Restless legs syndrome: Over 50 years of European contribution.

Restless legs syndrome (RLS) is a sensorimotor neurological disorder characterised by an urge to move the limbs with a circadian pattern (occurring in the evening/at night), more prominent at rest, and relieved with movements. RLS is one of the most prevalent sleep disorders, occurring in 5%-10% of the European population. Thomas Willis first described RLS clinical cases already in the 17th century, and Karl-Axel Ekbom described the disease as a modern clinical entity in the 20th century. Despite variable severity, RLS can markedly affect sleep (partly through the presence of periodic leg movements) and quality of life, with a relevant socio-economic impact. Thus, its recognition and treatment are essential. However, screening methods present limitations and should be improved. Moreover, available RLS treatment options albeit providing sustained relief to many patients are limited in number. Additionally, the development of augmentation with dopamine agonists represents a major treatment problem. A better understanding of RLS pathomechanisms can bring to light novel treatment possibilities. With emerging new avenues of research in pharmacology, imaging, genetics, and animal models of RLS, this is an interesting and constantly growing field of research. This review will update the reader on the current state of RLS clinical practice and research, with a special focus on the contribution of European researchers.

Principles of practice parameters for the treatment of sleep disordered breathing in the elderly and frail elderly: the consensus of the International Geriatric Sleep Medicine Task Force.

Sleep disordered breathing (SDB) is a leading cause of morbidity worldwide. Its prevalence increases with age. Due to the demographic changes in industrial societies, pulmonologists and sleep physicians are confronted with a rapidly growing number of elderly SDB patients. For many physicians, it remains unclear how current guidelines for SDB management apply to elderly and frail elderly patients. The goal of this consensus statement is to provide guidance based on published evidence for SDB treatment in this specific patient group.Clinicians and researchers with expertise in geriatric sleep medicine representing several countries were invited to participate in a task force. A literature search of PubMed from the past 12 years and a systematic review of evidence of studies deemed relevant was performed.Recommendations for treatment management of elderly and frail elderly SDB patients based on published evidence were formulated via discussion and consensus.In the last 12 years, there have been surprisingly few studies examining treatment of SDB in older adults and even fewer in frail older adults. Studies that have been conducted on the management of SDB in the older patient population were rarely stratified for age. Studies in SDB treatment that did include age stratification mainly focused on middle-aged and younger patient groups. Based on the evidence that is available, this consensus statement highlights the treatment forms that can be recommended for elderly SDB patients and encourages treatment of SDB in this large patient group.

Defining morphology of periodic leg movements in sleep: an evidence-based definition of a minimum window of sustained activity.

OBJECTIVE: Current standard guidelines for scoring periodic leg movements (PLM) define the start and end of a movement but fail to explicitly specify the movement morphology necessary to classify an EMG event as a PLM, rather than some other muscle event. This is currently left to the expert visual scorer to determine. This study aimed to define this morphology to provide a consistent standard for visual scoring and to improve automatic periodic leg movements in sleep scoring. METHODS: A review of expert PLM scoring produced a hypothesized morphology criterion: a window of high EMG activity within the movement lasting at least 0.5 s. Two diverse expert visual scorers were independently presented with images of EMG tracings from candidate leg movements (CLM) that either passed or failed this requirement (aka "full" or "empty" movements, respectively), and indicated whether each should be scored as CLM. The 0.5-s window was compared with alternatives of 0.25 and 0.75 windows. RESULTS: Expert scorers on average identified 94 % of "full" movements as CLM in contrast to only 8.5 % of "empty" movements. The proposed minimum window of 0.5 s also resulted in the highest agreement between visual scorers and between scorers and an automatic program. CONCLUSION: An added criterion requiring 0.5 s of high EMG activity within a valid CLM improves the accuracy of automatic scoring algorithms in relation to the gold standard of expert visual scorers. Our results suggest that this rule is an accurate representation of the morphology feature used by experts. This new rule has the potential to improve consistency and accuracy of visual and automatic scoring of PLM.

Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions.

Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

Longitudinal polysomnographic assessment from acute to subacute phase in infratentorial versus supratentorial stroke.

BACKGROUND: Regulation of sleep and sleep-related breathing resides in different brain structures. Vascular lesions can be expected to differ in their consequences on sleep depending on stroke topography. However, studies addressing the differences in sleep and sleep-related breathing depending on stroke topography are scarce. The aim of the present investigation was to compare the sleep and sleep-related breathing of patients with supratentorial versus infratentorial stroke. METHODS: This study was part of the prospective multicenter study SAS-CARE-1 (Sleep-Disordered Breathing in Transient Ischemic Attack (TIA)/Ischemic Stroke and Continuous Positive Airway Pressure (CPAP) Treatment Efficacy (SAS-CARE); NCT01097967). We prospectively included 14 patients (13 male, age 66 ± 6 years) with infratentorial lesions and 14 patients (14 male, age 64 ± 7 years) with supratentorial lesions, matched for age and stroke severity. Polysomnography was recorded in all during the acute phase within 9 days after stroke onset and 3 months later. RESULTS: During the acute phase after stroke, patients with infratentorial lesions had significantly more sleep-related breathing disorders than patients with supratentorial lesions with an apnea-hypopnea index >20 observed in 8 (57%) patients with infratentorial stroke and in only 2 (14%) patients with supratentorial stroke. Sleep-related breathing improved from the acute to the subacute phase (3 months), albeit remaining elevated in a significant proportion of subjects. Sleep parameters did not differ between the two patient groups but there was a general improvement of sleep from the acute to the subacute phase which was comparable for both patient groups. Although stroke severity was mild, recovery after 3 months was worse in patients with infratentorial stroke with 12 of 14 patients with supratentorial stroke being symptom free (NIHSS = 0), while this was the case for only 6 of 14 patients with infratentorial stroke. CONCLUSIONS: Patients with infratentorial lesions are at an increased risk for sleep-related breathing disorders, which are frequent in this group. Monitoring of sleep-related breathing is therefore especially recommended in patients with infratentorial stroke. Because of the absence of reliable differences in sleep parameters between the two patient groups, polygraphy, with reduced diagnostic costs, rather than polysomnography could be considered. The higher prevalence of sleep-related breathing disorders and the poorer recovery of patients with infratentorial lesions suggest that early treatment interventions should be considered.

Dissociation of periodic leg movements from arousals in restless legs syndrome.

OBJECTIVE: The purpose of this study was to characterize the nature of the relation between periodic leg movements during sleep (PLMS) and cortical arousals to contribute to the debate on the clinical significance and treatment of PLMS. METHODS: A prospective, placebo-controlled, single-blind, parallel group study was carried out including 46 drug-naive patients with idiopathic restless legs syndrome (RLS). Each patient underwent 2 consecutive full-night polysomnographic studies. The first night was the baseline night. Prior to the second night, 1 group received a single oral dose of 0.25mg pramipexole, whereas a second group received a single oral dose of 0.5mg clonazepam, and the remaining patients received placebo. Sleep stages, cyclic alternating pattern (CAP), and leg movement activity were scored following standard criteria; symptoms of RLS were also assessed. RESULTS: Pramipexole suppressed PLMS without affecting electroencephalographic (EEG) instability (CAP) and arousals (corresponding to CAP A3 and, partially, A2 subtypes), whereas clonazepam did the opposite, reducing non-rapid eye movement sleep EEG instability without effects on PLMS. Both drugs were effective on sensory RLS symptoms. INTERPRETATION: This study demonstrates that a selective pharmacological approach can disconnect PLMS from arousal events, suggesting an indirect relation between each other. These results might weaken the hypothesis of a direct pathological role of PLMS in sleep disruption and can be important for the discussion on the existence of a distinct entity called periodic limb movements disorder. Moreover, the study opens the doors to the possibility of a joint treatment for RLS targeting sensory and motor symptoms, as well as sleep instability.

Time to rest a hypothesis? Accumulating evidence that periodic leg movements during sleep are not increased in children with attention-deficit hyperactivity disorder (ADHD): results of a case-control study and a meta-analysis.

STUDY OBJECTIVES: To address the hypothesis that periodic leg movements during sleep (PLMS) are more frequent in children with attention-deficit hyperactivity disorder (ADHD) when compared with typically developing (TD) children. To that end, we analyzed PLMS in a recent case-control study and conducted a systematic review and meta-analysis of PLMS frequency in children with ADHD and TD children. METHODS: In our case-control study, we compared the PLMS frequency of 24 children with ADHD (mean age 11 years, 17 males) to that of 22 age-matched typically developing (TD) children (mean age 10 years, 12 males). A subsequent meta-analysis included 33 studies that described PLMS frequency in groups of children with ADHD and/or groups of TD children. RESULTS: The case-control study did not show any differences in the frequency of PLMS between children with ADHD and TD children, a result that was consistent across a range of different definitions of PLMS, which in turn had a significant and systematic effect on PLMS frequency. The meta-analysis compared the average PLMS indices and the proportion of children with elevated PLMS indices between children with ADHD and TD children and across a number of analyses did not find any meta-analytic results that supported the hypothesis that PLMS are more frequent in children with ADHD. CONCLUSIONS: Our results suggest that PLMS are not more frequent in children with ADHD compared with TD children. A finding of frequent PLMS in a child with ADHD should therefore be considered a separate disorder and prompt specific diagnostic and therapeutic strategies.

Weight-gain independent effect of mirtazapine on fasting plasma lipids in healthy men.

Treatment with mirtazapine, a widely prescribed antidepressant, has been linked to weight gain and dyslipidemia. Whether dyslipidemia occurs secondary to increased appetite due to antidepressant treatment, or due to direct pharmacological effects of mirtazapine is unknown. The aim of this analysis is to complement our previously published results of the effect of mirtazapine on metabolism and energy substrate partitioning from a proof-of-concept, open-label clinical study (ClinicalTrials.gov NCT00878540) in 12 healthy males (20-25 years). We report the effect of a seven-day administration of mirtazapine 30 mg per day on weight and lipid metabolism in healthy men under highly standardized conditions with respect to diet, physical activity and day-night-rhythm and under continuous clinical observation. After a 7-day administration of mirtazapine 30 mg, we observed a statistically significant increase in triglyceride levels (mean change + 4.4 mg/dl; 95% CI [- 11.4; 2.6]; p = 0.044) as well as TG/HDL-C ratio (mean change + 0.2; 95% CI [- 0.4; 0.1]; p = 0.019) and a decrease in HDL-cholesterol (mean change - 4.3 mg/dl; 95% CI [2.1; 6.5]; p = 0.004), LDL-cholesterol (mean change - 8.7 mg/dl; 95% CI [3.8; 13.5]; p = 0.008), total cholesterol (mean change - 12.3 mg/dl; 95% CI [5.4; 19.1]; p = 0.005), and non-HDL-C (mean change - 8.0 mg/dl; 95% CI [1.9; 14.0]; p = 0.023). Notably, weight (mean change - 0.6 kg; 95% CI [0.4; 0.8]; p = 0.002) and BMI (mean change - 0.2; 95% CI [0.1; 0.2]; p = 0.002) significantly decreased. No change in waist circumference (mean change - 0.4 cm; 95% CI [- 2.1; 2.9]; p = 0.838) or waist-to-hip-ratio (mean change 0.0; 95% CI [- 0.0; 0.0]; p = 0.814) was observed. This is the first study showing unfavorable changes in lipid metabolism under mirtazapine in healthy individuals despite highly standardized conditions including dietary restriction, and despite the observation of a decrease of weight. Our findings support the hypothesis that mirtazapine has direct pharmacological effects on lipid metabolism. ClinicalTrials.gov: NCT00878540.

A quantitative analysis of the submentalis muscle electromyographic amplitude during rapid eye movement sleep across the lifespan.

The current definition of rapid eye movement (REM) sleep without atonia has no quantitative character, and cut-off values above which the level of electromyographic tone can be considered to be 'excessive' are unclear. The aim of this study was to analyse the characteristics of chin electromyographic amplitude by means of an automatic approach in a large group of normal controls, subdivided into different age groups. Eighty-eight normal controls were included, subdivided into six age groups: preschoolers (≤6 years); schoolers (6-10 years); preadolescents (10-13 years); young adults (24-40 years); middle-aged (58-65 years); and old (>65 years). The average amplitude of the rectified submentalis muscle electromyographic signal was used for the computation of the REM sleep Atonia Index. Chin muscle activations were detected, and their amplitude, duration and interval analysed. REM sleep Atonia Index showed a progressive and rapid increase from the preschool age to school and preadolescent age, reaching the maximum in the young adult group; after this age a small decline was observed in the middle-aged and old subjects. Conversely, the number of movements per hour in REM sleep showed a 'U'-shaped distribution across these age groups, with the minimum in the preadolescent group and the two extremes (preschool age and old) showing similar average levels of activity. Our results show that REM sleep atonia develops continuously during the lifespan, and undergoes complex changes with different developmental trajectories for REM atonia and electromyographic activations during REM sleep. Different mechanisms might subserve these two phenomena and their differential developmental dynamics.

Rapid eye movements during sleep in mice: high trait-like stability qualifies rapid eye movement density for characterization of phenotypic variation in sleep patterns of rodents.

BACKGROUND: In humans, rapid eye movements (REM) density during REM sleep plays a prominent role in psychiatric diseases. Especially in depression, an increased REM density is a vulnerability marker for depression. In clinical practice and research measurement of REM density is highly standardized. In basic animal research, almost no tools are available to obtain and systematically evaluate eye movement data, although, this would create increased comparability between human and animal sleep studies. METHODS: We obtained standardized electroencephalographic (EEG), electromyographic (EMG) and electrooculographic (EOG) signals from freely behaving mice. EOG electrodes were bilaterally and chronically implanted with placement of the electrodes directly between the musculus rectus superior and musculus rectus lateralis. After recovery, EEG, EMG and EOG signals were obtained for four days. Subsequent to the implantation process, we developed and validated an Eye Movement scoring in Mice Algorithm (EMMA) to detect REM as singularities of the EOG signal, based on wavelet methodology. RESULTS: The distribution of wakefulness, non-REM (NREM) sleep and rapid eye movement (REM) sleep was typical of nocturnal rodents with small amounts of wakefulness and large amounts of NREM sleep during the light period and reversed proportions during the dark period. REM sleep was distributed correspondingly. REM density was significantly higher during REM sleep than NREM sleep. REM bursts were detected more often at the end of the dark period than the beginning of the light period. During REM sleep REM density showed an ultradian course, and during NREM sleep REM density peaked at the beginning of the dark period. Concerning individual eye movements, REM duration was longer and amplitude was lower during REM sleep than NREM sleep. The majority of single REM and REM bursts were associated with micro-arousals during NREM sleep, but not during REM sleep. CONCLUSIONS: Sleep-stage specific distributions of REM in mice correspond to human REM density during sleep. REM density, now also assessable in animal models through our approach, is increased in humans after acute stress, during PTSD and in depression. This relationship can now be exploited to match animal models more closely to clinical situations, especially in animal models of depression.

Periodic Leg Movements During Sleep.

Periodic leg movements during sleep (PLMS) are a frequent finding in nocturnal sleep registrations that include tibialis anterior electromyographic signals. Different PLMS scoring rules exist and can have a major impact on PLMS frequency, which tends to be underappreciated. There is no consistent evidence that frequent PLMS are a causal risk factor for clinically significant outcomes. Several critical open questions are identified that need to be addressed, including but not limited to the consideration of the full range of all sleep-related leg movement activity.

Cortico-autonomic local arousals and heightened somatosensory arousability during NREMS of mice in neuropathic pain.

Frequent nightly arousals typical for sleep disorders cause daytime fatigue and present health risks. As such arousals are often short, partial, or occur locally within the brain, reliable characterization in rodent models of sleep disorders and in human patients is challenging. We found that the EEG spectral composition of non-rapid eye movement sleep (NREMS) in healthy mice shows an infraslow (~50 s) interval over which microarousals appear preferentially. NREMS could hence be vulnerable to abnormal arousals on this time scale. Chronic pain is well-known to disrupt sleep. In the spared nerve injury (SNI) mouse model of chronic neuropathic pain, we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices, although sleep macroarchitecture appeared unaltered. Closed-loop mechanovibrational stimulation further revealed higher sensory arousability. Chronic pain thus preserved conventional sleep measures but resulted in elevated spontaneous and evoked arousability. We develop a novel moment-to-moment probing of NREMS vulnerability and propose that chronic pain-induced sleep complaints arise from perturbed arousability.

We need to do better: A systematic review and meta-analysis of diagnostic test accuracy of restless legs syndrome screening instruments.

This systematic review and meta-analysis evaluated the diagnostic accuracy of screening instruments for restless legs syndrome (RLS) and reports sensitivity, specificity, positive (PPV) and negative predictive values (NPV). Searches for primary studies were conducted in electronic databases. Of the 1541 citations identified, 52 were included in the meta-analysis. The methodological quality of each study was evaluated using QUADAS-2. Only 14 studies assessed the reference standard in all participants or in all screen-positives and a selection of screen-negatives. Bivariate meta-analysis of these 14 studies estimated median sensitivity to be 0.88 (0.72-0.96) and specificity 0.90 (0.84-0.93); based on a population prevalence of 5%, the calculated PPV was 0.31 (0.27-0.34). For all 52 studies, with either full or partial verification of RLS status, we constructed best-case scenario sensitivities and specificities at pre-defined levels of prevalence: across all samples, when prevalence is 5%, the median best-case scenario PPV is 0.48 with significant between-study heterogeneity. No RLS screening instruments can currently be recommended for use without an expert clinical interview in epidemiological studies. For conditions with statistically low prevalence such as RLS, the specificity, not the sensitivity, of a screening instrument determines true prevalence. Therefore, future instruments should maximize specificity. We provide guidelines on RLS ascertainment in epidemiological studies that requires a two-step process with clinical interview following a screening test, and given the poor reporting quality of many RLS epidemiological studies, we include an RLS reporting checklist.

Short-term attention and verbal fluency is decreased in restless legs syndrome patients.

Restless legs syndrome (RLS) is a frequent sleep-related movement disorder with disturbed sleep and quality of life. RLS patients complain about increased daytime sleepiness, but there are only few and inconsistent reports about cognitive functioning in this group. We compared cognitive performance of 23 unmedicated RLS patients to that of 23 healthy controls matched individually for age, gender, and educational level. Cognitive tasks were chosen to assess short-term attention, working memory, learning and memory, verbal fluency, and executive functioning. RLS patients performed worse than controls in the area of attention and verbal fluency, and performance in these tasks was associated with RLS severity, sleep quality, depression scores, and memory. There was no difference for working memory, memory, learning, cognitive flexibility, and abstract reasoning. We conclude that there is evidence for deficits in short-term attention and verbal fluency in RLS patients.

Sleep-related leg movements in obstructive sleep apnea: definitions, determinants, and clinical consequences.

STUDY OBJECTIVES: To investigate (1) the effect of different scoring rules on leg movement (LM) classification in patients with obstructive sleep apnea (OSA); (2) determinants of respiratory event related leg movements (rLM); and (3) to relate LM parameters to clinical outcomes. METHODS: (1) LM classification was compared between the World Association of Sleep Medicine (WASM) 2006 and the WASM 2016 rules in 336 participants with apnea hypopnea index (AHI) ≥ 5; (2) determinants and features of rLM were investigated with logistic mixed regression in 172 participants with AHI ≥ 10 and respiratory disturbance index (RDI) ≥ 15, and (3) LM parameters were compared for patients with and without cardiovascular events and related to continuous positive airway pressure (CPAP) adherence. RESULTS: WASM-2016 scoring significantly reduced periodic limb movements of sleep (PLMS) frequency in OSA participants even when only considering the new periodicity criteria. Probability of rLM was strongly increased when respiratory events ended with an arousal, but rLM probability was lower for hypopneas and respiratory effort-related sleep arousal (RERAs) than for obstructive apneas. In participants with frequent non-respiratory PLMS, rLM were more frequent and behaved more PLMS-like. In participants without PLMS, rLM probability mostly depended on respiratory event features. LM parameters were neither related to cardiovascular event risk nor to CPAP-adherence. CONCLUSIONS: It is likely that the PLMS frequency in OSA populations has been previously overestimated. Our results suggest that there are two types of rLM, true periodic ones that happen to synchronize with the respiratory events, and periodic appearing but respiratory driven LM, and that the presence of non-respiratory PLMS is instrumental in distinguishing between the two.

Ultradian modulation of cortical arousals during sleep: effects of age and exposure to nighttime transportation noise.

STUDY OBJECTIVES: The present study aimed at assessing the temporal non-rapid eye movement (NREM) EEG arousal distribution within and across sleep cycles and its modifications with aging and nighttime transportation noise exposure, factors that typically increase the incidence of EEG arousals. METHODS: Twenty-six young (19-33 years, 12 women) and 16 older (52-70 years, 8 women) healthy volunteers underwent a 6-day polysomnographic laboratory study. Participants spent two noise-free nights and four transportation noise exposure nights, two with continuous and two characterized by eventful noise (average sound levels of 45 dB, maximum sound levels between 50 and 62 dB for eventful noise). Generalized mixed models were used to model the time course of EEG arousal rates during NREM sleep and included cycle, age, and noise as independent variables. RESULTS: Arousal rate variation within NREM sleep cycles was best described by a u-shaped course with variations across cycles. Older participants had higher overall arousal rates than the younger individuals with differences for the first and the fourth cycle depending on the age group. During eventful noise nights, overall arousal rates were increased compared to noise-free nights. Additional analyses suggested that the arousal rate time course was partially mediated by slow wave sleep (SWS). CONCLUSIONS: The characteristic u-shaped arousal rate time course indicates phases of reduced physiological sleep stability both at the beginning and end of NREM cycles. Small effects on the overall arousal rate by eventful noise exposure suggest a preserved physiological within- and across-cycle arousal evolution with noise exposure, while aging affected the shape depending on the cycle.

Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies.

The restless legs syndrome (RLS) is a common sensory-motor disorder of sleep/wake motor regulation with prevalence rates between 3% and 10%. In its more severe forms, RLS is a burdening disorder with disturbed sleep and significantly impaired quality of life. Restless legs symptoms are dramatically relieved with levodopa and dopamine agonists, which are first-line treatment for this disorder. In addition, opioids have been shown to provide a marked symptomatic relief. This unique responsiveness of RLS to both dopaminergic agents and opioids places it at the crossroad of the two systems implicated in the placebo response. Indeed, in recent large-scale studies a substantial placebo response was observed. We performed a meta-analysis to provide an evidence-based estimate of the magnitude of the placebo response in RLS. Search strategies included the electronic databases PubMed and the Cochrane Clinical Trials Registry (from 1966 to March 2007), the reference lists of retrieved articles, hand-searching abstract books of sleep, neurology and movement disorder congresses and visiting clinical trial register web sites. All randomized, double-blind, placebo-controlled studies exploring a pharmacological treatment in subjects with RLS were considered. Outcome measures from five domains were extracted: RLS severity, subjective sleep parameters, sleep parameters derived from nocturnal polysomnography, periodic leg movements during sleep (PLMS) and daytime functioning. We identified 60 clinical trials and 36 of them were eligible for the meta-analysis. In 24 trials, the pooled placebo response rate was 40.09% (95% CI: 31.99-48.19). The placebo effect was large for the primary outcome measure in most studies, which is the International Restless Legs Severity Scale (-1.48, CI: -1.81 to -1.14), notably smaller for other RLS severity scales, moderate for daytime functioning, small to moderate for subjective and objective sleep parameters, very small for PLMS and absent for sleep efficiency. This meta-analysis yields several implications for the planning of both clinical RLS treatment studies and basic research programs.

Effect of mirtazapine on metabolism and energy substrate partitioning in healthy men.

BACKGROUND: Weight gain and metabolic changes during treatment with antidepressant drugs have emerged as an important concern, particularly in long-term treatment. It is still a matter of ongoing debate whether weight gain and metabolic perturbations with antidepressant use are the consequence of increased appetite and weight gain, respectively, or represents direct pharmacological effects of the drug on metabolism. METHODS: We therefore conducted a proof-of-concept, open-label clinical trial, hypothesizing that in exceptionally healthy men no change of metabolic parameters would occur under mirtazapine, when environmental factors such as nutrition, sleep, and physical exercise were controlled and kept constant. Over a 3-week preparation phase, 10 healthy, young men were attuned to a standardized diet adjusted to their individual caloric need, to a regular sleep/wake cycle and moderate exercise. Continuing this protocol, we administered 30 mg mirtazapine daily for 7 days. RESULTS: While no significant weight gain or changes in resting energy expenditure were observed under these conditions, hunger and appetite for sweets increased with mirtazapine, accompanied by a shift in energy substrate partitioning towards carbohydrate substrate preference as assessed by indirect calorimetry. Furthermore, with mirtazapine, insulin and C-peptide release increased in response to a standardized meal. CONCLUSION: Our findings provide important insights into weight-independent metabolic changes associated with mirtazapine and allow a better understanding of the long-term metabolic effects observed in patients treated with antidepressant drugs. CLINICALTRIALS: gov NCT00878540. FUNDING: Nothing to declare.

Characteristics and Determinants of Respiratory Event-Associated Leg Movements.

STUDY OBJECTIVES: To (1) replicate the recently described distribution of respiratory event-associated leg movements (rLMs) in participants with mild-to-moderate obstructive sleep apnea syndrome (OSAS), (2) explore global and local factors associated with the presence of rLMs, and (3) investigate differences related to OSAS severity and periodic leg movements during sleep (PLMS) status. METHODS: We randomly selected six groups of participants without restless legs syndrome (12-15 participants in each group), stratified by apnea-hypopnea index (AHI) severity (AHI 10-20, 20-30, and 30-40) and PLMS status (PLMS index <15 and >15 per hr) from the population-based HypnoLaus study that assessed full polysomnography at home in participants aged 40 to 80 years, randomly selected from the population register of the city of Lausanne, Switzerland. RESULTS: Our results confirmed the distribution of leg movement activity at the end of respiratory events (-2.0 to +10.25 s). Mixed effects logistic regression modeling rLM-probability showed that rLMs were more frequent in participants with high-PLMS, at the end of obstructive apneas (vs. hypopneas) and in the presence of arousals at the end of the events. In participants with high-PLMS, rLM-probability decreased with time of night and was more reduced during REM sleep (vs. NREM sleep), whereas the duration of the respiratory event had a significant effect only in participants with low-PLMS. CONCLUSIONS: We confirm the previously reported distribution of rLMs in participants with mild-to-moderate OSAS and our results suggest that rLMs are sensitive to both sleep-related and respiratory-related factors in a complex interaction with the PLMS status.