737 Prediction of drop out in an adjunctive light treatment trial in patients with non-seasonal depression and evening chronotype

Introduction Drop out during treatment hampers therapeutic effect of interventions. The current study examines the possible predictors of drop out during the five-week light treatment in patients with unipolar non-seasonal depression and evening-chronotype. Methods Baseline characteristics including demographics, sleep diary parameters, light treatment prescribed, and early clinical outcomes changes were compared between the Drop out and Non drop out group. Logistic regression analysis was used to examine predictors for drop out. All data were analyzed in a modified intention to treat analysis with last observation carried forward approach. Results A total of 91 subjects (Female 79%, 46.3 ± 11.8 years old) were included in the analysis. There was no significant difference in the baseline demographic and clinical characteristics between the Drop out and Non drop out group. There was also no significant difference in the improvement of clinical parameters over the first week among the two groups. However, treatment non-adherence (in terms of compliance of less than 80% of prescribed duration) over the first treatment week predicts a five-fold increase in risk of drop out during light therapy. (OR: 5.85, CI: 1.414–24.205, p=0.015) after controlling for potential confounders including age, gender, treatment group, patient expectation, and treatment-emergent adverse events. Conclusion This study found that baseline clinical characteristics including depression severity and improvement of depressive symptoms in the initial week did not differ between the Drop out and Non drop out group. The drop out was also not affected by the type of light (dim red versus bright red light), indirectly supporting dim red light as a valid placebo in bright light therapy trial. Treatment adherence is the early phase of light treatment is an important predictor of drop out. Support (if any):

The Circadian Phase Response Curve to Light: Conservation across Seasons and Anchorage to Sunset

Predictions about circadian light responses are largely based on photic phase-response curves (PRCs) generated from animals housed under seasonally agnostic equatorial photoperiods with alternating 12-hour segments of light and darkness. Most of the human population, however, lives at northerly latitudes where seasonal variations in the light-dark schedule are pronounced. Here, we address this disconnect by constructing the first high-resolution seasonal atlas for light-induced circadian phase-resetting. Testing the light responses of nearly 4,000 Drosophila at 120 timepoints across 5 seasonally relevant photoperiods, we determined that many aspects of the circadian PRC waveform are conserved with increasing daylength. Surprisingly though, irrespective of LD schedule, the start of the PRCs always remained anchored to the timing of subjective sunset, creating a differential overlap of the advance zone with the morning hours after subjective sunrise that was maximized under summer photoperiods and minimized under winter photoperiods. These data suggest that circadian photosensitivity is effectively extinguished by the early winter morning and out of optimal phase alignment with the wake schedules of many individuals. They raise the possibility that phototherapy protocols for conditions such as seasonal depression might be improved with programmed light exposure during the final hours of sleep.

Astroglia in lateral habenula is essential for antidepressant efficacy of light

Successful antidepressant (AD) treatments are still difficult to achieve. Recently, bright light stimulation (BLS) was shown effective in non-seasonal depression but its mode of action remains elusive. We demonstrate here, using a new mouse model of depression resistant to ADs including ketamine, that chemogenetic activation of lateral habenula (LHb) astroglia prevented the potentiating effect of BLS on the AD response. Additionally, the beneficial action of BLS was associated with upregulation of a specific part of the prefrontal cortex opioid system. These results show that improved behavioral outcome produced by BLS requires habenular astroglia and endogenous opioids as crucial buffer systems.

Light stimulation into dorsal raphe nucleus contributes to antidepressant effect for a stressed rat model

BackgroundLight therapy is frequently demonstrated by clinical trials to be effective to seasonal or non-seasonal major depression. However, the pathway underlying the light effect on mood remains unclear. Since a retino-raphe pathway was previously indicated to modulate 5-HT production, we hypothesize that the retinal projection into dorsal raphe nucleus (DRN) may play an important role in the light therapy for depression.MethodsA rat model of 14-day corticosterone administration (40 mg/kg/day subcutaneous injection) was mainly used to test the effect of light therapy on non-seasonal depressant-like behavior, and the involved neural circuitry and neurochemistry as well.ResultsBehavior results revealed that the bright light therapy especially with the blue light of 470 nm and 400 lux, effectively reversed the depression-like responses in those stressed rats. After elimination of retino-raphe projection using immunotoxin (Saporin) the effect of light therapy was significantly attenuated. Whereas activation of retino-raphe projection using HM3q chemogenetics was shown an effect similar to fluoxetine treatment. Furthermore, 5-HT3A positive GABA cells in the DRN were activated with high c-Fos expression that involved in an inhibition of 5-HT synthesis and a subsequent depressive behavior. While light therapy through retino-raphe projection deactivated the hyperaction of those GABA cells in the DRN; that eventually contributed to the antidepressant effect from light therapy.ConclusionsOur results indicate that the retino-raphe circuitry engaged antidepressant effect in DRN that contributed to the light therapy to the non-seasonal depression. 5-HT3A positive GABA cells in DRN was indicated to mediate this function of retino-raphe projection.