Effect of RANKL on Lower Depressive Symptoms In Hemodialysis Patients.

Depression and osteoporosis are common diseases in dialysis patients. In addition, patients with osteoporosis are more susceptible to depression. Contrary to previous anti-osteoporosis agents, denosumab and romosozumab could be used in dialysis patients and have similar action mechanisms for blocking RANKL. RANKL causes bone resorption after binding RANKL, but binding with OPG leads to suppress of bone resorption. In recent mice study, inhibition of RANKL with denosumab improved depressive-like phenotype. Besides, it was found that OPG was associated with depression. Therefore, this study aimed to investigate the association of depressive symptoms with RANKL and OPG in hemodialysis patients. We conducted a cross-sectional study with a total of 172 hemodialysis patients. The participants were measured for plasma RANKL, OPG, MMP-2, and MMP-9 levels. Logistic regression analysis was performed to evaluate the effect of RANKL and OPG on the presence of depressive symptoms. The depressive symptoms were observed in 90 (52.3%) subjects. RANKL tertile 3 had negative association with BDI score (ß - 4.527, 95% CI - 8.310 to - 0.743) in univariate analysis, and this association persisted even after multivariate adjustments (ß - 5.603, 95% CI - 9.715 to -1.491) in linear regression. In logistic regression between RANKL tertiles and depressive symptoms, RANKL tertile 3 had significantly lower unadjusted OR (0.40, 95% CI 0.19-0.86), and multivariate-adjusted OR (0.31, 95% CI 0.12-0.82) for depressive symptoms. OPG was not significantly associated with depressive symptoms. Higher plasma RANKL concentrations were significantly associated with lower depressive symptoms in HD patients.Trial registration WHO registry, No. KCT0003281, date: January 12, 2017.

Relative associations of behavioral and physiological risks for cardiometabolic disease with cognition in bipolar disorder during mid and later-life: findings from the UK biobank.

BACKGROUND: Cardiometabolic disease risk factors are disproportionately prevalent in bipolar disorder (BD) and are associated with cognitive impairment. It is, however, unknown which health risk factors for cardiometabolic disease are relevant to cognition in BD. This study aimed to identify the cardiometabolic disease risk factors that are the most important correlates of cognitive impairment in BD; and to examine whether the nature of the relationships vary between mid and later life. METHODS: Data from the UK Biobank were available for 966 participants with BD, aged between 40 and 69 years. Individual cardiometabolic disease risk factors were initially regressed onto a global cognition score in separate models for the following risk factor domains; (1) health risk behaviors (physical activity, sedentary behavior, smoking, and sleep) and (2) physiological risk factors, stratified into (2a) anthropometric and clinical risk (handgrip strength, body composition, and blood pressure), and (2b) cardiometabolic disease risk biomarkers (CRP, lipid profile, and HbA1c). A final combined multivariate regression model for global cognition was then fitted, including only the predictor variables that were significantly associated with cognition in the previous models. RESULTS: In the final combined model, lower mentally active and higher passive sedentary behavior, higher levels of physical activity, inadequate sleep duration, higher systolic and lower diastolic blood pressure, and lower handgrip strength were associated with worse global cognition. CONCLUSIONS: Health risk behaviors, as well as blood pressure and muscular strength, are associated with cognitive function in BD, whereas other traditional physiological cardiometabolic disease risk factors are not.

An Evidence-Based Update on Anticholinergic Use for Drug-Induced Movement Disorders.

Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually.

Longitudinal assessment of chemotherapy-induced brain connectivity changes in cerebral white matter and its correlation with cognitive functioning using the GQI.

Objective: Breast cancer was the most prevalent type of cancer and had the highest incidence rate among women worldwide. The wide use of adjuvant chemotherapy might have a detrimental effect on the human brain and result in chemotherapy-related cognitive impairment (CICI) among breast cancer patients. Furthermore, prior to chemotherapy, patients reported cancer-related cognitive impairment (CRCI), which might be due to physiological factors or mood symptoms. The present longitudinal study aimed to investigate microstructural and macroscale white matter alterations by generalized q-sampling imaging (GQI). Methods: The participants were categorized into a pre-chemotherapy group (BB) if they were diagnosed with primary breast cancer and an age-matched noncancer control group (HC). Some participants returned for follow-up assessment. In the present follow up study, 28 matched pairs of BB/BBF (follow up after chemotherapy) individuals and 28 matched pairs of HC/HCF (follow up) individuals were included. We then used GQI and graph theoretical analysis (GTA) to detect microstructural alterations in the whole brain. In addition, we evaluated the relationship between longitudinal changes in GQI indices and neuropsychological tests as well as psychiatric comorbidity. Findings: The results showed that disruption of white matter integrity occurred in the default mode network (DMN) of patients after chemotherapy, such as in the corpus callosum (CC) and middle frontal gyrus (MFG). Furthermore, weaker connections between brain regions and lower segregation ability were observed in the post-chemotherapy group. Significant correlations were observed between neuropsychological tests and white matter tracts of the CC, MFG, posterior limb of the internal capsule (PLIC) and superior longitudinal fasciculus (SLF). Conclusion: The results provided evidence of white matter alterations in breast cancer patients, and they may serve as potential imaging markers of cognitive changes. In the future, the study may be beneficial to create and evaluate strategies designed to maintain or improve cognitive function in breast cancer patients undergoing chemotherapy.

Psychotropic Drug-Related Weight Gain and Its Treatment.

Psychotropic drug-related weight gain (PDWG) is a common occurrence and is highly associated with non-initiation, discontinuation, and dissatisfaction with psychiatric drugs. Moreover, PDWG intersects with the elevated risk for obesity and associated morbidity that has been amply reported in the psychiatric population. Evidence indicates that differential liability for PDWG exists for antipsychotics, antidepressants, and anticonvulsants. During the past two decades, agents within these classes have become available with significantly lower or no liability for PDWG and as such should be prioritized. Although lithium is associated with weight gain, the overall extent of weight gain is significantly lower than previously estimated. The benefit of lifestyle and behavioral modification for obesity and/or PDWG in psychiatric populations is established, with effectiveness similar to that in the general population. Metformin is the most studied pharmacological treatment in the prevention and treatment of PDWG, and promising data are emerging for glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., liraglutide, exenatide, semaglutide). Most pharmacologic antidotes for PDWG are supported with low-confidence data (e.g., topiramate, histamine-2 receptor antagonists). Future vistas for pharmacologic treatment for PDWG include large, adequately controlled studies with GLP-1 receptor agonists and possibly GLP-1/glucose-dependent insulinotropic polypeptide co-agonists (e.g., tirzepatide) as well as specific dietary modifications.

The association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicidality: reports to the Food and Drug Administration Adverse Event Reporting System (FAERS).

INTRODUCTION: Recently, the European Medicines Agency (EMA) received reports of suicidal thoughts and self-injury associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide. RESEARCH DESIGN AND METHODS: Herein, we sought to evaluate suicidality associated with all GLP-1 RAs relative to other glucose-lowering agents currently approved by the United States Food and Drug Administration (FDA). Reports of suicidal ideation, "depression/suicidal", suicidal behavior, suicidal attempts, and completed suicide associated with GLP-1 RA exposure reported to the FDA between 2005 and October 2023 were obtained from the FDA Adverse Event Reporting System (FAERS). We present data using the reporting odds ratio (ROR). The ROR was considered significant when the lower limit of the 95% confidence interval (CI) was greater than 1.0. RESULTS: Disproportionate reporting of suicidal ideation and "depression/suicidal" was observed with semaglutide and liraglutide. Disproportionate reporting of suicidal behavior, suicide attempts, and completed suicide was not observed for any of the FDA-approved GLP-1 RAs. CONCLUSIONS: Using the Bradford Hill criteria, however, and taking into consideration confounders, no causal link between GLP-1 RAs and suicidality exists.

Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials.

BACKGROUND: A significant proportion of adults with major depressive disorder (MDD) do not respond to treatments which are currently used in clinical practice such as first-generation monoamine-based antidepressants. OBJECTIVES: The objective of this systematic review was to assess the efficacy, safety, and mechanisms of action of AXS-05, a combination of the NMDA-receptor antagonist dextromethorphan with bupropion, in adults with MDD. METHODS: We searched PubMed, Embase, Google Scholar, and ClinicalTrials.gov for current studies reporting on efficacy and/or safety of AXS-05 in patients with MDD. The search terms included: "AXS-05" OR "dextromethorphan and bupropion" AND "depression". Studies from database inception to January 2023 were evaluated. Risk of bias was assessed using the Cochrane Risk of Bias tool. RESULTS: The search yielded 54 studies of which 5 were included. All studies had low risk of bias. Depression severity, measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) significantly decreased as early as 1-week post-treatment from baseline when compared to a placebo-controlled group (LS mean difference 2.2; 95% CI 0.6-3.9; p = 0.007) and at 2 weeks compared to an active control group (LS mean difference 4.7; 95% CI 0.6-8.8; p = 0.024). Treatment efficacy could be maintained for up to 12 months with mean MADRS score reduction of 23 points from baseline. Clinical remission and response rates also improved at week 1 and were maintained for 12 months. The treatment was well-tolerated, with some transient adverse events reported. CONCLUSION: Current evidence suggests that the combination of dextromethorphan and bupropion is a well-tolerated, rapid-acting treatment option for adults with MDD. Initial success with AXS-05 supports the mechanistic role of glutamatergeric and sigma 1 signaling in the pathophysiology of MDD.

Psilocybin-assisted therapy for depression: A systematic review and meta-analysis.

The aim of this review was to determine the effect of psilocybin on depressive symptoms in patients diagnosed with life-threatening illnesses or major depressive disorder. Systematic searches were conducted to search for randomized clinical trials and open-label trials that evaluated depression symptoms after psilocybin therapy. Data was pooled using a random-effects model. The primary outcome was the standardized mean difference (SMD) in depression severity, determined by calculating the change in depression ratings from baseline to the primary endpoint in the psilocybin arm versus the control arm. The literature search yielded 1734 studies, and 13 studies (n = 686) were included in either qualitative and/or quantitative analyses. The meta-analysis included 9 studies (pooled n = 596) and yielded a large effect size in favour of psilocybin (SMD = -0.78; p<0.001). Risk ratios for response and remission were large and significant in favour of psilocybin. A review of open-label trials showed robust decreases in depressive symptoms following psilocybin administration. These findings provide preliminary evidence for antidepressant efficacy with psilocybin-assisted psychotherapy, however, further studies are needed to evaluate safety and efficacy and to optimize treatment protocols.

Combined Administration of Escitalopram Oxalate and Nivolumab Exhibits Synergistic Growth-Inhibitory Effects on Liver Cancer Cells through Inducing Apoptosis.

Liver cancer is one of the most lethal malignant cancers worldwide. However, the therapeutic options for advanced liver cancers are limited and reveal scant efficacy. The current study investigated the effects of nivolumab (Niv) and escitalopram oxalate (Esc) in combination on proliferation of liver cancer cells both in vitro and in vivo. Significantly decreased viability of HepG2 cells that were treated with Esc or Niv was observed in a dose-dependent manner at 24 h, 48 h, and 72 h. Administration of Esc (50 µM) + Niv (20 µM), Esc (75 µM) + Niv (5 µM), and Esc (75 µM) + Niv (20 µM) over 24 h exhibited synergistic effects, inhibiting the survival of HepG2 cells. Additionally, treatment with Esc (50 µM) + Niv (1 µM), Esc (50 µM) + Niv (20 µM), and Esc (75 µM) + Niv (20 µM) over 48 h exhibited synergistic effects, inhibiting the survival of HepG2 cells. Finally, treatment with Esc (50 µM) + Niv (1 µM), Esc (50 µM) + Niv (20 µM), and Esc (75 µM) + Niv (20 µM) for 72 h exhibited synergistic effects, inhibiting HepG2 survival. Com-pared with controls, HepG2 cells treated with Esc (50 µM) + Niv (20 µM) exhibited significantly increased sub-G1 portion and annexin-V signals. In a xenograft animal study, Niv (6.66 mg/kg) + Esc (2.5 mg/kg) significantly suppressed the growth of xenograft HepG2 tumors in nude mice. This study reports for the first time the synergistic effects of combined administration of Niv and Esc for inhibiting HepG2 cell proliferation, which may provide an alternative option for liver cancer treatment.

Suicidal ideation and attempts in brain tumor patients and survivors: A systematic review.

Background: Subsequent to a diagnosis of a brain tumor, psychological distress has been associated with negative effects on mental health as well as suicidality. The magnitude of such impact has been understudied in the literature. We conducted a systematic review to examine the impact of a brain tumor on suicidality (both ideation and attempts). Methods: In accordance with the PRISMA guidelines, we searched for relevant peer-reviewed journal articles on PubMed, Scopus, and Web of Science databases from inception to October 20, 2022. Studies investigating suicide ideation and/or attempt among patients with brain tumors were included. Results: Our search yielded 1,998 articles which were screened for eligibility. Seven studies consisting of 204,260 patients were included in the final review. Four studies comprising 203,906 patients (99.8%) reported elevated suicidal ideation and suicide attempt incidence compared with the general population. Prevalence of ideation and attempts ranged from 6.0% to 21.5% and 0.03% to 3.33%, respectively. Anxiety, depression, pain severity, physical impairment, glioblastoma diagnosis, male sex, and older age emerged as the primary risk factors associated with increased risk of suicidal ideation and attempts. Conclusion: Suicidal ideation and attempts are increased in patients and survivors of brain tumors compared to the general population. Early identification of patients exhibiting these behaviors is crucial for providing timely psychiatric support in neuro-oncological settings to mitigate potential harm. Future research is required to understand pharmacological, neurobiological, and psychiatric mechanisms that predispose brain tumor patients to suicidality.

Detecting microstructural alterations of cerebral white matter associated with breast cancer and chemotherapy revealed by generalized q-sampling MRI.

Objective: Previous studies have discussed the impact of chemotherapy on the brain microstructure. There is no evidence of the impact regarding cancer-related psychiatric comorbidity on cancer survivors. We aimed to evaluate the impact of both chemotherapy and mental health problem on brain microstructural alterations and consequent cognitive dysfunction in breast cancer survivors. Methods: In this cross-sectional study conducted in a tertiary center, data from 125 female breast cancer survivors who had not received chemotherapy (BB = 65; 49.86 ± 8.23 years) and had received chemotherapy (BA = 60; 49.82 ± 7.89 years) as well as from 71 age-matched healthy controls (47.18 ± 8.08 years) was collected. Chemotherapeutic agents used were docetaxel and epirubicin. We used neuropsychological testing and questionnaire to evaluate psychiatric comorbidity, cognitive dysfunction as well as generalized sampling imaging (GQI) and graph theoretical analysis (GTA) to detect microstructural alterations in the brain. Findings: Cross-comparison between groups revealed that neurotoxicity caused by chemotherapy and cancer-related psychiatric comorbidity may affect the corpus callosum and middle frontal gyrus. In addition, GQI indices were correlated with the testing scores of cognitive function, quality of life, anxiety, and depression. Furthermore, weaker connections between brain regions and lower segregated ability were found in the post-treatment group. Conclusion: This study suggests that chemotherapy and cancer-related mental health problem both play an important role in the development of white matter alterations and cognitive dysfunction.

A Phase II, Open-Label Clinical Trial of Intranasal Ketamine for Depression in Patients with Cancer Receiving Palliative Care (INKeD-PC Study).

Antidepressants require several weeks for the onset of action, a lag time that may exceed life expectancy in palliative care. Ketamine has demonstrated rapid antidepressant effects, but has been minimally studied in cancer and palliative care populations. Herein, the objective was to determine the feasibility, safety, tolerability and preliminary efficacy of intranasal racemic ketamine for major depressive disorder (MDD) in patients with advanced cancer. We conducted a single-arm, open-label phase II trial at the Princess Margaret Cancer Centre in Toronto, ON, Canada. Participants with advanced cancer with moderate to severe MDD received three flexible doses of intranasal (IN) ketamine (50−150 mg) over a one-week period. The primary efficacy outcome was an antidepressant response and remission rates as determined by the Montgomery−Åsberg Depression Rating Scale (MADRS) from baseline to the Day 8 primary endpoint. Twenty participants were enrolled in the trial, receiving at least one dose of IN ketamine, with fifteen participants receiving all three doses. The Day 8 antidepressant response (MADRS decreased by >50%) and remission (MADRS < 10 on Day 8) rates were high at 70% and 45%, respectively. Mean MADRS scores decreased significantly from baseline (mean MADRS of 31, standard deviation 7.6) to Day 8 (11 +/− 7.4) with an overall decrease of 20 points (p < 0.001). Antidepressant effects were partially sustained in the second week in the absence of additional ketamine doses, with a Day 14 mean MADRS score of 14 +/− 9.9. Common adverse effects included fatigue, dissociation, nausea, dysgeusia and headaches; almost all adverse effects were mild and transient, resolving within 2 h of each ketamine dose with one dropout related to adverse effects (negative dissociative episode). Given these promising findings, larger, controlled trials are merited.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder.

OBJECTIVE: Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder. METHODS: A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria. RESULTS: Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient. CONCLUSIONS: There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.

Synergistic Effects of the Combinational Use of Escitalopram Oxalate and 5-Fluorouracil on the Inhibition of Gastric Cancer SNU-1 Cells.

Owing to its high recurrence rate, gastric cancer (GC) is the leading cause of tumor-related deaths worldwide. Besides surgical treatment, chemotherapy is the most commonly used treatment against GC. However, the adverse events associated with chemotherapy use limit its effectiveness in GC treatment. In this study, we investigated the effects of using combinations of low-dose 5-fluorouracil (5-FU; 0.001 and 0.01 mM) with different concentrations of escitalopram oxalate (0.01, 0.02, 0.06, and 0.2 mM) to evaluate whether the assessed combination would have synergistic effects on SNU-1 cell survival. 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.06 mM) administered over 24 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Moreover, 5-FU (0.001 mM) + escitalopram oxalate (0.02 or 0.06 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.02, 0.06, or 0.2 mM) administered over 48 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Compared with controls, SNU-1 cells treated with 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) exhibited significantly increased levels of annexin V staining, reactive oxygen species, cleaved poly (ADP-ribose) polymerase, and caspase-3 proteins. Furthermore, 5-FU (12 mg/kg) + escitalopram oxalate (12.5 mg/kg) significantly attenuated xenograft SNU-1 cell proliferation in nude mice. Our study is the first to report the synergistic effects of the combinational use of low-dose 5-FU and escitalopram oxalate on inhibiting SNU-1 cell proliferation. These findings may be indicative of an alternative option for GC treatment.

Association between depressive symptoms and bone density in elderly patients with non-dialysis dependent chronic kidney disease.

BACKGROUND: Depression is a disease that is commonly accompanied by elderly chronic kidney disease (CKD) patients, but when the two diseases are accompanied, etiology or combination are not well known. We aimed to evaluate the etiology of CKD and comorbid depression by investigating bone disorders that are observed in persons affected by both CKD and depression. METHODS: We conducted a cross-sectional study with a total of 646 patients with CKD. We compared the sociodemographic factors, kidney function, markers for CKD-Mineral and Bone Disorder (CKD-MBD) and bone mineral density according to the depressive symptoms. We conducted a univariate and multivariate logistic regression analysis to calculate odd ratios (95 % confidence interval) between depressive symptoms and low bone mineral density. RESULTS: Individuals with CKD and depressive symptoms were associated with lower level of education attained, living alone, exercising less, low 24-hour urine phosphorus, and low bone density. Depressive symptoms were significantly associated with low bone density in lowest parts (1.55 [1.06-2.29]) and in total hip (1.72 [1.17-2.53]) even after adjusting for diabetes mellitus, hypertension, kidney function, proteinuria, age, sex, smoking, and body mass index. LIMITATIONS: A cross-sectional design was used in this study and the bone biopsy for diagnosis of CKD-MBD was not done because of invasiveness and practical difficulties. CONCLUSION: Low bone density was associated with depressive symptoms in elderly patients with non-dialysis chronic kidney disease.

Associations between childhood maltreatment and oxidative nucleoside damage in affective disorders.

BACKGROUND: Childhood maltreatment is an established risk factor for incident unipolar disorder and bipolar disorder. It is separately observed that affective disorders (AD) are also associated with higher nucleoside damage by oxidation. Childhood maltreatment may induce higher levels of nucleoside damage by oxidation and thus contribute to the development of AD; however, this relation is only sparsely investigated. METHODS: In total, 860 participants (468 patients with AD, 151 unaffected first-degree relatives, and 241 healthy control persons) completed the Childhood Trauma Questionnaire (CTQ). The association between CTQ scores and markers of systemic DNA and RNA damage by oxidation as measured by urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) levels, respectively, was investigated. RESULTS: In multiple regression models adjusted for sex- and age, 8-oxodG and 8-oxoGuo levels were found to be higher in individuals who had experienced more childhood maltreatment. These associations persisted in models additionally adjusted for body mass index, alcohol, and current smoking status. Emotional abuse, sexual abuse, and emotional neglect were principally responsible for the foregoing associations. CONCLUSIONS: Our findings of an association between childhood maltreatment and oxidative stress markers suggest that childhood maltreatment overall, notably emotional abuse and emotional neglect, is associated with enhanced systemic damage to DNA and RNA in adulthood. Further, individuals with AD reported a higher prevalence of childhood maltreatment, which may induce higher levels of nucleoside damage by oxidation in adulthood, possibly leading to increased risk of developing AD. Longitudinal studies are needed to clarify this relationship further.

Impact of cognitive-affective and somatic symptoms in subthreshold depression transition in adults: Evidence from Depression Cohort in China (DCC).

BACKGROUND: Symptoms of subthreshold depression may differentially affect the illness transition. We examined the impact of cognitive-affective and somatic symptoms on different subthreshold depression transitions as well as risk factors influencing the aforementioned symptoms changes. METHODS: Adults with subthreshold depression in the Depression Cohort in China were enrolled. Data collection was conducted at baseline, 6 and 12 months from 2019 to 2020. Cognitive-affective and somatic symptoms were assessed using the Patient Health Questionnaire-9. A total of 993 participants completed 12-month follow-up and were divided into persistent, intermittent and remission groups according to change in depressive symptoms. The longitudinal change of cognitive-affective and somatic symptoms in the three groups, as well as risk factors was analyzed using the generalized linear mixed-model. RESULTS: There were 24.07 %, 34.04 % and 41.89 % of participants proceeding into persistent, intermittent and remission subthreshold depression groups, respectively. Cognitive-affective symptoms were the core symptoms for predicting the deterioration in persistent subthreshold depression (t = 2.48, P = 0.013), whereas somatic symptoms improved over time (t = -2.82, P = 0.005). Anxiety symptoms were the primary risk factors for worsening cognitive-affective symptoms (P < 0.001), following by insomnia symptoms, age, marital status, resilience and social functions. Somatic symptoms were affected by insomnia symptoms, anxiety symptoms and Body Mass Index successively. LIMITATIONS: Major Depressive Episode was not explored in follow-up. CONCLUSION: Cognitive-affective symptoms in subthreshold depression are at greater risk of illness deterioration. Future studies should endeavor to identify specific risk factors in different symptoms to forestall the transition from subthreshold to Major Depressive Disorder.

Association of Risperidone With Gastric Cancer: Triangulation Method From Cell Study, Animal Study, and Cohort Study.

Purpose: To examine the effects of risperidone, an atypical antipsychotic agent, on gastric cancer. Methods: A triangulation method comprising bench studies, including cell and animal experiments, and a retrospective cohort study, was subsequently performed. Results: The bench study indicated that risperidone exerted more prominent tumor inhibition effects than other atypical antipsychotics on the proliferation of KATO-III cells, a human gastric cancer cell line. Significant and dose-dependent cell viability was observed in Hs27 cells (control cells) in the presence of risperidone compared with in KATO-III cells. Both in vivo and in vitro results indicated that risperidone significantly inhibited the proliferation of KATO-III cells by inducing ROS and apoptosis, and that it suppressed the growth of xenografted KATO-III tumors in nude mice. In addition, the population-based cohort study found that risperidone users had reduced risks of gastric cancer compared with non-users, with lowered adjusted hazard ratios (HRs) for two induction periods (HR = 0.75; 95% confidence interval [CI] 0.68-0.83 for the one-year induction period, and HR = 0.68; 95% CI 0.61-0.75 for the two-year induction period). Conclusion: The findings are consistent with anticancer effects associated with risperidone, but further research and evaluations are warranted.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce.

OBJECTIVES: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations. METHODS: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed. RESULTS: Amongst nutraceuticals with Grade A evidence, positive directionality and varying levels of support (recommended, provisionally recommended, or weakly recommended) was found for adjunctive omega-3 fatty acids (+++), vitamin D (+), adjunctive probiotics (++), adjunctive zinc (++), methylfolate (+), and adjunctive s-adenosyl methionine (SAMe) (+) in the treatment of unipolar depression. Monotherapy omega-3 (+/-), folic acid (-), vitamin C (-), tryptophan (+/-), creatine (+/-), inositol (-), magnesium (-), and n-acetyl cysteine (NAC) (+/-) and SAMe (+/-) were not supported for this use. In bipolar disorder, omega-3 had weak support for bipolar depression (+), while NAC was not currently recommended (+/-). NAC was weakly recommended (+) in the treatment of OCD-related disorders; however, no other nutraceutical had sufficient evidence in any anxiety-related disorder. Vitamin D (+), NAC (++), methylfolate (++) were recommended to varying degrees in the treatment of the negative symptoms in schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for prevention of transition to psychosis in high-risk youth, with potential pre-existing fatty acid deficiency. Micronutrients (+) and vitamin D (+) were weakly supported in the treatment of ADHD, while omega-3 (+/-) and omega-9 fatty acids (-), acetyl L carnitine (-), and zinc (+/-) were not supported. Phytoceuticals with supporting Grade A evidence and positive directionality included St John's wort (+++), saffron (++), curcumin (++), and lavender (+) in the treatment of unipolar depression, while rhodiola use was not supported for use in mood disorders. Ashwagandha (++), galphimia (+), and lavender (++) were modestly supported in the treatment of anxiety disorders, while kava (-) and chamomile (+/-) were not recommended for generalised anxiety disorder. Ginkgo was weakly supported in the adjunctive treatment of negative symptoms of schizophrenia (+), but not supported in the treatment of ADHD (+/-). With respect to safety and tolerability, all interventions were deemed to have varying acceptable levels of safety and tolerability for low-risk over-the-counter use in most circumstances. Quality and standardisation of phytoceuticals was also raised by the taskforce as a key limiting issue for firmer confidence in these agents. Finally, the taskforce noted that such use of nutraceuticals or phytoceuticals be primarily recommended (where supportive evidence exists) adjunctively within a standard medical/health professional care model, especially in cases of more severe mental illness. Some meta-analyses reviewed contained data from heterogenous studies involving poor methodology. Isolated RCTs and other data such as open label or case series were not included, and it is recognised that an absence of data does not imply lack of efficacy. CONCLUSIONS: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.

Repetitive Transcranial Magnetic Stimulation for Fibromyalgia: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: Meta-analysis was performed to evaluate the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in fibromyalgia on the domains of pain, depression, anxiety and quality of life. METHOD: Publications were searched with the keywords "repetitive transcranial magnetic stimulation" and "fibromyalgia" for randomized controlled trials that compare rTMS with sham stimulation for treating pain, depression, anxiety, and quality of life. Trials available until April 2021 were searched through PubMed, Scopus, Web of Science, and Cochrane Controlled Trials Register. The postintervention scores after 4 weeks for pain, depression, anxiety, and quality of life were extracted to compare the effects of rTMS and sham. Subgroup analysis was conducted based on the stimulation site. RESULTS: From 265 screened articles, 11 eligible randomized controlled trials involving 303 patients were included. The results show that rTMS is more effective than sham stimulation in improving pain (standardized mean difference [SMD] = -0.35; 95% confidence interval [CI] = -0.62 to -0.08; p = .01) and quality of life (SMD = -0.51; 95% CI = -0.78 to -0.23; p = .0003). It is not more effective than sham stimulation for depression, and anxiety. After sensitivity analysis, subgroup analysis revealed that primary motor cortex stimulation was more effective than sham for improving pain (SMD = -0.57; 95% CI = -0.91 to -0.23; p = <0.01). Neither dorsolateral prefrontal cortex nor primary motor cortex stimulation was more effective than sham in improving depression and anxiety. CONCLUSIONS: rTMS is more effective than sham in improving pain and quality of life, but it does not demonstrate reduction in depression or anxiety.