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Modafinil Augmentation of SSRI Therapy in Patients with Major Depressive Disorder and Excessive Sleepiness and Fatigue: A 12-Week, Open-label, Extension Study

  • Michael E. Thase, Maurizio Fava, Charles DeBattista, Sanjay Arora and Rod J. Hughes...



Many patients with major depressive disorder (MDD) treated with selective serotonin reuptake inhibitors have residual symptoms (eg, persistent fatigue, excessive sleepiness) despite an overall antidepressant response. Placebo-controlled studies indicate that modafinil, a wake-promoting agent, may relieve residual symptoms.


This 12-week, open-label, dose titration, extension study followed an 8-week placebo-controlled study of modafinil augmentation in patients with MDD. The dose was 100–400 mg/day. The median stable dose was 300 mg/day. Assessments were the Epworth Sleepiness Scale, Brief Fatigue Inventory, Clinical Global Impression of Improvement scale, 17-item Hamilton Rating Scale for Depression, and Montgomery-Åsberg Depression Rating Scale.


Of the 245 patients treated, 194 completed the study; 70% reported Clinical Global Impression of Improvement scale responses of “much improved” or “very much improved” between open-label baseline and final visit (previous randomized modafinil group: 74%; placebo group: 66%). When data were analyzed for four subsets of patients (former modafinil responders, placebo responders, modafinil nonresponders, and placebo nonresponders), improvements in scores on all outcome measures were at least twice as great among former modafinil and placebo nonresponders compared with responders. Most common adverse events were headache (18%), nausea (9%), and dizziness (7%); all were generally mild to moderate in severity.


Twelve weeks of modafinil augmentation relieved excessive sleepiness, reduced fatigue, and improved patients' overall clinical condition, including mood.


Corresponding author

Please direct all correspondence to: Michael E. Thase, MD, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, PA 15260; Tel: 412-246-5290, Fax: 412-246-5340; E-mail:


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1.Maurice-Tison, S, Verdoux, H, Gay, B, Perez, P, Salamon, R, Bourgeois, ML. How to improve recognition and diagnosis of depressive syndromes using international diagnostic criteria. Br J Gen Pract. 1998;48:12451246.
2.Tylee, A, Gastpar, M, Lepine, JP, Mendlewicz, . DEPRES II (Depression Research in European Society II): a patient survey of the symptoms, disability and current management of depression in the community. DEPRES Steering Committee. Int Clin Psychopharmacol. 1999;14:139151.
3.Nierenberg, AA, Keefe, BR, Leslie, VC, et al.Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry. 1999;60:221225.
4.Fava, GA, Fabbri, S, Sonino, N. Residual symptoms in depression: an emerging therapeutic target. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:10191027.
5.Fava, M. Symptoms of fatigue and cognitive/executive dysfunction in major depressive disorder before and after antidepressant treatment. J Clin Psychiatry. 2003;64(suppl 14):3034.
6.Judd, LL, Akiskal, HS, Maser, JD, et al.Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as a predictor of rapid relapse. J Affect Disord 1998;50:97108.
7.Beasley, CM Jr, Koke, SC, Nilsson, ME, Gonzales, JS. Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: an updated meta-analysis. Clin Ther. 2000;22:13191330.
8.Zajecka, JM. Clinical issues in long-term treatment with antidepressants. J Clin Psychiatry. 2000;61 (suppl 2):2025.
9.Thase, ME. Therapeutic alternatives for difficult-to-treat depression: a narrative review of the state of the evidence. CNS Spectr. 2004;9:808821.
10.Sharpley, AL, Cowen, PJ. Effect of pharmacologic treatments on the sleep of depressed patients. Biol Psychiatry. 1995;37:8598.
11.Bauer, M, Forsthoff, A, Baethge, C, et al.Lithium augmentation therapy in refractory depression–update 2002. Eur Arch Psychiatry Clin Neurosci. 2003;253:132139.
12.Collaborative Working Group on Clinical Trial Evaluations. Atypical antipsychotics for treatment of depression in schizophrenia and affective disorders. J Clin Psychiatry. 1998;59(suppl 12):4145.
13.Joffe, RT, Schuller, DR. An open study of buspirone augmentation of serotonin reuptake inhibitors in refractory depression. J Clin Psychiatry. 1993;54:269271.
14.Dimitriou, EC, Dimitriou, CE. Buspirone augmentation of antidepressant therapy. J Clin Psychopharmacol. 1998;18:465469.
15.Marangell, LB. Augmentation of standard depression therapy. Clin Ther. 2000;22(suppl A):A25A38.
16.Baumgartner, A. Thyroxine and the treatment of affective disorders: an overview of the results of basic and clinical research. Int J Neuropsychoparmacol. 2000;3:149165.
17.Bauer, M, Whybrow, PC. Thyroid hormone, neural tissue and mood modulation. World J Biol Psychiatry. 2001;2:5969.
18.Prange, AJ Jr.Novel uses of thyroid hormones in patients with affective disorders. Thyroid. 1996;6:537543.
19.Markovitz, PJ, Wagner, S. An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol. 2003;23:207209.
20.Menza, MA, Kaufman, KR, Castellanos, A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry. 2000;61:378381.
21.Schwartz, TL, Azhar, N, Cole, JK, et al.An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy. J Clin Psychiatry. 2004;65:12231227.
22.DeBattista, C, Lembke, A, Solvason, HB, Ghebremichael, R, Poirier, J. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol. 2004;24:8790.
23.DeBattista, C, Doghramji, K, Menza, MA, et al.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;64:10571064.
24.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;66:8593.
25.Hamilton, M. Hamilton Depression Scale. In: Guy, W, ed. ECDEU Assessment Manual for Psychopharmacology Revised Edition. Rockville, Md: National Institute of Mental Health, U.S. Department of Health, Education, and Welfare: 1976:179192.
26.Johns, MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14:540545.
27.Krupp, LB, LaRocca, NG, Muir-Nash, J, Steinberg, AD. The Fatigue Severity Scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46:112111234.
28.Guy, W. ECDEU Assessment Manual for Psychopharmacology, Revised. Rockville, Md. U.S. Department of Health, Education and Welfare; 1976.
29.Mendoza, TR, Wang, XS, Cleeland, CS, et al.The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer. 1999;85:11861196.
30.Montgomery, SA, Åsberg, M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382389.
31.Iosifescu, DV, Nierenberg, AA, Mischoulon, D, et al.An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder. J Clin Psychiatry. 2005;66:10381042.
32.Papakostas, GI, Petersen, TJ, Nierenberg, AA, et al.Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry. 2004;65:217221.
33.Boutrel, B, Koob, GF. What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications. Sleep. 2004;27:11811194.
34.Engber, TM, Dennis, SA, Jones, BE, Miller, MS, Contreras, PC. Brain regional substrates for the actions of the novel wake-promoting agent modafinil in the rat: comparison with amphetamine. Neuroscience. 1998;87:905911.
35.Saletu, B, Frey, R, Krupka, M, et al.Differential effects of a new central adrenergic agonist—modafinil—and D-amphetamine on sleep and early morning behaviour in young healthy volunteers. Int J Clin Pharmacol Res. 1989;9:183195.
36.Deroche-Gamonet, V, Darnaudery, M, Bruino-Slot, L, Piat, F, Le Moal, M, Piazza, PV. Study of the addictive potential of modafinil in naive and cocaine-experienced rats. Psychopharmacology (Berl). 2002;161:387395.
37.Myrick, H, Malcolm, R, Taylor, B, LaRowe, S. Modafinil: preclinical, clinical, and post-marketing surveillance—a review of abuse liability issues. Ann Clin Psychiatry. 2004;16:101109.


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