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Generalized anxiety disorder (GAD) is a common and persistent mental illness accompanied by uncontrollable worries for daily staff. Physiological, environmental, genetic, and daily stress from surroundings is involved in developing GAD. Here, we aimed to assess the association of stromal cell-derived factor-1 (SDF-1) and epidermal growth factor (EGF) in the pathophysiology of GAD and their role as diagnostic tools. This case-control study recruited 50 GAD patients from the psychiatry department of a tertiary care teaching hospital in Dhaka city and 38 age-sex-matched healthy controls (HCs) from the surrounding areas. A qualified psychiatrist conducted standardized psychiatric interview to diagnose GAD patients and evaluate HCs by applying the diagnostic and statistical manual for mental disorders, 5th edition (DSM-5) and used the GAD-7 scale to assess the severity of the GAD symptoms. After confirming the inclusion and exclusion criteria, we collected 5 ml blood samples from each participant. We measured serum SDF-1 and EGF levels using ELISA techniques. We observed increased serum levels of EGF in GAD patients compared to HCs (5.91 ± 3.90 ng/ml vs. 1.59 ± 1.08 ng/ml; p < 0.001). Also, this increment is positively associated with the severity of GAD in patients (r = 0.479, p = 0.002). The receiver operating characteristic analysis showed good diagnostic performance (AUC 0.869, p < 0.001) with high sensitivity (82.5%), and specificity (81.1%) at cut off value of 2.31 ng/ml. However, we didn't find significant differences in serum SDF-1 levels between GAD patients and HCs (11.96 ± 4.50 ng/ml vs. 12.70 ± 11.76 ng/ml; p = 0.337). The present study suggests that GAD patients have increased serum EGF levels but not SDF-1 levels compared to HCs and that increased EGF levels are associated with increased GAD symptoms as well. Moreover, EGF levels could serve as a biomarker for GAD However, further interventional studies with larger and homogeneous samples are suggested to confirm and establish these findings., (© 2024. The Author(s).)

Importance: Research suggests that low-grade, nonresolving inflammation may predate adult mental and physical illness. However, evidence to date is largely cross-sectional or focuses on single disorder outcomes., Objectives: To examine trajectories of inflammation as measured by C-reactive protein (CRP) levels in a large sample of children and adolescents, and to explore associations between different identified trajectories and mental and related cardiometabolic health outcomes in early adulthood., Design, Setting, and Participants: In a longitudinal cohort study using data from the large UK-based Avon Longitudinal Study of Parents and Children (ALSPAC), latent class growth analysis (LCGA) was used to explore different trajectories of inflammation, with logistic regression exploring association with mental and physical health outcomes. Participants with measurable CRP data and associated mental and cardiometabolic health outcomes recorded were included in the analysis. Data analysis was performed from May 1, 2023, to March 30, 2024., Exposures: Inflammation was assessed via CRP levels at ages 9, 15, and 17 years. LCGA was used to identify different trajectories of inflammation., Main Outcomes and Measures: Outcomes assessed at age 24 years included psychotic disorders, depressive disorders, anxiety disorders, hypomania, and, as a measure of insulin resistance, Homeostasis Model Assessment (HOMA2) score., Results: A total of 6556 participants (3303 [50.4%] female) were included. Three classes of inflammation were identified: persistently low CRP levels (reference class, n = 6109); persistently raised CRP levels, peaking at age 9 years (early peak, n = 197); and persistently raised CRP levels, peaking at age 17 years (late peak, n = 250). Participants in the early peak group were associated with a higher risk of psychotic disorder (odds ratio [OR], 4.60; 95% CI, 1.81-11.70; P = .008), a higher risk of severe depression (OR, 4.37; 95% CI, 1.64-11.63; P = .02), and higher HOMA2 scores (β = 0.05; 95% CI, 0.01-0.62, P = .04) compared with participants with persistently low CRP. The late peak group was not associated with any outcomes at age 24 years., Conclusions and Relevance: Low-grade systemic inflammation peaking in midchildhood was associated with specific mental and cardiometabolic disorders in young adulthood. These findings suggest that low-grade persistent inflammation in early life may be an important shared common factor for mental-physical comorbidity and so could be relevant to future efforts of patient stratification and risk profiling.

Purpose: Few longitudinal studies have investigated the mediating role of inflammation during childhood in associations between prenatal maternal stress and adolescent mental health. The objective of this study was to examine the associations between prenatal maternal stress, concentrations of immune markers at age 9, and symptoms of generalized anxiety disorder (GAD) and depression during adolescence., Methods: This study included 3723 mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Prenatal maternal stress was examined using 55 items measured during pregnancy. Inflammation was assessed using serum concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP) when children were 9 years old. GAD and depression were assessed when children were 16 and 18 years of age, respectively. Analyses comprised of structural equation models., Results: Prenatal maternal stress was associated with higher concentrations of IL-6 in childhood, and with greater symptoms of depression and GAD in adolescence. However, we did not observe associations between prenatal maternal stress and CRP; also, CRP and IL-6 were not associated with depression and GAD. There was no evidence that CRP and IL-6 mediated the associations between prenatal maternal stress and either GAD or depression., Conclusions: Prenatal maternal stress is associated with IL-6 levels in childhood, and with GAD and depression during adolescence. Future studies should examine immune activity at multiple points during development in relation to mental health into adulthood to determine whether inflammation at different points during development could increase risk for mental health problems among children whose mothers experienced significant stressors during pregnancy., Competing Interests: Declaration of Competing Interest No conflict, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Both anxiety symptoms and suicide risk are common in schizophrenia. However, previous findings about the association between anxiety and suicide risk in schizophrenia were controversial. This study is the first to examine the prevalence of suicide risk and related demographic, clinical features in a large sample of first episode drug-naïve (FEDN) schizophrenia patients with comorbid severe anxiety., Methods: In total, 316 patients with FEDN schizophrenia were enrolled in this study. Patients' symptoms were assessed using the Hamilton Depression Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), and Positive and Negative Syndrome Scale (PANSS). Serum levels of glucose, insulin, uric acid, and lipids including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), were evaluated., Results: In the current study, 56.3% patients presented comorbid severe anxiety. The rate of suicide risk was higher in the severe anxiety group (55.6%) than in the mild-moderate anxiety group (33.3%). The interactions among severe anxiety, uric acid and HDL-C were associated with suicide risk. Compared with patients with normal uric acid, those with abnormal uric acid exhibited a stronger association between HAMA scores and HAMD-suicide item scores. This enhanced association was also observed for patients with abnormal HDL-C levels., Conclusions: In FEDN schizophrenia patients with comorbid severe anxiety, our findings suggested a high incidence of suicide risk. Abnormal levels of uric acid and low levels of HDL-C, as well as high depression may be associated with an increased risk of suicide in FEDN schizophrenia patients with comorbid severe anxiety., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In recent times, the pathogenesis of generalized anxiety disorder (GAD) and the influence of pro- and anti-inflammatory cytokines on it have garnered considerable interest. Cytokine research, especially Th-17 cytokine research on GAD patients, is limited. Here, we aim to assess the role of interleukin-17A (IL-17A) and interleukin-23A (IL-23A) in the pathophysiology and development of GAD. This investigation included 50 GAD patients and 38 age-sex-matched healthy controls (HCs). A psychiatrist diagnosed patients with GAD and assessed symptom severity using the DSM-5 and the GAD-7 scales. The serum concentrations of IL-17A and IL-23A were determined using commercially available ELISA kits. GAD patients exhibited elevated levels of IL-17A (77.14 ± 58.30 pg/ml) and IL-23A (644.90 ± 296.70 pg/ml) compared to HCs (43.50 ± 25.54 pg/ml and 334.40 ± 176.0 pg/ml). We observed a positive correlation between disease severity and cytokine changes (IL-23A: r = 0.359, p = 0.039; IL-17A: r = 0.397, p = 0.032). These findings indicate that IL-17A and IL-23A may be associated with the pathophysiology of GAD. ROC analysis revealed moderately higher AUC values (IL-23A: 0.824 and IL-17A: 0.710), demonstrating their potential to discriminate between patients and HCs. Also, the sensitivity values of both cytokines were relatively higher (IL-23A: 80.49% and IL-17A: 77.27%). According to the present findings, there may be an association between peripheral serum levels of IL-17A and IL-23A and the pathophysiology and development of GAD. These altered serum IL-17A and IL-23A levels may play a role in directing the early risk of developing GAD. We recommend further research to ascertain their exact role in the pathophysiology and their performance as risk assessment markers of GAD., (© 2024. The Author(s).)

Background: Inflammatory biomarkers may differentiate clinical disorders, which could lead to more targeted interventions. Analyses within a clinical sample (May et al., 2021) revealed that females with substance use disorders (SUD) exhibited lower C-reactive protein (CRP) and higher interleukin (IL)-8 and -10 concentrations than females without SUD who met criteria for mood/anxiety disorders. We aimed to replicate these findings in a new sample., Methods: Hypotheses and analyses were preregistered. Treatment-seeking individuals with mood/anxiety disorders and/or SUD (N = 184) completed a blood draw, clinical interview, and questionnaires. Participants were categorized as SUD+ (45F, 43M) and SUD- (78F, 18M). Principal component analysis (PCA) of questionnaire data resulted in two factors reflecting appetitive and aversive emotional states. SUD group and nuisance covariates (PCA factors, age, body mass index [BMI], medication, nicotine [and hormones in females]) predicted biomarker concentrations (CRP, IL-8, and IL-10) in regressions., Results: In females, the omnibus CRP model [F(8, 114) = 8.02, p <.001, R²-adjusted =.32] indicated that SUD+ exhibited lower CRP concentrations than SUD- (β = -.33, t = -3.09, p =.002, 95% CI [-.54, -.12]) and greater BMI was associated with higher CRP levels (β =.58, t = 7.17, p <.001, 95% CI [.42,.74]). SUD+ exhibited higher IL-8 levels than SUD- in simple but not omnibus regression models., Conclusion: Findings across two samples bolster confidence that females with SUD show attenuated CRP-indexed inflammation. As SUD+ comorbidity was high, replication is warranted with respect to specific SUD classes (i.e., stimulants versus cannabis)., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Generalized anxiety disorder (GAD) is a devastating mental health condition characterized by constant, uncontrolled worrying. Recent hypotheses indicate that pro-inflammatory cytokines and chemokines are potential contributors to the pathogenesis of GAD. Here, we aimed to assess the role of interleukin-2 (IL-2) and interleukin-10 (IL-10) in the pathophysiology and development of GAD., Methods: This study recruited 50 GAD patients diagnosed according to the DSM-5 criteria and 38 age-sex-matched healthy controls (HCs). A qualified psychiatrist evaluated all study subjects. The socio-demographic and clinical characteristics of the study population were determined using pre-structured questionnaires or interviews, and cytokine serum levels were estimated using commercially available ELISA kits., Results: We observed reduced serum IL-10 levels in GAD patients compared to HCs (33.69 ± 1.37 pg/ml vs. 44.12 ± 3.16 pg/ml). Also, we observed a significant negative correlation between altered IL-10 levels and GAD-7 scores (r=-0.315, p = 0.039). Moreover, IL-10 serum measurement exhibited good predictive value in receiver operating characteristics (ROC) analysis with an area under the curve (AUC) value of 0.793 (p < 0.001) with 80.65% sensitivity and 62.79% specificity at a cutoff value of 33.93 pg/ml. Conversely, we noticed elevated serum IL-2 levels in GAD patients than in HCs (14.81 ± 2.88 pg/ml vs. 8.08 ± 1.1 pg/ml); however, it failed to maintain any significant association with GAD-7 scores, implying that IL-2 might not be involved in GAD pathogenesis. The lower AUC value (0.640; p > 0.05) exhibited by IL-2 serum measurement in ROC analysis further supported that IL-2 might not be associated with GAD., Conclusion: This study provides new insights into the complex interplay between anti-inflammatory cytokines and GAD pathogenesis. Based on the present findings, we can assume that IL-10 but not IL-2 may be associated with the pathophysiology and development of GAD. However, further research with a larger population size and longitudinal design is required to confirm the potential diagnostic efficacy of IL-10., (© 2024. The Author(s).)

Purpose: Poor sleep quality, mood disorders, and vitamin D deficiency are common in stroke. We investigated the association between serum vitamin D levels and pre-stroke sleep quality and the occurrence of poststroke depression (PSD) and poststroke anxiety (PSA) in acute ischemic stroke (AIS)., Methods: This prospective cross-sectional study included hospitalized patients with AIS and age- and sex-matched controls. Vitamin D levels were measured within 24 h of admission. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) at admission. The severity of depression and anxiety symptoms was evaluated according to Beck Depression Inventory and Beck Anxiety Inventory scores, respectively, within 72 h after admission., Results: Comparing 214 AIS patients with 103 controls, patients had significantly higher scores of Beck Depression Inventory, Beck Anxiety Inventory, and PSQI and lower vitamin D levels (p < 0.001). Among AIS patients, Beck Depression Inventory (p = 0.004) and Beck Anxiety Inventory (p = 0.018) scores were significantly higher in bad sleepers (PSQI score ≥ 6) than in good sleepers (PSQI score ≤ 5). Correlation analysis revealed negative correlations between serum vitamin D levels and Beck Depression Inventory (r =  - 0.234; p < 0.001), Beck Anxiety Inventory (r =  - 0.135; p = 0.016), and PSQI (r =  - 0.218; p < 0.001) scores., Conclusion: Decreased serum vitamin D levels at admission are associated with a high risk for PSD and PSA in patients with poor pre-stroke sleep quality during the early stages of AIS., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Major depressive disorder is the leading cause of disability worldwide. Yet, there remain significant challenges in predicting new cases of major depression and devising strategies to prevent the disorder. An important first step in this process is identifying risk factors for the incidence of major depression. There is accumulating biological evidence linking insulin resistance, another highly prevalent condition, and depressive disorders. The objectives of this study were to examine whether three surrogate measures of insulin resistance (high triglyceride-HDL [high-density lipoprotein] ratio; prediabetes, as indicated by fasting plasma glucose level; and high central adiposity, as measured by waist circumference) at the time of study enrollment were associated with an increased rate of incident major depressive disorder over a 9-year follow-up period and to assess whether the new onset of these surrogate measures during the first 2 years after study enrollment was predictive of incident major depressive disorder during the subsequent follow-up period., Methods: The Netherlands Study of Depression and Anxiety (NESDA) is a multisite longitudinal study of the course and consequences of depressive and anxiety disorders in adults. The study population comprised 601 NESDA participants (18-65 years old) without a lifetime history of depression or anxiety disorders. The study's outcome was incident major depressive disorder, defined using DSM-IV criteria. Exposure measures included triglyceride-HDL ratio, fasting plasma glucose level, and waist circumference., Results: Fourteen percent of the sample developed major depressive disorder during follow-up. Cox proportional hazards models indicated that higher triglyceride-HDL ratio was positively associated with an increased risk for incident major depression (hazard ratio=1.89, 95% CI=1.15, 3.11), as were higher fasting plasma glucose levels (hazard ratio=1.37, 95% CI=1.05, 1.77) and higher waist circumference (hazard ratio=1.11 95% CI=1.01, 1.21). The development of prediabetes in the 2-year period after study enrollment was positively associated with incident major depressive disorder (hazard ratio=2.66, 95% CI=1.13, 6.27). The development of high triglyceride-HDL ratio and high central adiposity (cut-point ≥100 cm) in the same period was not associated with incident major depression., Conclusions: Three surrogate measures of insulin resistance positively predicted incident major depressive disorder in a 9-year follow-up period among adults with no history of depression or anxiety disorder. In addition, the development of prediabetes between enrollment and the 2-year study visit was positively associated with incident major depressive disorder. These findings may have utility for evaluating the risk for the development of major depression among patients with insulin resistance or metabolic pathology.

Background: Previous studies showed the possible association between obesity, dietary pattern, and depressive symptoms. Due to the lack of enough data to confirm the association of obesity and depression in the Middle East, here, we aimed to explore the possible mediatory role of adipokines Galectin-3, transforming growth factor-beta (TGF-β), and endothelial plasminogen activator inhibitor (PAI-1) in the association between low carbohydrate diet (LCD) and depressive symptoms., Methods: A total of 256 women aged 17-56 years old were grouped based on their LCD score. Depression anxiety stress scales-21 (DASS-21) self-administered questionnaire was used to evaluate the three negative emotional states of stress, depressive symptoms, and anxiety. Body composition and dietary intake were assessed. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of Galectin-3, TGF-β, and PAI-1., Results: No significant difference was observed regarding Galectin-3, TGF-β, and PAI-1 levels between the groups with dissimilar adherence to LCD or the groups with different levels of depressive symptoms (P>0.05). However, there was a negative association between LCD score as a covariant and depressive symptoms as an independent variable (P = 0.02) and remarkably, a regression model linear analysis using Galectin-3, TGF-β, and PAI-1 as confounding variables indicated the mediatory role of these adipokines in this association (P>0.05). In other words, adipokines eliminated the significance of the relationship between adherence to LCD and depressive symptoms., Conclusion: It seems that higher adherence to LCD is probably associated with a lower prevalence of depressive symptoms in obese adults through the mediatory role of adipokines., Competing Interests: The authors have declared that no competing interests exist.

Context: Excess glucocorticoids impact fetal health. Maternal glucocorticoids peak in early morning. Fetoplacental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to cortisone, protecting the fetus from high glucocorticoids. However, time-specific alterations of human fetoplacental 11β-HSD2 have not been studied., Objective: We hypothesized that fetoplacental 11β-HSD2 activity shows time-specific alteration and acute affective or anxiety disorders impact fetoplacental 11β-HSD2 activity., Methods: In this observational study we investigated 78 pregnant European women undergoing amniocentesis (15.9 ± 0.9 weeks of gestation). Amniotic fluid was collected (8:00 to 16:30 hours) for analysis of fetoplacental 11β-HSD2 activity, using cortisol (F):cortisone (E) ratio in amniotic fluid, E/(E + F). Fetoplacental 11β-HSD2 rhythm and association with "acute affective or anxiety disorder" (patients with at least one of: a major depressive episode, specific phobia, panic disorder, generalized anxiety disorder, mixed anxiety and depressive disorder) and "acute anxiety disorder" (one of: panic disorder, generalized anxiety disorder, mixed anxiety, depressive disorder), assessed using Mini International Neuropsychiatric Interview, were investigated., Results: Activity of 11β-HSD2 correlated with time of amniocentesis, peaking in the morning (r = -0.398; P < 0.001) and increased with acute affective or anxiety disorder (mean [M] = 0.70 vs M = 0.74; P = 0.037) and acute anxiety disorder (M = 0.70 vs M = 0.75; P = 0.016). These associations remained significant when controlling for confounders. 11β-HSD2 activity correlated negatively with pre-pregnancy body mass index (r = -0.225; P = 0.047)., Conclusion: Our study indicates a time-specific alteration of fetoplacental 11β-HSD2 activity with peaking levels in the morning, demonstrating a mechanism of fetal protection from the morning maternal glucocorticoid surge., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Anxiety disorders are a group of mental illnesses that cause constant and overwhelming feelings of anxiety and fear. Excessive anxiety can make an individual avoid work, school, family get-togethers, and other social situations that in turn might amplify these symptoms. According to the World Health Organization (WHO), one in thirteen persons globally suffers from anxiety. It is high time to understand the roles of various clinical biomarker measures that can diagnose the types of anxiety disorders. In this study, we apply machine learning (ML) techniques to understand the importance of a set of biomarkers with four types of anxiety disorders-Generalized Anxiety Disorder (GAD), Agoraphobia (AP), Social Anxiety Disorder (SAD) and Panic Disorder (PD). We used several machine learning models and extracted the variable importance contributing to a type of anxiety disorder. The study uses a sample of 11,081 Dutch citizens' data collected by the Lifelines, Netherlands. The results show that there are significant and low correlations among GAD, AP, PD and SAD and we extracted the variable importance hierarchy of biomarkers with respect to each type of anxiety disorder which will be helpful in designing the experimental setup for clinical trials related to influence of biomarkers on type of anxiety disorder., Competing Interests: The authors have declared that no competing interests exist.

The aim of the study was to explore the metabolic characteristics and outcome parameters in youth with type 1 diabetes and anxiety disorders. HbA1c levels, rates of severe hypoglycemia, diabetic ketoacidosis (DKA), and hospital admission in children, adolescents, and young adults with type 1 diabetes and an anxiety disorder from 431 diabetes-care-centers participating in the nationwide German/Austrian/Swiss/Luxembourgian diabetes survey DPV were analyzed and compared with youth without anxiety disorders. Children, adolescents, and young adults with type 1 diabetes and anxiety disorders (n = 1325) had significantly higher HbA1c (8.5% vs. 8.2%), higher rates of DKA (4.2 vs. 2.5 per 100 patient-years), and higher hospital admission rates (63.6 vs. 40.0 per 100 patient-years) than youth without anxiety disorders (all p < 0.001). Rates of severe hypoglycemia did not differ. Individuals with anxiety disorders other than needle phobia (n = 771) had higher rates of DKA compared to those without anxiety disorders (4.2 vs. 2.5 per 100 patient-years, p = 0.003) whereas the rate of DKA in individuals with needle phobia (n = 555) was not significantly different compared to those without anxiety disorders. Children, adolescents, and young adults with anxiety disorders other than needle phobia had higher hospitalization rates (73.7 vs. 51.4 per 100 patient-years) and more inpatient days (13.2 vs. 10.1 days) compared to those with needle phobia (all p < 0.001). Children, adolescents, and young adults with type 1 diabetes and anxiety disorders had worse glycemic control, higher rates of DKA, and more hospitalizations compared to those without anxiety disorders. Because of the considerable consequences, clinicians should screen for comorbid anxiety disorders in youth with type 1 diabetes., (© 2021 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

Prolonged stress has been associated with elevated levels of circulating proinflammatory cytokines. Cyclo-oxygenase-2 inhibitors such as celecoxib exert anti-inflammatory effects and may enhance the response to antidepressant drug treatment in patients with depressive disorders, but their effect on anxiety symptoms in patients with anxiety disorders is uncertain. Patients with a primary diagnosis of an anxiety disorder, with stabilised symptoms, underwent either 6 weeks of celecoxib augmentation of continued treatment (n = 18) or continued 'treatment as usual' (n = 9). Assessments included the Warwick-Edinburgh mental well-being Scale (WEMWEBS), Hospital Anxiety and Depression Scale (HADS), Oxford questionnaire of emotional side effects of antidepressants (OQUESA) and Clinical Global Impression of Illness Severity (CGI-S). Venous blood samples were collected for assays of inflammatory cytokines. Patients who underwent celecoxib augmentation showed significant reductions in anxiety (HADS-A -3.17) and depressive (HADS-D -2.11) symptoms and in overall illness severity (CGI-S -1.11), and improvements in mental well-being (WEMWBS 7.5) and positive changes in emotional responsiveness (OQUESA-RP -3.56; OQUESA-AC -4.22): these were not seen with 'treatment as usual'. There were no significant changes in blood levels of inflammatory cytokines in either group. Celecoxib augmentation appeared associated with beneficial effects on anxiety and depressive symptoms and mental well-being. The findings from this pilot study merit further exploration within a double-blind, randomised placebo-controlled study., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Substance use disorders (SUD) with comorbid depression and anxiety are linked to poor treatment outcome and relapse. Although some depressed individuals exhibit elevated blood-based inflammation (interleukin-6 [IL-6] and C reactive protein [CRP]), few studies have examined whether the presence of SUD exacerbates inflammation., Methods: Treatment-seeking individuals with major depressive disorder (MDD), anxiety disorders, and/or SUD (N = 160; 80 % with MDD) recruited into the Tulsa 1000 study provided blood samples, participated in clinical interviews, and completed a questionnaire battery querying symptoms of current psychopathology and emotional processing. Analyses followed a multistep process. First, groups were created on the presence versus absence of 1+ lifetime SUD diagnoses: SUD+ (37 F, 43 M) and SUD- (60 F, 20 M). Second, a principal component analysis (PCA) of questionnaire data resulted in two factors, one indexing negative emotionality/withdrawal motivation and one measuring positive emotionality/approach motivation. Third, SUD groups, extracted PCA factors, and nuisance covariates (age, body mass index [BMI], nicotine use, psychotropic medication [and hormone/contraception use in females]) were entered as simultaneous predictors of blood-based inflammation (IL-6, IL-8, IL-10, tumor necrosis factor-α, and CRP)., Results: Within females, SUD + exhibited higher IL-8 and IL-10 but lower CRP levels than SUD-. In contrast, SUD was not associated with biomarker levels in males. Across sexes, higher BMI was linked to higher IL-6 and CRP levels, and within the five biomarkers, IL-6 and CRP shared the most variance., Conclusion: These findings point to sex-specific inflammatory profiles as a function of SUD that may provide new targets for intervention., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Anxiety disorder is a common non-motor symptom in patient with Parkinson's disease (PD). We aimed to explore its pathogenesis and identify plasma biomarkers using untargeted metabolomics analysis., Methods: Consecutive PD patients and healthy controls were recruited. Clinical data were assessed and patients with Parkinson's disease related anxiety disorder (PDA) were recognized. Fast plasma samples were obtained and untargeted liquid chromatography-mass spectrometry-based metabolomics analysis was performed. Based on the differentially expressed metabolites from the above metabolomics analysis, correlation analyses and receiver operating characteristic curves (ROC) were further employed., Results: According to the clinical data, PDA patients had lower plasma levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and apolipoprotein B. There were thirty-nine differentially expressed metabolites in PDA patients when compared with the other two groups from the metabolomics analysis, respectively. Fourteen lipid metabolites were simultaneously altered between these two groups, and all of them were significantly decreased. They can be further subcategorized into fatty acyls, glycerolipids, sterol lipids, sphingolipids, and prenol lipids. The plasma levels of thirteen metabolites were negatively correlated with HAMA scores except 10-oxo-nonadecanoic acid. Based on the ROC curves, the fourteen lipid metabolites can be diagnostic biomarkers for PDA patients separately and the areas under the curve of the fourteen lipid metabolites ranged from 0.681 to 0.798., Conclusions: Significantly lower plasma lipoproteins can be found in PDA patients. A panel of fourteen lipid metabolites were also significantly decreased and can be clinical biomarkers for the diagnosis of PDA patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Preliminary evidence is promising regarding the anxiolytic effects of statins in animal models of anxiety. Hence, this study aimed to evaluate the efficacy of simvastatin augmentation versus placebo in the treatment of patients with generalized anxiety disorder (GAD) with residual symptoms despite treatment with selective serotonin reuptake inhibitors (SSRIs)., Methods: A double-blind, 8-week controlled trial was conducted from August 2018 to December 2019 in an outpatient psychiatry clinic in Hamadan, Iran. A total of 138 patients with a diagnosis of GAD were assessed for eligibility. Of them, 84 patients who met the study criteria were randomly assigned either to the adjuvant simvastatin (20 mg/day) or to the placebo group. Standard medication consisting of SSRIs was consistent 2 months prior to and during the study. The severity of anxiety symptoms for each patient was assessed based on the Hamilton Anxiety Rating Scale (HAM-A) score at baseline, week 4, and week 8 after treatment. Additionally, blood lipid values were assessed at baseline and on completion of the study., Results: Thirty-three out of 42 patients in the intervention group and 35 out of 42 patients in the control group completed the 8 weeks of the study period. Compared to the placebo group, in the simvastatin group cholesterol, triglycerides, and low-density lipoprotein significantly decreased, and high-density lipoprotein significantly increased over time. General linear model analysis demonstrated that although over time a higher decrease in mean HAM-A scores was observed in the intervention group compared to the control group, this difference was not statistically significant (p = 0.11). In addition, at the end of the study, the number of responders and remitters was comparable in the two groups., Conclusions: The results from this clinical study did not support the potential efficacy of adjunctive simvastatin in the treatment of patients with GAD. Thus, large-scale and long-term clinical trials are required to more accurately assess the potential efficacy of statins in the treatment of patients with anxiety disorders., (© 2020 S. Karger AG, Basel.)

The two peptides phoenixin and nesfatin-1 are colocalized in hypothalamic nuclei involved in the mediation of food intake and behavior. Phoenixin stimulates food intake and is anxiolytic, while nesfatin-1 is an anorexigenic peptide shown to increase anxiety and anhedonia. Interestingly, central activation of both peptides can be stimulated by restraint stress giving rise to a role in the mediation of stress. Thus, the aim of the study was to test whether also peripheral circulating levels of NUCB2/nesfatin-1 and phoenixin are altered by restraint stress. Male ad libitum fed Sprague Dawley rats equipped with a chronic intravenous catheter were subjected to restraint stress and plasma levels of NUCB2/nesfatin-1, phoenixin and cortisol were measured over a period of 240 min and compared to levels of freely moving rats. Peripheral cortisol levels were significantly increased in restrained rats at 30, 60, 120 and 240 min compared to controls (p < 0.05). In contrast, restraint stress decreased plasma phoenixin levels at 15 min compared to unstressed conditions (0.8-fold, p < 0.05). Circulating NUCB2/nesfatin-1 levels were increased only at 240 min in restrained rats compared to those in unstressed controls (1.3-fold, p < 0.05). In addition, circulating NUCB2/nesfatin-1 levels correlated positively with phoenixin levels (r = 0.378, p < 0.001), while neither phoenixin nor nesfatin-1 were associated with cortisol levels (r = 0.0275, and r=-0.143, p> 0.05). These data suggest that both peptides, NUCB2/nesfatin-1 and phoenixin, are affected by restraint stress, although less pronounced than circulating cortisol., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Major depressive disorder (MDD) is associated with alterations in circulatory cytokines, in adults as well as in children and adolescents. Administration of selective serotonin reuptake inhibitors (SSRIs) to MDD pediatric patients modifies cytokine levels. However, most studies only assessed changes over a short time period. In this study, we evaluated long-term effects of the SSRI fluoxetine (FLX) in children and adolescents treated for anxiety and/or MDD, including a high-risk group with pre-treatment suicidality. The study group included ninety-two patients (35 boys and 57 girls) with MDD and/or anxiety disorders, aged 13.90 ± 2.41 years. All patients were treated with FLX and followed for 6 months. The study group included children with pretreatment suicidality (high-risk group;N = 62) and without pretreatment suicidality (N = 30) according to the Columbia Suicide Severity Rating Scale. Plasma concentrations of TNFα, IL-6, and IL-1β were measured by enzyme linked immunosorbent assays before and after six months of treatment. IL-6 and IL-1β significantly increased as a factor of time after 6 months of treatment. The elevation was statistically significant confined to children with pretreatment suicidality. Within the children with pretreatment suicidality, IL-6 levels increased significantly after 6 months only in the children who developed SSRI-associated suicidality. To summarize, an increase in IL-6 levels after 6 months of treatment may be associated with SSRI-emergent suicidality in children with pretreatment suicidality. Further studies are needed to clarify the role and mechanism(s) of IL-6 in the pathogenesis of this life-threatening adverse event., Competing Interests: Conflict of Interest None., (Copyright © 2020. Published by Elsevier B.V.)

Omega-3 long-chain polyunsaturated fatty acid ( n -3 FA) status may be associated with mood disorders. Here, we evaluated the potential association between antenatal depression/anxiety and n -3/ n -6 FA in (a) maternal erythrocytes and (b) human milk. In addition, we explored associations between n -3/ n -6 FA in erythrocytes and in human milk and postpartum depression, while controlling for antenatal depression. Twenty-seven pregnant women diagnosed with a current major depressive disorder (MDD; n = 9), anxiety disorder (AD; n = 10) or a mixed anxiety-depression disorder (MADD; n = 8), and 40 healthy controls were included. n -3/ n -6 FA were determined in maternal erythrocytes in gestational week 32 and in human milk in postpartum week 1. In the first week postpartum, the Edinburgh - Postnatal - Depression - Questionnaire was used to assess postpartum depression. Results show that women with M(A)DD had significantly lower erythrocyte levels of total n -3 FA, EPA, DHA and DGLA, and significantly higher n -6 DPA, and n -6: n -3, AA:EPA and n -6 DPA:DHA ratios compared to healthy controls. No significant associations between antenatal depression or anxiety and n -3/ n -6 FA in human milk were found. After controlling for antenatal mental health, n -3/ n -6 FA in maternal erythrocytes or in human milk were not significantly associated with postpartum depression. In conclusion, antenatal depression, alone or with an anxiety disorder, was associated with lower n -3 FA levels and higher n -6: n -3 FA ratios in maternal erythrocytes during gestation. This study provides some insights into the associations between n -3/ n -6 FA levels during pregnancy and lactation and perinatal mental health.

Mild traumatic brain injury (mTBI) has been linked to mental health disorders (MHDs) and pituitary function alterations. Due to the complex relationship of mTBI, the neuroendocrine system, and MHDs, we propose that neuroendocrine dysfunction (NED) may play a role in negative long-term health outcomes. The goal of this study was to determine if blast-concussed service members (SMs) have a stronger likelihood of developing NED. We hypothesized that NED either pre- or post-injury is associated with poor mental and physical health outcomes. Serum samples from the Armed Forces Health Surveillance Branch were obtained from concussed (n = 59) and non-concussed (n = 72) SMs treated at the Concussion Restoration Care Center (CRCC) in Afghanistan. Serum was collected within 2 years prior to deployment and one or two times within 3 years following their CRCC visit. Samples were analyzed for luteinizing hormone (LH), testosterone, human growth hormone, cortisol, and prolactin to assess post-injury neuroendocrine function. Results indicate that SMs who incurred an mTBI exhibited long-term LH and testosterone deficiencies 3 years following injury compared to controls. Specifically, 47.6% of head-injured SMs displayed hypofunction in at least one of five hormones at 3 years post-injury. Anxiety disorders were the most common MHD observed in concussed SMs with hypopituitarism, while there was also a trend for SMs with chronic pituitary dysfunction to have MHD diagnoses. Findings indicate blast-related mTBI may be associated with long-term health outcomes following a period of incubation. Neuroendocrine screenings may increase treatment opportunities, inform rehabilitation strategies, and improve overall quality of life for patients., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: The purpose of this study was to evaluate the differences among panic disorder (PD), generalised anxiety disorder (GAD) and controls in inflammatory cytokines. We also analysed the correlation between inflammatory cytokines and response to escitalopram in PD and GAD patients., Methods: Eighty-six patients with PD, 86 patients with GAD and 86 healthy controls were recruited for this study. All participants were, respectively, assessed for severity of anxiety and panic symptoms using the Hamilton Anxiety Rating Scale (HAMA) and the Panic Disorder Severity Scale (PDSS); all patients in the study were also assessed after 4 weeks of treatment. The serum levels of cytokines were measured using a flow fluorescence microsphere assay., Results: Both PD and GAD patients had higher serum levels of interleukin 6 (IL-6) than controls, and patients with PD showed significantly higher IL-6 than GAD patients. Significant positive correlations were found between the IFN-γ levels and the severity of anxiety in GAD patients. Higher level of IL-6 was associated with better response to escitalopram treatment in PD patients. However, the baseline levels of cytokines were not associated with treatment responses in GAD patients., Conclusion: The present findings suggest that patients with PD may have higher levels of IL-6 than GAD, and higher baseline levels of IL-6 may be a better response to escitalopram in the treatment of PD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The study examined the effect on cardiac autonomic tone via heart rate variability (HRV), brain derived neurotrophic factor (BDNF) in newly diagnosed generalised anxiety disorder (GAD) cases with paroxetine-controlled release (PX) CR intervention. Methods: Fifty GAD cases using DSM-5 criteria, matched with healthy controls (HC) were assessed with clinical measures (Hamilton Anxiety Scale (HAM-A), Clinical Global Impression- Severity Scale (CGI-Severity), General Health Questionnaire -12 (GHQ-12), HRV, plasma BDNF levels initially and 6 weeks postintervention with paroxetine CR. Results: HRV parameters were significantly lower in GAD vs HC at baseline for standard deviation of normal to normal intervals (SDNN) and proportion of differences in consecutive NN intervals that are longer than 50 ms (pNN50). Significantly higher plasma BDNF levels were noted between HC versus GAD at baseline. Postintervention HAM-A, CGI scores, GHQ-12 item scores showed significant reduction. Significant differences also noted in square root of mean squared difference of successive NN intervals (RMSSD), (SDNN), pNN50 and in plasma BDNF levels after intervention within GAD group. Significant negative correlation observed between HAM-A scores and SDNN parameter after taking PX CR in GAD. Conclusion: GAD showed cardiac autonomic dysfunction, lowered plasma BDNF levels and their improvement with paroxetine CR.Key messageGAD is associated with significantly lower HRV, suggestive of cardiac autonomic dysfunction and lowered plasma BDNF levels, an indicator of stress.Therapeutic intervention with Paroxetine in GAD patients showed clinically significant improvement reflecting restoration of the cardiac autonomic tone and BDNF levels, thus implying their role as potential biomarkers.

Objectives: The relationships between orexins and stress-related conditions have been well documented in animal studies. However, human studies confirming this relationship are limited. The aim of this study was to investigate the association between orexin-A and anxiety disorders in adolescents. Additionally, we aimed to examine the relationship between orexin-A and cortisol levels in those with anxiety disorders. Methods: A total of 56 medication-free adolescents diagnosed with any anxiety disorder, except for specific phobias, and 32 healthy controls were included in this study. Depression, state and trait anxiety levels of the participants were measured using self-report scales. Orexin-A and cortisol levels were measured by an enzyme-linked immunosorbent assay (ELISA). Results: Analysis of covariance (ANCOVA) indicated that serum orexin-A levels were significantly higher in the anxiety disorder group than in the control group while controlling for age, sex and depression levels. After controlling for age and sex, orexin-A levels were positively and negatively correlated to depression and cortisol levels, respectively. In addition, a positive correlation trend between trait anxiety and orexin-A was found. Conclusions: Orexin-A levels are higher in adolescents with anxiety disorder; however, depressive symptoms should be considered when investigating this relationship.

Background: Placental endocrine insufficiency may increase the risk of depression and anxiety during pregnancy and/or after birth. This study investigated the association between serum human placental lactogen (hPL) and measures of perinatal mental health, accounting for selective serotonin-reuptake inhibitor (SSRI) usage., Method: Caucasian women with singleton, term pregnancies recruited at their pre-surgical appointment prior to an elective caesarean section (ELCS) were studied. Serum hPL levels were measured by ELISA in maternal blood collected at the pre-surgical appointment. Depression and anxiety scores were derived from Edinburgh Postnatal Depression Scale (EPDS) and the trait subscale of the State-Trait Anxiety Inventory (STAI) questionnaires completed at recruitment and three postnatal time points. Data was analysed by unadjusted and adjusted multiple linear regression., Results: In adjusted linear regressions, term maternal serum hPL levels were negatively associated with postnatal EPDS and STAI score ten weeks postnatal for mothers who had girls (B= -.367, p = .022, 95% CI -.679, -.056; and B= -.776, p = .030, 95% CI -1.475, -.077 respectively). Excluding women prescribed SSRIs strengthened the relationship at 10 weeks and uncovered an earlier association between hPL and mood scores within one week of delivery (EPDS B= -.357, p = .041, 95 % CI -.698, -.015; and STAI B= -.737, p = .027, 95 % CI -1.387, -.086). In mothers who had boys, there were no associations between hPL and mood scores at any time point., Conclusion: Low hPL at term associated with postnatal depression and anxiety symptoms exclusively in mothers of girls. Insufficiency in hPL may contribute to maternal mood symptoms., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Although anxiety disorders are among the most prevalent of psychiatric disorders, childhood trauma-related studies seldom consider anxiety proneness as distinct aetiological contributor. We aimed to distinguish between trauma- and anxiety-associated physiological profiles. South African adolescent volunteers were categorised for trauma exposure (CTQ, mean score 39±11) and anxiety proneness (AP)(CASI, mean score 37±7, STAI-T, mean score 41±8). Circulating hormone and leukocyte glucocorticoid receptor levels, as well as leukocyte functional capacity, were assessed. AP was associated with lower DHEAs (P<0.05) and higher leukocyte GR expression (P<0.05). DHEAs was also negatively correlated with anxiety sensitivity (CASI, P<0.05). In conclusion, AP may have more predictive power than trauma in terms of health profile. Increased glucocorticoid sensitivity previously reported after trauma, may be a unique function of anxiety and not trauma exposure per se. DHEAs concentration was identified as potentially useful marker for monitoring progressive changes in HPA-axis sensitivity and correlated with psychological measures of anxiety., Competing Interests: The authors have declared that no competing interests exist.

Background: The postpartum period can be a vulnerable time during which many women are prone to mood disturbances. Since telomere length (TL) is known to be associated with dysphoric moods, inflammation, and stress in many populations, this study's objective was to assess the relationships among TL, dysphoric moods, stress, and inflammation during the postpartum period., Method: This cross-sectional pilot study is a secondary analysis of data collected in a larger parent study of anti-thyroid peroxidase (TPO) enzyme antibody positive versus negative women. The parent study followed selected mothers every month for 6 postpartum months. From this parent study, a random sample of preserved peripheral blood mononuclear cells from 97 participants collected at 2-4 months postpartum were measured for TL. Data were available on the production of interleukin-6 (IL-6), an inflammatory cytokine, in stimulated ex vivo cultures for 59 of these women. Dysphoric moods and stress were measured. Pearson correlations and linear regressions were performed, controlling for postpartum thyroiditis status and age., Results: There were no statistically significant relationships between TL and demographic factors, stress, depression, or TPO status. There were significant negative correlations between TL and anxiety and a trend for a relationship between TL and IL-6 levels. IL-6 levels were significantly, positively associated with negative moods., Conclusions: Higher anxiety scores and inflammation were associated with shorter TL. Inflammation was related to anxiety and other dysphoric moods and was marginally associated with shorter TLs.

Background: Generalized anxiety disorder (GAD) is a persistent and common mental disorder that entails significant impairments in role functioning and quality of life. Currently available effective interventions include psychological therapies, self-help approaches, and pharmacological treatments, which do not quite meet clinical needs, and the ideal anxiolytic is still being sought. Shu-gan-qing-re (SGQR) formula, a Chinese patent medicine, has been well received by patients with GAD in Chinese clinical practice for years. The present prospective, double-blind, double-dummy, randomized controlled trial is designed to investigate the efficacy and safety of SGQR formula for GAD., Methods/design: A total of 200 eligible participants will be recruited from four hospitals in different parts of China. They will be randomly assigned to either the study group or the control group in a ratio of 1:1. Participants allocated to the study group will receive SGQR formula and buspirone placebo, while buspirone and SGQR placebo will be applied in the control group. Six scheduled visits will be conducted over the course of 8 weeks. Outcome measurements include Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale-17 (HAMD-17), Clinical Global Impression-Improvement Scale (CGI-I), Traditional Chinese Medicine Syndrome Scale for GAD, and pro-inflammatory cytokine tests: interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha. Adverse reactions will be evaluated by using the Treatment Emergent Symptom Scale (TESS). Safety outcomes and adverse events will also be recorded., Discussion: The study will provide scientific and objective assessments for the efficacy and safety of SGQR formula for patients with GAD, hopefully offering clinicians an alternative approach to GAD., Trial Registration: Chinese Clinical Trial Registry, ID: ChiCTR-IPR-17013058. Registered on October 20, 2017.

Background: The bidirectional interaction between melatonin and the immune system has largely gone unexplored in a clinical context and especially in a psychiatric population. This study explored the association between melatonin during the day and inflammatory cytokines in young adult patients seeking psychiatric care., Methods: Samples and data were collected from 108 young adults (mean age 21, SD = 2) at an outpatient clinic for affective disorders. Daytime saliva melatonin levels were analyzed with enzyme-linked immunosorbent assay (ELISA) in relation to normalized serum expression levels of 72 inflammatory markers in a proximity extension assay (PEA). In a post hoc analysis the markers associated with melatonin were tested in a generalized linear model to see whether there is a relationship to anxiety disorder or depression., Results: After Bonferroni correction for multiple testing, melatonin levels at 11:00 were positively correlated with CD5 (p = 4.2e-4). Melatonin levels after lunch were correlated with CCL2/MCP-1 (p = 4.2e-4), CCL3/MPI-1α (p = 6.5e-4) and VEGF-A (p = 5.3e-6). In the generalized linear model, positive associations were found for the presence of any anxiety disorder with melatonin after lunch (p = 0.046), VEGF-A (p = 0.001) and CCL3/MPI-1α (p = 0.001)., Conclusion: Daytime saliva levels of melatonin were related to several inflammatory markers in young adults with psychiatric disorders. This observation likely reflects the bidirectional relationship between melatonin production and the immune system. These findings may have relevance for the understanding of psychiatric disorders and other conditions associated with low-grade inflammation., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Subjective, disabling fatigue is a common complaint and a key feature of numerous medical conditions, and is a transdiagnostic feature of psychiatric disorders. Despite physical and mental fatigue being associated with functional impairment and reduced quality of life, little is understood about its underlying mechanisms or modulating factors. Women commonly experience exacerbation of other (non-fatigue related) psychiatric symptoms during the luteal phase of the menstrual cycle, and report greater fatigue prevalence compared to men. It is therefore plausible that subjective fatigue may similarly fluctuate across the menstrual cycle. Here we compared physical and mental fatigue in the early-follicular (lower ovarian hormones) and mid-luteal (higher ovarian hormones) phases of a single menstrual cycle, while controlling for sleep disruption, in women with (n = 18) and without (non-anxious; n = 20) generalised anxiety disorder (GAD). As expected, women with GAD reported greater physical and mental fatigue than healthy women. Further, although there were no changes in physical fatigue from the early-follicular to mid-luteal phases in both groups, mental fatigue in non-anxious women increased to levels equivalent to those experienced by their GAD counterparts in the mid-luteal phase. Although salivary levels of estradiol and progesterone increased from the early-follicular to mid-luteal phase, hormones did not significantly predict fatigue in either phase. These findings are consistent with the exacerbations of state anxiety and mood disturbance recognised to occur in the luteal phase of the menstrual cycle. We speculate that increased mental fatigue in the luteal phase may represent a vulnerable period for the development and maintenance of psychiatric disorders, potentially via compromised emotional regulation., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Anxiety, mood, trauma- and stressor-related disorders confer increased risk for metabolic disease. Adiponectin, a cytokine released by adipose tissue is associated with these disorders and obesity via inflammatory processes. Available data describing associations with mental disorders remain limited and conflicted., Methods: A systematic search was conducted for English, peer-reviewed articles from inception until February 2019 that assessed for serum or plasma adiponectin levels in adults with an anxiety, mood or trauma-related disorder. Diagnoses were determined by psychiatric interview, based on DSM-IV, DSM-5 or ICD-10 criteria. Analyses were performed using STATA 15 and Standardized mean difference (SMD) with 95% confidence interval was applied to pool the effect size of meta-analysis studies., Results: In total 65 eligible studies were included in the systematic review and 30 studies in this meta-analysis. 19,178 participants (11,262 females and 7916 males), comprising healthy adults and adults with anxiety, mood and trauma-related disorders, were included. Overall results indicated an inverse association between adiponectin levels and examined mental disorders. Specifically, patients with an anxiety disorder (SMD  = -1.18 µg/mL, 95% CI, -2.34; -0.01, p  = 0.047); trauma or stressor-related disorder (SMD  =  -0.34 µg/mL, 95% CI, -0.52; -0.17, p  = 0.0000) or bipolar disorder (SMD  =  -0.638 µg/mL, 95% CI, -1.16, -0.12, p  = 0.017) had significant lower adiponectin levels compared to healthy adults., Limitations: Heterogeneity, potential publication bias, and lack of control for important potential confounders were significant limitations., Conclusion: Peripheral adiponectin levels appear to be inversely associated with anxiety, mood, trauma- and stressor related disorders and may be a promising biomarker for diagnosis and disease monitoring., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims and Objective: The plasma level of mirtazapine (MIR) varies between individuals primarily depending on the differences in metabolism during pharmacotherapy. CYP2D6 takes the role as a major enzyme in MIR metabolism and POR enzyme donates an electron to CYP2D6 for its activity. Single nucleotide polymorphisms in the genes encoding pharmacokinetic enzymes may cause changes in enzyme activity, leading to differences in metabolism of the drug. Our aim was to assess the influence of CYP2D6*4 and POR*28 polymorphisms on MIR plasma levels in Turkish psychiatric patients., Materials and Methods: The association between genetic variations and plasma level of MIR was investigated on 54 patients. CYP2D6*4 and POR*28 polymorphisms were analysed using Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) and plasma MIR levels were measured using HPLC., Results: Allele frequencies of CYP2D6*4 and POR*28 were 0.11 and 0.39, respectively in the study population. The results showed that CYP2D6*4 allele carriers have higher C/D MIR levels while POR*28 allele carriers have lower C/D MIR levels. Combined genotype analyses also revealed that individuals with CYP2D6*1/*1 - POR*28/*28 genotype have a statistically lower C/D MIR level (0.95 ng/ml/dose) when compared with individuals with CYP2D6*1/*1 - POR*1/*1 genotype (1.52 ng/ml/dose)., Conclusion: Our results indicate that CYP2D6*4 and POR*28 polymorphisms may have a potential in the explanation of differences in plasma levels in MIR treated psychiatric patients. A combination of these variations may be beneficial in increasing drug response and decreasing adverse drug reactions in MIR psychopharmacotherapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study investigated the effects of vitamin D supplementation on Generalized Anxiety Disorder (GAD) clinical symptoms and neurochemical biomarkers including serotonin, neopterin and kynurenine. Thirty male and female patients diagnosed with GAD and had vitamin D deficiency were recruited from the psychiatric clinic at King Abdulaziz University Hospital and divided into two groups; one group of patients (n = 15) received standard of care (SOC) plus 50,000 IU vitamin D (once/week) for 3 months, while the other group (n = 15) received SOC alone. Biochemical parameters including serum vitamin D, serotonin, neopterin and kynurenine were measured for all patients enrolled in the trial. In addition, the Generalized Anxiety Disorder 7-item (GAD-7) scale was used to measure the severity of GAD symptoms in both vitamin D treated- and untreated-patients. Significant improvements in GAD scores were observed in the vitamin D-treated group compared to the group that did not receive vitamin D. In addition, serum serotonin concentrations were significantly increased while serum neopterin were significantly decreased in vitamin D-treated vs. untreated patients. In contrast, no significant differences were found in serum kynurenine concentrations at the end of the study period between the two groups. No changes either in GAD-7 scores or in any of the biochemical measurements were observed in the group that received only SOC after 3 months. Vitamin D supplementation was effective in ameliorating the severity of GAD symptoms by increasing serotonin concentrations and decreasing the levels of the inflammatory biomarker neopterin in GAD patients.

Background: Kynurenine pathway metabolites and endocannabinoids both exert potent regulatory effects on the immune system, but the relationship between these molecules is unknown. The role of these immunobiological mediators in emotionality and personality traits is not previously characterized., Methods: Interleukin-6 (IL-6), 2-arachidonoylglycerol (2-AG) and picolinic acid (PIC) were measured in the plasma of physically healthy individuals who had history of mood, anxiety, and personality disorders (n = 96) or who had no history of any psychiatric disorder (n = 56) by DSM-5 Criteria. Dimensional assessments of personality were performed using the Eysenck Personality Questionnaire (EPQ) and the Tridimensional Personality Questionnaire (TPQ)., Results: Plasma IL-6 levels were significantly associated with plasma 2-AG levels and plasma PIC levels across all subjects. PIC levels were also negatively associated with 2-AG levels across all subjects, independent of IL-6 levels. In our analysis of the biological determinants of personality factors, we identified significant associations between IL-6 and novelty seeking assessment, and between PIC and neuroticism assessment., Conclusions: These data provide evidence of a biological link between metabolites of the kynurenine pathway, the endocannabinoid system and IL-6 and suggest that these factors may influence personality traits., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background Anxiety disorders are common psychiatric disorders in childhood and an important health problem that is associated with the risk of serious mental, educational and economical problems. Researchers have mentioned many different mechanisms in the etiopathology of anxiety disorders. This study aimed to investigate ghrelin and leptin levels in children with anxiety disorders and thus to contribute to the clarification of anxiety in children. Methods Forty-three children aged 6-12 years with a diagnosis of the Anxiety Disorder according to DSM 5 and 21 healthy children age- and gender-matched to the study group were included. All the subjects were assessed with Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) and State-Trait Anxiety Inventory for Children (STAI-C) scale. Blood samples were obtained in the morning and serum ghrelin and leptin levels were measured with enzyme-linked immunosorbent assay (ELISA) kits. Results In the anxiety group the ghrelin levels were higher than the control group (p = 0.037) but there was no significant difference between the leptin levels (p = 0.430). Also, when the girls in the anxiety group and the girls in the control group were compared, ghrelin levels were higher in the anxiety group (p < 0.01). Conclusions These findings suggest that ghrelin may play a significant role in the etiologic mechanisms of anxiety disorders. However, more detailed studies are needed to explain the linkage between anxiety disorders and neuropeptides.

Background: Extensive research into psychoneuroimmunology has led to substantial advances in our understanding of the reciprocal interactions between the central nervous system and the immune system in neuropsychiatric disorders. To date, inflammation has been implicated in the pathogenesis of depression and anxiety. The immunomodulating effects of antidepressants on depression have been reported, however, there is no evidence of the similar effects of antidepressants on anxiety. The aim of the study was to investigate the effects of selective serotonin reuptake inhibitors (SSRIs) on peripheral inflammatory cytokines in patients with first episode generalized anxiety disorder (GAD)., Methods: A prospective cohort design was employed: 42 patients with first episode GAD were treated with either escitalopram or sertraline for 12 weeks. Anxiety was measured by the Generalized Anxiety Disorder Scale and the State Trait Anxiety Inventory, serum pro-inflammatory cytokine levels were measured by the enzyme-linked immunosorbent assay (ELISA), and CRP determined by an immunoturbidimetric method before and after SSRIs treatment RESULTS: Baseline levels of anxiety and pro-inflammatory cytokines including IL-1α, IL-6, IL-8, IL-12, IFN-γ, and CRP were significantly reduced after treatment of SSRIs (p < 0.05 in all cases). In addition, the change of anxiety measures co-vary with the change of peripheral cytokine levels (p < 0.05 in all cases). The regression model revealed that log transformed baseline levels of CRP and IL-6 predicted treatment response (p < 0.05 in both cases)., Conclusions: This study is the first to investigate the effects of SSRIs on pro-inflammatory cytokines in patients with first episode GAD. The findings indicate moderate acute anti-inflammatory effects of SSRIs in GAD, and suggest that these anti-inflammatory effects may underlie anxiolytic effects of SSRIs. The study also indicates that serum levels of CRP and IL-6 may predict treatment response. However, data from randomized controlled trials is warranted to confirm these findings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To determine the prevalence of abnormal thyroid-stimulating hormone (TSH) measures in youth with severe mood and anxiety disorders and to examine clinical and demographic predictors of abnormal TSH measures., Methods: We retrospectively examined screening TSH concentrations in psychiatrically hospitalized children and adolescents (3-19 years) with mood/anxiety disorders (DSM-IV and DSM-5 criteria) at a large, urban, pediatric hospital between September 2013 and April 2017. Symptoms were extracted from the medical record using adaptive natural language processing algorithms, and the utility of demographic, clinical, and treatment variables as predictors of abnormal TSH measures was evaluated using logistic regression., Results: In this sample (N = 1,017, mean ± SD age = 14.7 ± 2.24 years), 62 patients had a TSH concentration > 3.74 μIU/mL (5.3% [n = 6] of patients < 12 years of age and 6.2% [n = 56] of patients ≥ 12 years of age), and 7 patients had a TSH concentration < 0.36 μIU/mL. Elevated TSH concentrations were associated with a recent weight gain (odds ratio [OR] = 3.60; 95% CI, 1.13-9.61; P = .017), a history of thyroid disease (OR = 6.88; 95% CI, 2.37-10.7; P ≤ .0001), abnormal menstrual bleeding/menometrorrhagia (OR = 2.03; CI, 1.04-3.63; P = .024), and benzodiazepine treatment (OR = 2.29; 95% CI, 1.07-4.52; P = .02). No association was observed for sex, age, or body mass index z score. Among patients with elevated TSH measures, 12.9% (n = 8, mean ± SD age = 16.5 ± 1.5 years, 87.5% female) had an abnormal free/total thyroxine (T₄) level or other biochemical findings consistent with thyroid disease. Patients with thyroid disease (compared to those patients with elevated TSH and normal active thyroid hormone concentrations) were older (16.5 ± 1.5 vs 14.6 ± 2.3 years, P = .020) but did not differ in sex distribution (87.5% vs 63.6% female, P = .444)., Conclusions: TSH concentrations are abnormal in approximately 6% of psychiatrically hospitalized youth, although thyroid disease was present in < 1% of the total sample. Targeted screening should focus on patients with recent weight gain, those treated with benzodiazepines, and girls with a history of abnormal uterine bleeding/menometrorrhagia., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Background: An association between the level of total cholesterol and psychopathology has been the focus of numerous studies. Low total cholesterol has been found to be related to depression, personality disorders, and dissociative disorder. High cholesterol has been associated with schizophrenia, obsessive-compulsive disorder (OCD), panic disorder, generalized anxiety disorder, and posttraumatic stress disorder. However, no reviews of the psychiatric correlates of high-density lipoprotein (HDL) have been published. We reviewed the literature for studies reporting a significant association between low or high levels of HDL and psychopathology., Methods: A search of major databases (PubMed and CINAHL) was conducted using the following keywords: HDL, depression, anxiety, schizophrenia, OCD, and psychiatric disorders., Results: Eight studies met our search criteria. Six of the 8 studies reported significantly higher rates of depression, anxiety, suicide attempts, and violent behaviors in participants with low HDL., Conclusions: Overall, a low HDL may not only be associated with risk for cardiac disease, but also with increased risk for serious psychiatric disorders. Further controlled studies are warranted.

Anxiety disorders (ADs) are chronic conditions that often have their onset in childhood and adolescence. Inflammation and oxidative stress markers have been associated with the vulnerability to ADs, however it is not known if ADs in childhood can influence these biomarkers levels longitudinally. This study aims to investigate a possible association between ADs and serum levels of IL-10, IL-6, IL-1β, TNF-α, BDNF, and protein carbonyl content, assessed after 5 years of follow-up. Moreover, we studied possible mediators for these associations, including physical activity, metabolic markers and childhood trauma. From 240 individuals evaluated at baseline, 73 were re-evaluated in the follow-up. Psychiatric diagnoses were assessed with the K-SADS or the MINI and child trauma questionnaire (CTQ) to evaluate presence of trauma. We searched serum levels of IL-10, IL-6, IL-1β and TNF-α (flow cytometry), BDNF (sandwich-ELISA) and carbonyl content in proteins (PCC method). We found a significant direct association between ADs at baseline and log IL-6 (B = 0.34, S.E. = 0.11, p = 0.002) and between AD and log BDNF (B = -0.10, S.E. = 0.05, p = 0.033) five years later. Searching for possible mediators of these association, we found that levels of HDL-cholesterol (ΔB = -0.148) partially mediated the association between ADs and IL-6. No significant mediators were found in the association between ADs and BDNF. Moreover, this association is no longer significant after controlling for the presence of depression. Our results demonstrated that previous AD diagnosis was associated with higher levels of IL-6 in the follow-up evaluation, suggesting that the presence of anxiety in childhood could influence altered inflammatory markers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Inflammation has been implicated in the aetiology of mental illness. We conducted the first systematic review and meta-analysis of the association between peripheral markers of inflammation and generalised anxiety disorder (GAD)., Design: Systematic review and meta-analysis of studies measuring peripheral cytokine levels in people with GAD compared with controls., Data Sources: MEDLINE (1950-), EMBASE (1947-), PsycINFO (1872-) and Web of Science (1945-) databases up until January 2018., Eligibility Criteria: Primary, quantitative research studies of people with a diagnosis of GAD assessed using a standardised clinical interview that measured peripheral inflammatory markers., Data Extraction and Synthesis: Two independent reviewers extracted data and assessed study quality. Meta-analysis using a random-effects model was conducted for individual cytokines where data from three or more studies were available., Results: 14 of 1718 identified studies met the inclusion criteria, comprising 1188 patients with GAD and 10 623 controls. In total 16 cytokines were evaluated. Significantly raised levels of C reactive protein (CRP), interferon-γ and tumour necrosis factor-α were reported in patients with GAD compared with controls in two or more studies. Ten further proinflammatory cytokines were reported to be significantly raised in GAD in at least one study. However, 5 of 14 studies found no difference in the levels of at least one cytokine. Only CRP studies reported sufficient data for meta-analysis. CRP was significantly higher in people with GAD compared with controls, with a small effect size (Cohen's d=0.38, 0.06-0.69), comparable with that reported in schizophrenia. However, heterogeneity was high (I 2 =75%), in keeping with meta-analyses of inflammation in other psychiatric conditions and reflecting differences in participant medication use, comorbid depression and cytokine sampling methodology., Conclusion: There is preliminary evidence to suggest an inflammatory response in GAD, but it remains unclear whether inflammatory cytokines play a role in the aetiology. GAD remains a poorly studied area of neuroinflammation compared with other mental disorders, and further longitudinal studies are required., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

This study was performed to check the hypothesis that low serum vitamin D and reduced calcium intake may contribute to the comorbidity of psychological symptoms (anxiety and depression) and non-cardiac chest pain (NCCP). The design was a case-control study that involved 40 subjects with NCCP and 40 age and gender-matched healthy controls. Serum vitamin D was assessed using electrochemiluminescence immunoassay; anxiety and depression symptoms were assessed using Hospital Anxiety and Depression Scale, and dietary calcium intake was assessed by self-reporting. Subjects with NCCP had higher anxiety and depression scores and lower vitamin D and dietary calcium intake compared to healthy controls (p < .05). NCCP was associated with anxiety score (odds ratio = 1.40, p < .01). Prevalence of abnormal anxiety score was much higher in subjects with NCCP (47.5%) compared to healthy controls (7.5%). Anxiety score was inversely correlated with vitamin D level and dietary calcium intake (p < .01). Anxiety score was inversely associated with vitamin D level (R 2  = .32, p < .05). In conclusion, development of NCCP can be predicted from increased anxiety score which in turn can be predicted from low vitamin D levels. This suggests physicians to consider anxiety and vitamin D deficiency as possible causes for NCCP.

Background: While cross-sectional associations of inflammatory markers interleukin-6 (IL-6) and C-reactive protein with major depressive disorder are well established, evidence for longitudinal associations mostly comes from studies on depression symptoms, not diagnoses. This study examined cross-sectional and bidirectional longitudinal associations between depression diagnosis and symptoms in an adult sample over a 6-year period., Methods: Data were obtained from the baseline (n = 2416) and 2- and 6-year follow-up assessments (n = 1925 and n = 1924, respectively) of the Netherlands Study of Depression and Anxiety. C-reactive protein and IL-6 were assessed at each wave, as were the Composite International Diagnostic Interview and Inventory of Depressive Symptomatology. Linear mixed models and generalized estimating equation models with a binomial distribution were used to study longitudinal associations between depression and inflammation and vice versa., Results: There was a consistent cross-sectional association between current depressive disorder (vs. no current disorder) and symptoms with IL-6 across all follow-up measurements (Cohen's d depression diagnosis  = 0.06, p = .017; B standardized Inventory of Depressive Symptomatology  = 0.029, SE = 0.011, p = .008). In longitudinal analyses, higher IL-6 levels predicted subsequent chronic course in those with a diagnosis at baseline in women but not in men (odds ratio women  = 1.13, 95% confidence interval = 1.04-1.23), and both depressive disorder and high severity predicted higher IL-6 levels at the subsequent follow-up (p values < .01). In contrast, C-reactive protein was not associated with current depression in cross-sectional and longitudinal analyses., Conclusions: In this longitudinal study, cross-sectional and bidirectional longitudinal associations were found between depression and IL-6 levels. This underlines the importance of targeting inflammation pathways in the treatment of major depressive disorder. IL-6 could be a potential marker for patient profiling in personalized medicine approaches., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: As many as 20% of women will experience an anxiety disorder during the perinatal period. Women with pre-existing anxiety disorders are at increased risk of worsening during this time, yet little is known about its predictors., Study Aim: To investigate the psychosocial and biological risk factors for anxiety worsening in the postpartum in women with pre-existing anxiety disorders., Methods: Thirty-five (n = 35) pregnant women with pre-existing DSM-5 anxiety disorders were enrolled in this prospective study investigating the psychosocial (e.g., childhood trauma, intolerance of uncertainty, depression) and biological risk factors (e.g. C-reactive protein, interleukin-6, tumor necrosis factor-α) for anxiety worsening in the postpartum period. Anxiety worsening was defined as an increase of ≥50% or greater on Hamilton Anxiety Rating Scale scores from the third trimester of pregnancy (32.94 ± 3.35 weeks) to six weeks postpartum., Results: Intolerance of uncertainty, depressive symptom severity, and obsessive-compulsive disorder symptoms present in pregnancy were significant predictors of anxiety worsening in the postpartum., Limitations: Sample heterogeneity and limited sample size may affect study generalizability., Conclusions: To our knowledge, this is the first longitudinal study to investigate psychosocial and biological risk factors for anxiety worsening in the postpartum in women with pre-existing anxiety disorders. Continued research investigating these risk factors is needed to elucidate whether they differ from women experiencing new-onset anxiety disorders in the perinatal period, and those in non-puerperal groups. Identifying these risk factors can guide the development of screening measures for early and accurate symptom detection. This can lead to the implementation of appropriate interventions aimed at decreasing the risk of perinatal anxiety worsening., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Indigenous populations in India are amongst the poorest and most marginalized population groups experiencing severe health deprivation., Aim: The present study is the first study that aims to understand the association of micronutrient deficiencies (vitamin B12 and folate) and MTHFR C677T gene polymorphism with depression and generalized anxiety disorder (GAD) among the Bhil indigenous population of India., Methods: A total of 303 participants aged 25-65 years of both sexes and unrelated up to first cousins belonging to Bhil indigenous population were recruited for the present study. Depression and generalized anxiety disorder were assessed using Patient Health Questionnaire and Generalized Anxiety Disorder scale, respectively. Biochemical analysis, DNA extraction and MTHFR C677T gene polymorphism analysis were done using standard protocols., Results: Although, vitamin B12 and folate status was not found to be directly associated with depression and GAD, but hyperhomocysteinemia was posing more than three folds and six folds significant increased risk for depression and GAD, respectively. Further, it seems hyperhomocysteinemia was mediated by vitamin B12 deficiency among depressed and anxious individuals. T allele of MTHFR C677T gene polymorphism was posing increased risk for depression and anxiety disorder though not significant., Conclusion: The present study highlights the significance of micronutrient deficiencies in the causation of depression and anxiety disorder., (Copyright © 2019 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Etiological research of depression and anxiety disorders has been hampered by diagnostic heterogeneity. In order to address this, researchers have tried to identify more homogeneous patient subgroups. This work has predominantly focused on explaining interpersonal heterogeneity based on clinical features (i.e. symptom profiles). However, to explain interpersonal variations in underlying pathophysiological mechanisms, it might be more effective to take biological heterogeneity as the point of departure when trying to identify subgroups. Therefore, this study aimed to identify data-driven subgroups of patients based on biomarker profiles., Methods: Data of patients with a current depressive and/or anxiety disorder came from the Netherlands Study of Depression and Anxiety, a large, multi-site naturalistic cohort study (n = 1460). Thirty-six biomarkers (e.g. leptin, brain-derived neurotrophic factor, tryptophan) were measured, as well as sociodemographic and clinical characteristics. Latent class analysis of the discretized (lower 10%, middle, upper 10%) biomarkers were used to identify different patient clusters., Results: The analyses resulted in three classes, which were primarily characterized by different levels of metabolic health: 'lean' (21.6%), 'average' (62.2%) and 'overweight' (16.2%). Inspection of the classes' clinical features showed the highest levels of psychopathology, severity and medication use in the overweight class., Conclusions: The identified classes were strongly tied to general (metabolic) health, and did not reflect any natural cutoffs along the lines of the traditional diagnostic classifications. Our analyses suggested that especially poor metabolic health could be seen as a distal marker for depression and anxiety, suggesting a relationship between the 'overweight' subtype and internalizing psychopathology.

Background: Findings on associations of androgens and sex hormone-binding globulin (SHBG) with anxiety and depressive disorders in the general population remain inconclusive., Methods: We used data of n = 993 men and n = 980 women from the Study of Health in Pomerania (SHIP, a prospective-longitudinal general population study from northeastern Germany). Immunoassay-measured serum concentrations of total testosterone, androstenedione and SHBG were assessed when participants were aged 20-80. 12-month, lifetime and incident DSM-IV anxiety and depressive disorders were assessed with the DIA-X/M-CIDI at 10-year follow-up, when participants were aged 29-89. Logistic regressions were adjusted for age, smoking, alcohol consumption, physical activity, waist circumference, hypertension and oral contraceptive use (women only) at baseline and follow-up interval., Results: In men and women, androgens and SHBG were not associated significantly with incident anxiety and depressive disorders. In men, higher total testosterone predicted any 12-month (OR = 1.46) and lifetime (OR = 1.34) anxiety disorder, lifetime social phobia (OR = 2.15), and 12-month (OR = 1.48) and lifetime (OR = 1.39) specific phobia, but neither 12-month nor lifetime depression. Moreover, androstenedione in men interacted with age in predicting lifetime anxiety disorders (OR = 0.98): Higher androstenedione more strongly predicted lifetime anxiety in younger vs. older men. These findings, however, did not survive correction for multiple testing. In women, androgens and SHBG were not associated significantly with 12-month and lifetime anxiety and depressive disorders., Limitations: The follow-up period was relatively long and other factors might have affected the examined associations., Conclusions: Higher serum total testosterone in men and androstenedione in younger men may relate to an increased risk of anxiety disorders., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Recent adult etiologic studies indicated evidence linking increased inflammatory parameters with psychiatric disorders. The neutrophil-lymphocyte ratio and platelet-lymphocyte ratio are easily obtainable clinical markers of inflammation and have been found to be increased in various medical and mental disorders. In this study, we aimed to investigate the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in adolescents with obsessive-compulsive disorder (OCD). Secondarily, the effect of comorbid anxiety disorder with OCD on the inflammatory response was investigated. Sixty drug-naïve adolescents with OCD aged 12 to 18 years were enrolled in the patient group. Twenty-three of the OCD group had comorbid anxiety disorder (AD) and 37 had no comorbidities. One hundred twenty-eight adolescents in the same age range with no psychiatric disorders were recruited as the healthy control group. The severity of OCD symptoms was evaluated using the Children's Yale-Brown Obsessive Compulsive Scale. There were statistically significant differences in the neutrophil-lymphocyte ratio, white blood cell, neutrophil, and platelet counts among the three groups, even after adjusting for age and sex. The adolescents with OCD and AD had the highest neutrophil-lymphocyte ratio and white blood cell counts. A comorbid anxiety disorder diagnosis in addition to obsessive-compulsive disorder may increase the inflammatory response., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Hypoglycemia is a common and dangerous complication of type 1 diabetes (T1D). Although some worry about hypoglycemia is adaptive, some individuals develop severe and impairing anxiety symptoms about hypoglycemic episodes. This presentation, known as severe fear of hypoglycemia (FOH), is similar to a specific phobia, and becomes problematic when it interferes with one's quality of life or T1D management. Although FOH is common, there have not yet been any treatment studies to address severe and impairing levels of FOH in the T1D population. The purpose of the following case report is to: (a) describe the presentation of a severe case of FOH in a young adult with T1D; (b) demonstrate the effectiveness of graduated exposure therapy for treatment of severe FOH; and (c) provide implications for clinical practice. A previously developed conceptual model for FOH management guided treatment. Treatment using graduated exposure therapy for FOH resulted in reduced worry about low blood glucose (BG) and significant reduction in behaviors to maintain high BG levels. Assessment of FOH and the risk and benefits of using a continuous glucose monitor among individuals with T1D and their families are discussed., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Compensated Leydig cell (LC) dysfunction, defined by elevated serum levels of luteinizing hormone (LH) in combination with normal total testosterone levels, is common in testicular cancer (TC) survivors. The association between this condition and quality of life is unknown. We aimed to clarify if TC survivors with compensated LC dysfunction have impaired quality of life., Patients and Methods: In total, 147 long-term TC survivors were included. On the basis of a single measurement of testosterone and LH, compensated LC dysfunction was defined by age-adjusted levels of LH above normal range combined with testosterone levels within the normal range. Quality-of-life outcomes including sexual function, anxiety and depression, fatigue, and overall self-evaluated quality of life were compared between patients with and without compensated LC dysfunction with adjustment for age., Results: In total, 60 TC survivors had compensated LC dysfunction and 87 TC survivors had normal LC function. TC survivors with compensated LC dysfunction had lower serum levels of total testosterone (11 vs. 13 nmol/L, P = .016). There were no significant differences in the investigated quality-of-life outcomes (anxiety, depression, sexual function, fatigue) between the 2 groups., Conclusion: Compensated LC dysfunction in TC survivors was not associated with symptoms of depression, anxiety, sexual dysfunction, fatigue, or impaired overall self-evaluated quality of life. Limitations include the few cases of symptoms of depression (n = 7). Our findings do not suggest that testosterone substitution is indicated in TC survivors with compensated LC dysfunction., (Copyright © 2018 Elsevier Inc. All rights reserved.)