BACKGROUND: Medication-supplemented psychotherapy is the primary treatment for mild major depressive disorder (MDD). However, limited resources and patient non-adherence present challenges, necessitating innovative and less burdensome interventions. This study aimed to compare the effectiveness of active and placebo violet light irradiation goggles for treating mild MDD. METHODS: The present study was a randomized, double-blind, placebo-controlled trial with a crossover design conducted at the Shinjuku-Yoyogi Mental Lab Clinic between June 2021 and December 2023. A total of 57 Japanese outpatients aged 20-74 years diagnosed with mild MDD were randomly assigned to use active or placebo 40-Hz violet light irradiation goggles for 4 weeks by adaptive allocation. Each participant wore their goggles for 4 weeks with 4-week washout intervals, while their medications for depression remained unchanged. The primary endpoints were the changes in the Montgomery-Åsberg Depression Rating Scale score (Phases I and II) 4 weeks after wearing the active and placebo goggles and differences between the group's scores. The safety of the violet light irradiation goggles was also investigated. RESULTS: The Montgomery-Åsberg Depression Rating Scale scores of the participants who wore active violet light irradiation goggles significantly improved compared with those of their counterparts, who wore placebo goggles (95 % confidence interval: -2.5 to -0.1
p = 0.042). No adverse events related to wearing the violet light irradiation goggles were observed. CONCLUSIONS: Violet light irradiation goggles are non-invasive and may be effective for treating mild MDD. Neuromodulation of the depression network via OPN5 by violet light may contribute to the anti-depressant effects. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs032210260
https://jrct.niph.go.jp/latest-detail/jRCTs032210260).