title: A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness.
abstract: BACKGROUND
  Up to one half of depressed patients have partial or no response to antidepressant monotherapy. This multicenter, placebo-controlled study evaluated the efficacy of modafinil augmentation in major depressive disorder (MDD) patients with fatigue and excessive sleepiness despite selective serotonin reuptake inhibitor (SSRI) monotherapy.
  
  
  METHODS
  Patients (18-65 years) with a DSM-IV diagnosis of MDD and partial response to SSRI monotherapy (> or = 8 weeks) at a stable dose for > or = 4 weeks were eligible. Patients had screening/baseline 31-item Hamilton Rating Scale for Depression (HAM-D) scores of 14 to 26, Epworth Sleepiness Scale (ESS) scores > or = 10, and Fatigue Severity Scale (FSS) scores > or = 4. Patients were randomly assigned to augmentation therapy with modafinil 200 mg/day or placebo for 8 weeks. Assessments included the ESS, Clinical Global Impressions-Improvement scale (CGI-I), 31- and 17-item HAM-D, FSS, Brief Fatigue Inventory (BFI), and Montgomery-Asberg Depression Rating Scale (MADRS).
  
  
  RESULTS
  Of 311 enrolled patients who received > or = 1 dose of study drug, 158 were randomly assigned to modafinil (70% women) and 153 to placebo (72% women); 85% of each treatment group completed the study. At final visit, modafinil significantly improved patients' overall clinical condition compared with placebo on the basis of CGI-I scores (p = .02), and there were trends toward greater mean reductions in ESS, 31- and 17-item HAM-D, and MADRS scores versus placebo. Modafinil significantly reduced BFI scores for worst fatigue at final visit (p < .05 vs. placebo). There were no significant differences between modafinil and placebo at final visit in FSS or BFI total scores. Adverse events significantly more common during modafinil compared with placebo treatment were nausea (9% vs. 2%; p = .01) and feeling jittery (4% vs. 1%; p = .03).
  
  
  CONCLUSIONS
  These findings suggest that modafinil is a well-tolerated and potentially effective augmenting agent for SSRI partial responders with fatigue and sleepiness.
authors.affiliation: Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. MFava@Partners.org
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fava
authors.forename: Michael E
authors.initials: ME
authors.lastname: Thase
authors.forename: Charles
authors.initials: C
authors.lastname: DeBattista
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D004359:Drug Therapy, Combination; D005221:Fatigue / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D010919:Placebos; D011569:Psychiatric Status Rating Scales; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D012893:Sleep Wake Disorders / Q000139:chemically induced / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D000077408:Modafinil; D010919:Placebos; D017367:Selective Serotonin Reuptake Inhibitors