Anethole as a promising antidepressant for maternal separation stress in mice by modulating oxidative stress and nitrite imbalance.

The occurrence of major depressive disorder is widespread and can be observed in individuals belonging to all societies. It has been suggested that changes in the NO pathway and heightened oxidative stress may play a role in developing this condition. Anethole is a diterpene aromatic compound found in the Umbelliferae, Apiaceae, and Schisandraceae families. It has potential pharmacological effects like antioxidant, anxiolytic, analgesic, anti-inflammatory, antidiabetic, gastroprotective, anticancer, estrogenic, and antimicrobial activities. This study aimed to investigate the potential antidepressant properties of Anethole in a mouse model experiencing maternal separation stress while also examining its impact on oxidative stress and nitrite levels. The research involved the participation of 40 male NMRI mice, separated into five distinct groups to conduct the study. The control group was administered 1 ml/kg of normal saline, while the MS groups were given normal saline and Anethole at 10, 50, and 100 mg/kg doses. The study comprised various behavioural tests, including the open field test (OFT), forced swimming test (FST), and splash test, to assess the effects of Anethole on the mice. In addition to the behavioural tests, measurements were taken to evaluate the total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels in the hippocampus of the mice. According to the findings, maternal separation stress (MS) led to depressive-like conduct in mice, including a rise in immobility duration during the FST and a reduction in the duration of grooming behaviour in the splash test. Additionally, the results indicated that MS correlated with an increase in the levels of MDA and nitrite and a reduction in the TAC in the hippocampus. However, the administration of Anethole resulted in an increase in grooming activity time during the splash test and a decrease in immobility time during the FST. Anethole also exhibited antioxidant characteristics, as demonstrated by its ability to lower MDA and nitrite levels while increasing the TAC in the hippocampus. The results suggest that Anethole may have an antidepressant-like impact on mice separated from their mothers, likely partly due to its antioxidant properties in the hippocampus.

Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets.

The involvement of central and peripheral inflammation in the pathogenesis and prognosis of major depressive disorder (MDD) has been demonstrated. The increase of pro-inflammatory cytokines (interleukin (IL)-1ß, IL-6, IL-18, and TNF-α) in individuals with depression may elicit neuroinflammatory processes and peripheral inflammation, mechanisms that, in turn, can contribute to gut microbiota dysbiosis. Together, neuroinflammation and gut dysbiosis induce alterations in tryptophan metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related mechanisms, and glutamate-mediated excitotoxicity. This review aims to highlight the inflammatory mechanisms (neuroinflammation, peripheral inflammation, and gut dysbiosis) involved in the pathophysiology of MDD and to explore novel anti-inflammatory therapeutic approaches for this psychiatric disturbance. Several lines of evidence have indicated that in addition to antidepressants, physical exercise, probiotics, and nutraceuticals (agmatine, ascorbic acid, and vitamin D) possess anti-inflammatory effects that may contribute to their antidepressant properties. Further studies are necessary to explore the therapeutic benefits of these alternative therapies for MDD.

Omega-3 fatty acids for inflamed depression - A match/mismatch study.

Despite decades of research on the pathophysiology of depression, the development of new therapeutic interventions has been slow, and no biomarkers of treatment response have been clinically implemented. Several lines of evidence suggest that the clinical and biological heterogeneity among patients with major depressive disorder (MDD) has hampered progress in this field. MDD with low-grade inflammation - "inflamed depression" - is a subtype of depression that may be associated with a superior antidepressant treatment response to anti-inflammatory compounds. Omega-3 fatty acid eicosapentaenoic acid (EPA) has anti-inflammatory properties, and preliminary data suggest that it may be particularly efficacious in inflamed depression. In this study we tested the hypothesis that add-on EPA has greater antidepressant efficacy in MDD patients with high baseline high-sensitivity C-reactive protein (hs-CRP) compared to MDD patients with low hs-CRP. All subjects received 2.2 g EPA, 400 mg docosahexaenoic acid and 800 mg of other fatty acids daily for 8 weeks, added to stable ongoing antidepressant treatment. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAMD-17). Patients and raters were blind to baseline hs-CRP status. In an intention-to-treat analysis including all subjects with at least one post baseline visit (n = 101), ahs-CRPcut-off of ≥1 mg/L, but not ≥3 mg/L, was associated with a greater improvement in HAMD-17 total score. In addition to a general antidepressant effect among patients with hs-CRP ≥ 1 mg/L, adjuvant EPA treatment improved symptoms putatively related to inflamed depression such as fatigue and sleep difficulties. This adds to the mounting evidence that delineation of MDD subgroups based on inflammation may be clinically relevant to predict treatment response to anti-inflammatory interventions.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Psilocybin.

BACKGROUND: The primary psychoactive drug in magic mushrooms, psilocybin, induces profound alterations in consciousness through the 5-HT2A receptor. This review consolidates current research findings to elucidate the pharmacology, safety profile, and clinical applications of psilocybin. AREAS OF UNCERTAINTY: Despite initial concerns that psilocybin could cause psychosis, contemporary research has demonstrated that psilocybin is generally safe. The most common adverse effects are nausea and headache, yet both tend to be transient. Serious adverse events can generally be avoided in controlled settings such as clinical trials. However, in the largest clinical trial to date, there were a total of 7 reported cases of suicidal ideation, up to 12 weeks after receiving a single 25 mg dose of psilocybin. That being said, all 7 cases did not respond to the treatment. Although selective serotonin reuptake inhibitors may blunt the hallucinogenic qualities of psilocybin, preliminary research suggests that they may enhance its antidepressant effects. THERAPEUTIC ADVANCES: In clinical trials, psilocybin has shown promise for treating major depressive disorder and treatment-resistant depression. Initial studies indicated that 42%-57% of patients underwent remission after psilocybin-assisted therapy, which suggests that psilocybin is more effective than existing antidepressant medications. Clinical data have also demonstrated that psilocybin can manage substance use disorders and end-of-life anxiety with clinical outcomes that are sustained for months and sometimes years after 1 or 2 doses. LIMITATIONS: However, larger Phase II trials with more than 100 depressed participants have shown a much smaller remission rate of 25%-29%, though these studies still observed that psilocybin causes a significant reduction in depressive symptoms. CONCLUSIONS: Aside from ketamine, psilocybin is the most clinically well-researched psychedelic drug, with trials that have enrolled hundreds of participants and multiple therapeutic applications. Phase III trials will determine whether psilocybin lives up to the promise that it showed in previous clinical trials.

Mind shift I: Fructus Aurantii - Rhizoma Chuanxiong synergistically anchors stress-induced depression-like behaviours and gastrointestinal dysmotility cluster by regulating psycho-immune-neuroendocrine network.

BACKGROUND: Researchers have not studied the integrity, orderly correlation, and dynamic openness of complex organisms and explored the laws of systems from a global perspective. In the context of reductionism, antidepressant development formerly focused on advanced technology and molecular details, clear targets and mechanisms, but the clinical results were often unsatisfactory. PURPOSE: MDD represents an aggregate of different and highly diverse disease subtypes. The co-occurrence of stress-induced nonrandom multimorbidity is widespread, whereas only a fraction of the potential clusters are well known, such as the MDD-FGID cluster. Mapping these clusters, and determining which are nonrandom, is vital for discovering new mechanisms, developing treatments, and reconfiguring services to better meet patient needs. STUDY DESIGN: Acute stress 15-minute forced swimming (AFS) or CUMS protocols can induce the nonrandom MDD-FGID cluster. Multiple biological processes of rats with depression-like behaviours and gastrointestinal dysmobility will be captured under conditions of stress, and the Fructus Aurantii-Rhizoma Chuanxiong (ZQCX) decoction will be utilized to dock the MDD-FGID cluster. METHODS/RESULTS: Here, Rhizoma Chuanxiong, one of the seven components of Chaihu-shugan-San, elicited the best antidepressant effect on CUMS rats, followed by Fructus Aurantii. ZQCX reversed AFS-induced depression-like behaviours and gastrointestinal dysmobility by regulating the glutamatergic system, AMPAR/BDNF/mTOR/synapsin I pathway, ghrelin signalling and gastrointestinal nitric oxide synthase. Based on the bioethnopharmacological analysis strategy, the determined meranzin hydrate (MH) and senkyunolide I (SI) by UPLC-PDA, simultaneously absorbed by the jejunum and hippocampus of rats, have been considered major absorbed bioactive compounds acting on behalf of ZQCX. Cotreatment with MH and SI at an equivalent dose in ZQCX synergistically replicated over 50.33 % efficacy of the parent formula in terms of antidepressant and prokinetic actions by modulating neuroinflammation and ghrelin signalling. CONCLUSION: Brain-centric mind shifts require the integration of multiple central and peripheral systems and the elucidation of the underlying neurobiological mechanisms that ultimately contribute to novel therapeutic options. Ghrelin signalling and the immune system may partially underlie multimorbidity vulnerability, and ZQCX anchors stress-induced MDD-FGID clusters by docking them. Combining the results of micro details with the laws of the macro world may be more effective in finding treatments for MDD.

The magnitude and sustainability of treatment benefit of zuranolone on function and well-being as assessed by the SF-36 in adult patients with MDD and PPD: An integrated analysis of 4 randomized clinical trials.

BACKGROUND: Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact of zuranolone-a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid under investigation for adults with MDD and approved as an oral, once-daily, 14-day treatment course for adults with PPD in the US-on health-related quality of life, including functioning and well-being, as assessed using the 36-item Short Form Health Survey V2 (SF-36). METHODS: Integrated data from 3 MDD (201B, MOUNTAIN, WATERFALL) and 1 PPD trial (ROBIN) for individual SF-36 domains were compared for zuranolone (30- and 50-mg) vs placebo at Day (D)15 and D42. Comparisons between zuranolone responders (≥50 % reduction from baseline in 17-item Hamilton Depression Rating Scale total score) and nonresponders were assessed. RESULTS: Overall, 1003 patients were included (zuranolone, n = 504; placebo, n = 499). Significant differences in change from baseline (CFB) to D15 for patients in zuranolone vs placebo groups were observed in 6/8 domains; changes were sustained or improved at D42, with significant CFB differences for all 8 domains. Zuranolone responders had significantly higher CFB scores vs nonresponders for all domains at D15 and D42 (p < 0.001). LIMITATIONS: Two zuranolone doses were integrated across populations of 2 disease states with potential differences in functioning, comorbidities, and patient demographics. All p-values presented are nominal. CONCLUSIONS: Integrated data across 4 zuranolone clinical trials showed improvements in functioning and well-being across all SF-36 domains. Benefits persisted after completion of treatment course at D42.

Major depressive disorder: hypothesis, mechanism, prevention and treatment.

Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.

Modulating the default mode network: Antidepressant efficacy of transcutaneous electrical cranial-auricular acupoints stimulation targeting the insula.

BACKGROUND: Transcutaneous electrical cranial-auricular acupoint stimulation (TECAS) is a novel non-invasive therapy for major depressive disorder (MDD) that stimulates acupoints innervated by the trigeminal and auricular vagus nerves. However, there are few neuroimaging studies involving the TECAS for the treatment of MDD. Therefore, this study aimed to investigate the treatment response and neurological effects of TECAS using resting-state functional magnetic resonance imaging (rs-fMRI). METHOD: A total of 34 patients with mild-to-moderate MDD and 34 demographically matched healthy controls (HCs) were recruited. After an eight-week treatment the primary outcome was clinical response, defined as a baseline-to-endpoint ≥ 50 % reduction in the 17-item Hamilton Depression Rating Scale (HAMD-17). The low-frequency fluctuations (ALFF) method were used to investigate the brain abnormalities of MDD patients and HCs, and altered brain networks were analyzed between pre- and post-treatment using seed-based functional connectivity (FC) analysis. RESULTS: We found no significant differences in terms of gender, age, and years of education between the two groups. After treatment, the response rate was 58.82 %. Compared to HCs, MDD patients showed lower ALFF values in the left insula(t = -4.298,P < 0.005), the insula-based FC revealed in the right middle frontal gyrus (MFG)/ right superior frontal gyrus, orbital part (ORBsupmed) (t = -5.29,P < 0.005) and the right anterior cingulate gyrus (ACC)were decreased (t = -6.08,P < 0.005). Furthermore, Compared to pre-treatment, abnormal FC values in the ACC /orbital superior frontal gyrus (SFG) (t = 3.42,P < 0.005) and left superior frontal gyrus (SFG)/ supplement motor area (SMA) were enhanced (t = 3.34,P < 0.005). CONCLUSION: TECAS exhibits antidepressant efficacy, particularly influencing the insula-based functional connections within the Default Mode Network (DMN) related to emotion processing in individuals with MDD.

Effectiveness of Medical Cannabis for the Treatment of Depression: A Naturalistic Outpatient Study.

BACKGROUND: There is a lack of studies on the course and effectiveness of medical cannabis in the treatment of major depressive disorder (MDD). METHODS: Retrospective longitudinal (18 weeks) study of n=59 outpatients with MDD, treated with medical cannabis via a telemedical platform. Previous treatment with antidepressant medication was required for inclusion into the study. Standardized data collection was carried out at entry and during monthly consultations. Severity of depression was measured on a 0-10 point rating scale. Side-effects were assessed by a checklist. RESULTS: Patients were 20-54 years old; 72.9% were male; one third reported times of regular cannabis consumption within the previous five years. Drop-out rate was 22% after 18 weeks. Mean severity of depression decreased from 6.9 points (SD 1.5) at entry to 3.8 points (2.7) at week 18 (baseline observation carried forward; 95% CI for the mean difference: 2.4 to 3.8; p<0.001). A treatment response (>50% reduction of the initial score) was seen in 50.8% at week 18. One third of patients complained about side effects, none was considered as severe. Concomitant antidepressant medication (31% of patients) was not associated with outcome. CONCLUSIONS: Medical cannabis was well tolerated and dropout rate was comparable to those in clinical trials of antidepressant medication. Patients reported a clinically significant reduction of depression severity. Further research on the effectiveness of medical cannabis for MDD seems warranted. Risks of this medication, such as sustaining or inducing a cannabis use disorder, or side effects such as poor concentration, must be taken into consideration.

S-Adenosylmethionine (SAMe) as an adjuvant therapy for patients with depression: An updated systematic review and meta-analysis.

BACKGROUND: Major depressive disorder (MDD) is an intractable disease requiring long-term treatment. S-adenosyl-L-methionine (SAMe), a natural substance, has antidepressant effects, but the exact effect remains unclear. This study examines the evidence concerning the efficacy of SAMe as a monotherapy or in combination with antidepressants. METHODS: The PubMed, EMBASE, and Cochrane electronic databases were searched for meta-analyses of randomized controlled clinical trials (RCTs) until June 30, 2023. We performed a systematic review and meta-analysis of the enrolled trials that met the inclusion criteria, with the aim to compare the effects of SAMe to those of a placebo or active agents, or SAMe combined with other antidepressants in the treatment of MDD. RESULTS: Fourteen trials, with a total of 1522 subjects, were included in this review. The daily dose of SAMe varied from 200 to 3200 mg and the study duration ranged between 2 and 12 weeks. The results of SAMe versus placebo as a monotherapy, SAMe versus imipramine or escitalopram as a monotherapy, and SAMe versus placebo as an adjunctive therapy, showed no significant difference in depression with SAMe compared to the comparison treatment. CONCLUSIONS: SAMe may provide relief of depression symptoms similar to imipramine or escitalopram. However, the results of the comparisons should be interpreted with caution due to the small number of studies and the large range of SAMe doses that were used in the included trials. Therefore, we recommend that patients discuss treatment options with their doctor before taking SAMe.

Omega-3 polyunsaturated fatty acids supplementation improves memory in first-diagnosed, drug-naïve patients with depression: Secondary analysis of data from a randomized controlled trial.

INTRODUCTION: Cognitive impairments are found in most patients with major depressive disorder (MDD). It is believed that low Omega-3 polyunsaturated fatty acids (n-3 PUFAs) level raise the risk of anxiety, depressive symptoms and cognition dysfunction. Since our previous research has found n-3 PUFAs supplementation improves anxiety in MDD, this study was to further explore the effectiveness on cognitive impairment among depressed patients. METHODS: A total of 72 venlafaxine treated outpatients with first-diagnosed, drug-naïve depression were enrolled. Daily n-3 PUFAs supplementation (2.4 g/d of fish oil, including 1440 mg eicosapentaenoic acid and 960 mg of docosahexaenoic acid) or placebo was used for 12 weeks. Cognitive function, measure by repeatable battery for the assessment of neuropsychological status ([RBANS]) scores, was compared over time. RESULTS: Immediate memory, delayed memory and RBANS total scores were significant higher in both groups at week 4 and week 12 compared with baseline. Both groups exhibited improvement on attention scores at week 12. No significant differences were observed comparing n-3 PUFAs with placebo groups in the improvement of total RBANS scores and other subscales except in the change of immediate memory at both week 4 and week 12 (p < 0.05). LIMITATIONS: Sample size was relatively low. Moreover, multiple ethnic populations and the income of patients should be considered. Lastly, we used raw scores instead of the standardized scores of RBANS. CONCLUSION: N-3 PUFAs supplementation yielded a small but statistically significant improvement on immediate memory in first-diagnosed, drug-naïve depressed patients. While, antidepressant treatment resulted in significant improvement of cognitive function.

Cool the Inflamed Brain: A Novel Anti-inflammatory Strategy for the Treatment of Major Depressive Disorder.

BACKGROUND: Abundant evidence suggests that inflammatory cytokines contribute to the symptoms of major depressive disorder (MDD) by altering neurotransmission, neuroplasticity, and neuroendocrine processes. Given the unsatisfactory response and remission of monoaminergic antidepressants, anti-inflammatory therapy is proposed as a feasible way to augment the antidepressant effect. Recently, there have been emerging studies investigating the efficiency and efficacy of anti-inflammatory agents in the treatment of MDD and depressive symptoms comorbid with somatic diseases. METHODS: In this narrative review, prospective clinical trials focusing on anti-inflammatory treatment for depression have been comprehensively searched and screened. Based on the included studies, we summarize the rationale for the anti-inflammatory therapy of depression and discuss the utilities and confusions regarding the anti-inflammatory strategy for MDD. RESULTS: This review included over 45 eligible trials. For ease of discussion, we have grouped them into six categories based on their mechanism of action, and added some other anti-inflammatory modalities, including Chinese herbal medicine and non-drug therapy. Pooled results suggest that anti-inflammatory therapy is effective in improving depressive symptoms, whether used as monotherapy or add-on therapy. However, there remain confusions in the application of anti-inflammatory therapy for MDD. CONCLUSION: Based on current clinical evidence, anti-inflammatory therapy is a promisingly effective treatment for depression. This study proposes a novel strategy for clinical diagnosis, disease classification, personalized treatment, and prognostic prediction of depression. Inflammatory biomarkers are recommended to be assessed at the first admission of MDD patients, and anti-inflammatory therapy are recommended to be included in the clinical practice guidelines for diagnosis and treatment. Those patients with high levels of baseline inflammation (e.g., CRP > 3 mg/L) may benefit from adjunctive anti-inflammatory therapy.

The use of sertraline to treat an adolescent of dystonia comorbid with major depressive disorder with psychotic features.

Dystonia is characterized by sustained or intermittent involuntary muscle contractions. Psychiatric symptoms are essential non-motor features of dystonia, and higher risks of depressive and anxiety disorders have been reported. The precedence of psychiatric to motor symptoms in some patients and the dopaminergic and serotonergic system involvement in both the motor and psychiatric aspects suggest these psychiatric disorders may be intrinsic to the neurobiology of dystonia. Nevertheless, psychiatric comorbidities are often construed as secondary reactions to motor disabilities and the negative bio-psycho-social impacts of dystonia, leading to underdiagnosis and undertreatment. Research on antidepressant use in dystonia is scarce, especially in children and adolescents. This report presents a 17-year-old female with dystonia comorbid with depression with psychotic features, whose motor symptoms improved but psychiatric symptoms persisted with dopaminergic pharmacotherapy. Sertraline was finally added 5 years after the onset and successfully managed her psychotic depression without worsening motor symptoms. Early detection, prompt diagnosis, and timely holistic treatment with dopaminergic agents, antidepressants, and psychosocial interventions are critical for the mental health of dystonia patients.

Evaluating the impact of adjunct bright light therapy on subjective sleep quality in major depressive disorder.

BACKGROUND: Sleep disturbances are a fundamental feature of depression, with their persistence after remission serving as a key risk factor for recurrence of depressive episodes, suicide, and hypnotics abuse. Though Adjunct Bright Light Therapy (BLT) has shown efficacy in treating depression by improving sleep duration and timing, its impact on subjective sleep quality remains underexplored. OBJECTIVE: This study investigates the effect of adjunct BLT on the subjective experience of sleep quality of Major Depressive Disorder (MDD) inpatients. METHODS: A randomized controlled trial was undertaken with 100 MDD consecutively admitted inpatients on consistent antidepressant regimens. Participants were divided into two groups; Group A, received pharmacotherapy augmented with BLT, Group B, received pharmacotherapy alone. The Hamilton Depression Rating Scale assessed depressive symptoms, while the Pittsburgh Sleep Quality Index (PSQI) evaluated subjective sleep quality. RESULTS: While both groups displayed enhanced depressive symptomatology, only Group A manifested significant improvement in perceived sleep quality (PSQI scores: A T0 8.05 ± 5.07 vs. T1 5.64 ± 3.64, p < 0.001; B T0 7.11 ± 3.17 vs. T1 6.50 ± 3.04, p = 0.072). LIMITATIONS: Study limitations include its single-site design, lack of objective sleep measurement, and exclusive SSRI use, suggesting caution in generalizing findings. Further, the absence of placebo control and unmeasured expectancy effects may influence treatment outcomes. CONCLUSIONS: These findings underscore the criticality of subjective sleep quality in clinical evaluations and highlight the potential of adjunct BLT as an augmentation therapeutic strategy to ameliorate sleep perception in MDD patients, emphasizing its potential role in enhancing therapeutic outcomes.

Metformin prescription for U.S. veterans with prediabetes, 2010-2019.

Affecting an estimated 88 million Americans, prediabetes increases the risk for developing type 2 diabetes mellitus (T2DM), and independently, cardiovascular disease, retinopathy, nephropathy, and neuropathy. Nevertheless, little is known about the use of metformin for diabetes prevention among patients in the Veterans Health Administration, the largest integrated healthcare system in the U.S. This is a retrospective observational cohort study of the proportion of Veterans with incident prediabetes who were prescribed metformin at the Veterans Health Administration from October 2010 to September 2019. Among 1,059,605 Veterans with incident prediabetes, 12,009 (1.1%) were prescribed metformin during an average 3.4 years of observation after diagnosis. Metformin prescribing was marginally higher (1.6%) among those with body mass index (BMI) ≥35 kg/m2, age <60 years, HbA1c≥6.0%, or those with a history of gestational diabetes, all subgroups at a higher risk for progression to T2DM. In a multivariable model, metformin was more likely to be prescribed for those with BMI ≥35 kg/m2 incidence rate ratio [IRR] 2.6 [95% confidence intervals (CI): 2.1-3.3], female sex IRR, 2.4 [95% CI: 1.8-3.3], HbA1c≥6% IRR, 1.93 [95% CI: 1.5-2.4], age <60 years IRR, 1.7 [95% CI: 1.3-2.3], hypertriglyceridemia IRR, 1.5 [95% CI: 1.2-1.9], hypertension IRR, 1.5 [95% CI: 1.1-2.1], Major Depressive Disorder IRR, 1.5 [95% CI: 1.1-2.0], or schizophrenia IRR, 2.1 [95% CI: 1.2-3.8]. Over 20% of Veterans with prediabetes attended a comprehensive structured lifestyle modification clinic or program. Among Veterans with prediabetes, metformin was prescribed to 1.1% overall, a proportion that marginally increased to 1.6% in the subset of individuals at highest risk for progression to T2DM.

Microbiota-Induced Epigenetic Alterations in Depressive Disorders Are Targets for Nutritional and Probiotic Therapies.

Major depressive disorder (MDD) is a complex disorder and a leading cause of disability in 280 million people worldwide. Many environmental factors, such as microbes, drugs, and diet, are involved in the pathogenesis of depressive disorders. However, the underlying mechanisms of depression are complex and include the interaction of genetics with epigenetics and the host immune system. Modifications of the gut microbiome and its metabolites influence stress-related responses and social behavior in patients with depressive disorders by modulating the maturation of immune cells and neurogenesis in the brain mediated by epigenetic modifications. Here, we discuss the potential roles of a leaky gut in the development of depressive disorders via changes in gut microbiota-derived metabolites with epigenetic effects. Next, we will deliberate how altering the gut microbiome composition contributes to the development of depressive disorders via epigenetic alterations. In particular, we focus on how microbiota-derived metabolites such as butyrate as an epigenetic modifier, probiotics, maternal diet, polyphenols, drugs (e.g., antipsychotics, antidepressants, and antibiotics), and fecal microbiota transplantation could positively alleviate depressive-like behaviors by modulating the epigenetic landscape. Finally, we will discuss challenges associated with recent therapeutic approaches for depressive disorders via microbiome-related epigenetic shifts, as well as opportunities to tackle such problems.

Developmental fluoxetine exposure affects adolescent and adult bone depending on the dose and period of exposure in mice.

At the end of gestation, fetal skeleton rapidly accumulates calcium, and bone development continues in offspring postnatally. To accommodate, maternal skeletal physiology is modulated in a serotonin-dependent manner. Selective serotonin reuptake inhibitors (SSRIs) are generally considered safe for treatment of major depressive disorder, postpartum depression, and other psychiatric illnesses during the peripartum period, but because serotonin affects bone remodeling, SSRIs are associated with decreased bone mass across all ages and sexes, and the impact of SSRIs during fetal and postnatal development has not been fully investigated. In the present study, our aim was to examine developmental fluoxetine exposure on offspring skeleton and to assess varying degrees of impact depending on dose and window of exposure in short-term and long-term contexts. We established that a low dose of lactational fluoxetine exposure caused a greater degree of insult to offspring bone than either a low dose during fetal and postpartum development or a high dose during lactation only in mice. We further discovered lasting impacts of developmental fluoxetine exposure, especially during lactation only, on adult bone and body composition. Herein, we provide evidence fluoxetine exposure during early development may have detrimental effects on the skeleton of offspring at weaning and into adulthood.

Machine Learning Prediction of Quality of Life Improvement During Antidepressant Treatment of Patients With Major Depressive Disorder: A STAR*D and CAN-BIND-1 Report.

Background: Quality of life (QoL) is an important patient-centric outcome to evaluate in treatment of major depressive disorder (MDD). This work sought to investigate the performance of several machine learning methods to predict a return to normative QoL in patients with MDD after antidepressant treatment.Methods: Several binary classification algorithms were trained on data from the first 2 weeks of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (n = 651, conducted from 2001 to 2006) to predict week 9 normative QoL (score ≥ 67, based on a community normative sample, on the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form [Q-LES-Q-SF]) after treatment with citalopram. Internal validation was performed using a STAR*D holdout dataset, and external validation was performed using the Canadian Biomarker Integration Network in Depression-1 (CAN-BIND-1) dataset (n = 175, study conducted from 2012 to 2017) after treatment with escitalopram. Feature importance was calculated using SHapley Additive exPlanations (SHAP).Results: Random Forest performed most consistently on internal and external validation, with balanced accuracy (area under the receiver operator curve) of 71% (0.81) on the STAR*D dataset and 69% (0.75) on the CAN-BIND-1 dataset. Random Forest Classifiers trained on Q-LES-Q-SF and Quick Inventory of Depressive Symptomatology-Self-Rated variables had similar performance on both internal and external validation. Important predictive variables came from psychological, physical, and socioeconomic domains.Conclusions: Machine learning can predict normative QoL after antidepressant treatment with similar performance to that of prior work predicting depressive symptom response and remission. These results suggest that QoL outcomes in MDD patients can be predicted with simple patient-rated measures and provide a foundation to further improve performance and demonstrate clinical utility.Trial Registration: ClinicalTrials.gov identifiers NCT00021528 and NCT01655706.

THE EFFECT OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION AND PHARMACOTHERAPY ON SERUM PROTEIN S100B IN TREATMENT-RESISTANT DEPRESSION.

BACKGROUND: Transcranial magnetic stimulation (TMS) is considered an effective and fast option for treating patients with major depressive disorder. With the increase in treatment options, the determination of biomarkers that predict which treatment will benefit patients the most has been a matter of curiosity for researchers. SUBJECTS AND METHODS: In this study, we aimed to determine the changes in serum concentrations of S100B, a neurotrophic factor thought to play a role in psychiatric disorders after repetitive TMS (rTMS) and anti-depressant drugs (AD) therapy in patients with major depressive disorder(MDD).In this cohort study, rTMS was applied to the left dorsolateral prefrontal cortex(DLPFC) of drug-resistant MDD patients, while another group of MDD patients was treated with AD for three weeks. Patients were evaluated by psychometric tests and serum S100B concentration at baseline and following intervention. There was also a healthy control group in which patients' S100B values were compared at baseline. RESULTS: There is a population with a total of 48 participants.(16 healthy controls,16 anti-depressant treatment groups, 16 individuals who received rTMS in addition to anti-depressant ) A total of 48 participants completed the study, and the S100B levels of the rTMS group and the anti-depressant drug group were found to be significantly higher than the healthy control group. S100B values, which were higher in the anti-depressant and rTMS groups compared to healthy controls, showed a significant reduction in group time interaction (start and end of treatment). CONCLUSION: rTMS of DLPFC demonstrated an effective complementary treatment for treatment-resistant patients with MDD, especially for patients with relatively high serum S100B concentrations.

Potential use of psilocybin drugs in the treatment of depression.

INTRODUCTION: Depression is a common disabling psychiatric disorder, which - in extreme cases - may lead to suicide if untreated or inadequately treated. Despite the availability of various treatments for depression, including pharmacotherapy, there is still a need to search for new agents with higher effectiveness and faster onset of action, especially for patients with treatment-resistant depression. AREAS COVERED: A substance that has attracted considerable attention for nearly a decade is psilocybin, a natural psychedelic found in psilocybin mushrooms. In this study, we evaluated the efficacy and safety of psilocybin in the treatment of depression, based on pivotal randomized clinical trials. Moreover, we used findings from observational studies regarding recreational use. We also looked at ongoing clinical trials and discussed the registration status and clinical potential of the drug. EXPERT OPINION: Clinical phase I-II trials published to date reported promising results for psilocybin in the treatment of patients with major depressive disorder and treatment-resistant depression, in a relatively short time after administration. However, before psilocybin is approved for use and administered to patients with depression, the results of large ongoing phase III clinical trials are needed to confirm its efficacy and safety and to change the way it is perceived by physicians and patients.