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The relationship between sleep disorders and depression is a bidirectional one. A meta-analysis published in 2022, for example, found that a number of sleep disorders and traits predict the future risk for depression, including insomnia, hypersomnia, short or long sleep duration, and even an “eveningness orientation,” marked by late meal patterns. Persistent insomnia at baseline was associated with a 2-fold increase in the development of depression, with a dose-response effect.
Evidence also exists for a relationship in the alternate direction; in one cross-sectional analysis with 3,000 participants, a baseline of anxiety or depression was associated with over a 4-fold and 2-fold increase in risk for developing insomnia, respectively. Another larger prospective population-based study included nearly 25,000 individuals (the Nord-Trøndelag Health Studies, or HUNT) who responded to surveys between 1995-1997 (HUNT 2) and then again between 2006-2008 (HUNT 3). People who had insomnia in both surveys but not depression (in HUNT 2) had a 6.2-fold increase in risk for developing depression in HUNT 3. Similarly, people who had depression in both surveys but did not initially have insomnia had a 6.7-fold increase in risk for developing insomnia by the latter survey. Between 80-90% of people with depression report experiencing insomnia.
Indeed, an observational cohort study published in JAMA Psychiatry found that among people with remitted major depressive disorder, sleep actigraphy (measured frequently over 1-2 years) was associated with depressive relapse, i.e., indicators of poor sleep (worse regularity, efficiency, etc.) could predict a relapse in depression. In addition to insomnia, other sleep disorders have been bidirectionally associated with depression, including hypersomnia, obstructive sleep apnea, and restless legs syndrome. In addition to depression, sleep disorders have been linked to dysglycemia, cardiovascular events, as well as emotional and cognitive dysregulation. It’s not surprising given that REM and NREM sleep regulate many brain structures, and impact a variety of functions and physiological processes, including emotional regulation, glucose metabolism, immunity, cognitive function, etc.
There does appear to be some overlap in the pathophysiology that may underlie both depression and sleep disorders. The Human Connectome Project included over 1,000 participants to examine the neural mechanisms driving both depression and impaired sleep; JAMA Psychiatry reported an increase in the functional connectivity of a number of brain regions, evaluated via functional magnetic resonance imaging. This included 162 functional connectivity links that involved areas associated with sleep, 39 of which were associated with depression scores (such as the lateral orbitofrontal cortex, dorsolateral prefrontal cortex, anterior and posterior cingulate cortices, etc.).
Depression can also be characterized by neuroinflammation, hypothalamic-pituitary-adrenal axis (HPA axis) hyperactivity, and other changes that can also be linked to insomnia. Neuroinflammation, for example, as well as impaired activity of the “glymphatic system” (a mechanism for waste removal in the brain), have been implicated as pathways related to insomnia as well as both depression and dementia. As one review concisely notes, “viewing the brain as an organ that depends on nightly fluid clearance reframes psychiatric pathophysiology and care.” The damage from the lack of clearance of neurotoxins promotes neuroinflammation and oxidative stress, which may drive depression, neurodegenerative disease, and even promotes further sleep disruption.
Importantly, there is some evidence that specific therapies, such as cognitive behavioral therapy for insomnia (CBT-I), not only can improve objective measures of sleep, but can also improve depression (though larger and well-controlled trials are needed). Bright light therapy has also been shown to influence glymphatic function among people with subthreshold depression in a randomized placebo-controlled trial, as well as improve depressive symptoms, reduce inflammation, and enhance prefrontal cortex activity. A meta-analysis of bright light therapy found improvements in both sleep and depression during pregnancy and the postnatal period.
Omega-3 fatty acids also appear to target pathophysiology common to both depression and sleep disorders. For example, omega-3 fatty acids have antioxidant effects and are shown to support a normal inflammatory response, both which help neuronal function and plasticity as well as glymphatic function. Meta-analyses support omega-3 intake for both mitigating depression as well as improving both sleep efficiency and sleep quality.
It’s worth noting that poor sleep has been associated with more rapid aging of the brain, in part mediated by systemic inflammation, and that persistent systemic inflammation may be the bridge that connects depression to its many comorbidities. In a recent interesting clinical trial, the actions of omega-3 fatty acids in supporting a healthy inflammatory response appeared particularly important. EPA/DHA was given daily to all participants (2.2 g EPA, 0.4g DHA, and 0.8 g other fatty acids) with major depressive disorder already receiving medication. Using an hs-CRP cut-off of ≥1 mg/L, participants above this threshold had significant improvements in depression scores (HAMD-17), as well as symptoms such as sleep and fatigue, when compared to those with an hs-CRP below the threshold, with the authors suggesting this may point to greater efficacy for “inflamed depression.” As we continue to unravel the overlapping pathologies that tie sleep, depression, and other related comorbidities together, more targeted therapies that address the root causes should emerge.
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