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In 2013, it was reported that pulsed radiofrequency (PRF) could be applied to obtain a systemic anti-inflammatory effect. Patients with chronic pain and patients with an inflammatory condition from other disciplines could potentially profit from this finding. At that time, intravenous application was used, but since then, it became clear that it could be applied transcutaneously as well. This procedure was named RedoxPRF. This can be used both for regional and for systemic application. Recently, the basic element of the mode of action has been clarified from the analysis of the effects of PRF on a standard model of muscle injury in rats. The objective of this paper is to present a hypothesis on the mode of action of RedoxPRF now that the basic mechanism has become known. Cell stress causes an increased production of free radicals, disturbing the redox equilibrium, causing oxidative stress (OS) either directly or secondarily by other types of stress. Eventually, OS causes inflammation and an increased sympathetic (nervous) system activity. In the acute form, this leads to immune paralysis; in the chronic form, to immune tolerance and chronic inflammation. It is hypothesized that RedoxPRF causes a reduction of free radicals by a recombination of radical pairs. For systemic application, the target cells are the intravascular immune cells that pass through an activated area as on an assembly line. Hypothesis conclusions: 1. RedoxPRF treatment works selectively on OS. It has the unique position of having a point of engagement at the most upstream level of the train of events. 2. RedoxPRF has the potential of being a useful tool in the treatment of inflammatory diseases and possibly of stage 4 cancer. 3. In the treatment of chronic pain, RedoxPRF is an entirely new method because it is different from ablation as well as from stimulation. We propose the term "functional restoration". 4. Controlled studies must be conducted to develop this promising new field in medicine further.

Abstract This study explored the link between diet and major depressive disorder (MDD) to provide fresh insights for MDD prevention. Single nucleotide polymorphisms (SNPs) associated with common foods, such as meat, bread, cheese, fruits, cereals, vegetables, and four alcohol intake categories, were leveraged as instrumental variables. Accordingly, this study employed the inverse variance weighting (IVW) method to evaluate the genetically predicted associations of different food phenotypes with MDD risk. The sensitivity analysis involved MR‒Egger regression and Mendelian random polymorphism residuals, along with outlier tests, to assess instrumental variable pleiotropy. Additional analysis methods, such as MR‒Egger, the weighted median method, and the weighted model, were used to validate the robustness and reliability of the findings. The results of the univariable Mendelian randomization(UVMR) analysis using IVW indicated that genetically predicted consumption of cheese [OR = 0.841, 95% CI: 0.737–0.959, P = 0.0099], dried fruit [OR = 0.7922, 95% CI: 0.644–0.973, P = 0.0264], beer [OR = 1.284, 95% CI: 1.026–1.608, P = 0.0291], and spirits [OR = 3.837, 95% CI: 1.993–7.387, P = 0.0001] were significantly associated with the risk of developing major depressive disorder. Specifically, cheese and dried fruit intake exhibited a inverse correlation with MDD risk, whereas beer and spirits intake showed a positive correlation, with spirits showing a stronger positive correlation. Fourteen other foods, including meat, vegetables, fruits, red wine, and white wine, displayed no significant association with the occurrence of major depression through either type of alcohol intake. In the multivariable Mendelian randomization(MVMR) analysis, considering potential confounding factors such as insomnia, smoking, and the use of contraceptive pills, cheese was identified to have an independent causal relationship with MDD (OR: 0.754, 95% CI: 0.591–0.962, p = 0.0229). No independent causal relationships were identified between dried fruit, beer, or spirits and MDD. The reverse Mendelian randomization (rMR) analysis indicated that MDD did not have a significant effect on the intake of cheese, dried fruit, beer, or spirits, supporting the presence of a unidirectional causal relationship. Finally, the study examined the relationships between dietary characteristics, per capita alcohol intake, and depression incidence among residents of Shanghai, Peking, and Guangdong Provinces of Asian ethnicity in China. These findings align with the conclusions drawn from Mendelian randomization analysis, suggesting that maintaining a diverse diet, sensibly consuming cheese and dried fruit, and reducing beer and spirit intake may prevent MDD.

Abstract Background Empathy is an important factor in the doctor-patient relationship, but mental illness is more difficult to understand than other diseases. Besides traditional skills, virtual reality (VR) has been identified as a promising tool in empathy education. This study aimed to investigate the ability of empathy enhancement, the feasibility of depression education, and the changes in thoughts and attitudes in medical students through a single VR experience. Methods We recruited medical students and randomly assigned them to two groups based on their completed Interpersonal Response Index scores. Two sets of VR systems were provided; the intervention group experienced the daily life of the depressed medical student, while the control group experienced the general medical student scenario. The improvement of empathy was assessed using the Jefferson Scale of Empathy-Health Professional Students (JSE-HPS), and the change of attitude was assessed through the Implicit Association Test. In addition, other questionnaires were used to evaluate the user experience of this VR system, and correlation analysis was conducted to examine the association between the use of VR and changes in the JSE and IAT scores. Results A total of 59 medical students were enrolled in this study. The intervention group showed a significant increase in the perspective-taking (pre: mean 5.817, SD 0.536; post: mean 5.947, SD 0.620; P = .03) and compassionate care (pre: mean 5.546, SD 0.581; post: mean 5.721, SD 0.629; P = .01) domains of the JSE score and a significant decrease in the standing in the patient’s shoes (SP) domain (pre: mean 3.583, SD 1.253; post: mean 2.967, SD 1.252; P = .002). The Pearson correlation analysis found a significant positive correlation between the JSE score with immersion aspect (r = .308, P = .049) and presence aspect (r = .415, P = .01), and we also found a significant negative correlation between the IAT score and presence aspect (r=-.333, P = .04). Conclusions This study is the first randomized case-control study to investigate the effect of two different versions of VR on empathy development toward depression for medical students. Although the single VR experience was unable to induce a great improvement in empathy or attitude, the VR system could help medical students enhance their understanding of depressive disorders. Trial registration This trial was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) (21/03/2024, ACTRN12624000297527). https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386683&isReview=true .

Abstract Background Inflammatory bowel disease (IBD) is a chronic, inflammatory, and autoimmune disorder, and its incidence of comorbid with major depressive disorder (MDD) is significantly higher than the general population. However, many patients lack proper recognition and necessary psychological health treatments. We aimed to identify potential biomarkers and mechanisms involved in the development of IBD comorbid with MDD (IBD-MDD). Methods We utilized IBD and MDD-related datasets from the GEO database for differential gene expression analysis, protein-protein interaction (PPI) and pathway enrichment analysis, random forest algorithm, LASSO regression analysis, and construction of a disease prediction model. We assessed the accuracy of the model using ROC curve, explored potential mechanisms through immune infiltration analysis, and validated candidate biomarkers using peripheral blood samples from patients in our center’s cohort. Results We identified 484 IBD-related secreted proteins and 142 key module genes associated with MDD. PPI analysis revealed two crucial modules primarily involved in inflammation and immune regulation. We identified four diagnostic genes (HGF, SPARC, ADAM12, and MMP8) from the 21 shared genes between IBD-related secreted proteins and MDD key module genes, constructed a nomogram model and confirmed its accuracy using ROC curve from an external independent dataset. Immune infiltration analysis revealed significant associations between the four diagnostic genes, and cellular immune dysregulation in MDD. Finally, we validated the expression patterns of the four diagnostic genes in our cohort. Conclusions Our study discovered four candidate biomarkers for IBD-MDD, providing new insights for the diagnosis and therapeutic intervention of serum-based IBD comorbid with MDD.

Abstract In patients with major depressive disorder, various functional areas are impaired, negatively impacting the quality of life. Remission can restore pre-depression functions; however, some patients may still have residual impairments. Distinguishing between near-normal recovery and residual impairment helps identify those at a high risk of relapse risk and helps tailor treatment. Accordingly, we aimed to discover and validate biomarkers that distinguish between near-normal recovery and residual impairment in remission states through serum proteome analysis. Pooled serum and individual serum samples from three groups (depression status, remission status with residual impairment, and remission status with normal recovery) were analyzed using liquid chromatography-tandem mass spectrometry. The combination of four proteins—antithrombin-III, serum amyloid A4 protein, C1q subcomponent subunit B, and serum amyloid P-component—was selected as a candidate biomarker. The trend of protein changes suggests complement C1q subcomponent subunit B and serum amyloid P-component as potential biomarkers for distinguishing remission from residual impairment. Changes in complement C1q subcomponent subunit B and serum amyloid P-component suggest that the complement system and inflammation-related immune mechanisms are associated with residual impairment in remittent major depressive disorder.

Background: Bipolar disorder (BD) is one of the most studied psychiatric disorders, this being one of the leading causes of disability in young individuals. In search for its predictive biomarker, serum uric acid (UA) level was seen to have a pathophysiologic role in the genesis of BD through oxidative stress and other mechanism. Aims and Objectives: The aim of the study was to estimate serum UA levels in patients with 1st episode depression, to compare serum UA levels between patients and matched healthy controls and to compare serum UA levels between patients with and without hidden bipolarity and therefore, and to evaluate whether it can be used as a predictor of bipolarity. Materials and Methods: A study was conducted in a tertiary care center in Eastern India for a duration of 3 months with a sample size of 92, comprising 46 cases with major depressive disorder (MDD) and 46 control groups of healthy subjects. Their serum UA levels were estimated. The study population was subjected to a mood disorder questionnaire (MDQ) and Montgomery–Asberg Depression Rating Scale (MADRS) scoring. All these data were tabulated in a master sheet and analyzed using Statistical Packages for the Social Sciences 25 software. Results: The mean age of the study population was 32 years with 46 males and 46 females. The mean UA levels for MDD group was 5.27±1.14 mg/dL and for control group was 4.6±1.2 mg/dL, which was seen to be statistically significant (P=0.001). No statistically significant association was seen between the group with a high likelihood of bipolarity versus a low chance of bipolarity with respect to UA levels. A positive correlation was seen between MDQ scores and UA levels of depressed individuals (using Spearmen’s rho: rs=0.345, P=0.019), but not with their MADRS scores. Conclusion: Serum UA levels are significantly higher in depressed patients as compared to healthy subjects. A non-statistical association was seen between UA levels and their bipolar tendencies, owing to a small sample size of comparable groups. However, a higher MDQ score was associated with high UA levels. A larger study population is needed to conclusively establish the predictive role of UA with respect to BD.

Background: Cognitive and autonomic dysfunction is increasingly being recognized as an important clinical dimension in major depressive disorder. AIM: The aim of this study is to evaluate the effect of a combined approach of yoga and diet intervention on cognitive and autonomic functions in individuals with major depressive disorders. Methods: This experimental observational study was conducted at RUHS College of Medical Sciences and Associated Hospitals, Jaipur, on the major depressive disorder population of either sex cognitive function (mini-mental score, Montreal cognitive protocol A and B, P300 latency and amplitude) and autonomic function parameters (frequency and time domain) were recorded at baseline and after three months of a combined approach of yoga and diet intervention. Results: This study compared cognitive and autonomic function parameters at baseline and after three months of yoga and diet intervention in a major depressive disorder population. Analysis revealed a significant decrease in body mass index (

Abstract The neuropathology of mood disorders, including the diagnostic transition from major depressive disorder (MDD) to bipolar disorder (BD), is poorly understood. This study investigated resting-state electroencephalography (EEG) activity in patients with MDD and those whose diagnosis changed from MDD to BD. Among sixty-eight enrolled patients with MDD, the diagnosis of 17 patients converted to BD during the study period. We applied machine learning techniques to differentiate the two groups using sensor- and source-level EEG features. At the sensor level, patients with BD showed higher theta band power at the AF3 channel and low-alpha band power at the FC5 channel compared to patients with MDD. At the source level, patients with BD showed higher theta band activity in the right anterior cingulate and low-alpha band activity in the left parahippocampal gyrus. These four EEG features were selected for discriminating between BD and MDD with the best classification performance showing an accuracy of 80.88%, a sensitivity of 76.47%, and a specificity of 82.35%. Our findings revealed distinct theta and low-alpha band activities in patients with BD and MDD. These differences could potentially serve as candidate neuromarkers for the diagnosis and diagnostic transition between the two distinct mood disorders.

Abstract Background Air pollution, a reversible environmental factor, was significantly associated with the cognitive domains that are impaired in major depressive disorder (MDD), notably processing speed. Limited evidence explores the interactive effect of air pollution and the genetic risk of depression on cognition. This cross-sectional study aims to extend the research by specifically examining how this interaction influences depression-related cognitive impairment and resting-state brain function. Methods Eligible participants were 497 healthy adult volunteers (48.7% males, mean age 24.5) living in Beijing for at least 1 year and exposed to relatively high air pollution from the local community controlling for socioeconomic and genomic. Six months’ ambient air pollution exposures were assessed based on residential addresses using monthly averages of fine particulate matter with a diameter of less than or equal to 2.5 μm (PM2.5). A cross-sectional analysis was conducted using functional magnetic resonance imaging (fMRI) and cognitive performance assessments. The polygenic risk score (PRS) of MDD was used to estimate genetic susceptibility. Results Using a general linear model and partial least square regression, we observed a negative association between resting-state local connectivity in precuneus and PRS-by-PM2.5 interactive effect (P FWE = 0.028), indicating that PM2.5 exposure reduced the spontaneous activity in precuneus in individuals at high genetic risk for MDD. DNA methylation and gene expression of the SLC30A3 gene, responsible for maintaining zinc-glutamate homeostasis, was suggestively associated with this local connectivity. For the global functional connectivity, the polygenic risk for MDD augmented the neural impact of PM2.5 exposure, especially in the frontal-parietal and frontal-limbic regions of the default mode network (P FDR

Major depressive disorder (MDD) is a common mental illness. Currently, nearly 16% of the global population is affected by depression-related symptoms, while the diagnosis and treatment rate of MDD patients in China is only 9.5%. MDD is characterised by high morbidity and low recovery rate, and how to effectively improve its therapeutic effect has been a hot research topic in recent years. Antidepressants, as the main treatment for MDD, have the disadvantages of many adverse effects and slow onset of action, prompting people to pay attention to the non-pharmacological treatments of MDD. Dietary intervention is a kind of non-pharmacological treatment by changing dietary structures and rhythms; the current application of dietary intervention to psychiatry is very extensive, and it has been proved to be effective in the treatment of depression. Recent research suggests that dietary interventions can treat and ameliorate depressive symptoms by influencing brain-gut axis-related eating mechanisms. This article reviews the multidimensional exploration of dietary interventions in the treatment of depression: dietary structure interventions, dietary rhythm interventions, and the role of intestinal flora. It details the modalities of dietary interventions and the related mechanisms involved, and provides reference for dietary interventions in the treatment of depression-related symptoms.

Abstract Background Cognitive dysfunction is one of the common symptoms in patients with major depressive disorder (MDD). Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been studied separately in the treatment of cognitive dysfunction in MDD patients. We aimed to investigate the effectiveness and safety of rTMS combined with tDCS as a new therapy to improve neurocognitive impairment in MDD patients. Methods In this brief 2-week, double-blind, randomized, and sham-controlled trial, a total of 550 patients were screened, and 240 MDD inpatients were randomized into four groups (active rTMS + active tDCS, active rTMS + sham tDCS, sham rTMS + active tDCS, sham rTMS + sham tDCS). Finally, 203 patients completed the study and received 10 treatment sessions over a 2-week period. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess patients’ cognitive function at baseline and week 2. Also, we applied the 24-item Hamilton Depression Rating Scale (HDRS-24) to assess patients’ depressive symptoms at baseline and week 2. Results After 10 sessions of treatment, the rTMS combined with the tDCS group showed more significant improvements in the RBANS total score, immediate memory, and visuospatial/constructional index score (all p

Abstract Background Epidemiological studies have revealed a significant association between impaired kidney function and certain mental disorders, particularly bipolar disorder (BIP) and major depressive disorder (MDD). However, the evidence regarding shared genetics and causality is limited due to residual confounding and reverse causation. Methods In this study, we conducted a large-scale genome-wide cross-trait association study to investigate the genetic overlap between 5 kidney function biomarkers (eGFRcrea, eGFRcys, blood urea nitrogen (BUN), serum urate, and UACR) and 2 mental disorders (MDD, BIP). Summary-level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Psychiatric Genomics Consortium. Results Using LD score regression, we found moderate but significant genetic correlations between kidney function biomarker traits on BIP and MDD. Cross-trait meta-analysis identified 1 to 19 independent significant loci that were found shared among 10 pairs of 5 kidney function biomarkers traits and 2 mental disorders. Among them, 3 novel genes: SUFU, IBSP, and PTPRJ, were also identified in transcriptome-wide association study analysis (TWAS), most of which were observed in the nervous and digestive systems (FDR

At least in some individuals, the development of major depressive disorder (MDD) appears to be significantly influenced by neuroinflammation. Microglia, which are situated within the brain, represent a type of immune cell that exhibits the capability to transform into a reactive state in response to inflammatory attacks. This unique ability substantiates the critical role microglia play in the initial stages of neuroinflammation. Empirical studies have revealed that microglia are proficient in discerning infections or damaged cells, thereby instigating a cytotoxic response that exacerbates the damage inflicted on brain cells. However, microglia display a wide range of reactions to injury and may potentially contribute to the process of recuperation and the reinstatement of impaired tissues. It is possible that changing the phenotype of microglia through the regulation of inflammatory pathways is essential in order to harness neuroinflammation in MDD. This study examines potential new treatment paths for modulating neuroinflammation in brain disorders by analyzing canonical proinflammatory, anti-inflammatory, and metabolic mechanisms in microglia. the primary focus is on the major depressive disorder (MDD), but will also discuss other brain diseases.

Obsessive-Compulsive Disorder (OCD) and Major Depressive Disorder (MDD) are prevalent psychiatric conditions, each affecting a substantial portion of the global population. When these conditions coexist with a Substance Use Disorder (SUD), the complexity of the clinical presentation is heightened. Herein, we describe two cases of individuals who have comorbid OCD and/or MDD and substance use disorder that highlight the importance of addressing the coexisting psychiatric illness when treating the SUD. These cases highlight the importance of tailored, multidisciplinary care, offering a potential therapeutic strategy based on medications for comprehensive recovery in individuals facing complex comorbid disorders. An integrated treatment approach, encompassing both psychiatric and substance treatment perspectives, is imperative.

Background: Alterations in the level of neurotransmitters are evident in patients with major depressive disorder (MDD). Vitamin B12 mediates the synthesis of neurotransmitters, and hence, vitamin B12 deficiency could be associated with depression. Aims and Objectives: To assess the levels of serum vitamin B12, homocysteine (Hcy), and haematological profiles in patients of MDD. Materials and Methods: Fifty-nine patients with MDD were recruited based on ICD-10 criteria. Severity of depression was assessed by HAM-D scale. Vitamin B12, Hcy levels, and haematological profiles were analysed. Results: Vitamin B12 was deficient or depleted in all patients with MDD. The median level of vitamin B12 in serum was 164.2 pg./ml and significantly lower in patients with severe MDD. The mean value of Hcy was 18.34 μmol/L, which was high compared to the normal reference range. The red cell distribution width (RDW-CV) varied significantly between the three groups of MDD patients. Patients consuming non-vegetarian food had a significantly higher median value of serum vitamin B12. Conclusion: Vitamin B12 deficiency is found in patients with MDD and varies inversely with severity of MDD. Hcy is found to be higher in patients with MDD. The manifestation of depressive symptoms precedes the more commonly known haematological manifestations of vitamin B12 deficiency in this study.

Abstract Background This study evaluates longitudinal associations between glycaemic control, measured by mean and within-patient variability of glycated haemaglobin (HbA1c) levels, and major depressive disorder (MDD) in individuals with type 2 diabetes (T2D), focusing on the timings of these diagnoses. Methods In UK Biobank, T2D was defined using self-report and linked health outcome data, then validated using polygenic scores. Repeated HbA1c measurements (mmol/mol) over the 10 years following T2D diagnosis were outcomes in mixed effects models, with disease duration included using restricted cubic splines. Four MDD exposures were considered: MDD diagnosis prior to T2D diagnosis (pre-T2D MDD), time between pre-T2D MDD diagnosis and T2D, new MDD diagnosis during follow-up (post-T2D MDD) and time since post-T2D MDD diagnosis. Models with and without covariate adjustment were considered. Results T2D diagnostic criteria were robustly associated with T2D polygenic scores. In 11,837 T2D cases (6.9 years median follow-up), pre-T2D MDD was associated with a 0.92 increase in HbA1c (95% CI: [0.00, 1.84]), but earlier pre-T2D MDD diagnosis correlated with lower HbA1c. These pre-T2D MDD effects became non-significant after covariate adjustment. Post-T2D MDD individuals demonstrated increasing HbA1c with years since MDD diagnosis ( $$\beta =0.51$$ β = 0.51 , 95% CI: [0.17, 0.86]). Retrospectively, across study follow-up, within-patient variability in HbA1c was 1.16 (95% CI: 1.13–1.19) times higher in post-T2D MDD individuals. Conclusions The timing of MDD diagnosis is important for understanding glycaemic control in T2D. Poorer control was observed in MDD diagnosed post-T2D, highlighting the importance of depression screening in T2D, and closer monitoring for individuals who develop MDD after T2D.

Abstract Despite the critical role of self-disturbance in psychiatric diagnosis and treatment, its diverse behavioral manifestations remain poorly understood. This investigation aimed to elucidate unique patterns of self-referential processing in affective disorders and first-episode schizophrenia. A total of 156 participants (41 first-episode schizophrenia [SZ], 33 bipolar disorder [BD], 44 major depressive disorder [MDD], and 38 healthy controls [HC]) engaged in a self-referential effect (SRE) task, assessing trait adjectives for self-descriptiveness, applicability to mother, or others, followed by an unexpected recognition test. All groups displayed preferential self- and mother-referential processing with no significant differences in recognition scores. However, MDD patients showed significantly enhanced self-referential recognition scores and increased bias compared to HC, first-episode SZ, and BD. The present study provides empirical evidence for increased self-focus in MDD and demonstrates that first-episode SZ and BD patients maintain intact self-referential processing abilities. These findings refine our understanding of self-referential processing impairments across psychiatric conditions, suggesting that it could serve as a supplementary measure for assessing treatment response in first-episode SZ and potentially function as a discriminative diagnostic criterion between MDD and BD.

Aims: Due to the paucity of studies in and out of India that dealt with treatment awareness of major depressive disorder (MDD), we decided to assess the awareness of MDD patients, and since adherence and awareness are linked to each other, we assessed adherence too. Prescription pattern studies identify changes in prescriptions due to poor initial response or adverse drug reactions (ADRs), which may result in dose reduction or switching medications and delay remission. Therefore, the study assessed the ADR pattern. Methodology: A cross-sectional questionnaire-based study was carried out on 200 MDD patients with treatment records for at least 3 months after getting approval from the Institutional Ethics Committee and consent from the patients. The data obtained were entered in Microsoft Excel and analyzed using descriptive statistics. Results: The mean age was 44.65 ± 12.02 years, and females were 70%. Maximum patients (98%) were aware of the consequence of stopping the drugs suddenly, and only 12.5% were aware of the onset of response to treatment. Escitalopram was the most common antidepressant prescribed (43.77%), and 67 ADRs out of 136 were attributable to it. Weakness and fatigue were the most common ADRs. The majority (97) of the ADRs were possibly related to antidepressants, and 65% of patients showed optimal adherence to medications. Conclusions: This study sheds light on the treatment awareness and adherence of MDD patients in India and highlights the need for educating patients about treatment response. It also emphasizes the importance of monitoring ADRs and adjusting prescription patterns accordingly to improve treatment outcomes.

Objectives Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints, causing inflammation, pain, and potential joint damage. Patients with RA are at high risk of developing psychiatric morbidity; it is important to recognize these psychiatric manifestations. The relationship between psychiatric symptoms and RA is complex and can involve various factors, including the impact of chronic pain, inflammation, medications, and the overall burden of managing a chronic illness. Aim of the study was to systematically investigate and analyze the patterns and prevalence of psychiatric morbidity among individuals diagnosed with RA, with the aim of identifying common mental health conditions, understanding the interplay between RA and psychiatric disorders, and providing valuable insights for improved holistic patient care. Material and methods This was a prospective, observational cross-sectional study conducted over a period of three years in patients with RA. Psychiatric morbidity was assessed using International Classification of Diseases-10 criteria and Mini-Plus by dedicated psychiatrists. The diagnosis of RA was confirmed using the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) diagnostic criteria for RA and the disease activity was calculated by Disease Activity Score with 28-joint count (DAS28) using the calculator from the RheumaHelper application. The data were analyzed using SPSS, version 23.0. Results A total of 1,000 patients with RA were included in this study. Nearly two-thirds of the patients were female (64.8%). The majority of patients belonged to the age group of 41 to 54 years. Total 47.5% of the patients were unemployed, 27.0% were salaried, 19.0% were businessman, while 6.5% of the patients were students. More than half of the patients (53.2%) had moderate disease activity. Major depressive disorder was the most commonly observed comorbidity (41.0%), followed by somatoform disorder (28.5%), and generalized anxiety disorder was found in 13.5%. No psychiatric manifestations were found in 17% of studied individuals. Conclusions Psychiatric morbidity is associated with RA and there is a need for psychiatric services to be made available to these patients.

Summary: Background: Controllability analysis is an approach developed for evaluating the ability of a brain region to modulate function in other regions, which has been found to be altered in major depressive disorder (MDD). Both depressive symptoms and cognitive impairments are prominent features of MDD, but the case–control differences of controllability between MDD and controls can not fully interpret the contribution of both clinical symptoms and cognition to brain controllability and linked patterns among them in MDD. Methods: Sparse canonical correlation analysis was used to investigate the associations between resting-state functional brain controllability at the network level and clinical symptoms and cognition in 99 first-episode medication-naïve patients with MDD. Findings: Average controllability was significantly correlated with clinical features. The average controllability of the dorsal attention network (DAN) and visual network had the highest correlations with clinical variables. Among clinical variables, depressed mood, suicidal ideation and behaviour, impaired work and activities, and gastrointestinal symptoms were significantly negatively associated with average controllability, and reduced cognitive flexibility was associated with reduced average controllability. Interpretation: These findings highlight the importance of brain regions in modulating activity across brain networks in MDD, given their associations with symptoms and cognitive impairments observed in our study. Disrupted control of brain reconfiguration of DAN and visual network during their state transitions may represent a core brain mechanism for the behavioural impairments observed in MDD. Funding: National Natural Science Foundation of China (82001795 and 82027808), National Key R&D Program (2022YFC2009900), and Sichuan Science and Technology Program (2024NSFSC0653).

Background: The increasing global prevalence of major depressive disorder (MDD) has become an important challenge, leading to a heightened demand for oral medicine in developed nations. This demand arises from the recognition of the association between psychiatric disorders and other conditions, including various orofacial pain disorders. Objective: This study are to evaluate oral conditions such as recurrent aphthous ulcers, burning mouth syndrome, and altered taste and to assess salivary alpha-amylase in individuals diagnosed with major depressive disorder. Methods: This research uses a cross-sectional study design that includes a sample of 49 patients who have been diagnosed with major depressive disorder and who have undergone treatment for at least two weeks. The control group consists of 34 healthy subjects with no signs or symptoms of systemic disease. The study group received the diagnosis in Najaf City according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). With respect to recurrent aphthous ulcers, the results of this study show the percentage of patients with oral ulcers is significantly higher than in the control group. Results: The results also show that the prevalence of burning mouth syndrome is significantly higher in patients with major depressive disorder than in healthy controls. A highly statistically significant difference was found between the study group and the control group regarding altered taste. There is also a significant difference in salivary alpha-amylase levels between the study and control groups (p = 0.009). Conclusion: Major depressive disorder patients have much higher incidences of reported recurrent aphthous ulcers, burning mouth syndrome, and altered taste than healthy subjects, indicating the importance of psychological factors in these conditions. Additionally, salivary alpha-amylase levels were higher in patients with major depressive disorder than in the control group.

Abstract Background Major depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signalling during inflammation, is dysregulated in many chronic inflammatory disorders; however, its role in depression and the associated sex differences have yet to be explored. Here, we investigated the sex-specific antidepressant and cognitive effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles. Methods Male and female rats were treated with vehicle or DMF (25 mg/kg) whilst subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Sex differences in hippocampal (HIP) gene expression responses were also evaluated. Results DMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, and DMF treatment rescued these deficits. Further, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, most of the differentially expressed genes in males normalized by DMF were related to antioxidant, inflammatory or immune responses. Conclusions Collectively, these findings may support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression.

Abstract Background Major depressive disorder (MDD) is a common mental illness that affects millions of people worldwide and imposes a heavy burden on individuals, families and society. Previous studies on MDD predominantly focused on neurons and employed bulk homogenates of brain tissues. This paper aims to decipher the relationship between oligodendrocyte lineage (OL) development and MDD at the single-cell resolution level. Methods Here, we present the use of a guided regularized random forest (GRRF) algorithm to explore single-nucleus RNA sequencing profiles (GSE144136) of the OL at four developmental stages, which contains dorsolateral prefrontal cortex of 17 healthy controls (HC) and 17 MDD cases, generated by Nagy C et al. We prioritized and ordered differentially expressed genes (DEGs) based on Nagy et al., which could predominantly discriminate cells in the four developmental stages and two adjacent developmental stages of the OL. We further screened top-ranked genes that distinguished between HC and MDD in four developmental stages. Moreover, we estimated the performance of the GRRF model via the area under the curve value. Additionally, we validated the pivotal candidate gene Malat1 in animal models. Results We found that, among the four developmental stages, the onset development of OL (OPC2) possesses the best predictive power for distinguishing HC and MDD, and long noncoding RNA MALAT1 has top-ranked importance value in candidate genes of four developmental stages. In addition, results of fluorescence in situ hybridization assay showed that Malat1 plays a critical role in the occurrence of depression. Conclusions Our work elucidates the mechanism of MDD from the perspective of OL development at the single-cell resolution level and provides novel insight into the occurrence of depression.

Abstract Background The causal associations between psychiatric disorders and falls risk remains uncertain. Consequently, this study aimed to explore the causal relationship between genetically determined three common psychiatric disorders and the risk of falls based on Mendelian randomization (MR). Methods The genome-wide association study (GWAS) data for schizophrenia (SCZ) (N = 320,404), major depressive disorder (MDD) (N = 480,359), and Alzheimer's disease (AD) (N = 63,926) were obtained as exposures. The GWAS data for falls risk (N = 451,179) was obtained as outcome. Univariate Mendelian randomization (UVMR) was used to evaluate the direct causal relationship between SCZ, MDD, AD, and risk of falls. Inverse variance weighting (IVW) was used as the primary analysis method. Sensitivity analysis was performed to assess the validity of the casualty. Multivariate Mendelian randomization (MVMR) analysis was conducted after adjusting body mass index and smoking initiation. Mediating MR was conducted to calculate the mediating effects of potential intermediaries. Results UVMR analysis showed that SCZ (OR 1.02, 95% CI 1.01–1.04, p = 8.03E−03) and MDD (OR 1.15, 95% CI 1.08–1.22, p = 1.38E−05) were positively associated with the risk of falls. Sensitivity analysis results were reliable and robust. MVMR results indicated that the relationship between MDD and SCZ and falls risk remained significant. Mediating MR results demonstrated that smoking initiation mediated partial causal effect of SCZ (0.65%, P = 0.03) and MDD (14.82%, P = 2.02E−03) on risk of falls. Conclusions This study provides genetic evidence for a causal relationship of individuals with SCZ and MDD on an increased risk of falls. Healthcare providers should be aware of the risk of falls in MDD and SCZ patients and develop strategies accordingly.

Prior to the introduction of COVID-19 vaccines, patients with severe mental illness (SMI) were at greater risk of COVID-19-related outcomes than the general population. It is not yet clear whether COVID-19 vaccines have reduced the risk gap. We systematically searched nine international databases and three Chinese databases to identify relevant studies from December 2020 to December 2023 to compare the risk of COVID-19-related outcomes for SMI patients to those without SMI after vaccination. Random effects meta-analysis was performed to estimate the pooled odds ratio (OR) with 95% confidence intervals (CI). Subgroup analysis, sensitivity analysis, and publication bias analysis were conducted with R software 4.3.0. A total of 11 observational studies were included. Compared with controls, SMI patients were associated with a slightly increased risk of infection (pooled OR = 1.10, 95% CI, 1.03–1.17, I2 = 43.4%), while showing a 2-fold higher risk of hospitalization (pooled OR = 2.66, 95% CI, 1.13–6.22, I2 = 99.6%), even after both groups have received COVID-19 vaccines. Limited evidence suggests a higher mortality risk among SMI patients compared to controls post vaccination, but the findings did not reach statistical significance. SMI patients remain at increased risk compared to their peers in COVID-19-related outcomes even after vaccination. Vaccination appears an effective approach to prevent severe COVID-19 illness in SMI patients, and actions should be taken by healthcare providers to improve vaccination coverage in these vulnerable groups.

AbstractBackground Major depressive disorder (MDD) is a debilitating condition that affects more than 300 million people worldwide. Current treatments are based on a trial-and-error approach, and reliable biomarkers are needed for more informed and personalized treatment solutions. One of the potential biomarkers, gamma-frequency (30–80 Hz) brainwaves, are hypothesized to originate from the excitatory-inhibitory interaction between the pyramidal cells and interneurons. The imbalance between this interaction is described as a crucial pathological mechanism in neuropsychiatric conditions, including MDD, and the modulation of this pathological interaction has been investigated as a potential target. Previous studies attempted to induce gamma activity in the brain using rhythmic light and sound stimuli (GENUS – Gamma Entrainment Using Sensory stimuli) that resulted in neuroprotective effects in Alzheimer’s disease (AD) patients and animal models. Here, we investigate the antidepressant, cognitive, and electrophysiological effects of the novel light therapy approach using 40 Hz masked flickering light for patients diagnosed with MDD.Methods and design Sixty patients with a current diagnosis of a major depressive episode will be enrolled in a randomized, double-blinded, placebo-controlled trial. The active treatment group will receive 40 Hz masked flickering light stimulation while the control group will receive continuous light matched in color temperature and brightness. Patients in both groups will get daily light treatment in their own homes and will attend four follow-up visits to assess the symptoms of depression, including depression severity measured by Hamilton Depression Rating Scale (HAM-D17), cognitive function, quality of life and sleep, and electroencephalographic changes. The primary endpoint is the mean change from baseline to week 6 in depression severity (HAM-D6 subscale) between the groups.

Summary: Background: Sleep and circadian rhythm disruptions are common in patients with mood disorders. The intricate relationship between these disruptions and mood has been investigated, but their causal dynamics remain unknown. Methods: We analysed data from 139 patients (76 female, mean age = 23.5 ± 3.64 years) with mood disorders who participated in a prospective observational study in South Korea. The patients wore wearable devices to monitor sleep and engaged in smartphone-delivered ecological momentary assessment of mood symptoms. Using a mathematical model, we estimated their daily circadian phase based on sleep data. Subsequently, we obtained daily time series for sleep/circadian phase estimates and mood symptoms spanning >40,000 days. We analysed the causal relationship between the time series using transfer entropy, a non-linear causal inference method. Findings: The transfer entropy analysis suggested causality from circadian phase disturbance to mood symptoms in both patients with MDD (n = 45) and BD type I (n = 35), as 66.7% and 85.7% of the patients with a large dataset (>600 days) showed causality, but not in patients with BD type II (n = 59). Surprisingly, no causal relationship was suggested between sleep phase disturbances and mood symptoms. Interpretation: Our findings suggest that in patients with mood disorders, circadian phase disturbances directly precede mood symptoms. This underscores the potential of targeting circadian rhythms in digital medicine, such as sleep or light exposure interventions, to restore circadian phase and thereby manage mood disorders effectively. Funding: Institute for Basic Science, the Human Frontiers Science Program Organization, the National Research Foundation of Korea, and the Ministry of Health & Welfare of South Korea.

IntroductionDecades of research in population health have established depression as a likely precursor to Alzheimer's disease. A combination of causal estimates and machine learning methods in artificial intelligence could identify internal and external mediating mechanisms that contribute to the likelihood of progression from depression to Alzheimer's disease.MethodsWe developed an integrated predictive model, combining the marginal structural model and an artificial intelligence predictive model, distinguishing between patients likely to progress from depressive states to Alzheimer's disease better than each model alone.ResultsThe integrated predictive model achieved substantial clinical relevance when using the area under the curve measure. It performed better than the traditional statistical method or a single artificial intelligence method alone.DiscussionThe integrated predictive model could form a part of a clinical screening tool that identifies patients who are likely to progress from depression to Alzheimer's disease for early behavioral health interventions. Given the high costs of treating Alzheimer's disease, our model could serve as a cost-effective intervention for the early detection of depression before it progresses to Alzheimer's disease.

Summary: Background: Pharmacogenomics (PGx) holds promise to revolutionize modern healthcare. Although there are several prospective clinical studies in oncology and cardiology, demonstrating a beneficial effect of PGx-guided treatment in reducing adverse drug reactions, there are very few such studies in psychiatry, none of which spans across all main psychiatric indications, namely schizophrenia, major depressive disorder and bipolar disorder. In this study we aim to investigate the clinical effectiveness of PGx-guided treatment (occurrence of adverse drug reactions, hospitalisations and re-admissions, polypharmacy) and perform a cost analysis of the intervention. Methods: We report our findings from a multicenter, large-scale, prospective study of pre-emptive genome-guided treatment named as PREemptive Pharmacogenomic testing for preventing Adverse drug REactions (PREPARE) in a large cohort of psychiatric patients (n = 1076) suffering from schizophrenia, major depressive disorder and bipolar disorder. Findings: We show that patients with an actionable phenotype belonging to the PGx-guided arm (n = 25) present with 34.1% less adverse drug reactions compared to patients belonging to the control arm (n = 36), 41.2% less hospitalisations (n = 110 in the PGx-guided arm versus n = 187 in the control arm) and 40.5% less re-admissions (n = 19 in the PGx-guided arm versus n = 32 in the control arm), less duration of initial hospitalisations (n = 3305 total days of hospitalisation in the PGx-guided arm from 110 patients, versus n = 6517 in the control arm from 187 patients) and duration of hospitalisation upon readmission (n = 579 total days of hospitalisation upon readmission in the PGx-guided arm, derived from 19 patients, versus n = 928 in the control arm, from 32 patients respectively). It was also shown that in the vast majority of the cases, there was less drug dose administrated per drug in the PGx-guided arm compared to the control arm and less polypharmacy (n = 124 patients prescribed with at least 4 psychiatric drugs in the PGx-guided arm versus n = 143 in the control arm) and smaller average number of co-administered psychiatric drugs (2.19 in the PGx-guided arm versus 2.48 in the control arm. Furthermore, less deaths were reported in the PGx-guided arm (n = 1) compared with the control arm (n = 9). Most importantly, we observed a 48.5% reduction of treatment costs in the PGx-guided arm with a reciprocal slight increase of the quality of life of patients suffering from major depressive disorder (0.935 versus 0.925 QALYs in the PGx-guided and control arm, respectively). Interpretation: While only a small proportion (∼25%) of the entire study sample had an actionable genotype, PGx-guided treatment can have a beneficial effect in psychiatric patients with a reciprocal reduction of treatment costs. Although some of these findings did not remain significant when all patients were considered, our data indicate that genome-guided psychiatric treatment may be successfully integrated in mainstream healthcare. Funding: European Union Horizon 2020.

Background and purpose: Major depressive disorder (MDD) is among the most common psychiatric diseases. Brain-derived neurotrophic factor (BDNF) is a suitable biomarker for treatment response. In the present research، serum changes of this biomarker were assessed between the two groups of MDD patients undergoing Fluoxetine therapy and cognitive-behavioral therapy (CBT). Materials and methods: In this randomized controlled trial study, 40 female MDD patients (DSM-V criteria) were assigned to two Fluoxetine therapy (20 mg/d for 3 months) (N=20) and CBT (90-minute sessions، once a week، for 12 weeks) (N=20) groups. The Beck Depression Inventory-II (BDI-II) score and serum BDNF concentration were measured before and after the treatment. The data were analyzed at a significance level of P≤0.05 using Graphpad prism 9 statistical software. Results: The BDI-II score significantly decreased in both Fluoxetine therapy (from 23.2±1.5 to 11.1±1.01) and CBT (from 26.8±0.6 to 9.5±0.8) groups. No significant change was observed in the serum BDNF level in the Fluoxetine therapy group، while it was increased in the CBT group (from 1.13±0.71 to 3 ± 0.72 ). The intergroup comparison after treatment indicated that the BDI-II score decrease and the serum BDNF increase were higher in the CBT group than in the Fluoxetine therapy group. Conclusion: The BDI-II score decrease and the serum BDNF increase were higher in the CBT group than in the Fluoxetine therapy group. Thus، it seems appropriate for MDD treatment. Serum BDNF is not an appropriate biomarker for treatment response. It is suggested that a study be conducted with a larger sample size and a longer investigation period. (Clinical Trials Registry Number: IRCT20190710044171N1)

Aim:In this study, we aimed to assess the sociodemographic and clinical characteristics of adolescents diagnosed with major depressive disorder (MDD), with and without suicide attempts, as well as to investigate the factors predicting suicide attempts.Materials and Methods:This study included 151 adolescents aged between 12 and 18 years, who were diagnosed with MDD between January 2021 and June 2022. This study has a retrospective design, and data including family sociodemographic characteristics, suicide attempts and characteristics, non-suicidal self-injury (NSSI) attempts, history of abuse, comorbid psychiatric disorders, and scores on depression and anxiety scales were extracted from the cases’ polyclinic records. The participants were divided into two groups as those with suicide attempts (n=40) and those without suicide attempts (NSSI n=111), and the sociodemographic and clinical data were compared between the groups. In addition, a binary logistic regression analysis was performed to identify the predictors for suicide attempts.Results:The results of the study revealed that the suicide attempt group had a higher age (p=0.023), less maternal years of education (p=0.026), higher rates of self-injurious behavior (p

Major depressive disorder (MDD) is a mood disorder that has become a global health emergency according to the World Health Organization (WHO). It affects 280 million people worldwide and is a leading cause of disability and financial loss. Patients with MDD present immunoendocrine alterations like cortisol resistance and inflammation, which are associated with alterations in neurotransmitter metabolism. There are currently numerous therapeutic options for patients with MDD; however, some studies suggest a high rate of therapeutic failure. There are multiple hypotheses explaining the pathophysiological mechanisms of MDD, in which several systems are involved, including the neuroendocrine and immune systems. In recent years, inflammation has become an important target for the development of new therapeutic options. Extracellular monomeric ubiquitin (emUb) is a molecule that has been shown to have immunomodulatory properties through several mechanisms including cholinergic modulation and the generation of regulatory T cells. In this perspective article, we highlight the influence of the inflammatory response in MDD. In addition, we review and discuss the evidence for the use of emUb contained in Transferon as a concomitant treatment with selective serotonin reuptake inhibitors (SSRIs).

Abstract Introduction: Alleviation of symptom severity for major depressive disorder (MDD) is known to be associated with a lagged improvement of functioning. Pharmacotherapy guidelines support algorithms for MDD treatment. However, it is currently unclear whether concordance with guidelines influences functional recovery. A guideline concordance algorithm (GCA-8) was used to measure this pathway in a naturalistic clinical setting. Methods: Data from 1403 adults (67% female, 84% non-Hispanic/Latino White, mean age of 43 years) with nonpsychotic MDD from the Penn State Psychiatry Clinical Assessment and Rating Evaluation System registry (visits from 02/01/2015 to 04/13/2021) were evaluated. Multivariable linear regression measured associations between GCA-8 and World Health Organization Disability Assessment Schedule 2.0 (WHODAS) scores. Mediation by MDD symptom severity using the Patient Health Questionnaire depression module (PHQ-9) was also evaluated. Results: This study found a statistically significant improvement in WHODAS scores (functioning) between baseline and final measures (−2 points, P < .001) within one year. A one standard deviation increase in the GCA-8 score was associated with a 0.48-point reduction in mean disability score (total effect; P = .02) with significant mediation by the change in MDD symptom severity (coefficient = −0.51, P < .001) and a nonsignificant natural direct effect of the GCA-8 independent of PHQ-9 change (coefficient = −0.02, P = .92). Conclusions: Higher pharmacotherapy guideline concordance is associated with better functioning for MDD patients; this association likely occurs through improvement in MDD symptom severity rather than directly.

Background: The majority of antidepressants have been reported to cause metabolic syndrome (MetS). Paucity of information available for the effect of Vortioxetine on MetS. The study aims to assess the systematic review of Vortioxetine on depressive patients' blood pressure (BP), central obesity, fasting plasma glucose (FPG), triglycerides (TGs), and high-density lipoprotein (HDL) levels, which are risk factors for the MetS. Methods: PRISMA guidelines were followed in conducting this systematic review. The protocol has been registered with PROSPERO (CRD42021272614). Randomized controlled trials (RCTs) that evaluated the effect of Vortioxetine on MetS risk indicators were searched in electronic databases. RCTs that included adult patients 18–75 years of age, Major depression patients (MDD) and prescribed with Vortioxetine drug. Preclinical research, editorials, letters, reviews, case reports, studies in pediatric populations, unpublished gray literature were excluded Abstract and title screening was performed, followed by full-text screening using the Covidence software. Data were extracted, and analysis was done using Cochrane Review Manager (RevMan v5.1). Results: Following the screening process, 8 RCTs (6 blinded and 2 open-label) were selected for systematic review. The MetS risk factors for Vortioxetine treatment in depressed patients were ambiguous from the available research. However, 4 of 8 RCTs have shown that Vortioxetine is an effective and safe treatment for depression. All the trials were methodological of high quality. Conclusions: A single study evaluating all the five MetS risk variables in depressed patients on Vortioxetine therapy is needed before recommending Vortioxetine as a first-line or switch therapy for depression.

Background Considerable evidence suggests that people with depressive disorder are at higher risk for somatic symptoms than normal people, but the mechanisms of susceptibility are unclear. Some studies suggest that the levels of precursor of brain-derived neurotrophic factor (ProBDNF) and inflammatory cytokines in depressive disorder patients are higher, but it is still unclear whether this is related to the accompanying somatic symptoms. Objective To explore the characteristics of somatic symptoms, and their correlations with BDNF and inflammatory cytokines in patients with major depressive disorder (MDD) . Methods A total of 59 MDD outpatients and inpatients from Mental Health Department, First Hospital of Shanxi Medical University and 32 healthy volunteers from the community were recruited from February 2019 to December 2020. Somatic symptoms were diagnosed using the Somatic Self-rating Scale (SSS, SSS score >36 and SSS score ≤36 were defined as with somatic symptoms or without, respectively) . Depression was assessed using the Hamilton Depression Rating Scale (HAMD-17) . Clinical data were collected, including gender, age, years of education, HAMD-17 score, SSS score, absorbance of ProBDNF and BDNF, and inflammatory cytokines (CRP, IL-4, IL-10, IL-18, IL-23a, HMGB1, IL-6, TNF-α, IFN-α) . Spearman's rank correlation analysis was used to investigate the correlation of somatic symptoms (including dizziness and headache, frequent and urgency of urination, cardiovascular symptoms, muscle soreness, gastrointestinal symptoms, tingling and twitching of hands and feet, choking and sighing, blurred vision, and discomfort of the throat) , SSS-S factor score and HAMD-17 score with ProBDNF and BDNF, and inflammatory cytokines. Results MDD patients with somatic symptoms had higher total HAMD-17 score than those without (P

Background: People at risk of exercise addiction report increased symptoms of psychopathology. The aim of this study was to clinically assess the lifetime prevalence of depressive disorders in individuals at risk of exercise addiction and to determine whether depressive symptoms tend to precede or follow excessive exercising. Methods: Based on the Exercise Dependence Scale-21, a total of 31 individuals categorized at risk of exercise addiction underwent the Structured Clinical Interview for DSM-5 to assess major depressive disorder (MDD). Findings: The results showed 16 of the 31 participants suffered from MDD. The onset of MMD occurred in 10 participants after excessive exercising and in 5 before excessive exercising. In one participant, the symptom onset was unclear. Conclusion: MDD is far more prevalent in patients with exercise addiction compared to the general population and develops more often after the beginning of exercise addiction. Caution in the use of exercise to treat depression may be warranted

Abstract Background Major depressive disorder causes a great burden on patients and societies. Venlafaxine and mirtazapine are commonly prescribed as second-line treatment for patients with major depressive disorder worldwide. Previous systematic reviews have concluded that venlafaxine and mirtazapine reduce depressive symptoms, but the effects seem small and may not be important to the average patient. Moreover, previous reviews have not systematically assessed the occurrence of adverse events. Therefore, we aim to investigate the risks of adverse events with venlafaxine or mirtazapine versus ‘active placebo’, placebo, or no intervention for adults with major depressive disorder in two separate systematic reviews. Methods This is a protocol for two systematic reviews with meta-analysis and Trial Sequential Analysis. The assessments of the effects of venlafaxine or mirtazapine will be reported in two separate reviews. The protocol is reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, risk of bias will be assessed with the Cochrane risk-of-bias tool version 2, clinical significance will be assessed using our eight-step procedure, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. We will search for published and unpublished trials in major medical databases and trial registers. Two review authors will independently screen the results from the literature searches, extract data, and assess risk of bias. We will include published or unpublished randomised clinical trial comparing venlafaxine or mirtazapine with ‘active placebo’, placebo, or no intervention for adults with major depressive disorder. The primary outcomes will be suicides or suicide attempts, serious adverse events, and non-serious adverse events. Exploratory outcomes will include depressive symptoms, quality of life, and individual adverse events. If feasible, we will assess the intervention effects using random-effects and fixed-effect meta-analyses. Discussion Venlafaxine and mirtazapine are frequently used as second-line treatment of major depressive disorder worldwide. There is a need for a thorough systematic review to provide the necessary background for weighing the benefits against the harms. This review will ultimately inform best practice in the treatment of major depressive disorder. Systematic review registration PROSPERO CRD42022315395.

Ketamine is a potential rapid-onset antidepressant characterized by sympathomimetic effects. However, the question of ketamine’s use in treating adolescents’ major depressive disorder (MDD) is still discussed. Thus, we aimed to study the acute effect of ketamine infusion treatment on sympathetic regulation using electrodermal activity (EDA) in addition to an assessment of depressive symptomatology in MDD adolescents. Twenty hospitalized adolescent girls with MDD (average age: 15.0 ± 1.46 yrs.) were examined before and two hours after a single intravenous infusion of ketamine. EDA was continuously recorded for 6 min, and depressive symptoms were assessed before and two hours after ketamine administration. The evaluated parameters included skin conductance level (SCL), nonspecific electrodermal responses (NS-SCRs), MADRS (questions no. 1–10, total score), and CDI (items A–E, total score). EDA parameters showed no significant changes after the ketamine treatment, and depressive symptoms were significantly reduced after the ketamine infusion. The analysis revealed a significant negative correlation between index SCL and CDI-A, CDI-E, and the total CDI score and between index NS-SCRs and MADRS no. 4 before the ketamine treatment. In conclusion, ketamine improved depressive symptomatology without a significant effect on EDA, indicating its potential safety and efficiency as an acute antidepressant intervention in adolescent MDD.

Key Clinical Message Hemolacria can occur on the basis of a psychiatric disorder without an organic cause. However, this should be a diagnosis of exclusion. Treatment of the underlying psychiatric illness may relieve this condition. Abstract A 24‐year‐old man presented with the chief complaint of bloody tears, which began 4 months earlier after commencing mandatory military service. He had no underlying diseases, and all work‐ups returned normal, though a microscopic examination confirmed red blood cells. He was diagnosed with hemolacria secondary to generalized anxiety disorder and major depressive disorder, responding to propranolol and sertraline. Hemolacria was totally cured after 6 months of treating the underlying psychiatric illness.

Abstract Background Evidence linking air pollution to major depressive disorder (MDD) remains sparse and results are heterogeneous. In addition, the evidence about the interaction and joint associations of genetic risk and lifestyle with air pollution on incident MDD risk remains unclear. We aimed to examine the association of various air pollutants with the risk of incident MDD and assessed whether genetic susceptibility and lifestyle influence the associations. Methods This population-based prospective cohort study analyzed data collected between March 2006 and October 2010 from 354,897 participants aged 37 to 73 years from the UK Biobank. Annual average concentrations of PM2.5, PM10, NO2, and NOx were estimated using a Land Use Regression model. A lifestyle score was determined based on a combination of smoking, alcohol drinking, physical activity, television viewing time, sleep duration, and diet. A polygenic risk score (PRS) was defined using 17 MDD-associated genetic loci. Results During a median follow-up of 9.7 years (3,427,084 person-years), 14,710 incident MDD events were ascertained. PM2.5 (HR: 1.16, 95% CI: 1.07–1.26; per 5 μg/m3) and NOx (HR: 1.02, 95% CI: 1.01–1.05; per 20 μg/m3) were associated with increased risk of MDD. There was a significant interaction between the genetic susceptibility and air pollution for MDD (P-interaction < 0.05). Compared with participants with low genetic risk and low air pollution, those with high genetic risk and high PM2.5 exposure had the highest risk of incident MDD (PM2.5: HR: 1.34, 95% CI: 1.23–1.46). We also observed an interaction between PM2.5 exposure and unhealthy lifestyle (P-interaction < 0.05). Participants with the least healthy lifestyle and high air pollution exposures had the highest MDD risk when compared to those with the most healthy lifestyle and low air pollution (PM2.5: HR: 2.22, 95% CI: 1.92–2.58; PM10: HR: 2.09, 95% CI: 1.78–2.45; NO2: HR: 2.11, 95% CI: 1.82–2.46; NOx: HR: 2.28, 95% CI: 1.97–2.64). Conclusions Long-term exposure to air pollution is associated with MDD risk. Identifying individuals with high genetic risk and developing healthy lifestyle for reducing the harm of air pollution to public mental health.

Background There are many subtypes of major depressive disorder (MDD) . Evidence about the differentiation of them is mostly based on symptomatological characteristics, but rarely by objective biological indicators. Objective To explore the differences in event-related potential (ERP) N400 between patients with different subtypes of depression, providing an objective electrophysiological basis for subtyping depression. Methods Two hundred and nine outpatients and inpatients who met the diagnostic criteria of MDD in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition were selected from First Hospital of Shanxi Medical University from February 2019 to December 2021, including 78 with anxious depression (ASD+MD-) , 46 with melancholic depression (ASD-MD+) , 61 with anxious and melancholic depression (ASD+MD+) , and 24 with non-anxious and melancholic depression (ASD-MD-) subtyped using the 30-item Inventory of Depressive Symptomatology (IDS-30) and 17-item Hamilton Depression Rating Scale (HAMD-17) . Thirty-five community-living health volunteers were recruited as controls at the same time.The factor and total scores of the HAMD-17 and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) of all subjects were collected. And the latency and amplitude of N400 component of all subjects were collected by inducing N400 components through understanding ambiguous words at the end of sentences. Results (1) The total score and factor scores of HAMD-17 differed significantly across MDD subgroups and control group (P< 0.05) . The total score of HAMD-17 in each of the four MDD subgroups was much higher than that in control group (P0.05) .There were no significant differences in latency and amplitude of N400 component across different electrode sites (P>0.05) , and there were no interaction between no-depression or each of the four subtypes of MDD and electrode sites (P>0.05) . (4) The N400 amplitude value at Fz electrode was negatively correlated with the cognitive impairment factor score (r=-0.170, P=0.016) .The N400 amplitude value at Cz electrode was positively correlated with the block factor score (r=0.151, P=0.033) .The N400 amplitude valueat Pz electrode was positively correlated with the block factor score (r=0.174, P=0.014) .The N400 amplitude value of the Fz electrode was positively correlated with the immediate memory score (r=0.138, P=0.050) .The N400 latency value at Cz electrode was negatively correlated with the delayed memory score (r=-0.155, P=0.028) . Conclusion Extensive cognitive impairment was found in MDD patients, including impaired immediate memory, speech function, attention and delayed memory. ASD+MD+ and ASD+ MD-patients had more severe symptoms, and ASD+MD+ patients had the most severe cognitive impairment. N400 amplitude value was negatively correlated with cognitive impairment and positively correlated with block factor in MDD patients. But these patients demonstrated no impaired function of speech integration induced by ambiguous words at the end of sentences.

Background: Unrecognized bipolar spectrum disorder under cover diagnosis of major depression disorder leads to wrong medications (antidepressants in absence of mood stabilizer), which may switch to mania. Aim and Objectives: A study was to identify unrecognized bipolar disorder in patients of major depressive disorder taking antidepressants. Materials and Methods: This is an observational and cross-sectional study of 150 patients previously diagnosed as major depressive disorder taking antidepressants from tertiary care hospital. Patients were assessed by proforma containing demographic details, Questionnaire of mood disorder questionnaire (MDQ), and Hamilton depression rating scale (HAMD) followed by clinical interview according to DSM-5 to confirm diagnosis. Statistical analysis was done. Results: We found 6.67% depression patients screened positive on MDQ for bipolar disorder and diagnosis is confirmed by interview according to DSM-5. MDQ positive patients have early age of onset of depression(P=0.0109), long duration of depression(P=0.0478), presence of previous suicide attempt(P=0.0130), and family history of bipolar disorder(P=0.0361). No statistically significant difference was observed between mean HAMD score and severity of depression between MDQ positive and negative group. Conclusion: Among patients prescribed antidepressants for depression, there is a substantial proportion with unrecognized bipolar disorder and most of them had never received diagnosis of bipolar disorder. When seeing patients with depression disorder, clinicians should review the life history for screening of unrecognized bipolar disorder by looking for early age onset of depressive episode and long lifetime duration of depression, previous suicide attempt, and family history of bipolar disorder.

Objectives The COVID-19 pandemic has caused unseen pressure on healthcare systems in many countries, jeopardizing the mental well-being of healthcare workers. The authors aimed to assess the mental well-being of Finnish healthcare workers from 2 hospital districts (Helsinki University Hospital [HUS] and Social and Health Services in Kymenlaakso [Kymsote]) with differing COVID-19 incidence rates during the first wave of the COVID-19 pandemic in spring 2020. Material and Methods A total number of 996 healthcare workers (HUS N = 862, Kymsote N = 134) participated in this prospectively conducted survey study during summer 2020. Symptom criteria of self-reported mental health symptoms followed ICD-10 classification, excluding duration criteria. Participants were divided into symptom categories “often/sometimes”, and “rarely/never”. These groups were compared to sociodemographic factors and factors related to work, workload, and well-being. Results The degree of mental health symptoms did not differ between the 2 healthcare districts despite differing COVID-19 incidences (p = 1). The authors observed a significant relationship between self-reported diagnostic mental health symptoms and experiences of insufficient instructions for protection against COVID-19 (in HUS cohort p < 0.001), insufficient recovery from work (p < 0.001), and subjective increased workload (p < 0.001). Conclusions The authors’ results show the importance of well-planned and sufficient instructions for protection from SARS-CoV-2 for healthcare workers, indicating their need to feel safe and protected at work. The workload of healthcare workers should be carefully monitored to keep it moderate and ensure sufficient recovery. Sufficient control of the epidemic to keep the burden of the healthcare system low is vital for healthcare workers’ well-being. Int J Occup Med Environ Health. 2022;35(6):708–18

Major depressive disorder is a serious disease that impacts human health worldwide. Traditional antidepressant medications are limited by the delayed onset of therapeutic effects and the unacceptable side effects. Recently, the rapid antidepressant effect of ketamine, which decreases depressive symptoms within hours, has been a very attractive finding in the field, but the underlying mechanisms mediating this rapid response remain unclear. Besides, the clinical application of ketamine still carries risks, such as addiction and deleterious side effects. In May 2022, Rawat et al. reported that the acute activation of adult-born immature granule neurons (ABINs) in the dentate gyrus played a key role in the rapid antidepressant effects of ketamine. This commentary reviews the important findings of this research and looks forward to the future work.

Background: Major depressive disorder is identified as a mood disorder characterized by episodically recurring and potentially life-threatening negative symptoms. It is currently important for study, as it involves high morbidity, mortality and prevalence, as well as unsatisfactory treatment results. Aim: Establish an outpatient model from an integrative approach promoting the diversified development of traditional Chinese and Western medicine cooperation, leading to a holistic intervention for patients with depression. Experimental procedure: Fifteen participants with moderate to severe depression were followed up for eight weeks in the Acupuncture Department of the China Medical University Hospital in Taichung, Taiwan, under a collaborative outpatient model that combined Western psychiatry and traditional Chinese medicine (TCM). Interdisciplinary Intervention included manual acupuncture twice a week (16 sessions), tai chi, yoga meditation, and nutritional assessment. Symptomatology was measured with primary outcomes (self-reporting via questionnaires) and secondary outcomes (heart rate variability [HRV] and blood samples to measure inflammation via high-sensitivity C-reactive protein [hs-CRP]). Results: The response rate was 80% (12/15 participants), with a statistically and clinically significant decrease in depression severity according to the 21-question Hamilton depression rating scale (HDRS21) (p

Introduction: The word “psychedelic” derives from the Greek language and can be loosely translated as “mind manifesting” which is to convey that these substances allow the mind to unleash its hidden potential. Psilocybin is considered to be a “classic psychedelic” and is most commonly found in the form of so-called “magic mushrooms”. Due to its unique properties psilocybin has been used during religious ceremonies and rituals for centuries and more recently also explored in a medical context. Nowadays many studies are being carried out to prove the efficacy of its use in the treatment of various psychiatric disorders. Aim of study: Review of the current knowledge on the subject of psilocybin applied in the treatment of psychiatric disorders, such as major depressive disorder, treatment-resistant depression and addiction. Methods and materials: A review of chosen literature was carried out in the PubMed database and Google Scholar using the following phrases: psilocybin, psychedelics, psychedelic-assisted therapy, major depressive disorder, addiction. Results: Recent studies suggest that psilocybin may be an effective form of treatment for cancer-related psychiatric distress, treatment-resistant depression and addiction. There are some reports of psilocybin being useful when treating obsessive-compulsive disorder and cluster headaches. Conclusions: More large-scale, randomized, placebo-controlled studies are required to prove these promising findings. Psychological support is crucial during the treatment with psilocybin.

Depression is a common mental disorder with a high burden of disease worldwide and requires effective treatment. On behalf of the General Advisory Council for Psychiatry, clinical recommendations were formed to help clinicians make decisions to improve the treatment of patients with unipolar depressive disorder; several international guidelines served as the basis for developing these recommendations. In terms of therapeutic approaches, pharmacological treatment is discussed with additional recommendations on the management of a partial response to treatment and treatment resistance. Psychotherapy, psychoeducation, and other psychosocial approaches represent non-pharmacological interventions for the treatment of depressive disorder. Biological methods for treating depression include non-invasive brain stimulation methods. The second part of the recommendations addresses special populations: children and adolescents, the elderly, and the treatment of depression in the perinatal period.

Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90, was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 (NRG3) as one of the targets of SNORD90, which we show is regulated through the accumulation of N6-methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.

Summary: Background: Socioeconomic pressures, sex, and physical health status strongly influence the development of major depressive disorder (MDD) and mask other contributing factors in small cohorts. Resilient individuals overcome adversity without the onset of psychological symptoms, but resilience, as for susceptibility, has a complex and multifaceted molecular basis. The scale and depth of the UK Biobank affords an opportunity to identify resilience biomarkers in rigorously matched, at-risk individuals. Here, we evaluated whether blood metabolites could prospectively classify and indicate a biological basis for susceptibility or resilience to MDD. Methods: Using the UK Biobank, we employed random forests, a supervised, interpretable machine learning statistical method to determine the relative importance of sociodemographic, psychosocial, anthropometric, and physiological factors that govern the risk of prospective MDD onset (total n = 15,710). We then used propensity scores to rigorously match individuals with a history of MDD (n = 491) against a resilient subset of individuals without an MDD diagnosis (retrospectively or during follow-up; n = 491) using an array of key social, demographic, and disease-associated drivers of depression risk. 381 blood metabolites and clinical chemistry variables and 4 urine metabolites were integrated to generate a multivariate random forest-based algorithm using 10-fold cross-validation to predict prospective MDD risk and resilience. Outcomes: In unmatched individuals, a first case of MDD, with a median time-to-diagnosis of 72 years, can be predicted using random forest classification probabilities with an area under the receiver operator characteristic curve (ROC AUC) of 0.89. Prospective resilience/susceptibility to MDD was then predicted with a ROC AUC of 0.72 (x˜ = 3.2 years follow-up) and 0.68 (x˜ = 7.2 years follow-up). Increased pyruvate was identified as a key biomarker of resilience to MDD and was validated retrospectively in the TwinsUK cohort. Interpretation: Blood metabolites prospectively associate with substantially reduced MDD risk. Therapeutic targeting of these metabolites may provide a framework for MDD risk stratification and reduction. Funding: New York Academy of Sciences’ Interstellar Programme Award; Novo Fonden; Lincoln Kingsgate award; Clarendon Fund; Newton-Abraham studentship (University of Oxford). The funders had no role in the development of the present study.