Evaluate the evidence that circadian rhythm disruption has a causal role in psychiatric disorders

Sleep is a recurring state of body and mind where biological systems enter an anabolic state. Anabolism helps to restore the nervous, skeletal, immune, and muscular systems. These systems in turn are vital in the maintenance of the body’s essential functions. Aristotle wrote that sleep was a “seizure of the primary sense organ… for the sake of its conservation” (Huffington, 2014). Even in ancient Greece they seem to have understood that sleep was necessary in order to have a healthy life. Sleep is divided into 5 stages. Of these, the first 4 stages are non-Rapid Eye Movement (non-REM) and the 5th stage is that of Rapid Eye Movement (REM) sleep. An example of the conservative and restorative elements of sleep can be seen in the non-REM stages of sleep. During these stages, the brain uses less energy, which has a noticeable effect on overall energy consumption. Specifically, studies have shown that during non-REM sleep there is a 44% reduction in the cerebral metabolic consumption of glucose (Maquet, 1995). This metabolic phenomenon could possibly contribute to the observation that sleeping persons perceive fewer stimuli. Overall, sleep ostensibly provides the mind and body with greater energy stores giving an individual a fresh start to each day.

Sleep is a behaviour driven at the molecular level via a transcriptional–translational feedback loop. This feedback loop putatively involves clock genes and their associated proteins such as cryptochrome (Jagannath, Pierson, and Foster, 2013). It is the cycling of these molecular mechanics that gives rise to what is called the circadian rhythm. This rhythm has been shown to be sensitive to multiple stimuli including the rotation of the earth and cues from the external environment. Explicitly, it is synchronized to external light–dark cycles by retinal light input. The expression for these inputs in German is zietgebers, meaning “time givers”. They inform the system on whether to speed up or slow down. Opportunely, evolution has conserved these molecular mechanisms through all mammalian species as well as most organisms with lifespans longer than 24 hours (Klein, Moore, and Rupert, 1991). For example, plants as well as unicellular organisms also show daily variations in metabolic activity and locomotion. These rhythms help the organisms anticipate and adapt to changing conditions in the local environment.

The aforementioned inclines one to think that sleep is only regulated by the circadian rhythm. This in fact is not the case. In addition to the circadian influences on sleep there are also homeostatic processes involved. These processes appear to be related to levels of adenosine (Borbely, 1984). Currently, the most comprehensive model to describe the regulation of sleep is the two-process model described by Borbely (Borbely, 1984). Sleep-wake homeostasis, or “Process S”, stands for the accumulation of sleep-inducing substances in the brain. This accumulation reminds the human body that it needs to sleep. This means that the longer someone is awake, the stronger the desire for sleep becomes. The circadian process, or “Process C”, refers to the cycling of the body’s internal biological mechanisms previously mentioned. To create a balanced sleep-wake cycle, these two processes should work together. If these two processes are not aligned, one’s quality of sleep will decline. A deficit in “Process S” can manifest as either a different rate of decline during sleep or in a slower build-up of sleep pressure during wakefulness. A deficit in “Process C” can manifest as a changed phase, amplitude, and/or endogenous period.

Regardless of type of deficit present, manipulations of the sleep–wake cycle, either in duration or timing, have profound and rapid effects on mood (Jagannath, Pierson, and Foster, 2013). This is most clearly seen in a phenomenon called shift work. Shift work drastically alters an individual’s sleep schedule. It requires multiple groups of people doing the same job in rotation, with some working standard daytime hours. The majority, however, will be working during the evening or in some cases overnight. For those who work in the evening or overnight, they will follow a schedule that contradicts the cues coming from the environment. Because of this, the clock genes in the suprachiasmatic nucleus (SCN) adapt to the phase shift of the light–dark cycle. These phase shifts and work schedules are associated with multiple adverse health effects. One specific example is its major effect on sleep and mood, which then can contribute to the development of affective disorders (Asaoka et al., 2013). Also, these individuals often have excessive sleepiness, sleep disruption, are more likely to be involved in accidents, and have a serious injury on the job (Colquhoun, 1976).

Shift work is one example of many recently classified sleep disorders. Clinically speaking, patients with sleep disorders generally have difficulty in any one (or all) of the following areas: (1) difficulty initiating sleep, (2) poor quality sleep, (3) early morning awakening, and (4) difficulty with sleep initiation (Roth , 2007). Another common sleep disorder is jet lag disorder. Jet lag disorder, which is also called circadian dysynchrony, is also caused when there is a mismatch between the person’s natural circadian rhythm and the external environment. This most commonly occurs when one travels between time zones and the body does not have the opportunity to adjust to the change. In addition to shift work and jet lag disorder, there are myriad other circadian rhythm sleep disorders that I will briefly mention here. They include;

Delayed sleep phase disorder (DSP):

This is a situation where the individual goes to bed and consistently wakes up two or more hours later than is considered normal. This disorder is more common in adolescents (American Academy of Sleep Medicine, 2008) .

Advanced phase sleep disorder (ASP):

In this condition, the individual goes to bed at a regular time and consistently gets up several hours earlier than most people. This is more common in the middle aged and older adults (American Academy of Sleep Medicine, 2008).

Irregular sleep-wake rhythm:

These individuals have a sleep wake pattern that is undefined. Their sleep is fragmented into steps over a 24hr period (American Academy of Sleep Medicine, 2008).

Nonentrained (free range) type:

These people have a variable sleep wake cycle. It is often associated with mental retardation and dementia (American Academy of Sleep Medicine, 2008).

Evidence supporting that a shift in light-dark cycles impacts mood state is further corroborated through studies investigating what has been termed as the photoperiod. For example, changes in day length (changes in photoperiod) are associated with changes in mood (Friborg et al., 2011). This finding is associated with the fact that rates of depression are higher in countries where the number of daylight hours is decreased for several months of the year (ex. Northern hemisphere countries like Norway and Sweden). The concept of photoperiod is also the basis of seasonal affective disorder. Because of this, understanding the way seasonal changes and light cycles impact the circuitry involved in mood regulation is of the utmost importance. Hopefully with continued research, improved preventative measures and treatments will be discovered.

In addition to sleep disturbances, acute and chronic sleep deprivation changes the neurobehavioral responses in humans. The most common of these changes include slower cognitive and psychomotor processing. These broader deleterious health effects could possibly be due to the circadian clock genes regulation of other physiologic functions such as glucocorticoid (GC) release, blood pressure, and body temperature (Jagannath, Pierson, and Foster, 2013). These glucocorticoids have a reciprocal effect on the clock itself. In cases where the production of glucocorticoid is excessive and abnormal, it can be toxic to many bodily processes. Some people have postulated that some psychiatric disorders might be the product of not only a dysfunctional clock, but also dysfunction in the hypothalamic-pituitary axis as evidenced by excessive amounts of glucocorticoid in the system. One psychiatric condition that is thought to fit this description is (PTSD) Post Traumatic Stress Disorder ( Sapolsky R.M., 2000). This disorder requires an environmental stimulus (the traumatic incident), dysfunction of the clock genes, and an inappropriate release of glucocorticoids. The glucocorticoids in high levels are neurotoxic, especially to the hippocampus. This is an area of the brain implicated in PTSD and might explain working memory deficits seen in this population (Sapolsky R.M., 2000).

A psychiatric disorder is defined in the Diagnostic and Statistical Manual (DSM-V) as being “a syndrome characterized by clinically significant disturbance in an individual’s cognition, emotional regulation, or behaviour that reflects a dysfunction in the psychological, biological, or developmental processes underlying function” (American Psychiatric Association, 2013). Psychiatric disorders carry with them a significant morbidity and mortality. They also present a unique and significant challenge to science because one cannot easily study the human brain in vivo. The advent of functional magnetic resonance imaging (fMRI) has created an avenue for addressing this challenge. Through this process we can now visualize activity in various regions of the brain under given conditions in vivo (Scarapicchia et. al., 2017).

In addition to these sophisticated clinical and diagnostic tools, the development of a myriad treatments is beginning to emerge. Currently, there is no specific treatment for these symptoms and conditions, but a combination of broad treatments can be helpful. These include improvement in sleep hygiene, use of sedative–hypnotic medication, change in lifestyle to increase exposure to daytime sunlight, and following a strict sleep schedule.

Another treatment that has shown great promise is light therapy. Existing literature has already demonstrated external light as an important synchronizer of the circadian rhythm and influencer of serotonin levels in mood disorders. Because of this, light therapy has become ubiquitous in treating sleep disturbances. Also, it is utilized for some affective disorders and serves as an adjuvant to antidepressants in major non-seasonal depression (Shirani and St. Louis , 2009).

Whether an individual has a sleep or psychiatric disorder, the treatments mentioned above are applicable to both. The treatments available engender hope and excitement for those who are currently suffering with these conditions. However, although much has been learned about the psychiatric disorder-sleep relationship, much remains unknown. Problems with sleep are one of the most common reasons for seeking medical attention and is common across most psychiatric illnesses like bipolar disorder, major depressive disorder and schizophrenia (Jagannath, et. al, 2013). This is a strong impetus for the medical community to continue to investigate the neural correlates involved with sleep and psychiatric conditions.

One study conducted by Pigeon and associates looked at major depressive disorder in an elderly cohort. They found that those who were persistently depressed, and less likely to sleep, were more likely to be depressed at the 6 month and 12 month points during treatment. Those without persistent depression improved faster. (Pigeon et al., 2005) The same type of phenomenon has been seen in studies with schizophrenic patients who also had significant sleep related symptoms. When treatments were targeted toward sleep and circadian rhythm disruption (SCRD) they reported improved sleep as well as improvement in some of their psychiatric symptoms. (Kantrowitz et. al., 2010).

There are many neuropsychiatric disorders which are characterized by circadian timing abnormalities, also referred to as SCRD. The main problem in SCRD is the inability to achieve sleep during the desired sleep time. That is why targeting circadian rhythm dysfunction may be useful in understanding psychiatric disorders and in the development of appropriate treatments. One approach to discovering how this system works is to mutate the clock genes and study the effect of the specific mutations on the performance of the system. Mutation of the circadian clock genes in animal studies resulted in disruptions in locomotor activity and reward processing function. This supports the idea of a connection between circadian rhythm and psychiatric illnesses (Landgraf et al., 2014). These findings also have significant implications in the development of addictive behaviours in humans (Rosenwasser, 2010).

One potential caveat to this research was the possibility of sleep disorders in psychiatric patients being caused by specific medications commonly prescribed to this population. Although this concern has been raised, research has shown that medication naïve patients with psychiatric disorders have the same types of sleep disorders as their medication taking counterparts (Chouinard et.al, 2004). This evidence further corroborates an endogenous circadian disruption in psychiatric patients.

There are instances where a single medication is used to treat both psychiatric and sleep disorders (ex. Mirtazapine or Trazodone). These chemical therapies have shown great promise. The same pattern seen in poor sleep is also seen in cases of sleep deprivation. Studies have found that even healthy adults can have an increased frequency of mood related symptoms when deprived of sleep ( Khan – Green et. al., 2007).

The evidence that sleep disturbances are associated with an increased risk of psychiatric problems is not new. One example of their interrelated nature is the observation that the frequency of nightmares is related to the risk of suicide in depressed patients (Tanskanen, Tuomieleho, and Viinamaki, 2001). In addition to these examples, it is also estimated that 30-80% of patients with schizophrenia have some type of SCRD (Cohrs, 2008). This data compounded with the aforementioned clearly demonstrates the complexity of relationship between psychiatric disorders and sleep. Included in this complexity is a bi-directional causation (sleep issues promoting mental health challenges as well as the converse). One of the reasons that this interaction is so complex is the fact that multiple components are involved. These components can include hormones, genetics, social, and psychosocial factors. This connection is most clearly illustrated by looking at specific psychiatric conditions.

Major Depressive Disorder (MDD) is a psychiatric condition characterized by depressed mood, anhedonia, sleep disturbance, fatigue, weight change, feelings of guilt, psychomotor retardation, difficulty concentrating, and frequents thoughts about death. Tragically suicidal ideation, attempts and completed suicide are common in these patients. Some studies have even shown that having insomnia significantly increases the risk for the development of new onset MDD (Chang et al. 1997). This evidence again reveals the tangled relationship between sleep disturbances and psychiatric illness. Intriguingly, a sleep disorder even has an effect on the rate of response to anti-depressant treatment. For example, MDD patients with a sleep problem have slower treatment response than those without sleep disturbance (Winokur et. al. , 1994). This suggests an alteration in neural correlates involving serotonergic circuits, which have been strongly implicated in MDD.

Patients with MDD not only have disturbed sleep, but they also have circadian rhythm abnormalities (Armitage , 2007). A very interesting discovery has been the development of the anti-depressant drug Agomelatine, which is approved in the United States for the treatment of MDD. This drug is a melatonin derivative with serotonergic properties. It not only acts as an anti-depressant, but also increases the relative amplitude of circadian rhythms in the rest–activity cycle (Deboudinat, et.al., 2010). This is achieved by targeting the melatonergic receptors that are located in the SCN which are known to synchronize circadian rhythms (Yang et. al., 2016). Agolmeltine has been shown to improve sleep quality and reduce waking after sleep onset in depressed patients (Yang et. al., 2016). Here is strong evidence again suggesting circadian disruption contributes to the onset of MDD.

Conversely, when Soutre and colleagues (1989) looked at 16 endogenously depressed patients and an equal number of matched controls, they found that blunted amplitude was the main chronobiological abnormality in the depressed patients. These patients were able to regain normal circadian profiles once their depression was treated and resolved (Soutre et al., 1989). Here is evidence that MDD contributes to the development of circadian disruption. With all the evidence presented it remains unclear whether the circadian disruption is causing new onset MDD or MDD is causing the circadian disruption. Further investigative studies need to be conducted in order to answer this question.

Another related psychiatric condition is Bipolar Disorder. This is a broad term which refers to a group of conditions that all share some common elements. These elements include a decreased need for sleep and a distinct period of elevated or irritable mood that seems to be inconsistent with events in the external environment. When scientists looked at the circadian rhythm of patients with Bipolar Disorder they found that patients had 3 basic types of circadian disturbances. They had (1) blunting of the circadian rhythm amplitude, (2) advanced position of the circadian rhythm phases, and (3) doubling of the length of sleep–wake cycles (Wehr et. al., 1983). It is believed that these changes can trigger the onset or the offset of episodes of mania or depression (Wehr et. al., 1983). Other research shows that preventing patients with bipolar disorder from sleeping predisposes them to the development of mania (Wehr, 1991). This is also a widely known concept in clinical practice where patients are encouraged to follow a strict sleep schedule to minimize manic episodes.

Patients with anxiety disorders also tend to exhibit multiple pathological sleep symptoms. Generally, they experience a greater number of arousals and longer sleep onset latency (Papadimitriou and Linkowski , 2005). This holds true for almost all of the recognized anxiety disorders (generalized anxiety disorder, post-traumatic stress disorder, and others). Chronic insomnia has been found to be a risk factor for the development of anxiety disorders (Neckleman et. al., 2007). The irony here being that sleep disturbance (SCRD) is also a cardinal feature of the disorder itself. For both bipolar disorder and anxiety disorders the evidence suggests circadian rhythm disruption contributes to development of the disorder. However, sleep disturbances are key features of both disorders as well which undermines the assertion of causality.

Schizophrenia is a unique psychiatric condition. It is a chronic psychotic condition in which affected individuals have hallucinations and delusions as their most prominent symptoms. Sleep disturbance is common in schizophrenia, despite it not being a defining characteristic of the illness. Disturbances of sleep are seen at every stage of the illness. It is even seen in (schizophreniform disorder) the schizophrenia prodromal stages ( Miller et al., 2003). Because of this, a cohort of schizophrenic patients was matched with a control group and had their rest – activity patterns examined. All of the schizophrenic subjects showed abnormalities in their sleep/circadian cycle (Wulff, et.al., 2012).

Schizophrenics also have significant cognitive deficits. It has been suggested that SCRD may play a large role in these cognitive problems. Specifically, aspects of memory processing and consolidation that usually occur during sleep are affected (Horne, 1993). The fact that sleep deprivation negatively effects cognition in healthy individuals has been known for some time, but the connection between SCRD and cognitive deficits in schizophrenic patients was not embraced until recently. This is of great clinical significance because the degree of cognitive deficits is the strongest predictor of functional outcome in this condition (Green, et. al., 2000). If researchers were able to find a way to correct the SCRD issues found in schizophrenia, it may have a positive effect on the level of cognitive impairment in patients with this disorder and thus reducing the morbidity associated with this condition.

Although it is often treated as a separate category of conditions, substance abuse and dependence are a major psychiatric issue effecting many populations around the world. This category includes a wide variety of substances such as cannabis, cocaine, opiates, nicotine and alcohol. Regardless of the specific substance involved, the underlying process of drug reward (and addiction) is the same. In the last 10 years there has been a focus on using mutations in the clock genes to disrupt the process of addiction (Falcon and McClung, 2009). The thought was that altering the clock gene would change an individual’s sensitivity to a substance of abuse. The majority of the research has been done with cocaine, but other studies have involved the use of opiates and alcohol as well. These studies suggest an important role for these genes in the limbic system which surrounds the SCN (Falcon and McClung, 2009).

Of these substance abuse conditions, alcoholism is very case in point. In alcoholism those affected often have disruption of the circadian sleep-wake rhythm. Insomnia is common among people who suffer from alcohol dependence. The prevalence rate is estimated to be between 36-72% (Baekeland et.al., 1974). It is also thought that the genesis of sleep disturbance in most alcoholics is related to the issue of timing. Ostensibly, people who drink in the daytime, also sleep in the daytime. This daytime sleeping activity is thought to erode the person’s normal circadian rhythm. The link between poor sleep during abstinence, and relapse to drinking alcohol has been identified in previous studies (Brower et. al., 2001).

Finally, the same common elements are seen when you look at sleep disorders and the incidence of psychiatric illness. In 2001, a retrospective cross-sectional database review of patients receiving care in the United States Veterans Administration healthcare system, during the period between 1998 and 2001, was conducted. They found that patients who were diagnosed with sleep apnoea had a higher prevalence of comorbid psychiatric disorders than those who did not have a diagnosis of sleep apnoea. This held true for the psychiatric diagnoses of depression, anxiety disorders, psychotic disorders, and bipolar disorder. (Sharafkhaneh et. al., 2005). The findings of the above study lead to a change in policy that provided for more intensive psychiatric screening for the patients who carried the diagnosis of sleep apnoea.

The aforementioned provides many examples of correlation between circadian rhythm disruption and psychiatric disorders. However, despite this surplus of evidence there is a very limited amount of evidence that implies causality. It boils down to the adage “what came first, the chicken or the egg?” And just to clarify, the question is: did the psychiatric disorder cause the sleep circadian rhythm disorder, or conversely did the sleep circadian rhythm disorder cause the psychiatric disorder? This is the part that is not completely clear. Hopefully, with continued research using molecular biology to examine specific mutations to the clock genes as well as enhanced studies of the individuals who are at risk to develop psychiatric illness, clarity on the issue of causality will be found. In the end, I believe that it will probably be a combination of factors that include some amount of SCRD, environmental stress, and genetic predisposition. This implies that there will be no simple path to effective new treatments for these conditions due to the multiple interacting factors.

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