Bright light therapy in pregnant women with major depressive disorder: Study protocol for a randomized, double-blind, controlled clinical trial

Background: Depression during pregnancy is a common and high impact disease. Generally, 5-10 % of pregnant women suffer from depression. Children who have been exposed to maternal depression during pregnancy have a higher risk of adverse birth outcomes and more often show cognitive, emotional and behavioural problems. Therefore, early detection and treatment of antepartum depression is necessary. Both psychotherapy and antidepressant medication, first choice treatments in a non-pregnant population, have limitations in treating depression during pregnancy. Therefore, it is urgent and relevant to investigate alternative treatments for antepartum depression. Bright light therapy (BLT) is a promising treatment for pregnant women with depressive disorder, for it combines direct availability, sufficient efficacy, low costs and high safety, taking the safety for the unborn child into account as well. Methods: In this study, 150 pregnant women (12-18 weeks pregnant) with a DSM-V diagnosis of depressive disorder will be randomly allocated in a 1:1 ratio to one of the two treatment arms: treatment with BLT (9.000 lux) or treatment with dim red light therapy (100 lux). Both groups will be treated for 6 weeks at home on a daily basis for 30 min, within 30 min of habitual wake-up time. Follow-up will take place after 6 weeks of therapy, 3 and 10 weeks after end of therapy, at birth and 2, 6 and 18 months postpartum. Primary outcome will be the average change in depressive symptoms between the two groups, as measured by the Structured Interview Guide for the Hamilton Depression Scale - Seasonal Affective Disorder version and the Edinburg Postnatal Depression Scale. Changes in rating scale scores of these questionnaires over time will be analysed using generalized linear mixed models. Secondary outcomes will be the changes in maternal cortisol and melatonin levels, in maternal sleep quality and gestational age, birth weight, infant behaviour, infant cortisol exposure and infant cortisol stress response. Discussion: If BLT reduces depressive symptoms in pregnant women, it will provide a safe, cheap, non-pharmacological and efficacious alternative treatment for psychotherapy and antidepressant medication in treating antepartum depression, without any expected adverse reactions for the unborn child. Trial registration: Netherlands Trial Register NTR5476. Registered 5 November 2015

From animal cage to aircraft cabin: An overview of evidence translation in jet lag research

Recent laboratory experiments on rodents have increased our understanding of circadian rhythm mechanisms. Typically, circadian biologists attempt to translate their laboratory-based findings to treatment of jet lag symptoms in humans. We aimed to scrutinise the strength of the various links in the translational pathway from animal model to human traveller. First, we argue that the translation of findings from pre-clinical studies to effective jet lag treatments and knowledge regarding longer-term population health is not robust, e.g. the association between circadian disruption and cancer found in animal models does not translate well to cabin crew and pilots, who have a lower risk of most cancers. Jet lag symptoms are heterogeneous, making the true prevalence and the effects of any intervention difficult to quantify precisely. The mechanistic chain between in vitro and in vivo treatment effects has weak links, especially between circadian rhythm disruption in animals and the improvement of jet lag symptoms in humans. While the number of animal studies has increased exponentially between 1990 and 2014, only 1–2 randomised controlled trials on jet lag treatments are published every year. There is one relevant Cochrane review, in which only 2–4 studies on melatonin, without baseline measures, were meta-analysed. Study effect sizes reduced substantially between 1987, when the first paper on melatonin was published, and 2000. We suggest that knowledge derived from a greater number of human randomised controlled trials would provide a firmer platform for circadian biologists to cite jet lag treatment as an important application of their findings

A New Integrated Variable Based on Thermometry, Actimetry and Body Position (TAP) to Evaluate Circadian System Status in Humans

The disruption of the circadian system in humans has been associated with the development of chronic illnesses and the worsening of pre-existing pathologies. Therefore, the assessment of human circadian system function under free living conditions using non-invasive techniques needs further research. Traditionally, overt rhythms such as activity and body temperature have been analyzed separately; however, a comprehensive index could reduce individual recording artifacts. Thus, a new variable (TAP), based on the integrated analysis of three simultaneous recordings: skin wrist temperature (T), motor activity (A) and body position (P) has been developed. Furthermore, we also tested the reliability of a single numerical index, the Circadian Function Index (CFI), to determine the circadian robustness. An actimeter and a temperature sensor were placed on the arm and wrist of the non-dominant hand, respectively, of 49 healthy young volunteers for a period of one week. T, A and P values were normalized for each subject. A non-parametric analysis was applied to both TAP and the separate variables to calculate their interdaily stability, intradaily variability and relative amplitude, and these values were then used for the CFI calculation. Modeling analyses were performed in order to determine TAP and CFI reliability. Each variable (T, A, P or TAP) was independently correlated with rest-activity logs kept by the volunteers. The highest correlation (r = −0.993, p<0.0001), along with highest specificity (0.870), sensitivity (0.740) and accuracy (0.904), were obtained when rest-activity records were compared to TAP. Furthermore, the CFI proved to be very sensitive to changes in circadian robustness. Our results demonstrate that the integrated TAP variable and the CFI calculation are powerful methods to assess circadian system status, improving sensitivity, specificity and accuracy in differentiating activity from rest over the analysis of wrist temperature, body position or activity alone

Sex differences in mood disorders: Perspectives from humans and rodent models

Mood disorders are devastating, often chronic illnesses characterized by low mood, poor affect, and anhedonia. Notably, mood disorders are approximately twice as prevalent in women compared to men. If sex differences in mood are due to underlying biological sex differences, a better understanding of the biology is warranted to develop better treatment or even prevention of these debilitating disorders. In this review, our goals are to: 1) summarize the literature related to mood disorders with respect to sex differences in prevalence, 2) introduce the corticolimbic brain network of mood regulation, 3) discuss strategies and challenges of modeling mood disorders in mice, 4) discuss mechanisms underlying sex differences and how these can be tested in mice, and 5) discuss how our group and others have used a translational approach to investigate mechanisms underlying sex differences in mood disorders in humans and mice