Are Cardiometabolic and Endocrine Abnormalities Linked to Sleep Difficulties in Schizophrenia? A Hypothesis Driven Review
Abstract
INTRODUCTION
Schizophrenia affects 0.5-1% of the population, a prevalence that is consistent across the world population.1,2) This chronic psychiatric disorder causes mental perturbations that significantly alter social and occupational functioning with important consequences on the course and quality of life.
The main features of schizophrenia include delusions, hallucinations, disordered thoughts, disorganized or catatonic behaviour, blunted affect, alogia, avolition, cognitive dysfunctions and sleep difficulties.3-5) In addition to these mental and affective symptoms, several physiological disturbances also increase the burden of schizophrenia. Changes in endocrine, metabolic and cardiovascular functions, with associated disorders affecting weight, glucose regulation, lipid metabolism and blood pressure are the source of major health problems commonly affecting people with schizophrenia. The mechanisms underlying these cardiometabolic changes are not yet fully understood.
In healthy individuals, alterations in the metabolic, cardiac and endocrine systems have been associated with chronically shortened sleep duration and circadian disruption.3-6) To our knowledge, no study has directly addressed the possible relation between cardiometabolic dysfunctions and sleep/wake abnormalities in the schizophrenia population. Since circadian and sleep disturbances are often comorbid with schizophrenia, it could be hypothesised that sleep/circadian factors may play a role in the high rates of co-occurrence of cardiovascular and metabolism abnormalities in patients with schizophrenia.
This non-systematic review presents evidence supporting this hypothesis. The characteristics of sleep and circadian rhythms in schizophrenia will be briefly summarized before the cardiovascular, metabolic and endocrine profiles typical of this population will be exposed. Evidence on the implications of sleep in cardiometabolic, endocrine and metabolic functions obtained from studies in the general population will then be discussed. This evidence will lay the rationale supporting the possible role of sleep as a modulating factor in the association between cardiometabolic abnormalities and schizophrenia. The implications of common genes linked with schizophrenia, sleep patterns and cardiometabolic functions will be discussed.
SLEEP AND CIRCADIAN DISTURBANCES IN SCHIZOPHRENIA
Up to 55% of medicated patients with schizophrenia report sleep problems.7,8) While sleep-wake abnormalities may be exacerbated by antipsychotics, especially first generation antipsychotics, evidence suggests that sleep and circadian disruptions are linked to schizophrenia independent of pharmacological treatment.5,7,9)
Sleep-wake cycle regulation operates through two interactive but distinct processes.10) The circadian process represents the rhythmic variation of sleep and wake propensity over 24 hours that is regulated by the body clock. The homeostatic process represents the accumulation of sleep pressure (relating to the notion of sleep 'debt') with increasing time awake and its dissipation during sleep.11) A precise interaction between the circadian and homeostatic processes defines the timing of sleep and wake periods. It also supports the maintenance of consolidated sleep episodes during the night and consolidated wake episodes during the day.10,12) These two processes may come to play in the sleep disturbances experienced by people with schizophrenia.
Homeostatic Aspects of Sleep in Schizophrenia
Sleep studies in patients with schizophrenia highlight objective abnormalities in sleep quality and quantity that can lead to increased sleep pressure. A meta-analytic review of 20 studies with a total of 652 subjects with schizophrenia concluded that, compared to healthy controls, patients with schizophrenia take longer to fall asleep and have shorter sleep duration with lower sleep efficiency (i.e., proportion of the time in bed that is spent sleeping).13) Additionally, there is decreased rapid eye movement (REM) sleep latency,14) and reduced stage 4 of non-REM sleep.15) Over time, these changes are likely to lead to a progressive accumulation of sleep debt, pressuring the homeostatic sleep system.
Because they tend to intensify before psychotic episodes, sleep disturbances are thought to be precursor symptoms of decompensation in patients with schizophrenia.16-21) Accordingly, the sleep literature provides examples depicting how sustained increases in homeostatic pressure caused by multiple sleepless days with psychostimulant intake can induce psychotic symptoms such as depersonalization, reduced connection with reality, visual hallucinations and persecutory ideation, even in non-clinical populations.20,22-24) Such findings suggest that sleep disturbances may play a role in the pathogenesis of symptoms associated with schizophrenia.
Circadian Aspects of Sleep in Schizophrenia
Circadian rhythms refer to 24 hours endogenous biological variations originating from the body clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus and from peripheral oscillators located in various organs across the body that are synchronised by the SCN.25) SCN dysfunction leads to alteration in the timing and duration of sleep, often misaligning sleep episodes with socially adequate timing (i.e., delaying or advancing the internal rhythms) and/or fragmenting the sleep-wake cycle with intrusions of numerous awakenings during the night and naps during the day.
Inferences about circadian rhythms are generally made by measuring 24-hour variations of behavioural/biological functions known to follow a robust circadian rhythm. These include activity levels, core body temperature and hormonal secretion. Melatonin and cortisol are often used as endocrine markers to read endogenous circadian rhythms. Melatonin is a soporific hormone secreted by the pineal gland during the night, which shows very low levels during the day. Cortisol, a glucocorticoid catabolic hormone regulated through the hypothalamic-pituitary-adrenal (HPA) axis, is associated with vigilance and stress and reaches its higher levels during the day with lower levels during the night.
Circadian studies in the schizophrenia population have reported abnormalities in the timing of these physiological rhythms in the form of phase advances and delays.26-31) It is not yet clear what shifts circadian rhythms in one direction or the other in patients with schizophrenia. Many factors such as the phase of illness, the presence of other comorbidities, occupational status and schedules imposed by the living environment vary substantially within the schizophrenia population and are likely to influence circadian rhythms differently from one individual to another.
More consistent findings have shown that people with schizophrenia have lower melatonin levels.32-35) and higher cortisol levels at night.36) Consistent with these physiological changes, schizophrenia is also associated with a global disorganisation of sleep-wake episodes, with more diurnal sleep and nocturnal wake periods.27)
It has recently been proposed that the sleep-wake disturbances in schizophrenia may reflect SCN dysfunctions.37,38) Importantly, the nitric oxide synthase immuno-reactive neurons in the SCN have been reported to be significantly less numerous in patients with schizophrenia.37) This physiological characteristic of patients with schizophrenia could possibly come to play in the emergence of sleep-wake regulation as nitric oxide is thought to modulate sleep.39,40)
The many negative outcomes resulting from sleep and circadian difficulties may have more disturbing effects on the life of people with schizophrenia compared to the general population. Notably, it has been proposed that sleep abnormalities in schizophrenia may impair memory consolidation processes occurring during sleep and could therefore contribute to the altered cognitive profile associated with schizophrenia.41) Sleep loss has also been associated with poorer quality of life and reduced coping resources in people with schizophrenia.42-44) Globally, poor sleep is likely to further impair the already fragile social and occupational functioning of persons experiencing schizophrenia.45) Social functioning may also be secondarily impaired due to the schizophrenia patient having reversed sleep/wake periods along with fragmented daytime sleep. Physiologically, these phenomena might manifest behaviourally as, or at least contribute to, negative symptoms such as anergia, and apathetic social engagement. Negative symptoms have been associated with lower counts of frontal delta waves, and loss of asymmetry in studies of all night sleeping, suggesting that there may be also physiological impairments at work too.46)
CARDIOMETABOLIC AND ENDOCRINE ABNORMALITIES ASSOCIATED WITH SCHIZOPHRENIA
Sudden cardiac deaths are three times more frequent in patients with schizophrenia than in the general population.47,48) Moreover, the prevalence of natural deaths related to cardiovascular diseases in the schizophrenia population is estimated to range between 40 to 45%.49) However, it is premature death from cardiovascular disease that is alarming, with persons with schizophrenia having ≥20% shorter life spans with up to 25 years of life lost.50,51) While patient care in schizophrenia often primarily addresses mental disturbances, these statistics highlight the importance of monitoring and treating cardiovascular and metabolic functions in this population, especially when one considers that the gap in the differential rates of standardised mortality between the general population and those with schizophrenia is widening.52) Understanding of the phenomenon of cardiometabolic disorders in the specific context of schizophrenia is necessary to develop adapted therapeutic interventions for these patients.
While antipsychotic medication is often linked to cardiovascular and metabolic perturbations, important cardiometabolic abnormalities have been reported in drug naïve or drug-withdrawn patients with schizophrenia.53) Therefore, even though cardiometabolic changes are likely to be modulated to a variable degree by different antipsychotic medications, schizophrenia per se is thought to be associated with cardiovascular and metabolic abnormalities independently of the concomitant effect of pharmacological agents.53)
Cardiovascular Function
Despite the wide promotion of good life habits and cardiovascular health, rates of cardiovascular abnormalities remain especially high in people with schizophrenia, who experience multiple barriers to receiving adequate physical health care.53)
Notably, Bär et al.54) found that mean systolic and diastolic blood pressure were significantly higher in adults with schizophrenia (135 mmHg/84 mmHg) compared to healthy control subjects (120 mmHg/74 mmHg). This difference raises the average blood pressure values close to the clinical threshold for hypertension, in the hazardous range of pre-hypertension (120-139 mmHg/80-89 mmHg; American Heart Association, 2010). Not surprisingly, comorbidity studies estimate that the prevalence of hypertension in the schizophrenia population ranges between 27% and 45%.55-57) This high prevalence bears considerable clinical significance, since high blood pressure is a risk factor for the development of many life-threatening conditions such as cardiovascular diseases, strokes and renal failure. Aside from these physical health concerns, hypertension has also been linked with decreased cognitive skills,58) therefore further altering a dimension of life already vulnerable in schizophrenia.
While comparing the baroreflex sensitivity of patients with schizophrenia with healthy controls, Bär et al.54) found significant alterations in the coordination of blood pressure with heart rate. These authors suggested that the decreased parasympathetic activity in schizophrenia constituted a lower counterweight to sympathetic stimulation. Moreover, compared to healthy controls, the heart rate of people with schizophrenia is more than 25% faster and shows lower variability, suggesting altered cardiac autonomic function.54,59) Importantly, reduced baroreflex sensitivity and heart rate have been associated with increased risk of vascular events and mortality.60,61)
Smoking and Lifestyle
A recent study revealed that the prevalence of smoking in the schizophrenia population is almost two times more frequent than in the general population. These smokers with schizophrenia have been reported to have unhealthy life habits (e.g., poor diet, high intake of alcohol and caffeine, sedentary lifestyle) and to be at increased long term risk of cerebrovascular events.62) Hence, while the full aetiology of cardiovascular abnormalities in schizophrenia remains multi-factorial, modifiable life habits are likely to potentiate them.
Body Weight
Overweight and obesity are estimated to be 1.5 to 2 times more frequent in patients with schizophrenia than in the general population.50,63-66) Accordingly, body mass index, waist-hip ratio and waist circumference have all been shown to be significantly higher in people with schizophrenia.36,56,67) Importantly, the fat distribution characteristic of schizophrenia differs to that of the general population. While total body fat, as measured by computed tomography scan, and subcutaneous fat are similar in schizophrenia and controls, people with schizophrenia have three times as much intra-abdominal (or central) fat.36,68) This specific fat distribution is highly associated with cardiovascular disturbances, hypertension, type 2 diabetes and dyslipidaemia.69,70) Central adiposity is thought to contribute to the insulin resistance syndrome and in conjunction with its enhanced inflammatory status, in turn enhances cardiovascular risk.71)
Aside from its damaging physiological consequences, decreased physical fitness resulting from weight gain may confer an aversive aspect to physical activity and further contribute to sedentary lifestyle in schizophrenia. Alteration of body image following weight gain is thought to be a potential factor for low self-esteem and further social marginalisation in people with mental illness.72)
Chronic antipsychotic medication, especially atypical antipsychotics, has been shown to increase weight in up to 80% of patients with schizophrenia73,74) and to have a prominent effect on abdominal fat.75-77) For those on antipsychotics, antipsychotics, central H1, alpha-1-adrenergic, and 5-HT2C antagonism is highly predictive of poor hypothalamic energy balance control with subsequent weight increase.78)
Some authors have proposed that the consequences of weight gain can be distressing enough to threaten medication adherence.72,79) Inactivity, apathy, lower socioeconomic status and bad diet have also been suggested to play a role in the aetiology of weight problems in schizophrenia.80) Importantly, epidemiological studies have reported that patients with schizophrenia have significantly higher weight levels even when compared to lifestyle-matched controls.68) This suggests that, while possibly intensified by external factors such as medication, socio-economic variables, eating habits, or exercise levels, and weight gain in schizophrenia operates through endogenous mechanisms. Notably, the higher caloric intake associated with schizophrenia is thought to result in part from increased appetite and decreased satiation,81,82) which could in turn be explained by endocrine and metabolic changes.
Eating Habits and Endocrine Abnormalities
Schizophrenia has been associated with altered self-control and cognitive distortions regarding one's relation to food, such as rigid weight regulation and fear of weight gain.80) This combination is likely to generate maladaptive eating behaviour. In fact, food intake in schizophrenia has been paralleled with several types of eating behaviour disturbances such as pica, gorging, anhedonia, and paranoia-induced starvation.83) Moreover, the diet of patients with schizophrenia has been observed to includes increased levels of saturated fat and food with high glycaemic index. Conversely, their diet tends to be low in fibre, fruits and vegetables.84-87) While socioeconomic and cognitive variables may contribute to this eating profile, important perturbations of hormones implicated in the regulation of appetite, weight and metabolism may also come to play as primary drivers of poor diet choices.
Ghrelin is a hunger stimulating hormone released mainly by the stomach that is associated with increased body fat88) and is reduced by glucose and insulin.89) Medicated patients with schizophrenia have higher ghrelin levels than healthy controls.67,90) This endocrine imbalance is thought to contribute to the increased food-intake characteristic of schizophrenia.67)
Leptin, a hormone derived from the cells composing adipose tissues, signals satiety by sending information about ongoing energy reserves to the hypothalamus. These signals lead to a decrease in appetite. Because leptin levels are correlated with fat mass, some authors have proposed that obesity may be linked with a decreased reaction to leptin signals.91) Some studies have found higher leptin levels in medicated schizophrenia patients compared to healthy controls.90,92) However, when body mass index is controlled, patients with schizophrenia are no different from groups of healthy subjects, suggesting that the high leptin levels associated with schizophrenia may be mediated by overweight.92-95)
Cortisol is implicated in glucose homeostasis, suppresses insulin and is thought to promote obesity. Patients with schizophrenia have been reported to have higher cortisol levels than healthy controls,96-100) possibly because of alterations in the suppression mechanisms regulating this hormone.101-103) Cortisol receptors are especially dense in visceral fat stores and potentiate the activity of lipoprotein lipase, an enzyme implicated in fat deposition that is also highly concentrated in intra-abdominal fat stores.104) Hence, it has been proposed that hypercortisolaemia associated with schizophrenia may increase lipoprotein lipase's central fat deposition, which is in turn associated with several cardiovascular and metabolic abnormalities.36,67)
Cortisol has an important modulatory influence on cardiovascular and metabolic activity, notably to restore physiological homeostasis after stress. Hence, abnormalities affecting HPA axis functions can interact with cardiovascular and metabolic disturbances. Notably, high levels of anxiety have been shown to be significantly correlated with elevated diastolic blood pressure and heart rate in patients with schizophrenia.105) Furthermore, it has recently been suggested that higher levels of stress in people suffering from schizophrenia and the subsequent frequent activation of the HPA axis could trigger symptoms associated with the metabolic syndrome.106,107)
Importantly, alterations in leptin, ghrelin and cortisol have all been associated with cardiovascular and metabolic disturbances.108-110) Therefore, their disturbed dynamics could possibly be implicated in the high occurrence of weight gain and other cardiometabolic abnormalities in schizophrenia.
Metabolic Perturbations
The rate of metabolic disorders is markedly high in the schizophrenia population.111-113) Notably, epidemiological studies estimate that type 2 diabetes is 2 to 3 times higher in people with schizophrenia compared to the general population.114) Similarly, metabolic syndrome, characterised by multiple metabolic risk factors such as overweight, elevated triglycerides, lowered high-density lipoprotein cholesterol, impaired fasting glucose levels and hypertension, is almost 2 times more prevalent in patients with schizophrenia.50)
Compared to healthy controls, patients with schizophrenia show higher glucose and insulin plasma fasting levels as well as a higher increases following glucose intake.98,115) Schizophrenia has also been associated with hepatic insulin resistance, a condition often leading to type 2 diabetes98,116,117) that is also thought to mediate the association between intra-abdominal fat and cardiovascular problems.118) Since cortisol is known to lower insulin inhibition of hepatic glucose,119) hypercortisolaemia has been proposed to be implicated in the pathogenesis of diabetes in schizophrenia.106,107,120)
In summary, many endogenous physiological abnormalities observed in schizophrenia are likely to affect cardiovascular, endocrine and metabolic functions. Higher blood pressure, reduced baroreflex sensitivity and slower heart rate put patients with schizophrenia at higher risk of cardiovascular events. Higher levels of ghrelin and cortisol, two hormones that respectively promote food intake and central fat deposition, may contribute to endogenous weight gain mechanisms. Furthermore, interactions between these cardiovascular and weight problems are catalysed by high rates of diabetes related to insulin and glucose dysregulation. Because these factors are not easily modifiable by life habits changes, in the context of schizophrenia, they add to the obstacles complicating weight management.
CARDIOMETABOLIC SENSITIVITY TO VARIATIONS IN SLEEP AND THE CIRCADIAN SYSTEM
Ongoing research constantly deepens our understanding of the various functions of sleep, including its contribution to the maintenance of physical health. Multiple studies in healthy subjects have proposed that the homeostatic and circadian processes can impact on the regulation of many cardiovascular, endocrine and metabolic parameters that have been reported to be abnormal in schizophrenia.
Increased Homeostatic Sleep Pressure
In healthy volunteers, it has been experimentally demonstrated that increased homeostatic pressure through sleep deprivation causes a raise in systolic and diastolic blood pressure.56,121,122) Moreover, sleep deprivation has been shown to reduce the decrease in systolic blood pressure after an orthostatic perturbation.123) Hence, sleep loss not only increases basal blood pressure but also induces alterations in arterial regulation, putting individuals with sleep difficulties at higher risk for vascular events.
Studies in chronic short sleepers and experimental studies using several days of sleep restriction indicate that high homeostatic pressure also alters metabolic and endocrine functions. For instance, shortened sleep increases morning glucose levels following food intake and reduces the insulin response to glucose.6,124,125) These changes heighten the susceptibility of short sleepers to develop type 2 diabetes. Sleep restriction has also been shown to reduce leptin while increasing ghrelin levels,125) an imbalance likely to potentiate weight gain. Accordingly, several epidemiological studies have linked sleep disturbances with being overweight.126)
Circadian Rhythms Disruptions
Aside from regulating the sleep-wake cycle, the circadian system also has a strong influence on many cardiovascular and endocrine functions.
Leptin is subjected to a clear circadian modulation, reaching its maximum level in the evening and its lowest point in the morning. Although, ghrelin fluctuations are more affected by food intake than by circadian modulation, this hormone has also been shown to increase in the evening.127) The secretion of cortisol by the adrenal gland also follows precise variations across 24 hours. Evening cortisol levels have been shown to increase in conditions of sleep restriction in healthy humans and high corticosterone, the dominant glucocorticoid in rodents, is associated with sleep fragmentation and lower deep sleep time.6,128) Consequently, people with sleep difficulties are more likely to have high level of cortisol, especially in the evening when it is more likely to affect sleep onset. Glucose levels also fluctuate across 24 hours, peaking during the night. Moreover, serum glucose has a higher sensitivity to glucose intake in the evening and early night than in the morning and early afternoon,129) while the insulin increase following glucose intake shows the reverse pattern.130-132)
The SCN synchronises the circadian rhythms of blood pressure (through the myocardium), white adipose tissues, liver, and pancreas. When measured throughout a 24-hour cycle, blood pressure reaches its higher levels during the day and its lower levels during the night.133)
Disorganization of some of those rhythms have been shown to lead to cardiovascular and metabolic disorders.134-136) Moreover, using a 10-day forced desynchrony protocol, Scheer et al.137) recently found that shifting eating and sleep-wake rhythms of healthy adults 12 hours from their usual schedule causes an increase in postprandial glucose, insulin and blood pressure, as well as a reduction in leptin.
In summary, studies in the healthy population have revealed that chronic short sleep is associated with high blood pressure, altered arterial regulation, increased postprandial glucose, decreased postprandial insulin, increased ghrelin and cortisol and reduced leptin. Importantly, some experimental studies demonstrated that sleep loss and circadian disruptions can play a causal role in those cardiometabolic and endocrine disturbances. Hence, the various physiological responses to increased homeostatic sleep pressure and deregulation of the circadian clock could contribute to the development of weight gain, cardiovascular and metabolic disorders in schizophrenia.
SLEEP AND CIRCADIAN RHYTHMS AS MODULATORS OF CARDIOMETABOLIC ABNORMALITIES IN SCHIZOPHRENIA
Because of their impacts on cardiovascular, metabolic and endocrine functions, the high prevalence of sleep and circadian disruptions in schizophrenia may play a role in the pathogenesis of cardiometabolic abnormalities. Additionally circadian dysregulation may effect inflammation, fibrinolysis, fluid balance, and vascular reactivity.138) Metabolic disturbance may also disturb circadian rhythms in animal models.
By increasing blood pressure, ghrelin and cortisol levels, sleep loss may trigger a cascade of cardiovascular and endocrine changes increasing the risk for cardiovascular events and weight gain. Additionally, circadian misalignment observed in patients with schizophrenia may alter the circadian regulation of appetite and weight-related hormones as well as glucose tolerance and insulin dynamics.
Chronic sleep loss increases evening cortisol and high levels of cortisol are likely to reduce the ability to initiate and/or maintain consolidated sleep. Hence, bidirectional interactions between higher cortisol levels and sleep disruptions may contribute to the perpetuation of sleep and cardiometabolic disturbances in schizophrenia.
Importantly, in the general population, reversal of sleep loss and circadian disruption minimises/ameliorates negative metabolic and cardiovascular effects. Therefore, if cardiometabolic problems in schizophrenia are linked to sleep/wake difficulties, sleep could be an efficient intervention target.
GENETIC EVIDENCE
The pathogenesis of schizophrenia is thought to result from the interaction between genetic and environmental factors.139) For instance, the risk associated with genetic predisposition thought to be is further increased by exposure to prenatal infection,140) depression of the mother during pregnancy,141) birth in an urbanised milieu142) and cannabis use, among others.143)
While studies assessing the contribution of specific genes and genome-wide studies have not yet reach a consensus about the genetic profile of schizophrenia, recent research has highlighted associations with genes implicated in circadian rhythms and sleep homeostasis. Notably, these studies suggested that the schizophrenia phenotype was linked with some of the core molecular clock components, such as CLOCK, ARNTL, TIMELESS, NPAS2, PER1, PER2, PER3 and RORβ144-146) (See Fig. 1 in Maury et al.138).
Importantly, some of those circadian genes have also been associated with cardiovascular dysfunction.147) and the metabolic syndrome.138) Notably, CLOCK has been linked with lipid and glucose metabolism, platelet rhythmic activity and response of cardiomyocytes to fatty acids.148-150) PER2 has been associated with variations in cholesterol and with the aortic endothelial function, while PER3 is linked with sympathovagal balance.151,152) Moreover, an animal study has shown that mutation of the CLOCK gene leads to hyperphagia, obesity and metabolic syndrome characterised by hyperleptinemia, hyperlipidaemia, hepatic steatosis, hyperglycaemia, and hypoinsulinaemia.153)
These overlaps between the clock genes associated with schizophrenia and cardiovascular/metabolic factors support the hypothesis that common mechanisms may be implicated in the pathogenesis of sleep/circadian disorders and cardiometabolic disturbances in schizophrenia.
CONCLUSION
Cardiometabolic disorders, such as hypertension, type 2 diabetes, obesity and the metabolic syndrome pose a serious threat to the physical health of people with schizophrenia. Many cardiometabolic and endocrine functions are modulated by sleep and circadian factors in the general population. This hypothesis driven review proposed that the high prevalence of sleep and circadian disturbances in people with schizophrenia might impact on their cardiovascular and metabolic health.
Management of cardiometabolic disturbances in schizophrenia should include support for a healthier lifestyle and diet, appropriate psychosocial interventions, close medical monitoring with proper pharmacological treatment and careful selection of antipsychotic medication in relation to each patient's cardiometabolic risk factors. Because treatment of sleep and circadian disorders has been shown to have positive outcomes on cardiometabolic functions in the general population, future empirical studies should assess the association between sleep and cardiometabolic disturbances in patients with schizophrenia. If such an association is confirmed, it would be important to integrate the management of sleep and circadian difficulties as an additional intervention target for cardiovascular and metabolic disorders in schizophrenia.
Simple non-pharmacological interventions have proven useful to address sleep and circadian disturbances in the general population. Notably, restoration of healthy sleep habits can be achieved through behavioural and cognitive interventions, and luminotherapy can be used to realign circadian rhythms.154-159) The efficiency of these interventions in the schizophrenia population and the subsequent effects on cardiometabolic factors should be examined to assess their possible contribution to holistic physical health intervention programs in schizophrenia. It is feasible to suggest that the measurement of basic sleep and circadian parameters should be part of any new outcomes trial for the treatment of schizophrenia, perhaps revealing an independent axis of intervention for later studies.
References
- 1. Schizophrenia: recent epidemiologic issuesEpidemiol Rev1995171020[PubMed][Google Scholar]
- 2. Schizophrenia, "just the facts" what we know in 2008. 2. Epidemiology and etiologySchizophr Res2008102118[PubMed][Google Scholar]
- 3. Cognitive functioning in schizophrenia, schizoaffective disorder and affective psychoses: meta-analytic studyBr J Psychiatry2009195475482[PubMed][Google Scholar]
- 4. American Psychiatric AssociationDiagnostic and statistical manual of mental disorders IV revised2000ArlingtonAmerican Psychiatric Publishing
- 5. Sleep disturbance in schizophreniaInt Rev Psychiatry200517247253[PubMed][Google Scholar]
- 6. Impact of sleep debt on metabolic and endocrine functionLancet199935414351439[PubMed][Google Scholar]
- 7. Sleep disturbance in schizophreniaBr J Psychiatry1994165697698[PubMed][Google Scholar]
- 8. Sleep in schizophrenia: a preliminary study using the Pittsburgh Sleep Quality IndexNeurobiol Sleep-Wakefulness Cycle200223739[Google Scholar]
- 9. First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysisBr J Psychiatry2008192406411[PubMed][Google Scholar]
- 10. A two process model of sleep regulationHum Neurobiol19821195204[PubMed][Google Scholar]
- 11. A model of human sleep homeostasis based on EEG slow-wave activity: quantitative comparison of data and simulationsBrain Res Bull19933197113[PubMed][Google Scholar]
- 12. The three-process model of alertness and its extension to performance, sleep latency, and sleep lengthChronobiol Int199714115123[PubMed][Google Scholar]
- 13. Sleep in untreated patients with schizophrenia: a meta-analysisSchizophr Bull200430957967[PubMed][Google Scholar]
- 14. Abnormal rapid eye movement latencies in schizophreniaArch Gen Psychiatry1987444548[PubMed][Google Scholar]
- 15. Stage 4 sleep in schizophreniaArch Gen Psychiatry196921262266[PubMed][Google Scholar]
- 16. Sleep in schizophrenia: impairments, correlates, and treatmentPsychiatr Clin North Am20062910331045[PubMed][Google Scholar]
- 17. Predicting relapse in schizophrenia: the development and implementation of an early signs monitoring system using patients and families as observers, a preliminary investigationPsychol Med198919649656[PubMed][Google Scholar]
- 18. Insomnia as a predictor for symptom worsening following antipsychotic withdrawal in schizophreniaCompr Psychiatry200243393396[PubMed][Google Scholar]
- 19. Sleep disturbance in schizophreniaClinical Pharmacology of Sleep2006BaselBirkhäuser125131[Google Scholar]
- 20. The psychosis of sleep deprivationAnn N Y Acad Sci1962966670[PubMed][Google Scholar]
- 21. BPRS symptom factors and sleep variables in schizophreniaPsychiatry Res199766111120[PubMed][Google Scholar]
- 22. Delusion and sleep deprivationEncephale199622229231[PubMed][Google Scholar]
- 23. Insomnia and paranoiaSchizophr Res2009108280284[PubMed][Google Scholar]
- 24. Sleep deprivation: effects on behavior, thinking, motor performance, and biological energy transfer systemsPsychosom Med196022182192[PubMed][Google Scholar]
- 25. The human circadian timing system and sleep-wake regulationPrinciples and Practices in Sleep Medicine20054th edPhiladelphiaElsevier/Saunders375394[Google Scholar]
- 26. Sleep and daily activity preferences in schizophrenia: associations with neurocognition and symptomsJ Nerv Ment Dis2003191408410[PubMed][Google Scholar]
- 27. Circadian body temperature in chronic schizophreniaBr J Psychiatry1976129350354[PubMed][Google Scholar]
- 28. Circadian and sleep-related endocrine rhythms in schizophreniaArch Gen Psychiatry199148348356[PubMed][Google Scholar]
- 29. A schizophrenic patient with an arrhythmic circadian rest-activity cyclePsychiatry Res1997738390[PubMed][Google Scholar]
- 30. Disturbed circadian rest-activity cycles in schizophrenia patients: an effect of drugs?Schizophr Bull200127497502[PubMed][Google Scholar]
- 31. The suitability of actigraphy, diary data, and urinary melatonin profiles for quantitative assessment of sleep disturbances in schizophrenia: a case reportChronobiol Int200623485495[PubMed][Google Scholar]
- 32. Melatonin and schizophreniaEncephale198915505510[PubMed][Google Scholar]
- 33. Reduced nocturnal melatonin secretion in chronic schizophrenia: relationship to body weightClin Endocrinol (Oxf)198217181187[PubMed][Google Scholar]
- 34. Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjectsPsychiatry Res199034243257[PubMed][Google Scholar]
- 35. Serum melatonin levels in schizophrenic and schizoaffective hospitalized patientsActa Psychiatr Scand199184221224[PubMed][Google Scholar]
- 36. Increased visceral fat distribution in drug-naive and drug-free patients with schizophreniaInt J Obes Relat Metab Disord200226137141[PubMed][Google Scholar]
- 37. Hypothalamic nitric oxide synthase in affective disorder: focus on the suprachiasmatic nucleusCell Mol Biol (Noisy-le-grand)200551279284[PubMed][Google Scholar]
- 38. Schizophrenia as a possible dysfunction of the suprachiasmatic nucleusMed Hypotheses201074127131[PubMed][Google Scholar]
- 39. Spontaneous sleep in mice with targeted disruptions of neuronal or inducible nitric oxide synthase genesBrain Res2003973214222[PubMed][Google Scholar]
- 40. Inducible and neuronal nitric oxide synthases (NOS) have complementary roles in recovery sleep inductionEur J Neurosci20062414431456[PubMed][Google Scholar]
- 41. Impairment of visuospatial memory is associated with decreased slow wave sleep in schizophreniaJ Psychiatr Res200438591599[PubMed][Google Scholar]
- 42. Quality of sleep in patients with schizophrenia is associated with quality of life and copingBMC Psychiatry2005513[PubMed][Google Scholar]
- 43. Actigraphic estimates of circadian rhythms and sleep/wake in older schizophrenia patientsSchizophr Res2001477786[PubMed][Google Scholar]
- 44. Perceived quality of life in schizophrenia: relationships to sleep qualityQual Life Res200413783791[PubMed][Google Scholar]
- 45. Circadian rhythm sleep disordersChest200613019151923[PubMed][Google Scholar]
- 46. Reduced frontal asymmetry of delta waves during all-night sleep in schizophreniaSchizophr Bull20073313071311[PubMed][Google Scholar]
- 47. Sudden unexplained death in psychiatric in-patientsBr J Psychiatry2000176405406[PubMed][Google Scholar]
- 48. Sudden death in psychiatric patientsBr J Psychiatry1998172331336[PubMed][Google Scholar]
- 49. Mortality among patients with schizophrenia and reduced psychiatric hospital carePsychol Med200535725732[PubMed][Google Scholar]
- 50. Schizophrenia and increased risks of cardiovascular diseaseAm Heart J200515011151121[PubMed][Google Scholar]
- 51. Increasing global burden of cardiovascular disease in general populations and patients with schizophreniaJ Clin Psychiatry200768Suppl 447[PubMed][Google Scholar]
- 52. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time?Arch Gen Psychiatry20076411231131[PubMed][Google Scholar]
- 53. Antipsychotic medications: metabolic and cardiovascular riskJ Clin Psychiatry200768Suppl 4813[PubMed][Google Scholar]
- 54. Loss of efferent vagal activity in acute schizophreniaJ Psychiatr Res200539519527[PubMed][Google Scholar]
- 55. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controlsSchizophr Res2005804553[PubMed][Google Scholar]
- 56. Effects of sleep deprivation on neural circulatory controlHypertension20003511731175[PubMed][Google Scholar]
- 57. Psychiatric and general medical conditions comorbid with schizophrenia in the National Hospital Discharge SurveyPsychiatr Serv20096010591067[PubMed][Google Scholar]
- 58. Blood pressure, cognitive functions, and prevention of dementias in older patients with hypertensionArch Intern Med2001161152156[PubMed][Google Scholar]
- 59. Cardiac risk and schizophreniaJ Psychiatry Neurosci200530393395[PubMed][Google Scholar]
- 60. Orthostatic hypotension predicts all-cause mortality and coronary events in middle-aged individuals (The Malmo Preventive Project)Eur Heart J2010318591[PubMed][Google Scholar]
- 61. Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart StudyCirculation19969428502855[PubMed][Google Scholar]
- 62. Healthy lifestyle habits and 10-year cardiovascular risk in schizophrenia spectrum disorders: an analysis of the impact of smoking tobacco in the CLAMORS schizophrenia cohortSchizophr Res2010119101109[PubMed][Google Scholar]
- 63. Sociodemographic characteristics and cardiovascular risk factors in patients with severe mental disorders compared with the general populationJ Clin Psychiatry200667425433[PubMed][Google Scholar]
- 64. Obesity among individuals with serious mental illnessActa Psychiatr Scand2006113306313[PubMed][Google Scholar]
- 65. The cardiovascular and respiratory health of people with schizophreniaActa Psychiatr Scand2006113298305[PubMed][Google Scholar]
- 66. Obesity and associated complications in patients with severe mental illnesses: a cross-sectional surveyJ Clin Psychiatry200566167173[PubMed][Google Scholar]
- 67. Correlation of serum ghrelin levels with body mass index and carbohydrate metabolism in patients treated with atypical antipsychoticsDiabetes Res Clin Pract200568Suppl 1S60S64[PubMed][Google Scholar]
- 68. The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naive patients with schizophreniaLife Sci20047419992008[PubMed][Google Scholar]
- 69. Metabolic implications of body fat distributionDiabetes Care19911411321143[PubMed][Google Scholar]
- 70. Regional adiposity and morbidityPhysiol Rev199474761811[PubMed][Google Scholar]
- 71. American College of Cardiology FoundationLipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology FoundationDiabetes Care200831811822[PubMed][Google Scholar]
- 72. Weight gain associated with neuroleptic medication: a reviewSchizophr Bull199521463472[PubMed][Google Scholar]
- 73. Body weight gain induced by antipsychotic drugs: mechanisms and managementActa Psychiatr Scand1999100316[PubMed][Google Scholar]
- 74. Novel antipsychotics: comparison of weight gain liabilitiesJ Clin Psychiatry199960358363[PubMed][Google Scholar]
- 75. Weight gain from novel antipsychotic drugs: need for actionGen Hosp Psychiatry200022224235[PubMed][Google Scholar]
- 76. The distribution of adipose tissue in female in-patients receiving psychotropic drugsBr J Psychiatry1993162249250[PubMed][Google Scholar]
- 77. Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patientsJ Psychiatr Res200337193220[PubMed][Google Scholar]
- 78. From the Cover: Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinaseProc Natl Acad Sci U S A200710434563459[PubMed][Google Scholar]
- 79. A review of the effect of atypical antipsychotics on weightPsychoneuroendocrinology200328Suppl 18396[PubMed][Google Scholar]
- 80. Eating and weight related cognitions in people with Schizophrenia : a case control studyClin Pract Epidemiol Ment Health2006229[PubMed][Google Scholar]
- 81. Serum leptin levels increase rapidly after initiation of clozapine therapyMol Psychiatry199837680[PubMed][Google Scholar]
- 82. Clozapine-induced weight gain: prevalence and clinical relevanceAm J Psychiatry19921496872[PubMed][Google Scholar]
- 83. Schizophrenia and eating disordersPsychiatr Clin North Am200932809819[PubMed][Google Scholar]
- 84. The unhealthy lifestyle of people with schizophreniaPsychol Med199929697701[PubMed][Google Scholar]
- 85. Dietary intake of schizophrenic patients in Nithsdale, Scotland: case-control studyBMJ1998317784785[PubMed][Google Scholar]
- 86. Scottish Schizophrenia Lifestyle GroupDiet, smoking and cardiovascular risk in people with schizophrenia: descriptive studyBr J Psychiatry2003183534539[PubMed][Google Scholar]
- 87. Dietary improvement in people with schizophrenia: randomised controlled trialBr J Psychiatry2005187346351[PubMed][Google Scholar]
- 88. Leptin and ghrelin levels in patients with schizophrenia during different antipsychotics treatment: a reviewSchizophr Bull20083411891199[PubMed][Google Scholar]
- 89. Obesity: epidemiology and clinical aspectsBest Pract Res Clin Gastroenterol20041811251146[PubMed][Google Scholar]
- 90. Glucose and lipid metabolism of long-term risperidone monotherapy in patients with schizophreniaPsychiatry Clin Neurosci2007615458[PubMed][Google Scholar]
- 91. The function of leptin in nutrition, weight, and physiologyNutr Rev200260S1S14[PubMed][Google Scholar]
- 92. Association of olanzapine-induced weight gain with an increase in body fatAm J Psychiatry200115817191722[PubMed][Google Scholar]
- 93. Insulin resistance and increased leptin concentrations in noncompliant schizophrenia patients but not in antipsychotic-naive first-episode schizophrenia patientsJ Clin Psychiatry20046513351342[PubMed][Google Scholar]
- 94. Plasma nitric oxide and leptin values in patients with olanzapine-induced weight gainJ Psychiatr Res2007417479[PubMed][Google Scholar]
- 95. Endocrine and metabolic abnormalities involved in obesity associated with typical antipsychotic drug administrationPharmacopsychiatry200134223231[PubMed][Google Scholar]
- 96. 7. Corticosteroid secretion--clinical aspects. Plasma cortisol concentrations in the functional psychoses and Alzheimer type dementia: a neuroendocrine day approach in drug-free patientsJ Steroid Biochem198319247250[PubMed][Google Scholar]
- 97. Diurnal rhythm of plasma beta endorphin, cortisol and growth hormone in schizophrenics as compared to control subjectsPsychopharmacology (Berl)198688496499[PubMed][Google Scholar]
- 98. Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophreniaAm J Psychiatry2003160284289[PubMed][Google Scholar]
- 99. Cognitive functioning, cortisol release, and symptom severity in patients with schizophreniaBiol Psychiatry20004811211132[PubMed][Google Scholar]
- 100. Selective increase in plasma luteinising hormone concentrations in drug free young men with maniaBr Med J (Clin Res Ed)198529099102[Google Scholar]
- 101. Combined dexamethasone/corticotropin-releasing hormone test in patients with schizophrenia and in normal controls: IIBiol Psychiatry199538803807[PubMed][Google Scholar]
- 102. Platelet serotonin, plasma cortisol, and dexamethasone suppression test in schizophrenic patientsBiol Psychiatry19994514331439[PubMed][Google Scholar]
- 103. Platelet 5-HT levels and hypothalamic-pituitary-adrenal axis activity in schizophrenic patients with positive and negative symptomsNeuropsychobiology1997361921[PubMed][Google Scholar]
- 104. The effects of cortisol on the regulation of lipoprotein lipase activity in human adipose tissueJ Clin Endocrinol Metab199479820825[PubMed][Google Scholar]
- 105. Blood pressure, heart rate, and anxiety in schizophreniaPsychiatry Res2007151155157[PubMed][Google Scholar]
- 106. Stress axis dysfunction: A common finding in schizophrenia and the metabolic syndrome?Metabolic Effects of Psychotropic Drugs. Mod Trends Pharmacopsychiatry2009BaselKarger8289[Google Scholar]
- 107. A systematic review of hypothalamic-pituitary-adrenal axis function in schizophrenia: implications for mortalityJ Psychopharmacol2010244 Suppl91118[PubMed][Google Scholar]
- 108. The hypothalamic-pituitary-adrenal axis activity in obesity and the metabolic syndromeAnn N Y Acad Sci20061083111128[PubMed][Google Scholar]
- 109. Leptin: linking obesity, the metabolic syndrome, and cardiovascular diseaseCurr Hypertens Rep200810131137[PubMed][Google Scholar]
- 110. Low plasma ghrelin concentration is an indicator of the metabolic syndromeAnn Med200638274279[PubMed][Google Scholar]
- 111. Prevalence of diabetes and impaired glucose tolerance in patients with schizophreniaBr J Psychiatry Suppl200447S67S71[PubMed][Google Scholar]
- 112. Hyperglycemia and diabetes in patients with schizophrenia or schizoaffective disordersDiabetes Care200629786791[PubMed][Google Scholar]
- 113. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES IIISchizophr Res2005801932[PubMed][Google Scholar]
- 114. Diabetes and schizophrenia 2005: are we any closer to understanding the link?J Psychopharmacol2005196 Suppl5665[PubMed][Google Scholar]
- 115. Glucose metabolism in Japanese schizophrenia patients treated with risperidone or olanzapineJ Clin Psychiatry20097095100[PubMed][Google Scholar]
- 116. Insulin resistance and adiponectin levels in drug-free patients with schizophrenia: A preliminary reportCan J Psychiatry200651382386[PubMed][Google Scholar]
- 117. Hepatic insulin resistance in antipsychotic naive schizophrenic patients: stable isotope studies of glucose metabolismJ Clin Endocrinol Metab200893572577[PubMed][Google Scholar]
- 118. Clustering of dyslipidemia, hyperuricemia, diabetes, and hypertension and its association with fasting insulin and central and overall obesity in a general population. Atherosclerosis Risk in Communities Study InvestigatorsMetabolism199645699706[PubMed][Google Scholar]
- 119. Glucocorticoid-induced insulin resistance and diabetes mellitus. Receptor-, postreceptor mechanisms, local cortisol action, and new aspects of antidiabetic therapyMed Klin (Munich)200398266270[PubMed][Google Scholar]
- 120. Stress and the genesis of diabetes mellitus in schizophreniaBr J Psychiatry Suppl200447S72S75[PubMed][Google Scholar]
- 121. Total sleep deprivation elevates blood pressure through arterial baroreflex resetting: a study with microneurographic techniqueSleep200326986989[PubMed][Google Scholar]
- 122. Effects of insufficient sleep on blood pressure monitored by a new multibiomedical recorderHypertension1992713181324[PubMed][Google Scholar]
- 123. Sleep deprivation increases blood pressure in healthy normotensive elderly and attenuates the blood pressure response to orthostatic challengeSleep201134335339[PubMed][Google Scholar]
- 124. Sleep loss results in an elevation of cortisol levels the next eveningSleep199720865870[PubMed][Google Scholar]
- 125. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetiteAnn Intern Med2004141846850[PubMed][Google Scholar]
- 126. Meta-analysis of short sleep duration and obesity in children and adultsSleep200831619626[PubMed][Google Scholar]
- 127. Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesityProc Natl Acad Sci U S A20041011043410439[PubMed][Google Scholar]
- 128. High corticosterone levels in prenatally stressed rats predict persistent paradoxical sleep alterationsJ Neurosci19991986568664[PubMed][Google Scholar]
- 129. Circadian modulation of glucose and insulin responses to meals: relationship to cortisol rhythmAm J Physiol1992262E467E475[PubMed][Google Scholar]
- 130. Circadian variation of the blood glucose, plasma insulin and human growth hormone levels in response to an oral glucose load in normal subjectsDiabetes197423132137[PubMed][Google Scholar]
- 131. Diurnal variation in glucose tolerance and in insulin secretion in manDiabetes197322333348[PubMed][Google Scholar]
- 132. Diurnal variation in glucose tolerance: associated changes in plasma insulin, growth hormone, and non-esterified fatty acidsBr Med J19741485488[PubMed][Google Scholar]
- 133. Circadian variation of blood-pressureLancet19781795797[PubMed][Google Scholar]
- 134. Blood pressure rhythm and prevalence of vascular events in hypertensive subjectsAge Ageing1999282328[PubMed][Google Scholar]
- 135. Associations between nondipping of nocturnal blood pressure decrease and cardiovascular target organ damage in strictly selected community-dwelling normotensivesAm J Hypertens200316434438[PubMed][Google Scholar]
- 136. Roles of circadian rhythmicity and sleep in human glucose regulationEndocr Rev199718716738[PubMed][Google Scholar]
- 137. Adverse metabolic and cardiovascular consequences of circadian misalignmentProc Natl Acad Sci U S A200910644534458[PubMed][Google Scholar]
- 138. Circadian rhythms and metabolic syndrome: from experimental genetics to human diseaseCirc Res2010106447462[PubMed][Google Scholar]
- 139. The role of genetics in the etiology of schizophreniaPsychiatr Clin North Am2010333566[PubMed][Google Scholar]
- 140. Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophreniaAm J Psychiatry200916610251030[PubMed][Google Scholar]
- 141. Schizophrenia in the offspring of antenatally depressed mothers in the northern Finland 1966 birth cohort: relationship to family history of psychosisAm J Psychiatry20101677077[PubMed][Google Scholar]
- 142. Confirmation of synergy between urbanicity and familial liability in the causation of psychosisAm J Psychiatry200416123122314[PubMed][Google Scholar]
- 143. The environment and schizophreniaNature2010468203212[PubMed][Google Scholar]
- 144. The role of circadian clock genes in mental disordersDialogues Clin Neurosci20079333342[PubMed][Google Scholar]
- 145. Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophreniaBipolar Disord200911701710[PubMed][Google Scholar]
- 146. Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophreniaGenes Brain Behav20065150157[PubMed][Google Scholar]
- 147. Clock genes in health and diseasesJ Appl Biomed200971533[Google Scholar]
- 148. The circadian clock within the cardiomyocyte is essential for responsiveness of the heart to fatty acidsJ Biol Chem20062812425424269[PubMed][Google Scholar]
- 149. Metabolic homeostasis in mice with disrupted Clock gene expression in peripheral tissuesAm J Physiol Regul Integr Comp Physiol2007293R1528R1537[PubMed][Google Scholar]
- 150. CLOCK regulates circadian platelet activityThromb Res2009123523527[PubMed][Google Scholar]
- 151. Time-domain optimized near-field estimator for ultrasound imaging: initial development and resultsIEEE Trans Med Imaging20082799110[PubMed][Google Scholar]
- 152. Mutation of the circadian clock gene Per2 alters vascular endothelial functionCirculation200711521882195[PubMed][Google Scholar]
- 153. Obesity and metabolic syndrome in circadian Clock mutant miceScience200530810431045[PubMed][Google Scholar]
- 154. Dose-response relationships for resetting of human circadian clock by lightNature1996379540542[PubMed][Google Scholar]
- 155. Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trialJAMA200128518561864[PubMed][Google Scholar]
- 156. The clinical effectiveness of cognitive behaviour therapy for chronic insomnia: implementation and evaluation of a sleep clinic in general medical practiceBehav Res Ther2001394560[PubMed][Google Scholar]
- 157. A phase response curve to single bright light pulses in human subjectsJ Physiol2003549945952[PubMed][Google Scholar]
- 158. Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacyAm J Psychiatry199415111721180[PubMed][Google Scholar]
- 159. Intrinsic period and light intensity determine the phase relationship between melatonin and sleep in humansJ Biol Rhythms200520168177[PubMed][Google Scholar]