Sex differences in circulating inflammatory mediators as a function of substance use disorder.

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.

Restraint stress affects circulating NUCB2/nesfatin-1 and phoenixin levels in male rats.

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.

An increase in IL-6 levels at 6-month follow-up visit is associated with SSRI-emergent suicidality in high-risk children and adolescents treated with fluoxetine.

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-1ß were measured by enzyme linked immunosorbent assays before and after six months of treatment. IL-6 and IL-1ß 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.

Efficacy and safety of Shu-gan-qing-re formula for generalized anxiety disorder: study protocol for a multi-center, prospective, double-blind, double-dummy, randomized controlled trial.

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-1ß), 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.

Differences in cytokines between patients with generalised anxiety disorder and panic disorder.

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.

Neuroendocrine function and associated mental health outcomes following mild traumatic brain injury in OEF-deployed service members.

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.

Physical and mental fatigue across the menstrual cycle in women with and without generalised anxiety disorder.

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.

Daytime melatonin levels in saliva are associated with inflammatory markers and anxiety disorders.

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.

Role of the kynurenine pathway and the endocannabinoid system as modulators of inflammation and personality traits.

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.

Systematic review and meta-analysis of the association between peripheral inflammatory cytokines and generalised anxiety disorder.

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 (I2=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.

Effects of SSRIs on peripheral inflammatory cytokines in patients with Generalized Anxiety Disorder.

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.

Anxiety disorders in childhood are associated with youth IL-6 levels: A mediation study including metabolic stress and childhood traumatic events.

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-1ß, 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-1ß 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.

Biological and psychosocial predictors of anxiety worsening in the postpartum period: A longitudinal study.

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.

Longitudinal Association Between Depression and Inflammatory Markers: Results From the Netherlands Study of Depression and Anxiety.

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 ddepression diagnosis = 0.06, p = .017; Bstandardized 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 ratiowomen = 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.

Prospective associations of androgens and sex hormone-binding globulin with 12-month, lifetime and incident anxiety and depressive disorders in men and women from the general population.

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.

Quality of Life in Long-Term Testicular Cancer Survivors With Compensated Leydig Cell Dysfunction.

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.

Peripheral proinflammatory cytokines in Chinese patients with generalised anxiety disorder.

BACKGROUND: Inflammatory responses and inflammatory cytokines have been implicated in the pathogenesis of affective disorders, particularly major depression. Given the limited evidence relating to the potential role of proinflammatory cytokines in generalised anxiety disorder (GAD), we aimed to examine peripheral proinflammatory cytokines in Chinese patients with GAD. METHODS: A case-controlled cross-sectional study design, with recruitment of 48 patients with first episode GAD and 48 matched healthy controls. All participants completed measures of anxiety using well-established questionnaires, and serum levels of pro-inflammatory cytokines were measured using multiplex technology. RESULTS: Serum levels of CRP, IL-1α, IL-2, IL-6, IL-8, IL-12, IFN-γ, and GM-CSF were significantly higher in the GAD group in comparison to the control group (p < 0.05). Pearson correlation revealed significant positive correlations between anxiety measures and serum levels of CRP, IL-1α, IL-6, IL-8, IFN-γ, and GM-CSF (p < 0.05). LIMITATIONS: The cross-sectional study design does not permit definite conclusions on causal directions between inflammation and GAD. The study was limited to a panel of 8 cytokines and does not exclude the possibility of other important cytokines being involved. CONCLUSIONS: These findings indicate an elevated peripheral proinflammatory response, and provide further support for low grade inflammation in GAD. Further research may identify an 'inflammatory signature' for diagnosis and treatment response, and guide the search for novel pharmacological interventions.

Associations between severity of anxiety and clinical and biological features of major affective disorders.

Patients with major affective disorders (MAFD) with comorbid anxiety show a greater functional impairment than those without anxiety. The aim of this study is to delineate the associations between severity of anxiety in MAFD, namely bipolar disorder (BD) and major depression (MDD), and MAFD characteristics and serum high-density lipoprotein (HDL)-cholesterol levels. Recruited were 82 participants with anxiety disoders and 83 without anxiety disoders, including 101 MAFD patients and 51 healthy controls. We used the Hamilton Anxiety Rating Scale (HAM-A) to measure severity of anxiety and made the diagnoses of posttraumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD) and phobias. The HAM-A score is significantly predicted by higher number of depressive episodes, GAD and phobias, childhood trauma, tobacco use disorder, metabolic syndrome and lowered HDL-cholesterol. Increased HAM-A scores are, independently from severity of depression, associated with lowered quality of life, increased disabilities and suicidal ideation. Lithium treatment significantly lowers HAM-A scores. It is concluded that severity of anxiety significantly worsens the phenomenology of MAFD. Therefore, treatments of MAFD should target increased severity of anxiety and its risk factors including low HDL-cholesterol, metabolic syndrome, childhood trauma and tobacco use disorder.

Elevation of plasma neutrophil gelatinase-associated lipocalin (NGAL) levels in schizophrenia patients.

BACKGROUND: Psychiatric diseases are usually accompanied by immune dysregulation and activation of the inflammatory response system. However, the characteristics of immunoinflammatory markers in psychiatric diseases are not well defined. METHODS: Seventy-three patients with psychiatric diseases were divided into four groups, including a schizophrenia group, an anxiety disorder group, a unipolar depression group, and a bipolar disorder group, according to the ICD-10 and DSM-IV codes. Neutrophil gelatinase-associated lipocalin (NGAL) and associated classical immunoinflammatory markers including C-reactive protein (CRP), Th1/Th2 cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ), total leukocyte count (TLC), and neutrophilic granulocyte percentage (NEU%) were analysed; patients with physical diseases were excluded to avoid confounders. Fifteen healthy, age- and gender-matched individuals served as controls. RESULTS: Compared with the corresponding values in the control group, the level of CRP in each psychiatric disease group, the levels of IFN-γ and NGAL in the schizophrenia group, and the NEU% in the depression group were significantly elevated (P < 0.05). Compared with the levels in the schizophrenia group, the levels of CRP in the bipolar disorder and depression groups, the level of IFN-γ in the bipolar disorder group, and the levels of NGAL in the anxiety disorder and depression groups were significantly decreased (P < 0.05). Compared with the depression group, the bipolar disorder group showed significant elevation the NGAL level. LIMITATION: The sample size was relatively small. CONCLUSIONS: Immunoinflammatory markers were elevated in patients with psychiatric diseases, especially schizophrenia. We are the first to report that the level of NGAL is significantly increased in schizophrenia patients.

The bidirectional relationship between anxiety disorders and circulating levels of inflammatory markers: Results from a large longitudinal population-based study.

BACKGROUND: Although there has been abundant research on chronic low-grade inflammation as a potential mechanism underlying the link between mood disorders and cardiovascular risk, less is known about the role of inflammatory factors and anxiety disorders. The aim of this paper is to evaluate the bi-directional associations between inflammatory markers including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and high sensitivity C-reactive protein (hsCRP) with anxiety disorders and its subgroups. METHODS: The sample consisted of 3,113 participants (53.7% women; mean age: 51.0, S.D. 8.8 years), randomly selected from the general population, who underwent comprehensive somatic and psychiatric evaluations at baseline and follow-up (mean follow-up duration = 5.5 years, S.D. 0.6). Anxiety disorders were assessed with semistructured diagnostic interviews. Inflammatory biomarkers were analyzed in fasting blood samples. RESULTS: After adjustment for potential confounders, current anxiety disorders (ß = 0.09, 95% CI 0.00-0.17) and agoraphobia (ß = 0.25, 95% CI: 0.07-0.43) at baseline were associated with a steeper increase of hsCRP levels over the follow-up period. Current posttraumatic stress disorder (PTSD) was associated with a lower increase of IL-6 levels over the follow-up period (ß = -0.52, 95% CI: -1.00/-0.04). There was no evidence for an association between inflammation markers at baseline and anxiety disorders at follow-up. CONCLUSIONS: The prospective association between agoraphobia at baseline and hsCRP levels over the follow-up period suggests that chronic low-grade inflammation may be a consequence of this condition. The decrease in IL-6 in PTSD also requires further investigation. No evidence was found for chronic low-grade inflammation as a predictor of future anxiety disorders.