Off-label use of clomiphene citrate to treat anabolic androgenic steroid induced hypogonadism upon cessation among men (CloTASH) - A pilot study protocol.

Background: Non-prescribed anabolic androgenic steroid (AAS) use is associated with AAS-induced hypogonadism (ASIH), and metabolic, cardiovascular, and mental health risks. Symptoms of ASIH (fatigue, depression, anxiety, sexual dysfunction) are hard to endure following cessation, but there is no consensus on whether endocrine treatment should be used to treat ASIH. This proof-of-concept study aims to explore safety of off-label clomiphene citrate therapy, whether the treatment will reduce the symptoms of androgen deficiency, and to study changes in health risks after cessation. Methods: In this open-labeled non-randomized off-label hormone intervention pilot study, we shall include males with AAS dependence intending to cease use. The 16-week intervention included clomiphene citrate, transdermal testosterone gel for the first four weeks and optional human chorionic gonadotropin (hCG) from week 4 if low treatment response. Measures of physical and mental health will be examined from ongoing AAS use, during the intervention, and at 6- and 12 months post cessation. Change in self-reported symptoms of hypogonadism and other withdrawal symptoms will be compared with data from a group of men who ended AAS use temporarily without the medical intervention. The study may provide valuable clinical insights and may be used to inform the design of future intervention studies.

Peripheral blood cellular immunophenotype in suicidal ideation, suicide attempt, and suicide: a systematic review and meta-analysis.

Previous meta-analyses have documented the association of immune-inflammatory pathways with the pathophysiology of Major Depressive Episode (MDE), as reflected by alterations in peripheral blood immune cell counts. However, it remains unclear whether these immunological changes are distinct in individuals experiencing suicidal ideation (SI) or suicidal behavior (SB), beyond the context of an MDE. This systematic review and meta-analysis aimed to examine peripheral immune cell profiles across samples with SI/SB and compare them to healthy controls or patients with MDE. A systematic literature search was conducted in MEDLINE, Embase, and PsycINFO for articles published from inception until June 12, 2023. Two independent reviewers screened the articles for inclusion, extracted data, and assessed the risk of bias using the Newcastle-Ottawa scale. Meta-analyses were performed using a random-effects model to calculate standardized mean differences (SMDs) and 95% confidence intervals (CIs) for immune cell counts or ratios between groups with and without SI/SB. Heterogeneity across studies was assessed using the restricted maximum-likelihood estimator for tau statistic and I2-statistic and tested by the Q test. Publication bias was evaluated using the Egger´s test and funnel plots. Meta-regression analyses were conducted to explore the potential moderating effects of age, gender, current or lifetime SI/SB, and the type of self-harming behavior (SI or SB). The study was registered with PROSPERO (CRD42023433089). The systematic review included 30 studies, with data from 19 studies included in the meta-analyses comprising 139 unique comparisons. Eleven different cell populations or ratios were included, comprising 1973 individuals with SI/SB and 5537 comparison subjects. White blood cell (WBC) and neutrophil counts were higher in individuals with SI/SB than in controls (WBC: SMD = 0.458; 95% CI = 0.367-0.548; p value ≤ 0.001; I2 = 0.002% and; Neutrophils: SMD = 0.581; 95% CI = 0.408-0.753; p < 0.001), indicating an inflammatory process. The neutrophil-to-lymphocyte ratio (NLR) emerged as a potential marker, demonstrating a notable elevation in individuals with SI/SB (SMD = 0.695; 95% CI = 0.054-1.335; p value = 0.033; I2 = 94.281%; Q test p value ≤ 0.001). The elevated NLR appears to be primarily driven by the increase in neutrophil counts, as no significant differences were found in lymphocyte counts between groups. Comparisons among participants with and without SI/SB and depression revealed similar trends with increased NLR, monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) observed in depressed individuals with SI/SB compared to those without SI/SB. Broad alteration in the peripheral immune cell populations and their ratios were observed in individuals with SI/SB, indicating an immune activation or dysfunction. Notably, these immunological changes were also evident when comparing MDE individuals with and without SI/SB, suggesting that such immune dysfunction associated with suicidality cannot be solely attributed to or explained by depressive symptoms. The NLR, MLR, and PLR ratios, in combination with novel immune cellular and protein biomarkers, open new avenues in understanding the immunological underpinnings of SI/SB. These findings highlight the potential utility of immune markers as part of a multi-modal approach for risk stratification and therapeutic monitoring in SI/SB.

Psychotropic medication use among adolescents participating in three randomized trials of DBT.

BACKGROUND: Frequently presenting with symptoms of mood or anxiety disorders, substance abuse or borderline personality disorder, suicidal and self-harming adolescents often are prescribed psychotropic medication. Though such treatment may be warranted, recurrent suicidal and self-harming behaviour is often linked to emotion dysregulation where pharmacological treatment has weak empirical support. There is a need for more clinical research into the frequency, type and rationale for pharmacological treatment in this group. In this secondary analysis of three randomized clinical trials of dialectical behaviour therapy for adolescents, we report on psychotropic medication use in the respective samples at the time of recruitment, compare use of psychotropic medication across trials and describe sample characteristics that may be associated with possible differences in psychotropic medication. FINDINGS: Trials were conducted in Norway, the US and Spain (labelled the Oslo, US and Barcelona samples). At baseline, 86% of the Barcelona sample, 67% of the US sample and 12% of the Oslo sample were taking at least one psychotropic medication with antidepressants as the most frequent, followed by antipsychotics (72%, 22% and 1.3% respectively) and mood stabilizers (14.2%, 16.2% and 0%). In the Oslo sample there was a significant association between receiving a diagnosis of major depression and the likelihood of receiving antidepressants, but no such association was found in the Barcelona and US samples. The overall 7-8 times higher proportion of participants in the US and Barcelona samples treated with psychotropic medication could only partially be explained by differences between the samples in diagnostic profiles, symptom severity or level of dysfunction. CONCLUSIONS: Highly prevalent in use among suicidal and self-harming adolescents with borderline features, psychotropic medication was still very unevenly prescribed across trials, differences not explained by differences in sample characteristics suggesting that current treatment practices are not fully empirically supported. We call for continued medical education and increased availability of evidence-based psychosocial interventions.

Immune-related biomarkers and suicidal behaviors: A meta-analysis.

Biomarkers that can differentiate between psychiatric disorders with and without suicidal behavior history from each other and from healthy volunteers may explain part of the pathogenesis of suicidal behavior. We conducted the hitherto largest meta-analysis comparing immune biomarkers between subjects with and without suicide attempt history or death by suicide. The study protocol was registered with PROSPERO, CRD42020212841. Standardized mean differences (SMD) were pooled with random-effects models. Heterogeneity between studies was assessed with the I2-statistic and publication bias was evaluated by the Egger test and funnel plots. Data were based on 36 studies including 2679 persons with suicidal behaviors and 6839 comparison subjects, and four immune-related biomarkers (CRP, IL-6, TNF-α and IL-1ß). Suicidal behavior was associated with higher CRP blood levels compared with: healthy controls (SMD [95%CI] = 1.42[0.85-1.98]); patients with depression alone (SMD [95%CI] = 1.23[0.20-2.26]); and patients with any psychiatric disorders (SMD [95%CI] = 0.39[0.22-0.55]). IL-6 blood level was higher in patients with suicidal behaviors compared with healthy controls (SMD [95%CI] = 1.13[0.45-1.82]) and when compared with psychiatric patients without suicidal behaviors (SMD [95%CI] = 0.22 [0.11-0.33]). Meta-regression and subgroup analyses revealed that increased CRP in suicidal behavior is primarily driven by recent suicidal behavior. These results implicate the immune system and inflammatory response in suicidal behavior independent of a relationship to major psychiatric disorders, and that these biological measures are predominantly state-dependent markers. Future studies are needed to determine the cause-and-effect relationship of these immune system biomarkers with suicidal behavior, and their potential predictive properties.

Adolescents With Non-Suicidal Self-Harm-Who Among Them Has Attempted Suicide?

We aimed to determine differences between adolescents with non-suicidal self-harm with and without a history of suicide attempt (SA). Sixty-eight adolescents with a mean age of 15.6 years (SD = 1.5) attending child and adolescent psychiatric outpatient clinics for repeated self-harm in Oslo, Norway, were included. A battery of instruments was used to assess sociodemographic information and psychopathology such as Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses, emotional and behavioral problems, borderline symptoms, depression, hopelessness, suicidal ideation, and history of SA. Twenty-six participants (38.2%) reported a lifetime history of SA. Compared to the participants without a history of SA, those with an SA history had used a higher number of methods of self-harm and methods with higher lethality and had higher degrees of emotional and behavioral problems. They also scored higher in depressive symptoms, borderline pathology, emotional dysregulation, hopelessness, and suicidal ideation. History of SA was independently associated with perceived moderate to high risk of death on the most severe episode of self-harm (adjusted odds ratio [aOR], 15.93; 95% confidence interval [CI], 1.96-129.66), a longer duration (months) since self-harm debut (aOR, 1.07; 95% CI, 1.01-1.13), and suicidal ideation severity (aOR, 1.05; 95% CI, 1.01-1.11). Parental report of behavioral problems associated with SA suggested a strong association with externalizing problems. A combination of having a high level of psychopathology, externalizing problems, an extended history of self-harm behavior and use of more lethal self-harm methods seems to entail a significantly increased risk for making SAs among adolescents with non-suicidal self-harm. HIGHLIGHTSNon-suicidal self-harm (NSSH) with suicide attempt may be distinctive from NSSH without suicide attempt.Adolescents with NSSH with suicide attempt had relatively greater psychopathology.Protracted/lethal self-harm methods and externalizing problems indicate comorbidity.

Use of High-Dose Androgens Is Associated with Reduced Brain-Derived Neurotrophic Factor in Male Weightlifters.

INTRODUCTION: Use of high-dose androgens causes drastic changes in hormonal milieu and is associated with adverse medical, psychological, and cognitive effects. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors plays a critical role in neuroplasticity, with implications for cognitive function and mental health. The impact of long-term, high-dose androgen use on BDNF in a natural setting has not been investigated. This study examined the association between long-term androgen exposure and BDNF levels, and the links between BDNF, heavy resistance exercise, hormones, androgens, and mental health. METHODS: We measured serum levels of BDNF and sex steroid hormones in male weightlifters (N = 141) with a history of current (n = 59), past (n = 29), or no (n = 52) androgen use. All participants completed questionnaires assessing maximum strength and measures of anxiety and depression. Group differences in BDNF were tested using general linear models adjusting for age and associations between BDNF and strength, anxiety, and depression using Pearson's or Kendall's correlations. RESULTS: Both current (mean: 44.1 ng/mL [SD: 12.7]) and past (39.5 ng/mL [SD: 13.9]) androgen users showed lower serum BDNF levels compared to nonusing controls (51.5 [SD: 15.3], p < 0.001, ηp2 = 0.10). BDNF levels were negatively related to maximal strength, and with hormonal status in past androgen users, but no significant associations were found with measures of depression and anxiety. CONCLUSION: Lower circulating BDNF concentrations in current and past androgen users suggest that high-dose androgen exposure triggers persistent changes in BDNF expression. Further studies are needed to verify the relationship and its potential clinical implications.

Biomarkers common for inflammatory periodontal disease and depression: A systematic review.

Background: Dysregulated immune response arising in the periphery can induce depressive symptoms through neuroimmune interactions. Inflammatory oral pathology can be a potent inducer of chronic neuroimmune response relevant to depression. We aimed to synthesize available evidence for the association between inflammatory periodontal diseases (IPD) and major depression (MD) in relation to a broad range of biomarkers. Methods: Medline, Embase, PsycInfo, Cochrane Library, Web of Science and Scopus databases were searched from inception until January 27, 2022. Search terms included subject headings and synonyms for inflammatory periodontal disease and depression. Studies that reported data on both depression and inflammatory periodontal disease as categories along with measurement of a biomarker were considered. Two reviewers independently selected the articles for inclusion, extracted data and assessed the quality of each study. The protocol for this study was registered with PROSPERO, CRD42021215524. Results: Twenty-eight studies were included in the final review-eleven cross-sectional studies, seven case-control studies, and six prospective cohort studies conducted in humans; the remaining four were experimental animal studies. Eighteen studies including all animal studies reported a positive association between depression and periodontal disease; one study reported a negative association and another nine studies found no such associations. Twenty studies reported mixed associations between IPD and biomarkers (i.e, salivary, serum, urine or gingival crevicular fluid cortisol, C reactive protein, cytokines, etc.). Biomarkers related to depression were gingival crevicular fluid cortisol, interleukin 6 (IL-6), Il-1ß, immunoglobulin G against Bacterioides forsythus; root canal lipopolysaccharides; blood IL-6, IL-1ß, cortisol, advanced oxidation protein products, nitric oxide metabolites, lipid hydroperoxides and trapping antioxidant parameter; whereas five studies found no associations between depression and a biomarker. Although animal studies showed interaction of immune, inflammatory and neurotrophic biomarkers in the relationship between depression and periodontal disease, human studies showed mixed findings. In most studies, there were risks of bias due to the sample selection and assessment protocol. Study heterogeneity and limited number of comparable studies reporting on shared biomarkers precluded a meta-analysis. Conclusion: Immune-inflammatory contribution to depression was evident in the context of inflammatory periodontal diseases, but whether biomarkers mediate the associations between IPD and MD needs to be tested through methodologically rigorous studies aiming specifically at this hypothesis.

Psychoneuroimmunology: The new frontier in suicide research.

Elucidating complex, multifactorial phenomena like suicide and suicidal behaviors (SSB) require multidisciplinary fields such as Psychoneuroimmunology (PNI). Indeed, our appreciation of the bidirectional communication channels between the brain and the rest of the body with its immune arsenal as the key player has positioned PNI as a promising field of research. We now know that major psychiatric, behavioral, and somatic disorders related to SSB accompany neuroimmune dysregulation. These disorders range from depression, emotional dysregulation, atopy, and epilepsy to certain viral and parasitic infections. By utilizing epidemiological, genetic, microbial, and molecular approaches, the PNI research community has excogitated novel biomarker candidates and pathways in support of SSB risk stratification at individual level. This remarkable progress in just two previous decades shall, if successful, help implement personalized prevention and treatment strategies, using PNI-assisted tools. The aims of this narrative review and opinion piece are to summarize important discoveries concerning the role of neuroimmune activation in SSB and to highlight important future directions for the field. Major caveats of the findings concerning methodological approaches, clinical reality of frequent comorbid psychopathology, and novel molecular targets are presented. Finally, this review calls on the PNI research community for increased attention towards factors that promote resilience to suicide, while accepting "consciousness" under its wing. Thus, PNI represents the new frontier in suicide research. Future breakthroughs in this discipline shall bring us closer to understanding the biological substrates of qualia i.e., subjective, and experiential meanings of life and death.

Plasma cytokine levels in patients with chronic alcohol overconsumption: Relations to gut microbiota markers and clinical correlates.

BACKGROUND: Alcohol-related morbidity may involve changes in the gut microbiota and immune dysregulation. We have previously demonstrated alterations in gut microbiota composition and functions in patients with alcohol overconsumption, and now aimed to investigate possible associations between cytokine levels, gut microbiota, and clinical symptoms. METHODS: We included hospital inpatients with a history of chronic alcohol overconsumption. For comparison, we included control patients with a low alcohol intake. Cytokine levels (TGF-ß1, TNF-α, IL-10, IL-8, IL-6, IFN-γ, MCP-1, IL-1RA, IL-1ß, and IL-17) were determined using a customized V-plex assay. We then examined associations of cytokine levels with the abundance of Proteobacteria and Faecalibacterium, percentage of the short-chain fatty acid butyrate, psychiatric symptoms (Hospital Anxiety and Depression Scale), and biochemical liver variables. RESULTS: We included 28 patients with alcohol overconsumption (79% men), and 25 control patients (72% men). Patients with alcohol overconsumption had higher levels of IL-6 (p = 0.002), IFN-γ (p = 0.018), and MCP-1 (p = 0.006), and lower levels of TGF-ß1 (p = 0.017) compared with control patients. Inverse correlations were found between Proteobacteria abundance and TNF-α (Rs = -0.55, p = 0.02) and IL-8 (Rs = -0.58, p = 0.014), and between Faecalibacterium and MCP-1 levels (Rs = -0.56, p = 0.02) in the control patients, but not in patients with alcohol overconsumption. Patients with alcohol overconsumption reported more psychiatric symptoms, and these symptoms were inversely correlated with IL-10 levels. There were positive correlations between several of the assessed cytokines and biochemical liver variables, and negative correlations between cytokine levels and albumin. CONCLUSION: Patients with alcohol overconsumption had a cytokine profile suggestive of increased systemic inflammatory activity, with higher levels of pro-inflammatory cytokines (IL-6, IFN-γ, and MCP-1) and lower levels of anti-inflammatory cytokines (TGF-ß1). The findings may represent a link between alcohol use and alcohol-related morbidity.

Characterization of gut microbiota composition and functions in patients with chronic alcohol overconsumption.

Excessive alcohol intake can alter the gut microbiota, which may underlie the pathophysiology of alcohol-related diseases. We examined gut microbiota composition and functions in patients with alcohol overconsumption for >10 years, compared to a control group of patients with a history of no or low alcohol intake. Faecal microbiota composition was assessed by 16S rRNA sequencing. Gut microbiota functions were evaluated by quantification of short-chain fatty acids (SCFAs) and predictive metagenome profiling (PICRUSt). Twenty-four patients, mean age 64.8 years (19 males), with alcohol overconsumption, and 18 control patients, mean age 58.2 years (14 males) were included. The two groups were comparable regarding basic clinical variables. Nutritional assessment revealed lower total score on the screening tool Mini Nutritional Assessment, lower muscle mass as assessed by handgrip strength, and lower plasma vitamin C levels in the alcohol overconsumption group. Bacteria from phylum Proteobacteria were found in higher relative abundance, while bacteria from genus Faecalibacterium were found in lower relative abundance in the group of alcohol overconsumers. The group also had higher levels of the genera Sutterella, Holdemania and Clostridium, and lower concentration and percentage of butyric acid. When applying PICRUSt to predict the metagenomic composition, we found that genes related to invasion of epithelial cells were more common in the group of alcohol overconsumers. We conclude that gut microbiota composition and functions in patients with alcohol overconsumption differ from patients with low consumption of alcohol, and seem to be skewed into a putative pro-inflammatory direction.

PTSD patients show increasing cytokine levels during treatment despite reduced psychological distress.

BACKGROUND: A reciprocal relationship between activated innate immune system and changes in mood and behavior has been established. There is still a paucity of knowledge on how the immune system responds during psychiatric treatment. We aimed to explore circulating cytokines and assess psychiatric symptom severity scores during 12 weeks of inpatient psychiatric treatment. METHODS: The study was a longitudinal assessment of 124 patients (88 women and 36 men) in treatment at Modum Psychiatric Center, Norway. The patient sample comprised a mixed psychiatric population of whom 39 were diagnosed with posttraumatic stress disorder (PTSD). Serum blood samples for cytokine analysis and measures of mental distress using Global Severity Index were collected at admission (T0), halfway (T1), and before discharge (T2). Other factors assessed were age, gender, and the use of antidepressants and anti-inflammatory drugs. Multilevel modeling was used for longitudinal analyses to assess the repeated cytokine samples within each patient. RESULTS: Overall level of IL-1RA was higher in PTSD patients when compared to those without PTSD (P=0.021). The level of IL-1ß, MCP-1, and TNF-α increased over time in PTSD compared to non-PTSD patients (P=0.025, P=0.011 and P=0.008, respectively). All patients experienced reduced mental distress as measured by self-reported Global Severity Index scores. Stratified analysis showed that PTSD patients who used anti-inflammatory drugs had higher levels of IL-1ß (P=0.007) and TNF-α (P=0.049) than PTSD patients who did not use such drugs. CONCLUSION: The study indicates that traumatized patients may have a distinct neuroimmune development during recovery. Their activated immune system shows even further activation during their rehabilitation despite symptom reduction.

The effect of trauma and alcohol on the relationship between level of cytokines and depression among patients entering psychiatric treatment.

BACKGROUND: Depression is associated with immunological responses as reflected by altered levels of circulating cytokines. Alcohol use and trauma may modulate immune activity, and few studies have investigated these factors in depressed patients. We aimed to explore the association between circulating peripheral cytokine levels and degree of depressive symptoms, taking trauma and alcohol into account. METHODS: The study was a cross-sectional assessment of patients at admission to a specialized psychiatric center in Norway. A total of 128 patients were included. Information was gathered using the self-administered questionnaires Beck Depression Inventory-II (BDI-II) and the Alcohol Use Disorders Identification Test (AUDIT), in addition to clinical interviews recording childhood or adult life trauma. Serum levels of the cytokines Interleukin-1ß (IL-1ß), Interleukin-1 Receptor Antagonist (IL-1RA), Tumor Necrosis Factor-α (TNF-α) and the chemokine Monocyte Chemoattractant Protein-1 (MCP-1) were assessed. A Luminex bead-based multiplex assay was used for cytokine measurements. Patient cytokine levels were compared to those of healthy volunteers by the Mann-Whitney U test. RESULTS: Levels of cytokines did not differ across patients with mild, moderate and severe depression. AUDIT score was not related to cytokine levels, but to level of depression. A history of trauma was related to higher levels of IL-1RA and TNF-α (p = 0.048 and p = 0.033, respectively), especially among the severely depressed. Serum levels of MCP-1 and TNF-α were significantly higher among psychiatric patients than in healthy volunteers. CONCLUSIONS: Findings indicate that depression was not related to levels of circulating cytokines among patients in treatment, but that traumatized patients had higher levels of IL-1RA and TNF-α than patients without trauma experience. The lack of relationship between cytokine level and depression was evident both in those without and with trauma.

Circulating cytokine levels are associated with symptoms of depression and anxiety among people with alcohol and drug use disorders.

BACKGROUND: Psychological distress is common among people with a substance abuse disorder in treatment. Identifying correlates of psychological distress may serve as points of intervention to improve substance abuse treatment outcomes. Immune function measured as cytokine levels have been associated with psychological distress, but this association remains unexplored among people with a substance abuse disorder in treatment. This study aimed to examine whether cytokine levels in patients treated for a substance use disorder were related to depression, anxiety, and overall psychological distress, and to observe these associations separately among people with a past year alcohol use disorder and those with a past year drug use disorder. METHODS: We collected cross-sectional data from 80 inpatients at five alcohol and substance abuse treatment centers in Norway. We determined alcohol and drug diagnoses, and assessed symptoms of depression, anxiety, and overall psychological distress. We tested blood samples for IL-1, IL-6, TNF-α, INF-γ, and IL-10. We used multivariate linear regressions to examine the associations between cytokine levels and psychological distress measures. RESULTS: All cytokines were significantly and positively associated with depression score. INF-γ was significantly and negatively associated with anxiety, and IL-6 was significantly and positively associated psychological distress. Among people with only an alcohol use disorder, IL-6 was positively associated with depression and psychological distress scores, and IL-10 was negatively associated with anxiety score. Among people with only a drug use disorder, TNF-α was positively associated with depression score. CONCLUSION: The relationship between immune function and psychological distress is robust in the context of substance abuse, and further research is warranted.

Comorbid post-traumatic stress disorder in alcohol use disorder: relationships to demography, drinking and neuroimmune profile.

BACKGROUND: This study examined how alcohol use disorder (AUD) patients with post-traumatic stress disorder (PTSD) differed from those without PTSD in terms of demography, drinking patterns and C-reactive protein, inflammatory cytokines, tryptophan metabolism parameters, and brain-derived neurotrophic factor (BDNF). METHODS: A consecutive sample (N = 187) of treatment-receiving AUD individuals were recruited from Nepalese facilities. They underwent fully structured psychiatric interviews. Serum levels of inflammatory cytokines [interleukin (IL)-6, IL-1 Receptor antagonist (IL-1Ra), IL-10, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ)] were determined by a multiplex assay, kynurenine and tryptophan levels by high-performance liquid chromatography, and BDNF by enzyme-linked immunosorbent assay (ELISA). RESULTS: The prevalence of exposure to severe trauma and PTSD was 74% and 17%, respectively. PTSD comorbidity was not associated with age, gender, or socioeconomic status, but with co-occurring major depression, history of attempted suicide, earlier peak of drinking problems, higher drinking quantity and withdrawal symptoms, experiencing alcoholic blackouts, and drinking problems among parents. None of the assessed neuroimmune parameters was related to comorbid PTSD. CONCLUSIONS: The findings support routine trauma screening in AUD treatment samples and screening for risky drinking in trauma populations to help guide interventions. The expected aberrations in neuroimmune functioning may not be found when examined in a sample with multiple psychiatric morbidities.

Cytokine Changes following Acute Ethanol Intoxication in Healthy Men: A Crossover Study.

Alcohol is a known modulator of the innate immune system. Owing to the absence of human studies, alcohol's effect on circulating cytokine profile remains unclear. We investigated the effect of acute high dose alcohol consumption on systemic cytokine release. After an overnight fasting, alcohol-experienced healthy male volunteers (N = 20) aged 25-45 years were given oral ethanol in the form of vodka (4.28 mL/kg) which they drank over a period of 30 minutes reaching peak blood alcohol concentration of 0.12% (SD 0.028). Blood samples were obtained prior to alcohol intake as well as 2, 7, and 12 hours thereafter. Serum levels of the inflammatory cytokines IL-1ß, IL-1Ra, IL-6, IL-10, IL-17, IFN-γ, MCP-1, and TNF-α were determined by the multibead-based assay. Baseline cytokine levels were not related to BMI, hepatic parameters, electrolytes, glucose, or morning cortisol levels. Within 2 hours of alcohol intake, levels of IL-1Ra were elevated and remained so throughout the assessment period (p for trend = 0.015). In contrast, the levels of the chemokine MCP-1 dropped acutely followed by steadily increasing levels during the observation period (p < 0.001). The impact of sustained elevated levels of MCP-1 even after the clearance of blood alcohol content deserves attention.

Neuroimmune Interface in the Comorbidity between Alcohol Use Disorder and Major Depression.

Bidirectional communication links operate between the brain and the body. Afferent immune-to-brain signals are capable of inducing changes in mood and behavior. Chronic heavy alcohol drinking, typical of alcohol use disorder (AUD), is one such factor that provokes an immune response in the periphery that, by means of circulatory cytokines and other neuroimmune mediators, ultimately causes alterations in the brain function. Alcohol can also directly impact the immune functions of microglia, the resident immune cells of the central nervous system (CNS). Several lines of research have established the contribution of specific inflammatory mediators in the development and progression of depressive illness. Much of the available evidence in this field stems from cross-sectional data on the immune interactions between isolated AUD and major depression (MD). Given their heterogeneity as disease entities with overlapping symptoms and shared neuroimmune correlates, it is no surprise that systemic and CNS inflammation could be a critical determinant of the frequent comorbidity between AUD and MD. This review presents a summary and analysis of the extant literature on neuroimmune interface in the AUD-MD comorbidity.

Vitamin D status in pre-school children in rural Nepal.

OBJECTIVE: Vitamin D plays a major role in Ca and bone metabolism, and its extraskeletal functions are being appraised. Although inadequate vitamin D concentrations have been reported in populations worldwide, too little is known about vitamin D status and its determinants among children in developing countries. We aimed to determine vitamin D status and its determinants in Nepalese children of pre-school age. DESIGN: A community-based, cross-sectional study. SETTING: Rural Nepal at latitude 27.39° N. SUBJECTS: Healthy children (n 280) aged 12-60 months, selected randomly from the records of a vitamin A supplementation programme. Blood samples were collected using the dried blood spot technique and analysed for serum 25-hydroxyvitamin D (s-25(OH)D) concentration using liquid chromatography-tandem mass spectrometry. Ca intake and background variables were assessed with a structured questionnaire. RESULTS: Hypovitaminosis D, defined as s-25(OH)D concentration less than 50 nmol/l, was found in 91.1% of the children. S-25(OH)D concentration was not related to gender, socio-economic indicators, sun exposure or nutritional status. Currently breast-fed children had higher s-25(OH)D concentrations (36.4 (sd 13.2) nmol/l) than those who were not (28.6 (sd 9.8) nmol/l, P<0.001). Adjustment for sociodemographic factors did not alter the results. CONCLUSION: There is widespread vitamin D deficiency among pre-school children in a rural area of Nepal. In our sample, sociodemographic factors did not affect the vitamin D status of children, but prolonged breast-feeding was associated with higher s-25(OH)D concentrations. Further research is required to investigate the health consequences of poor vitamin D status for this population.

The association between alcohol use and depressive symptoms across socioeconomic status among 40- and 45-year-old Norwegian adults.

BACKGROUND: Little population-based data among middle-aged adults exists examining the relationships between depressive symptoms, alcohol use, and socio-economic status (SES). This study aimed to describe the relationships between depressive symptoms and alcohol use at different levels of SES and to determine differences across SES levels among a population-based sample of 40 and 45 year old adults in Norway. METHODS: This analysis was based on data from two Norwegian health studies conducted in 2000 and 2001, and included community-dwelling Norwegian men and women aged 40 and 45 years. Self-reported frequency and quantity of alcoholic drinks was used to calculate past-year typical quantity of drinks consumed and frequency of 5+ drinks per occasion, or heavy episodic drinking (HED). Depressive symptoms were assessed with the 10-item Hopkins Symptom Checklist, and SES was measured as education level and employment status. To observe the association between depressive symptoms and alcohol use at each level of SES we fitted multinomial logistic regression models using each alcohol outcome as a dependent variable stratified by level of education and employment. To observe differences across levels of SES, we examined the interaction between depressive symptoms and SES level in multinomial logistic regression models for each alcohol measures. RESULTS: Having depressive symptoms was significantly associated with an increased risk of 5+ typical drinks among people in the lowest (RRR = 1.60, p ≤ 0.05) education level, and not among people in the highest. Conversely, significant associations were observed among all levels of employment. For frequency of HED, depressive symptoms was not significantly associated with frequency of HED at any education level. Depressive symptoms was associated with 13+ past year HED episodes among people with no employment (RRR = 1.97, p ≤ 0.05), and part-time employment (RRR = 2.33, p ≤ 0.01), and no association was observed among people with full-time employment. A significant interaction was observed for depressive symptoms and employment for risk of 13+ past-year HED episodes. CONCLUSIONS: The results show a variety of associations between depressive symptoms and alcohol use among people with lower SES, and suggest type of alcohol use and SES measure may influence the observation of an association between depressive symptoms and alcohol use at different SES levels.

Serum brain-derived neurotrophic factor levels in relation to comorbid depression and cytokine levels in Nepalese men with alcohol-use disorders.

Neurodegenerative and inflammatory processes are involved separately in major depression (MD) and alcohol-use disorders (AUD). Little is known about the nature of this relationship in the context of comorbid AUD and depression disorders. In this study, we determined brain-derived neurotrophic factor (BDNF) serum levels in patients with AUD and tested whether BDNF levels were related to history of major depression, recent depressive symptoms, AUD severity, and TNF-α and IL-6 levels. Nepalese male AUD inpatients (N=152) abstinent from alcohol for an average of 34 days were administered structured interviews to assess depression symptoms and pattern and extent of alcohol use, and to generate research diagnoses for AUD and MD. AUD severity was assessed by scores on the Alcohol Use Disorder Identification Test. Serum BDNF and cytokines were measured using ELISA and multiplex technology, respectively. Although serum BDNF levels were unrelated to MD history, patients with recent depressive symptoms (n=42) had lower (mean±SD) BDNF serum levels compared to those without (n=110) (21.6±8.1 ng/mL vs. 26.0±9.6 ng/mL; p=0.010), and patients with higher AUD severity and binge-drinking patterns had higher mean serum BDNF levels compared to lower AUD severity and non-binging (25.9±9.7 ng/mL vs. 22.1±8.7 ng/mL; p=0.022 and 25.7±9.3 vs. 21.8±9.7 ng/mL; p=0.029, respectively). Positive correlations were present between BDNF and TNF-α (r=0.39, p<0.001) and IL-6 (r=0.2, p=0.027). In particular, TNF-α levels were predictive of BDNF levels after controlling for confounders (B=0.3 [95% CI=0.2-0.5], p<0.001). These findings show that in alcohol-using populations, peripheral BDNF levels are related to severity of AUD as well as presence of depressive symptoms. The significant associations between inflammatory and neurotrophic factors may have implications for neuroadaptive changes during recovery from AUD.