<b><i>Introduction:</i></b> The global disease burden of major depressive disorder urgently requires prevention in high-risk individuals, such as recently discovered insomnia subtypes. Previous studies targeting insomnia with fully automated eHealth interventions to prevent depression are inconclusive: dropout was high and likely biased, and depressive symptoms in untreated participants on average improved rather than worsened. <b><i>Objective:</i></b> This randomized controlled trial aimed to efficiently prevent the worsening of depressive symptoms by selecting insomnia subtypes at high risk of depression for internet-based circadian rhythm support (CRS), cognitive behavioral therapy for insomnia (CBT-I), or their combination (CBT-I+CRS), with online therapist guidance to promote adherence. <b><i>Methods:</i></b> Participants with an insomnia disorder subtype conveying an increased risk of depression (<i>n</i> = 132) were randomized to no treatment (NT), CRS, CBT-I, or CBT-I+CRS. The Inventory of Depressive Symptomatology – Self Report (IDS-SR) was self-administered at baseline and at four follow-ups spanning 1 year. <b><i>Results:</i></b> Without treatment, depressive symptoms indeed worsened (<i>d</i> = 0.28, <i>p</i> = 0.041) in high-risk insomnia, but not in a reference group with low-risk insomnia. Therapist-guided CBT-I and CBT-I+CRS reduced IDS-SR ratings across all follow-up assessments (respectively, <i>d</i> = –0.80, <i>p</i> = 0.001; <i>d</i> = –0.95, <i>p</i> &#x3c; 0.001). Only CBT-I+CRS reduced the 1-year incidence of clinically meaningful worsening (<i>p</i> = 0.002). Dropout during therapist-guided interventions was very low (8%) compared to previous automated interventions (57–62%). <b><i>Conclusions:</i></b> The findings tentatively suggest that the efficiency of population-wide preventive strategies could benefit from the possibility to select insomnia subtypes at high risk of developing depression for therapist-guided digital CBT-I+CRS. This treatment may provide effective long-term prevention of worsening of depressive symptoms. <b><i>Trial registration:</i></b> the Netherlands Trial Register (NL7359).

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful col-How to cite this article: Tahmasian M, Aleman A, Andreassen OA, et al. ENIGMA-Sleep: Challenges, opportunities, and the road map.