Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine.

BACKGROUND: Patients with schizophrenia show reduced NMDA glutamate receptor-dependent auditory plasticity, which is rate limiting for auditory cognitive remediation (AudRem). We evaluate the utility of behavioral and neurophysiological pharmacodynamic target engagement biomarkers, using a d-serine+AudRem combination. METHODS: Forty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each. In AudRem, participants indicated which paired tone was higher in pitch. The primary outcome was plasticity improvement, operationalized as change in pitch threshold between AudRem tones [(test tone Hz - reference tone Hz)/reference tone Hz] between the initial plateau pitch threshold (mean of trials 20-30 of treatment visit 1) to pitch threshold at the end of visit(s). Target engagement was assessed by electroencephalography outcomes, including mismatch negativity (pitch primary). RESULTS: There was a significant overall treatment effect for plasticity improvement (p = .014). Plasticity improvement was largest within the 80 and 100 mg/kg groups (p < .001, d > 0.67), while 120 mg/kg and placebo-treated participants showed nonsignificant within-group changes. Plasticity improvement was seen after a single treatment and was sustained on subsequent treatments. Target engagement was demonstrated by significantly larger mismatch negativity (p = .049, d = 1.0) for the 100 mg/kg dose versus placebo. CONCLUSIONS: Our results demonstrate sufficient proof of principle for continued development of both the d-serine+AudRem combination and our target engagement methodology. The ultimate utility is dependent on the results of an ongoing larger, longer study of the combination for clinically relevant outcomes.

The Association Between Habitual Sleep Duration and Blood Pressure Control in United States (US) Adults with Hypertension.

Purpose: This study examined the relationship between habitual sleep duration and blood pressure (BP) control in adults with hypertension. Methods: This cross-sectional study used data of 5163 adults with hypertension obtained from the 2015-2018 National Health and Nutrition Examination Survey (NHANES). Multivariable logistic regression was used to analyze the association between habitual sleep duration and BP control. Habitual sleep duration was self-reported and defined as the amount of sleep usually obtained in a night or main sleep period during weekdays or workdays. It was categorized as <6, 6 - <7, 7-9, and >9 hours. BP control was defined as average systolic BP <130mmHg and diastolic BP <80mmHg. Results: Results from the fully adjusted models show that among all adults with hypertension, habitual sleep duration of <6 hours night/main sleep period was associated with reduced odds of BP control (OR = 0.53, 95% CI: 0ss.37-0.76, P = 0.001) when compared to 7-9 hours. In the subpopulation of adults who were on antihypertensive medication, those with a sleep duration of <6 hours had lower odds of BP control than those with a sleep duration of 7-9 hours (OR = 0.53, 95% CI: 0.36-0.77, P = 0.002). No significant differences were noted in all adults with hypertension and in the subpopulation of those on antihypertensive medication in BP control between the reference sleep duration group (7-9 hours) and the 6 - <7 or >9 hours groups. There were no significant differences across age groups or gender in the relationship between habitual sleep duration and BP control. Conclusion: Sleep duration of <6 hours is associated with reduced odds of hypertension control. These significant findings indicate that interventions to support adequate habitual sleep duration may be a promising addition to the current hypertension management guidelines.

Factors associated with habitual sleep duration in US adults with hypertension: a cross-sectional study of the 2015-2018 National Health and Nutrition Examination Survey.

BACKGROUND: The relationship between inadequate sleep duration and hypertension risk has been established in the general population, but there is a gap in the literature on predictors of habitual sleep duration in adults with hypertension. This study examined factors associated with habitual sleep duration among adults with hypertension in the United States (US). METHODS: Data of 5660 adults with hypertension were obtained by combining the 2015-2018 cycles of the National Health and Nutrition Examination Survey (NHANES). Survey weighted multinomial logistic regression models were fit to examine factors associated with short (< 7 h) and long (> 9 h) sleep duration with adequate sleep duration (7-9 h) as the reference. RESULTS: The prevalence of self-reported adequate sleep duration was 65.7%, while short sleep duration was 23.6%, and long sleep duration 10.7%. Short sleep duration (compared to adequate sleep duration) was positively associated with history of seeking help for sleeping difficulties (relative risk ratio [RRR], 1.25; 95% confidence interval [CI], 1.02-1.53), Non-Hispanic Black race/ethnicity (RRR, 2.08; 95% CI, 1.61-2.67), working ≥45 h/week (RRR, 1.81; 95% CI, 1.32-2.48), and negatively associated with older age ≥ 65 years (RRR, 0.63; 95% CI, 0.45-0.91) and female gender (RRR, 0.70; 95% CI, 0.56-0.88). Long sleep duration was positively associated with female gender (RRR, 1.24; 95% CI, 1.001-1.54), chronic kidney disease (RRR, 1.48; 95% CI, 1.14-1.92), moderate depressive symptoms (RRR, 1.62; 95% CI, 1.08-2.44), moderately severe to severe depressive symptoms (RRR, 1.89; 95% CI, 1.05-3.43), being in retirement (RRR, 3.46; 95% CI, 2.18-5.49), and not working due to health reasons (RRR, 4.87; 95% CI, 2.89-8.22) or other reasons (RRR, 3.29; 95% CI, 1.84-5.88). CONCLUSION: This population-based study identified factors independently associated with habitual sleep duration in adults with hypertension. These included help-seeking for sleeping difficulty, gender, age, chronic kidney disease, depressive symptoms, race/ethnicity, and employment status. These findings can help in the development of tailored approaches for promoting adequate sleep duration in adults with hypertension.

Grant Report on d-Serine Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia †.

We report on the rationale and design of an ongoing NIMH sponsored R61-R33 project in schizophrenia/schizoaffective disorder. This project studies augmenting the efficacy of auditory neuroplasticity cognitive remediation (AudRem) with d-serine, an N-methyl-d-aspartate-type glutamate receptor (NMDAR) glycine-site agonist. We operationalize improved (smaller) thresholds in pitch (frequency) between successive auditory stimuli after AudRem as improved plasticity, and mismatch negativity (MMN) and auditory θ as measures of functional target engagement of both NMDAR agonism and plasticity. Previous studies showed that AudRem alone produces significant, but small cognitive improvements, while d-serine alone improves symptoms and MMN. However, the strongest results for plasticity outcomes (improved pitch thresholds, auditory MMN and θ) were found when combining d-serine and AudRem. AudRem improvements correlated with reading and other auditory cognitive tasks, suggesting plasticity improvements are predictive of functionally relevant outcomes. While d-serine appears to be efficacious for acute AudRem enhancement, the optimal dose remains an open question, as does the ability of combined d-serine + AudRem to produce sustained improvement. In the ongoing R61, 45 schizophrenia patients will be randomized to receive three placebo-controlled, double-blind d-serine + AudRem sessions across three separate 15 subject dose cohorts (80/100/120 mg/kg). Successful completion of the R61 is defined by ≥moderate effect size changes in target engagement and correlation with function, without safety issues. During the three-year R33, we will assess the sustained effects of d-serine + AudRem. In addition to testing a potentially viable treatment, this project will develop a methodology to assess the efficacy of novel NMDAR modulators, using d-serine as a "gold-standard".

High glycemic index and glycemic load diets as risk factors for insomnia: analyses from the Women's Health Initiative.

BACKGROUND: Previous studies have shown mixed results on the association between carbohydrate intake and insomnia. However, any influence that refined carbohydrates have on risk of insomnia is likely commensurate with their relative contribution to the overall diet, so studies are needed that measure overall dietary glycemic index (GI), glycemic load, and intakes of specific types of carbohydrates. OBJECTIVE: We hypothesized that higher GI and glycemic load would be associated with greater odds of insomnia prevalence and incidence. METHODS: This was a prospective cohort study with postmenopausal women who participated in the Women's Health Initiative Observational Study, investigating the relations of GI, glycemic load, other carbohydrate measures (added sugars, starch, total carbohydrate), dietary fiber, and specific carbohydrate-containing foods (whole grains, nonwhole/refined grains, nonjuice fruits, vegetables, dairy products) with odds of insomnia at baseline (between 1994 and 1998; n = 77,860) and after 3 y of follow-up (between 1997 and 2001; n = 53,069). RESULTS: In cross-sectional and longitudinal analyses, higher dietary GI was associated with increasing odds of prevalent (fifth compared with first quintile OR: 1.11; CI: 1.05, 1.16; P-trend = 0.0014) and incident (fifth compared with first quintile OR: 1.16; CI: 1.08, 1.25; P-trend < 0.0001) insomnia in fully adjusted models. Higher intakes of dietary added sugars, starch, and nonwhole/refined grains were each associated with higher odds of incident insomnia. By contrast, higher nonjuice fruit and vegetable intakes were significantly associated with lower odds of incident insomnia. Also, higher intakes of dietary fiber, whole grains, nonjuice fruit, and vegetables were significantly associated with lower odds of prevalent insomnia. CONCLUSIONS: The results suggest that high-GI diets could be a risk factor for insomnia in postmenopausal women. Substitution of high-GI foods with minimally processed, whole, fiber-rich carbohydrates should be evaluated as potential treatments of, and primary preventive measures for, insomnia in postmenopausal women.

Familial aggregation of major depressive disorder in an African-American community.

BACKGROUND: African Americans (AAs) with major depressive disorder (MDD) experience more impairment and poorer treatment outcomes relative to Whites, yet are underrepresented in family studies of MDD. This is the first study to investigate the familial aggregation of major depression among AAs. METHODS: Participants' reports of depression from clinical and family history (FH) interviews were used to examine depression rates among 435 first-degree relatives and half-siblings of 63 depressed cases and 222 relatives of 33 nondepressed controls. Binary logistic regression was used to compute odds ratios (ORs) for FH of MDD and level of trauma exposure (high and low) in cases versus controls. Poisson regression models with generalized estimating equations were used to assess MDD in relatives of cases versus relatives of controls. RESULTS: Cases and controls did not differ in either FH of MDD (OR = 1.2, 95% confidence interval [CI] = 0.5-2.9), or prevalence of MDD in relatives (relative risk [RR] = 1.5, 95% CI = 0.8-2.5). However, exposure to high trauma was associated with increased risk of MDD (OR = 3.0, 95% CI = 1.22-7.17) and the combined effect of FH and trauma was greater than expected under an additive model. Similarly, the RR for MDD among relatives of cases with high-trauma levels was 2.2 (1.24-4.2), compared to relatives of controls with low trauma. CONCLUSION: The effect of FH of MDD appears to be exacerbated among individuals exposed to high trauma. Replication and further research on the chronology and subtypes of trauma and MDD, and their interactions, remain essential in AA populations.

Differential Associations Between Depression, Risk Factors for Insulin Resistance and Diabetes Incidence in a Large U.S. Sample.

BACKGROUND: Depression frequently co-occurs with diabetes. The associations between risk factors for insulin resistance and depression and diabetes can help determine the relative importance of factors that contribute toward the comorbidity. METHOD: Analyses of the NHANES I (n = 10,025) to examine the cross-sectional relationships between depression and risk factors for insulin resistance at baseline using logistic regression and to explore the longitudinal relationships between risk factors for insulin resistance and diabetes incidence using Cox proportional hazards modeling. RESULTS: Many risk factors for insulin resistance were associated with depression and diabetes incidence. Depression was cross-sectionally associated with diabetes, but did not increase the risk for diabetes incidence.These counterintuitive results can be explained primarily by the differing relationships between risk factors for insulin resistance, depression, and diabetes. LIMITATIONS: Lack of repeated measures of depression. CONCLUSIONS: Lack of physical activity, hypertension, and inadequate sleep were the risk factors for insulin resistance with the highest associations with both depression and diabetes incidence.

Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion.

The American Academy of Sleep Medicine and Sleep Research Society recently released a Consensus Statement regarding the recommended amount of sleep to promote optimal health in adults. This paper describes the methodology, background literature, voting process, and voting results for the consensus statement. In addition, we address important assumptions and challenges encountered during the consensus process. Finally, we outline future directions that will advance our understanding of sleep need and place sleep duration in the broader context of sleep health.

Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion.

The American Academy of Sleep Medicine and Sleep Research Society recently released a Consensus Statement regarding the recommended amount of sleep to promote optimal health in adults. This paper describes the methodology, background literature, voting process, and voting results for the consensus statement. In addition, we address important assumptions and challenges encountered during the consensus process. Finally, we outline future directions that will advance our understanding of sleep need and place sleep duration in the broader context of sleep health.

High glycemic index diet as a risk factor for depression: analyses from the Women's Health Initiative.

BACKGROUND: The consumption of sweetened beverages, refined foods, and pastries has been shown to be associated with an increased risk of depression in longitudinal studies. However, any influence that refined carbohydrates has on mood could be commensurate with their proportion in the overall diet; studies are therefore needed that measure overall intakes of carbohydrate and sugar, glycemic index (GI), and glycemic load. OBJECTIVE: We hypothesized that higher dietary GI and glycemic load would be associated with greater odds of the prevalence and incidence of depression. DESIGN: This was a prospective cohort study to investigate the relations between dietary GI, glycemic load, and other carbohydrate measures (added sugars, total sugars, glucose, sucrose, lactose, fructose, starch, carbohydrate) and depression in postmenopausal women who participated in the Women's Health Initiative Observational Study at baseline between 1994 and 1998 (n = 87,618) and at the 3-y follow-up (n = 69,954). RESULTS: We found a progressively higher dietary GI to be associated with increasing odds of incident depression in fully adjusted models (OR for the fifth compared with first quintile: 1.22; 95% CI: 1.09, 1.37), with the trend being statistically significant (P = 0.0032). Progressively higher consumption of dietary added sugars was also associated with increasing odds of incident depression (OR for the fifth compared with first quintile: 1.23; 95% CI: 1.07, 1.41; P-trend = 0.0029). Higher consumption of lactose, fiber, nonjuice fruit, and vegetables was significantly associated with lower odds of incident depression, and nonwhole/refined grain consumption was associated with increased odds of depression. CONCLUSIONS: The results from this study suggest that high-GI diets could be a risk factor for depression in postmenopausal women. Randomized trials should be undertaken to examine the question of whether diets rich in low-GI foods could serve as treatments and primary preventive measures for depression in postmenopausal women.

Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society.

ABSTRACT: Sleep is essential for optimal health. The American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) developed a consensus recommendation for the amount of sleep needed to promote optimal health in adults, using a modified RAND Appropriateness Method process. The recommendation is summarized here. A manuscript detailing the conference proceedings and evidence supporting the final recommendation statement will be published in SLEEP and the Journal of Clinical Sleep Medicine.

Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society.

Sleep is essential for optimal health. The American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) developed a consensus recommendation for the amount of sleep needed to promote optimal health in adults, using a modified RAND Appropriateness Method process. The recommendation is summarized here. A manuscript detailing the conference proceedings and evidence supporting the final recommendation statement will be published in SLEEP and the Journal of Clinical Sleep Medicine.

Invited commentary: nighttime light exposure as a risk factor for obesity through disruption of circadian and circannual rhythms.

In this issue of the American Journal of Epidemiology, McFadden et al. (Am J Epidemiol. 2014;180(3):245-250) report findings on the relationship between light exposure at night and obesity from a cross-sectional study of United Kingdom women. Their research extends findings from a previous study with elderly participants by including a larger sample size of over 100,000 women and a broader age range of 16 years or older. The findings are consistent with animal studies showing that prolonged light exposure leads to weight gain. Humans' circadian, circannual, and metabolic regulatory systems evolved to be adaptive in environments that were quite different from those faced in modern industrial society. Technology has allowed exposures to levels and timing of light, nutrient intake, and physical activity never before possible. This commentary discusses how nighttime light exposure can increase the risk of obesity and the metabolic syndrome by disrupting circadian and circannual rhythms.

Daytime sleepiness and risk of coronary heart disease and stroke: results from the Nurses' Health Study II.

OBJECTIVE: The objective of this study was to determine whether daytime sleepiness is independently associated with coronary heart disease (CHD) and stroke or whether the positive association is explained by short sleep duration, disturbed sleep, and circadian disruption, conditions that are associated with cardiometabolic risk factors for vascular events. METHODS: Longitudinal analyses of data from the Nurses' Health Study II comprising 84,003 female registered nurses aged 37-54 at baseline were conducted in 2001 with follow-up until 2009. Multivariate Cox regression was used to explore the relationship between reported daytime sleepiness and the incidence of either CHD or stroke (n=500 cases). RESULTS: Women who reported daytime sleepiness almost every day, compared with rarely/never, had an elevated adjusted risk of cardiovascular disease (CVD) (hazard ratio (HR)=1.58, 95% confidence interval (CI) 1.15-2.17). Controlling for sleep variables (sleep duration, snoring, shift work, and sleep adequacy) or potential metabolic biological mediators of disrupted sleep (diabetes, hypercholesterolemia, and hypertension) appreciably attenuated the relationship (HR=1.17, 95% CI 0.84-1.65; and HR=1.34, 95% CI 0.97-1.85, respectively). Controlling for both sleep variables and metabolic risk factors eliminated an independent association (HR=1.09, 95% CI 0.77-1.53). A similar pattern was observed for CHD and stroke individually. CONCLUSIONS: Daytime sleepiness was not an independent risk factor for CVD in this cohort of women, but rather, was associated with sleep characteristics and metabolic abnormalities that are risk factors for CVD.

A review of evidence for the link between sleep duration and hypertension.

There are lines of evidence from experimental sleep deprivation studies, population-based epidemiological studies, and an interventional study that point to the potential efficacy of adequate quality sleep to prevent and treat hypertension. Experimental sleep restriction has been shown to raise blood pressure and heart rate. Insufficient sleep on a chronic basis can raise average 24-hour blood pressure and lead to structural adaptations that entrain the cardiovascular system to operate at an elevated blood pressure equilibrium and increase the risk for hypertension. Disruptions in the timing and duration of sleep could also disrupt circadian rhythmicity and autonomic balance, which can increase the prevalence of the nondipping pattern, disturb diurnal rhythm of cardiac output, and increase blood pressure variability. Short sleep duration has been found to be associated with higher blood pressure and hypertension in both cross-sectional and longitudinal epidemiological studies. The association appears stronger in middle-aged adults and in women. Experimental sleep extension has been shown to significantly reduce blood pressure in individuals with prehypertension or stage 1 hypertension. The observed association between sleep duration and hypertension raises the hypothesis that interventions to extend sleep and improve sleep quality could serve as effective primary, secondary, and tertiary preventive measures for hypertension.