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To investigate effects of agomelatine and mirtazapine on sleep disturbances in patients with major depressive disorder. A total of 30 depressed patients with sleep disturbances, 27 of which completed the study, took agomelatine or mirtazapine for 8 weeks. Subjective scales were administered, and polysomnography was performed at baseline and at the end of week 1 and 8. Functional magnetic resonance imaging was performed at baseline and at the end of week 8. Compared with baseline, scores on the Hamilton Depression Scale, Hamilton Anxiety Scale, Pittsburgh Sleep Quality Index, Sleep Dysfunction Rating Scale, and Insomnia Severity Index after 8 weeks of treatment significantly decreased in both groups, with no significant differences between groups, accompanied by significant increases in total sleep time, sleep efficiency, and rapid eye movement (REM) sleep and significant decrease in wake after sleep onset. Mirtazapine treatment increased N3 sleep at week 1 compared with agomelatine treatment, but this difference disappeared at week 8. The increases in the percentage and duration of N3 sleep were positively correlated with increases in connectivity between right dorsal lateral prefrontal cortex (dlPFC) and right precuneus and between left posterior cingulate cortex and right precuneus in both groups, respectively. Functional connectivity (FC) between right dlPFC and left precuneus in mirtazapine group was higher compared with agomelatine group after 8 weeks of treatment. These findings indicated that both agomelatine and mirtazapine improved sleep in depressed patients, and the effect of mirtazapine was greater than agomelatine with regard to rapidly increasing N3 sleep and gradually improving FC in the brain.

Background: Patients with depression often suffer from circadian rhythm disruptions, such as insomnia and a lower amplitude of daily rhythms of locomotor activity. However, whether circadian disorders precede depression and act as a predictor for subsequent depression have not been unanimously approved. In light of increasing evidence of an association between disrupted circadian rhythms and affective symptoms, a meta-analysis was conducted to examine the effect of circadian disruptions on incident depression. Methods: A systematic search was performed in PubMed, Embase, Web of Science, PsycINFO, PsycArticles, CINAHL database. The search results were restricted to be published in English up to April 10, 2020.Reference lists from included studies and relevant reviews were also screened. We included longitudinal cohort studies that examined the predictive role of all various types of circadian disruption in incident depression. Two reviewers independently extracted information on study design, participants’ characteristics and diagnostic criteria for circadian disruption and depression. Study quality was assessed using the Newcastle-Ottawa Scale. Random-effect models were applied to all meta-analyses given potential heterogeneity. For insomnia, subgroup analyses were performed based on subject’s characteristics, insomnia symptom domains and numbers and the investigated methods. Pool-effect estimates of relative risks to develop incident depression in groups with circadian disruption compared to groups without. This study is registered with PROSPERO, CRD42020179135. Findings: A total of 49 studies were eligible for this meta-analysis. Of 49 eligible studies, included types of circadian disruption were sleep disturbances (n = 45), chronotype (n = 2), cortisol awakening response (n = 1) and rest - activity rhythm (n = 1). Insomnia, hypersomnia, excessive daytime sleepiness (EDS), short sleep duration, obstructive sleep apnea (OSA), restless legs syndrome (RLS), an evening preference, heightened levels of cortisol in awakening response and low robustness of rest - activity rhythm all acted as significant predictors of occurrence of depression. Among insomnia subtypes, difficulty initiating sleep (DIS) and difficulty maintaining sleep (DMS) predicted future depression. Of note, persistent insomnia (OR: 5.02) contributed to more than two - fold risk of incident depression compared to insomnia (OR: 2.34). Moreover, insomnia symptom numbers were associated with incident depression in a gradient trend. Interpretation: Different types of circadian disorders act as risk factors of onset of depression, which clinicians should be informed of. Future research should be aimed to determine the casual relationship between other types of circadian disorders and onset of depression, and moreover to further elucidate the underlying mechanisms. Funding Statement: This work was supported in part by the National Natural Science Foundation of China (no. 81871071 and 81171251) and Beijing Municipal Natural Science Foundation (no. 7162101). Declaration of Interests: All of the authors declare no conflict of interest.

Patients with depression often suffer from sleep disorders and non-sleep circadian disorders. However, whether they precede and predict subsequent depression is unclear. We conducted a meta-analysis of studies on sleep disorders and non-sleep circadian disorders. We found insomnia, hypersomnia, short and long sleep duration, obstructive sleep apnea, restless legs syndrome and eveningness orientation at baseline all led to subsequent depression. Those with propensity to late meal patterns, heightened levels of cortisol in awakening response and low robustness of rest-activity rhythm at baseline had higher risks for later depression. Among insomnia subtypes, difficulty initiating sleep and difficulty maintaining sleep predicted future depression. Notably, persistent insomnia at baseline contributed to more than two-fold risk of incident depression compared to insomnia. Moreover, insomnia symptom numbers showed dose-dependent relationship with the incident depression. In conclusion, different types of sleep disorders and non-sleep circadian disorders were proven to be risk factors of subsequent depression, and mechanisms underlying the relationship between sleep disorders, non-sleep circadian disorders and subsequent depression should be further elucidated in the future.