Astrocytic Kir4.1 potassium channels as a novel therapeutic target for epilepsy and mood disorders

Astrocytic Kir4.1 channels and spatial potassium buffering：Astrocytes play a crucial role in maintaining the structural and functional integrity of the brain,which includes formation of the blood-brain barrier,maintenance of water and ion homeostasis,metabolism of neurotransmitters and secretion of various neuroactive molecules.

Neuroimmune crosstalk through brain-derived neurotrophic factor and its precursor pro-BDNF: New insights into mood disorders

Mood disorders are the most common mental disorders, affecting approximately350 million people globally. Recent studies have shown that neuroimmuneinteraction regulates mood disorders. Brain-derived neurotrophic factor (BDNF)and its precursor pro-BDNF, are involved in the neuroimmune crosstalk duringthe development of mood disorders. BDNF is implicated in the pathophysiologyof psychiatric and neurological disorders especially in antidepressant pharmacotherapy.In this review, we describe the functions of BDNF/pro-BDNF signalingin the central nervous system in the context of mood disorders. In addition, wesummarize the developments for BDNF and pro-BDNF functions in mooddisorders. This review aims to provide new insights into the impact ofneuroimmune interaction on mood disorders and reveal a new basis for furtherdevelopment of diagnostic targets and mood disorders.

Metabolic syndrome and childhood trauma: Also comorbidity and complication in mood disorder

Studies for prevalence and causal relationship established that addressing comorbidities of mental illnesses with medical disease will be another revolution in psychiatry. Increasing number of evidence shows that there is a bidirectional connection between mood disorders and some medical diseases. Glucocorticoid/insulin signal mechanisms and immunoenflammatory effector systems are junction points that show pathophysiology between bipolar disorder and general medical situations susceptible to stress. A subgroup of mood disorder patients are under risk of developing obesity and diabetes. Their habits and life styles, genetic predisposition and treatment options are parameters that define this subgroup. Medical disease in adults had a significant relationship to adverse life experiences in childhood. This illustrates that adverse experiences in childhood are related to adult disease by two basic etiologic mechanisms:(1) conventional risk factors that actually are compensatory behaviors, attempts at selfhelp through the use of agents and foods; and(2) the effects of chronic stress.

Contingent negative variation of mood disorder patients

Studies on brain-evoked potential and contingent negative variation （CNV） in mood disorder remain controversial. To date, no CNV difference between unipolar and bipolar depression has been reported. Brain-evoked potentials were measured in the present study to analyze CNV in three subtypes of mood disorder （mania, unipolar depression, and bipolar depression）, and these results were compared with normal controls. In the mania group, CNV amplitude B was greater than in controls, and the depression group exhibited lower CNV amplitude B and smaller A-S＇2 area, and prolonged post-imperative negative variation latency. The CNV comparison between unipolar and bipolar depression found that the prolonged post-imperative negative variation latency was only in unipolar depression. These results suggest that prolonged post-imperative negative variation latency is a characteristic of unipolar depression, and CNV amplitude change is a state characteristic of mood disorder patients.

False dogmas in mood disorders research:Towards a nomothetic network approach

The current understanding of major depressive disorder(MDD)and bipolar disorder(BD)is plagued by a cacophony of controversies as evidenced by competing schools to understand MDD/BD.The DSM/ICD taxonomies have cemented their status as the gold standard for diagnosing MDD/BD.The aim of this review is to discuss the false dogmas that reign in current MDD/BD research with respect to the new,data-driven,machine learning method to model psychiatric illness,namely nomothetic network psychiatry(NNP).This review discusses many false dogmas including:MDD/BD are mind-brain disorders that are best conceptualized using a bio-psycho-social model or mind-brain interactions;mood disorders due to medical disease are attributable to psychosocial stress or chemical imbalances;DSM/ICD are the gold standards to make the MDD/BD diagnosis;severity of illness should be measured using rating scales;clinical remission should be defined using threshold values on rating scale scores;existing diagnostic BD boundaries are too restrictive;and mood disorder spectra are the rule.In contrast,our NNP models show that MDD/BD are not mind-brain or psycho-social but systemic medical disorders;the DSM/ICD taxonomies are counterproductive;a shared core,namely the reoccurrence of illness(ROI),underpins the intertwined recurrence of depressive and manic episodes and suicidal behaviors;mood disorders should be ROI-defined;ROI mediates the effects of nitro-oxidative stress pathways and early lifetime trauma on the phenome of mood disorders;severity of illness and treatment response should be delineated using the NNP-derived causome,pathway,ROI and integrated phenome scores;and MDD and BD are the same illness.

Hypomanic/manic switch after transcranial magnetic stimulation in mood disorders:A systematic review and meta-analysis

BACKGROUND Nowadays there is an increasing use of transcranial magnetic stimulation(TMS)both in neurological and psychiatric fields.After Food and Drug Administration approval of TMS for the therapy of treatment-resistant depression,TMS has been widely used in the context of mood disorders(MD).However,growing reports regarding the possibility of developing hypomanic/manic switch(HMS)have generated concern regarding its use in MDs.AIM To investigate the actual risk of developing HMS due to TMS in the treatment of MD.METHODS We led our research on PubMed,Scopus and Web of Science on March 22,2020,in accordance to the PRISMA guidelines for systematic review.Only double blind/single blind studies,written in English and focused on the TMS treatment of MD,were included.A meta-analysis of repetitive TMS protocol studies including HMS was conducted using RevMan 5.4 software.The assessment of Risk of Bias was done using Cochrane risk of bias tool.This protocol was registered on PROSPERO with the CRD42020175811 code.RESULTS Twenty-five studies were included in our meta-analysis:Twenty-one double blind randomized controlled trials(RCT)and four single blind-RCT(no.of subjects involved in active stimulation=576;no.of subjects involved in sham protocol=487).The most frequently treated pathology was major depressive episode/major depressive disorder,followed by resistant depression,bipolar depression and other MD.The majority of the studies used a repetitive TMS protocol,and the left dorsolateral prefrontal cortex was the main target area.Side effects were reported in eight studies and HMS(described as greater energy,insomnia,irritability,anxiety,suicidal attempt)in four studies.When comparing active TMS vs sham treatment,the risk of developing HMS was not significantly different between conditions.CONCLUSION Applying the most usual protocols and the appropriate precautionary measures,TMS seems not to be related to HMS development.

Correlation of preoperative inflammatory factors and emotional disorders with postoperative delirium in patients with craniocerebral trauma

BACKGROUND Traumatic brain injury(TBI)imposes a substantial societal and familial burden due to its high disability and fatality rates,rendering it a serious public health problem.Some patients with TBI have poor treatment outcomes and are prone to postoperative delirium(POD),which affects their quality of life.Anxiety has been linked to increased POD incidence in some studies,while others have found no correlation.AIM To investigate the correlation of POD risk factors,preoperative inflammatory factors,and mood disorders in patients with TBI.METHODS We retrospectively collected data on the treatment of 80 patients with TBI from November 2021 to September 2023.Patients were grouped as POD and non-POD,according to their POD status,and the general data of the two groups were compared.Inflammatory factor levels were detected preoperatively,and the Hamilton Depression Scale(HAMD)and Hamilton Anxiety Scale(HAMA)were used to investigate the risk factors associated with POD in these patients.Logistic regression was used to identify the independent risk factors.RESULTS Twenty-one patients(26.25%)developed POD,including 7,10,and 4 cases of the excitatory,inhibitory,and mixed types,respectively.There were 59 cases(73.75%)in the non-POD group.Compared with the non-POD group,the POD group had a significantly higher proportion of patients with low Glasgow Coma Scale(GCS)scores before admission,unilateral mydriasis,preoperative hemorrhagic shock,intraventricular hemorrhage(IVH),and postoperative hyperglycemic hyperosmolar disease(P<0.05).In the POD group,interleukin-6(IL-6),human tumor necrosis factor-α(TNF-α),myeloperoxidase levels,HAMA,and HAMD scores were higher than those in the non-POD group(all P<0.05).Logistic multivariate analysis showed that GCS score at admission,IVH,IL-6,TNF-α,HAMA,and HAMD were independent risk factors for POD in patients with TBI(P<0.05).CONCLUSION Low GCS score at admission,IVH,elevated IL-6 and TNF-α,other inflammatory indicators,anxiety,and depression,can increase the risk of POD in patients with TBI after surgery.

Shumian capsule(舒眠胶囊) improves symptoms of sleep mood disorder in convalescent patients of Corona Virus Disease 2019

OBJECTIVE:To evaluate the clinical effectiveness of Shumian capsule(舒眠胶囊)in improving the symptoms of insomnia,anxiety,depression,and other symptoms of convalescent patients of COVID-19.METHODS:Totally 200 patients were collected and randomly divided into experiment group(n=100)and control group(n=100).The control group was treated with Shumian capsule simulator,and the experiment group was treated with Shumian capsule.The improvement of TCM symptom score,the total effective rate and symptom disappearance rate of TCM symptoms in the two groups before and after treatment were observed,and the clinical effect was evaluated.RESULTS:One week after treatment,the scores of anxiety symptoms in the experiment group were significantly different from those in the control group(P<0.05),but there was no significant difference in the scores of insomnia and depression between the experiment group and the control group(P>0.05).There was no significant difference in the total effective rate and disappearance rate of TCM symptoms of insomnia,anxiety and depression between the experiment group and the control group(P>0.05).After 2 weeks of treatment,the scores of insomnia,anxiety,depression and the total effective rate of TCM symptoms in the experiment group were significantly different from those in the control group(P<0.05).There was no significant difference in the disappearance rate of insomnia,anxiety and depression between the experiment group and the control group(P>0.05).There were no significant differences in heart rate,respiration,systolic blood pressure and diastolic blood pressure between the experiment group and the control group(P>0.05).CONCLUSION:Shumian capsule can significantly improve the symptoms of insomnia,anxiety and depression in COVID-19’s convalescent patients with sleep and mood disorders.

Psychotic and nonpsychotic mood disorders in autoimmune encephalitis:diagnostic issues and research implications

Recent research on autoimmune disorders suggests additional links between systemic and central nervous system(CNS)pathophysiology,among which the identification of antibody-induced limbic encephalitis provided the strongest evidence for the potential involvement of autoimmunity in the pathogenesis of severe mood and psychotic symptoms.In these illnesses,psychiatric symptoms predominate in the initial phase of the disorder in up to 70%of the cases,and they often lead patients to early psychiatric evaluation.For this reason,it is very important to increase the limited knowledge among psychiatrists about these autoimmune neuropsychiatric diseases,which can mimic psychiatric syndromes,in particular,those typically presented in severe mood disorders and schizophrenia.On the other hand,similarities in clinical presentation suggest that neuroinflammation and systemic immune dysregulation may play a role in the pathophysiology of severe mood and psychotic disorders.A complex interaction between periphery and immune cells of the CNS may result in cellular damage through mechanisms involving excitotoxicity,oxidative stress,and mitochondrial dysfunction.These pathways are possibly shared between comorbid medical disorders and severe mood and psychotic disorders and may reflect common underlying vulnerability.

Agomelatine:a potential novel approach for the treatment of memory disorder in neurodegenerative disease

Agomelatine is a selective agonist of melatonin receptor 1A/melatonin receptor 1B(MT/MT)and antagonist of 5-hydroxytryptamine 2C receptors.It is used clinically to treat major depressive episodes in adults.The pro-chronobiological activity of agomelatine reconstructs sleep-wake rhythms and normalizes circadian disturbances via its agonistic effect of melatonin receptor 1A/melatonin receptor 1B,which work simultaneously to counteract depression and anxiety disorder.Moreover,by antagonizing neocortical postsynaptic 5-hydroxytryptamine 2C receptors,agomelatine enhances the release of dopamine and noradrenaline in the prefrontal cortex,increases the activity of dopamine and noradrenaline,and thereby reduces depression and anxiety disorder.The combination of these two effects means that agomelatine exhibits a unique pharmacological role in the treatment of depression,anxiety,and disturbance of the circadian rhythm.Emotion and sleep are closely related to memory and cognitive function.Memory disorder is defined as any forms of memory abnormality,which is typically evident in a broad range of neurodegenerative diseases,including Alzheimer’s disease.Memory impairment and cognitive impairment are common symptoms of neurodegenerative and psychiatric diseases.Therefore,whether agomelatine can improve memory and cognitive behaviors if used for alleviating depression and circadian-rhythm sleep disorders has become a research“hotspot”.This review presents the latest findings on the effects of agomelatine in the treatment of psychologic and circadian-rhythm sleep disorders in clinical trials and animal experiments.Our review evaluates recent studies on treatment of memory impairment and cognitive impairment in neurodegenerative and psychiatric diseases.

The role of anti-glutamic acid decarboxylase autoantibodies in mood disorders

Gamma-aminobutyric acid(GABA)possibly plays a causative role in mood disorders.This hypothesis originated with studies on the beneficial effect of valproate in mania and as a mood stabilizer.Since valproate is known for its action in increasing the level of GABA,it was indirectly suggested that decreasing levels of GABA were responsible for mood alterations.To identify factors causing the decreased levels of GABA,studies have concentrated on the activity of the enzyme L-glutamic acid decarboxylase(GAD),which catalyzes the transformation of glutamate to GABA,as a decreasing function of this enzyme induces lower levels of the neurotransmitter.Moreover,a very limited amount of research investigated the possible role of glutamic acid decarboxylase antibodies(GADA)in determining a decreased enzymatic function of GAD.If these findings are confirmed,it will be possible to improve diagnosis and treatment of mood disorders.In addition,if the presence of GADA is associated with a genetic trait,this would allow and facilitate early diagnoses.

PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton,modulating emotional behavior

Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function.Synaptic abnormalities,such as defects in the density and morphology of postsynaptic dendritic spines,underlie the pathology of various neuropsychiatric disorders.Protocadherin 17(PCDH17)is associated with major mood disorders,including bipolar disorder and depression.However,the molecular mechanisms by which PCDH17 regulates spine number,morphology,and behavior remain elusive.In this study,we found that PCDH17 functions at postsynaptic sites,restricting the number and size of dendritic spines in excitatory neurons.Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety-and depression-like behaviors in mice.Mechanistically,PCDH17 interacts with actin-relevant proteins and regulates actin filament(F-actin)organization.Specifically,PCDH17 binds to ROCK2,increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3(Ser3).Inhibition of ROCK2 activity with belumosudil(KD025)ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression,suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development.Hence,these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior,providing pathological insights into the neurobiological basis of mood disorders.

Saffron (Crocus sativus L.) and major depressive disorder:a meta-analysis of randomized clinical trials

Due to safety concerns and side effects of many antidepressant medications, herbal psychopharmacology research has increased, and herbal remedies are becoming increasingly popular as alternatives to prescribed medications for the treatment of major depressive disorder （MDD）. Of these, accumulating trials reveal positive effects of the spice saffron （Crocus sativus L.） for the treatment of depression. A comprehensive and statistical review of the clinical trials examining the effects of saffron for treatment of MDD is warranted. OBJECTIVE： The purpose of this study was to conduct a meta-analysis of published randomized controlled trials examining the effects of saffron supplementation on symptoms of depression among participants with MDD. SEARCH STRATEGY： We conducted electronic and non-electronic searches to identify all relevant randomized, double-blind controlled trials. Reference lists of all retrieved articles were searched for relevant studies. INCLUSION CRITERIA： The criteria for study selection included the following： （1） adults （aged 18 and older） with symptoms of depression, （2） randomized controlled trial, （3） effects of saffron supplementation on depressive symptoms examined, and （4） study had either a placebo control or antidepressant comparison group. DATA EXTRACTION AND ANALYSIS： Using random effects modeling procedures, we calculated weighted mean effect sizes separately for the saffron supplementation vs placebo control groups, and for the saffron supplementation vs antidepressant groups. The methodological quality of all studies was assessed using the Jadad score. The computer software Comprehensive Meta- analysis 2 was used to analyze the data. RESULTS： Based on our pre-specified criteria, five randomized controlled trials （n = 2 placebo controlled trials, n = 3 antidepressant controlled trials） were included in our review. A large effect size was found for saffron supplementation vs placebo control in treating depressive symptoms （M ES = 1.62, P 〈 0.001）, revealing that saffron supplementation significantly reduced depression symptoms compared to the placebo control. A null effect size was evidenced between saffron supplementation and the antidepressant groups （M ES = -0.15） indicating that both treatments were similarly effective in reducing depression symptoms. The mean Jadad score was 5 indicating high quality of trials. CONCLUSION： Findings from clinical trials conducted to date indicate that saffron supplementation can improve symptoms of depression in adults with MDD. Larger clinical trials, conducted by research teams outside of Iran, with long-term follow-ups are needed before firm conclusions can be made regarding saffron＇s efficacy and safety for treating depressive symptoms.

Neurochemical metabolites in the medial prefrontal cortex in bipolar disorder A proton magnetic resonance spectroscopy study

The aim of this study was to investigate proton magnetic resonance spectroscopy metabolite values in the medial prefrontal cortex of individuals with euthymic bipolar disorder. The subjects consisted of 15 patients with euthymic bipolar disorder type I and 15 healthy controls. We performed proton magnetic resonance spectroscopy of the bilateral medial prefrontal cortex and measured levels of N-acetyl aspartate, choline and creatine. Levels of these three metabolites in the medial prefrontal cortex were found to be lower in patients with bipolar disorder compared with healthy controls. A positive correlation was found between illness duration and choline levels in the right medial prefrontal cortex. Our study suggests that during the euthymic period, there are abnormalities in cellular energy and membrane phospholipid metabolism in the medial prefrontal cortex, and that this may impair neuronal activity and integrity.

Psychoeducation in bipolar disorder: A systematic review

BACKGROUND Bipolar disorder(BD)is a severe psychiatric disorder characterized by mood swings.Psychosocial interventions,such as psychoeducation,play an essential role in promoting social rehabilitation and improving pharmacological treatment.AIM To investigate the role of psychoeducation in BD.METHODS A systematic review of original studies regarding psychoeducation interventions in patients with BD and their relatives was developed.A systematic literature search was performed using the Medline,Scopus,and Lilacs databases.No review articles or qualitative studies were included in the analysis.There were no date restriction criteria,and studies published up to April 2021 were included.RESULTS A total of forty-seven studies were selected for this review.Thirty-eight studies included patients,and nine included family members.Psychoeducation of patients and family members was associated with a lower number of new mood episodes and a reduction in number and length of stay of hospitalizations.Psychoeducational interventions with patients are associated with improved adherence to drug treatment.The strategies studied in patients and family members do not interfere with the severity of symptoms of mania or depression or with the patient's quality of life or functionality.Psychoeducational interventions with family members do not alter patients'adherence to pharmacotherapy.CONCLUSION Psychoeducation as an adjunct strategy to pharmacotherapy in the treatment of BD leads to a reduction in the frequency of new mood episodes,length of hospital stay and adherence to drug therapy.

The renin-angiotensin system,mood,and suicide:Are there associations?

Available evidence points to a possible role of the renin-angiotensin system(RAS)in the pathophysiology of mood disorders and suicide.We carried out a critical analysis of literature data regarding this role,with a focus on the proposed association between RAS dysfunction and suicidal behavior.Epidemiological,genetic,and biochemical findings are described,and the pathophysiological hypothesis aiming at explaining the possible relationship between RAS and suicide are discussed.Available findings do support the involvement of the RAS in the neurobiology of suicide,although the exact mechanisms underlying this involvement are still unknown.

Association study of obstetrical complication and depressive disorder

Objective：To investigate the correlation between obstetrical complications and depressive disorder. Methods：Depressive disorder probands and their adult sibling were diagnosed using CCMD-3 criteria. Obstetrical data from maternal reports were scored, applying published scales that take into account number and severity of complication. Results：The scores of obstetric complication and prenatal complications and low birth weight were significantly worse in probands than siblings without depressive disorders. Conclusion： Results suggest obstetric complications are etiologically significant in depressive disorder.

Epigenetics in psychiatry:Beyond DNA methylation

The global burden of psychopathologies appears to be underestimated,since the global psychiatric disorder burden is exceeding other medical burdens.To be able to address this problem more effectively,we need to better understand the etiology of psychiatric disorders.One of the hallmarks of psychiatric disorders appears to be epigenetic dysregulation.While some epigenetic modifications(such as DNA methylation)are well known and studied,the roles of others have been investigated much less.DNA hydroxymethylation is a rarely studied epigenetic modification,which as well as being an intermediate stage in the DNA demethylation cycle is also an independent steady cell state involved in neurodevelopment and plasticity.In contrast to DNA methylation,DNA hydroxymethylation appears to be related to an increase in gene expression and subsequent protein expression.Although no particular gene or genetic locus can be at this point linked to changes in DNA hydroxymethylation in psychiatric disorders,the epigenetic marks present good potential for biomarker identification because the epigenetic landscape is a result of the interplay between genes and environment,which both influence the development of psychiatric disorders,and because hydoxymethylation changes are particularly enriched in the brain and in synapse-related genes.

Effectiveness of Xiaoyao capsule(逍遥丸)on sleep disorders and mood disturbance in patients in recovery from coronavirus disease 2019:a randomized controlled trial

OBJECTIVE:To study the efficacy of Xiaoyao capsule(逍遥丸)in improving the clinical symptoms of sleep and mood disorders during recovery from coronavirus disease 2019(COVID-19).METHODS:The study cohort comprised 200 patients with sleep and mood disorders during recovery from COVID-19.Patients were randomized into the control group and the experimental group in a 1:1 ratio by blocked randomization.The patients received either Xiaoyao capsule(experimental group)or a placebo Xiaoyao capsule(control group)for 2 weeks.The improvements in the Traditional Chinese Medicine(TCM)syndrome scales,total effective rates,and disappearance rates of irritability,anxiety,and poor sleep were compared between the two groups.RESULTS:The TCM syndrome pattern scales,total effective rates,and disappearance rates of irritability,anxiety,and poor sleep did not significantly differ between the experimental group versus the control group in the full analysis set and the per protocol set after 1 and 2 weeks of treatment(P>0.05).CONCLUSIONS:Xiaoyao capsule do not significantly improve the clinical symptoms of sleep and mood disorders in patients in recovery from COVID-19.

Suicide Attempts in a General Hospital: A Case-Control

Objective: This study aims is to conduct a comparative analysis of the clinical and sociodemographic profiles of individuals referred to Consultation-Liaison Psychiatry (CLP) at a tertiary general hospital, specifically focusing on those seeking assistance due to suicide attempts (TS) versus CLP requests for other reasons (non-TS) between the years 2010 and 2020. Additionally, we aim to assess factors associated with suicide attempts. Method: This retrospective controlled study involves a thorough examination of medical records encompassing 3913 patients who received CLP services at the Hospital de Base (HB) and the Children and Maternity Hospital (HCM) of São José do Rio Preto Medical School Foundation (Funfarme) from June 2010 to June 2020. The patient cohort is categorized into two groups: those with requests for SA (n = 677) and those with requests for other reasons. Results: In the SA group, as opposed to the non SA group, statistically significant differences were observed for gender (predominantly female), employment status (employed), marital status (single), and age (younger). Notably, a higher prevalence of psychiatric antecedents (88.7%, n = 555 vs. 73.6% n = 2018) was found in the SA group, indicating a significant association. The frequency of SA requests remained stable over the years. Among the SA group, mood disorders were the most prevalent (39%, n = 372), followed by disorders related to substance use (21.2%, n = 202), and personality disorders (16%, n = 152). A history of previous suicide attempts emerged as a crucial factor for the recurrence of SA (p-value ≤ 0.001). Exogenous intoxication emerged as the most frequently employed method in attempts (79.6%, n = 539), particularly prevalent among patients diagnosed with mood disorders (41%, n = 314). A significant association was observed between the method of attempt and the nosological psychiatric diagnosis (χ2 = 42.277;p ≤ 0.001). Regarding outcomes, the majority of patients were referred for outpatient follow-up (23%, n = 336) in specialized mental health services or at the Primary Healthcare Unit, highlighting the general hospital’s pivotal role in integrating patients into the broader healthcare network. Conclusion: Variables such as gender (female), age group (young adults), and psychiatric history exhibited stronger associations with suicide attempts compared to the group assisted by CLP for other reasons. Furthermore, a noteworthy correlation between the method employed and the psychiatric diagnosis was identified.