Leonid Kayumov

Melatonin in mood disorders

The cyclic nature of depressive illness, the diurnal variations in its symptomatology and the existence of disturbed sleep–wake and core body temperature rhythms, all suggest that dysfunction of the circadian time keeping system may underlie the pathophysiology of depression. As a rhythm-regulating factor, the study of melatonin in various depressive illnesses has gained attention. Melatonin can be both a ‘state marker’ and a ‘trait marker’ of mood disorders. Measurement of melatonin either in saliva or plasma, or of its main metabolite 6-sulfatoxymelatonin in urine, have documented significant alterations in melatonin secretion in depressive patients during the acute phase of illness. Not only the levels but also the timing of melatonin secretion is altered in bipolar affective disorder and in patients with seasonal affective disorder (SAD). A phase delay of melatonin secretion takes place in SAD, as well as changes in the onset, duration and offset of melatonin secretion. Bright light treatment, that suppresses melatonin production, is effective in treating bipolar affective disorder and SAD, winter type. This review discusses the role of melatonin in the pathophysiology of bipolar disorder and SAD.

Subjective fatigue and subjective sleepiness: two independent consequences of sleep disorders?

The objective of this investigation was to evaluate subjective fatigue versus subjective sleepiness as independent consequences of sleep disorders. Furthermore, we tried to explore how these symptoms relate to alertness, depressive symptoms and illness intrusiveness. In a prospective observational study, 283 sleep‐disordered patients referred to a hospital‐based sleep laboratory for various indications over a 1‐year period were evaluated vis‐à‐vis fatigue and sleepiness. All patients completed five subjective questionnaires, underwent objective sleep recording and attended a clinical interview with a sleep specialist. The subjective questionnaires included the Epworth Sleepiness Scale, the Fatigue Severity Scale, the Toronto Hospital Alertness Test, the Illness Intrusiveness Rating Scale and the Center for Epidemiologic Studies‐Depression Scale. Only 4% of the total sample was referred to the sleep clinic due to a complaint of excessive fatigue compared with 17% for excessive daytime sleepiness. However, during the assessment, 64% of referred patients reported pathological fatigue without overlap of sleepiness and only 4% reported pathological sleepiness without overlap of fatigue. Pearsons correlation analysis indicated a weak association (r = 0.18) between subjective fatigue and sleepiness in the total sample. Analysis of variance testing showed strong association between those patients with prominent fatigue and depressive symptoms (P < 0.01) and illness intrusiveness (P < 0.001). The findings support the notion that subjective fatigue and sleepiness can be independent manifestations of sleep disorders. Furthermore, predominantly fatigued individuals with sleep disorders seem vulnerable to additional negative consequences due to possible interplay between amplified fatigue and psychological distress.

A Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effect of Exogenous Melatonin on Delayed Sleep Phase Syndrome

Objective The effects of exogenous melatonin on sleep, daytime sleepiness, fatigue, and alertness were investigated in 22 patients with delayed sleep phase syndrome whose nocturnal sleep was restricted to the interval from 24:00 to 08:00 hours. This study was a randomized, double-blind, placebo-controlled crossover trial. Subjects received either placebo or melatonin (5 mg) daily for 4 weeks, underwent a 1-week washout period, and then were given the other treatment for an additional 4 weeks. Patients could take the melatonin between 19:00 and 21:00 hours, which allowed them to select the time they felt to be most beneficial for the phase-setting effects of the medication. Methods Two consecutive overnight polysomnographic recordings were performed on three occasions: at baseline (before treatment), after 4 weeks of melatonin treatment, and after 4 weeks of placebo treatment. Results In the 20 patients who completed the study, sleep onset latency was significantly reduced while subjects were taking melatonin as compared with both placebo and baseline. There was no evidence that melatonin altered total sleep time (as compared with baseline total sleep time), but there was a significant decrease in total sleep time while patients were taking placebo. Melatonin did not result in altered scores on subjective measures of sleepiness, fatigue, and alertness, which were administered at different times of the day. After an imposed conventional sleep period (from 24:00 to 08:00), subjects taking melatonin reported being less sleepy and fatigued than they did while taking placebo. Conclusions Melatonin ameliorated some symptoms of delayed sleep phase syndrome, as confirmed by both objective and subjective measures. No adverse effects of melatonin were noted during the 4-week treatment period.

Sleep disorders, sleepiness and traffic safety: a public health menace

Sleep disorders are not uncommon and have been widely reported throughout the world. They have a profound impact on industrialized 24-h societies. Consequences of these problems include impaired social and recreational activities, increased human errors, loss of productivity, and elevated risk of accidents. Conditions such as acute and chronic insomnia, sleep loss, excessive sleepiness, shift-work, jet lag, narcolepsy, and sleep apnea warrant public health attention, since residual sleepiness during the day may affect performance of daily activities such as driving a car. Benzodiazepine hypnotics and zopiclone promote sleep, both having residual effects the following day including sleepiness and reduced alertness. In contrast, the non-benzodiazepine hypnotics zolpidem and zaleplon have no significant next-day residual effects when taken as recommended. Research on the effects of wakefulness-promoting drugs on driving ability is limited. Countermeasures for excessive daytime sleepiness have a limited effect. There is a need for a social awareness program to educate the public about the potential consequences of various sleep disorders such as narcolepsy, sleep apnea, shift-work-related sleep loss, and excessive daytime sleepiness in order to reduce the number of sleep-related traffic accidents.

Clinical efficacy of dim light melatonin onset testing in diagnosing delayed sleep phase syndrome

BACKGROUND Delayed Sleep Phase Syndrome (DSPS) arises from biological clock desynchrony and accounts for 10% of chronic insomnia patients. Currently DSPS is diagnosed based on sleep/wake cycle disruptions rather than examining the underlying biological clock alterations. The objective of the study was to determine the sensitivity and specificity of the Dim Light Melatonin Onset (DLMO) Test in diagnosing DSPS in a clinical setting. METHODS Fifty-six patients (mean age 28 years) symptomatic of DSPS participated in the study. Following an initial assessment of DSPS using sleep diaries, participants underwent two consecutive nights of polysomnography (PSG), with an imposed sleep period on the second night to demonstrate the delay in the timing of habitual sleep period and to thereby confirm DSPS. Circadian phase delays were also measured using melatonin secretion profiles, and the efficacy of diagnosing DSPS using DLMO was compared to using sleep diaries and PSG. Melatonin secretion was assayed for each individual by ELISA using saliva samples. RESULTS Main outcome measures included the time of melatonin secretion onset, clinical sensitivity and specificity of the DLMO test. The time of melatonin secretion onset was significantly delayed in DSPS patients. Clinical sensitivity and specificity of the DLMO test in diagnosing DSPS were 90.3% and 84.0%, respectively. CONCLUSIONS The DLMO test is an accurate tool for differentiating between sleep disorder patients with or without underlying circadian rhythm disruption. It is effective for phase typing DSPS patients in a clinical setting.

Antidepressant action of melatonin in the treatment of Delayed Sleep Phase Syndrome

BACKGROUND Depression is a common problem in patients with Delayed Sleep Phase Syndrome (DSPS). This study used a randomized, double-blind, crossover, placebo-controlled approach to test the hypothesis that exogenous melatonin (5mg) can attenuate depressive symptomatology in DSPS patients. METHODS Twenty patients with an established diagnosis of DSPS were dichotomized into DSPS with depressive symptoms (Group I; n=8) and without depressive symptoms (Group II; n=12) based on structured clinical interviews and a score greater than 17 on Center for Epidemiologic Studies Depression Scale (CES-D). Both groups received melatonin and placebo treatment for 4 weeks with a 1-week washout period in between. Participants underwent a clinical interview and psychometric evaluation to assess depression, and overnight polysomnographic sleep studies were carried out at baseline and at the end of melatonin and placebo treatments. Furthermore, melatonin secretion rhythm as a circadian phase marker was assessed by measuring urinary 6-sulphatoxymelatonin levels. RESULTS Melatonin treatment significantly reduced depression scores in the depressed patients as measured by the CES-D and Hamilton Depression Rating Scale--17. Melatonin treatment improved sleep continuity in both groups compared to placebo and baseline conditions. Group I individuals showed marked alterations in melatonin rhythms compared to Group II individuals. CONCLUSION Exogenous melatonin treatment may be an effective treatment modality for individuals with circadian rhythm sleep disorders and associated comorbid depressive symptomatology.

Polysomnographic and Symptomatological Analyses of Major Depressive Disorder Patients Treated With Mirtazapine

Objective: This study aimed to characterize the effects of mirtazapine on polysomnographic sleep, especially slow wave sleep (SWS) and rapid eye movement (REM) sleep, as well as its effects on clinical symptoms in patients with major depressive disorder (MDD). Method: Sixteen MDD patients were treated with mirtazapine 30 mg taken 30 minutes before bedtime. Polysomnographic and subjective sleep, as well as other clinical data, were collected at baseline and on Days or Nights 2, 9, 16, 30, and 58 during treatment. We used repeated measures analysis of variance, including pairwise comparison, to analyze data statistically. Results: Mirtazapine administration increased total SWS and the SWS in the first sleep cycle, but not SWS in the second sleep cycle. The medication increased REM latency and the duration of the first REM episode; it also decreased the number of REM episodes. Simultaneously, mirtazapine significantly reduced wake-after-sleep onset and scores on the Athens Insomnia Scale. After patients took the medication, scores on the Hamilton Depression Rating Scale-17 (HDRS-17) decreased rapidly and continuously. The changes on the Beck Depression Inventory-II were consistent with those on the HDRS-17. The medication has a tendency to increase weight. Conclusions: Mirtazapine significantly improved sleep quality, reversed sleep markers of depression, and reduced depressive symptoms in this group of MDD patients.

Underlying sleep pathology may cause chronic high fatigue in shift-workers

About 20–25% of the population in primary healthcare settings complains of chronic fatigue but this symptom has been under‐emphasized compared with sleepiness in clinical practice. Shift‐workers are particularly vulnerable because of various fatigue‐related personal and public morbidity and mortality. The goal of this cross‐sectional study was to explore if fatigue severity could be used as an independent predictive tool to identify underlying sleep pathology. The 21 most‐fatigued (study group) and 23 least‐fatigued (control) miners were selected on the basis of the Fatigue Severity Scale (FSS), which was administered to 195 subjects in an underground mine in Timmins, a town in northern Ontario. The two groups were matched for age, gender, and body mass index (BMI). Mean FSS score for the most‐fatigued subjects was 4.9 ± 0.5 and the least‐fatigued was 2.2 ± 0.5 (P < 0.0001). The subjects from each group were studied polysomnographically to identify sleep disorders. The polysomnographic data in 15 of 21 (71.4%) of the most‐fatigued subjects displayed significant sleep pathology compared with only three of 23 (13.0%) in the least‐fatigued subjects. Based on Fishers exact test, the difference between the two groups was highly significant (P < 0.0001). Also, in the total subject pool (n = 195), the correlation between subjective fatigue and sleepiness was not very strong (Pearsons r = 0.45), suggesting that these two symptoms can be independent phenomena. It is concluded that chronic high fatigue can be an independent manifestation of underlying sleep pathology, which warrants independent subjective and objective assessment.

What Is the Driving Performance of Ambulatory Surgical Patients after General Anesthesia

Background:Ambulatory surgical patients are advised to refrain from driving for 24 h postoperatively. However, currently there is no strong evidence to show that driving skills and alertness have resumed in patients by 24 h after general anesthesia. The purpose of this study was to determine whether impaired driver alertness had been restored to normal by 2 and 24 h after general anesthesia in patients who underwent ambulatory surgery. Methods:Twenty patients who underwent left knee arthroscopic surgery were studied. Their driving simulation performance, electroencephalographically verified parameters of sleepiness, subjective assessment of sleepiness, fatigue, alertness, and pain were measured preoperatively and 2 and 24 h postoperatively. The same measurements were performed in a matched control group of 20 healthy individuals. Results:Preoperatively, patients had significantly higher attention lapses and lower alertness levels versus normal controls. Significantly impaired driving skills and alertness, including longer reaction time, higher occurrence of attention lapses, and microsleep intrusions, were found 2 h postoperatively versus preoperatively. No significantly differences were found in any driving performance parameters or electroencephalographically verified parameters 24 h postoperatively versus preoperatively. Conclusions:Patients showed lower alertness levels and impaired driving skills preoperatively and 2 h postoperatively. Based on driving simulation performance and subjective assessments, patients are safe to drive 24 h after general anesthesia.

Subjective and objective evaluation of sleep and performance in daytime versus nighttime sleep in extended-hours shift-workers at an underground mine

Extended hours of shift work has the potential for adverse consequences for workers, particularly during the nightshift, such as poorer sleep quality during the day, increased worker fatigue, and fatigue-related accidents and decreased work performance. This study examined subjective and objective measurements of sleep and performance in a group of underground miners before and after the change from a backward-rotating 8-hour to a forward-rotating 10-hour shift schedule. The purpose of this study was to evaluate the short- and long-term impact of a shift schedule change on sleep and performance. The results demonstrated improved subjective and objective measures of sleep and performance on the new 10-hour nightshift schedule. The 10-hour nightshift workers subjectively reported more refreshing sleep, fewer performance impairments and driving difficulties than 8-hour nightshift workers. The results of the objective measures of sleep and performance on the 10-hour nightshifts were overall similar or possibly better than those measured on the 10-hour dayshifts. These are some of the first data to suggest that a nightshift that does not encompass the entire night period could have significant benefits to shift-workers. We suggest that these benefits are mostly the result of the timing of the new nightshift start and end times rather than other shift-schedule factors.