The Glutamatergic Effects of Clinical Repetitive Transcranial Magnetic Stimulation in Depressed Populations: A Preliminary Meta-Analysis of Proton Magnetic Resonance Spectroscopy Studies.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) alleviates symptoms of major depressive disorder, but its neurobiological mechanisms remain to be fully understood. Growing evidence from proton magnetic resonance spectroscopy (1HMRS) studies suggests that rTMS alters excitatory and inhibitory neurometabolites. This preliminary meta-analysis aims to quantify current trends in the literature and identify future directions for the field. METHODS: Ten eligible studies that quantified Glutamate (Glu), Glu+Glutamine (Glx), or GABA before and after an rTMS intervention in depressed samples were sourced from PubMed, MEDLINE, PsychInfo, Google Scholar, and primary literature following PRISMA guidelines. Data were pooled using a random-effects model, Cohen's d effect sizes were calculated, and moderators, such as neurometabolite and 1HMRS sequence, were assessed. It was hypothesized that rTMS would increase cortical neurometabolites. RESULTS: Within-subjects data from 224 cases encompassing 31 neurometabolite effects (k) were analyzed. Active rTMS in clinical responders (n = 128; k = 22) nominally increased glutamatergic neurometabolites (d = 0.15 [95% CI: -0.01, 0.30], p = 0.06). No change was found in clinical nonresponders (p = 0.8) or sham rTMS participants (p = 0.4). A significant increase was identified in Glx (p = 0.01), but not Glu (p = 0.6). Importantly, effect size across conditions were associated with the number of rTMS pulses patients received (p = 0.05), suggesting dose dependence. CONCLUSIONS: Clinical rTMS is associated with a nominal, dose-dependent increase in glutamatergic neurometabolites, suggesting rTMS may induce Glu-dependent neuroplasticity and upregulate neurometabolism. More, larger scale studies adhering to established acquisition and reporting standards are needed to further elucidate the neurometabolic mechanisms of rTMS.

Entactogen Effects of Ketamine: A Reverse-Translational Study.

OBJECTIVE: The authors sought to assess the prosocial, entactogen effects of ketamine. METHODS: Pleasure from social situations was assessed in a sample of participants with treatment-resistant depression from randomized, double-blind, placebo-controlled studies, using four items of the Snaith-Hamilton Pleasure Scale (SHAPS) at five time points over 1 week following treatment with ketamine (0.5 mg/kg intravenously) or placebo. The primary endpoint was postinfusion self-reported pleasure on the four SHAPS items pertaining to social situations, including the item on helping others, between the ketamine and placebo groups. In a rodent experiment, the impact of ketamine on helping behavior in rats was assessed using the harm aversion task. The primary endpoint was a reduction in lever response rate relative to baseline, which indicated the willingness of rats to forgo obtaining sucrose to help protect their cage mate from electric shock. RESULTS: Relative to placebo, ketamine increased ratings of feeling pleasure from being with family or close friends, seeing other people's smiling faces, helping others, and receiving praise, for 1 week following treatment. In the rodent experiment, during the harm aversion task, ketamine-treated rats maintained lower response rates relative to baseline to a greater extent than what was observed in vehicle-treated rats for 6 days posttreatment and delivered fewer shocks overall. CONCLUSIONS: In patients with treatment-resistant depression, ketamine treatment was associated with increased pleasure from social situations, such as feeling pleasure from helping others. Ketamine-treated rats were more likely to protect their cage mate from harm, at the cost of obtaining sucrose. These findings suggest that ketamine has entactogen effects.

Association Between Intrauterine System Hormone Dosage and Depression Risk.

OBJECTIVE: The authors compared the associated risk of incident depression between first-time users of low-, medium-, and high-dose levonorgestrel-releasing intrauterine systems (LNG-IUSs). METHODS: This national cohort study was based on Danish register data on first-time users of LNG-IUSs, 15-44 years of age, between 2000 and 2022. Cox regression and a G-formula estimator were used to report 1-year average absolute risks, risk differences, and risk ratios of incident depression, defined as initiation of an antidepressant or receipt of a depression diagnosis, standardized for calendar year, age, education level, parental history of mental disorders, endometriosis, menorrhagia, polycystic ovary syndrome, dysmenorrhea, leiomyoma, and postpartum initiation. RESULTS: In total, 149,200 women started using an LNG-IUS, among whom 22,029 started a low-dose one (mean age, 22.9 years [SD=4.5]), 47,712 a medium-dose one (mean age, 25.2 years [SD=6.2]), and 79,459 a high-dose one (mean age, 30.2 years [SD=5.6]). The associated subsequent 1-year adjusted absolute risks of incident depression were 1.21% (95% CI=1.06-1.36), 1.46% (95% CI=1.33-1.59), and 1.84% (95% CI=1.72-1.96), respectively. For the users of high-dose LNG-IUSs, the risk ratios were 1.52 (95% CI=1.30-1.74) and 1.26 (95% CI=1.10-1.41) compared with users of the low- and medium-dose LNG-IUSs, respectively. For users of medium-dose LNG-IUSs, the risk ratio was 1.21 (95% CI=1.03-1.39) compared with users of low-dose LNG-IUSs. CONCLUSIONS: First-time use of an LNG-IUS was positively associated with incident depression in an LNG-dose-dependent manner across low-, medium-, and high-dose LNG-IUSs. Although the observational design of the study does not permit causal inference, the dose-response relationship contributes to the body of evidence suggesting a relationship between levonorgestrel exposure and risk of depression.

Long-term Exposure to Ambient Air Pollution and its Association with Mental Well-Being, Depression and Anxiety: A Nationally Representative Study.

INTRODUCTION: Exposure to ambient air pollution may play a role in the onset of common mental disorders like depressive and anxiety disorders. The association of long-term exposure to particles smaller than 10 µm (PM10) with these diseases remains unclear. This study aimed to estimate the association of long-term exposure to PM10 with mental well-being and the frequency of probable diagnosis of common mental disorders. METHODS: A nationally representative cross-sectional study was done in mainland Portugal. Long-term exposure was estimated through one-year average concentrations of PM10, calculated with data from the Portuguese Environment Agency, attributed individually considering individuals' postal codes of residence. The mental well-being and the probable diagnosis of common mental disorders were ascertained through the five-item Mental Health Inventory scale. Linear and Robust Poisson regression models were computed to estimate change percentages, prevalence ratios (PR), and their 95% confidence intervals (95% CI). RESULTS: The median (interquartile range) concentration of PM10 was 18.6 (15.3 - 19.3) µg/m3. The mental well-being score was 72 (56 - 84) points, on a scale from 0 to 100. A probable diagnosis of common mental disorders was found in 22.7% (95% CI: 20.0 to 25.6). Long-term exposure to PM10 was associated with a non-statistically significant decrease in the mental well-being score [for each 10 µg/m³ increment in one-year average PM10 concentrations, there was a 2% (95% CI: -8 to 4) decrease], and with a non-statistically significant increase in the common mental health frequency (PR = 1.012, 95% CI: 0.979 to 1.045). CONCLUSION: We did not find statistically significant associations between long-term exposure to PM10 and mental well-being or the frequency of probable diagnosis of common mental disorders. These results may be explained by the reduced variability in the exposure values, given the geographical distribution and functioning of the network of air quality monitoring stations. This study contributes with evidence for low levels of air pollutants, being one of the first to adjust for individual and aggregate-level variables. Moreover, to the best of our knowledge, this was the first nationally representative, population-based study conducted on the Portuguese population using real-life data. Maintaining a robust and nationwide air quality monitoring network is essential for obtaining quality exposure data.

A Randomized Controlled Trial Comparing the Quality of Life and Medication Adherence in Patients on Antidepressant Monotherapy.

Background and objectives The quality of life declines with the growing severity of major depressive disorder (MDD). In depressed people, medication adherence and the quality of life are mutually corrosive. These concerns spurred the investigation of relationships between treatment outcomes and adherence levels. Limited studies are looking at how vortioxetine, escitalopram, and vilazodone affect these parameters. We aimed to detect how the Short Form-36 (SF-36) had changed 16 weeks after the baseline. The connection between treatment results (as expressed by the Hamilton Depression Rating Scale or HDRS) and medication adherence (as reflected by the Morisky Medication Adherence Scale-8 or MMAS-8) was also explored. Methods An open-label, randomized, three-arm trial with 96 MDD patients was conducted. For 16 weeks, the participants were put into three groups per a 1:1:1 ratio and administered tablets of vilazodone (20-40 mg/day), escitalopram (10-20 mg/day), or vortioxetine (5-20 mg/day). There were two test drugs: vilazodone and vortioxetine; the control was escitalopram. Four weeks apart, follow-up appointments were set after the baseline visit. The HDRS, mental and physical components of SF-36, and MMAS-8 scores were evaluated in the per-protocol (PP) population. Reduced HDRS scores were indicative of improved depression symptoms. Higher MMAS-8 and SF-36 scores indicated high drug adherence and enhanced quality of life. Our analysis used the Kruskal-Wallis test, the Bonferroni correction, and the Sankey diagram. In the Clinical Trial Registry-India (CTRI), we recorded this study prospectively (2022/07/043808). Results One hundred nine (81.34%) of the 134 individuals we examined were eligible. The PP population consisted of 96 (88.07%) of them who wrapped up the 16-week study. The mean age of the group was 46.3 ± 6.2 years. For each of the three groups, the SF-36 physical component scores revealed a median difference of 24.5 (23.8-26.0), 24.0 (22.8-25.3), and 27.0 (25.0-29.0) (p = 0.001). Accordingly, the mental components of their SF-36 scores showed a median difference of 32.0 (31.0-33.3), 31.0 (29.8-34.3), and 36.0 (33.0-38.0) (p = 0.001). A median difference of -15.0 (-16.0 to -14.0), -16.0 (-17.0 to -15.0), and -16.0 (-17.0 to -15.8) was observed in the HDRS scores after 16 weeks, with respect to the baseline (p < 0.001). The median MMAS-8 scores at 16 weeks were 6.0 (6.0-7.0), 6.8 (6.0-7.0), and 7.5 (6.5-8.0) (p = 0.031). The Sankey diagram illustrated the connection between better treatment results, increased medication compliance, and decreased symptoms of depression. Conclusion In comparison to vilazodone and escitalopram, vortioxetine demonstrated a statistically significant decrease in HDRS scores and an improvement in the physical and mental component scores of the SF-36. Clinical improvements were evident in the individuals' drug adherence levels. Larger-scale studies are advised to investigate the effects of these medications on the quality of life, medication adherence, and treatment outcomes.

Global burden of major depressive disorders attributable to intimate partner violence against women: Magnitude, temporal trends, and regional inequalities.

AIMS: This study aimed to analyze the temporal trends, spatial heterogeneities, and potential improvements in the burden of major depressive disorders (MDD) attributable to intimate partner violence (IPV) against women across 21 global burden of disease (GBD) regions, and 204 countries and territories from 1990 to 2019. METHODS: We evaluated the burden of MDD attributable to IPV in women as measured in disability-adjusted life years (DALYs) per 100,000 people, across 20 age groups and GBD regions, countries, and territories, using data from the 2019 GBD Study. The average annual percent change (AAPC) of DALY age-standardized rates (ASRs) were used to reflect trends over time. LOESS and quantile regression were used to model the relationship between the five GBD sociodemographic index (SDI) categories and DALY ASRs. Frontier analysis determined the minimum achievable DALY ASR associated with developmental status, as measured by the SDI. RESULTS: Despite the overall global decline (AAPC -0.08 [95 % UI -0.2, 0.03]), certain GBD regions, particularly high-income North America and Central Latin America, have experienced increases in DALY ASRs. The relationship between SDI and MDD burden showed a U-shaped variability, with low-SDI regions consistently exhibiting higher and stable DALY rates. Frontier analysis revealed that several countries, regardless of their SDI, have substantial gaps between observed and potentially achievable DALY rates, indicating areas for targeted intervention to reduce the burden of MDD due to IPV. CONCLUSIONS: Significant spatial and temporal heterogeneity in MDD due to IPV occurred globally from 1990 to 2019, highlighting the substantial potential for improvement in various countries. Protective measures should be customized to suit the unique cultural contexts, developmental statuses, and regional disparities of each country.

Intrusive thoughts and memories in adolescents with major depressive disorder or post-traumatic stress disorder.

OBJECTIVES: Research in adults suggests that intrusive memories and intrusive thoughts (often referred to as intrusive cognitions) are common in members of the general population and are often seen in clinical disorders. However, little is known about the experience of intrusive cognitions in adolescents, particularly in adolescents with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The present study sought to gather fundamental data on these phenomena (i.e., frequency, characteristics and appraisals of intrusive cognitions) in adolescents with MDD and PTSD. METHODS: Adolescents aged 11-18 with MDD (n = 11), PTSD (n = 13) and a non-clinical control group (n = 25) completed structured interviews concerning their intrusive memories and thoughts. RESULTS: Intrusive thoughts were common in all three groups but were particularly frequently experienced in the MDD group. Intrusive memories were expectedly very common in the PTSD group but also experienced by over half of the adolescents with MDD. Both clinical groups reported more negative emotions in response to their intrusive thoughts or memories and appraised these cognitions more negatively than the non-clinical group. CONCLUSION: Intrusive memories and thoughts are common experiences in adolescents with MDD and PTSD. Emotions and appraisals relating to these cognitions may be targets for psychological intervention in this age group. However, small sample sizes limit the conclusions that can be drawn. Replication is needed with larger numbers of clinical participants.

MAJOR DEPRESSIVE DISORDERS IN PAEDIATRIC SURGICAL PATIENTS: AN OVERVIEW OF THE NIGERIAN ADOLESCENTS.

Introduction: Less than three decades ago, depression was seen as a predominantly adult disorder as children were considered too developmentally immature to experience depressive disorders, and adolescent low mood was considered as part of 'normal' teenage mood swings. Major depressive disorder in children and adolescents is a serious psychiatric illness especially in paediatric surgical patients. This may be due to their altered metabolic rate and heighten metabolic response to trauma which has significant implications for the psychological development of the child, yet it remains under-recognized and undertreated. The well-being of the care givers is also not left out as the care givers are inundated with the task of sourcing and providing finance for hospital care., in addition to the stress of providing care for the patient. This may result in loss of man hour, sleeplessness, and physical exhaustion associated with caring for these ill children which can ultimately significantly increase the risk of them having depressive episode. The aim of this commentary is to highlight the fact that paediatric surgical patients are not exempt to having a major depressive disorder and the care givers should also be evaluated during hospital admission of their wards. Methodology: This is a commentary on depressive disorders among Nigerian paediatric surgical patients. Related publications on children and adolescents presenting to hospital were searched using the domain - Depression in Nigerian adolescent, Paediatric surgery patients on PubMed, Google Scholar, and MEDLINE to appraise this review. Conclusion: Mood disorders, especially depression in children and adolescents have been studied increasingly over the last two decades and surgical conditions worsen the outlook, culminating in increased knowledge about the presentation, and treatment. Despite this, it is still often missed or misdiagnosed because it sometimes presents with uncharacteristic symptoms. Prevalence of depressiion among paediatric surgical patient were found to be between 46-82% in this review among Nigerian patients.

Association of four metalloids in the serum and urine of individuals with major depressive disorders: a case-control study.

Background: Major depressive disorder (MDD) pathogenesis may involve metalloids in a significant way. The aim of our study was to identify potential links between MDD and metalloid elements [boron (B), germanium (Ge), arsenic (As), antimony (Sb)]. Methods: A total of 72 MDD cases and 75 healthy controls (HCs) were recruited from Zhumadian Second People's Hospital in Henan Province, China. The levels of four metallic elements (B, Ge, As, and Sb) in the serum and urine were measured using inductively coupled plasma mass spectrometry (ICP-MS). Results: In comparison to the HCs, the B, As, and Sb levels were considerably lower in the MDD group (p < 0.05) in the serum; the MDD group had significantly higher (p < 0.05) and significantly lower (p < 0.001) B and Sb levels in the urine. After adjusting for potential confounders, serum B (OR = 0.120; 95% CI, 0.048, 0.300; p < 0.001) and Sb (OR = 0.133; 95% CI, 0.055, 0.322; p < 0.001) showed a negative correlation with MDD. Urine B had a negative correlation (OR = 0.393; 95% CI, 0.193, 0.801; p = 0.01) with MDD, while urine Sb had a positive correlation (OR = 3.335; 95% CI, 1.654, 6.726; p = 0.001) with MDD. Conclusion: Our current research offers insightful hints for future investigation into the function of metalloids in connection to MDD processes.

Intensification of anxiety, symptoms of depression, and level of social support among women in pathological pregnancy - a cross-sectional preliminary study.

INTRODUCTION AND OBJECTIVE: Women in pathological pregnancy are a group of patients especially exposed to the risk of occurrence of psychological complications. The aim of the study was assessment of the risk of depressive and anxiety disorders, and the relationship between the intensity of symptoms and social support. MATERIAL AND METHODS: The study group were 300 patients hospitalized in the Department of Pathology of Pregnancy. The study was conducted using the State-Trait Anxiety Inventory (STAI), the Hospital Anxiety and Depression Scale (HADS), the Inventory of Socially Supportive Behaviours (ISSB), and an author-constructed socio-demographic questionnaire. RESULTS: The level of State Anxiety (STAI) was higher in respondents from the study group, compared to the control group. The level of anxiety (HADS-A) was higher in the control group than in women from the study group. The level of social informational support was higher in those from the control group, compared to those from the study group. The level of emotional support was lower in respondents from the study group, compared to those from the control group. Instrumental support negatively correlated with the symptoms of depression among women in physiological pregnancy. The lack of evaluative support statistically significantly correlated with anxiety among women hospitalized before labour. CONCLUSIONS: The results obtained suggest the necessity for the substantive preparation of medical and psychological staff employed in departments of pathology of pregnancy to provide proper emotional and informational support for hospitalized women.

Efficacy and acceptability of anti-inflammatory agents in major depressive disorder: a systematic review and meta-analysis.

Background: Anti-inflammatory agents have emerged as a potential new therapy for major depressive disorder (MDD). In this meta-analysis, our aim was to evaluate the antidepressant effect of anti-inflammatory agents and compare their efficacy. Methods: We conducted a comprehensive search across multiple databases, including PubMed, Embase, Web of Science, Cochrane Review, Cochrane Trial, and ClinicalTrials.gov, to identify eligible randomized clinical trials. The primary outcome measures of our meta-analysis were efficacy and acceptability, while the secondary outcome measures focused on remission rate and dropout rate due to adverse events. We used odds ratio (OR) and 95% confidence interval (95% CI) to present our results. Results: A total of 48 studies were included in our analysis. In terms of efficacy, anti-inflammatory agents demonstrated a significant antidepressant effect compared to placebo (OR = 2.04, 95% CI: 1.41-2.97, p = 0.0002). Subgroup analyses revealed that anti-inflammatory agents also exhibited significant antidepressant effects in the adjunctive therapy subgroup (OR = 2.17, 95% CI: 1.39-3.37, p = 0.0006) and in MDD patients without treatment-resistant depression subgroup (OR = 2.33, 95% CI: 1.53-3.54, p < 0.0001). Based on the surface under the cumulative ranking curve (SUCRA) value of network meta-analysis, nonsteroidal anti-inflammatory drugs (NSAIDs) (SUCRA value = 81.6) demonstrated the highest acceptability among the included anti-inflammatory agents. Conclusion: In summary, our meta-analysis demonstrates that anti-inflammatory agents have significant antidepressant effects and are well-accepted. Furthermore, adjunctive therapy with anti-inflammatory agents proved effective in treating MDD. Among the evaluated anti-inflammatory agents, NSAIDs exhibited the highest acceptability, although its efficacy is comparable to placebo. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=422004), identifier CRD42023422004.

Effects of routine repetitive transcranial magnetic stimulation on the sleep duration of patients with treatment-resistant depression: A prospective cohort study.

Aim: The aim of this study was to evaluate the short-term and long-term effects of routine repetitive transcranial magnetic stimulation (rTMS) on the sleep duration, depressive symptoms, and quality of life of patients with treatment-resistant depression (TRD). Methods: In this prospective cohort study, 25 participants with TRD were assessed using the Insomnia Severity Index (ISI) and four sleep duration components of the Pittsburgh Sleep Quality Index (PSQI). Depression severity was measured with Hamilton's Depression Rating Scale (HDRS) and Beck's Depression Inventory (BDI-II), and patient-perceived quality of life with the 36-Item Short-Form Survey (SF-36). All of these measures were evaluated at baseline (T0), and immediately (T1), 6 weeks (T2), and 12 weeks (T3) after the end of intervention. Results: At T1 endpoint, HDRS, BDI, SF-36, ISI, and three PSQI items (time to wake up, time taken to fall asleep, and Real Sleep Time) significantly improved, though these gains were reduced at follow-up endpoints (T2 and T3). Adjusting for confounders (age, sex, occupational status, BMI, and hypnotic medication) revealed that only improvements in HDRS, BDI, and time taken to fall asleep at T1 remained statistically significant. Linear regression analyses showed no significant association between reduced time taken to fall asleep and depression symptoms, suggesting rTMS can independently enhance this parameter, irrespective of depression resolution. Conclusion: Routine rTMS therapy can potentially enhance sleep duration in TRD individuals, alongside improved depressive symptoms and quality of life. However, these benefits tend to decrease over long-term follow-up, emphasizing a more pronounced short-term efficacy of rTMS.

Use of voice features from smartphones for monitoring depressive disorders: Scoping review.

Object: This review evaluates the use of smartphone-based voice data for predicting and monitoring depression. Methods: A scoping review was conducted, examining 14 studies from Medline, Scopus, and Web of Science (2010-2023) on voice data collection methods and the use of voice features for minitoring depression. Results: Voice data, especially prosodic features like fundamental frequency and pitch, show promise for predicting depression, though their sole predictive power requires further validation. Integrating voice with multimodal sensor data has been shown to improve accuracy significantly. Conclusion: Smartphone-based voice monitoring offers a promising, noninvasive, and cost-effective approach to depression management. The integration of machine learning with sensor data could significantly enhance mental health monitoring, necessitating further research and longitudinal studies for validation.

Notable dysthymia: evolving trends of major depressive disorders and dysthymia in China from 1990 to 2019, and projections until 2030.

BACKGROUND: Depressive disorders have been identified as a significant contributor to non-fatal health loss in China. Among the various subtypes of depressive disorders, dysthymia is gaining attention due to its similarity in clinical severity and disability to major depressive disorders (MDD). However, national epidemiological data on the burden of disease and risk factors of MDD and dysthymia in China are scarce. METHODS: This study aimed to evaluate and compare the incidence, prevalence, and disability-adjusted life-years (DALYs) caused by MDD and dysthymia in China between 1990 and 2019. The temporal trends of the depressive disorder burden were evaluated using the average annual percentage change. The comparative risk assessment framework was used to estimate the proportion of DALYs attributed to risk factors, and a Bayesian age-period-cohort model was applied to project the burden of depressive disorders. RESULTS: From 1990 to 2019, the overall age-standardized estimates of dysthymia in China remained stable, while MDD showed a decreasing trend. Since 2006, the raw prevalence of dysthymia exceeded that of MDD for the first time, and increased alternately with MDD in recent years. Moreover, while the prevalence and burden of MDD decreased in younger age groups, it increased in the aged population. In contrast, the prevalence and burden of dysthymia remained stable across different ages. In females, 11.34% of the DALYs attributable to depressive disorders in 2019 in China were caused by intimate partner violence, which has increasingly become prominent among older women. From 2020 to 2030, the age-standardized incidence, prevalence, and DALYs of dysthymia in China are projected to remain stable, while MDD is expected to continue declining. CONCLUSIONS: To reduce the burden of depressive disorders in China, more attention and targeted strategies are needed for dysthymia. It's also urgent to control potential risk factors like intimate partner violence and develop intervention strategies for older women. These efforts are crucial for improving mental health outcomes in China.

Depressive Disorder and Dermatological Autoimmune Diseases.

Depressive disorders are a growing problem worldwide. They are also characterized by high comorbidity, including from the circle of dermatological diseases. Autoimmune diseases seem to be particularly correlated with depressive comorbidity, raising the question of their possible common pathomechanism. The PubMed database was searched, focusing on results published after 2016. A particular reciprocal correlation of depressive disorders with psoriasis, atopic dermatitis, alopecia areata, impetigo, lupus and systemic scleroderma was found. One possible explanation for the co-occurrence of the above diseases is that the inflammatory theory may be applicable to depression, the various elements of which also apply to autoimmune diseases.

Genome-Wide Association Study of Treatment-Resistant Depression: Shared Biology With Metabolic Traits.

OBJECTIVE: Treatment-resistant depression (TRD) occurs in roughly one-third of all individuals with major depressive disorder (MDD). Although research has suggested a significant common variant genetic component of liability to TRD, with heritability estimated at 8% when compared with non-treatment-resistant MDD, no replicated genetic loci have been identified, and the genetic architecture of TRD remains unclear. A key barrier to this work has been the paucity of adequately powered cohorts for investigation, largely because of the challenge in prospectively investigating this phenotype. The objective of this study was to perform a well-powered genetic study of TRD. METHODS: Using receipt of electroconvulsive therapy (ECT) as a surrogate for TRD, the authors applied standard machine learning methods to electronic health record data to derive predicted probabilities of receiving ECT. These probabilities were then applied as a quantitative trait in a genome-wide association study of 154,433 genotyped patients across four large biobanks. RESULTS: Heritability estimates ranged from 2% to 4.2%, and significant genetic overlap was observed with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits, and body mass index. Two genome-wide significant loci were identified, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications. CONCLUSIONS: This work provides support for the utility of estimation of disease probability for genomic investigation and provides insights into the genetic architecture and biology of TRD.

RE104: Synthesis and Activity of a Novel Serotonergic Psychedelic Prodrug of 4-Hydroxy-N,N-diisopropyltryptamine.

Results from randomized clinical trials of psilocybin in depressive disorders highlight the therapeutic potential of serotonergic psychedelic compounds in mental health disorders. The synthetic 5-hydroxytryptamine 2A receptor agonist 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) is structurally similar to psilocin but is reported to have a shorter duration (2-3 h) of psychedelic effects, suggesting the potential for psilocybin-like therapeutic activity with reduced clinical resource burden. Here, we describe the preclinical and translational characterization of RE104, a 4-OH-DiPT prodrug comprising a glutarate moiety designed to cleave rapidly in situ and thus provide reasonable bioavailability of the active drug. Plasma concentration of 4-HO-DiPT over time in PK experiments in rats was correlated with head-twitch intensity. The half-life of 4-OH-DiPT was 40 min after subcutaneous administration of RE104 in rats. In a forced swim test, a single dose of RE104 (1 mg/kg) significantly reduced mean immobility time at 1 week compared with vehicle (P < 0.001), confirming translational antidepressant potential. Taken together, these data with RE104 show that the glutarate ester can act as an efficient prodrug strategy for 4-HO-DiPT, a unique short-duration psychedelic with potential in depressive disorders.