Disrupted circadian rhythms and mental health

Abstract

During the evolution of life, the temporal rhythm of our rotating planet was internalized in the form of circadian rhythms. Circadian rhythms are ~24 h internal manifestations that drive daily patterns of physiology and behavior. These rhythms are entrained (synchronized) to the external environment, primarily by the light–dark cycle, and precisely controlled via molecular clocks located within the suprachiasmatic nucleus of the hypothalamus. Misalignment and/or disruption of circadian rhythms can have detrimental consequences for human health. Indeed, studies suggest strong associations between mental health and circadian rhythms. However, direct interactions between mood regulation and the circadian system are just beginning to be uncovered and appreciated. This chapter examines the relationship between disruption of circadian rhythms and mental health. The primary focus will be outlining the association between circadian disruption, in the form of night shift work, exposure to light at night, jet lag, and social jet lag, and psychiatric illness (i.e., anxiety, major depressive disorder, bipolar disorder, and schizophrenia). Additionally, we review animal models of disrupted circadian rhythms, which provide further evidence in support of a strong association between circadian disruption and affective responses. Finally, we discuss future directions for the field and suggest areas of study that require further investigation.

INTRODUCTION

Outside of the highest latitudes, life on this planet evolved under daily light–dark cycles. Early during the evolution of life, the temporal rhythm of our rotating planet was internalized. Virtually, all organisms on the planet now display self-sustaining, internal biological clocks that drive daily rhythms of physiology and behavior. These so-called circadian (circa = about; diem = day) rhythms have periods approximating a solar day and are set to precisely 24 h by exposure to bright light during the day. In plants, these clocks likely evolved to forecast light and dark to efficiently orchestrate photosynthesis or counteract harmful redox reactions on a daily basis. As complexity of organisms increased, these internal clocks regulated not only metabolism but additional functions as well. In humans, virtually every aspect of our physiology and behavior, ranging from hormone secretion to body temperature regulation, to food intake, to sleep, and to mood is mediated by our internal circadian clocks (Bedrosian and Nelson, 2013; Walker et al., 2020b).

Functional circadian rhythms rely on precise entrainment (synchronization) to the environment, primarily via light information. Since the invention and widespread use of electric lights, however, individuals are more likely to entrain their activities to artificial light schedules, as well as social, school, and work schedules (Depner et al., 2018; McHill and Wright, 2019). Most North Americans and Europeans are exposed to artificial light at night (LAN) (Navara and Nelson, 2007) and approximately 20% of those populations work night shifts, which negatively affect sleep and other aspects of circadian organization (Boivin and Boudreau, 2014; Books et al., 2017). Exposure to light at night may hinder typical entrainment of circadian rhythms resulting in misalignment of physiological and behavioral processes with the solar day (Bedrosian and Nelson, 2013; Walker et al., 2020a,b). Other aspects of modern life including jet travel across time zones produces a well-known desynchronization of circadian rhythms termed jet lag. Indeed, even small temporal changes such as the switch between standard and daylight saving time impairs circadian organization and biological function (Kantermann et al., 2007; Roenneberg et al., 2019). Most of us do not travel extensively or frequently across multiple time zones; however, most of us regularly experience what is termed, “social jet lag” (Roenneberg et al., 2003; Wittmann et al., 2006). Social jet lag is caused by the shift in sleep–wake schedules between school/work days and weekends/holidays; it is defined as the difference between the midpoint of sleep on school or workdays compared to the midpoint of sleep on free days reflecting the misalignment of individuals’ circadian rhythms and social constraints (Roenneberg et al., 2003). Disrupted circadian rhythms by exposure to light and social jet lag are the most common factors responsible for temporal physiological and behavioral misalignment. Temporal misalignment among hormones, neuropeptides, neurotransmitters, and their receptors may contribute to behavioral and affective disorders (Walker et al., 2020a,b). As described later, all forms of disrupted circadian rhythms, exposure to light at night, night shift work, jet lag, and social jet lag affect mood.

CIRCADIAN SYSTEM

Virtually all cells in the body display circadian rhythms, but the mammalian master clock, located in the suprachiasmatic nuclei (SCN) of the hypothalamus, directs the daily cycles in physiology and behavior throughout the body (Hastings et al., 2018). Within SCN neurons, a transcription–translation feedback loop generates endogenous rhythms of approximately 24 h; the gene and protein components of this cycle are primarily entrained to the daily 24 h temporal environment via light information sent directly to the SCN via the retinohypothalamic tract (RHT). Correctly timed light information is crucial to precise biological timekeeping because without light and dark input, the endogenous clock rapidly goes out of phase with the external environment. The retina is the sole mechanism of light detection in mammals (Nelson et al., 1981; Lockley et al., 1999), comprised of image-forming photoreceptors (i.e., rods and cones) and nonimage forming, intrinsically photosensitive retinal ganglion cells (ipRGCs) (Lucas, 2013). IpRGCs are depolarized in response to light and are principally responsible for circadian photoentrainment.

The ipRGCs, a small fraction of the total retinal ganglion cells, express melanopsin, a photopigment that displays peak sensitivity to blue light (~480 nm); in contrast, melanopsin displays minimal sensitive to red light (>600 nm) (Brainard et al., 2001; Berson et al., 2002). The spectral composition of sunlight varies across the day, with enriched short wavelengths (blue) during twilight hours around dusk and dawn, and enriched longer wavelengths (red) peaking around midday (Hut et al., 2000). The spectrum of sensitivity for melanopsin may be an adaptation to the natural solar cycle, allowing for ipRGCs to differentiate twilight from midday and permitting precise entrainment of circadian rhythms (Bedrosian and Nelson, 2017). When stimulated, ipRGCs send neural signals via the RHT directly to the SCN. This monosynaptic pathway sends light information through glutamate release resulting in Ca²⁺ influx and activation of intracellular signaling cascades that affect the gene expression of canonical clock genes within SCN neurons (see later) (Partch et al., 2014). IpRGCs also project both directly and indirectly to additional targets within the brain, encompassing multiple mood-related structures (e.g., habenula and amygdala) (Hattar et al., 2006).

The molecular mechanism of the cellular clock reflects an autoregulatory transcriptional/translational feedback loop, generated via a specific class of genes, including genes encoding brain and muscle ARNT-like protein 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), Cryptochrome (CRY 1,2), Period (PER 1,2,3), and others. For a detailed review of the molecular clock mechanism, see Takahashi (2017). Briefly, CLOCK and BMAL1 proteins increasingly form heterodimers at the beginning of the circadian day which function as a transcription factor to stimulate Cry (1,2), Per (1,2,3), and additional clock gene expression. PER and CRY protein products accumulate over the day and upon reaching a critical threshold, feedback to the nucleus, thus repressing transcription of CLOCK and BMAL1 (Takahashi, 2016). Notably, this feedback cycle requires ~24 h, hence driving circadian rhythms. Several other regulatory loops, in addition to this core feedback loop, are involved in the strict generation of circadian rhythms. Additional mechanisms, including posttranslational modifications, appear crucial for precise molecular clock function; e.g., methylation, phosphorylation, sumoylation, and additional modifications determine the localization, activity, and degradation of essential components within the molecular timing loop (Partch et al., 2014).

The molecular clock of the SCN, in the absence of environmental signals, will continue to generate circadian rhythms. However, light typically serves as the primary environmental entraining cue, thus precisely sustaining internal synchrony with the environment. Exposure to light at night phase shifts the clock by rapidly inducing expression of Per1 or Per2, depending on whether the light occurs during the early or late night (Challet et al., 2003; Ikeno and Yan, 2016). Although minor phase shifts can be advantageous for adapting to slight day length changes across the seasons, abrupt phase shifts due to night-time light exposure or trans-meridian jet travel can be problematic for maintaining temporal integration. For instance, electronics use during the night can unintentionally phase shift circadian rhythms, uncoupling them from the environmental light–dark cycles (e.g., Chang et al., 2015) and potentially affecting physiology, behavior, and mood (Bedrosian and Nelson, 2017; Walker et al., 2020b). All hormones display circadian secretory and functional rhythms, but glucocorticoids and melatonin are the prominent markers of circadian function. Melatonin is secreted exclusively at night and exquisitely sensitive to light; > 3 lux of light at night can suppress the onset of melatonin secretion and shorten melatonin secretion duration in humans (Gooley et al., 2011). In contrast, glucocorticoid concentrations (cortisol in humans) tend to peak in humans just prior to awakening and decrease throughout the day (Son et al., 2011). These two types of hormones are important in several behavioral health conditions; indeed dysregulated cortisol and melatonin have been associated with multiple psychiatric illnesses (e.g., Srinivasan et al., 2006; Watson and Mackin, 2006; Dedovic and Ngiam, 2015; Caumo et al., 2019). The preclinical and clinical effects of disrupted circadian rhythms are reviewed later.

DISRUPTION OF CIRCADIAN RHYTHMS AND ANXIETY

Anxiety disorders are the most common psychiatric illnesses in the world, with current prevalence rates estimated between 1% and 28% and lifetime prevalence rates as high as 30% (Wittchen et al., 2011; Kessler et al., 2012; Baxter et al., 2013; Bandelow et al., 2017). Anxiety disorders represent a group of psychiatric illnesses that include generalized anxiety disorder, specific phobias, panic disorder, social anxiety disorder, selective mutism, and others (Bandelow et al., 2017). Anxiety is a common healthy emotion in which one experiences temporary worry or fear in anticipation of a future threat. However, anxiety disorders differ from “healthy” anxiety due to an excessive or persistent worry or fear that typically interferes with daily functions (American Psychiatric Association, 2013). Anxiety disorders demonstrated high comorbidity with a secondary psychiatric illness, particularly depressive disorders, and a prominent sex difference in their diagnosis (i.e., women are more likely than men to be diagnosed with an anxiety disorder) (Maeng and Milad, 2015; Thibaut, 2017).

Clinical studies examining the relationship between disrupted circadian rhythms and anxiety have produced modest evidence of an association. For example, night shift and rotating shift work have been associated with a development or worsening of symptoms of anxiety (Flo et al., 2012; Chang et al., 2014; Kalmbach et al., 2015; Aburuz and Hayeah, 2017; Booker et al., 2020). Indeed, nurses working permanent nightshifts demonstrated higher levels of anxiety, as measured by the hospital anxiety and depression scale (HADS), relative to their daytime counterparts (Aburuz and Hayeah, 2017). However, studies suggest that elevated anxiety may reflect alterations in sleep, rather than disruptions in circadian rhythms per se. For example, day shift workers without prior sleep disturbances who transitioned to rotating shift work reported elevated anxiety along with altered sleep (Kalmbach et al., 2015). Additionally, nurses who develop shift work disorder, a circadian rhythm sleep disorder characterized by excessive sleepiness and/or insomnia due to the work schedule, report higher anxiety levels on the HADS (Flo et al., 2012; Waage et al., 2014). Some studies, however, failed to demonstrate an association between shift work and anxiety (Øyane et al., 2013). Studies examining the association among jet lag, social jet lag, and anxiety are sparse; nonetheless, these few studies have suggested a possible link (Montange et al., 1981; Mathew et al., 2019; Zhang et al., 2020). Among adolescents social jet lag is positively associated with the symptoms of anxiety (Mathew et al., 2019). Additionally, participants experiencing jetlag via a long-haul flight across six time zones demonstrated higher anxiety scores relative to a 50-day follow-up assessment (Zhang et al., 2020). Further, jet lag via a 7-h westward time shift by jet and, 1 month later, a 7-h eastward shift was associated with disrupted sleep and elevated anxiety and depression scores, particularly in eastward travel (Montange et al., 1981). Additional support for an association between circadian rhythm disruptions and anxiety disorders comes from the fact that studies have reported circadian fluctuations in anxiety symptoms, anxiety symptoms tended to be more severe in the afternoon or evening than in the morning (Cameron et al., 1986), and that most successful treatments of anxiety, SSRIs, SNIRs, and benzodiazepines can affect circadian rhythms (Buxton et al., 2000; Mcclung, 2011; Walker et al., 2020b).

Rodent studies have demonstrated associations among anxiety-like behaviors and the circadian system. For example, CLOCK mutant mice (Δ19 mutation) display reduced anxiety-like behavior on the elevated plus maze and during the open field test (Roybal et al., 2007). Expression of functional CLOCK protein via viral injection into the ventral tegmental area rescued the reduced anxiety-like behavior (Roybal et al., 2007). Additionally, mutant mice lacking both functional Per1 and Per2 display elevated anxiety-like behavior (Spencer et al., 2013). Anxiety-like behavior was unaltered, however, in mice that lack either Per1 or Per2. Knockdown of both Per1 and Per2 expression in the nucleus accumbens (NAc) similarly increased anxiety-like behavior as seen in the mutant animals, suggesting a causal role for these core clock genes in the NAc for regulating anxiety (Spencer et al., 2013). More recent studies have demonstrated that optogenetic stimulation of the SCN induces anxiety-like behavior; particularly SCN-mediated dampening of rhythms was directly correlated with increased anxiety-like behavior (Vadnie et al., 2020).

Additional rodent studies have investigated how circadian rhythm disruption alters anxiety-like behavior. Many studies have examined the effects of bright light or dim light at night on anxiety-like responses (Castro et al., 2005; Ashkenazy et al., 2009; Fonken et al., 2009; Borniger et al., 2014; Cisse et al., 2016; Ikeno and Yan, 2016; Walker et al., 2020a). However, the effects of light on anxiety-like responses are inconsistent across studies, which may reflect the species studied, time-of-day of behavioral assessments, type of light, duration of light exposure, intensity of light, as well as the developmental time window in which circadian disruption occurs. For example, disrupted circadian rhythms in rats via constant light at night increase anxiety-like behavior (Tapia-Osorio et al., 2013), although constant light exposure in mice either reduces or does not affect anxiety-like behavior (Castro et al., 2005; Fonken et al., 2009). Additionally, exposure to dim light at night during early development increases adult mouse anxiety-like responses (Borniger et al., 2014; Cisse et al., 2016). Other studies have reported that exposure of adult mice to light at night either reduces anxiety-like responses or does not alter anxiety-like behavior (Fonken et al., 2009; Walker et al., 2020a). Additional circadian rhythm disruption paradigms demonstrate a possible relationship between circadian disruption and anxiety-like behavior. Indeed, mice housed in 20-h light–dark cycles reduced complexity and dendritic length in neurons of the prelimbic prefrontal cortex, with a concurrent anxiolytic response (Karatsoreos et al., 2011). Further, simulating chronic jet lag in rats increased anxiety-like behavior (Horsey et al., 2020). Together these data provide modest evidence in support of an association between disruption of circadian rhythms and anxiety.

DISRUPTION OF CIRCADIAN RHYTHMS AND MAJOR DEPRESSIVE DISORDER

Major depressive disorder (MDD) affects vast numbers of people world-wide. Indeed, it is estimated that MDD affects approximately 6% of the adult population each year (Otte et al., 2016). The incidence of MDD worldwide continues to rise; diagnoses of depression increased by ~18% from 2005 to 2015 (Walker et al., 2020b). Notably, the increased incidence of MDD correlate with the modernization of society (Hidaka, 2012), which may be explained by reduced stigmatization of MDD, better diagnostic tests. However, the increased disruption of circadian rhythms as society modernizes (i.e., night shift work, light at night, social jet lag, and jet lag) may contribute to the increases in MDD. MDD is typified by changes in mood, particularly increased sadness or irritability that is accompanied with psychophysiological symptoms (e.g., inability to experience pleasure, crying, suicidal thoughts, alterations in sleep, sexual desire, or appetite, and slowing of speech or actions) (Belmaker and Agam, 2008). Diagnosis of MDD requires these symptoms to interfere with normal daily functions and persist for at least 2 weeks (Belmaker and Agam, 2008). Similar to anxiety disorders, diagnosis of MDD occurs approximately twice as often in women as in men (Otte et al., 2016).

Human studies have demonstrated strong associations between MDD and the circadian system. Indeed, disruption of biological rhythms underlie hallmarks of MDD. For example, patients with MDD display alterations in hormone rhythms, body temperature rhythms, and sleep/wake states (Vadnie and Mcclung, 2017). Postmortem examination within the brains of MDD patients demonstrates alterations in circadian patterns of gene expression, specifically, altered phase relationship between genes, reduced amplitude in gene expression, and shifted peaks in core clock genes (Li et al., 2013). Similar to anxiety, studies have reported circadian fluctuations in MDD symptoms, with patients exhibiting symptoms in a morning-worse or evening-worse pattern (Rusting and Larsen, 1998). MDD patients who display more severe symptoms in the morning, typically experience a more severe form of depression (Rusting and Larsen, 1998). Further, the degree of misalignment of circadian rhythms is correlated with the severity of MDD (Emens et al., 2009). Additional support for an association between circadian rhythm disruptions and MDD comes from the observation that treatments of depression, antidepressants (SSRIs, SNRIS, and agomelatine), bright light therapy, social therapy, and wake therapy directly affect circadian rhythms (Germain and Kupfer, 2008). Indeed, administration of antidepressants or morning bright light therapy result in a phase advance of circadian rhythms (Terman et al., 2001; Mcclung, 2011; Robillard et al., 2018). The degree of phase advancement due to morning bright light therapy or antidepressant treatment is correlated with the reduction of depressive symptoms (Terman et al., 2001; Robillard et al., 2018). Together, diurnal variation in symptoms as well as successful treatment of MDD with chronotherapies provides evidence for an association between MDD and the circadian system.

Most human studies combine all forms of depression when examining associations between circadian rhythm disruption and MDD. The few studies that have assessed MDD specifically, however, have reported inconsistent results (Ohayon and Hong, 2006; Murcia et al., 2013; Oenning et al., 2018). Indeed, one such study, examined ~4000 South Koreans and demonstrated that the prevalence of MDD was significantly higher in night shift workers relative to daytime workers (Ohayon and Hong, 2006). In a large Brazilian cohort of ~36,000 workers, night shift work was significantly associated with MDD only in women (Oenning et al., 2018). Additionally, in a French study, the authors reported no association between MDD and shift work (Murcia et al., 2013). A clear association between night shift work and depression appears when all forms of depression are combined (Moon et al., 2015; Lee et al., 2016, 2017; Booker et al., 2020). A meta-analysis containing 11 studies reported that night shift workers are ~40% more likely to develop depression compared to daytime workers (Lee et al., 2017). Even fewer human studies have examined the effects of social jet lag or jet lag on MDD (Knapen et al., 2018). One such study examined the amount of social jet lag in patients with MDD and healthy individuals and concluded that there was no association between social jet lag and severity of depressive symptoms (Knapen et al., 2018). However, similar to shift work, combining all types of depression results in a strong association among jet lag, social jet lag, and depression (Young, 1995; Katz et al., 2001; Srinivasan et al., 2010; Levandovski et al., 2011; McNeely et al., 2018).

Rodent studies have provided ample evidence to support a clear association between disruption of circadian rhythms and depressive-like behavior. Indeed, rats housed in constant light lose diurnal rhythms in activity, melatonin, and corticosterone with a concurrent increase in depressive-like behavior (Tapia-Osorio et al., 2013). Agomelatine administration to rats housed in constant light restored diurnal corticosterone and melatonin rhythms and eliminated the increase in depressive-like behavior (Tchekalarova et al., 2018, 2019). Numerous studies have examined the effects of dim light at night on depressive-like behavior in multiple species of rodents (Fonken et al., 2012; Bedrosian et al., 2013; Fonken and Nelson, 2013; Walker et al., 2020a). For example, female Siberian hamsters housed in 5 lux of dim light at night for 4 weeks display reduced dendritic spine density within the hippocampus with concurrent increases in neuroinflammation and depressive-like behavior (Bedrosian et al., 2013). Additionally, diurnal rats housed in 5 lux of dim light at night for 3 weeks demonstrate reduced dendriticlengthwithinCA1 and dentate gyrus and increased depressive-like behavior (Fonken et al., 2012). Dim light at night can rapidly alter depressive-like responses. Indeed, housing mice in 5 lux of dim light at night for 3 nights increased depressive-like behavioral responses (Walker et al., 2020a). Studies in C57Bl/6 mice have not reported any association between light at night and affective responses suggesting a potential strain specific effect of LAN (Martynhak et al., 2017; Cleary-Gaffney and Coogan, 2018). Taken together, there is a sizable amount of clinical and preclinical evidence to support a link between disruptions of circadian rhythms and MDD/depression.

CIRCADIAN RHYTHM DISRUPTION AND BIPOLAR DISORDER

Bipolar disorder (BD), previously called manic depression or manic-depressive disorder, is marked by divergent atypical episodes of extreme mood swings. These episodes, which can last for days or weeks, cycle between depression and mania, with intervening periods of normal affect. Onset of BD usually occurs between 20 and 30 years of age, and BD has an estimated lifetime prevalence of about 2.4%. Current diagnosis of BD is divided into three main categories of increasing severity: Cyclothymic, characterized by episodes of hypomania and depressive symptoms over a period of at least 2 years, Bipolar II, characterized by at least one major depressive episode and at least one hypomanic episode, and Bipolar I, characterized by a manic episode that may or may not be followed by a hypomanic or major depressive episodes. Individual symptoms vary by severity during episodes, but usually involve concomitant changes in energy, activity, and sleep. Although not traditionally thought of as a circadian disorder, there is emerging evidence that the circadian system is strongly implicated in this disorder. Genetic studies have reported almost 90% heritability of BD (McGuffin et al., 2003; Etain et al., 2011) and revealed that multiple components of the molecular circadian clock are associated with BD (Le-Niculescu et al., 2009; Etain et al., 2011). Furthermore, gene polymorphisms in, and dysregulation of, the molecular circadian clock contribute to both susceptibility to develop BD and to relapse into bipolar episodes (Bellivier et al., 2015). Although more than 40 clinical studies have investigated and reported disruption of circadian rhythms in BD, these studies have not been able to determine the cause–effect relationships due to their cross-sectional designs (Melo et al., 2017). Further clinical studies properly designed will be necessary to determine whether disruption of circadian rhythms in BD is secondary to other factors, or if it is a primary pathophysiology of the disease. Regardless, circadian markers, such as cortisol rhythms and buccal cell molecular circadian clock rhythms, have been proposed as biomarkers of mania (phase-advanced circadian rhythms) and depression (phase-delayed circadian rhythms) in BD patients (Moon et al., 2016).

As a therapeutic approach, stabilizing and normalizing circadian rhythmicity has proven effective against both symptoms and relapses in BD over time (Pinho et al., 2016; Gold and Kinrys, 2019). Preliminary circadian studies in BD patients reported that they suffered from chronic circadian rhythm disruption due to fast running circadian clocks; thus, treatments that slowed the molecular circadian clock, such as lithium, stabilized circadian rhythms and helped to resolve BD symptoms (Kripke et al., 1978). More recently, circadian rhythm normalization via mid-day bright light therapy has proven effective as a treatment for bipolar depression in some patients; however, bright light therapy in the morning should be avoided as it can induce mixed states (Sit et al., 2007, 2018). Similarly, manipulation of the photic environment to normalize circadian rhythms via enforced darkness or blue light blocking glasses can help alleviate mania in some BD patients (Barbini et al., 2005; Henriksen et al., 2016). On the flip side of the coin, disruption of circadian rhythms appears to be able to induce BD episodes. For example, major social disruptive events have been reported to induce episodes of mania, but not depression (Malkoff-Schwartz et al., 2000). Additionally, jet lag can induce bipolar episodes in a longitudinally specific fashion: phase advances in rhythms from flying across time zones west to east can induce mania, whereas phase delays in rhythms induced by traveling east to west can induce episodes of depression (Jauhar and Weller, 1982; Young, 1995; Katz et al., 2002).

Taken together, these clinical data suggest that dysregulated circadian rhythmicity is both a trait and a state marker of BD. Dysregulation arising from both environmental (jet lag, social jet lag) and internal (genetic/molecular) factors can induce and predispose individuals to bipolar episodes; the type of which (mania or depression) is dependent upon the phase relationship of the internal circadian rhythm with the environmental circadian rhythm. Chronotherapeutic approaches are effective in treatment and prevention of BD, providing strong support that BD has a significant circadian rhythm component. However, advances in the treatment and understanding of the underlying mechanisms of BD have been hampered by the lack of valid animal models of this disease in which to conduct translational research (Machado-Vieira et al., 2004; Malkesman et al., 2009; Nestler and Hyman, 2010).

The majority of animal models probe the specific states of BD, viz., depression and mania. Animal models of circadian rhythm disruption in depression are discussed previously in the MDD section. For bipolar mania, converging preclinical and clinical data have implicated dysregulation of protein kinase c (PKC) signaling, potentially by environmental disruption of circadian rhythms (Saxena et al., 2017). Although there are few preclinical models of circadian rhythm disruption and mania in rodents, transient mania-like states can be induced in mice via sleep deprivation (Benedetti et al., 2008). Furthermore, mice that fail to recover from sleep disruption (i.e., do not reentrain to their original circadian rhythm) induced by a 72-h exposure to inverted environmental light dark cycles also display mania-like behavior (hyperactivity) in the absence of increases in depressive-like behavior, which is associated with dysregulated PKC signaling in frontal and limbic brain regions (Jung et al., 2014; Moon et al., 2018). In addition to PKC, dysregulated central dopaminergic signaling has also been implicated in circadian rhythm disruption in bipolar mania. Genetic disruption of the molecular circadian clock via deletion of ClockΔ19 induces mania-like behavior in mice that are normalized by either lithium treatment or by restoring a functional molecular circadian clock to the ventral tegmental area to normalize dopaminergic neuronal activity (Roybal et al., 2007). Although the ClockΔ19 mouse model of mania recapitulates much of the pathophysiology of bipolar mania in humans, the fundamentally disrupted molecular circadian clock precludes it from studying external (environmental) influences on circadian rhythm disruption in BD. Among the animal models of mania and depression discussed previously, none have successfully recapitulated the state switching between mania and depression that is prevalent in BD (Logan and McClung, 2016). Recently, a mouse model of state switching was proposed in mice with reduced dopamine transporter expression in which mania-like and depressive-like behaviors were displayed dependent upon environmental day length (Young et al., 2018); however, these results have not been replicated nor validated as a model of state switching in BD (Rosenthal and McCarty, 2019). Regardless, current evidence strongly supports the association between disrupted circadian rhythms and the onset and severity of BD, and this disorder is in critical need of both preclinical and clinical research with circadian rhythms as a key biological variable.

CIRCADIAN RHYTHM DISRUPTION AND SCHIZOPHRENIA

Schizophrenia (SZ) has a low lifetime prevalence (~0.5%), yet it is an extremely disabling mental disorder with onset typically occurring around 20–30 years of age (McGrath et al., 2008; Simeone et al., 2015). SZ is characterized by cognitive impairments, negative symptoms (impaired avolition and sociality, alogia, and anhedonia), and positive symptoms (movement disorders, disorganized speech, hallucinations, and delusions). Heritability of ~80% strongly suggests a genetic component to SZ; however, environmental or epigenetic factors significantly influence risk as demonstrated by much lower concordance rates (40%–65%) found in monozygotic twin studies of SZ (Cardno and Gottesman, 2000; Bromundt et al., 2011). Disrupted circadian rhythms have been identified as a prodrome of SZ, and symptom severity has been associated with levels of circadian rhythm and sleep disruption (Bromundt et al., 2011). In common with other psychiatric disorders discussed previously in this chapter, several case studies indicate that circadian rhythm disruption via jet lag appears to be able to induce or cause relapses in SZ (Oyewumi, 1998; Katz et al., 1999).

Several genes that have been implicated in SZ are also involved in circadian organization. Blunted expression of CRY1, PER1, and CLOCK was reported in mononuclear blood cells collected from SZ patients after their first psychotic episode (Johansson et al., 2016). Similarly, skin fibroblasts collected and cultured from chronic SZ patients lacked rhythmic expression of PER2 and CRY1, yet circadian expression of CLOCK, PER1, CRY2, DBP, REV-ERBα, and BMAL1 did not differ from healthy controls (Johansson et al., 2016). One study investigating SNPs in eight circadian genes reported modest associations with SNPs on PER3 and TIME-LESS in SZ patients (Mansour et al., 2006). A follow-up study of 276 SNPs on 21 circadian genes identified significant associations of eight individual SNPs on NPAS2, PER2, PER3, and RORB in SZ samples; however, these associations did not confer a substantial risk for SZ (OR >1.5) (Mansour et al., 2009). In addition to these core clock gene SNP associations with SZ, copy number variants also enhance risk for SZ. Several studies have reported a strong association of vasoactive polypeptide receptor (VIPR2) duplication with SZ in humans (Vacic et al., 2011). Vasoactive polypeptide (VIP) neurons in the SCN core and neurons expressing its receptor (VIPR2) in the SCN shell are critical for circadian rhythmicity and entrainment (Vosko et al., 2007). Indeed, in mice, deletion of VIPR2 (VPAC2) not only affects cognition in a manner similar to SZ (Chaudhury et al., 2008) it also disrupts adrenal clock genes which in turn disrupts circadian rhythms in glucocorticoid secretion (Fahrenkrug et al., 2012). Of note, there is an abundance of VIPR2 in the cortex and the knock out of the VIP receptor will also affect cortical transmission.

In addition to the aforementioned altered circadian genes, altered circadian rhythms in the neuroendocrine system, specifically in two prominent transducers of circadian synchronization discussed previously—cortisol and melatonin, also contribute to the etiology of SZ. Circadian cortisol rhythms generally remain intact in SZ (Rao et al., 1995; Sun et al., 2016), yet elevated cortisol levels and hyperreactivity of the HPA axis are common in SZ and in people at risk for developing SZ (Ryan et al., 2004; Sun et al., 2016). Additionally, these altered circadian patterns of cortisol secretion are associated with increased severity of SZ symptoms (Kaneko et al., 1992; Ho et al., 2016); however, the antipsychotic olanzapine, when used to treat negative symptoms, can blunt the elevated cortisol levels found in SZ (Mann et al., 2006). Among unmedicated individuals with SZ, melatonin rhythms are blunted and peak concentrations are reduced when compared to healthy individuals (Ferrier et al., 1982; Monteleone et al., 1992; Viganò et al., 2001). Additionally, melatonin acrophase is advanced in unmedicated individuals with SZ (Rao et al., 1994). However, in SZ patients who are medicated, melatonin rhythms can be similarly blunted without or with a phase shift (Bromundt et al., 2011), or display either a phase advance or a phase delay (Wirz-Justice et al., 1997; Wulff et al., 2012). The alteration in neuroendocrine circadian rhythms and sleep in SZ has been attributed to both compromised responses to the effects of melatonin on sleep and to social withdrawal resulting in reduced zeit-geber exposure (Afonso et al., 2011; Bromundt et al., 2011). Regardless of direction of phase shift or change in levels in circulation, dysregulation of neuroendocrine circadian rhythms represents an uncoupling of internal circadian rhythms from environmental rhythms, resulting in desynchronization of behavioral and physiological process which contribute to susceptibility and severity of psychiatric diseases such as SZ.

CONCLUSIONS AND FUTURE DIRECTIONS

Taken together, this chapter supports a strong association between disruption of circadian rhythms and psychiatric illness. As evidenced previously, disruptions of the circadian system and/or misalignment of circadian rhythms can have detrimental consequences for mental health. However, the relationship between the pathophysiology of psychiatric illness and circadian rhythm disruption remains poorly defined. The bulk of clinical evidence suggesting a relationship between psychiatric illness and circadian rhythm disruption are correlational. Thus, causation cannot definitively be assigned. The current association between misalignment of circadian rhythms and mental health may reflect any of the following: (1) disruption of circadian rhythms drives psychiatric illness, (2) psychiatric illness leads to circadian rhythm disruption, or (3) there is no causative relationship between psychiatric illness and misalignment of circadian rhythms. However, careful examination of the rodent literature provides strong support that disruptions of circadian rhythms can alter affective responses. Further, targeted resynchronization of circadian rhythms in rodents can alleviate alteration in the symptomology of mood disorders. Future studies are needed to expand both the clinical and basic science literature in relation to circadian misalignment and mental health. Focus should be placed on examining the effects of jet lag and social jet lag on various psychiatric illnesses, as numerous clinical studies have typically focused on the effects of shift work on psychiatric health. Particular focus should be placed on uncovering associations among BD, SZ, and circadian rhythm disruptions, as relative to anxiety disorders and depressive disorders; these areas remain vastly understudied. In sum, although our current knowledge does not allow for assignment of a causative role in circadian disruption eliciting psychiatric illness, it does support a strong association between the two.