Effects of erythropoietin on cognitive impairment and prefrontal cortex activity across affective disorders: A randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Persistent cognitive impairment is frequent across bipolar disorder (BD) and major depressive disorder (MDD), highlighting an urgent need for pro-cognitive treatments. AIM: This study investigated effects of erythropoietin (EPO) on cognitive impairment and dorsal prefrontal cortex (dPFC) activity in affective disorders. METHODS: In this randomized, double-blinded, placebo-controlled trial, cognitively impaired patients with remitted BD or MDD received 1 weekly recombinant human EPO (40,000 IU/mL) or saline infusion for a 12-week period. Assessments were conducted at baseline, after 2 weeks of treatment (week 3), immediately after treatment (week 13) and at 6-months follow-up. Participants underwent functional MRI during performance on a n-back working memory (WM) task at baseline and week 3, and for a subgroup 6 weeks post-treatment (week 18). The primary outcome was a cognitive composite score at week 13, whereas secondary outcomes comprised sustained attention and functioning. WM-related dPFC activity was a tertiary outcome. RESULTS: Data were analysed for 101 of the 103 included patients (EPO, n = 58; saline, n = 43). There were no effects of EPO over saline on any cognitive or functional outcomes or on WM-related dPFC activity. CONCLUSIONS: The absence of treatment-related changes in cognition and neural activity was unexpected and contrasts with multiple previous preclinical and clinical studies. It is possible that the lack of effects resulted from a recent change in the manufacturing process for EPO. Nevertheless, the findings support the validity of dPFC target engagement as a biomarker model for pro-cognitive effects, according to which treatments that do not improve cognition should not modulate dPFC activity. TRIAL REGISTRATIONS: EudraCT no.: 2016-004023-24; ClinicalTrials.gov identifier: NCT03315897.

BLUES - stabilizing mood and sleep with blue blocking eyewear in bipolar disorder - a randomized controlled trial study protocol.

INTRODUCTION: Chronotherapeutic interventions for bipolar depression and mania are promising interventions associated with rapid response and benign side effect profiles. Filtering of biologically active short wavelength (blue) light by orange tinted eyewear has been shown to induce antimanic and sleep promoting effects in inpatient mania. We here describe a study protocol assessing acute and long-term stabilizing effects of blue blocking (BB) glasses in outpatient treatment of bipolar disorder. PATIENTS AND METHODS: A total of 150 outpatients with bipolar disorder and current symptoms of (hypo)-mania will be randomized 1:1 to wear glasses with either high (99%) (intervention group) or low (15%) (control group) filtration of short wavelength light (<500 nm). Following a baseline assessment including ratings of manic and depressive symptoms, sleep questionnaires, pupillometric evaluation and 48-h actigraphy, participants will wear the glasses from 6 PM to 8 AM for 7 consecutive days. The primary outcome is the between group difference in change in Young Mania Rating Scale scores after 7 days of intervention (day 9). Following the initial treatment period, the long-term stabilizing effects on mood and sleep will be explored in a 3-month treatment paradigm, where the period of BB treatment is tailored to the current symptomatology using a 14-h antimanic schedule during (hypo-) manic episodes (BB glasses or dark bedroom from 6 PM to 8 AM) and a 2-h maintenance schedule (BB glasses on two hours prior to bedtime/dark bedroom) during euthymic and depressive states.The assessments will be repeated at follow-up visits after 1 and 3 months. Throughout the 3-month study period, participants will perform continuous daily self-monitoring of mood, sleep and activity in a smartphone-based app. Secondary outcomes include between-group differences in actigraphic sleep parameters on day 9 and in day-to-day instability in mood, sleep and activity, general functioning and objective sleep markers (actigraphy) at weeks 5 and 15. TRIAL REGISTRATION: The trial will be registered at www.clinicaltrials.gov prior to initiation and has not yet received a trial reference. ADMINISTRATIVE INFORMATION: The current paper is based on protocol version 1.0_31.07.23. Trial sponsor: Lars Vedel Kessing.

[Light therapy for depression].

Artificial light has been used as a treatment for depression since the 1980s. The indications have since broadened from seasonal depression to non-seasonal depression including bipolar, geriatric, and chronic depression. Light acts through retinohypothalamic connections from specialised retinal neurons to central nuclei involved in circadian and emotional regulation. This review illuminates the current strategies directed towards utilising natural daylight or electric lighting mimicking the dynamic spectrum and intensity of daylight to improve treatment in modern hospital settings.

Light therapy for seasonal affective disorder in visual impairment and blindness - a pilot study.

OBJECTIVE: Seasonal and non-seasonal depression are prevalent conditions in visual impairment (VI). We assessed the effects and side effects of light therapy in persons with severe VI/blindness who experienced recurrent depressive symptoms in winter corresponding to seasonal affective disorder (SAD) or subsyndromal SAD (sSAD). RESULTS: We included 18 persons (11 with severe VI, 3 with light perception and 4 with no light perception) who met screening criteria for sSAD/SAD in a single-arm, assessor-blinded trial of 6 weeks light therapy. In the 12 persons who completed the 6 weeks of treatment, the post-treatment depression score was reduced (p < 0.001), and subjective wellbeing (p = 0.01) and sleep quality were improved (p = 0.03). In 6/12 participants (50%), the post-treatment depression score was below the cut-off set for remission. In four participants with VI, side effects (glare or transiently altered visual function) led to dropout or exclusion. CONCLUSION: Light therapy was associated with a reduction in depressive symptoms in persons with severe VI/blindness. Eye safety remains a concern in persons with residual sight.

Melanopsin-mediated pupillary responses in bipolar disorder-a cross-sectional pupillometric investigation.

BACKGROUND: Visible light, predominantly in the blue range, affects mood and circadian rhythm partly by activation of the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). The light-induced responses of these ganglion cells can be evaluated by pupillometry. The study aimed to assess the blue light induced pupil constriction in patients with bipolar disorder (BD). METHODS: We investigated the pupillary responses to blue light by chromatic pupillometry in 31 patients with newly diagnosed bipolar disorder, 22 of their unaffected relatives and 35 healthy controls. Mood state was evaluated by interview-based ratings of depressive symptoms (Hamilton Depression Rating Scale) and (hypo-)manic symptoms (Young Mania Rating Scale). RESULTS: The ipRGC-mediated pupillary responses did not differ across the three groups, but subgroup analyses showed that patients in remission had reduced ipRGC-mediated responses compared with controls (9%, p = 0.04). Longer illness duration was associated with more pronounced ipRGC-responses (7% increase/10-year illness duration, p = 0.02). CONCLUSIONS: The ipRGC-mediated pupil response to blue light was reduced in euthymic patients compared with controls and increased with longer disease duration. Longitudinal studies are needed to corroborate these potential associations with illness state and/or progression.

Mood and behavior seasonality in glaucoma; assessing correlations between seasonality and structure and function of the retinal ganglion cells.

AIM: In glaucoma, depression and disturbed sleep has been associated with degeneration of the intrinsically photosensitive retinal ganglion cells, that mediate non-image forming effects of light such as regulation of circadian rhythm, alertness and mood. In this study we assessed associations between seasonal mood and behavior variation and retinal ganglion cell damage in outpatients with glaucoma. METHODS: The seasonal pattern assessment questionnaire was administered to outpatients with glaucoma. Data on visual field defects identified by autoperimetry and retinal nerve fiber layer thickness visualized by ocular coherence tomography were collected from patient charts. The correlations between seasonality and retinal damage were tested and the adjusted effects of retinal function on seasonality were evaluated in a linear regression model. RESULTS: In total, 113 persons completed the questionnaire. Of these, 4% fulfilled the criteria for seasonal affective disorder (SAD) and 8% for subsyndromal seasonal affective disorder (sSAD). Mean global seasonal score was 4.3. There were no significant correlations between seasonality and either visual field or retinal nerve fiber layer thickness. In the adjusted analysis there were trends toward differential effects of visual field on seasonality in subgroups with different sex and type of glaucoma. CONCLUSION: There were no strong associations between seasonality and visual field or retinal nerve fiber layer thickness. Sex, age and glaucoma subtype may modify light effects on complex regulatory systems.

Dynamic LED-light versus static LED-light for depressed inpatients: study protocol for a randomised clinical study.

INTRODUCTION: Retrospective studies conducted in psychiatric inpatient wards have shown a relation between the intensity of daylight in patient rooms and the length of stay, pointing to an antidepressant effect of ambient lighting conditions. Light therapy has shown a promising antidepressant effect when administered from a light box. The emergence of light-emitting diode (LED) technology has made it possible to build luminaires into rooms and to dynamically mimic the spectral and temporal distribution of daylight. The objective of this study is to investigate the antidepressant efficacy of a newly developed dynamic LED-lighting system installed in an inpatient ward. METHODS AND ANALYSIS: In all, 150 inpatients with a major depressive episode, as part of either a major depressive disorder or as part of a bipolar disorder, will be included. The design is a two-arm 1:1 randomised study with a dynamic LED-lighting arm and a static LED-lighting arm, both as add-on to usual treatment in an inpatient psychiatric ward. The primary outcome is the baseline adjusted score on the 6-item Hamilton Depression Rating Scale at week 3. The secondary outcomes are the mean score on the Suicidal Ideation Attributes Scale at week 3, the mean score on the 17-item Hamilton Depression Rating Scale at week 3 and the mean score on the World Health Organisation Quality of Life-BREF (WHOQOL-BREF) at week 3. The spectral distribution of daylight and LED-light, with a specific focus on light mediated through the intrinsically photosensitive retinal ganglion cells, will be measured. Use of light luminaires will be logged. Assessors of Hamilton Depression Rating Scale scores and data analysts will be blinded for treatment allocation. The study was initiated in May 2019 and will end in December 2021. ETHICS AND DISSEMINATION: No ethical issues are expected. Results will be published in peer-reviewed journals, disseminated electronically and in print and presented at symposia. TRIAL REGISTRATION NUMBER: NCT03821506; Pre-results.

[Psychiatry and circadian rhythms].

Circadian and seasonal rhythm disturbances are prominent in patients with psychiatric disorders. Properly timed and dosed light of specific spectral composition stabilises mood and sleep through serotonergic mechanisms and through input to the master circadian clock in the hypothalamus. Correctly administered, light can be used as an effective treatment for seasonal and non-seasonal depression and for stabilising the sleep-wake cycle. Blocking blue light in the evening may provide a non-pharmacological anti-manic tool. Current developments use dynamic lighting built into somatic and psychiatric hospitals to maximise the beneficial effects of light.

High prevalence of seasonal affective disorder among persons with severe visual impairment.

BACKGROUND: Light severely affects the occurrence of seasonal affective disorder (SAD). AIMS: To compare the prevalence of SAD in persons with severe visual impairment and persons with full sight, and in persons with severe visual impairment with or without light perception. METHOD: This cross-sectional study assessed the Global Seasonality Score (GSS) and the prevalence of SAD among 2781 persons with visual impairment and 4099 persons with full sight using the Seasonal Pattern Assessment Questionnaire (SPAQ). RESULTS: Respondents with visual impairment had significantly higher GSS and prevalence of SAD compared with full sight controls, P<0.001. Light perception respondents were more vulnerable to seasonal change than both full sight and no light perception respondents. CONCLUSIONS: The study showed a highly significant association between visual impairment and SPAQ-defined SAD parameters, supporting the hypothesis that decreased retinal light input plays a role in the pathogenesis of SAD.

Study protocol: a cross-sectional survey of seasonal affective disorder in Danish populations with and without severe visual impairments.

INTRODUCTION: People with seasonal affective disorder (SAD) experience recurrent seasonal fluctuations in energy, mood and appetite. Retinal light exposure is suggested to play an important role in the pathogenesis and treatment of SAD. The aim of the study is to determine the prevalence of SAD in persons with severe visual impairments or blindness and to compare the results to a control group without visual impairments. Moreover, the authors wish to investigate whether SAD is correlated to the degree of impairment or to the diagnosis. METHODS AND ANALYSIS: 2781 persons with visual impairments ranging from total blindness to Snellen visual acuity 6/60 receive information letter and questionnaire by post. Completed questionnaires can be returned by post, email or telephone. For each respondent, all eye-related diagnoses will be obtained from national registries. Normally sighted and demographically matched control respondents will be contacted in a similar manner the subsequent winter season. The Seasonal Pattern Assessment Questionnaire rates seasonal variation within the six items: sleep, appetite, social activity, mood, energy and body weight. The Seasonal Pattern Assessment Questionnaire yields a Global Seasonal Score and a prevalence of SAD. Outcomes from the two groups will be compared. Moreover, outcomes from subgroups of the visually impaired population will be compared. ETHICS AND DISSEMINATION: The study is approved by the Danish Data Protection Agency. Results will be published in a relevant scientific journal and be communicated to respondents and relevant institutions through cooperation with the Danish Association of the Blind.

[More than every tenth person have symptoms of seasonal affective disorder]. / Mere end hver tiende har symptomer på vinterdepression.

Seasonal affective disorder is a syndrome of classical depressive symptoms such as reduced energy, initiative and mood combined with atypical symptoms of increased appetite, weight and sleep duration. The symptoms recur each winter and disappear again in spring or early summer. The prevalence ranges from 1% to 10% in Scandinavian populations. Reduced light exposure, melatonergic and serotonergic disturbances are suggested pathogenetic factors. Light therapy offers convincing effect with minimal adverse effects and remains first-line treatment along with selective serotonin reuptake inhibitors.

Costing of severe pneumonia in hospitalized infants and children aged 2-36 months, at a secondary and tertiary level hospital of a not-for-profit organization.

OBJECTIVES: To determine health care provider cost and household cost of the treatment of severe pneumonia in infants and young children admitted to secondary and tertiary level health care facilities. METHODS: The study was done in a private, not-for-profit medical college hospital, in Vellore, India, in mid-2008. Children aged 2-36 months admitted with severe pneumonia with no underlying chronic disease were included in the study. The relatives were interviewed daily on matters relating to patients' view point of the costs. These were direct medical costs, direct non-medical costs which comprised travel, accommodation and special food during the period of illness, and indirect costs of productivity loss for family members. Patient specific resource consumption and related charges were recorded from charts, nursing records, pharmacy lists and hospital bills, and the providers view point of the costs was estimated. Unit cost estimates for bed days, treatment and investigation inputs were calculated. RESULTS: Total cost to health care provider for one episode of hospitalized childhood pneumonia treated at secondary level was US$ 83.89 (INR 3524) and US$ 146.59 (INR 6158) at tertiary level. At both levels the greatest single cost was the hospital stay itself, comprising 74% and 56% of the total cost, respectively. Diagnostic investigations were a large expense and supportive treatment with nebulization and oxygen therapy added to the costs. Mean household expenditure on secondary level was US$ 41.35 (INR 1737) and at tertiary level was US$ 134.62 (INR 5655), the largest single expense being medicines in the former and the hospitalization in the latter. (one US$=INR 42.1 at time of study) CONCLUSIONS: A considerable cost difference exists between secondary and tertiary level treatment. Admission at lowest possible treatment level for appropriate patients could decrease the costs borne by the provider and the patient.