Modafinil-associated psychosis: a systematic review of case characteristics and management strategies

Background: Modafinil is a wakefulness-promoting agent widely used for narcolepsy and other sleep disorders. Although considered relatively safe, psychotic episodes associated with its use have been reported. However, no systematic review has focused on modafinil-associated psychosis. Objectives: To synthesize and describe the clinical characteristics, diagnostic backgrounds, and treatment outcomes of modafinil-associated psychosis through a systematic review of case reports and series. Design: Systematic review of published case reports and case series. Data sources and methods: A systematic literature search was conducted using PubMed and Web of Science. Case reports and series in English describing psychosis related to modafinil or armodafinil use were included. Age, sex, dose, diagnosis, symptoms, treatment, and outcomes were extracted and descriptively analyzed. Results: Twenty-four patients (13 men and 11 women, mean age 37.4 years) from 21 articles were included. The most common symptoms were hallucinations (66.7%) and delusions (58.3%). Median modafinil dose was 250 mg/day; however, some patients received excessive doses. The diagnoses included narcolepsy (33.3%), schizophrenia (20.8%), and depression (20.8%). Eighteen patients (75.0%) were treated with antipsychotics, and 16 (66.7%) discontinued modafinil. Most patients (70.8%) showed marked improvement. Conclusion: Modafinil-associated psychosis can develop across wide diagnostic and age ranges, and sometimes even at therapeutic doses. Although the potential risk factors remain unclear, caution should be exercised regarding the drug’s use at high doses, in patients with comorbid psychiatric conditions, and in cases of off-label usage for cognitive enhancement. Long-term follow-up is necessary to monitor outcomes and transition to schizophrenia. Further research is needed to identify the predictive factors and elucidate the underlying neurobiological mechanisms. Trial registration: Not registered.