The role of immuno-metabolic depression features in the effects of light therapy in patients with depression and type 2 diabetes mellitus: A randomized controlled trial.

OBJECTIVE: Immuno-metabolic depression (IMD) is proposed to be a form of depression encompassing atypical, energy-related symptoms (AES), low-grade inflammation and metabolic dysregulations. Light therapy may alleviate AES by modulating inflammatory and metabolic pathways. We investigated whether light therapy improves clinical and biological IMD features and whether effects of light therapy on AES or depressive symptom severity are moderated by baseline IMD features. Associations between changes in symptoms and biomarkers were explored. METHODS: In secondary analyses, clinical trial data was used from 77 individuals with depression and type 2 diabetes mellitus (T2DM) randomized to four weeks of light therapy or placebo. AES severity and depressive symptom severity were based on the Inventory of Depressive Symptomatology. Biomarkers included 73 metabolites (Nightingale) summarized in three principal components and CRP, IL-6, TNF-α, INF-γ. Linear regression analyses were performed. RESULTS: Light therapy had no effect on AES severity, inflammatory markers and metabolite principle components versus placebo. None of these baseline features moderated the effects of light therapy on AES severity. Only a principle component reflecting metabolites implicated in glucose homeostasis moderated the effects of light therapy on depressive symptom severity (ßinteraction = 0.65, P = 0.001, FDR = 0.003). Changes in AES were not associated with changes in biomarkers. CONCLUSION: Findings do not support the efficacy of light therapy in reducing IMD features in patients with depression and T2DM. We find limited evidence that light therapy is a more beneficial depression treatment among those with more IMD features. Changes in clinical and biological IMD features did not align over four-weeks' time. TRIAL REGISTRATION: The Netherlands Trial Register (NTR) NTR4942.

Symptoms of depression and insomnia in older age: A within-individual analysis over 20 years.

BACKGROUND: Depression and insomnia often co-occur, and precede one another. Possibly, insomnia gives rise to depression, and vice versa. We tested whether insomnia symptoms of an older individual are associated with later depressive symptoms in that older individual, and vice versa. METHODS: We performed a longitudinal analysis of data from a prospective cohort study in a large sample of community-dwelling older people (N = 3081), with measurements every three years, over a time period of 20 years. The within-individual longitudinal reciprocal relationship between symptoms of depression (Center for Epidemiological Studies Depression Scale), and symptoms of insomnia (three-item questionnaire, including difficulty initiating sleep, nightly awakenings, and early morning awakening) was modeled by means of a bivariate linear growth model. We tested whether symptoms of insomnia were associated with symptoms of depression three years later, and vice versa. RESULTS: Severity of symptoms of depression and insomnia and their within-individual average change over time were moderately correlated (correlation of intercepts: rho 0.41, 95% CI: 0.36 to 0.46 p < 0.001; correlation of slopes: rho 0.39, 95% CI: 0.25 to 0.52, p < 0.001). Symptoms of depression were not found to be associated with an additional risk of higher symptoms of insomnia three years later, and vice versa (p = 0.329 and p = 0.919, respectively). Similar results were found when analyses were corrected for covariates. CONCLUSIONS: In older individuals, depression and insomnia are associated and tend to increase concurrently over time, but constitute no additional risk for one another over repeated three-year intervals. These findings contradict previous research that suggests that depression and insomnia are risk factors for one another over time. The current study stands out due to the longitudinal within-individual statistical approach, but is limited by the three-year interval between measures.

Insulin resistance as a marker for the immune-metabolic subtype of depression.

OBJECTIVE: Insulin resistance (IR), a marker of metabolic dysregulation and pro-inflammatory state, moderates the antidepressant treatment effect in patients with type 2 diabetes (T2D) and is therefore a potential marker for personalized treatment. Based on data from a light therapy trial (NTR4942), we aimed to evaluate whether 1) depression symptoms differ according to the level of IR, and 2) improvement of specific depression symptoms drive the positive effects of light therapy in those with higher IR. METHODS: This secondary analysis in 59 individuals with depression and T2D explored differences in depressive symptom profile (30-item Inventory of Depressive Symptomatology (IDS)) at baseline and in response to light therapy (versus placebo), between lower and higher IR individuals, using Likelihood Ratio tests and Linear-by-linear association. IR was measured using the gold standard, a hyperinsulinemic-euglycaemic clamp. RESULTS: At baseline, higher IR individuals reported more symptoms of irritability (p=0.024) anhedonia (no interest in people and activities: p=0.011; absence of pleasure and enjoyment: p=0.021), fatigue (fatigue: p=0.036; physical fatigue: p=0.035) and hypersomnia (p=0.029) relative to persons with lower IR, who reported more insomnia (nightly awakening: p=0.041; early morning awakening: p=0.012). Light therapy led to an improvement across IDS symptoms in higher IR individuals, while in lower IR individuals, light therapy improved early morning awakening (p=0.005) and interest in people and activities (p=0.015), but worsened mood (feeling sad: p=0.001; feeling irritable: p=0.002; interpersonal sensitivity: p=0.014). CONCLUSIONS: Results add to the hypothesis of an immune-metabolic subtype of depression, and suggest that IR might be a promising focus for precision medicine.

Glucose variability and mood in adults with diabetes: A systematic review.

Aims: To systematically review the literature regarding the association between glucose variability (GV) and mood in adults with diabetes, appraise the used methods and make suggestions for future research. Methods: A systematic review of literature published up to May 2019 was performed. Abstracts and full texts were screened independently in duplicate. Experimental and observational studies reporting the association between GV and mood in adults with type 1 diabetes or type 2 diabetes were evaluated. A descriptive analysis of the extracted data was conducted, along with a quality assessment. Results: Out of the 2.316 studies screened, eight studies met our criteria. Studies used a variety of measures and metrics to determine GV and mood. Four studies used continuous glucose monitoring (CGM). An association between GV and mood was found in four studies when correlating either postprandial glucose rate of increase with current mood or multiday GV with mood measured retrospectively. The other four studies did not find any association. Conclusions: There is no clear empirical support for a link between GV and mood in adults with type 1 and type 2 diabetes. More rigorous research is warranted using CGM and ecological momentary assessment of mood to assess if and under what conditions an association between GV and mood exists.

Impact of sleep deprivation and high-fat feeding on insulin sensitivity and beta cell function in dogs.

AIMS/HYPOTHESIS: Insufficient sleep is increasingly recognised as a major risk factor for the development of obesity and diabetes, and short-term sleep loss in clinical studies leads to a reduction in insulin sensitivity. Sleep loss-induced metabolic impairments are clinically relevant, since reductions in insulin sensitivity after sleep loss are comparable to insulin sensitivity differences between healthy individuals and those with impaired glucose tolerance. However, the relative effects of sleep loss vs high-fat feeding in the same individual have not been assessed. In addition, to our knowledge no diurnal (active during the daytime) non-human mammalian model of sleep loss-induced metabolic impairment exists, which limits our ability to study links between sleep and metabolism. METHODS: This study examined the effects of one night of total sleep deprivation on insulin sensitivity and beta cell function, as assessed by an IVGTT, before and after 9 months of high-fat feeding in a canine model. RESULTS: One night of total sleep deprivation in lean dogs impaired insulin sensitivity to a similar degree as a chronic high-fat diet (HFD)(normal sleep: 4.95 ± 0.45 mU-1 l-1 min-1; sleep deprivation: 3.14 ± 0.21 mU-1 l-1 min-1; HFD: 3.74 ± 0.48 mU-1 l-1 min-1; mean ± SEM). Hyperinsulinaemic compensation was induced by the chronic HFD, suggesting adequate beta cell response to high-fat feeding. In contrast, there was no beta cell compensation after one night of sleep deprivation, suggesting that there was metabolic dysregulation with acute sleep loss that, if sustained during chronic sleep loss, could contribute to the risk of type 2 diabetes. After chronic high-fat feeding, acute total sleep deprivation did not cause further impairments in insulin sensitivity (sleep deprivation + chronic HFD: 3.28 mU-1 l-1 min-1). CONCLUSIONS/INTERPRETATION: Our findings provide further evidence that sleep is important for metabolic health and establish a diurnal animal model of metabolic disruption during insufficient sleep.

Sleep and HbA1c in Patients With Type 2 Diabetes: Which Sleep Characteristics Matter Most?

OBJECTIVE: Poor sleep has been identified as a risk factor for poor glycemic control in individuals with type 2 diabetes (T2D). As optimal sleep can be characterized in several ways, we evaluated which sleep characteristics are most strongly associated with glycated hemoglobin A1c (HbA1c). RESEARCH DESIGN AND METHODS: A total of 172 patients with T2D completed 7-day wrist-actigraphy and sleep questionnaires. Linear regression was used to evaluate associations between sleep measures (total sleep duration, variability in sleep duration, midsleep time, variability in midsleep time, sleep efficiency, subjective sleep quality, and subjective insomnia symptoms) and HbA1c, individually and in concert. RESULTS: Variability in sleep duration was individually most strongly associated with HbA1c (ß = 0.239; P = 0.002; R 2 = 4.9%), followed by total sleep duration (U-shaped: ß = 1.161/ß2 = 1.044; P = 0.017/0.032; R 2 = 4.3%), subjective sleep quality (ß = 0.191; P = 0.012; R 2 = 3.6%), variability in midsleep time (ß = 0.184; P = 0.016; R 2 = 3.4%), and sleep efficiency (ß = -0.150; R 2 = 2.3%). Midsleep time and subjective insomnia symptoms were not associated with HbA1c. In combination, variability in sleep duration, total sleep duration, and subjective sleep quality were significantly associated with HbA1c, together explaining 10.3% of the variance in HbA1c. Analyses adjusted for covariates provided similar results, although the strength of associations was generally decreased and showing total sleep duration and subjective sleep quality to be most strongly associated with HbA1c, together explaining 6.0% of the variance in HbA1c. CONCLUSIONS: Sleep in general may be a modifiable factor of importance for patients with T2D. The prevention of sleep curtailment may serve as a primary focus in the sleep-centered management of T2D.

Effects of Light Therapy on Mood and Insulin Sensitivity in Patients With Type 2 Diabetes and Depression: Results From a Randomized Placebo-Controlled Trial.

OBJECTIVE: Depression is common in patients with type 2 diabetes and adversely affects quality of life and diabetes outcomes. We assessed whether light therapy, an antidepressant, improves mood and insulin sensitivity in patients with depression and type 2 diabetes. RESEARCH DESIGN AND METHODS: This randomized, double-blind, placebo-controlled trial included 83 patients with depression and type 2 diabetes. The intervention comprised 4 weeks of light therapy (10,000 lux) or placebo light therapy daily at home. Primary outcomes included depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and insulin sensitivity (M-value derived from the results of a hyperinsulinemic-euglycemic clamp). Secondary outcomes were related psychological and glucometabolic measures. RESULTS: Intention-to-treat analysis showed that light therapy was not superior to placebo in reducing depressive symptoms (-3.9 IDS points [95% CI -9.0 to 1.2]; P = 0.248) and had no effect on insulin sensitivity (0.15 mg/kg*min [95% CI -0.41 to 0.70]; P = 0.608). Analyses incorporating only those participants who accurately adhered to the light therapy protocol (n = 51) provided similar results, but did suggest positive effects of light therapy on depression response rates (≥50% reduction in IDS points) (26% more response; P = 0.031). Prespecified analysis showed effect moderation by baseline insulin sensitivity (P = 0.009) and use of glucose-lowering medication (P = 0.023). Light therapy did not affect depressive symptoms in participants with higher insulin sensitivity or those who use only oral glucose-lowering medication or none at all, but it did produce a relevant effect in participants with lower insulin sensitivity (-12.9 IDS points [95% CI -21.6 to -4.2]; P = 0.017) and a trend toward effectiveness in those using insulin (-12.2 IDS points [95% CI -21.3 to -3.1]; P = 0.094). Light therapy was well tolerated. CONCLUSIONS: Although this trial is essentially inconclusive, secondary analyses indicate that light therapy might be a promising treatment for depression among a subgroup of highly insulin-resistant individuals with type 2 diabetes.

Light therapy for better mood and insulin sensitivity in patients with major depression and type 2 diabetes: a randomised, double-blind, parallel-arm trial.

BACKGROUND: Major depression and type 2 diabetes often co-occur. Novel treatment strategies for depression in type 2 diabetes patients are warranted, as depression in type 2 diabetes patients is associated with poor prognosis and treatment results. Major depression and concurrent sleep disorders have been related to disturbances of the biological clock. The biological clock is also involved in regulation of glucose metabolism by modulating peripheral insulin sensitivity. Light therapy has been shown to be an effective antidepressant that 'resets' the biological clock. We here describe the protocol of a study that evaluates the hypothesis that light therapy improves mood as well as insulin sensitivity in patients with a major depressive episode and type 2 diabetes. METHODS/DESIGN: This study is a randomised, double-blind, parallel-arm trial in 98 participants with type 2 diabetes and a major depressive episode, according to DSM-IV criteria. We will assess whether light therapy improves depressive symptoms and insulin sensitivity, our primary outcome measures, and additionally investigate whether these effects are mediated by restoration of the circadian rhythmicity, as measured by sleep and hypothalamic-pituitary-adrenal axis activity. Participants will be randomly allocated to a bright white-yellowish light condition or dim green light condition. Participants will undergo light therapy for half an hour every morning for 4 weeks at home. At several time points, namely before the start of light therapy, during light therapy, after completion of 4 weeks of light therapy and after 4 weeks follow-up, several psychometrical, psychophysiological and glucometabolic measures will be performed. DISCUSSION: If light therapy effectively improves mood and insulin sensitivity in type 2 diabetes patients with a major depressive episode, light therapy may be a valuable patient friendly addition to the currently available treatment strategies. Additionally, if our data support the role of restoration of circadian rhythmicity, such an observation may guide further development of chronobiological treatment strategies in this patient population. TRIAL REGISTRATION: The Netherlands Trial Register (NTR) NTR4942 . Registered 13 January 2015.

NMDA-receptor coagonists in serum, plasma, and cerebrospinal fluid of schizophrenia patients: a meta-analysis of case-control studies.

Serine and other amino acids that function as coagonists at the N-methyl-d-aspartate receptor (NMDAR) have been extensively investigated in schizophrenia (SCZ). However, studies comparing amino acid levels in body fluids of SCZ patients with healthy controls have yielded inconsistent results. We therefore conducted a meta-analysis (search: May 9, 2013) of serine, l-serine, d-serine, glycine, alanine, proline, and aspartate levels in blood and cerebrospinal fluid (CSF) obtained from adult SCZ patients and healthy controls. Standardized differences of means (SDMs) were computed, and heterogeneity, subgroup, sensitivity, and publication bias analyses were conducted. Blood serine levels were found to be significantly higher in SCZ patients compared to healthy controls (SDM=0.280 (0.021-0.540), p=0.034; N=1671 subjects), whereas CSF serine, l-serine, d-serine, glycine, alanine, proline, and aspartate levels did not differ. Stratification by sex suggested that the case-control difference in blood serine levels particularly applies to male subjects. These results provide support for blood serine level aberrations in SCZ patients and warrant further research to disentangle the involvement of serine with SCZ in both sexes.

Involvement of the endocannabinoid system in reward processing in the human brain.

RATIONALE: Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear. OBJECTIVES: The current study uses functional magnetic resonance imaging (fMRI) to investigate the role of the eCB system in reward processing in humans by examining the effect of the eCB agonist Δ(9)-tetrahydrocannabinol (THC) on reward-related brain activity. METHODS: Eleven healthy males participated in a randomized placebo-controlled pharmacological fMRI study with administration of THC to challenge the eCB system. We compared anticipatory and feedback-related brain activity after placebo and THC, using a monetary incentive delay task. In this task, subjects are notified before each trial whether a correct response is rewarded ("reward trial") or not ("neutral trial"). RESULTS: Subjects showed faster reaction times during reward trials compared to neutral trials, and this effect was not altered by THC. THC induced a widespread attenuation of the brain response to feedback in reward trials but not in neutral trials. Anticipatory brain activity was not affected. CONCLUSIONS: These results suggest a role for the eCB system in the appreciation of rewards. The involvement of the eCB system in feedback processing may be relevant for disorders in which appreciation of natural rewards may be affected such as addiction.