Insomnia and inflammation: a two hit model of depression risk and prevention

Depression is projected to increase by 2030 to a position of the greatest contributor to illness burden, due to its nearly 20% prevalence and its over 75% rate of recurrence. Moreover, even when pharmacological treatments are delivered, only about 30% of depressed adults achieve remission. The National Academy of Medicine has called for efforts to develop, evaluate and implement prevention strategies focused on depression1. However, to define those to be targeted for depression prevention, it is first necessary to identify biobehavioral factors of greatest risk salience.

Sleep disturbance (i.e., insomnia) is estimated to occur in 15% of the population, with rates as high as 70% in primary care patients2. Among depressed patients, sleep disturbance is one of the most frequent complaints, which often persists to serve as a potent predictor of depression recurrence2. Because use of antidepressant medications does not mitigate this risk3, interventions that target sleep disturbance to prevent depression relapse are needed.

Yet, not all persons with sleep disturbance develop an incident depression, which raises the possibility that other factors act in concert with insomnia to instigate the onset of clinically significant depressive symptoms. In addition, it is not known how insomnia gets converted into biological and affective risk for depression, which is critical for identification of molecular targets for pharmacological interventions, and for refinement of insomnia treatments that target affective responding.

Substantial observational, prospective and experimental data show that sleep disturbance is associated with increases in systemic markers of inflammation, such as C‐reactive protein and interleukin‐64, which have been found to predict depression2, 4, 5. Similarly, extremes of sleep duration, such as sleeping less than 6 hours or more than 8 hours per night, lead to elevated levels of systemic inflammation4. Finally, experimental sleep loss is found to induce an activation of inflammatory biology dynamics at multiple levels of analysis, including increases in systemic inflammation; monocytic production of pro‐inflammatory cytokines; activation of the nuclear factor (NF)‐κB transcription control pathway and the signal transducer and activator of transcription (STAT) family proteins; transcription of interleukin‐6 and tumor necrosis factor mRNA; and expression of the pro‐inflammatory transcriptome6. Interestingly, such immune activation in response to sleep loss is more robust in younger aged adults, and in women as compared to men, consistent with epidemiologic evidence showing that younger aged women are at greatest risk of depression.

Given that inflammation can elicit profound behavioral changes, which include the initiation of depressive symptoms such as sad mood, anhedonia, fatigue, psychomotor retardation and social‐behavioral withdrawal5, 7, 8, the inflammatory biotype induced by sleep disturbance may be a key phenomenon driving depression pathogenesis and recurrence. Indeed, sleep disturbance and depression overlap with several somatic conditions known to have an inflammatory basis, such as asthma, rheumatoid arthritis and cardiovascular disease.

Inflammation is not static, but rather shows dynamic variability, due in part to many contributing factors, including specific diseases (i.e., infections) and psychosocial factors (i.e., interpersonal stress)5. Such acute increases in inflammation may account for the prospective association between these multi‐level processes and subsequent onset of depression.

For example, in controlled experimental models that mimic exposure to an infectious challenge, inflammatory activation induces increases in depressed mood which correlate with activation of brain regions recognized for their role in the pathophysiology of major depressive disorder, and with decreases in reward processing or anhedonia, which correlate with a down‐regulation of ventral striatum activity5.

Moreover, such experimental strategies have yielded support for a “two hit” model of depression, in which sleep disturbance serves as a vulnerability factor to increase severity of depressive symptoms following exposure to an inflammatory challenge6, consistent with clinical observations that risk of depression is heightened when sleep disturbance occurs in concert with inflammatory states such as an infectious challenge or psychological stress. Alternatively, there is evidence that inflammation itself can serve as a vulnerability factor and increase the risk of depression when persons with the inflammatory biotype experience sleep disturbance.

If insomnia is associated with both inflammation and depression, and in turn, inflammation signals depressive symptom onset, then a credible hypothesis posits that treatment of sleep disturbance might reverse inflammation, and reduce the risk of depression. Emerging evidence supports this possibility.

Among the various treatment options for insomnia, cognitive behavioral therapy for insomnia (CBT‐I) is recognized to be the “gold standard”, with effects as robust and more durable than pharmacological therapies. Using randomized controlled trial designs, CBT‐I induces robust improvements in insomnia outcomes, which map onto long‐term (i.e., one year) and large (>50%) decreases in levels of C‐reactive protein, as well as decreases in the proportion of insomnia patients whose C‐reactive protein levels are considered high risk (>3.0 mg/dl)6. Importantly, these improvements in insomnia and inflammation temporally coincide with decreases in depressive symptoms.

Additionally, mind‐body interventions such as tai chi (i.e., a movement meditation) and mindfulness meditation, known to target stress response mechanisms, have been found to be non‐inferior to CBT‐I in the treatment of insomnia9, and also to reverse the insomnia related inflammatory leukocyte transcriptional profile (i.e., genes regulated by the pro‐inflammatory NF‐κB/Rel family) and activation of cellular inflammation, with effects greater than those observed following treatment with CBT‐I.

Whereas antagonism of endogenous inflammation by potent cytokine antagonists appears to reduce depressive symptoms, at least in those depressed patients who evidence an inflammatory subtype of depression5, such treatments are expensive and carry the risk of adverse effects not reported to occur with behavioral or mind‐body interventions, making these latter non‐pharmacologic therapies scalable for delivery in the community to improve insomnia outcomes and reduce inflammation, with possible effects in preventing depression.

Insomnia and inflammation act in concert as “two hits” to identify a population who is especially vulnerable for the occurrence and/or recurrence of depression. Treatments that target the inflammatory biotype and/or the insomniac behavioral phenotype are emerging as promising strategies to prevent depression.

The authors acknowledge the support provided by US National Institutes of Health grants R01AG051944, R01AG026364, R01CA160245 and R01CA207130, Max Kade Foundation, and the Cousins Center for Psychoneuroimmunology.