Preliminary evidence that daily light exposure enhances the antibody response to influenza vaccination in patients with dementia.

Enhancing lighting conditions in institutions for individuals with dementia improves their sleep, circadian rhythms and well-being. Here, we report first findings that exposure to brighter light during daytime may support the immune response to the annual influenza vaccination. Eighty older institutionalised patients suffering from dementia (54 women and 26 men) continuously wore an activity tracker for 8 weeks to assess individual light exposure and rest-activity cycles. We analysed the patients' immune response from two blood samples taken before and 4 weeks after the annual influenza vaccination. Individual antibody concentrations to three influenza virus strains (H3N2, H1N1, IB) were quantified via hemagglutination inhibition assays. By quantifying individual light exposure profiles (including daylight), we classified the patients into a low and a high light exposure group based on a median illuminance of 392.6 lux. The two light exposure groups did not differ in cognitive impairment severity, age or gender distribution. However, patients in the high light exposure group showed a significantly greater circadian rest-activity amplitude (i.e., more daytime activity and less nighttime activity) along with a significantly greater antibody titer increase to the H3N2 vaccine than patients in the low light exposure group, despite similar pre-vaccination concentrations. Sufficient seroprotective responses to all three influenza virus strains were attained for ≥75% of participants. These data provide preliminary evidence for a potentially enhanced immune response in patients with dementia when they received more daily light. Future studies are needed to determine whether regular daily light exposure may have beneficial effects on the human immune system, either directly or via a stabilising circadian sleep-wake rhythms.

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.

[Chronotherapy of affective disorders: principles and clinical aspects]. / Chronotherapie affektiver Störungen: Grundlagen und klinische Aspekte.

BACKGROUND: Chronobiological processes play a critical role in the initial manifestation and course of affective disorders. Chronotherapeutic agents aim to improve sleep-wake cycle disturbances and affective symptoms by modulating the chronobiological neuronal circuitry. OBJECTIVE: To review the different chronotherapeutic procedures, the current evidence situation and recommendations for clinical applications. METHOD: Narrative review. RESULTS: Chronotherapeutic interventions for patients with affective disorders can be nonpharmacological, e.g., light therapy, sleep deprivation, sleep phase advance and dark therapy, pharmacological in the form of melatonin and psychological consisting of interpersonal and social rhythm therapy or cognitive behavioral therapy for insomnia modified for patients with bipolar disorder. Nearly all these interventions show promising data regarding their efficacy in acute depressive or manic episodes or as maintenance therapy. For melatonin, there is less evidence for improvement of affective symptoms than for stabilizing the sleep-wake cycle. Some interventions are well-suited for an outpatient setting, e.g., light therapy, dark therapy and psychotherapy, while others, such as triple chronotherapy consisting of sleep deprivation, sleep phase advance and light therapy, are more suited for in-patient treatment. CONCLUSION: Chronotherapeutic interventions are versatile in their application and can be combined with each other and used concomitantly with classical psychopharmacotherapy. With a benign side effect profile and good evidence for efficacy, they could play an important role in the treatment of affective disorders; however, this potential is used too rarely in the clinical context.

CME: Light Therapy: Why, What, for Whom, How, and When (And a Postscript about Darkness).

Light therapy has become established as an evidence-based treatment for Seasonal Affective Disorder. Light impacts the timing and stability of circadian rhythms as expressed in sleep, mood, alertness, and cognition. Forty years of clinical trials and open treatment have led to guidelines for patient selection, using light alone or in combination with antidepressants (or lithium for bipolar depression). Mood and sleep disturbances can also respond to adjunct light therapy in a broader set of psychiatric, neurologic and medical illnesses. We specify criteria for choice of treatment devices: optimum dose (10,000 lux), spectrum (white light), exposure duration (30-60 minutes) and timing (early morning). Protocol adjustment requires continual monitoring with attention to rate of improvement and management of potential side effects.

The relevance of daylight for humans.

Daylight is ubiquitous and is crucial for mammalian vision as well as for non-visual input to the brain via the intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the photopigment melanopsin. The ipRGCs project to the circadian clock in the suprachiasmatic nuclei and thereby ensure entrainment to the 24-hour day-night cycle, and changes in daylength trigger the appropriate seasonal behaviours. The ipRGCs also project to the perihabenular nucleus and surrounding brain regions that modulate mood, stress and learning in animals and humans. Given that light has strong direct effects on mood, cognition, alertness, performance, and sleep, light can be considered a "drug" to treat many clinical conditions. Light therapy is already well established for winter and other depressions and circadian sleep disorders. Beyond visual and non-visual effects via the retina, daylight contributes to prevent myopia in the young by its impact on eye development, and is important for Vitamin D synthesis and bone health via the skin. The sun is the most powerful light source and, dependent on dose, its ultraviolet radiance is toxic for living organisms and can be used as a disinfectant. Most research involves laboratory-based electric light, without the dynamic and spectral changes that daylight undergoes moment by moment. There is a gap between the importance of daylight for human beings and the amount of research being done on this subject. Daylight is taken for granted as an environmental factor, to be enjoyed or avoided, according to conditions. More daylight awareness in architecture and urban design beyond aesthetic values and visual comfort may lead to higher quality work and living environments. Although we do not yet have a factual basis for the assumption that natural daylight is overall "better" than electric light, the environmental debate mandates serious consideration of sunlight not just for solar power but also as biologically necessary for sustainable and healthy living.

The Role of Daylight for Humans: Gaps in Current Knowledge.

Daylight stems solely from direct, scattered and reflected sunlight, and undergoes dynamic changes in irradiance and spectral power composition due to latitude, time of day, time of year and the nature of the physical environment (reflections, buildings and vegetation). Humans and their ancestors evolved under these natural day/night cycles over millions of years. Electric light, a relatively recent invention, interacts and competes with the natural light-dark cycle to impact human biology. What are the consequences of living in industrialised urban areas with much less daylight and more use of electric light, throughout the day (and at night), on general health and quality of life? In this workshop report, we have classified key gaps of knowledge in daylight research into three main groups: (I) uncertainty as to daylight quantity and quality needed for "optimal" physiological and psychological functioning, (II) lack of consensus on practical measurement and assessment methods and tools for monitoring real (day) light exposure across multiple time scales, and (III) insufficient integration and exchange of daylight knowledge bases from different disciplines. Crucial short and long-term objectives to fill these gaps are proposed.

Perspectives in affective disorders: Clocks and sleep.

Mood disorders are often characterised by alterations in circadian rhythms, sleep disturbances and seasonal exacerbation. Conversely, chronobiological treatments utilise zeitgebers for circadian rhythms such as light to improve mood and stabilise sleep, and manipulations of sleep timing and duration as rapid antidepressant modalities. Although sleep deprivation ("wake therapy") can act within hours, and its mood-elevating effects be maintained by regular morning light administration/medication/earlier sleep, it has not entered the regular guidelines for treating affective disorders as a first-line treatment. The hindrances to using chronotherapeutics may lie in their lack of patentability, few sponsors to carry out large multi-centre trials, non-reimbursement by medical insurance and their perceived difficulty or exotic "alternative" nature. Future use can be promoted by new technology (single-sample phase measurements, phone apps, movement and sleep trackers) that provides ambulatory documentation over long periods and feedback to therapist and patient. Light combinations with cognitive behavioural therapy and sleep hygiene practice may speed up and also maintain response. The urgent need for new antidepressants should hopefully lead to reconsideration and implementation of these non-pharmacological methods, as well as further clinical trials. We review the putative neurochemical mechanisms underlying the antidepressant effect of sleep deprivation and light therapy, and current knowledge linking clocks and sleep with affective disorders: neurotransmitter switching, stress and cortico-limbic reactivity, clock genes, cortical neuroplasticity, connectomics and neuroinflammation. Despite the complexity of multi-system mechanisms, more insight will lead to fine tuning and better application of circadian and sleep-related treatments of depression.

Why Should We Abolish Daylight Saving Time?

Local and national governments around the world are currently considering the elimination of the annual switch to and from Daylight Saving Time (DST). As an international organization of scientists dedicated to studying circadian and other biological rhythms, the Society for Research on Biological Rhythms (SRBR) engaged experts in the field to write a Position Paper on the consequences of choosing to live on DST or Standard Time (ST). The authors take the position that, based on comparisons of large populations living in DST or ST or on western versus eastern edges of time zones, the advantages of permanent ST outweigh switching to DST annually or permanently. Four peer reviewers provided expert critiques of the initial submission, and the SRBR Executive Board approved the revised manuscript as a Position Paper to help educate the public in their evaluation of current legislative actions to end DST.

Effects of a dawn-dusk simulation on circadian rest-activity cycles, sleep, mood and well-being in dementia patients.

Light is the most powerful "zeitgeber" signal to synchronize circadian sleep-wake cycles. In dementia, these rhythms are often fragmented - probably due to loss of neuronal function of the suprachiasmatic nuclei (the biological "master clock" in the brain) and/or weakness of external zeitgebers. We investigated the effects of a prototype dawn-dusk simulator (DDS) on circadian rest-activity cycles, sleep, mood and well-being in a balanced crossover design during fall and winter in 20 institutionalized patients with dementia (86 ±â€¯6 y, 17 f). All participants had one baseline week followed by exposure to individually timed DDS over their beds for 7-8 weeks. They spent 8 weeks without DDS as a control. Mood, self-reliant daily activity, social behavior, agitation, and quality of life were assessed by standardized questionnaires and visual analogue scales, regularly rated by trained caregivers. Circadian and sleep characteristics of their rest-activity cycles were analyzed by actimetry over 17 weeks. DDS exposure led to significantly better mood in the morning hours after waking. The effects were most pronounced in the second 4 weeks with DDS, indicating that positive effects emerged gradually. Differences in circadian rest-activity cycles and sleep were mainly age-dependent. We found statistically significant correlations between measures of higher quality of life and better mood, greater alertness and circadian rhythm stability. We conclude that continuous, long-term application of dawn-dusk simulation at the sleep-wake transitions appears to increase external zeitgeber strength in institutionalized patients with dementia. The DDS may provide an effective, non-invasive tool to improve mood and ameliorate patients' quality of life.

Prevalence of seasonal depression in a prospective cohort study.

The prevalence of autumn/winter seasonality in depression has been documented in the longitudinal Zurich cohort study by five comprehensive diagnostic interviews at intervals over more than 20 years (N = 499). Repeated winter major depressive episodes (MDE-unipolar + bipolar) showed a prevalence of 3.44% (5× more women than men), whereas MDE with a single winter episode was much higher (9.96%). A total of 7.52% suffered from autumn/winter seasonality in major and minor depressive mood states. The clinical interviews revealed novel findings: high comorbidity of Social Anxiety Disorder and Agoraphobia within the repeated seasonal MDE group, high incidence of classic diurnal variation of mood (with evening improvement), as well as a high rate of oversensitivity to light, noise, or smell. Nearly twice as many of these individuals as in the other MDE groups manifested the syndrome of atypical depression (DSM-V), which supports the prior description of seasonal affective disorder (SAD) as presenting primarily atypical symptoms (which include hypersomnia and increase in appetite and weight). This long-term database of regular structured interviews provides important confirmation of SAD as a valid diagnosis, predominantly found in women, and with atypical vegetative symptoms.

Seasonality in affective disorders.

Humans retain neurobiological responses to circadian day-night cycles and seasonal changes in daylength in spite of a life-style usually independent of dawn-dusk signals. Seasonality has been documented in many functions, from mood to hormones to gene expression. Research on seasonal affective disorder initiated the first use of timed bright light as therapy, a treatment since extended to non-seasonal major depression and sleep-wake cycle disturbances in many psychiatric and medical illnesses. The growing recognition that sufficient light is important for psychological and somatic well-being is leading to the development of novel lighting solutions in architecture as well as focus on a more conscious exposure to natural daylight.

Stabilising sleep for patients admitted at acute crisis to a psychiatric hospital (OWLS): an assessor-blind pilot randomised controlled trial.

BACKGROUND: When patients are admitted onto psychiatric wards, sleep problems are highly prevalent. We carried out the first trial testing a psychological sleep treatment at acute admission (Oxford Ward sLeep Solution, OWLS). METHODS: This assessor-blind parallel-group pilot trial randomised patients to receive sleep treatment at acute crisis [STAC, plus standard care (SC)], or SC alone (1 : 1). STAC included cognitive-behavioural therapy (CBT) for insomnia, sleep monitoring and light/dark exposure for circadian entrainment, delivered over 2 weeks. Assessments took place at 0, 2, 4 and 12 weeks. Feasibility outcomes assessed recruitment, retention of participants and uptake of the therapy. Primary efficacy outcomes were the Insomnia Severity Index and Warwick-Edinburgh Mental Wellbeing Scale at week 2. Analyses were intention-to-treat, estimating treatment effect with 95% confidence intervals. RESULTS: Between October 2015 and July 2016, 40 participants were recruited (from 43 assessed eligible). All participants offered STAC completed treatment (mean sessions received = 8.6, s.d. = 1.5). All participants completed the primary end point. Compared with SC, STAC led to large effect size (ES) reductions in insomnia at week 2 (adjusted mean difference -4.6, 95% CI -7.7 to -1.4, ES -0.9), a small improvement in psychological wellbeing (adjusted mean difference 3.7, 95% CI -2.8 to 10.1, ES 0.3) and patients were discharged 8.5 days earlier. One patient in the STAC group had an adverse event, unrelated to participation. CONCLUSIONS: In this challenging environment for research, the trial was feasible. Therapy uptake was high. STAC may be a highly effective treatment for sleep disturbance on wards with potential wider benefits on wellbeing and admission length.

Bright Light Delights: Effects of Daily Light Exposure on Emotions, Restactivity Cycles, Sleep and Melatonin Secretion in Severely Demented Patients.

OBJECTIVE: We tested whether the effects of a dynamic lighting system are superior to conventional lighting on emotions, agitation behaviour, quality of life, melatonin secretion and circadian restactivity cycles in severely demented patients. As a comparison, an age matched control patient group was exposed to conventional lighting. For none of the output measures were significant differences between the two lighting conditions found during the 8 study weeks in fall/winter. METHODS: Thus, we divided the patient cohort (n = 89) into two groups, solely based on the median of their daily individual light exposure. Patients with higher average daily light exposure (>417 lx) showed significantly longer emotional expressions of pleasure and alertness per daily observations than patients with lower daily light exposure. Moreover, they had a higher quality of life, spent less time in bed, went to bed later and initiated their sleep episodes later, even though the two groups did not differ with respect to age, severity of cognitive impairment and mobility. In general, men were more agitated, had shorter sleep with more wake episodes, had a lower circadian amplitude of relative rest-wake activity and interdaily circadian stability than women. In particular, lower daily light exposures significantly predicted lower circadian amplitudes of rest-activity cycles in men but not in women. This may indicate sex specific susceptibility to daily light exposures for rest-activity regulation in older demented patients. RESULTS: Our results provide evidence that a higher daily light exposure has beneficial effects on emotions and thus improved quality of life in a severely demented patient group.

Subjective Mood in Young Unmedicated Depressed Women under High and Low Sleep Pressure Conditions.

Diurnal mood variations are one of the core symptoms in depression, and total sleep deprivation (SD) can induce rapid, short-lasting clinical improvement in depressed patients. Here, we investigated if differential sleep pressure conditions impact on subjective mood levels in young women with major depressive disorder (MDD) without sleep disturbances, and in healthy controls. Eight healthy and eight MDD women underwent 40-h SD (high sleep pressure) and 40-h multiple NAP (low sleep pressure) protocols under constant routine conditions during which subjective mood was assessed every 30-min. MDD women rated overall significantly worse mood than controls, with minimal values for both groups during the biological night (ca. 4 a.m.), under high and low sleep pressure conditions. During SD, nighttime mood ratings in MDD women were lower than in controls and partially recovered during the second day of SD, but never attained control levels. The degree of this diurnal time-course in mood under SD correlated positively with sleep quality in MDD women. Our data indicate that MDD women without sleep disturbances did not exhibit a SD-induced antidepressant response, suggesting that the mood enhancement response to sleep deprivation might be related to the co-existence of sleep disturbances, which is an association that remains to be fully established.

Melatonin rhythms in renal transplant recipients with sleep-wake disturbances.

We assessed salivary melatonin levels in renal transplant (RTx) recipients who participated in a randomised, multicentre wait-list controlled trial on the effect of bright light therapy on their sleep and circadian rhythms. A large proportion of RTx recipients in our cohort had unexpectedly low melatonin values, which precluded calculation of the dim-light melatonin onset (DLMO) as a circadian marker. Thus, the aim of this post hoc analysis was to describe the melatonin profile of home-dwelling RTx recipients diagnosed with sleep-wake disturbances (SWDs). The participants were characterised by means of sleep questionnaires, validated psychometric instruments [Pittsburgh sleep quality Index (PSQI), Epworth sleepiness scale (ESS), Morningness-Eveningness Questionnaire (MEQ) and Depression, Anxiety and Stress Scale (DASS)] in addition to melatonin assay in saliva. Data were analysed with descriptive statistics and group comparisons made with appropriate post hoc tests. RTx recipients [n = 29 (aged 54.83 ± 13.73, transplanted 10.62 ± 6.84 years ago)] were retrospectively grouped into two groups: RTx recipients whose dim light melatonin onset (DLMO) could be calculated (n = 11) and those whose DLMO could not be calculated (n = 18). RTx recipients having a measurable DLMO had a number of differences from those without DLMO: they were younger [46.4 ± 14.9 compared to 60.0 ± 10.3 (p = .007)], had higher haemoglobin values [135.36 ± 12.01 versus 122.82 ± 11.56 (p = .01)], less anxiety [4 (0;8) versus 12 (6.5;14) (p = .021)] and a better overall sense of coherence [SOC Score: 71.09 ± 12.78 versus 56.28 ± 15.48 (p = 0.013)]. These results suggest that RTx recipients whose DLMO could be calculated have less health impairments, underlying the relevance of a stable circadian system.

The two-process model of sleep regulation: a reappraisal.

In the last three decades the two-process model of sleep regulation has served as a major conceptual framework in sleep research. It has been applied widely in studies on fatigue and performance and to dissect individual differences in sleep regulation. The model posits that a homeostatic process (Process S) interacts with a process controlled by the circadian pacemaker (Process C), with time-courses derived from physiological and behavioural variables. The model simulates successfully the timing and intensity of sleep in diverse experimental protocols. Electrophysiological recordings from the suprachiasmatic nuclei (SCN) suggest that S and C interact continuously. Oscillators outside the SCN that are linked to energy metabolism are evident in SCN-lesioned arrhythmic animals subjected to restricted feeding or methamphetamine administration, as well as in human subjects during internal desynchronization. In intact animals these peripheral oscillators may dissociate from the central pacemaker rhythm. A sleep/fast and wake/feed phase segregate antagonistic anabolic and catabolic metabolic processes in peripheral tissues. A deficiency of Process S was proposed to account for both depressive sleep disturbances and the antidepressant effect of sleep deprivation. The model supported the development of novel non-pharmacological treatment paradigms in psychiatry, based on manipulating circadian phase, sleep and light exposure. In conclusion, the model remains conceptually useful for promoting the integration of sleep and circadian rhythm research. Sleep appears to have not only a short-term, use-dependent function; it also serves to enforce rest and fasting, thereby supporting the optimization of metabolic processes at the appropriate phase of the 24-h cycle.