3rd Year Neuroscience Essay (2)

Discuss the association between sleep/circadian disruptions and severe mental health disorders (such as schizophrenia and bipolar disorder) and how this might have implications for treatment?

Introduction

Sleep and circadian rhythm disruption (SCRD) is a common feature of neuropsychiatric disease, and has been known as such since it was first noted by Emil Kraepelin in 1883. Indeed, the DSM-IV and ICD-10 list changes in sleep behaviour and SCRD as key criteria for the diagnosis of affective and psychiatric disorders. Despite this, the relationship between sleep disturbances and mental health disorders remains unclear, partly due to the difficulties that arise in building links between them due to the variation in individual phenotypes (patients with the same diagnosis, age, gender, and medication can vary in the severity of their SCRD). It has been shown that normal brain function and the generation of sleep are linked by common neurotransmitter systems and regulatory pathways. Furthermore, the observation that mood and cognitive performance vary with time of day has led to the conclusion that they are, at least in part, regulated by circadian and homeostatic processes. Thus, it is now being proposed that brain disorders and abnormal sleep may have common mechanistic origins, and recent advances in our understanding of the mechanisms underlying sleep and circadian rhythms are helping to provide direct links between SCRD and neuropsychiatric disease, particularly in schizophrenia (SZ) and bipolar disorder (BD).

Sleep and circadian disturbances in mental health disorders

There is significant evidence for the association between sleep disruption and mental health disorders. For one, poor health in mental illness has a number of impacts, including impaired cognition and memory, increased substance abuse, metabolic abnormalities, reduced immunity, cardiovascular disease, and reduced life-expectancy, all of which are also seen in sleep disruption.

Abnormal sleep has been described in patients with SZ since the 1920s, with between 30-80% of patients reporting sleep disturbances, making it one of the most common symptoms and its improvement one of the highest priorities during treatment. Studies have related SZ with reduced REM latency, REM density, sleep efficiency, total sleep time, duration of NREM stage 4, and increase in sleep latency¹, in addition to circadian abnormalities including delayed phase, advanced phase, free-running and/or irregular sleep timing patterns (unpublished observations). In a recent study, Wulff et al., 2012,² used actigraphy as a measure of motor activity and light exposure and urine melatonin metabolite levels as a phase marker of the circadian clock. They found that SZ patients has significant SCRD, with one subgroup showing severe circadian misalignment (phase advance/delay or non-24hr period in sleep-wake and melatonin cycles), and the other showing excessive or highly irregular and/or fragmented sleep epochs but normally timed melatonin production. Though in the past it had been argued that SCRD in SZ might occur as a result of unemployment and a lack of daily routine, or as a side-effect of antipsychotic medication, this study provided evidence against this. There was no evidence that medication dose or type was related to the abnormalities, and their age, gender, and unemployment-matched controls showed no SCRD. The researchers concluded that severe circadian sleep/wake disruptions exist despite stability in mood, mental state and antipsychotic treatment, and that the disruptions could not be explained by the individuals every day level of function. Thus, we see there is evidence for a true association between SZ and SCRD that is not the result of secondary factors.

Sleep disruption is also an intrinsic clinical feature of all phases of BD. It has been shown that patients exhibit insomnia or hypersomnia during depressive episodes, an reduced need for sleep during (hypo-) manic episodes, with circadian instability being seen in 67% of patients between episodes^3,4. Studies of the relationship between BD and sleep are complicated by the inter-individual variability in number and severity of previous episodes. Rock et al., 2014⁵, assessed daily rest-activity patterns in euthymic, medication-na ve BD phenotype individuals. They found that BD phenotype resulted in increased movement during sleep, greater activity levels during the least active 5hrs (02:00-07:00), and lower circadian relative amplitude (smaller difference between the most active 10hr and least active 5hrs) relative to controls. Furthermore, to assess whether this difference seen was a result of BD diagnosis, they carried out further statistical analysis excluding those individuals diagnosed, and found that there still remained significant difference. Thus, they provide good evidence that actively moving during sleep may be associated with vulnerability for a BP phenotype. In addition, irregular sleep timing, reduction of total sleep, and travel across multiple time zones are triggers for manic episodes⁶.

Thus, we see that sleep disruption is common in patients with various mental health disorders. In the past, it was thought that the link between SCRD and psychiatric disorders may be a linear relationship, in which illness results in SCRD as a result of stress axis, social isolation and medication. However, this view is now being challenged, and it is thought that the relationship may be in fact better described as cyclical and overlapping, with each affecting the other. Based on this mechanistic relationship view, we are able to make a number of predictions: firstly, genes linked to mental illness should also affect sleep and/or clock secondly, genes linked to sleep and/or clock should also affect mental illness and finally, treatment reducing either SCRD or mental illness should improve the level of the other. Over the next few sections, I will discuss the evidence in favour of each of those predictions, and what implications this may have for future treatment.

Models of mental health disorders

Hypotheses on the mechanistic causes of SZ focus upon abnormal neurotransmission and neurodevelopment, and indeed genetic studies have implicated a number of proteins involved in glutamatergic synaptic transmission. The Blind-drunk (Bdr) mouse is a model of synaptosomal-associated protein (Snap)-25 exocytotic disruption that displays schizophrenic endophenotypes. These are modulated by prenatal factors and reversible by antipsychotic treatment. SNAP-25 has been implicated in SZ from genetic, pathological, and functional studies. In addition, SNAP-25 has been shown to play an important role in light-signalling to the circadian system, and in in vitro studies, inhibiting synaptic vesicle recycling by botulinum toxin A or dynasore in organotypic cultures of the SCN resulted in abnormal patterns of circadian gene expression in SCN neurons⁷. Furthermore, studies by Olivers et al., 2012⁸ showed that the rest and activity patterns of Bdr mice are phase-advanced and fragmented under a L:D cycle, which is reminiscent of the disturbed sleep pattern observed in SZ patients. They found that retinal inputs in these mice were normal, and that clock gene rhythms in the SCN were normally phased, indicating the core molecular clock of the mutant is not affected. However, they found that the 24hr rhythms of argenine vasopressin (AVP) within the SCN and plasma corticosterone are both markedly advanced in Bdr mice, and suggest that Bdr circadian phenotypes arise from a disruption of synaptic connectivity within the SCN that alters critical output signals. Thus, their data provides a link between disruption of circadian activity cycles and synaptic dysfunction in a model of neuropsychiatric disease. A number of other genetic mouse models for SZ show links to the circadian system, though Bdr remains the best, as it is the only one with a plausible biological connection (the others simply show significant association with SZ). Interestingly, thus far only genetic models of SZ have been studied in relation to SCRD. Thus, further study must be done to shed light on whether sleep is affected in the PCP, MK-801 and ketamine models of SZ. Similar studies have been carried out on models of BD. Kirschenbaum et al., 2011⁹, showed that Myshkin (Mrkl) mutant mice with a mutation in the Na⁺,K⁺-ATPase Atp1a3, provide an animal model of mania, and this mutation has been shown to have affect on the circadian system, most notably that the animals show lengthened circadian period (25hrs).

Models of SCRD

In order to fully establish mechanistic links, a parallel approach must be carried out to screen mouse models of circadian disruption for psychiatric-related behaviours. Clock mutants have extended circadian periods, and sleep significantly less than wild types, findings which are consistent with the decreased need for sleep observed in patients with mania. Their behavioural profile is reminiscent of bipolar patients in the manic state, as they show hyperactivity, excessive reward-seeking behaviour, reduced depression-like behaviour, reduced anxiety-like behaviour and increase exploratory behaviour. Furthermore, genetic association studies suggest that polymorphisms in some clock genes are linked to the frequency of depressive relapses, positive responses to sleep deprivation, and improved responses to long-term lithium treatment. Studies by Benedetti et al., 2008¹⁰, indicated that PER3^5/5 (the long allele variant of per homologue 3) was linked to the early onset of type I BD, which is a significant predictor of a more severe course of disorder.

Treatment

Finally, if there is a true association between mental illness and sleep disruption, then stabilisation of the sleep/circadian system should result in the reduction of symptoms in neuropsychiatric illness (and vice versa). Furthermore, sleep disruption may precede clinical diagnosis, so sleep disruption could also act as biomarkers. Thus, they may provide measures to support early screening and diagnoses, shed light on some of the underlying pathophysiological mechanisms involved, and clarify the rationale for sleep- and circadian-based treatment pathways. Evidence suggests that the early treatment of such disturbances is likely to improve prognosis and possibly prevent the development of full-blown disorders¹¹.

In unpublished studies, Freedman et al., look to see whether sleep disruption contributes to the occurrence of psychotic experiences. They carried out a randomized control trial of 3755 people with insomnia, and found that improving sleep led to significant reductions in levels of paranoia and hallucinations. These findings were supported by mediation analysis, and thus provided evidence that insomnia is one contributory factor to the occurrence of paranoia and hallucinations. Furthermore, Myers et al., 2011¹², found that CBT intervention for insomnia for individuals with persistent persecutory delusions and sleep difficulties resulted in significant reductions in both levels of insomnia and persecutory delusions (though the intervention did not discuss the delusions), with large effect sizes maintained at the next follow-up. These promising results are consistent with the casual role for insomnia in the maintenance of psychotic symptoms, and is of particular importance as long-term and difficult to treat patients took very well to this targeted intervention.

Studies by Harvey et al., 2015¹³, aimed to determine whether treatment for interepisode type I BD patients with insomnia via a BD specific modification of CBT (CBTI-BP) would improve mood state, sleep and functioning. Indeed, they found that CBTI-BT was associated with reduced risk of mood episode relapse and improved sleep and functioning on certain outcomes of BD, providing evidence for sleep disturbance as an important pathway contributing to BD.

Sleep deprivation is the most widely documented rapid-onset antidepressant therapy. It acts within 24-48hrs in 40-60% of depressed patients, whilst conventional antidepressants take 2-8weeks to meet response criteria. Wu et al., 2009¹⁴, evaluated the combined effects of three established circadian-related treatments (sleep deprivation, bright light, and sleep phase advance) as adjunctive treatments to lithium and antidepressants. They found that there were significant decreases in depression in the chronotherapeutic augmentation patients compared to medication-only patients within 48hrs of sleep deprivation, and these decreases were sustained over 7 weeks. This study was the first to demonstrate the benefit of adding circadian-related interventions in medicated patients to accelerate and sustain antidepressant responses, and provides a strategy for the safe, fast-acting and sustainable treatment of BD.

Conclusion

Thus, we see that psychiatric disorders often co-occur with SCRD, and there is increasing evidence for a mechanistic overlap between mental illness and the basic control mechanisms of sleep/circadian timing. Though SCRD is the most commonly reported sign that precedes the onset of many psychiatric disorders, sleep disruption is rarely used as a marker for the early detection and intervention of psychiatric disorders in high-risk subjects. In the future, more research must be done to provide a better understanding of the neural and genetic mechanisms that are common to sleep, sleep/wake timing, and neuropsychiatric illness. Furthermore, more must be done to use SCRD as a biomarker in the early diagnosis of neuropsychiatric conditions, and to use agents that regulate sleep and sleep timing for the reduction of symptoms and for an improved quality of life in neuropsychiatric illness.

References:

1. Cohrs, S. Sleep disturbances in patients with schizophrenia: Impact and effect of antipsychotics. CNS Drugs 22, 939 962 (2008).

2. Wulff, K., Dijk, D. J., Middleton, B., Foster, R. G. & Joyce, E. M. Sleep and circadian rhythm disruption in schizophrenia. Br. J. Psychiatry 200, 308 316 (2012).

3. Harvey, A. G., Schmidt, D. A., Scarn , A., Semler, C. N. & Goodwin, G. M. Sleep-Related Functioning in Euthymic Patients With Bipolar Disorder, Patients With Insomnia, and Subjects Without Sleep Problems. Am. J. Psychiatry 162, 50 57 (2005).

4. Harvey, A. G. Sleep and circadian rhythms in bipolar disorder: Seeking synchrony, harmony, and regulation. American Journal of Psychiatry 165, 820 829 (2008).

5. Rock, P., Goodwin, G., Harmer, C. & Wulff, K. Daily rest-activity patterns in the bipolar phenotype: A controlled actigraphy study. Chronobiol. Int. 31, 290 6 (2014).

6. McClung, C. A. Circadian genes, rhythms and the biology of mood disorders. Pharmacology and Therapeutics 114, 222 232 (2007).

7. Deery, M. J. et al. Proteomic Analysis Reveals the Role of Synaptic Vesicle Cycling in Sustaining the Suprachiasmatic Circadian Clock. Current Biology 19, (2009).

8. Oliver, P. L. et al. Disrupted circadian rhythms in a mouse model of schizophrenia. Current Biology 22, 314 319 (2012).

9. Kirshenbaum, G. S. et al. Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+-ATPase sodium pump. Proc. Natl. Acad. Sci. U. S. A. 108, 18144 9 (2011).

10. Benedetti, F. et al. A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. Neurosci. Lett. 445, 184 187 (2008).

11. Robillard, R. et al. Ambulatory sleep-wake patterns and variability in young people with emerging mental disorders. J. Psychiatry Neurosci. 40, 28 37 (2015).

12. Myers, E., Startup, H. & Freeman, D. Cognitive behavioural treatment of insomnia in individuals with persistent persecutory delusions: A pilot trial. J. Behav. Ther. Exp. Psychiatry 42, 330 336 (2011).

13. Harvey, A. G. et al. Treating insomnia improves mood state, sleep, and functioning in bipolar disorder: A pilot randomized controlled trial. J. Consult. Clin. Psychol. 83, 564 577 (2015).

14. Wu, J. C. et al. Rapid and Sustained Antidepressant Response with Sleep Deprivation and Chronotherapy in Bipolar Disorder. Biol. Psychiatry 66, 298 301 (2009).

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