Pharmacological responsiveness of periodic limb movements in patients with restless legs syndrome: a systematic review and meta-analysis.

STUDY OBJECTIVES: Periodic limb movements during sleep (PLMS) are a frequent finding in restless legs syndrome, but their impact on sleep is still debated, as well the indication for treatment. We systematically reviewed the available literature to describe which drug categories are effective in suppressing PLMS, assessing their efficacy through a meta-analysis, when this was possible. METHODS: The review protocol was preregistered on PROSPERO (CRD42021175848), and the systematic search was conducted on and EMBASE (last searched on March 2020). We included original human studies, which assessed PLMS modification on drug treatment with a full-night polysomnography, through surface electrodes on each tibialis anterior muscle. When at least 4 studies were available on the same drug or drug category, we performed a random-effect model meta-analysis. RESULTS: Dopamine agonists like pramipexole and ropinirole resulted the most effective, followed by l-dopa and other dopamine agonists. Alpha2delta ligands are moderately effective as well opioids, despite available data on these drugs are much more limited than those on dopaminergic agents. Valproate and carbamazepine did not show a significant effect on PLMS. Clonazepam showed contradictory results. Perampanel and dypiridamole showed promising but still insufficient data. The same applies to iron supplementation. CONCLUSIONS: Dopaminergic agents are the most powerful suppressors of PLMS. However, most therapeutic trials in restless legs syndrome do not report objective polysomnographic findings, there is a lack of uniformity in presenting results on PLMS. Longitudinal polysomnographic interventional studies, using well-defined and unanimous scoring criteria and endpoints on PLMS are needed. CITATION: Riccardi S, Ferri R, Garbazza C, Miano S, Manconi M. Pharmacological responsiveness of periodic limb movements in patients with restless legs syndrome: a systematic review and meta-analysis. J Clin Sleep Med. 2023;19(4):811-822.

Sustained remission from perinatal depression after bright light therapy: A pilot randomised, placebo-controlled trial.

OBJECTIVE: Perinatal depression (PND) is a severe complication of pregnancy, affecting both mothers and newborns. Bright light therapy (BLT) has only been tested in a few studies for treating either antenatal or postnatal depression. We conducted a pilot trial to investigate the efficacy and safety of BLT for PND occurring at any time across the perinatal period. METHODS: A single-blind RCT was carried out in women with an EPDS >12 from the 2nd gestational trimester until 9 months postpartum. Participants received either 30-minutes morning BLT (10'000 lux) or dim red light (DRL, 19 lux) for 6 weeks. RESULTS: Twenty-two women were randomised to BLT (n = 11) or DRL (n = 11). Among those receiving BLT, 73% achieved remission (improvement ≥50%, EPDS score ≤ 12), in contrast to 27% in the DRL group (p = 0.04). A significant influence of time on EPDS score and group-time interaction emerged, with a greater reduction in the BLT-group across the follow-up period. No women in either group reported major side effects. CONCLUSION: Morning BLT induced a significant remission from PND as compared to DRL and this effect was maintained across the perinatal period. BLT showed an excellent safety profile and was well-tolerated, thus representing a valid therapeutic strategy in this vulnerable perinatal population.

Effects of light on human circadian rhythms, sleep and mood.

Humans live in a 24-hour environment, in which light and darkness follow a diurnal pattern. Our circadian pacemaker, the suprachiasmatic nuclei (SCN) in the hypothalamus, is entrained to the 24-hour solar day via a pathway from the retina and synchronises our internal biological rhythms. Rhythmic variations in ambient illumination impact behaviours such as rest during sleep and activity during wakefulness as well as their underlying biological processes. Rather recently, the availability of artificial light has substantially changed the light environment, especially during evening and night hours. This may increase the risk of developing circadian rhythm sleep-wake disorders (CRSWD), which are often caused by a misalignment of endogenous circadian rhythms and external light-dark cycles. While the exact relationship between the availability of artificial light and CRSWD remains to be established, nocturnal light has been shown to alter circadian rhythms and sleep in humans. On the other hand, light can also be used as an effective and noninvasive therapeutic option with little to no side effects, to improve sleep,mood and general well-being. This article reviews our current state of knowledge regarding the effects of light on circadian rhythms, sleep, and mood.

Chronobiology, sleep-related risk factors and light therapy in perinatal depression: the "Life-ON" project.

BACKGROUND: Perinatal depression (PND) has an overall estimated prevalence of roughly 12 %. Untreated PND has significant negative consequences not only on the health of the mothers, but also on the physical, emotional and cognitive development of their children. No certain risk factors are known to predict PND and no completely safe drug treatments are available during pregnancy and breastfeeding. Sleep and depression are strongly related to each other because of a solid reciprocal causal relationship. Bright light therapy (BLT) is a well-tested and safe treatment, effective in both depression and circadian/sleep disorders. METHODS: In a 3-year longitudinal, observational, multicentre study, about 500 women will be recruited and followed-up from early pregnancy (10-15 gestational week) until 12 months after delivery. The primary aim of the present study is to systematically explore and characterize risk factors for PND by prospective sleep assessment (using wrist actigraphy, polysomnography and various sleep questionnaires) and bloodbased analysis of potential markers during the perinatal period (Life-ON study). Secondary aims are to explore the relationship between specific genetic polymorphisms and PND (substudy Life-ON1), to investigate the effectiveness of BLT in treating PND (substudy Life-ON2) and to test whether a short term trial of BLT during pregnancy can prevent PND (substudy Life-ON3). DISCUSSION: The characterization of specific predictive and risk factors for PND may substantially contribute to improve preventive medical and social strategies for the affected women. The study results are expected to promote a better understanding of the relationship between sleep disorders and the development of PND and to confirm, in a large sample of women, the safety and efficacy of BLT both in prevention and treatment of PND. TRIAL REGISTRATION: ClinicalTrials.gov NCT02664467 . Registered 13 January 2016.

Non-24-Hour Sleep-Wake Disorder Revisited - A Case Study.

The human sleep-wake cycle is governed by two major factors: a homeostatic hourglass process (process S), which rises linearly during the day, and a circadian process C, which determines the timing of sleep in a ~24-h rhythm in accordance to the external light-dark (LD) cycle. While both individual processes are fairly well characterized, the exact nature of their interaction remains unclear. The circadian rhythm is generated by the suprachiasmatic nucleus ("master clock") of the anterior hypothalamus, through cell-autonomous feedback loops of DNA transcription and translation. While the phase length (tau) of the cycle is relatively stable and genetically determined, the phase of the clock is reset by external stimuli ("zeitgebers"), the most important being the LD cycle. Misalignments of the internal rhythm with the LD cycle can lead to various somatic complaints and to the development of circadian rhythm sleep disorders (CRSD). Non-24-hour sleep-wake disorders (N24HSWD) is a CRSD affecting up to 50% of totally blind patients and characterized by the inability to maintain a stable entrainment of the typically long circadian rhythm (tau > 24.5 h) to the LD cycle. The disease is rare in sighted individuals and the pathophysiology less well understood. Here, we present the case of a 40-year-old sighted male, who developed a misalignment of the internal clock with the external LD cycle following the treatment for Hodgkin's lymphoma (ABVD regimen, four cycles and AVD regimen, four cycles). A thorough clinical assessment, including actigraphy, melatonin profiles and polysomnography led to the diagnosis of non-24-hour sleep-wake disorders (N24HSWD) with a free-running rhythm of tau = 25.27 h. A therapeutic intervention with bright light therapy (30 min, 10,000 lux) in the morning and melatonin administration (0.5-0.75 mg) in the evening failed to entrain the free-running rhythm, although a longer treatment duration and more intense therapy might have been successful. The sudden onset and close timely connection led us to hypothesize that the chemotherapy might have caused a mutation of the molecular clock components leading to the observed elongation of the circadian period.