Photoperiodic regulation of dopamine signaling regulates seasonal changes in retinal photosensitivity in mice.

At high latitudes, approximately 10% of people suffer from depression during the winter season, a phenomenon known as seasonal affective disorder (SAD). Shortened photoperiod and/or light intensity during winter season are risk factors for SAD, and bright light therapy is an effective treatment. Interestingly, reduced retinal photosensitivity along with the mood is observed in SAD patients in winter. However, the molecular basis underlying seasonal changes in retinal photosensitivity remains unclear, and pharmacological intervention is required. Here we show photoperiodic regulation of dopamine signaling and improvement of short day-attenuated photosensitivity by its pharmacological intervention in mice. Electroretinograms revealed dynamic seasonal changes in retinal photosensitivity. Transcriptome analysis identified short day-mediated suppression of the Th gene, which encodes tyrosine hydroxylase, a rate-limiting enzyme for dopamine biosynthesis. Furthermore, pharmacological intervention in dopamine signaling through activation of the cAMP signaling pathway rescued short day-attenuated photosensitivity, whereas dopamine receptor antagonists decreased photosensitivity under long-day conditions. Our results reveal molecular basis of seasonal changes in retinal photosensitivity in mammals. In addition, our findings provide important insights into the pathogenesis of SAD and offer potential therapeutic interventions.

Light and Hormones in Seasonal Regulation of Reproduction and Mood.

Organisms that inhabit the temperate zone exhibit various seasonal adaptive behaviors, including reproduction, hibernation, molting, and migration. Day length, known as photoperiod, is the most noise-free and widely used environmental cue that enables animals to anticipate the oncoming seasons and adapt their physiologies accordingly. Although less clear, some human traits also exhibit seasonality, such as birthrate, mood, cognitive brain responses, and various diseases. However, the molecular basis for human seasonality is poorly understood. Herein, we first review the underlying mechanisms of seasonal adaptive strategies of animals, including seasonal reproduction and stress responses during the breeding season. We then briefly summarize our recent discovery of signaling pathways involved in the winter depression-like phenotype in medaka fish. We believe that exploring the regulation of seasonal traits in animal models will provide insight into human seasonality and aid in the understanding of human diseases such as seasonal affective disorder (SAD).

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.

Seasonal and meteorological associations with depressive symptoms in older adults: A geo-epidemiological study.

BACKGROUND: Given increased social and physiological vulnerabilities, older adults may be particularly susceptible to environmental influences on mood. Whereas the impact of season on mood is well described for adults, studies rarely extend to elders or include objective weather data. We investigated the impact of seasonality and meteorological factors on risk of current depressive symptoms in older adults. METHODS: We used data on 8027 participants from the first wave of The Irish Longitudinal Study of Ageing, a population-representative cohort of adults aged 50+. Depressive symptoms were recorded using the Centre for Epidemiological Studies Depression Scale. Season was defined according to the World Meteorological Organisation. Data on climate over the preceding thirty years, and temperature and rain over the preceding month, were provided by the Irish Meteorological Service and linked using Geographic Information Systems techniques to participant's geo-coded locations at a resolution of one kilometre. RESULTS: The highest levels of depressive symptoms were reported in winter and the lowest in spring (mean 6.56 [CI95% 6.09, 7.04] vs. 5.81 [CI95%: 5.40, 6.22]). In fully adjusted linear regression models, participants living in areas with higher levels of rainfall in the preceding and/or current calendar month had greater depressive symptoms (0.04 SE 0.02; p=0.039 per 10mm additional rainfall per month) while those living in areas with sunnier climates had fewer depressive symptoms (-2.67 SE 0.88; p=0.003 for every additional hour of average annual daily sunshine). LIMITATIONS: This was a cross-sectional analysis thus causality cannot be inferred; monthly rain and temperature averages were available only on a calendar month basis while monthly local levels of sunshine data were not available. CONCLUSIONS: Environmental cues may influence mood in older adults and thus have relevance for the recognition and treatment of depression in this age group.

Seasonal affective disorder in patients with chronic tinnitus.

OBJECTIVES/HYPOTHESIS: To investigate the point prevalence of SAD, degrees of anxiety/depression/sleep disturbance, and characteristics of tinnitus in patients with chronic tinnitus. STUDY DESIGN: Cross-sectional survey study. METHODS: From December 2012 to February 2014, 100 patients with chronic persistent or intermittent tinnitus (>3 months) were enrolled. Audiograms, tinnitograms, and Visual Analogue Scales (VAS) were used to assess tinnitus. Tinnitus Handicap Inventory (THI) assessment and questionnaires about anxiety/depression/sleep disturbance/SAD were administered. RESULTS: The male:female ratio was 48:52, and the mean age was 55.0 years. The numbers of patients with suspected SAD and subsyndromal SAD (S-SAD) were nine (9.0%) and 11 (11.0%), respectively. Winter was the most uncomfortable season. Nine patients had a catastrophic THI score >76 (11.1% in the SAD group, 27.3% in the S-SAD group, and 6.3% in the control group), suggesting a significant correlation between SAD/S-SAD and THI (P = .042). Audiogram, tinnitogram, VAS assessment, and sleep disturbance testing revealed no significant differences among the three groups. Anxiety tests yielded more abnormal findings in the SAD group than in the control group (State Anxiety Inventory score: 33.3% vs. 3.3%, respectively, P = .012; Trait Anxiety Inventory score: 22.2% vs. 1.3%, respectively, P = .002). Depression test scores were significantly higher in the SAD/S-SAD groups than in the control group (35.0% vs. 21.3%, respectively; P = .005). CONCLUSIONS: Suspected SAD and/or S-SAD in chronic tinnitus patients were correlated with THI, anxiety, and depression. Understanding SAD in tinnitus patients may be important to manage these patients effectively. LEVEL OF EVIDENCE: 4.

Photoperiodic responses of depression-like behavior, the brain serotonergic system, and peripheral metabolism in laboratory mice.

Seasonal affective disorder (SAD) is characterized by depression during specific seasons, generally winter. The pathophysiological mechanisms underlying SAD remain elusive due to a limited number of animal models with high availability and validity. Here we show that laboratory C57BL/6J mice display photoperiodic changes in depression-like behavior and brain serotonin content. C57BL/6J mice maintained under short-day conditions, as compared to those under long-day conditions, demonstrated prolonged immobility times in the forced swimming test with lower brain levels of serotonin and its precursor l-tryptophan. Furthermore, photoperiod altered multiple parameters reflective of peripheral metabolism, including the ratio of plasma l-tryptophan to the sum of other large neutral amino acids that compete for transport across the blood-brain barrier, responses of circulating glucose and insulin to glucose load, sucrose intake under restricted feeding condition, and sensitivity of the brain serotonergic system to peripherally administered glucose. These data suggest that the mechanisms underlying SAD involve the brain-peripheral tissue network, and C57BL/6J mice can serve as a powerful tool for investigating the link between seasons and mood.

Chronotype and personality factors of predisposition to seasonal affective disorder.

The study aimed to recognize the personality factors of a predisposition to seasonal mood fluctuations in a non-clinical sample. A group of 101 subjects (57 women, 44 men; mean age 26.4 ± 6.5 years) completed a battery of tests comprising a Seasonal Pattern Assessment Questionnaire (SPAQ), Chronotype Questionnaire (ChQ), a NEO-Five Factor Inventory and a Coping Inventory for Stressful Situations (CISS). A smaller sample (n = 44) completed a Winter Blues Scale (WBS). Women scored significantly higher than men in seasonality (p = 0.014), neuroticism (p = 0.049), agreeableness (p = 0.010), and avoidance-oriented coping style (p = 0.041). Subjects with seasonal affective disorder (SAD) (n = 41) or sub-SAD (n = 33), as diagnosed with SPAQ, exhibited higher levels of neuroticism (p = 0.017) and openness (p = 0.016) in comparison to non-SAD individuals. The latter declared a less frequent avoidance coping style. Both measures of seasonality, i.e. the SPAQ Global Seasonality Score and WBS, correlated significantly (r = 0.28 and 0.44, respectively) with the subjective amplitude of the circadian rhythm, as described with the "distinctness" scale of ChQ. Female gender, neuroticism and openness were confirmed as factors linked to seasonal mood variability. Additionally, the study revealed an association between susceptibility to mild winter depression and an avoidance-oriented coping style. The avoidance coping style was correlated positively with all the aspects of seasonality described by SPAQ (correlation coefficients from 0.21 to 0.34). Both sub-types of avoidance-oriented style, i.e. distraction and social diversion, were associated with marked subjective seasonal changes in sleep length, mood and the energy level. While the subjective amplitude of circadian rhythm proved to be connected with seasonality, the subjective acrophase of the rhythm (morningness-eveningness preference) did not. It may be hypothesized that sensitivity to natural environmental conditions/synchronizers is a separate individual trait shaping the subject's proneness to energy and mood changes both in diurnal and year scale, i.e. circadian and seasonal mood variations.

[Can exposure to light drive you crazy?]. / Voiko valo tehdä hulluksi?

Scientific research efforts have elucidated the mechanisms with which light exposure to the eyes influences the functions of the body. These reports have also provided information about the importance of light exposures in terms of health. Individuals with mood disorder in particular experience the seasonal changes in general wellbeing. Seasonal variation in mood and behavior is a complex phenotype, to which the photoperiod and ambient temperatures over the day and across the year contribute. Therefore, to evaluate, whether exposure to light can drive you mad, is not a simple task.

Depression-like responses induced by daytime light deficiency in the diurnal grass rat (Arvicanthis niloticus).

Seasonal Affective Disorder (SAD) is one of the most common mood disorders with depressive symptoms recurring in winter when there is less sunlight. The fact that light is the most salient factor entraining circadian rhythms leads to the phase-shifting hypothesis, which suggests that the depressive episodes of SAD are caused by misalignments between the circadian rhythms and the habitual sleep times. However, how changes in environmental lighting conditions lead to the fluctuations in mood is largely unknown. The objective of this study is to develop an animal model for some of the features/symptoms of SAD using the diurnal grass rats Arvichantis niloticus and to explore the neural mechanisms underlying the light associated mood changes. Animals were housed in either a 12∶12 hr bright light∶dark (1000lux, BLD) or dim light∶dark (50lux, DLD) condition. The depression-like behaviors were assessed by sweet-taste Saccharin solution preference (SSP) and forced swimming test (FST). Animals in the DLD group showed higher levels of depression-like behaviors compared to those in BLD. The anxiety-like behaviors were assessed in open field and light/dark box test, however no significant differences were observed between the two groups. The involvement of the circadian system on depression-like behaviors was investigated as well. Analysis of locomotor activity revealed no major differences in daily rhythms that could possibly contribute to the depression-like behaviors. To explore the neural substrates associated with the depression-like behaviors, the brain tissues from these animals were analyzed using immunocytochemistry. Attenuated indices of 5-HT signaling were observed in DLD compared to the BLD group. The results lay the groundwork for establishing a novel animal model and a novel experimental paradigm for SAD. The results also provide insights into the neural mechanisms underlying light-dependent mood changes.

Role of serotonin in seasonal affective disorder.

This review was prepared with an aim to show role of serotonin in seasonal affective disorder. Seasonal affective disorder, which is also called as winter depression or winter blues, is mood disorder in which persons with normal mental health throughout most of the year will show depressive symptoms in the winter or, less commonly, in the summer. Serotonin is an important endogenous neurotransmitter which also acts as neuromodulator. The least invasive, natural, and researched treatment of seasonal affective disorder is natural or otherwise is light therapy. Negative air ionization, which acts by liberating charged particles on the sleep environment, has also become effective in treatment of seasonal affective disorder.  

'D' for depression: any role for vitamin D? 'Food for Thought' II.

OBJECTIVE: While there has long been interest in any nutritional contribution to the onset and treatment of mood disorders, there has been increasing scientific evaluation of several candidate nutritional and dietary factors in recent years. In this paper, we overview research into any vitamin D insufficiency and deficiency contribution to depression. METHOD: The relevant literature was reviewed. RESULTS: Cross-sectional studies have identified associations between depression and low vitamin D levels, but studies have failed to clarify whether vitamin D deficiency is an antecedent cause, correlate or consequence of depression. While vitamin D deficiency and insufficiency have been linked with seasonal affective disorder, suggested associations have not been rigorously tested. There has been insufficient research to establish whether and when vitamin D supplementation should be considered as an augmentation strategy with antidepressant drugs. CONCLUSION: There is currently insufficient evidence to argue strongly for vitamin D supplementation in patients with depression, but such a strategy is worthy of consideration in depressed patients whose lifestyle and geographical residence may indicate a risk of vitamin D insufficiency--or where low vitamin D levels have been quantified.

Vitamin D and depression.

Vitamin D is an essential nutrient proven to be important for bone health. It has other physiological functions, and there are plausible reasons for investigating vitamin D in depressive disorders. Some cross-sectional clinical and epidemiologic studies, but not all studies, have found that low levels of vitamin D are significantly associated with higher levels of depressive symptoms or with a depression diagnosis. However, cross-sectional studies cannot establish causality, and the methodology of these studies has been criticized. Due to the poor quality of the treatment studies, the effectiveness of vitamin D for depression cannot be adequately assessed. Current evidence does not definitively demonstrate that vitamin D deficiency is a cause of or risk for developing depression or that vitamin D is an effective therapy for depression.

[Diagnostic features, epidemiology, and pathophysiology of seasonal affective disorder]. / A szezonális depresszió patofiziológiája, diagnosztikai és epidemiológiai jellegzetességei.

Seasonal Affective Disorder (SAD) is characterized by patterns of major depressive episodes that occur and remit with the change of seasons. Two seasonal patterns have been identified: summer-type depression with typical depressive signs and symptoms, and winter-type depression with atypical features of depression. In the subsyndromal form of SAD (S-SAD) symptoms are milder, although vegetative symptoms are clinically significant. SAD needs to be differentiated from atypical depression, cyclothymic disorder, and dysthymia or chronic MDD which may be characterized by a winter worsening of symptoms. Full remission of symptoms must occur after the passing of the season for the disorder to merit the diagnosis of SAD. The mean prevalence of SAD in the temperate zone is 3 to 10%, while that of S-SAD is 6 to 20%. In Hungarian general population the occurrence of SAD is 4.6%, and S-SAD is 7.2%. The pathophysiology of SAD seems to be heterogeneous, studies suggest abnormal circadian rhythm and neurotransmitter function (phase shift hypothesis, role of serotonin, dopamin and norepinephrine). Genetic studies focusing on candidate genes involve 5-HTR2A, 5-HTR2C, DRD4, G protein, and clock-related genes.

Vitamin D, light and mental health.

Vitamin D receptors and vitamin D metabolizing enzymes are present in the central nervous system. Calcitriol (the active vitamin D hormone) affects numerous neurotransmitters and neurotrophic factors, relevant for mental disorders. In the case of depressive disorders, considerable evidence supports a role of suboptimal vitamin D levels. However, the data are not conclusive and further studies are necessary. Especially, the relative importance of the pineal-melatonin system versus the vitamin D-endocrine system for the pathogenesis of seasonal affective disorders is presently unresolved. Two diagnoses, schizophrenia and autism, have been hypothetically linked to developmental (prenatal) vitamin D deficiency, however, also in adult patients, low levels have been reported, supporting the notion that vitamin D deficiency may not only be a predisposing developmental factor but also relate to the adult patients' psychiatric state. Two cases are described, whose psychiatric improvement coincided with effective treatment of vitamin D deficiency.

[Etiopathology and therapy of seasonal affective disorder]. / A szezonális depresszió etiopatológiája és terápiás lehetöségei.

To understand the etiology of seasonal affective disorder (SAD) heterogeneous biological, psychological and environmental mechanisms needs to be considered. The aim of our study was to review theoretical hypotheses and therapeutic possibilities for seasonal affective disorder, which focus on alterations of circadian rhythms and monoaminergic neurotransmitter function as well as the role of vitamin D3 and possible implications of the cognitive-behavioral model. These discrepant hypotheses are insufficient alone to interpret the pathophysiology of SAD, but the integrative dual vulnerability hypothesis is an option to explain emergence of seasonal affective disorder. In addition to summarizing theoretical approaches we also review and evaluate the therapeutic possibilities derive form these hypotheses. In practice the most effective treatment for SAD is the combination of light therapy, antidepressants and psychotherapy.

Somatic therapies for seasonal affective disorder.

The syndrome of seasonal affective disorder (SAD) is defined as a history of major depressive episodes that recur regularly at a particular time of year, typically fall or winter, and completely remit in the spring. It has been hypothesized that photoperiod-related changes in the duration of melatonin secretion may be involved in the seasonal mood cycles of SAD in human beings, suggesting that artificial bright lights (mimicking daylight) might be used to treat SAD. This article reviews studies on the use of bright light therapy and antidepressant medication for the treatment of SAD. Studies have found that bright light therapy and antidepressant medication are both effective for the treatment of SAD. Bright light therapy may also be effective for treating nonseasonal depression.