TNF-α,IL-6 and hs CRP in patients with melancholic,atypical and anxious depression:an antibodyyarrayanalysis related to somatic symptoms

Background The association between inflammation and major depressive disorder(MDD)remains poorly understood,given the heterogeneity of patients with MDD.Aims We investigated inflammatory markers,such as interleukin(IL)-6,high-sensitivity C reactive protein(hsCRP)and tumour necrosis factor-α.(TNF-α)in melancholic,atypical and anxious depression and explored whether baseline inflammatory protein levels could indicate prognosis.Methods The sample consisted of participants(aged 18-55 years)from a previously reported multicentre randomised controlled trial with a parallel-group design registered with ClinicalTrials.gov,including melancholic(n=44),atypical(n=37)and anxious(n=44)patients with depression and healthy controls(HCs)(n=33).Subtypes of MDD were classified according to the 30-item Inventory of Depressive Symptomatology,Self-Rated Version and the.17-item Hamilton Depression Rating Scale.Blood levels.of TNF-α,IL-6 and hsCRP were assessed using antibody array analysis.Results Patients with MDD,classified according to melancholic,atypical and anxious depression subtypes,and HCs did not differ significantly in baseline TNF-α,IL-6 and hsCRP levels after adjustment.In patients with anxious depression,hsCRP levels increased significantly if they experienced no pain(adjusted(adj.)p=0.010)or mild to moderate pain(adj.p=0.038)compared with those with severe pain.However,the patients with anxious depression and severe pain showed a lower trend in hsCRP levels than patients with atypical depression who experienced severe pain(p=0.022;adj.p=0.155).Baseline TNF-α(adj.p=0.038)and IL-6(adj.p=0.006)levels in patients in remission were significantly lower than those in patients with no remission among the participants with the atypical depression subtype at the eighth-week follow-up.Conclusions This study provides evidence of differences in inflammatory proteins in patients with varied symptoms among melancholic,atypical and anxious depression subtypes.Further studies on the immunoinflammatory mechanism underlying different subtypes of depression are expected for improved individualised therapy.

Role of biological rhythm dysfunction in the development and management of bipolar disorders: a review

Disturbance of biological rhythms contributes to the onset of bipolar disorders and is an important clinical feature of the condition.To further explore the role of biological rhythms in bipolar disorders,95 English articles published between 1968 and 2019 were retrieved from the PubMed database and analysed.We herein review the outcomes of studies on biological rhythm disturbance in bipolar disorders,including the epidemiology,aetiology,clinical features(eg,sleep,feeding and eating disorders)and treatment of the condition evaluated by patients*selfreport and biological indicators such as melatonin.Our report supports the characterisation of biological rhythm disturbance as a significant clinical feature affecting the onset and development of bipolar disorders and reviews classical and novel treatments,such as chronotherapy,that can be applied in the clinical practice.Our analysis indicates that a more comprehensive study of the pathophysiology,clinical phenomenology and treatment of biological rhythm disturbance is required.

PAID study design on the role of PKC activation in immune/inflammation-related depression:a randomised placebo-controlled trial protocol

Background Inflammation that is mediated by microglia activation plays an important role in the pathogenesis of depression.Microglia activation can lead to an increase in the levels of proinflammatory cytokines,including TNF-α,which leads to neuronal apoptosis in the specific neural circuits of some brain regions,abnormal cognition and treatment-resistant depression(TRD).Protein kinase C(PKC)is a key regulator of the microglia activation process.We assume that the abnormality in PKC might result in abnormal microglia activation,neuronal apoptosis,significant changes in emotional and cognitive neural circuits,and TRD.In the current study,we plan to target at the PKC signal pathway to improve the TRD treatment outcome.Methods and analysis This is a 12-week,ongoing,randomised,placebo-controlled trial.Patients with TRD(N=180)were recruited from Shanghai Mental Health Center,Shanghai Jiao Tong University.Healthy control volunteers(N=60)were recruited by advertisement.Patients with TRD were randomly assigned to‘escitalopram+golimumab(TNF-αinhibitor)’,‘escitalopram+calcium tablet+vitamin D(PKC activator)’or‘escitalopram+placebo’groups.We define the primary outcome as changes in the 17-item Hamilton Depression Rating Scale(HAMD-17).The secondary outcome is defined as changes in anti-inflammatory effects,cognitive function and quality of life.Discussion This study might be the first randomised,placebo-controlled trial to target at the PKC signal pathway in patients with TRD.Our study might help to propose individualised treatment strategies for depression.Trial registration number The trial protocol is registered with ClinicalTrials.gov under protocol ID 81930033 and ClinicalTrials.gov ID NCT04156425.

Transmission of NOTCH4 and GRIK2 in a population of Han Chinese with schizophrenia and affective disorder

BACKGROUND： Increasing evidence suggests overlapped genetic susceptibility across traditional classification systems that divided psychotic disorders into schizophrenia or affective disorder. OBJECTIVE： This study aimed to explore whether schizophrenia and affective disorder share genetic susceptibility in NOTCH4 and GRIK2 loci in a population of Han Chinese. DESIGN： Repetitive measurements. SETTING： The experiment was carried out at Shanghai Mental Health Center and Hongkou Mental Health Center of Shanghai between January 2001 and June 2004. PARTICIPANTS： Sixty-five mixed pedigrees （suffering from various diseases, in combination with schizophrenia and affective disorder）, composed of 45 completed trios and 20 single-parent families, were selected from Shanghai Mental Health Center and Hongkou Mental Health Center of Shanghai between January 2001 and June 2004. Probands received clinical diagnosis according to ICD-10; an independent clinician used identical criteria to review all diagnoses. All subjects were Han Chinese in origin and provided informed consent. There were 65 probands and 110 parents among the subjects. The probands comprised 30 males and 35 females： 33 with schizophrenia, 32 with affective disorder, mean age of （30.9 ± 9.8） years, mean age of onset （24.3 ± 8.8） years, mean duration （6.6 ± 7.0） years, and mean age of parents （58.8 ±10.9） years. METHODS： DNA samples from probands and their biological parents were extracted from peripheral blood according to standard methods. Four polymorphisms, -1725T/G and -25T/C in NOTCH4, rs6922753T/C and rs2227283G/A in GRIK2, were amplified and genotyped with PCR-RFLP techniques. MAIN OUTCOME MEASURES： Association between NOTCH4, GRIK2 polymorphism, and schizophrenia was analyzed by transmission disequilibrium test （TDT）. RESULTS： Sixty-five probands and 110 parents were included in the result analysis, with no dropouts. The results showed that the -25T/C polymorphism of NOTCH4 associated significantly with affective disorder and -1725G/-25T haplotype with schizophrenia. SNP rs6922753 of GRIK2 did not associate with the two diseases; SNP rs2227283 and haplotypes, TG and CA, were significantly associated with both diseases. CONCLUSION： Schizophrenia and affective disorder might share genetic susceptibility among mixed pedigrees of the Han Chinese population. NOTCH4 and GRIK2 might be two of the most common susceptibility genes for these psychoses.

Clinical features and treatment outcomes of major depressive disorder with genital symptoms

To the Editor:Major depressive disorder(MDD)is a mood disorder characterized by complex patterns of emotional,cognitive,and behavioral symptomology and deficits in daily functioning.Genital symptoms,including a reduction in libido and menstrual disturbances,have been considered to be a classic symptom of MDD for many decades.Previous evidence has reached a broad consensus that the incidence of genital symptoms is higher in patients with MDD than in the general population.A systematic review and meta-analysis found a bidirectional association between MDD and genital symptoms,with patients with MDD showing a 50–70%increased risk of developing genital symptoms,while individuals with genital symptoms had a 130–210%increased risk of developing MDD.^([1])As previously reported,50–70%of people with MDD experience sexual dysfunction.^([2])To date,few studies have focused on the comparison of clinical features between patients with MDD with and without genital symptoms,and the longitudinal prognosis.

HTR2A agonists play a therapeutic role by restricting ILC2 activation in papain-induced lung inflammation

Group 2 innate lymphoid cells(ILC2s)are a category of heterogeneous cells that produce the cytokines IL-5 and IL-13,which mediate the type 2 immune response.However,specific drug targets on lung ILC2s have rarely been reported.Previous studies have shown that type 2 cytokines,such as IL-5 and IL-13,are related to depression.Here,we demonstrated the negative correlation between the depression-associated monoamine neurotransmitter serotonin and secretion of the cytokines IL-5 and IL-13 by ILC2s in individuals with depression.Interestingly,serotonin ameliorates papain-induced lung inflammation by suppressing ILC2 activation.Our data showed that the serotonin receptor HTR2A was highly expressed on ILC2s from mouse lungs and human PBMCs.Furthermore,an HTR2A selective agonist(DOI)impaired ILC2 activation and alleviated the type 2 immune response in vivo and in vitro.Mice with ILC2-specific depletion of HTR2A(Il5^(cre/+)·Htr2a^(flox/flox)mice)abolished the DOI-mediated inhibition of ILC2s in a papain-induced mouse model of inflammation.In conclusion,serotonin and DOI could restrict the type 2 lung immune response,indicating a potential treatment strategy for type 2 lung inflammation by targeting HTR2A on ST2+ILC2s.

Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications

Major depressive disorder(MDD),also referred to as depression,is one of the most common psychiatric disorders with a high economic burden.The etiology of depression is still not clear,but it is generally believed that MDD is a multifactorial disease caused by the interaction of social,psychological,and biological aspects.Therefore,there is no exact pathological theory that can independently explain its pathogenesis,involving genetics,neurobiology,and neuroimaging.At present,there are many treatment measures for patients with depression,including drug therapy,psychotherapy,and neuromodulation technology.In recent years,great progress has been made in the development of new antidepressants,some of which have been applied in the clinic.This article mainly reviews the research progress,pathogenesis,and treatment of MDD.

The Relationship Between Neuroimmunity and Bipolar Disorder:Mechanism and Translational Application

Neuroimmune system may be involved in the pathological process of bipolar disorder(BD),but the essential association is not fully understood.Accumulating evidence has shown that BD involves the activation of immune cells and the release of inflammatory substances in the central nerve system(CNS).Meanwhile,neuroimmune responses also interact with other hypothesis of the etiology of BD that are widely recognized,such as neurotransmitter systems,neuroendocrine systems,neurotrophic factors,and oxidative stress.Simultaneously,related genes and immune changes in peripheral blood vary with it.Overall,neuroimmunity may play an important role in the pathogenesis of BD,and the inflammatory cytokines,especially interleukin-6 and tumor necrosis factor-alpha,have potential value for the clinical diagnosis and prognosis of BD,as well as predicting the therapeutic effects of drugs.Large-scale studies are needed to extend the evidence on neuroimmunity in BD,and to examine its clinical value for applications such as early prediction and treatment.

The Risk and Prevention of Novel Coronavirus Pneumonia Infections Among Inpatients in Psychiatric Hospitals

Dear Editor,Since the middle of December 2019,human-to-human transmission of novel coronavirus pneumonia(NCP,also called COVID-19)has occurred among close contacts[1].After the outbreak on January 21,2020,it was swiftly included among the Class B infectious diseases stipulated in the Law of the People’s Republic of China on the Prevention and Control of Infectious Diseases,and measures for prevention and control of Class A infectious diseases were adopted.At 21:27 on February 12,2020,the China News Network updated information to include epidemic data from the National Health Commission and official channels in Hong Kong,Macao,and Taiwan regions:the highest death rate was in Wuhan City(Table 1).Overload of inpatients at hospitals may play a negative role in the overall therapeutic effect and contribute to the death rate.

Hypothalamic-Pituitary-End-Organ Axes:Hormone Function in Female Patients with Major Depressive Disorder

Classic hypothalamic-pituitary-end-organ feedback loops–the hypothalamic-pituitary-adrenal axis(HPAA),hypothalamic-pituitary-thyroidal axis(HPTA),and hypothalamic-pituitary-gonadal axis(HPGA)–are associated with the neuroendocrine and immune systems in major depressive disorder(MDD).Female patients with MDD present with evident neuroendocrine and immunological changes.Glucocorticoid,thyroid hormone,and reproductive steroid levels fluctuate with menstrual cycles,which might lead to glucocorticoid receptor resistance,impairment of triiodothyronine conversion,and sex hormone secretion disorders.In this review,we summarize the independent and interactive functions of these three axes in female MDD patients.The similar molecular structure of steroids implies an interrelationship between the hypothalamic-pituitary-end-organ axes and the competitive inhibitory effects at the receptor level,especially when considering the HPAA and HPGA.

Perspective on Etiology and Treatment of Bipolar Disorders in China: Clinical Implications and Future Directions

Bipolar disorder (BD) is a chronic, recurrent, disabling disease, even when given currently-available pharmacological and psychological treatments. Currently, the etiology and pathogenesis of BD remain unclear. As a consequence, patients with BD are frequently unrecognized, misdiagnosed, and inappropriately treated, which often yields a low treatment response and poor outcome.

Correction to: Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications

Correction to:Neurosci.Bull.2021 https://doi.org/10.1007/sl2264-021-00638-3 The original version of this article unfortunately contained two mistakes.1.In the“Acknowledgements”,the“the National Basic Research”should be changed into“the National Key Research”.

Early Diagnosis of Bipolar Disorder Coming Soon:Application of an Oxidative Stress Injury Biomarker(BIOS)Model

Early distinction of bipolar disorder(BD)from major depressive disorder(MDD)is difficult since no tools are available to estimate the risk of BD.In this study,we aimed to develop and validate a model of oxidative stress injury for predicting BD.Data were collected from 1252 BD and 1359 MDD patients,including 64 MDD patients identified as converting to BD from 2009 through 2018.30 variables from a randomly-selected subsample of 1827(70%)patients were used to develop the model,including age,sex,oxidative stress markers(uric acid,bilirubin,albumin,and prealbumin),sex hormones,cytokines,thyroid and liver function,and glycolipid metabolism.Univariate analyses and the Least Absolute Shrinkage and Selection Operator were applied for data dimension reduction and variable selection.Multivariable logistic regression was used to construct a model for predicting bipolar disorder by oxidative stress biomarkers(BIOS)on a nomogram.Internal validation was assessed in the remaining 784 patients(30%),and independent external validation was done with data from 3797 matched patients from five other hospitals in China.10 predictors,mainly oxidative stress markers,were shown on the nomogram.The BIOS model showed good discrimination in the training sample,with an AUC of 75.1%(95%CI:72.9%–77.3%),sensitivity of 0.66,and specificity of 0.73.The discrimination was good both in internal validation(AUC 72.1%,68.6%–75.6%)and external validation(AUC 65.7%,63.9%–67.5%).In this study,we developed a nomogram centered on oxidative stress injury,which could help in the individualized prediction of BD.For better real-world practice,a set of measurements,especially on oxidative stress markers,should be emphasized using big data in psychiatry.

Atypical features and treatment choices in bipolar disorders:a result of the National Bipolar Mania Pathway Survey in China

In this study,we examined the point prevalence rate of atypical features in bipolar disorder,and estimated the potential impact of these features on treatment practices in China. Using the atypical features criteria of the Diagnostic and Statistical Manual of the American Psychiatric Association（DSM-IV）,we documented the atypical symptoms in 3 906 consecutive participants with bipolar disorder enrolled at 26 psychiatric services across China. We further assessed the association between atypical features and the treatment approaches,including the prescription of antidepressants. The overall point prevalence rate of atypical features was 9.1% among patients with various bipolar disorder subtypes. When the definition was broadened to include atypical features B,the overall rate increased to 11.8%. Interestingly,among patients with the mixed state and remission subtypes,there was a significant difference in the rates of antidepressant medication usage between patients who met and those who did not meet the criteria for atypical features B. These fi ndings indicate a trend of using antidepressants for these two types of patients with atypical features. Further,for both mixed state and remission patients,treatment approaches were related to atypicalfeatures B. Our findings provide evidence to assist clinicians to readily recognize atypical features in bipolar subtypes and can propose treatments based on these diagnoses.

Disturbances of affective cognition in mood disorders

Mood disorders,also known as affective disorders,result in a consistent disturbance in mood.There are two major subtypes of mood disorders,i.e.,major depressive disorder(MDD)and bipolar disorder(BD).Mood disorders affect hundreds of millions of people and are the most common mental disorders.According to China’s national survey in2009(Phillips et al.,2009),the weighted 12-month prevalence of mental disorders was 17.5%and 9.3%,respectively.Mood disorders were among the highest prevalence rate disorders related to disease’s increased burdens.

Important clinical features of atypical antipsychotics in acute bipolar depression that inform routine clinical care: a review of pivotal studies with number needed to treat

English-language literature cited in MEDLINE from January,1980 to October 30,2014 was searched by using terms of antipsychotic,generic and brand names of atypical antipsychotics, ＂bipolar depression/bipolar disorder＂, ＂placebo＂,and ＂trial＂.The parameters of response（≥50%improvement on MADRS,Montgomery-Asberg Depression Rating Scale total score）,remission（either ≤12 or 8 on MADRS total score at endpoint）,discontinuation due to adverse events（DAEs）,somnolence,≥7%weight gain,overall extrapyramidal side-effects（EPSs）,and akathisia,were extracted from originally published primary outcome papers.The number needed to treat to benefit（NNT） for response and remission or harm（NNH） for DAEs or other side effects relative to placebo were estimated and presented with the estimate and 95%confidence interval.Olanzapine monotherapy,olanzapine-fluoxetine combination（OFC）,quetiapine-IR monotherapy,quetiapine-XR monotherapy,lurasidone monotherapy,and lurasidone adjunctive therapy were superior to placebo with NNTs for responses of 11-12,4,7-8,4,4-5,and 7,and NNTs for remission of 11-12,4,5-11,7,6-7,and 6,respectively.There was no significant difference between OFC and lamotrigine,and between aripiprazole or ziprasidone and placebo in response and remission.Olanzapine monotherapy,quetiapine-IR,quetiapine-XR,aripiprazole,and ziprasidone 120-160 mg/day had significantly increased risk for DAEs with NNHs of 24,8-14,9,12,and 10,respectively.For somnolence,quetiapine-XR had the smallest NNH of 4.For ≥7%weight gain,olanzapine monotherapy and OFC had the smallest NNHs with both of 5.For akathisia,aripiprazole had the smallest NNH of 5.These findings suggest that among the FDA-approved agents including OFC,quetiapine-IR and-XR,lurasidone monotherapy and adjunctive therapy to a mood stabilizer,the differences in the NNTs for response and remission are small,but the differences in NNHs for DAEs and common side-effects are large.Therefore,the selection of an FDA-approved atypical antipsychotic for bipolar depression should be based upon safety and tolerability.

A Breakthrough in Understanding the Rapid Antidepressant Effect of Ketamine Based on Structural Analysis

Major depressive disorder(MDD)is one of the most common and serious mental diseases.Its overall 12-month prevalence rate is〜6%,while the lifetime risk increases about twofold(15%-18%),which means almost one in five people will experience at least one depressive episode during their lifetime[1].MDD is characterized by sad emotion accompanied by anhedonia,lack of energy or appetite,sleep disturbance,and low self-evaluation.In severe cases,suicidal ideation/attemp^ehavior or self-injurious behavior may occur,which seriously affects patients'daily life and social function.In 2010,MDD was listed as the second greatest disease burden in the world,and is expected to rank first by 2030[2].

Potential contribution of increased soluble IL-2R to lymphopenia in COVID-19 patients

Since the outbreak of coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),more than 6 million cases are confirmed and over 300,000 cases are dead after infection.Dysfunction of immunity in COVID-19 patients has been considered as one of the fatal factors for patients,especially cytokine release syndrome and lymphopenia.1,2,3 The reduced number and increased exhaustion level of lymphocyte are associated with elevated inflammatory cytokines in COVID-19 patients.4,5 However,the mechanism of cytokine-induced lymphopenia in COVID-19 is very unclear.IL-2 is critical for the proliferation,differentiation,and function of T cells,including Tregs,CD4+,and CD8+effector cells.6 Here,we reported the negative relationship between the concentration of soluble IL-2 receptor(sIL-2R)and T-cell number in blood from COVID-19 patients.In vitro addition of recombinant CD25 could inhibit the proliferation and function of T cells from PBMC after stimulated with TCR signaling,which could be rescued by strong IL-2 signaling.Our data suggested the importance of IL-2 signaling in lymphopenia of COVID-19 patients.