Examining Fronto-limbic Brain and Sleep Mechanisms of Antidepressant Effects in Cognitive-Behavioral Therapy for Insomnia

Objectives: Treating insomnia with Cognitive-Behavioral Therapy for Insomnia (CBT-I) improves depression symptoms, but the underlying mechanisms remain unknown. This single-arm mechanistic trial (ClinicalTrials.gov, NCT04424407) examined fronto-limbic and sleep mechanisms of CBT-I's antidepressant response.Participants: 48 participants (64% female; age 25-60) with insomnia and depression symptoms. Design: Participants completed functional magnetic resonance imaging (fMRI), polysomnography (PSG), and symptom assessments before and after 6 CBT-I sessions. Results: CBT-I resulted in reduced amygdala reactivity to fearful faces (d=0.55, p=0.008). Depression and insomnia (objective and self-reported) symptoms also improved. However, fMRI-assessed fronto-limbic changes were not associated with reduction of depressive symptom severity. Instead, reduced depressive symptoms correlated with reduced self- reported insomnia symptoms (p=0.001, η2p=0.19) and increased objective sleep ejiciency (p=0.04, η2p=0.10). Notably, pre-treatment PSG-assessed sleep ejiciency, but not fronto- limbic function nor insomnia symptoms, predicted reduced depressive symptoms (p=0.007, η2p=0.16), suggesting individuals with severe objective sleep disturbance may experience the greatest antidepressant benefit from CBT-I.