Adjunctive Modafinil at Initiation of Treatment with a Selective Serotonin Reuptake Inhibitor Enhances the Degree and Onset of Therapeutic Effects in Patients with Major Depressive Disorder and Fatigue

Tomas Thorne

Last Updated: February 20, 2023



BACKGROUND: Benefit from selective serotonin reuptake inhibitor (SSRI) treatment in major depressive disorder (MDD) usually takes several weeks. Typically, a third of patients achieve remission and roughly half achieve response with acute treatment. This open-label study evaluated the efficacy and safety of modafinil treatment initiated with an SSRI in patients with MDD and fatigue.

METHOD: Twenty-nine patients with DSM-IV MDD, free from antidepressant therapy (>/= 4 weeks), were administered modafinil (titrated to 200 mg/day) and fluoxetine or paroxetine (20 mg/day) for 6 weeks. Assessments included the 21-item Hamilton Rating Scale for Depression (HAM-D), Structured Interview Guide for the HAM-D (SIGH-D), Fatigue Severity Scale (FSS), and Epworth Sleepiness Scale (ESS). The SIGH-D ratings were videotaped and rated by an independent rater masked to the visit schedule. Data were collected from August 2002 through March 2003.

RESULTS: Modafinil combined with an SSRI at treatment initiation significantly improved mean total SIGH-D scores within 1 week (-9.3, p <.001), and this improvement was progressive throughout the study (-21.2 at week 6, p <.001). Forty-two percent (11 of 26) and 79% (19 of 24) of patients were responders, and 39% (10 of 26) and 58% (14 of 24) of patients were remitters (HAM-D) by week 2 and week 6, respectively. Adjunct modafinil rapidly and significantly reduced fatigue (FSS score reduction from baseline = 0.7 at week 1, p <.01) and improved wakefulness (ESS score reduction from baseline = 3.6 at week 1, p <.01). The combination caused few adverse events, with nausea and headache being the most common.

CONCLUSION: Modafinil combined with an SSRI at treatment initiation may enhance the onset and degree of symptom benefit in patients with MDD and fatigue. Treatment with adjunct modafinil was generally well tolerated, with most adverse effects being mild or moderate in severity.


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