Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

Placebo effects in mental health disorders: protocol for an umbrella review.

INTRODUCTION: Given the high prevalence of mental health disorders and their significant socioeconomic burden, there is a need to develop improved treatments, and to evaluate them through placebo-controlled trials. However, the magnitude of the placebo response in randomised controlled trials to test medications may be substantial, affecting their interpretation. Therefore, improved understanding of the patient, trial and mental disorder factors that influence placebo responses would inform clinical trial design to better detect active treatment effects. There is a growing literature exploring the placebo response within specific mental health disorders, but no overarching synthesis of this research has been produced to date. We present a protocol for an umbrella review of systematic reviews and/or meta-analyses in which we aim to understand the effect size and potential predictors of placebo response within, and across, mental health disorders. METHODS AND ANALYSIS: We will systematically search databases (Medline, PsycINFO, EMBASE+EMBASE Classic, Web of Knowledge) for systematic reviews and/or meta-analyses that report placebo effect size in clinical trials in patients with mental health disorders (initial search date 23 October 2022). Screening of abstracts and full texts will be done in pairs. We will extract data to qualitatively examine how placebo effect size varies across mental health disorders. We also plan to qualitatively summarise predictors of increased placebo response identified either quantitatively (eg, through meta-regression) or qualitatively. Risk of bias will be assessed using the AMSTAR-2 tool. We aim to not only summarise the current literature but also to identify gaps in knowledge and generate further hypotheses. ETHICS AND DISSEMINATION: We do not believe there are any specific ethical considerations relevant to this study. We will publish the results in a peer-reviewed journal.

Effect of acceptance and commitment therapy for depressive disorders: a meta-analysis.

OBJECTIVE: To systematically evaluate the effect of Acceptance and Commitment Therapy (ACT) on depressive disorders. METHODS: The electronic databases of Web of Science Core Collection, Pubmed, EMBASE, Cochrane Library, PsycInfo, CNKI, Wanfang and Weipu were used to select relevant publications. Screening, data extraction, and quality assessment were undertaken following PRISMA guidelines for preferred reporting of systematic reviews and meta-analysis. RevMan5.4 was used for meta-analysis. RESULTS: 11 studies with a total of 962 patients were included. Random-effects model analysis showed that ACT could effectively reduce the level of depressive symptoms in patients with depressive disorders (SMD = - 1.05, 95% CI: - 1.43-- 0.66, P < 0.00001), improve psychological flexibility (MD = 4.84, 95% CI: 2.70-6.97, P < 0.00001), and have good maintenance effect (SMD = - 0.70, 95% CI: - 1.15-- 0.25, P = 0.002). All differences were statistically significant. CONCLUSIONS: ACT not only improves depressive symptoms and psychological flexibility, but also has a good maintenance effect, and it is particularly effective in Chinese patients. Large randomized controlled trials are needed to validate the findings from this meta-analysis.

An investigation of neuromelanin distribution in substantia nigra and locus coeruleus in patients with Parkinson's disease using neuromelanin-sensitive MRI.

Loss of neuromelanin in the midbrain is known in Parkinson's disease(PD), which can now be directly detected by neuromelanin-sensitive MRI(NM-MRI). This case-control study was to investigate the distribution of neuromelanin in the substantia nigra(SN) and the locus coeruleus(LC) using NM-MRI technique and evaluate its potential as a diagnostic marker for PD. 10 early PD patients(H&Y stage I, II), 11 progressive PD patients(H&Y stage III-V), and 10 healthy controls matched in age and gender were recruited. All participants completed clinical and psychometric assessments as well as NM-MRI scans. Neuromelanin signal intensities in SN and LC were measured by contrast-to-noise ratios(CNRs) derived from NM-MRI scans. There were significant decreases of CNRs in SNpc(including anterior, central, and posterior) and LC in PD patients compared to controls. There were also significant differences of CNR between the left and right sides. CNR in LC had a negative correlation with the Non-Motor Symptoms Scale(NMSS) score in PD patients(|R|=0.49), whereas CNR in SNpc did not correlate with Unified Parkinson Disease Rating Scale(UPDRS) score(|R|<0.3). The receiver operating characteristic(ROC) curves revealed that the CNR in LC had a high diagnostic specificity of 90.1% in progressive patients. This study provides new evidence for the asymmetric distribution of neuromelanin in SN and the LC of patients with PD. The neuromelanin loss is bilateral and more predominately in LC than that in SN. This distinct neuromelanin distribution pattern may offer a potential diagnostic marker and a potential neuropharmacological intervention target for PD patients.

The role of inflammation in anxiety and depression in the European U-BIOPRED asthma cohorts.

BACKGROUND: Growing evidence indicates high comorbid anxiety and depression in patients with asthma. However, the mechanisms underlying this comorbid condition remain unclear. The aim of this study was to investigate the role of inflammation in comorbid anxiety and depression in three asthma patient cohorts of the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) project. METHODS: U-BIOPRED was conducted by a European Union consortium of 16 academic institutions in 11 European countries. A subset dataset from subjects with valid anxiety and depression measures and a large blood biomarker dataset were analysed, including 198 non-smoking patients with severe asthma (SAn), 65 smoking patients with severe asthma (SAs), 61 non-smoking patients with mild-to-moderate asthma (MMA), and 20 healthy non-smokers (HC). The Hospital Anxiety and Depression Scale was used to measure anxiety and depression and a series of inflammatory markers were analysed by the SomaScan v3 platform (SomaLogic, Boulder, Colo). ANOVA and the Kruskal-Wallis test were used for multiple-group comparisons as appropriate. RESULTS: There were significant group effects on anxiety and depression among the four cohort groups (p < 0.05). Anxiety and depression of SAn and SAs groups were significantly higher than that of MMA and HC groups (p < 0.05. There were significant differences in serum IL6, MCP1, CCL18, CCL17, IL8, and Eotaxin among the four groups (p < 0.05). Depression was significantly associated with IL6, MCP1, CCL18 level, and CCL17; whereas anxiety was associated with CCL17 only (p < 0.05). CONCLUSIONS: The current study suggests that severe asthma patients are associated with higher levels of anxiety and depression, and inflammatory responses may underlie this comorbid condition.

Effects of exercise on obsessive-compulsive disorder symptoms: a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis assessed the efficacy of exercise in reducing OCD symptoms. METHODS: We searched PubMed, Cochrane Central Register of Controlled Trials, MEDLINE, Scopus and grey literature until March 2022. The study was preregistered at Prospero (CRD42021283931). We included randomised controlled and pre-post trials assessing physical activity as an intervention for OCD. Risk of bias was assessed using the Cochrane ROBINS-I tool and the RoB2 tool. RESULTS: The analysis included 6 trials (N = 92); 2 were RCTS and 4 were pre-post design studies. A random-effects meta-analysis of pre-post data identified a large reduction of OCD symptoms following exercise (g = 1.33 [95%CI 1.06-1.61]; k = 6). Exercise was also associated with significant pre-post reductions in anxiety (g = 0.71 [95%CI 0.37-1.05; k = 4) and depression (g = 0.57 [95%CI 0.26-0.89]; k = 2). Risk of bias was moderate-high in uncontrolled trials on the ROBINS-I and RCTs showed 'some concerns' on the RoB2. CONCLUSION: Exercise was associated with a large pre-post reduction of OCD symptoms; however, few trials were of robust quality and all were at risk of bias. Further well-powered and better quality RCTs are required to assess the role of exercise as an intervention for OCD.KEY POINTSStudies exploring exercise as an adjunct therapy for OCD have small participant numbers, therefore a systematic review and meta-analysis is needed to estimate potential efficacy.Pre-post analysis shows that exercise was associated with a large reduction of OCD symptomsThe current systematic review and meta-analysis points to the potential for exercise to be beneficial for the treatment for OCD symptoms. However, more well-powered and better controlled RCTs are required to fully assess the benefit of exercise for the treatment of OCD symptoms.

Correlation analysis between D-dimer-to-fibrinogen-ratio and carotid plaque in young patients aged 18-45 with acute cerebral infarction.

BACKGROUND: D-Dimer and fibrinogen were commonly used to detect the coagulation and fibrinolytic function, but D-dimer to fibrinogen ratio (DFR) in carotid plaque in young patients aged 18-45 with acute cerebral infarction (ACI) has not been used clinically. In this work, we focused on the evaluation of the DFR value of this group of patients and analyzed its possible correlation. METHODS: A total of 164 patients with ACI patients aged 18-45 were selected as research subjects after their first admission. They had undergone carotid plaque contrast-enhanced ultrasound (CEUS) and were divided into two groups with carotid plaque (n = 97) and with no carotid plaque (n = 67). According to NIHSS score and carotid plaque grade, the clinical symptoms of patients were judged. Univariate and multivariate analyses were conducted to compare the risk factors of carotid plaque in ACI patients. RESULTS: The DFR value of patients in the carotid plaque group (103.41 ± 20.81) was significantly higher than that of the no carotid plaque control group (88.9 ± 26.51). We also identified DFR X103 was the only independent risk factor (ß = 0.53; 95% CI, 0.914-0.984; P = 0.05). DFR X103 was increased with the severity of the disorder and with the CEUS grades. The area under the DFR curve was 0.673 (95% CI 0.584～0.762). CONCLUSION: The value of the DFR is positively correlated with CEUS carotid plaque grading and NIHSS score, which can predict the severity of carotid plaque in ACI patients aged 18-45. Therefore it is worthy of clinical application.

Prevalence of depressive disorders and associated demographic characteristics in Shandong: An epidemiological investigation.

BACKGROUND: Depression is characterized by debilitating symptoms and high recurrence rates, and there are relatively few large-scale epidemiological surveys of depressive disorders conducted in Shandong since 2005. Data from the largest Epidemiological Survey of Mental Disorders conducted in 2015 in Shandong were collected to investigate the prevalence of depressive disorders and associated demographic characteristics in general adult population. METHODS: A multi-stage stratified cluster sampling method was adopted to select residents and a two-stage screening and assessment process was used to define the prevalence and characteristics of depressive disorders. Respondents were initially screened using the General Health Questionnaire followed by a structured clinical interview using the DSM-IV criteria. RESULTS: Among 27,489 respondents who completed the survey, 1277 respondents met the diagnostic criteria for depressive disorders. The adjusted prevalence in the last month was 4.86%, among which the prevalence of major depressive disorder, dysthymia, and unspecified depressive disorder were 2.32%, 1.78%, and 0.75%, respectively. 40.35% of depression patients had moderate or severe functional impairment and only 10.65% of patients had visited a psychiatric service. Univariate and multivariate analyses revealed that age, gender, occupation, education, marital status, and urban/rural living were associated with the prevalence. LIMITATIONS: The key limitation is that this is a cross-sectional survey therefore cannot draw any causal relationship between risk factors and disease progression. CONCLUSIONS: Findings from this largest epidemiological study reveal current prevalence of depressive disorders and associated demographic factors and offers opportunities for policy makers and health-care professionals to improve mental health provision in Shandong.

Locus coeruleus in the pathogenesis of Alzheimer's disease: A systematic review.

The locus coeruleus (LC) is a nucleus in the brain stem producing noradrenaline. While cognitive decline in Alzheimer's disease (AD) has primarily been related to cholinergic depletion, evidence indicates extensive LC degeneration as its earliest pathological marker. The current study aimed to systematically evaluate current evidence investigating the role of the LC in the pathogenesis of AD. A systematic search of the literature was performed on electronic databases including PubMed and Web of Science. Twelve animal, human post mortem, and human imaging studies were included in this review. Screening, data extraction, and quality assessment were undertaken following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for preferred reporting of systematic reviews. Significant associations were identified between LC changes and cognitive decline. Significant reductions in fiber density, neuronal number, and LC volume were seen to correlate with other pathological degenerative markers. Current evidence indicates an important role of the LC in pathogenesis of AD and suggests its potential in both diagnosis and treatment of AD. This systematic review advances our understanding of the role of the LC in AD by synthesizing available evidence, identifying research gaps, highlighting methodological challenges, and making recommendations for future work.

Immune-endocrine biomarkers associated with mental health: A 9-year longitudinal investigation from the Hertfordshire Ageing Study.

BACKGROUND: The study of neural-endocrine-immune system interactions has led to substantial advances in our understanding of neuropsychiatric disorders. Growing evidence reveals the pivotal roles of inflammatory cytokines signalling the brain to produce neurochemical, neuroendocrine, and neuroimmune changes which affect mood and behaviour. Ageing is accompanied by the development of low-grade systemic inflammation which may promote changes in the neural systems predisposing to geriatric depression via the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to investigate the longitudinal associations between baseline values and conditional changes (independent of baseline) in immune-endocrine biomarkers and mental health status in a population-based cohort of older adults. METHODS: Data from 347 subjects (200 men, 147 women) who participated in the Hertfordshire Ageing Study at baseline (1994/5, mean age 67.3 years) and at 9-year follow-up were analysed. Serum samples for analysis of inflammatory and endocrinological measures were collected at baseline and follow-up. At follow-up, depression (Hospital Anxiety and Depression Scale) and mental health (Short Form-36 questionnaire) were assessed. Baseline values and changes in biomarkers in relation to risk of high depression scores (top sex-specific third) and low mental health scores (bottom sex-specific third) were examined using logistic regression. RESULTS: Lower baseline cortisol was related to greater risk of high depression scores; higher baseline cortisol: dehydroepiandrosterone sulphate ratio (men only) and higher baseline C-reactive protein (CRP) (women only) were related to greater risk of poor mental health scores. In addition, greater decline in cortisol was related to increased risk of high depression scores among men. These relationships were robust (p < 0.05) after controlling for sex, age, BMI, smoking, alcohol consumption and number of systems medicated. CONCLUSION: This study provides further evidence of the role of the HPA axis and inflammation in older adults with poor mental health. In addition, the findings highlight sex differences where increased inflammation in women and declines in cortisol in men were linked to poorer mental health. Further research is warranted to confirm these findings. This could lead to the search for potential biomarkers to stratify medications as well as developing novel intervention targets to improve mental health at older age.

The Locus Coeruleus in Aging and Alzheimer's Disease: A Postmortem and Brain Imaging Review.

The locus coeruleus (LC), a tiny nucleus in the brainstem and the principal site of noradrenaline synthesis, has a major role in regulating autonomic function, arousal, attention, and neuroinflammation. LC dysfunction has been linked to a range of disorders; however particular interest is given to the role it plays in Alzheimer's disease (AD). The LC undergoes significant neuronal loss in AD, thought to occur early in the disease process. While neuronal loss in the LC has also been suggested to occur in aging, this relationship is less clear as the findings have been contradictory. LC density has been suggested to be indicative of cognitive reserve and the evidence for these claims will be discussed. Recent imaging techniques allowing visualization of the LC in vivo using neuromelanin-sensitive MRI are developing our understanding of the role of LC in aging and AD. Tau pathology within the LC is evident at an early age in most individuals; however, the relationship between tau accumulation and neuronal loss and why some individuals then develop AD is not understood. Neuromelanin pigment accumulates within LC cells with age and is proposed to be toxic and inflammatory when released into the extracellular environment. This review will explore our current knowledge of the LC changes in both aging and AD from postmortem, imaging, and experimental studies. We will discuss the reasons behind the susceptibility of the LC to neuronal loss, with a focus on the role of extracellular neuromelanin and neuroinflammation caused by the dysfunction of the LC-noradrenaline pathway.

Psychological distress after subarachnoid haemorrhage: A systematic review and meta-analysis.

OBJECTIVE: Psychological distress is a common complication in patients after Subarachnoid haemorrhage (SAH) which often has significant impact on the prognosis. The objective of this study was to determine the pooled prevalence of anxiety symptoms and depressive symptoms in patients after SAH and identify relevant risk factors. METHODS: The study adopted a systematic review and meta-analysis protocol. Multiple databases including EMBASE, Medline, PsychInfo, and Web of Science were searched for publications before 1st January 2020. Screening, data extraction, and quality assessment were undertaken following the PRISMA guidelines for preferred reporting of systematic reviews and meta-analysis. The random-effects model was used to calculate pooled prevalence rates. Meta-analysis was conducted using Comprehensive Meta-analysis software. The review protocol was registered on PROSPERO (CRD42020182594). RESULTS: 42 studies reporting anxiety symptoms and 64 studies reporting depressive symptoms were included. The pooled short term(<3 years) and long term(≥3 years) prevalence rates of anxiety symptoms were 31.4%(95% CI: 23.6%, 40.4%) and 40.4%(95% CI: 31.6%, 49.8%), respectively, whereas the pooled short term and long term prevalence rates of depressive symptoms were 25.2%(95%CI: 17.8%, 34.5%) and 35.8%(95%CI: 28.6%, 43.6%), respectively. Gender and pre-existing psychiatric conditions were identified as potential risk factors. CONCLUSIONS: The high prevalence of anxiety symptoms and depressive symptoms after SAH highlights the need for appropriate assessment and management of psychological stress in patients after SAH. Further research is warranted to explore potential underlying mechanisms and to develop holistic interventions that incorporate understanding of both the biological and psychological impact of SAH.

Anxiety in asthma: a systematic review and meta-analysis.

BACKGROUND: Background: Growing evidence from observational studies indicates a high prevalence of anxiety in asthma. However, prevalence rates of coexisting anxiety symptoms and comorbid anxiety disorders vary widely across studies. We aimed to evaluate the associations between anxiety and asthma and provide more precise comorbidity estimates. METHODS: We systematically reviewed the literature from case-controlled studies and conducted a meta-analysis to evaluate the pooled prevalence estimates and risks of anxiety symptoms and anxiety disorders in asthma individuals. Screening, data extraction, and quality assessment were undertaken following PRISMA guidelines for preferred reporting of systematic reviews and meta-analysis. A random-effects model was used to calculate pooled prevalence rates. Meta-analysis was conducted using Review Manager 5.3. Multiple databases including PubMed, ScienceDirect, PsychINFO, and PsycARTICLES were searched for publications before 1 December 2019. The review protocol was registered on PROSPERO (ref: CRD42020176028). RESULTS: In total, 19 studies involving 106813 participants were included. The pooled prevalence of anxiety symptoms and anxiety disorders in individuals with asthma was 0.32 (95% CI 0.22-0.43) and 0.24 (95% CI 0.13-0.41), respectively. The risks of coexisting anxiety symptoms and comorbid anxiety disorders were significantly higher in asthma patients than in non-asthma controls indicated by OR 1.89 (95% CI 1.42-2.52; Z = 4.37; p < 0.001) and OR 2.08 (95% CI 1.70-2.56; Z = 6.97; p < 0.001), respectively. Anxiety symptoms and anxiety disorders occur at increased frequency among patients with asthma. CONCLUSIONS: Our findings highlight the need for appropriate assessments for these comorbid conditions, which may help to identify a subgroup of patients who might benefit from interventions designed to reduce anxiety and enhance the quality of life.

A case-control study of the locus coeruleus degeneration in Alzheimer's disease.

The locus coeruleus (LC) is the major source of noradrenaline, which plays a key role in cognition. We aimed to detect the extent of the LC signal attenuation in Alzheimer's disease (AD) patients using a neuromelanin (NM)-sensitive MRI and how it may correlate with inflammatory and autonomic measures. An individually matched case-control study design was employed. 24 patients with AD and 24 age and gender matched controls with no cognitive impairment were recruited. The primary outcome measure was the LC signal intensity indicated by the LC contrast ratio (CR) and measured by the NM-sensitive MRI. Secondary outcome measures included neuropsychometric tests of cognitive state, peripheral inflammatory and autonomic measures. Conditional logistic regression analysis revealed a significant 22% LC-CR reduction in the AD group compared with the control group. However, there was no statistical significance from inflammatory or autonomic measures. This is the largest individually-matched case-control study to visualise the LC degeneration in AD patients. The study revealed significant LC degeneration which holds promise to stratify patients who may benefit from treatment targeting noradrenergic dysfunction.

Caring for patients in mental health services during COVID-19 outbreak in China.

This article reflects on some radical changes made in mental health services in China which include the implementation of the initial triage system and the special isolation ward, the early screening and testing for both patients and staff, the smaller teams working on rotating shifts on-site, and the adequate provision of PPE. These measures would be of great value as a reference to the effective delivery of mental health services in other countries through this pandemic.

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.

Effects of SSRIs on peripheral inflammatory markers in patients with major depressive disorder: A systematic review and meta-analysis.

INTRODUCTION: Peripheral levels of inflammatory markers are elevated in major depressive disorder (MDD). Selective serotonin reuptake inhibitors (SSRIs) affect levels of inflammatory markers in patients with MDD, but studies have reported inconsistent findings. This systematic review and meta-analysis aims to investigate the effects of SSRI treatment on peripheral levels of a range of inflammatory markers in MDD patients. METHODS: Systematic literature search (Pubmed, Web of Science, Embase, Cochrane) for studies published before November 2018. Studies were included if they used SSRI monotherapy and peripheral levels of interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured before and after treatment in patients with MDD. Meta-analysis was conducted using Comprehensive Meta-analysis (version 2). Effect sizes were calculated using bias-corrected standardized mean difference (Hedges' g) between pre- and post-treatment. Sub-group analyses, meta-regression and publication bias estimates were undertaken; sensitivity analyses were performed using different estimated pre- and post-treatment correlations and after removing poor quality studies. RESULTS: Twenty two eligible studies including 827 MDD patients were included in the meta-analysis: fifteen studies for IL-6; eleven for TNF-α; eight for IL-10; seven for IL-1ß; six for IL-4; five for IL-2; and four for IFN-γ. The pooled effect estimate indicates SSRI treatment decreased levels of pro-inflammatory markers IL-6 (Hedges' g, -0.418; 95%CI, -0.663 to -0.174; I2 = 89.412), TNF-α (Hedges' g, -0.554; 95%CI, -0.990 to -0.118; I2 = 95.438) and IL-1ß (Hedges' g = -0.574; 95%CI, -1.014 to -0.135; I2 = 91.622), and anti-inflammatory marker IL-10 (Hedges' g = -0.615; 95%CI, -0.989 to -0.242; I2 = 90.406). There were no significant treatment effects on levels of IL-2, IL-4, or IFN-γ. There was a high level of heterogeneity between studies. Sensitivity analyses indicated the robustness of the primary analyses. CONCLUSIONS: The current review and meta-analysis indicates moderate immunomodulating effects of SSRI treatment for MDD, which suggests SSRIs may owe some of their therapeutic effect to their anti-inflammatory properties. High heterogeneity across studies may limit interpretation of the findings and larger randomized clinical trials are warranted.

Prevalence, clinical correlates and IQ of suicidal ideation in drug naïve Chinese Han patients with major depressive disorder.

BACKGROUND: Suicidal ideation (SI) is a common and serious clinical concern in people with major depressive disorder (MDD). Inconsistent evidence suggests that individuals with SI may have a lower measured intelligence quotient (IQ) than those without SI. The aims of this study were to examine SI prevalence and its associations with demographic, clinical variables and IQ in Chinese drug-naïve MDD patients. METHODS: 488 drug-naïve Chinese Han patients (male: 203, 41.6%) meeting a DSM-IV diagnosis of MDD were enrolled in a cross-sectional study involving seven hospitals. All participants were asked to complete a series of questionnaires, which include information on socio-demographic and clinical variables. The Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA) and Brief Psychiatric Rating Scale (BPRS) were also administered. Verbal IQ (VIQ), performance IQ (PIQ) and full-scale IQ (FIQ) scores were measured using the Chinese version of the Wechsler Adult Intelligence Scale-Ⅲ (WAIS-Ⅲ). We categorized patients with SI based on a cut-off score of ≥3 on HAMD item 3. RESULTS: An estimated prevalence 32.8% (160/488) of drug-naïve MDD patients experienced SI during the current episode of illness. Patients with SI were more likely to be divorced (x2 = 6.93, p = 0.031), male (x2 = 6.04, p = 0.014), had higher severity of depression and anxiety symptoms (t = -8.14, p < 0.001, t = -3.28, p < 0.001, respectively), comorbid psychotic features (t = -5.71, p < 0.001), and lower FIQ levels (t = -4.21, p < 0.001), when compared to patients without SI. Using logistic regression analysis and adjusting for confounding variables, the following variables were independently associated with SI: divorced marital status compared to married (OR=4.674, 95% CI: 1.676~13.036), severity of depression symptoms (OR=1.312, 95% CI: 1.196~1.440), psychotic features (OR=1.044; 1.012~1.077), and FIQ /PIQ levels which expressed in OR per SD increase in IQ score (OR=0.740, 95% CI: 0.561~0.977; OR=0.744, 95% CI: 0.557~0.994, respectively). LIMITATIONS: A cross-sectional study which did not assess the influence of severity of SI. CONCLUSIONS: The prevalence of SI in drug-naive Chinese patients with MDD is high, and associated with marital status, severity of depression, psychotic features and measured IQ. Further research is needed to further explore these and other potentially relevant risk factors which might affect clinical outcomes.

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.

Pharmacotherapy in Generalized Anxiety Disorder: Novel Experimental Medicine Models and Emerging Drug Targets.

Many pharmacological and psychological approaches have been found efficacious in patients with generalized anxiety disorder (GAD), but many treatment-seeking patients will not respond and others will relapse despite continuing with interventions that initially had beneficial effects. Other patients will respond but then stop treatment early because of untoward effects such as sexual dysfunction, drowsiness, and weight gain. There is much scope for the development of novel approaches that could have greater overall effectiveness or acceptability than currently available interventions or that have particular effectiveness in specific clinical subgroups. 'Experimental medicine' studies in healthy volunteers model disease states and represent a proof-of-concept approach for the development of novel therapeutic interventions: they determine whether to proceed to pivotal efficacy studies and so can reduce delays in translating innovations into clinical practice. Investigations in healthy volunteers challenged with the inhalation of air 'enriched' with 7.5% carbon dioxide (CO2) indicate this technique provides a validated and robust experimental medicine model, mirroring the subjective, autonomic, and cognitive features of GAD. The anxiety response during CO2 challenge probably involves both central noradrenergic neurotransmission and effects on acid-base sensitive receptors and so may stimulate development of novel agents targeted at central chemosensors. Increasing awareness of the potential role of altered cytokine balance in anxiety and the interplay of cytokines with monoaminergic mechanisms may also encourage the investigation of novel agents with modulating effects on immunological profiles. Although seemingly disparate, these two approaches to treatment development may pivot on a shared mechanism in exerting anxiolytic-like effects through pharmacological effects on acid-sensing ion channels.