Is there evidence that circadian rhythm disruption has a role in psychiatric disorders?


The link between sleep and psychiatric disorders has been long observed. In the 1980s, Wehr et al published his findings of circadian rhythm disturbances in manic-depressive illness (1). In the 1970s, Wirz-Justice at al reported the association of sleep deprivation in endogenous depression (2). Almost all psychiatric illnesses have circadian abnormalities with respect to sleep/wake cycles, melatonin and cortisol secretion as well as blood pressure and temperature rhythms. Interventions intended to resynchronise or stabilise circadian rhythms have been successful in treating psychiatric disorders.

Psychiatric disorders are common and serious disorders, with an increasing prevalence. Anti-depressants prescriptions in the United States have tripled over the last 15 years (3). This increase in prevalence of psychiatric diseases may be secondary to environmental changes that are linked to modern human life and circadian disruption. Compared to the past, we are now exposed to disruptions to our historical diurnal sleep/wake patterns. These include shift work, nocturnal exposure to artificial light, reduced exposure to natural light during daytime and air-travel across time zones. These changes have a deleterious effect on sleep and circadian rhythm in general.

In the 1980s, The Social Zeitgeber (time-giver) Theory of mood disorders was proposed (4). This theory proposes that stressful life events disrupts social routines, sleep/wake cycles and circadian rhythms. This leads to changes in cellular and molecular circadian rhythms throughout the body and consequently result in mood and psychiatric disorders. In the same way, the inherent disruptions of modern life may now trigger these circadian rhythm changes and lead to psychiatric disorders in vulnerable individuals.

Circadian rhythm disruptions affect not only the sleep/wake cycle but also the rhythms of temperature, blood pressure, hormone secretion and neurotransmitter signalling (5).These changes may propose possible mechanisms by which disruptions in circadian rhythm are linked to psychiatric disorders.

In this essay, we will attempt to look at circadian rhythm disruptions and their causal link to psychiatric disorders. Is there a clear genetic basis in the circadian system that eventually lead to psychiatric illnesses? Or does the disease effects lead to the observed features of circadian abnormality seen in disease phenotype? Another confounding factor is the 2 very distinct systems of circadian systems and sleep. Disruptions of sleep and circadian rhythms may be difficult to separate.


The circadian system is thought to be an evolutionary development that allows an organism to cater for the changing environmental conditions imposed by the Earth’s 24 hour day/night cycle. This enables an organism to efficiently carry out activities such as feeding, mating and avoidance of dangers by anticipating and synchronising to changing periods of light and temperature. It confers a survival advantage to an organism (6).

In mammals, this system comprises of a endogenous master pacemaker, which is located in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as autonomous molecular endogenous genetic clocks found in most cells throughout the body. The master clock entrains to the environment via a zeitgeber. It then synchronises the genetic clocks found throughout the body to adapt the organism’s physiology to the changing environment. The chief zeitgeber is the light/dark cycle as detected by photo retinal cells in the eye. The signals are relayed vis the retino-hypothalmic tract (RHT) to the SCN. In turn, numerous neural and hormonal outputs from the SCN go on to synchronise the entire circadian system. The autonomous molecular endogenous genetic clocks found in most cells throughout the body is governed by a transcriptional-translational feedback loop (TTFL). This loops consists of the transcription factors CLOCK and BMAL1 and the clock genes Period (PER) and Cryptochrome (CRY) as well as Rev-erbA. The transcription factors drive the clock gene expression and this regulates itself in a negative feedback loop (7). The TTFL rhythmically controls the expression of clock genes, allowing the 24 hour oscillatory nature of metabolic functions found within specific cells in specific sites. The circadian system is a vast network rather than a pathway. It is molecularly in-built, autonomous and specific to the individual cell and purpose, oscillates in a 24 hour pattern and is synchronised via a master clock to adapt to the changing environmental conditions (8).

We will now look at the possible mechanisms underlying psychiatric disease and their links to the circadian system.

The treatment of psychiatric disorders rely largely on medications that alter the mono-aminergic pathways, implicating this neurotransmitter system in the pathogenesis of psychiatric illness. The first antidepressant ever developed was a monoamine oxidase inhibitor (MAOI) (9). Monoamines affected include serotonin, dopamine and norepinephrine. Changes in dopamine levels in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) influence mood behaviours. The monoamine neurotransmitter system is governed by a circadian rhythm. Hampp et al found that the monoamine oxidase A promoter in mice is controlled by the transcription factor BMAL1 and clock gene PER2. Mice with a mutation in the clock gene Per2 show increased levels of dopamine in the NAc, therefore the circadian mood behavioural changes seen in Per2 mutant mice are thought be a result of these clock changes (10). In 2011, Coque et al found that mice with a CLOCK gene mutation (ClockΔ19) had increased dopaminergic activity and dopamine synthesis in the VTA. These mice show behaviour similar to the mania exhibited in bipolar disorder. The dopamine levels, dopaminergic neuronal activity and neuronal cell volume changes seen in these mice all revert to normal states with lithium administration (11).

The evidence that immune function is linked to psychiatric disorders have studied and reviewed (12). It has been shown that presence of abnormal levels of proinflammatory cytokines can lead to a state resembling depression with symptoms of mood disorders, fatigability and psychomotor retardation (13). These cytokines include tumour necrosis factor-alpha, macrophage inflammatory protein 2 and leukaemia inhibitory factor. Circadian rhythm disruption also leads to increase levels of these cytokines in the brain. Narasimamurthy R et al showed that the absence of the clock gene Cryptochrome (CRY) leads to an cell autonomous elevated level of proinflammatory cytokines. Cytokines cause alterations of the monoamine transmitter signalling system, reduced neurogenesis and neural plasticity as well as changes in the hypothalamus-pituitary-adrenal (HPA) axis (13). Could clock gene regulated cytokines be the common link? Raison et al (12) in a review article found no conclusive evidence to show that depression was an inflammatory disorder. Warner-Schmidt et al in 2011 investigated the effect of anti-inflammatory agents on mice and humans taking serotonergic agents (SSRIs). They looked at behaviours as well as a biochemical marker of depression (p11). They found antagonistic effect of the anti-inflammatory drugs on both biochemical and behavioural responses to the SSRIs.  This was further corroborated by data obtained from the  “sequenced treatment alternatives to relieve depression” (STAR*D), a 7 year large-scaled human study comprising of 4041 participants (15). The association of circadian disturbance causing depression via proinflammatory mediators therefore seems unlikely.

The hypothathalmic-pituitary-adrenal (HPA) axis is fundamental in the regulation of glucocorticoid production and metabolism. Glucocorticoids, produced by the adrenal gland, produce a wide range of effects in the body in response to stress. Glucocorticoid production and expression are under circadian rhythm timing (16). The peak activity of glucocorticoids occur just before the onset of wake. There is also a relationship of CLOCK and Cryptochromes (CRY) in the circadian rhythmic regulation of the glucocorticoid receptor (17, 18). Many studies have linked the hyperactivation of the HPA axis is to the risk of developing and eventual course of psychiatric illnesses. This is especially reported in perinatal and post-partum depression (19). However the mechanism and exact role of the HPA axis in the development of psychiatric disorders are unclear. Shah et al found that there was elevation and hyperactivation of the HPA axis in the early stages of psychosis but at the same time there was contradictory blunting of the dynamic response of HPA axis to encountered or anticipated stress (20). The secretory profile of glucocorticoid levels in major depression  have not been consistently demonstrated.

Cholecystokinin (CCK) is a metabolic peptide hormone secreted by endocrine cells in the small intestines. In the gut, it is responsible for controlling gallbladder contraction and pancreatic enzyme secretion. It can also be found in the central nervous system where it is a neurotransmitter. The expression of CCK is under circadian rhythmic control (21, 22). CCK has been implicated in the generation of anxiety and panic attacks. The pathways in which anxiety is generated is a complex network consisting of neuronal connections that link distinct areas in the brain (amygdala, hypothalamus, periaqueductal grey) that mediate fear. These pathways are modulated by CCK (23). Increase in CCK or CCK receptor agonist in these regions are shown to increase anxiety symptoms. When cholecystokinin tetrapeptide (a peptide fragment of CCK) is administered in humans, it trigger a panic attack. Conversely, when a CCK receptor antagonists is applied to mice, anti-depressant like effects are observed (24). As previously mentioned, mice with CLOCK gene mutation (ClockΔ19) exhibit signs of mania, One of the targets of CLOCK gene transcription is CCK and ClockΔ19 mice show reduced levels of expression of CCK in the VTA. Lithium administration reverses this observation of mania and restores CCK levels seen in wild type mice (25). Also noted was the inducement of manic like behaviours in wild mice, upon knockdown (through selective RNA interference) of CCK expression in the VTA of these mice. Another study done by Del Boca et al induced the knockdown of CCK expression in the basolateral amygdala in mice also via RNA interference. Using maze and forced swim tests, these knockdown mice exhibited reduced levels of anxiety and lower despair-like behaviour as compared to controls (26). These findings suggest that CCK, a neuropeptide associated with circadian rhythm, have close associations with psychiatric disordered effects.

There are other possible pathways that link circadian systems to psychiatric illnesses. Mitochondrial dysfunction has been hypothesised to be linked to psychiatric diseases, bipolar disorders in particular (27). Kato et al in 2000 found that deletions and polymorphism in the mitochondrial DNA were risk factors for bipolar disorder and he proposed the mitochondrial dysfunction hypothesis for bipolar disorders (28). The circadian nature of mitochondrial function has been described by Manella et al, where he detailed the circadian rhythmic physiology of mitochondrial composition, morphology, and function and the possible underlying basis. Chiefly, he looked at evidence from experiments performed with clock mutant models. These findings supports the involvement of circadian clocks in mitochondrial rhythmicity (29).

Another mechanism often discussed is that of neurogenesis. Animal studies have shown that stressful events reduce neurogenesis in parts of the brain including the hippocampus (30). This appears to play a part in the development of psychiatric disorders such as depression where cognitive deficits and reduced hippocampal volumes are observed. Conversely, antidepressant treatment are shown to reverse this effect and enhance neurogenesis (31). Neurogenesis has been shown to have circadian rhythmic links. Tamai et al showed in 2008 that there was an day/night variation in M-phase cell (mitoses) numbers in the cells of the hippocampus of mice, with significant rise during the night, leading to increased neurogenesis (32). Borgs et al in 2009 demonstrated that PER2  expression has a regulatory role in cellular proliferation in the adult hippocampus (33). Further evidence of the close links between the two processes are shown when circadian rhythm disruptions inhibits neurogenesis in the hippocampus. Gibson et al in 2010 showed that in female hamsters, circadian disruptions (via experimental jet lag) inhibited neurogenesis in the hippocampus. They also showed that these changes persisted after the circadian disruptions were stopped, which suggest that these effects were long-lasting (34). Kott et al showed the same effects in male rats subjected to chronic circadian disruptions via a weekly 6 hour phase shifting paradigm. In his study, he found that neurogenesis was direction dependant and neurogenesis was more marked in phase advancement as compared to phase delay. This mirrors the clock gene expressions seen in the SCN (35).

The above mentioned processes are links that tie the processes of psychiatric diseases to the circadian system. We will look at specific psychiatric illness and review the evidence of each disorder in relation to the circadian system. We will look the phenotype of the disease from a circadian gene expression perspective and a treatment perspective.

Psychiatric Conditions

Bipolar disorder

Bipolar disorder, also known as manic-depressive illness, is a psychiatric disorder characterised by shifting symptoms ranging from minor or major depression to minor or major mood elevation (mania). This leads to an unusual behavioural changes in mood, energy and activity levels. There are 4 types of bipolar disorders differentiated by symptom severity and duration.

The relationship between altered circadian rhythm and bipolar disorders have well been documented. The American Psychiatry Association recognises that sleep disturbance is a core symptom of bipolar disorder and mania is hallmarked by a reduction in need for sleep while maintaining activity levels (36). As for circadian disruptions, irregular sleep schedules, disrupted 24 hour sleep/wake cycles and jet lag are are known to trigger manic episodes in bipolar patients (5, 37), suggesting a circadian basis for symptom development. Plante et al in 2008 proposed that, in the treatment of bipolar disorders, the use of sleep disturbance can be used both as a target of treatment as well as a gauge of the treatment response in mania. He described the use of somatic therapies (a combination of psychotherapy and physical therapy) that target sleep and circadian rhythms (by promoting stable and adequate sleep) in the treatment of the depressive phases of bipolar disease (37).

While the exact pathophysiology of bipolar disorders is unclear, much of what we know of the disease has come from the use of Lithium, which remains a standard treatment of bipolar disorders. The effects of lithium are closely linked to the circadian system. The therapeutic targets of lithium include the core clock gene glycogen synthase kinase B (GSK3B). GSK3B plays an important role in the circadian system (38, 39). In a systematic review published analysing the effects of Lithium on circadian rhythms in 2016, Moreira et al concluded that lithium has a direct action on molecular clocks. The actions of lithium on the circadian system include phase delays, increasing free running rhythms and reduction of length of activity rhythms while chronic administration of lithium led to improvement of day-to-day rhythmicity. The responses are mediated via circadian genes (40).

As mentioned earlier, ClockΔ19 mice has similar behavioural characteristics to mania. These mice have been described by Roybal et al as having “hyperactivity, decreased sleep, lowered depression like behaviour, lower anxiety and an increased value for rewards” (41). The administration of lithium reverses these behaviours. These behaviours can be replicated in wild mice through RNA interference knockdown of the CLOCK gene in the VTA (42). This shows that mania can be induced by the disruption of a single clock gene in a single region of the brain.

In 2008, Benedetti et al studied the PER3 gene in patients with type 1 bipolar disorder. The PER3 gene contains a variable number tandem-repeat (VTRN) segment that exhibits polymorphism. This polymorphism have been shown to affect sleep structure in human. He found that PER3 VTRN variants affected the age of onset of type 1 bipolar disorder (43). This finding has implications on the disease prognosis and management as an early onset of bipolar disorder is associated with the subgrouping and severity of the disease (44).


Major depressive disorder (MDD) has been shown in large clinical data sets to be linked to the circadian system. During depressive episodes, there is alteration of the diurnal rhythmicity of physiological processes of sleep, temperature and HPA axis activity (45). Bunney at al (46) looked at the post-mortem brain tissue of depressed patients compared with time-of death matched samples. Using micro-array studies, they screened 12000 transcripts and found that in control subject, the core clock genes had normal 24 hour cyclical patterns of expression in 6 brain regions. In the patients with major depressive disorder, the patterns of expression of the same clock genes were significantly disrupted with marked reduction in expression. The affected clock genes included BMAL1, PER1, PER2, PER3 and Rev-ErbA. These were seen to be arrhythmic especially in the anterior cingulate cortex, an area that is involved in mood regulation. This suggests that there is a disruption of the circadian regulation of clock gene expression in MDD.

Another post-mortem study done by Wu et al examined the SCN of 14 depressed patient with 14 match controls for melatonin receptors MT1 and MT2. Melatonin is intrinsically involved in circadian rhythm and promotes sleep by inhibiting the SCN via MT1 receptors.  They found increased MT1 receptors in the SCN of depressed patients, signalling a greater inhibitory effect of melatonin on the SCN in depressed patients. The increase in MT1 receptors was negatively correlated with disease onset and positively correlated with disease duration, implying that these changes occurred as a result of the disease and not as a cause (47).

Work on circadian gene expression in peripheral cells also showed similar findings (48,49). Lavebratt et al found reduced levels of CRY2 mRNA in peripheral blood mononuclear cells in depressed patients as compared to controls. There was also no up-regulation of CRY mRNA after sleep deprivation which was observed in controls. Clock gene expression plays a role in the circadian rhythm disruptions seen in depression but a causal role is not directly evident.

No look in the circadian rhythm disturbance in psychiatric disorders would be complete without examining seasonal affective disorder (SAD), a sub-type of depression that is related to a change in seasons, most notably winter months. The most direct evidence of causality is shown in a study done by Partonnen et al in 2009. They studied 189 patients with SAD with matched controls. They found that SAD was associated with polymorphism in 3 clock genes, Per2, Arntl, and Npas2, a functional unit of circadian rhythm. The risk of developing SAD with the risk genotype was an odds ratio of 4.43 compared to the remaining genotype (50).

Roecklein et al in 2009 looked at the role of melanopsin (a non-visual photopigment) in SAD. They hypothesised that polymorphisms in the melanopsin gene (OPN4) could be the underlying cause for the increase in light requirement for normal functioning in SAD patients. They found an increased frequency of missense variant rs2675703 (P10L) in OPN4

that was 5.6 times more likely present in patients with SAD (51). Retinal ganglion cells containing melanopsin form a pathway via the retino-hypothalmic tract and transmits signals to the SCN and plays a critical role in the circadian response to light (52). Further evidence that melanopsin and possibly circadian rhythm disruption is involved in the development of depression was provided in a study performed by LeGates et al, who demonstrated that aberrant light cycles in mice produced an increase depression-like behaviours and impaired learning which were absent in similarly exposed mice that lack intrinsically photosensitive retinal ganglion cells (53). However, the authors of the study did maintain that circadian timing systems in these mice remained unchanged.

From a treatment perspective, causality can be assumed if mood disorders were successfully treated with interventions that directly affected circadian rhythms. The treatment of SAD has been traditionally been bright light therapy. Golden et al performed a meta-analyses looking at the efficacy of light therapy in treating mood disorders. They found that bright light therapy was also effective in the treatment of non-seasonal depression with an effect size similar to that of anti-depressants (54). However, besides circadian systems, light also has effects on sleep, neurocognitive function, which may confound this finding. Sleep deprivation has also been used in the treatment of depression over the last 30 years. The postulated mechanisms is the increase in sleep (slow-wave sleep in particular) propensity on the relationship between the disturbed circadian rhythm and sleep/wake cycle (55). Sleep deprivation also activates the monoamine signalling system, which is another possible mechanism through which the circadian rhythm effects depression. Sleep phase advancement has also shown to be effective in reducing symptoms in MDD and the combination of the 2 therapies prolong these beneficial effects (56). Further benefit was seen with the combination of sleep deprivation, sleep phase advance and bright light therapy. This triple therapy combination has shown to reduce depressive symptoms in drug-resistant MDD patient in a rapid manner and maintain this effect during the intervention period (57). 

The use of Agomelatine, a melatonin receptor agonist and weak serotonin antagonist, has also been shown to be effective in the treatment of MDD and other psychiatric illnesses like anxiety disorder (58). The mechanism of agomelatine were proposed to be based on the effects on chronobiology. Observed effects include stabilisation and reversal of circadian rhythm disruption and inducing neurogenesis in MDD (59). However, agomelatine also exert these effects through the monoamine signalling system


Schizophrenia is a disease where is the pathophysiology remains unclear. What has been observed are abnormal sleep patterns that include disrupted sleep onset, free-running circadian rhythms and irregular sleep-wake patterns. Changes also include reduced REM latency and density, reduced sleep efficiency and total sleep time, increase in sleep latency (60). An often cited study by Wulf at al in 2012 compared the rest-activity patterns of 20 patients with schizophrenia with 20 unemployed controls over a 6 week period. Half of the patients demonstrated severe misalignment in circadian rhythms of sleep/wake and melatonin cycles, with sleep/wake onset and melatonin peaks shifted to a much later clock time. The authors described this as a dyssynchronisation of the internal circadian rhythm of these patients and the day/night cycle (61).

One possible mechanism of schizophrenia has been postulated to be due to abnormal synaptic neurotransmission (62). In genetic studies of mice, 2 known synaptic proteins have been shown to be involved in circadian systems. They are the metabolic peptide vasoactive intestinal peptide receptor 2 (VIP2) and exophytic synaptic protein SNAP25. VIP2 acts as the vasoactive intestinal protein receptor in the SCN. VIP2 knockout mice show circadian rhythm disruptions with impaired SCN activity leading to abnormal sleep/wake cycles (63).

What was demonstrated in a genome wide association study was that the presence of a  VIP2 microduplication variant leads to a high risk of developing schizophrenia. This microduplication was detected in 0.35% of schizophrenic patients compared to 0.03% of controls (64). SNAP25 has also shown be an important regulator of SCN circadian rhythms through synchronisation to external environments (65). Mice with SNAP25 mutations (Blind-drunk mice) exhibit schizophrenic phenotypes reversible with the administration of antidepressants (66). The sleep phenotypes include sleep phase advancement and fragmented circadian rhythms. This mutation has been linked to schizophrenia by genetic association and linkage studies. Levels of SNAP25 have been shown to be reduced in the hippocampus of patients with schizophrenia (67).

Genetic evidence

Psychiatric illnesses are heritable, is there genetic evidence from a circadian clock gene variance? We have seen that in animal studies, polymorphisms in several clock genes have been linked to phenotypic expressions of psychiatric disease. These studies are usually hypothesis driven, small scale with specifically targeted gene candidates. How about the evidence from genome wide association studies (GWAS)? The MDD Working Group of Psychiatric GWAS Consortium found no clock gene single-nucleotide polymorphisms achieved genome wide significance in 9240 MDD patients and 9519 controls (68). Other large scale GWAS yielded similar findings including (69,70).


Circadian disruption is a hallmark of most psychiatric diseases. Interventions targeting chronobiology have shown effectiveness in treatment. It would seem logical that there was a circadian basis to the illness. However the circadian system is so physiologically far reaching that most mechanism associated with psychiatric disease have a circadian links. One difficulty with establishing a causal relationship is the overlap between sleep and circadian systems in the sleep/wake cycle. Another is that there are no accurate measures of circadian disruption. Do the phenotypes of psychiatric illness represent the cause or effect? Current evidence is unable to clear establish a difference. Even promising small genetic studies do not seem to show the same results in larger GWAS. At the moment, it would be fair to conclude from the evidence that circadian disruptions play a role in the onset, severity and prognosis of psychiatric illnesses. However, a direct causal relationship is not conclusive.


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