Cascading down into the complex interrelationship of chronobiology disturbances with other biological and behavioral disturbances is illuminating. For example, it is now well established that alterations in diet could result in significant changes in circadian clock activity and chronobiological processes.15 On a related note, obstructive sleep apnea is well known to be associated with positive energy balance, obesity, sleep alteration, and risk for mental disorders. Novel insights regarding the gut microbiota/microbiome indicate that commensal organisms within the gastrointestinal tract may influence circadian clock nuclei within the hypothalamus. This observation is intriguing in light of the replicated observation that the gut bacterial signature maybe relevant to the propensity for cardiometabolic disturbances and mental disorders.  

Further insights are provided by the association between common “functional” disorders, chronobiology, sleep disturbance, and mental disorders. For example, chronic fatigue syndrome (CFS) and irritable bowel syndrome (IBS) are common presentations in clinical settings and are associated with significant morbidity, chronicity of illness, and suboptimal treatment options. Moreover, CFS and IBS are highly associated with several mental disorders (eg, mood, anxiety, and somatoform). One of the most disabling complaints among individuals with CFS and IBS is disturbance in duration and quality of sleep. Moreover, it is also well established that both CFS and IBS are linked to disturbance in inflammatory homeostatic systems as well as changes in gut microbiota. It is a viable hypothesis that disturbance in sleep in both CFS and IBS may be a cause and/or consequence of altered inflammatory systems governed by changes in gut microbiota. Completing the complex pathogenetic framework of any mental disorder is not easy, but it is not without interest that early life adversity—which differentially affects CFS, IBS, and many other mental and/or medical disorders—is also highly associated with disturbance in gut microbiota.16

Taken together, the association between sleep and inflammation has both clinical and mechanistic implications. Clinicians are reminded to routinely assess patients for sleep disturbance and where applicable modify risk factors and offer multimodality treatment interventions (eg, cognitive behavioral therapy for insomnia).  Indeed, pharmacologic treatments are not infrequently required when lifestyle and/or nonpharmacologic approaches prove unsuccessful. Individuals who are at risk for mental/medical disorders (ie, familial loading) and who complain of sleep disturbance should be carefully monitored for the declaration of mental/medical disorders. It is tempting to speculate that targeting sleep in such circumstances may pre-empt and prevent a mental/medical disorder. Mechanistically, the association between sleep disturbance and inflammation provides empirical support for the possible etiopathogenic role of chronobiological disturbances. The introduced framework by the National Institutes of Health (ie, Research Domain Criteria) has a dedicated domain to circadian rhythm disturbances as they are known to be transdiagnostic. It would not be hyperbole to make the statement: “understand the biology of sleep” and you will likely understand the biology of many mental and medical disorders.


1. Patyar S, Patyar RR. Correlation between sleep duration and risk of stroke. J Stroke Cerebrovasc Dis. 2015;24(5):905-911.

2. Morin CM, LeBlanc M, Belanger L, Ivers H, Merette C, Savard J. Prevalence of insomnia and its treatment in Canada. Can J Psychiatry. 2011;56(9):540-548.

3. Niu J, Han H, Wang Y, Wang L, Gao X, Liao S. Sleep quality and cognitive decline in a community of older adults in Daqing City, China. Sleep Med. 2016;17:69-74.

4. Kupfer DJ, Himmelhoch JM, Swartzburg M, Anderson C, Byck R, Detre TP. Hypersomnia in manic-depressive disease (a preliminary report). Dis Nerv Syst. 1972;33(11):720-724.

5. Srinivasan V, Smits M, Spence W, et al. Melatonin in mood disorders. World J Biol Psychiatry. 2006;7(3):138-151.

6. Benedetti F, Radaelli D, Bernasconi A, et al. Clock genes beyond the clock: CLOCK genotype biases neural correlates of moral valence decision in depressed patients. Genes Brain Behav. 2008;7(1):20-25.

7. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160(4):636-645.

8. Mezick EJ, Hall M, Matthews KA. Are sleep and depression independent or overlapping risk factors for cardiometabolic disease? Sleep Med Rev. 2011;15(1):51-63.

9. Porkka-Heiskanen T, Zitting KM, Wigren HK. Sleep, its regulation and possible mechanisms of sleep disturbances. Acta Physiol (Oxford). 2013;208(4):311-328.

10. Kudlow PA, Cha DS, Lam RW, McIntyre RS. Sleep architecture variation: a mediator of metabolic disturbance in individuals with major depressive disorder. Sleep Med. 2013;14(10):943-949.

11. Rosenblat JD, Brietzke E, Mansur RB, Maruschak NA, Lee Y, McIntyre RS. Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: Evidence, pathophysiology and treatment implications. J Affect Disord. 2015;188:149-159.

12. McIntyre RS, Soczynska JK, Konarski JZ, et al. Should depressive syndromes be reclassified as “metabolic syndrome type 2”? Ann Clin Psychiatry. 2007;19(4):257-264.

13. Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab. 2010;24(5):775-784.

14. Briancon-Marjollet A, Weiszenstein M, Henri M, Thomas A, Godin-Ribuot D, Polak J. The impact of sleep disorders on glucose metabolism: endocrine and molecular mechanisms. Diabetol Metab Syndr. 2015; Mar 24. [Epub ahead of print]

15. Irwin MR, Olmstead R, Carroll JE. Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol Psychiatry. 2015; Jun 1. [Epub ahead of print]

16. Kohsaka A, Laposky AD, Ramsey KM, et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 2007;6(5):414-421.