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Modafinil: Not just for sleep disorders?
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
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
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 |
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.
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
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
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
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.
One double-blind, randomized, placebo-controlled crossover study of 20 patients with chronic schizophrenia found that modafinil, 200 mg/d, significantly improved short-term verbal memory span and attentional set shifting—the ability to discriminate and selectively attend to various stimulus dimensions (Table 5).33 Two other controlled studies showed no differences between the effects of modafinil and placebo on schizophrenia’s fatigue, cognition, or positive or negative symptoms.34,35
Summary. Although open-label studies have shown modafinil has beneficial effects on cognitive symptoms, controlled data are scarce. Reports of modafinil-induced psychosis or mania11 may limit the drug’s usefulness in schizophrenia patients.
Cocaine dependence. No medications are FDA-approved for treating cocaine dependence. A placebo-controlled, double-blind trial found that modafinil blunts cocaine euphoria under controlled conditions.36 This effect is hypothesized to be secondary to modafinil’s glutamate-enhancing and gamma-aminobutyric acid inhibitory effects.37
Summary. A single study supports using modafinil to improve outcomes in cocaine-dependent patients receiving standardized psychosocial treatment. More research is needed.
Table 4
Modafinil and ADHD: What the evidence says
| Author | Study design | Modafinil dosage | Conclusion |
|---|---|---|---|
| Wigal et al, 200629 | Analysis of data from 3 double-blind, placebo-controlled trials; total 638 children/adolescents, some of whom had received prior stimulant therapy | 170 to 425 mg/d | Whether or not patients received prior stimulant treatment, modafinil significantly improved ADHD symptoms and was well tolerated |
| Boellner et al, 200630 | 8-week, open-label extension of a 4-week double-blind, placebo-controlled trial; 220 subjects ages 6-14 | 100 to 400 mg/d | Modafinil improved ADHD symptoms and overall clinical condition |
| Taylor et al, 200031 | 2-week, double-blind, placebo-controlled crossover comparing modafinil with dextroamphetamine; 22 adults | Mean 206.8 mg/d | Both modafinil and dextroamphetamine significantly improved ADHD symptoms compared with placebo |
| Turner et al, 200432 | Double-blind, placebo-controlled crossover; 20 adults | Single 200-mg dose | Modafinil improved results on cognitive tests, including short-term memory span, visual memory, spatial planning, and sustained attention |
| ADHD: attention-deficit/hyperactivity disorder | |||
Table 5
Modafinil for schizophrenia or cocaine dependence:
More research is needed
| Author | Study design | Modafinil dosage | Conclusion |
|---|---|---|---|
| Schizophrenia | |||
| Turner et al, 200433 | Double-blind, placebo-controlled crossover; 20 adults | 200 mg/d | Modafinil significantly improved attentional set shifting and short-term verbal memory span |
| Sevy et al, 200534 | 8-week, double-blind, placebo-controlled; 24 subjects | Up to 200 mg/d | No significant difference between modafinil and placebo in reducing fatigue or positive or negative symptoms or in improving cognition |
| Pierre et al, 200735 | 8-week, double-blind, placebo-controlled; 20 subjects | 100 to 200 mg/d | Modafinil did not significantly improve neurocognitive or negative symptoms |
| Cocaine dependence | |||
| Dackis et al, 200538 | 8-week, double-blind, placebo-controlled; 62 cocaine-dependent subjects | 400 mg/d | Patients receiving modafinil provided significantly more cocaine-negative urine samples and were significantly more likely to achieve =3 weeks cocaine abstinence than those receiving placebo |
Related resource
- Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006;67(4):554-66.
- Atomoxetine • Strattera
- Bupropion • Wellbutrin
- Carbamazepine • Carbatrol, Tegretol, others
- Citalopram • Celexa
- Dextroamphetamine • Dexedrine, DextroStat
- Diazepam • Valium
- Erythromycin • Ery-Tab, Eryc, others
- Fluoxetine • Prozac
- Lithium • Eskalith, Lithobid
- Methylphenidate • Ritalin, others
- Modafinil • Provigil
- Phenytoin • Dilantin
- Sertraline • Zoloft
- Venlafaxine • Effexor
- Zolpidem • Ambien
Dr. Ramaswamy receives research support from Bristol-Myers Squibb, Shire, and Forest Pharmaceuticals and is a consultant to Dainippon Sumitomo Pharma.
Dr. Mattai reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Wilson receives research support from, is a consultant to, or is a speaker for the National Institute of Mental Health, the Substance Abuse and Mental Health Services Administration, the Veterans Administration, the State of Nebraska, the State of Ohio, Health Futures Foundation, Inc., Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Elan, Eli Lilly and Company, GlaxoSmithKline, Janssen, Ortho-McNeil, Pfizer, and Wyeth.
1. Mignot E, Nishino S, Guilleminault C, et al. Modafinil binds to dopamine uptake carrier site with low affinity. Sleep 1994;17:436-7.
2. Lin J-S, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine, methylphenidate, and modafinil induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci USA 1996;93:14128-33.
3. Scammell TE, Estabrooke IV, McCarthy MT, et al. Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 2000;20(22):8620-8.
4. Stenberg D. Neuroanatomy and neurochemistry of sleep. Cell Mol Life Sci 2007;64(10):1187-204.
5. Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology In press.
6. U.S. Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol 1998;43(1):88-97.
7. U.S. Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology 2000;54:1166-75.
8. Black JE, Hirshkowitz M. Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. Sleep 2005;28(4):464-71.
9. Pack AI, Black JE, Schwartz JR, Matheson JK. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med 2001;164(9):1675-81.
10. Czeisler CA, Walsh JK, Roth T, et al. and the U.S. Modafinil in Shift Work Sleep Disorder Study Group. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med. 2005;353(5):476-86. Published correction appears in: N Engl J Med 2005;353(10):1078.-
11. Provigil [package insert] West Chester, PA: Cephalon Inc; 2004.
12. Myrick H, Malcolm R, Taylor B, et al. Modafinil: preclinical, clinical, and post-marketing surveillance—a review of abuse liability issues. Ann Clin Psychiatry 2004;16(2):101-9.
13. Baldwin DS, Papakostas GI. Symptoms of fatigue and sleepiness in major depressive disorder. J Clin Psychiatry 2006;67(suppl 6):9-15.
14. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 2005;66(1):85-93.
15. DeBattista C, Doghramji K, Menza MA, et al. and the Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry 2003;64(9):1057-64.
16. Konuk N, Atasoy N, Atik L, Akay O. Open-label study of adjunct modafinil for the treatment of patients with fatigue, sleepiness, and major depression treated with selective serotonin reuptake inhibitors. Adv Ther 2006;23(4):646-54.
17. Markovitz PJ, Wagner S. An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol 2003;23(2):207-9.
18. Vaishnavi S, Gadde K, Alamy S, et al. Modafinil for atypical depression: effects of open-label and double-blind discontinuation treatment. J Clin Psychopharmacol 2006; 26(4): 373-8. Published correction appears in: J Clin Psychopharmacol. 2006;26(5):523.
19. Lundt L. Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study. J Affect Disord 2004;81(2):173-8.
20. DeBattista C, Lembke A, Solvason HB, et al. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol 2004;24(1):87-90.
21. Rasmussen NA, Schroder P, Olsen LR, et al. Modafinil augmentation in depressed patients with partial response to antidepressants: a pilot study on self-reported symptoms covered by the Major Depression Inventory (MDI) and the Symptom Checklist (SCL-92). Nord J Psychiatry 2005;59(3):173-8.
22. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 2007;164:1242-9.
23. Wolf J, Fiedler U, Anghelescu I, Schwertfeger N. Manic switch in a patient with treatment-resistant bipolar depression treated with modafinil. J Clin Psychiatry 2006;67(11):1817.-
24. Vorspan F, Warot D, Consoli A, et al. Mania in a boy treated with modafinil for narcolepsy. Am J Psychiatry 2005;162(4):813-4.
25. McClellan KJ, Spencer CM. Modafinil: a review of its pharmacology and clinical efficacy in the management of narcolepsy. CNS Drugs 1998;9(4):311-24.
26. Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006;67(4):554-66.
27. Dulcan M. Practice parameters for the assessment and treatment of children, adolescents and adults with attentiondeficit hyperactivity disorder. American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry 1997;36(suppl 10):85S-121S.
28. Lindsay SE, Gudelsky GA, Heaton PC. Use of modafinil for the treatment of attention deficit/hyperactivity disorder. Ann Pharmacother 2006;40(10):1829-33.
29. Wigal SB, Biederman J, Swanson JM, et al. Efficacy and safety of modafinil film-coated tablets in children and adolescents with or without prior stimulant treatment for attention-deficit/hyperactivity disorder: pooled analysis of 3 randomized, double-blind, placebo-controlled studies. Prim Care Companion J Clin Psychiatry 2006;8(6):352-60.
30. Boellner SW, Earl CQ, Arora S. Modafinil in children and adolescents with attention-deficit/hyperactivity disorder: a preliminary 8-week, open-label study. Curr Med Res Opin 2006;22(12):2457-65.
31. Taylor FB, Russo J. Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol 2000;10(4):311-20.
32. Turner DC, Clark L, Dowson J, et al. Modafinil improves cognition and response inhibition in adult attention-deficit/ hyperactivity disorder. Biol Psychiatry 2004;55(10):1031-40.
33. Turner DC, Clark L, Pomarol-Clotet E, et al. Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology 2004;29(7):1363-73.
34. Sevy S, Rosenthal MH, Alvir J, et al. Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications. J Clin Psychiatry 2005;66(7):839-43.
35. Pierre JM, Peloian JH, Wirshing DA, et al. A randomized, double-blind, placebo-controlled trial of modafinil for negative symptoms in schizophrenia. J Clin Psychiatry 2007;68(5):705-10.
36. Dackis CA, Lynch KG, Yu E, et al. Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol Depend 2003;70(1):29-37.
37. Perez de la Mora M, Aguilar-Garcia A, Ramon-Frias T, et al. Effects of the vigilance promoting drug modafinil on the synthesis of GABA and glutamate in slices of rat hypothalamus. Neurosci Lett 1999;259:181-5.
38. Dackis CA, Kampman KM, Lynch KG, et al. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology 2005;30(1):205-11.
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
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
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 |
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.
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
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
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
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.
One double-blind, randomized, placebo-controlled crossover study of 20 patients with chronic schizophrenia found that modafinil, 200 mg/d, significantly improved short-term verbal memory span and attentional set shifting—the ability to discriminate and selectively attend to various stimulus dimensions (Table 5).33 Two other controlled studies showed no differences between the effects of modafinil and placebo on schizophrenia’s fatigue, cognition, or positive or negative symptoms.34,35
Summary. Although open-label studies have shown modafinil has beneficial effects on cognitive symptoms, controlled data are scarce. Reports of modafinil-induced psychosis or mania11 may limit the drug’s usefulness in schizophrenia patients.
Cocaine dependence. No medications are FDA-approved for treating cocaine dependence. A placebo-controlled, double-blind trial found that modafinil blunts cocaine euphoria under controlled conditions.36 This effect is hypothesized to be secondary to modafinil’s glutamate-enhancing and gamma-aminobutyric acid inhibitory effects.37
Summary. A single study supports using modafinil to improve outcomes in cocaine-dependent patients receiving standardized psychosocial treatment. More research is needed.
Table 4
Modafinil and ADHD: What the evidence says
| Author | Study design | Modafinil dosage | Conclusion |
|---|---|---|---|
| Wigal et al, 200629 | Analysis of data from 3 double-blind, placebo-controlled trials; total 638 children/adolescents, some of whom had received prior stimulant therapy | 170 to 425 mg/d | Whether or not patients received prior stimulant treatment, modafinil significantly improved ADHD symptoms and was well tolerated |
| Boellner et al, 200630 | 8-week, open-label extension of a 4-week double-blind, placebo-controlled trial; 220 subjects ages 6-14 | 100 to 400 mg/d | Modafinil improved ADHD symptoms and overall clinical condition |
| Taylor et al, 200031 | 2-week, double-blind, placebo-controlled crossover comparing modafinil with dextroamphetamine; 22 adults | Mean 206.8 mg/d | Both modafinil and dextroamphetamine significantly improved ADHD symptoms compared with placebo |
| Turner et al, 200432 | Double-blind, placebo-controlled crossover; 20 adults | Single 200-mg dose | Modafinil improved results on cognitive tests, including short-term memory span, visual memory, spatial planning, and sustained attention |
| ADHD: attention-deficit/hyperactivity disorder | |||
Table 5
Modafinil for schizophrenia or cocaine dependence:
More research is needed
| Author | Study design | Modafinil dosage | Conclusion |
|---|---|---|---|
| Schizophrenia | |||
| Turner et al, 200433 | Double-blind, placebo-controlled crossover; 20 adults | 200 mg/d | Modafinil significantly improved attentional set shifting and short-term verbal memory span |
| Sevy et al, 200534 | 8-week, double-blind, placebo-controlled; 24 subjects | Up to 200 mg/d | No significant difference between modafinil and placebo in reducing fatigue or positive or negative symptoms or in improving cognition |
| Pierre et al, 200735 | 8-week, double-blind, placebo-controlled; 20 subjects | 100 to 200 mg/d | Modafinil did not significantly improve neurocognitive or negative symptoms |
| Cocaine dependence | |||
| Dackis et al, 200538 | 8-week, double-blind, placebo-controlled; 62 cocaine-dependent subjects | 400 mg/d | Patients receiving modafinil provided significantly more cocaine-negative urine samples and were significantly more likely to achieve =3 weeks cocaine abstinence than those receiving placebo |
Related resource
- Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006;67(4):554-66.
- Atomoxetine • Strattera
- Bupropion • Wellbutrin
- Carbamazepine • Carbatrol, Tegretol, others
- Citalopram • Celexa
- Dextroamphetamine • Dexedrine, DextroStat
- Diazepam • Valium
- Erythromycin • Ery-Tab, Eryc, others
- Fluoxetine • Prozac
- Lithium • Eskalith, Lithobid
- Methylphenidate • Ritalin, others
- Modafinil • Provigil
- Phenytoin • Dilantin
- Sertraline • Zoloft
- Venlafaxine • Effexor
- Zolpidem • Ambien
Dr. Ramaswamy receives research support from Bristol-Myers Squibb, Shire, and Forest Pharmaceuticals and is a consultant to Dainippon Sumitomo Pharma.
Dr. Mattai reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Wilson receives research support from, is a consultant to, or is a speaker for the National Institute of Mental Health, the Substance Abuse and Mental Health Services Administration, the Veterans Administration, the State of Nebraska, the State of Ohio, Health Futures Foundation, Inc., Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Elan, Eli Lilly and Company, GlaxoSmithKline, Janssen, Ortho-McNeil, Pfizer, and Wyeth.
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
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
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 |
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.
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
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
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
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.
One double-blind, randomized, placebo-controlled crossover study of 20 patients with chronic schizophrenia found that modafinil, 200 mg/d, significantly improved short-term verbal memory span and attentional set shifting—the ability to discriminate and selectively attend to various stimulus dimensions (Table 5).33 Two other controlled studies showed no differences between the effects of modafinil and placebo on schizophrenia’s fatigue, cognition, or positive or negative symptoms.34,35
Summary. Although open-label studies have shown modafinil has beneficial effects on cognitive symptoms, controlled data are scarce. Reports of modafinil-induced psychosis or mania11 may limit the drug’s usefulness in schizophrenia patients.
Cocaine dependence. No medications are FDA-approved for treating cocaine dependence. A placebo-controlled, double-blind trial found that modafinil blunts cocaine euphoria under controlled conditions.36 This effect is hypothesized to be secondary to modafinil’s glutamate-enhancing and gamma-aminobutyric acid inhibitory effects.37
Summary. A single study supports using modafinil to improve outcomes in cocaine-dependent patients receiving standardized psychosocial treatment. More research is needed.
Table 4
Modafinil and ADHD: What the evidence says
| Author | Study design | Modafinil dosage | Conclusion |
|---|---|---|---|
| Wigal et al, 200629 | Analysis of data from 3 double-blind, placebo-controlled trials; total 638 children/adolescents, some of whom had received prior stimulant therapy | 170 to 425 mg/d | Whether or not patients received prior stimulant treatment, modafinil significantly improved ADHD symptoms and was well tolerated |
| Boellner et al, 200630 | 8-week, open-label extension of a 4-week double-blind, placebo-controlled trial; 220 subjects ages 6-14 | 100 to 400 mg/d | Modafinil improved ADHD symptoms and overall clinical condition |
| Taylor et al, 200031 | 2-week, double-blind, placebo-controlled crossover comparing modafinil with dextroamphetamine; 22 adults | Mean 206.8 mg/d | Both modafinil and dextroamphetamine significantly improved ADHD symptoms compared with placebo |
| Turner et al, 200432 | Double-blind, placebo-controlled crossover; 20 adults | Single 200-mg dose | Modafinil improved results on cognitive tests, including short-term memory span, visual memory, spatial planning, and sustained attention |
| ADHD: attention-deficit/hyperactivity disorder | |||
Table 5
Modafinil for schizophrenia or cocaine dependence:
More research is needed
| Author | Study design | Modafinil dosage | Conclusion |
|---|---|---|---|
| Schizophrenia | |||
| Turner et al, 200433 | Double-blind, placebo-controlled crossover; 20 adults | 200 mg/d | Modafinil significantly improved attentional set shifting and short-term verbal memory span |
| Sevy et al, 200534 | 8-week, double-blind, placebo-controlled; 24 subjects | Up to 200 mg/d | No significant difference between modafinil and placebo in reducing fatigue or positive or negative symptoms or in improving cognition |
| Pierre et al, 200735 | 8-week, double-blind, placebo-controlled; 20 subjects | 100 to 200 mg/d | Modafinil did not significantly improve neurocognitive or negative symptoms |
| Cocaine dependence | |||
| Dackis et al, 200538 | 8-week, double-blind, placebo-controlled; 62 cocaine-dependent subjects | 400 mg/d | Patients receiving modafinil provided significantly more cocaine-negative urine samples and were significantly more likely to achieve =3 weeks cocaine abstinence than those receiving placebo |
Related resource
- Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006;67(4):554-66.
- Atomoxetine • Strattera
- Bupropion • Wellbutrin
- Carbamazepine • Carbatrol, Tegretol, others
- Citalopram • Celexa
- Dextroamphetamine • Dexedrine, DextroStat
- Diazepam • Valium
- Erythromycin • Ery-Tab, Eryc, others
- Fluoxetine • Prozac
- Lithium • Eskalith, Lithobid
- Methylphenidate • Ritalin, others
- Modafinil • Provigil
- Phenytoin • Dilantin
- Sertraline • Zoloft
- Venlafaxine • Effexor
- Zolpidem • Ambien
Dr. Ramaswamy receives research support from Bristol-Myers Squibb, Shire, and Forest Pharmaceuticals and is a consultant to Dainippon Sumitomo Pharma.
Dr. Mattai reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Wilson receives research support from, is a consultant to, or is a speaker for the National Institute of Mental Health, the Substance Abuse and Mental Health Services Administration, the Veterans Administration, the State of Nebraska, the State of Ohio, Health Futures Foundation, Inc., Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Elan, Eli Lilly and Company, GlaxoSmithKline, Janssen, Ortho-McNeil, Pfizer, and Wyeth.
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2. Lin J-S, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine, methylphenidate, and modafinil induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci USA 1996;93:14128-33.
3. Scammell TE, Estabrooke IV, McCarthy MT, et al. Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 2000;20(22):8620-8.
4. Stenberg D. Neuroanatomy and neurochemistry of sleep. Cell Mol Life Sci 2007;64(10):1187-204.
5. Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology In press.
6. U.S. Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol 1998;43(1):88-97.
7. U.S. Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology 2000;54:1166-75.
8. Black JE, Hirshkowitz M. Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. Sleep 2005;28(4):464-71.
9. Pack AI, Black JE, Schwartz JR, Matheson JK. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med 2001;164(9):1675-81.
10. Czeisler CA, Walsh JK, Roth T, et al. and the U.S. Modafinil in Shift Work Sleep Disorder Study Group. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med. 2005;353(5):476-86. Published correction appears in: N Engl J Med 2005;353(10):1078.-
11. Provigil [package insert] West Chester, PA: Cephalon Inc; 2004.
12. Myrick H, Malcolm R, Taylor B, et al. Modafinil: preclinical, clinical, and post-marketing surveillance—a review of abuse liability issues. Ann Clin Psychiatry 2004;16(2):101-9.
13. Baldwin DS, Papakostas GI. Symptoms of fatigue and sleepiness in major depressive disorder. J Clin Psychiatry 2006;67(suppl 6):9-15.
14. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 2005;66(1):85-93.
15. DeBattista C, Doghramji K, Menza MA, et al. and the Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry 2003;64(9):1057-64.
16. Konuk N, Atasoy N, Atik L, Akay O. Open-label study of adjunct modafinil for the treatment of patients with fatigue, sleepiness, and major depression treated with selective serotonin reuptake inhibitors. Adv Ther 2006;23(4):646-54.
17. Markovitz PJ, Wagner S. An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol 2003;23(2):207-9.
18. Vaishnavi S, Gadde K, Alamy S, et al. Modafinil for atypical depression: effects of open-label and double-blind discontinuation treatment. J Clin Psychopharmacol 2006; 26(4): 373-8. Published correction appears in: J Clin Psychopharmacol. 2006;26(5):523.
19. Lundt L. Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study. J Affect Disord 2004;81(2):173-8.
20. DeBattista C, Lembke A, Solvason HB, et al. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol 2004;24(1):87-90.
21. Rasmussen NA, Schroder P, Olsen LR, et al. Modafinil augmentation in depressed patients with partial response to antidepressants: a pilot study on self-reported symptoms covered by the Major Depression Inventory (MDI) and the Symptom Checklist (SCL-92). Nord J Psychiatry 2005;59(3):173-8.
22. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 2007;164:1242-9.
23. Wolf J, Fiedler U, Anghelescu I, Schwertfeger N. Manic switch in a patient with treatment-resistant bipolar depression treated with modafinil. J Clin Psychiatry 2006;67(11):1817.-
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25. McClellan KJ, Spencer CM. Modafinil: a review of its pharmacology and clinical efficacy in the management of narcolepsy. CNS Drugs 1998;9(4):311-24.
26. Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006;67(4):554-66.
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28. Lindsay SE, Gudelsky GA, Heaton PC. Use of modafinil for the treatment of attention deficit/hyperactivity disorder. Ann Pharmacother 2006;40(10):1829-33.
29. Wigal SB, Biederman J, Swanson JM, et al. Efficacy and safety of modafinil film-coated tablets in children and adolescents with or without prior stimulant treatment for attention-deficit/hyperactivity disorder: pooled analysis of 3 randomized, double-blind, placebo-controlled studies. Prim Care Companion J Clin Psychiatry 2006;8(6):352-60.
30. Boellner SW, Earl CQ, Arora S. Modafinil in children and adolescents with attention-deficit/hyperactivity disorder: a preliminary 8-week, open-label study. Curr Med Res Opin 2006;22(12):2457-65.
31. Taylor FB, Russo J. Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol 2000;10(4):311-20.
32. Turner DC, Clark L, Dowson J, et al. Modafinil improves cognition and response inhibition in adult attention-deficit/ hyperactivity disorder. Biol Psychiatry 2004;55(10):1031-40.
33. Turner DC, Clark L, Pomarol-Clotet E, et al. Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology 2004;29(7):1363-73.
34. Sevy S, Rosenthal MH, Alvir J, et al. Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications. J Clin Psychiatry 2005;66(7):839-43.
35. Pierre JM, Peloian JH, Wirshing DA, et al. A randomized, double-blind, placebo-controlled trial of modafinil for negative symptoms in schizophrenia. J Clin Psychiatry 2007;68(5):705-10.
36. Dackis CA, Lynch KG, Yu E, et al. Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol Depend 2003;70(1):29-37.
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