The hidden link between circadian entropy and mental health disorders

Abstract

The high overlapping nature of various features across multiple mental health disorders suggests the existence of common psychopathology factor(s) (p-factors) that mediate similar phenotypic presentations across distinct but relatable disorders. In this perspective, we argue that circadian rhythm disruption (CRD) is a common underlying p-factor that bridges across mental health disorders within their age and sex contexts. We present and analyze evidence from the literature for the critical roles circadian rhythmicity plays in regulating mental, emotional, and behavioral functions throughout the lifespan. A review of the literature shows that coarse CRD, such as sleep disruption, is prevalent in all mental health disorders at the level of etiological and pathophysiological mechanisms and clinical phenotypical manifestations. Finally, we discuss the subtle interplay of CRD with sex in relation to these disorders across different stages of life. Our perspective highlights the need to shift investigations towards molecular levels, for instance, by using spatiotemporal circadian "omic" studies in animal models to identify the complex and causal relationships between CRD and mental health disorders.

Fig. 1. Comorbidities between mental disorder groups.

Common characteristics across classically defined mental health disorders were used to determine grouped categories. Highly prevalent comorbidities between mental disorders are related by double-headed arrows illustrating the bifacial nature of each comorbid relationship [–157]. ADHD Attention deficiency and hyperactivity disorder, ASD autism spectrum disorder, TS Tourette syndrome, BD Bipolar disorder, SCZ schizophrenia spectrum disorder, MDD major depressive disorder, AXD anxiety disorders, AD Alzheimer’s disease.

Fig. 2. Overlap of symptoms across the major mental disorders with relation to the type of the symptoms and the age onset of disorders.

Dominant symptoms respective to age-related mental disorders are represented by respective labeled bars. The typical age-of-onset for each symptom is characterized by the linear start position of each bar, and symptoms have been separated according to classification whereby excessive (surfeit) symptoms are positioned above the horizontal axis and deficits are positioned below the horizontal axis. ADHD Attention deficiency and hyperactivity disorder, ASD autism spectrum disorder, TS Tourette syndrome, BD Bipolar disorder, SCZ schizophrenia spectrum disorder, MDD major depressive disorder, AXD anxiety disorders, AD Alzheimer’s disease.

Fig. 3. A model for the impact of CRD on genetic, neurological, and behavioral factors over lifespan.

The impact of CRD on brain disorders is pervasive and dynamic. Starting from the fetal stage through early life, the effects of maternal CRD (e.g., resultant from asynchronous light exposure) on development can impact genetic and neural activity with respect to individual genetic liability. During this period, estrogen is proposed to act as a buffer against neuropathological mechanisms. However, hormonal changes throughout life will eventually curb these protective effects. Moreover, behavioral factors play an increasingly significant role in directing the repercussions of CRD with age. The consequences of the interplay between circadian-sensitive genetic (red bar), neural (green bar), and behavioral (blue bar) factors through late age are profound and complex, as dynamic interactions over time result in bidirectional relationships among all circadian-sensitive factors. The labeled factors in each bar have been consistently associated with neurodevelopmental disorders (NDDs), adolescence and midlife psychiatric disorders, and aging-related neurodegenerative disorders. The ones highlighted in the figure do not represent a complete list.

Fig. 4. Annual costs of mental disorders.

The annual cost of mental health disorders in the U.S. per disorder (in USD). Mental health disorders are grouped according to typical age-of-onset (Data sources: [–162]). ADHD Attention deficiency and hyperactivity disorder, ASD autism spectrum disorder, TS Tourette syndrome, BD Bipolar disorder, SCZ schizophrenia spectrum disorder, MDD major depressive disorder, AXD anxiety disorders, AD Alzheimer’s disease. NA Not available (https://www.cdc.gov/ncbddd/tourette/bridgingthegap.html).

Fig. 5. Prevalence of mental disorders related by age.

The prevalence of mental health disorders as a percentage of age-matched. Mental disorders are grouped according to typical age of onset. Data sources: [–168]. ADHD: Attention deficiency and hyperactivity disorder, ASD autism spectrum disorder, TS Tourette syndrome, BD Bipolar disorder, SCZ schizophrenia spectrum disorder, MDD major depressive disorder, AXD anxiety disorders, AD Alzheimer’s disease.

Fig. 6. Sex-dependent prevalence of mental disorders as related to age.

Mental health disorder prevalence in males and females illustrated as ratios of the total affected population per disorder. Mental disorders are grouped according to typical age of onset. Data sources: references [, , –175]. ADHD Attention deficiency and hyperactivity disorder, ASD autism spectrum disorder, TS Tourette syndrome, BD Bipolar disorder, SCZ schizophrenia spectrum disorder, MDD major depressive disorder, AXD anxiety disorders, AD Alzheimer’s disease.