraline

Decreases absorption of ethinyl estradiol

Modafinil can decrease effectiveness of oral contraceptives

CYP: cytochrome P-450

Source:  Reference 11

Evidence for off-label uses

Major depressive disorder (MDD). The fatigue and excessive sleepiness often seen with MDD often persist after other depressive symptoms have remitted with antidepressant treatment.13 Patients with these symptoms might benefit from modafinil’s stimulating properties. Conventional stimulants such as methylphenidate have been used to improve neurovegetative symptoms of depression, but modafinil offers several advantages:

  • 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.

Matt’s parents request that their son be treated with a different type of agent. A trial of atomoxetine is not as effective as the initial methylphenidate dosage and produces similar side effects. We then consider modafinil because of its side effect profile. We start Matt on 100 mg once daily and titrate up to 200 mg/d 4 weeks later. Matt and his parents notice an immediate improvement in his ADHD symptoms with no side effects.

In children and adolescents. Wigal et al29 reviewed pooled data from 3 randomized, double-blind, placebo-controlled studies of modafinil in pediatric ADHD (Table 4). Modafinil was well tolerated and improved ADHD symptoms and behaviors regardless of patients’ stimulant use history.

In a recent open-label study, 220 children and young adolescents with ADHD who had completed 4 weeks of a double-blind, placebo-controlled trial were evaluated for an additional 8 weeks. Modafinil improved ADHD symptoms and overall clinical condition as determined by the parent- or clinician-completed ADHD Rating Scale-IV Home Version, the parent-completed Conners’ ADHD/DSM-IV Scale Parent Version, and the clinician-rated CGI scale.30 Insomnia, headache, and decreased appetite were the most commonly reported adverse events.

In adults. The results of 2 double-blind, placebo-controlled trials of modafinil in adults with ADHD have been positive:

  • In 1 study, modafinil (mean 206.8 mg/d) was more effective than placebo and comparable to dextroamphetamine in improving ADHD symptoms.31
  • In another, modafinil (a single 200-mg dose) increased cognitive performance during treatment.32

Summary. Once-daily dosing and minimal abuse potential make modafinil an attractive option for ADHD. Comparative studies with stimulants and nonstimulants such as atomoxetine as well as longer-term independent studies are needed. Modafinil might increase the risk of Stevens-Johnson syndrome when used in children and adolescents.11

Schizophrenia. Double-blind, randomized placebo-controlled studies have evaluated modafinil for improving cognitive function and reducing negative symptoms in patients with schizophrenia. Results have been inconsistent.

Continued...
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