OBJECTIVES: Modafinil is an approved medication primarily used for treating excessive daytime sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work sleep disorder. However, its usage extends beyond approved indications, including off-label use for major depressive disorder (MDD). This systematic review aims to comprehensively assess adverse events of both approved and unapproved applications of modafinil.

METHODS: A thorough search of PubMed, Embase, and Cochrane databases was conducted to retrieve relevant literature. The search employed MeSH terms and Emtree terms in combination. The literature review focused on 12 adverse events (i.e., headache, decreased appetite, abdominal pain, nausea, anxiety/nervousness, dizziness, insomnia, weight loss, diarrhea, dyspepsia, back pain, and rhinitis) known to occur in the modafinil group compared to the placebo group. The quality of the literature was evaluated using Risk of Bias ver. 2.0.

RESULTS: A total 10 and 4 randomized controlled trials (RCTs), satisfying inclusion and exclusion criteria, were included for assessing the safety of modafinil for approved and off-label use for MDD, respectively. The analysis of risk ratio (RR) for each adverse event revealed statistically significant associations between modafinil usage to treat narcolepsy and higher risks of nausea (RR: 2.44, 95% CI: 1.05-5.72) and diarrhea (RR: 2.81, 95% CI: 1.19-6.63). On the other hand, anxiety/nervousness (RR: 1.95, 95% CI: 1.11-3.42) was found to be a higher risk adverse event associated with modafinil usage in MDD patients.

CONCLUSIONS: Our findings highlight the specific adverse events that may occur in different patient populations when using modafinil and emphasize the need for careful consideration and monitoring when prescribing modafinil in different conditions.