The Relationship between Insomnia and the Pathophysiology of Major Depressive Disorder: An Evaluation of a Broad Selection of Serum and Urine Biomarkers.

Insomnia exhibits a clinically relevant relationship with major depressive disorder (MDD). Increasing evidence suggests that insomnia is associated with neurobiological alterations that resemble the pathophysiology of MDD. However, research in a clinical population is limited. The present study, therefore, aimed to investigate the relationship between insomnia and the main pathophysiological mechanisms of MDD in a clinical sample of individuals with MDD. Data were extracted from three cohorts (N = 227) and included an evaluation of depression severity (Quick Inventory of Depressive Symptomatology, QIDS-SR16) and insomnia severity (QIDS-SR16 insomnia items) as well as serum and urine assessments of 24 immunologic (e.g., tumour necrosis factor α receptor 2 and calprotectin), neurotrophic (e.g., brain-derived neurotrophic factor and epidermal growth factor), neuroendocrine (e.g., cortisol and aldosterone), neuropeptide (i.e., substance P), and metabolic (e.g., leptin and acetyl-L-carnitine) biomarkers. Linear regression analyses evaluating the association between insomnia severity and biomarker levels were conducted with and without controlling for depression severity (M = 17.32), antidepressant use (18.9%), gender (59.0% female; 40.5% male), age (M = 42.04), and the cohort of origin. The results demonstrated no significant associations between insomnia severity and biomarker levels. In conclusion, for the included biomarkers, current findings reveal no contribution of insomnia to the clinical pathophysiology of MDD.

SERIES: eHealth in primary care. Part 3: eHealth education in primary care.

BACKGROUND: Education is essential to the integration of eHealth into primary care, but eHealth is not yet embedded in medical education. OBJECTIVES: In this opinion article, we aim to support organisers of Continuing Professional Development (CPD) and teachers delivering medical vocational training by providing recommendations for eHealth education. First, we describe what is required to help primary care professionals and trainees learn about eHealth. Second, we elaborate on how eHealth education might be provided. DISCUSSION: We consider four essential topics. First, an understanding of existing evidence-based eHealth applications and conditions for successful development and implementation. Second, required digital competencies of providers and patients. Third, how eHealth changes patient-provider and provider-provider relationships and finally, understanding the handling of digital data. Educational activities to address these topics include eLearning, blended learning, courses, simulation exercises, real-life practice, supervision and reflection, role modelling and community of practice learning. More specifically, a CanMEDS framework aimed at defining curriculum learning goals can support eHealth education by describing roles and required competencies. Alternatively, Kern's conceptual model can be used to design eHealth training programmes that match the educational needs of the stakeholders using eHealth. CONCLUSION: Vocational and CPD training in General Practice needs to build on eHealth capabilities now. We strongly advise the incorporation of eHealth education into vocational training and CPD activities, rather than providing it as a separate single module. How learning goals and activities take shape and how competencies are evaluated clearly requires further practice, evaluation and study.

The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the sleep-promoting effects of tryptophan: A randomized placebo-controlled crossover study.

BACKGROUND: The low-expressive short (S) allele of a functional polymorphism (5-HTTLPR) within the serotonin (5-hydroxytriptamine; 5-HT) transporter gene (SLC6A4) has been associated with a reduced functioning of the brain 5-HT system relative to the long (L) allele. As a consequence, the S-allele is found to predispose individuals to a higher risk of sleep quality reduction and clinical insomnia. AIMS: The present study investigated whether subchronic pre-sleep tryptophan administration could compensate for this predisposition by improving sleep in 5-HTTLPR S-allele carriers. METHODS: In a double-blind placebo-controlled crossover design a sample of homozygous 5-HTTLPR S-allele (n = 47) and L-allele (n = 51) carriers were assessed for subjective (sleep diary) and objective (actigraphy) sleep during a treatment protocol consisting of 1 week of placebo (1000 mg/day) and 1 week of tryptophan administration (1000 mg/day). RESULTS: The results support the sleep-promoting effects of tryptophan. Tryptophan improved objective sleep efficiency and objective wake after sleep onset irrespective of allelic variation. There was a marginally significant improvement of subjective sleep quality in the 5-HTTLPR S-allele group but not in the L-allele group following tryptophan relative to placebo intake. In contrast, a significantly poorer sleep quality in the S-allele as opposed to the L-allele group in the placebo condition was not observed in the tryptophan condition. CONCLUSIONS: Tryptophan augmentation promises to be a valuable treatment strategy for sleep impairments related to genetic deficiencies in 5-HT functioning.

The involvement of sleep in the relationship between the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and depression: A systematic review.

BACKGROUND: Recent meta-analyses stimulate an ongoing debate whether 5-HTTLPR modulates the risk for depression including a more pronounced association between stress and depression in the short (S) allele relative to the long (L) allele. Elucidating the pathways by which 5-HTTLPR contributes to depression could resolve this controversy. Insomnia independently contributes to the onset and course of negative affective symptoms and, hence, represents one of the primary risk factors for depression. To evaluate the relevance of this relationship for the interaction between 5-HTTLPR and stress in depression, the present review investigated the moderating influence of 5-HTTLPR on the relationship between stress and sleep quality as well as on the relationship between sleep and affective symptomatology. METHODS: A systematic search was performed in the PubMed and PsycINFO databases to include a complete outline of studies investigating the relationships of interest. RESULTS: Results of the included articles reveal that the 5-HTTLPR S-allele relative to the L-allele increases the risk for stress-related sleep quality reductions and promotes the negative affective consequences of inadequate sleep. LIMITATIONS: The apparent involvement of sleep in the association between 5-HTTLPR and depression remains to be more directly (empirically) examined and studies exploring the influence of 5-HTTLPR on sleep quality produced inconsistent results. CONCLUSIONS: The reviewed findings support the involvement of sleep in the interaction between 5-HTTLPR and stress in depression. This could have important implications for the inconsistent findings characterizing this field of research and may provide valuable insight into the pathophysiological mechanisms underlying genetic contributions to depression.

The serotonin transporter polymorphism (5-HTTLPR) and cortisol stress responsiveness: preliminary evidence for a modulating role for sleep quality.

The short (S) allele of a functional polymorphism (5-HTTLPR) within the promoter region of the serotonin transporter gene (SLC6A4) is found to predispose the risk for stress-related affective disorders relative to the long (L) allele. Evidence suggests that elevated stress reactivity of the hypothalamic-pituitary-adrenal (HPA) axis might underlie this association although there is little understanding about the origin of inconsistent findings. Since inadequate sleep is commonly known to promote HPA stress reactivity, it might well play an important modulating role. The present study tested this hypothesis by investigating whether sleep quality moderates the relationship between 5-HTTLPR and cortisol stress responsiveness. From a large 5-HTTLPR database (n = 771), a sample of healthy male and female participants homozygous for either the 5-HTTLPR S-allele (n = 25) or L-allele (n = 25) were assessed for sleep quality and salivary cortisol secretion during acute laboratory stress. Diminished sleep quality was found to exclusively potentiate cortisol stress reactivity in the homozygous L-allele genotype. Accounting for this 5-HTTLPR-dependent influence enhanced the predictive value of 5-HTTLPR on cortisol stress responsiveness, revealing greater HPA reactivity in S-allele relative to L-allele carriers. Current findings suggest that variations in sleep quality may serve as a confounding factor in the search for genetic differences in stress sensitivity and related affective disorders.

The influence of sleep on human hypothalamic-pituitary-adrenal (HPA) axis reactivity: A systematic review.

Inadequate sleep is highly prevalent and known to decline both physical- and mental health. Literature suggests that altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis might underlie this association. This assumption is mainly based on changes in basal neuroendocrine activity and it is of equal importance to elucidate whether sleep may also influence HPA stress responsiveness. The present review provides a complete outline of recent human studies that have investigated how different aspects of sleep influence cortisol reactivity to laboratory stress. From the available data it can be concluded that both objective and subjective decrements in sleep quality potentiate the stress reactivity of the HPA axis. On the contrary, normal variations in sleep duration do not seem to influence cortisol stress responsiveness whereas excessive daytime sleepiness is associated with a blunting of the cortisol response. Given its well-established health consequences, sensitization of the HPA axis might well be a crucial component linking inadequate sleep to stress-related pathology.

Mind wandering during attention performance: Effects of ADHD-inattention symptomatology, negative mood, ruminative response style and working memory capacity.

OBJECTIVE: In adulthood, depressive mood is often comorbid with ADHD, but its role in ADHD-inattentiveness and especially relations with mind wandering remains to be elucidated. This study investigated the effects of laboratory-induced dysphoric mood on task-unrelated mind wandering and its consequences on cognitive task performance in college students with high (n = 46) or low (n = 44) ADHD-Inattention symptomatology and Hyperactivity/Impulsivity symptoms in the normal range. METHODS: These non-clinical high/low ADHD-Inattention symptom groups underwent negative or positive mood induction after which mind wandering frequency was measured in a sustained attention (SART), and a reading task. Effects of ruminative response style and working memory capacity on mind wandering frequency were also investigated. RESULTS: Significantly higher frequencies of self -reported mind wandering in daily life, in the SART and reading task were reported in the ADHD-Inattention symptom group, with detrimental effects on text comprehension in the reading task. Induced dysphoric mood did specifically enhance the frequency of mind wandering in the ADHD-Inattention symptom group only during the SART, and was related to their higher self-reported intrusive ruminative response styles. Working memory capacity did not differ between high/low attention groups and did not influence any of the reported effects. CONCLUSIONS: These combined results suggest that in a non-clinical sample with high ADHD-inattention symptoms, dysphoric mood and a ruminative response style seem to be more important determinants of dysfunctional mind wandering than a failure in working memory capacity/executive control, and perhaps need other ways of remediation, like cognitive behavioral therapy or mindfulness training.

Interaction between 5-HTTLPR genotype and cognitive stress vulnerability on sleep quality: effects of sub-chronic tryptophan administration.

BACKGROUND: Abundant evidence suggests that allelic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR) influences susceptibility to stress and its affective consequences due to brain serotonergic vulnerability. Based on recent assumptions, the present study examined whether the 5-HTTLPR genotype may also interact with a vulnerability to chronic stress experience (conceptualized by trait neuroticism) in order to influence sleep quality and, additionally, whether this is influenced by brain serotonergic manipulations. METHODS: In a well-balanced experimental design, homozygous S-allele (n = 57) and L-allele (n = 54) genotypes with high and low chronic stress vulnerability (neuroticism) were first assessed for general past sleep quality during a month before onset of the experiment. Then subjects were assessed for sleep quality following 7 days of tryptophan (3.0g/day) or placebo intake. RESULTS: Although high neuroticism was significantly related to a higher frequency of stressful life events and daily hassles, it did not interact with the 5-HTTLPR genotype on general past sleep quality. However, as expected, a 7 day period of tryptophan administration was exclusively associated with better sleep quality scores in the S'/S' genotype with high trait neuroticism. CONCLUSIONS: Current findings suggest that 5-HTTLPR does not directly interact with stress vulnerability in order to influence sleep quality. Instead, based on current and previous findings, it is suggested that the S'/S' 5-HTTLPR genotype promotes the risk for stress-related sleep disturbances because of an increased susceptibility to the depressogenic consequences of stress. Accordingly, by way of reducing depressive symptomatology, tryptophan augmentation may particularly improve sleep quality in stress-vulnerable individuals carrying the 5-HTTLPR S-allele.