Naomi L. Rogers

Novel melatonin-based therapies: potential advances in the treatment of major depression

Major depression is one of the leading causes of premature death and disability. Although available drugs are effective, they also have substantial limitations. Recent advances in our understanding of the fundamental links between chronobiology and major mood disorders, as well as the development of new drugs that target the circadian system, have led to a renewed focus on this area. In this review, we summarise the associations between disrupted chronobiology and major depression and outline new antidepressant treatment strategies that target the circadian system. In particular, we highlight agomelatine, a melatonin-receptor agonist and selective serotonergic receptor subtype (ie, 5-HT(2C)) antagonist that has chronobiotic, antidepressant, and anxiolytic effects. In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23·9%) than do those receiving placebo (50·0%). Patients with depression treated with agomelatine report improved sleep quality and reduced waking after sleep onset. As agomelatine does not raise serotonin levels, it has less potential for the common gastrointestinal, sexual, or metabolic side-effects that characterise many other antidepressant compounds.

Searching for the daytime impairments of primary insomnia

Primary insomnia is a sleep disorder where the subjective complaint of initiating or maintaining sleep, or the experience of sleep that is non-refreshing, cannot be directly attributed to a comorbid medical or psychiatric disorder. For a diagnosis of primary insomnia, a patient must also report that the nighttime sleep disturbance is impacting upon daytime functioning. Yet, while subjective complaints of impaired wake-time functioning are well documented, consistent objective evidence of these impairments has proved elusive, particularly with regard to cognitive functioning. We aimed to review the body of literature examining neurobehavioural impairments in primary insomnia to identify which cognitive domains appear to be most consistently impaired in this group. The relatively few studies that have investigated neurobehavioural performance deficits in patients with primary insomnia have produced inconsistent and sometimes conflicting findings. It is suggested that methodological limitations, including heterogeneous test populations, variable testing protocols and conditions as well as unsuitable cognitive tasks have contributed to our inability to describe unequivocally the daytime impairments associated with insomnia. Based on our review, it appears that the deficits associated with insomnia are relatively subtle and may be qualitatively different to those that result from other sleep disorders and from imposed sleep deprivation. Attention tasks, which have a high cognitive load, and working memory tasks appear to show performance deficits more often than not in insomnia patients. It is important to more definitively characterise the daytime impairments associated with primary insomnia so that the efficacy of treatments to remedy the wake-time consequences of the disorder, in addition to the nighttime symptoms, can be investigated.

Circadian Rhythm Profiles in Women with Night Eating Syndrome

Night eating syndrome (NES) is characterized by evening hyperphagia and frequent awakenings accompanied by food intake. Patients with NES display a delayed circadian pattern of food intake but retain a normal sleep-wake cycle. These characteristics initiated the current study, in which the phase and amplitude of behavioral and neuroendocrine circadian rhythms in patients with NES were evaluated. Fifteen women with NES (mean age ± SD, 40.8 ± 8.7 y) and 14 control subjects (38.6 ± 9.5 y) were studied in the laboratory for 3 nights, with food intake measured daily. Blood also was collected for 25 h (every 2 h from 0800 to 2000 h, and then hourly from 2100 to 0900 h) and assayed for glucose and 7 hormones (insulin, ghrelin, leptin, melatonin, cortisol, thyroid-stimulating hormone [TSH] and prolactin). Statistical analyses utilized linear mixed-effects cosinor analysis. Control subjects displayed normal phases and amplitudes for all circadian rhythms. In contrast, patients with NES showed a phase delay in the timing of meals, and delayed circadian rhythms for total caloric, fat, and carbohydrate intake. In addition, phase delays of 1.0 to 2.8 h were found in 2 food-regulatory rhythms—leptin and insulin—and in the circadian melatonin rhythm (with a trend for a delay in the circadian cortisol rhythm). In contrast, circulating levels of ghrelin, the primary hormone that stimulates food intake, were phase advanced by 5.2 h. The glucose rhythm showed an inverted circadian pattern. Patients with NES also showed reduced amplitudes in the circadian rhythms of food intake, cortisol, ghrelin, and insulin, but increased TSH amplitude. Thus, patients with NES demonstrated significant changes in the timing and amplitude of various behavioral and physiological circadian markers involved in appetite and neuroendocrine regulation. As such, NES may result from dissociations between central (suprachiasmatic nucleus) timing mechanisms and putative oscillators elsewhere in the central nervous system or periphery, such as the stomach or liver. Considering these results, chronobiologic treatments for NES such as bright light therapy may be useful. Indeed, bright light therapy has shown efficacy in reducing night eating in case studies and should be evaluated in controlled clinical trials.

Delayed sleep phase in young people with unipolar or bipolar affective disorders

BACKGROUND Circadian disturbances may play a key role in the pathogenesis of some forms of mood disorders. Despite marked changes in circadian rhythms during the normal course of adolescence and young adulthood, less is known about changes in the 24-h sleep-wake cycle in young persons with mood disorders. METHODS Seventy-five young participants with mood disorders (unipolar: n=46, 20.1 ± 4.7 years old; bipolar I or II: n=29, 23.2 ± 4.3) and 20 healthy participants (24.8 ± 2.5 years old) underwent actigraphy monitoring during a depressive phase over seven consecutive days and nights. Sleep phase delay was defined as mean sleep onset ≥ 1:30 am and/or sleep offset ≥ 1 0:00 am. RESULTS A delayed sleep phase was found in 62% of participants with bipolar disorders when depressed, compared with 30% of those with unipolar depression (χ(2)=6.0, p=0.014) and 10% of control participants (χ(2)=11.2, p<0.001). Sleep offset times were significantly later in subjects with mood disorders compared to the control group, and later in those with bipolar as compared with unipolar disorders (all p ≤ 0.043). LIMITATIONS This study was cross-sectional and the depressed groups were somewhat younger compared to the healthy controls. Longitudinal studies are required to determine the predictive significance of these findings. CONCLUSIONS Young patients with mood disorders, especially those with bipolar disorders, are particularly likely to have a delayed sleep phase. Therapies focused on advancing sleep phase may be of specific benefit to these young persons.

SLEEP AND METABOLIC CONTROL: WAKING TO A PROBLEM?

1 The aim of the present review is to outline: (i) the association between sleep and metabolism; (ii) how sleep duration influences the development of disease; and (iii) how sex differences, ageing and obesity may potentially influence the relationship between sleep, metabolic control and subsequent disease. 2 Sleep is associated with a number of endocrine changes, including a change in insulin action in healthy young individuals. Sleep duration shows a prospective U‐shaped relationship with all‐cause mortality, cardiovascular disease and Type 2 diabetes. 3 Chronic sleep restriction is becoming more common. Experimental sleep restriction impedes daytime glucose control and increases appetite. 4 The sex hormones oestrogen and testosterone influence sleep duration and quality and may account for sex differences in the prevalence of sleep‐related disorders. 5 Ageing is associated with a decreased sleep duration, decreased muscle mass and impaired insulin action. 6 Obesity impairs insulin action and is associated with the incidence and severity of obstructive sleep apnoea. 7 Sleep plays an integral role in metabolic control. Consequently, insufficient sleep may represent a modifiable risk factor for the development of Type 2 diabetes. The challenge ahead is to identify how sex differences, ageing and obesity could potentially influence the relationship between sleep and metabolism.

Sleep-wake cycle and melatonin rhythms in adolescents and young adults with mood disorders: Comparison of unipolar and bipolar phenotypes

This study evaluated the potential of circadian measures as early markers of mood disorders subtypes. Patients with bipolar disorders had significantly lower levels and later onset of melatonin secretion than those with unipolar depression. Furthermore, abnormal phase angles between sleep, melatonin and temperature were found in several patients.

A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome.

Individuals with Prader–Willi syndrome (PWS) have a significant reduction in the number of oxytocin‐producing neurons (42%) in the hypothalamic paraventricular nucleus. A number of animal studies and observations of humans show that lesions in this region can produce PWS‐like symptoms. Given the evidence for potential oxytocin deficiency, we tested the effects of a course of intranasal oxytocin on PWS symptoms. Thirty individuals with PWS aged 12–30 years participated in an 18‐week randomized double‐blind placebo‐controlled crossover trial. Participants received 8 weeks of oxytocin and 8 weeks of placebo with a minimum 2‐week washout period. The first 11 participants received the following oxytocin doses: 24 IU (twice daily) B.I.D for participants 16 years and over and 18 IU B.I.D for participants 13–15 years. The dose was increased for the remaining 18 participants to 40 IU B.I.D for participants 16 years and over and 32 IU B.I.D for 13–15 years. Measures used to assess changes were standardized well‐accepted measures, including the Developmental Behavior Checklist—Monitor, Parent, Teacher, and Adult; The Yale‐Brown Obsessive Compulsive Scale; The Dykens Hyperphagia questionnaire; Reading The Mind in the Eyes Test; Epworth Sleepiness Scale and the Movie Stills. Oxytocin had little impact on any measure. The only significant difference found between the baseline, oxytocin, and placebo measures was an increase in temper outbursts (P = 0.023) with higher dose oxytocin. The lack of effect of oxytocin nasal spray may reflect the importance of endogenous release of oxytocin in response to exogenous oxytocin.

Disturbances in melatonin secretion and circadian sleep–wake regulation in Parkinson disease

OBJECTIVE Using salivary dim light melatonin onset (DLMO) and actigraphy, our study sought to determine if Parkinson disease (PD) patients demonstrate circadian disturbance compared to healthy controls. Additionally, our study investigated if circadian disturbances represent a disease-related process or may be attributed to dopaminergic therapy. METHODS Twenty-nine patients with PD were divided into unmedicated and medicated groups and were compared to 27 healthy controls. All participants underwent neurologic assessment and 14 days of actigraphy to establish habitual sleep-onset time (HSO). DLMO time and area under the melatonin curve (AUC) were calculated from salivary melatonin sampling. The phase angle of entrainment was calculated by subtracting DLMO from HSO. Overnight polysomnography (PSG) was performed to determine sleep architecture. RESULTS DLMO and HSO were not different across the groups. However, the phase angle of entrainment was more than twice as long in the medicated PD group compared to the unmedicated PD group (U = 35.5; P = .002) and was more than 50% longer than controls (U = 130.0; P = .021). The medicated PD group showed more than double the melatonin AUC compared to the unmedicated group (U = 31; P = 0.001) and controls (U = 87; P = .001). There was no difference in these measures comparing unmedicated PD and controls. CONCLUSIONS In PD dopaminergic treatment profoundly increases the secretion of melatonin. Our study reported no difference in circadian phase and HSO between groups. However, PD patients treated with dopaminergic therapy unexpectedly showed a delayed sleep onset relative to DLMO, suggesting dopaminergic therapy in PD results in an uncoupling of circadian and sleep regulation.

Circadian profiles in young people during the early stages of affective disorder

Although disturbances of the circadian system are strongly linked to affective disorders, no known studies have examined melatonin profiles in young people in early stages of illness. In this study, 44 patients with an affective disorder underwent clinical and neuropsychological assessments. They were then rated by a psychiatrist according to a clinical staging model and were categorized as having an ‘attenuated syndrome’ or an ‘established disorder’. During the evening, salivary melatonin was sampled under dim light conditions over an 8-h interval and for each patient, the time of melatonin onset, total area under the curve and phase angle (difference between time of melatonin onset and time of habitual sleep onset) were computed. Results showed that there was no difference in the timing of melatonin onset across illness stages. However, area under the curve analyses showed that those patients with ‘established disorders’ had markedly reduced levels of melatonin secretion, and shorter phase angles, relative to those with ‘attenuated syndromes’. These lower levels, in turn, were related to lower subjective sleepiness, and poorer performance on neuropsychological tests of verbal memory. Overall, these results suggest that for patients with established illness, dysfunction of the circadian system relates clearly to functional features and markers of underlying neurobiological change. Although the interpretation of these results would be greatly enhanced by control data, this work has important implications for the early delivery of chronobiological interventions in young people with affective disorders.

Does sleep disturbance mediate neuropsychological functioning in older people with depression

BACKGROUND Depression in older adults is associated with neuropsychological dysfunction, fronto-subcortical brain changes and sleep disturbance. Research suggests that adequate sleep is critical for many aspects of cognition including processing speed, verbal skills and memory. However, the association between sleep disturbance and neuropsychological functioning in depression has not been well evaluated. The current study therefore aimed to investigate these relationships. METHODS Forty-eight people (mean age=59.6, sd=8.2) meeting DSM-IV criteria for unipolar major depression were included for analysis. Neuropsychological assessment included assessment of processing speed, learning and memory, verbal fluency and executive functions. Early and late insomnia were defined by scores on the Hamilton Depression Rating Scale. RESULTS While early insomnia was related to depression severity and poorer global cognition, late insomnia was associated with later age of depression onset, depression severity, and poorer scores on tests of verbal fluency and memory. The associations between cognition and late insomnia were not accounted for by depression severity or age of onset of disorder. LIMITATIONS This study was retrospective in nature, and did not include objective measures of sleep. CONCLUSIONS This is the first known study to indicate that late insomnia in older people with major depression may be independently and aetiologically linked to neuropsychological performance, particularly verbal fluency and memory. It may also indicate underlying structural and neurochemical changes. Sleep and circadian disturbance may serve as a biomarker for ongoing cognitive decline and may be a potentially modifiable risk factor.