Metabolomic Profiles of Shift Workers and Day Workers: A Cross-Sectional Study.

OBJECTIVE: The purpose of this study was to characterize the metabolomic profiles of shift workers and day workers and to discover the effect of shift work on workers' metabolic health. METHODS: A total of 824 participants aged 25 to 55 years were recruited, and 485 (275 shift workers and 210 day workers) completed the study. The mean age of the shift workers was 37.32 (5.53) years old, and that of day workers was 36.50 (7.83) years old. Serum and salivary samples were collected for the detection of key biochemical indicators (melatonin, cholesterol, and low-density lipoprotein cholesterol) and for metabolome profile analyses. RESULTS: Compared with female day workers, female shift workers had a higher BMI, waist circumference, and hip circumference. Correspondingly, we identified 76 significant metabolites (false discovery rate < 0.05) in shift workers, including L-tryptophan, acylcarnitines, and several fatty acids. Three pathways that presented significant differences were biosynthesis of unsaturated fatty acids, linoleic acid metabolism, and ubiquinone and other terpenoid-quinone biosynthesis. CONCLUSIONS: Compared with day workers, shift workers were more prone to weight gain and central obesity and were at a higher risk for impaired lipid metabolism with disrupted circadian rhythms.

Disrupted nocturnal melatonin in autism: Association with tumor necrosis factor and sleep disturbances.

Sleep disturbances, abnormal melatonin secretion, and increased inflammation are aspects of autism spectrum disorder (ASD) pathophysiology. The present study evaluated the daily urinary 6-sulfatoxymelatonin (aMT6s) excretion profile and the salivary levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in 20 controls and 20 ASD participants, as well as correlating these measures with sleep disturbances. Although 60% of ASD participants showed a significant night-time rise in aMT6s excretion, this rise was significantly attenuated, compared to controls (P < .05). The remaining 40% of ASD individuals showed no significant increase in nocturnal aMT6s. ASD individuals showed higher nocturnal levels of saliva TNF, but not IL-6. Dysfunction in the initiation and maintenance of sleep, as indicated by the Sleep Disturbance Scale for Children, correlated with night-time aMT6s excretion (r = -.28, P < .05). Dysfunction in sleep breathing was inversely correlated with aMT6s (r = -.31, P < .05) and positively associated with TNF level (r = .42, P < .01). Overall such data indicate immune-pineal axis activation, with elevated TNF but not IL-6 levels associated with disrupted pineal melatonin release and sleep dysfunction in ASD. It is proposed that circadian dysregulation in ASD is intimately linked to heightened immune-inflammatory activity. Such two-way interactions of the immune-pineal axis may underpin many aspects of ASD pathophysiology, including sleep disturbances, as well as cognitive and behavioral alterations.

Exposure to Radiation During Work Shifts and Working at Night Act as Occupational Stressors Alter Redox and Inflammatory Markers.

BACKGROUND: Studies of breast cancer etiology suggest evidence that night shift working and occupational exposure to ionizing radiation (IR) are defined risk factors for breast cancer development. There are few studies to clarify neuroendocrine and inflammatory status and the possible consequences particularly in occupational exposure. AIM OF THE STUDY: Our aim was to associate the redox and inflammatory biomarkers with either nightshift working or occupational radiation exposure, and to compare their levels between the two groups at Alexandria University Hospitals, Alexandria, Egypt. METHODS: We included 150 female nurses at Alexandria University Hospitals: 50 nightshift workers, 50 radiation workers, and 50 dayshift workers as a control group (neither work nightly nor radiation workers). In morning serum sample (7 am), we measured the concentrations of serum melatonin, Cortisol, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) by ELISA; malondialdehyde (MDA) and total antioxidant capacity (TAC) levels colorimetrically, and C-reactive protein (C-RP) levels by turbidimetric method. RESULTS: Nightshift workers had significantly lower levels of melatonin and TAC, and higher levels of serum inflammatory markers and cortisol, than day shift control group of workers. Workers occupationally exposed to IR had significantly higher levels of serum melatonin, MDA and inflammatory markers, lower levels of serum cortisol, and lower TAC than day shift workers. CONCLUSION: Occupational exposure to IR and working nightly alter circulating redox and inflammatory biomarkers.

Associated analysis of PER1/TUBB2B with endometrial cancer development caused by circadian rhythm disorders.

Endometrial cancer (EC) is one of the most common gynecologic malignancies, and the incidence rate of night shift among women workers is higher than that in the general population. Circadian rhythm disorder, mainly rhythm gene, is related to various tumor onset, including EC. This study described the sleep/night-shift features of EC patients, explored the mechanism of the circadian clock gene PER and investigated prognostic and functional values of Per1 caused by night shift. A total of 619 subjects were enrolled and divided into two groups according to night-shift duties (rhythm group and control group), analyzed for clinical risk factors and night shift features of endometrial carcinoma. Then samples were randomly selected for sequencing and western blot were performed, and the function of overexpressed PER1 in ishikawa cells was explored. We noticed that severer EC patients experienced night-shift more frequently and with longer durations. A total of 58,174 differentially expressed genes were discovered, mainly rhythm genes and related to up and downstream regulatory genes. Western blot showed that the rhythm group had elevated protein expression of BCAS4, TUBB2B and RSPO4, and decreased expression of PER1 and PER2 in night-shift. In TCGA-EC datasets, PER1 was decreased in the EC patients with a significantly positive correlation with PER2, and higher PER1 expression indicated longer survival, opposite to TUBB2B. The research of overexpressing PER1 gene in EC ishikawa cells found that PER1 can promote apoptosis, expression of TNF-a, IL-6 and PD-1/PD-L1, inhibit the tumor invasion and expression of TUBB2B gene. Together, EC severity was associated with night-shift and rhythm disorders. The rhythm relating factors PER1, TUBB2B and tumor immune factors may regulate the mechanisms of EC onset and progression.

Human CRY1 variants associate with attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.

Lemborexant: First Approval.

Lemborexant (DAYVIGO™) is an orally administered, dual orexin receptor (OXR) antagonist that exhibits reversible competitive antagonism at OXR1 and OXR2 (> affinity at OXR2) that was discovered and developed by Eisai Inc. for the treatment of adult patients with insomnia. In December 2019, lemborexant received its first approval (with final interim scheduling) in the USA for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. In January 2020, lemborexant also received approval in Japan for the treatment of insomnia. It is also being investigated for the treatment of irregular sleep-wake rhythm disorder (ISWRD) associated with mild to moderate Alzheimer's disease. This article summarizes the milestones in the development of lemborexant leading to its first global approval.

Relationship between Intrinsically Photosensitive Ganglion Cell Function and Circadian Regulation in Diabetic Retinopathy.

BACKGROUND: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control non-visual light responses (e.g. pupillary light reflex and circadian entrainment). Patients with diabetic retinopathy (DR) show reduced ipRGC function, as inferred by abnormalities in the post illumination pupil response (PIPR). We explored whether ipRGC function in DR is associated with circadian outputs and sleep/wake behavior. METHODS: Forty-five participants (15 without diabetes, 15 with type 2 diabetes (T2D) and no DR, 15 with T2D and DR) participated. ipRGC function was inferred from the PIPR (pupil size following stimulus offset). Circadian outputs were melatonin amplitude (overnight urinary 6-sulfatoxymelatonin (aMT6s)) and timing (dim light melatonin onset (DLMO)), and evening salivary cortisol levels. Sleep/wake patterns were measured with wrist actigraphy and insomnia symptoms were assessed subjectively. RESULTS: Patients with T2D and DR had smaller PIPR and lower urinary aMT6s than other groups (p < 0.001). In adjusted regression models, smaller PIPR was associated with lower urinary aMT6s (ß = 4.552, p = 0.005). Patients with DR were more likely to have no detectable DLMO (p = 0.049), higher evening salivary cortisol, greater insomnia symptoms and greater sleep variability compared to other groups. Sleep duration, efficiency and rest-activity rhythms were similar. CONCLUSION: Reduced ipRGC function in DR is associated with circadian dysregulation and sleep disturbances, although a causal relationship cannot be established in this cross-sectional study. Prospective mechanistic and intervention studies examining circadian and sleep health in these patients are warranted.

Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin.

From an evolutionary point of view, vitamin D and melatonin appeared very early and share functions related to defense mechanisms. In the current clinical setting, vitamin D is exclusively associated with phosphocalcic metabolism. Meanwhile, melatonin has chronobiological effects and influences the sleep-wake cycle. Scientific evidence, however, has identified new actions of both molecules in different physiological and pathological settings. The biosynthetic pathways of vitamin D and melatonin are inversely related relative to sun exposure. A deficiency of these molecules has been associated with the pathogenesis of cardiovascular diseases, including arterial hypertension, neurodegenerative diseases, sleep disorders, kidney diseases, cancer, psychiatric disorders, bone diseases, metabolic syndrome, and diabetes, among others. During aging, the intake and cutaneous synthesis of vitamin D, as well as the endogenous synthesis of melatonin are remarkably depleted, therefore, producing a state characterized by an increase of oxidative stress, inflammation, and mitochondrial dysfunction. Both molecules are involved in the homeostatic functioning of the mitochondria. Given the presence of specific receptors in the organelle, the antagonism of the renin-angiotensin-aldosterone system (RAAS), the decrease of reactive species of oxygen (ROS), in conjunction with modifications in autophagy and apoptosis, anti-inflammatory properties inter alia, mitochondria emerge as the final common target for melatonin and vitamin D. The primary purpose of this review is to elucidate the common molecular mechanisms by which vitamin D and melatonin might share a synergistic effect in the protection of proper mitochondrial functioning.

Circadian and wake-dependent changes in human plasma polar metabolites during prolonged wakefulness: A preliminary analysis.

Establishing circadian and wake-dependent changes in the human metabolome are critical for understanding and treating human diseases due to circadian misalignment or extended wake. Here, we assessed endogenous circadian rhythms and wake-dependent changes in plasma metabolites in 13 participants (4 females) studied during 40-hours of wakefulness. Four-hourly plasma samples were analyzed by hydrophilic interaction liquid chromatography (HILIC)-LC-MS for 1,740 metabolite signals. Group-averaged (relative to DLMO) and individual participant metabolite profiles were fitted with a combined cosinor and linear regression model. In group-level analyses, 22% of metabolites were rhythmic and 8% were linear, whereas in individual-level analyses, 14% of profiles were rhythmic and 4% were linear. We observed metabolites that were significant at the group-level but not significant in a single individual, and metabolites that were significant in approximately half of individuals but not group-significant. Of the group-rhythmic and group-linear metabolites, only 7% and 12% were also significantly rhythmic or linear, respectively, in ≥50% of participants. Owing to large inter-individual variation in rhythm timing and the magnitude and direction of linear change, acrophase and slope estimates also differed between group- and individual-level analyses. These preliminary findings have important implications for biomarker development and understanding of sleep and circadian regulation of metabolism.

Salivary melatonin onset in youth at familial risk for bipolar disorder.

Melatonin secretion and polysomnography (PSG) were compared among a group of healthy adolescents who were at high familial risk for bipolar disorder (HR) and a second group at low familial risk (LR). Adolescent participants (n = 12) were a mean age 14 ± 2.3 years and included 8 females and 4 males. Saliva samples were collected under standardized condition light (red light) and following a 200 lux light exposure over two consecutive nights in a sleep laboratory. Red Light Melatonin onset (RLMO) was defined as saliva melatonin level exceeding the mean of the first 3 readings plus 2 standard deviations. Polysomnography was also completed during each night. HR youth, relative to LR, experienced a significantly earlier melatonin onset following 200 lux light exposure. Polysomnography revealed that LR youth, relative to HR, spent significantly more time in combined stages 3 and 4 (deep sleep) following red light exposure. Additionally, regardless of the group status (HR or LR), there was no significant difference in Red Light Melatonin Onset recorded at home or in the laboratory, implying its feasibility and reliability.

Glutamate, Glutamate Transporters, and Circadian Rhythm Sleep Disorders in Neurodegenerative Diseases.

Glutamate, a primary excitatory neurotransmitter and an important intermediate in the cellular metabolism of the brain, has a widespread influence in the sleep-wake regulatory system. Glutamate transporters, including vesicular glutamate transporters and excitatory amino acid transporters, serve as the main force controlling the extracellular concentration of glutamate in the brain. These are likely to be critical tools needed for the brain to modulate the sleep-wake cycle and are likely innervated by the circadian rhythm system in a day-night variant pattern. Because in the initial stages, nearly all patients with neurodegenerative diseases have rhythmic sleep disorders that become aggravated with disease development and often exhibit glutamate uptake dysfunction, we examined whether the above glutamate transporters could be used as potential targets to help address circadian rhythm sleep disorders in patients with neurodegenerative diseases. Therefore, in this review, we sought to analyze the principles governing glutamate transmission and discuss whether the circadian rhythm regulatory properties of these processes endow glutamate transporters with unique functions in the sleep-wake shift of the brain. We attempt to provide a theoretical framework in this field for future studies, to help in the exploration of potential therapeutic targets to delay or prevent the development of neurodegenerative diseases.

The role of dopamine in mood disorders and the associated changes in circadian rhythms and sleep-wake cycle.

Dopamine is primarily produced in the substantia nigra (SN) and the ventral tegmentum area (VTA) in the brain. It plays a well-established role in the motor control, reward, mood regulation and addiction behaviour. Dopamine release has been shown to be regulated by the circadian clock and hence, plays a regulatory role in the sleep-wake cycle. Clinically, dopaminergic agents have been widely used to modulate alertness. The following review offers a demonstration of the heterogeneous dopamine system in the brain and the various studies investigating the circadian rhythmicity of the dopamine system and its regulation of sleep-wake behaviour. Additionally, it suggests a potential link between the circadian clock and the sleep-wake cycle in mood regulation through the dopaminergic system.

ER Lipid Defects in Neuropeptidergic Neurons Impair Sleep Patterns in Parkinson's Disease.

Parkinson's disease patients report disturbed sleep patterns long before motor dysfunction. Here, in parkin and pink1 models, we identify circadian rhythm and sleep pattern defects and map these to specific neuropeptidergic neurons in fly models and in hypothalamic neurons differentiated from patient induced pluripotent stem cells (iPSCs). Parkin and Pink1 control the clearance of mitochondria by protein ubiquitination. Although we do not observe major defects in mitochondria of mutant neuropeptidergic neurons, we do find an excess of endoplasmic reticulum-mitochondrial contacts. These excessive contact sites cause abnormal lipid trafficking that depletes phosphatidylserine from the endoplasmic reticulum (ER) and disrupts the production of neuropeptide-containing vesicles. Feeding mutant animals phosphatidylserine rescues neuropeptidergic vesicle production and acutely restores normal sleep patterns in mutant animals. Hence, sleep patterns and circadian disturbances in Parkinson's disease models are explained by excessive ER-mitochondrial contacts, and blocking their formation or increasing phosphatidylserine levels rescues the defects in vivo.

[Sleep-wake rhythm after extracorporeal circulation in New Zealand rabbits].

OBJECTIVE: To evaluate the change of sleep-wake rhythm after extracorporeal circulation (ECC) in New Zealand rabbits, and to explore the role of clock genes in sleep-wake rhythm disorder by ECC.
 Methods: A total of 54 New Zealand rabbits were randomly divided into 3 groups: a normal group (Group N), a sham group (Group S) and a model group (Group ECC). Electrocorticogram (ECOG), electroophthalmogram (EOG) and electromyogram (EMG) were respectively recorded by multipurpose EEG recorder, and the sleep-wake rhythm was also recorded. The mRNA and protein expressions of period1 (Per1) and cryptochrome1 (Cry1) were detected by semi-quantitative reverse transcriptase PCR (RT-PCR) and Western blot in pineal gland of rabbits. The differences between the 3 groups were compared.
 Results: 1) Compared with the Group N and Group S at 24, 48 h respectively, the total amount of sleep (TAS), light time, slow wave sleep (SWS) in the Group ECC at 24, 48 h were significantly reduced (all P<0.05), and the proportion of light sleep increased (all P<0.05), the proportion of SWS decreased (all P<0.05); 2) Compared with the Group N and Group S, the expression of Per1 mRNA in the Group ECC at 24, 48 h and Cry1 mRNA at 24 h significantly increased (all P<0.05); 3) Compared with the Group N and Group S, the expression of Per1 protein in the Group ECC at 48 h and Cry1 protein at 24 h significantly increased (all P<0.05); 4) In the Group ECC, the sleep-wake rhythm disorder and clock genes expression were ameliorated at 72 h after surgery.
 Conclusion: ECC can cause sleep-wake rhythm disorder in New Zealand rabbits, which may be related to the abnormal expression of Per1 and Cry1, and their transcription proteins.

The impact of stress on sleep: Pathogenic sleep reactivity as a vulnerability to insomnia and circadian disorders.

Sleep reactivity is the trait-like degree to which stress exposure disrupts sleep, resulting in difficulty falling and staying asleep. Individuals with highly reactive sleep systems experience drastic deterioration of sleep when stressed, whereas those with low sleep reactivity proceed largely unperturbed during stress. Research shows that genetics, familial history of insomnia, female gender and environmental stress influence how the sleep system responds to stress. Further work has identified neurobiological underpinnings for sleep reactivity involving disrupted cortical networks and dysregulation in the autonomic nervous system and hypothalamic-pituitary-adrenal axis. Sleep reactivity is most pathologically and clinically pertinent when in excess, such that high sleep reactivity predicts risk for future insomnia disorder, with early evidence suggesting high sleep reactivity corresponds to severe insomnia phenotypes (sleep onset insomnia and short sleep insomnia). High sleep reactivity is also linked to risk of shift-work disorder, depression and anxiety. Importantly, stress-related worry and rumination may exploit sensitive sleep systems, thereby augmenting the pathogenicity of sleep reactivity. With the development of cost-effective assessment of sleep reactivity, we can now identify individuals at risk of future insomnia, shift-work disorder and mental illness, thus identifying a target population for preventive intervention. Given that insomniacs with high sleep reactivity tend to present with severe insomnia phenotypes, patient sleep reactivity may inform triaging to different levels of treatment. Future research on sleep reactivity is needed to clarify its neurobiology, characterize its long-term prospective associations with insomnia and shift-work disorder phenotypes, and establish its prognostic value for mental illness and other non-sleep disorders.

Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy.

Narcolepsy-cataplexy is a chronic neurological disorder caused by loss of orexin (hypocretin)-producing neurons, associated with excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, hypnagogic hallucinations, and fragmentation of nighttime sleep. Currently, human narcolepsy is treated by providing symptomatic therapies, which can be associated with an array of side effects. Although peripherally administered orexin does not efficiently penetrate the blood-brain barrier, centrally delivered orexin can effectively alleviate narcoleptic symptoms in animal models. Chronic intrathecal drug infusion through an implantable pump is a clinically available strategy to treat a number of neurological diseases. Here we demonstrate that the narcoleptic symptoms of orexin knockout mice can be reversed by lumbar-level intrathecal orexin delivery. Orexin was delivered via a chronically implanted intrathecal catheter at the upper lumbar level. The computed tomographic scan confirmed that intrathecally administered contrast agent rapidly moved from the spinal cord to the brain. Intrathecally delivered orexin was detected in the brain by radioimmunoassay at levels comparable to endogenous orexin levels. Cataplexy and sleep-onset REM sleep were significantly decreased in orexin knockout mice during and long after slow infusion of orexin (1 nmol/1 µL/h). Sleep/wake states remained unchanged both quantitatively as well as qualitatively. Intrathecal orexin failed to induce any changes in double orexin receptor-1 and -2 knockout mice. This study supports the concept of intrathecal orexin delivery as a potential therapy for narcolepsy-cataplexy to improve the well-being of patients.

Circadian Phase and Phase Angle Disorders in Primary Insomnia.

Objectives: We aimed to identify the prevalence of circadian phase and phase angle abnormalities in patients with insomnia. Methods: We conducted a cross-sectional, multicenter study at three sleep laboratories in the United States and Australia. Patients with insomnia and healthy control participants completed a sleep log for 7 days. Circadian phase was assessed from salivary dim light melatonin onset (DLMO) time during a 12-hour laboratory visit. Results: Seventy-nine patients meeting the Research Diagnostic Criteria for Primary, Psychophysiological, Paradoxical, and/or Idiopathic Childhood Insomnia (46 females, 35.5 ± 12.3 years [M ± SD]) and 21 controls (14 females, 34.4 ± 11.8 years). As compared to controls, patients with insomnia tried to initiate sleep on average at the same clock time (24:17 ± 1:17 hours vs. 24:13 ± 1:30 hours, respectively; p = .84) but had a later average DLMO times (20:56 ± 1:55 hours, 18:17-01:21 vs. 22:02 ± 2:02 hours, 17:11-04:52, respectively; p = .04). Consequently, patients with insomnia slept at an earlier circadian phase than controls (phase angle, bedtime-DLMO 2:13 hours (± 1:43) vs. 3:10 hours (± 1:08), respectively; p = .008), of whom 10% tried to sleep at or before DLMO (compared to 0 controls), and 22% tried to sleep before or within 1 hour after DLMO (compared to 6% of controls). Conclusions: A substantial proportion (10%-22%) of patients with insomnia initiate sleep at too early a circadian phase, implicating a circadian etiology for their insomnia. Outpatient circadian phase assessments should be considered to improve differential diagnoses in insomnia and to inform the development of appropriately timed circadian-based treatments.

Sleep and circadian rhythm disturbance in bipolar disorder.

BACKGROUND: Subjective reports of insomnia and hypersomnia are common in bipolar disorder (BD). It is unclear to what extent these relate to underlying circadian rhythm disturbance (CRD). In this study we aimed to objectively assess sleep and circadian rhythm in a cohort of patients with BD compared to matched controls. METHOD: Forty-six patients with BD and 42 controls had comprehensive sleep/circadian rhythm assessment with respiratory sleep studies, prolonged accelerometry over 3 weeks, sleep questionnaires and diaries, melatonin levels, alongside mood, psychosocial functioning and quality of life (QoL) questionnaires. RESULTS: Twenty-three (50%) patients with BD had abnormal sleep, of whom 12 (52%) had CRD and 29% had obstructive sleep apnoea. Patients with abnormal sleep had lower 24-h melatonin secretion compared to controls and patients with normal sleep. Abnormal sleep/CRD in BD was associated with impaired functioning and worse QoL. CONCLUSIONS: BD is associated with high rates of abnormal sleep and CRD. The association between these disorders, mood and functioning, and the direction of causality, warrants further investigation.

CNS Drug Development, Lessons Learned, Part 4: The Role of Brain Circuitry and Genes-Tasimelteon as an Example.

This is the fourth in a series of columns discussing the rational and targeted development of drugs to affect specific central nervous system (CNS) circuits in specific ways based on knowledge gained by molecular biology and the human genome project. The first column in this series described 6 CNS drugs with novel mechanisms of action developed over the last 25 years. The second column discussed differences between syndromic diagnoses as exemplified by the third through the fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM III through DSM-5) and the new approach to psychiatric diagnoses championed by the National Institute of Mental Health in their Research Domain Criteria Initiative. The third column reviewed the last 9 years of drug development contrasting the development of drugs in other therapeutic areas (eg, cancer) with psychiatric and related CNS-active drugs. This column extends the discussion of modern drug development for psychiatric and other CNS-related indications, using the development of tasimelteon as an example of how modern drug development focuses rationally on novel targets of interest while simultaneously achieving "specificity." Tasimelteon, which is indicated for the treatment of non-24-hour sleep-wake disorder, was developed to be a selective agonist at the melatonin MT1 and MT2 receptors, with limited or no effects at other pharmacologically relevant receptors and enzymes to minimize the potential for off-target effects (eg, nuisance side effects), toxicity, drug-drug interactions, and effects on oxidative drug metabolizing enzymes. The next column in this series will continue the discussion of the development of CNS drugs with novel mechanisms of action, using suvorexant, which targets orexin-1 and orexin-2 receptors, to illustrate the preclinical and human studies that were carried out to assess its safety as part of a successful new drug application.

Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences, and Countermeasures.

Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important.