Treatment-resistant depression (TRD) is associated with poor quality of life, functional impairment, and increased healthcare use. Intranasal esketamine (IN-ESK) has demonstrated efficacy and safety in TRD. Patient-reported outcomes (PROMs) and experience measures (PREMs) are essential to assess functional recovery and quality of life.

To evaluate the clinical effectiveness, functional impact, and quality of life of intranasal esketamine in people with TRD, integrating the patient experience.

Retrospective, observational, multicenter study in 10 Spanish hospitals, with the approval of the local ethics committee. Subjects: 149 patients aged ≥18 years with TRD treated with IN-ESK. Assessments: depressive severity (MADRS), functional status (FAST), quality of life (EQ-5D). Outcomes: response (≥50% MADRS reduction), remission (MADRS < 7), functional improvement (FAST), EQ-5D changes. Time points: 4 weeks, 6 months, 12 months. Analysis: means, frequencies, chi-squared tests.

149 patients were included (mean age 50 years, 64% women, 58% living with a partner, 82% living in urban areas, 62% with children, and 42% on sick leave). 60% of patients had recurrent depressive disorder. Mean episode duration 21 months; 46% >1 year. Patients failed a mean of .4 antidepressants (range 2–12). Remission achieved in 41% (14% within four first weeks), response 34%. This represents 75% favourable clinical outcomes. Significant functional improvement was observed (mean FAST reduction 10 points at 4 weeks, >16 points at 6 months, and 17 points at 12 months). EQ-5D scores increased, reflecting improved quality of life (>16 points at 4 weeks, >30 points at 6 months, and 36 points at 12 months), achieving more than a 100% improvement in quality of life at one year compared with baseline before treatment. Remission and functional recovery were higher in episodes <2 years (48% vs 18%, p=0,001). Patients on sick leave improved more if leave ≤6 months (remission 59% vs 33%, p=0,05).

IN-ESK improves depressive symptoms, functioning, and quality of life in TRD. PROMs and PREMs provide complementary insight into effectiveness. Shorter episodes, and brief sick leave were associated with better outcomes. Earlier treatment initiation linked to higher clinical and functional recovery. Further studies are needed to confirm these results.

A.-I. De Santiago-Diaz Grant / Research support from: Johnson&Johnson, Speakers bureau of: Johnson& Johnson, S. Arostegui-Uranga Speakers bureau of: Johnson&Johnson, A. Pérez-Poza: None Declared, F. Rodríguez-Batista: None Declared, V. Roselló-Molina Speakers bureau of: Johnson&Johnson, F. Mora-Mínguez Speakers bureau of: Johnson&Johnson, L. Gutiérrez-Rojas Speakers bureau of: Johnson&Johnson, E. Sáez-Fuentes Speakers bureau of: Johnson&Johnson, L. Montes-Reula: None Declared, M. Madrazo-Maza Speakers bureau of: Johnson&Johnson.

Symptoms of depression are prevalent across major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia, yet treatment strategies are traditionally indication specific. Cariprazine, a dopamine D3/D2 partial agonist approved for all three disorders in the U.S., provides an opportunity to evaluate the efficacy of a single compound on depressive symptoms across diagnostic categories.

This meta-analysis aimed to pool clinical trial data to determine the efficacy of cariprazine versus placebo in alleviating depressive symptoms, regardless of primary diagnosis.

Only randomized controlled trials comparing cariprazine with placebo were included. Data were drawn from post-hoc and pooled analyses across different psychiatric indications and dose ranges. The primary outcome was change from baseline in depressive symptom scores, standardized across trials by converting effect sizes to Cohen’s d.

Meta-analyses were performed in RStudio (version 2024.04.2+764) using the metafor package. A multilevel random-effects model accounted for overlapping placebo groups in trials with multiple dose arms, with comparisons grouped by study (random = ~1 | STUDY). Effect sizes are reported as pooled standardized mean differences (Cohen’s d) with 95% confidence intervals. Between-study heterogeneity was assessed using Q, I², and τ². Forest plots display individual and pooled estimates of cariprazine’s antidepressant effects.

Four trials in bipolar depression (MD-52, MD-53, MD-54, MD-56; doses 1.5–3 mg/day) were included, alongside five adjunctive MDD trials (MD-71, MD-72, MD-75, 301, 302; doses 1–4.5 mg/day) and three schizophrenia studies (MD-04, MD-05, MD-16; pooled dose range 1.5–9 mg/day). Across all indications, the pooled least square mean difference in depressive symptoms for cariprazine versus placebo was –1.45 (95% CI: –2.18 to –0.71), indicating a significant overall benefit. The largest effects were observed in bipolar depression and MDD, with smaller but positive effects in schizophrenia, where depressive symptoms were assessed via the PANSS Depression/Anxiety Marder factor score rather than dedicated depression scales.Image 1:

Cariprazine significantly improved depressive symptoms across bipolar disorder, MDD, and schizophrenia. These findings support its potential as a transdiagnostic treatment for depression across psychiatric disorders.

Z. Dombi Employee of: Gedeon Richter Plc, R. Csehi Employee of: Gedeon Richter Plc, Á. Barabássy Employee of: Gedeon Richter Plc.

Highly processed food (HPF) consumption has been associated with increased risk of depression. However, the directionality of this relationship remains unclear. Understanding whether HPF consumption contributes to the development of depression, or if depression leads to greater intake of HPFs, is crucial for designing effective prevention strategies.

This study aims to examine the bidirectional association between HPF consumption and MDD in a sample of adults residing in Madrid and Barcelona. Specifically, it explores (1) whether higher levels of HPF intake are associated with greater odds of experiencing MDD, and (2) whether the presence of MDD is associated with higher HPF consumption.

We analyzed cross-sectional data from 1,378 adults participating in the Edad con Salud study, conducted in Madrid and Barcelona in 2023. HPF intake was assessed using the short-form Questionnaire for Highly Processed Food Consumption Frequency (sQ‑HPF) and categorized into tertiles (1 = low, 2 = medium, 3 = high). MDD during the past 12 months was assessed with the Composite International Diagnostic Interview (CIDI). Two weighted regression models were estimated: (1) a logistic regression assessing the association between HPF tertiles and 12-month MDD, and (2) an ordered logistic regression testing whether MDD predicts higher HPF consumption. Both models were adjusted for sex, marital status, age, education, and Functional Comorbidity Index (FCI).

Compared to participants in the lowest HPF consumption tertile, those in the medium tertile showed a non-significant trend toward higher odds of 12-month MDD (OR = 2.76; 95% CI: 0.85–8.95; p = 0.092), while those in the highest tertile had significantly increased odds (OR = 8.74; 95% CI: 3.00–25.53; p < 0.001). In the reverse model, participants with 12-month MDD had 4.39 times greater odds of being in a higher HPF consumption tertile (OR = 4.39; 95% CI: 2.22–8.68; p < 0.001).

Our findings reveal a strong bidirectional association between HPF consumption and MDD. Individuals with higher HPF intake are more likely to experience depression, and those with depression are more likely to report greater HPF consumption. These results highlight the need for integrated prevention strategies that address both dietary habits and mental health.

None Declared

Major Depressive Disorder (MDD) is a pervasive condition, affecting over 20% of the global population. ELS, encompassing events like abuse and neglect, is a well-documented risk factor for the development of MDD in later life. A significant dimension of this relationship involves epigenetic modifications, which are increasingly recognized as key mechanisms through which environmental exposures, such as ELS, interact with an individual’s genetic predispositions to shape the depression phenotype.

The present study investigated genome-wide DNA methylation profiles in individuals with MDD, stratified by ELS exposure, and included trauma-matched control groups.

The participants included 90 male and female adult patients aged 18-65 who met DSM-5 diagnostic criteria for MDD or volunteer controls as determined by the MINI International Neuropsychiatric Interview. Subjects comprised of MDD with ELS (n = 30), MDD without ELS (n = 30), and non-psychiatric controls with and without ELS (n = 30). The UAB IRB approved the protocol, and written informed consent was obtained from all participants. Early life trauma was assessed using the CTQ. Genome-wide methylation was done using reduced representation bisulfite sequencing. Differential methylation was evaluated by statistical tests conducted at each CpG location to determine significance, subsequently followed by the identification of differentially methylated regions (DMRs). The omics annotations derived from the ANNOVAR framework were integrated to determine biological implications and the CNS trait association of the DMR genes. To explore the functional relevance of genes associated with the DMRs, GENE2FUNC module in the Functional Mapping and Annotation (FUMA) platform was used.

We identified 128 DMRs in MDD vs. control, 29 in MDD+ELS vs. control+ELS, and 13 in MDD non-ELS vs. control non-ELS comparisons. Notable genes exhibiting DMRs in MDD+ELS included LONRF1, MAPK8IP1, SELENOO, PDXP, and CNNM3, showing strong enrichment in brain-related tissues and regulatory elements. Functional enrichment highlighted MAPK, synaptic vesicle, and JAK-STAT pathways. In contrast, MDD non-ELS DMRs included genes such as BCL7B, BLCAP, and NNAT, which exhibited elevated expression in multiple brain regions and were enriched in Hippo, Wnt, and Ras signaling pathways and chromatin remodeling.

This study provides compelling evidence of distinct DNA methylation signatures associated with ELS-induced MDD and MDD without ELS exposure, highlighting the complex interplay between genetic and environmental factors in the etiology of this complex disorder. These results contribute to our understanding of the molecular mechanisms underlying ELS-induced MDD and may have implications for the development of novel diagnostic and therapeutic strategies.

None Declared

Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. Efficacy and safety of lumateperone adjunctive to antidepressant therapy (ADT) was established in 2 Phase 3, randomized, double-blind, placebo-controlled trials (501, NCT04985942; 502, NCT05061706) in patients with major depressive disorder (MDD) with inadequate ADT response.

This pooled analysis of Studies 501/502 evaluated lumateperone 42mg+ADT in demographic and clinical subgroups of patients with MDD.

Data were pooled from Studies 501/502 which enrolled adults with DSM-5–diagnosed MDD with inadequate response to 1-2 ADT in the current depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥24, Clinical Global Impression-Severity [CGI-S] score ≥4). Patients were randomized to 6-week oral lumateperone 42mg+ADT or placebo+ADT. MADRS Total and CGI-S scores were evaluated in the pooled population and patient subgroups by demographic and clinical characteristics. Safety was assessed.

The pooled population comprised 950 patients (lumateperone+ADT, n = 471; placebo+ADT, n = 479). Lumateperone+ADT significantly improved MADRS Total score (least squares mean difference vs placebo [LSMD]=‒4.7; effect size [ES]=‒0.59; P < .0001) and CGI-S score (LSMD=‒0.6; ES=‒0.59; P < .0001) from baseline to Day 43 vs placebo+ADT.

Lumateperone+ADT significantly improved (P < .05) MADRS Total score at Day 43 in all patient subgroups vs placebo+ADT based on age (≤40 years: LSMD=‒4.5; >40 years: LSMD=‒4.9), sex (male: LSMD=‒4.2; female: LSMD=‒5.0), region (US: LSMD=‒4.7; non-US: LSMD=‒4.6), disease severity (baseline MADRS Total score <32: LSMD=‒4.6; baseline score ≥32: LSMD=‒5.0), type of ADT (SSRI: LSMD=‒4.9; SNRI: LSMD=‒3.8), number of ADT failures (1 failure: LSMD=‒4.5; 2 failures: LSMD=‒6.3), race (White: LSMD=‒5.0; non-White: LSMD=‒3.2), and baseline anxious distress (Yes: LSMD=-5.9; No: LSMD=-4.0). Lumateperone+ADT significantly improved (P<.01) CGI-S score vs placebo+ADT at Day 43 in all subgroups (age, sex, race, region, baseline disease severity, type of ADT, number of ADT failures, baseline anxious distress).

Lumateperone+ADT was generally well tolerated. Common treatment-emergent AEs (≥5%; twice placebo+ADT) were dizziness, dry mouth, somnolence, nausea, and fatigue. No notable changes occurred in body morphology, prolactin levels, cardiometabolic parameters, or extrapyramidal symptom scales with lumateperone+ADT.

In this pooled analysis, lumateperone 42mg+ADT had robust efficacy vs placebo+ADT in demographic and clinical subgroups and was generally well tolerated, indicating lumateperone as an adjunctive treatment option in patients with MDD with inadequate ADT response.

W. Earley Employee of: Intra-Cellular Therapies, a Johnson & Johnson Company, S. Durgam Employee of: Intra-Cellular Therapies, a Johnson & Johnson Company, C. Chen Employee of: Intra-Cellular Therapies, a Johnson & Johnson Company, R. Migliore Employee of: Intra-Cellular Therapies, a Johnson & Johnson Company, J. Riise Employee of: Johnson & Johnson, S. Kornstein Grant / Research support from: National Institutes of Health and the National Science Foundation, Consultant of: Lilly, Sage Therapeutics, Reunion Neuroscience, Relmada, AbbVie, Gerbera, and Arrivo Bioventures, R. McIntyre Grant / Research support from: CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute, Speakers bureau of: Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris Pharma, Sanofi, Eisai, Intra-Cellular Therapies, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences, M. Fava Shareholder of: Compellis; Neuromity; Psy Therapeutics; Revival Therapeutics; Sensorium Therapeutics, Grant / Research support from: AbbVie; Acadia Pharmaceuticals; Aditum Bio Management Company, LLC; Allergan, Alkermes, Inc.; Altimate Health Corporation; Alto Neuroscience, Inc.; Ancora Bio, Inc.; Angelini S.p.A; Aptinyx; Arbor Pharmaceuticals LLC; Avanir Pharmaceuticals Inc.; Axsome; Benckiser Pharmaceuticals, Inc.; BioClinica, Inc.; Biogen; BioHaven; BioShin Limited; Cambridge Science Corporation; Centrexion Therapeutics Corporation; Cerecor; Cybin IRL Limited; Damona Pharmaceuticals; EmbarkNeuro; Eliem Therapeutics LTD; Gate Neurosciences, Inc.; GenOmind, LLC; Gentelon, LLC; Gerbera Therapeutics, Inc.; Happify; Johnson & Johnson; Lundbeck Inc.; Marinus Pharmaceuticals; Medpace, Inc.; Methylation Sciences, Inc.; Millennium Pharmaceutics, Inc.; Minerva Neurosciences; Neuralstem; Neurocrine Biosciences, Inc.; NeuroRX Inc.; Novaremed; Novartis; Otsuka; Pfizer; Premiere Research International; Praxis Precision Medicines; Protagenic Therapeutics, Inc.; Relmada Therapeutics Inc.; Reckitt; Shenox Pharmaceuticals; Stanley Medical Research Institute (SMRI); Taisho; Takeda; University of Michigan; Vistagen; WinSanTor, Inc.; Xenon Pharmaceuticals, Inc.; National Institute of Drug Abuse (NIDA); National Institutes of Health (NIH); National Institute of Mental Health (NIMH); and PCORI, Consultant of: Massachusetts General Hospital, except for Revival Therapeutics and Sensorium Therapeutics

Treatment-resistant depression (TRD) is highly burdensome. Intranasal esketamine is effective, yet hospital-centric delivery adds travel and continuity barriers that may hinder adherence and outcomes. We hypothesize that community outpatient, patient-proximal delivery—often with the patient’s usual psychiatrist—improves effectiveness, engagement and acceptability, consistent with Spanish implementation experience and expert consensus (Molero et al. XLI Congr Nac Enferm Salud Ment 2024; — —; Ramos-Quiroga et al. Eur J Psychiatry 2025; 39(3) 100313; Young et al. Neurosci Appl 2024; 3 105240).

Primary: evaluate the effectiveness of intranasal esketamine for TRD in community outpatient clinics.

Secondary: trajectories of functioning, suicidality, well-being and treatment satisfaction; engagement/continuity and tolerability; exploratory association between proximity/continuity and outcomes.

Multicentre, prospective, pragmatic cohort across urban and rural public community mental-health clinics; consecutive recruitment. Adults with TRD (≥2 adequate antidepressant failures) initiated esketamine per routine care. Assessments: baseline; weeks 2, 4, 8, 16, 24; program discharge; and 3/6-month post-discharge. Outcomes: MADRS (primary; response ≥50%; remission ≤10), SDS, C-SSRS, SHS, SWLS, TSQM-9; engagement (retention, attendance, continuity with the same psychiatrist); safety/tolerability. Planned analyses: mixed-effects models and time-to-event.

Preliminary subset (n = 7, single site); median age 55 years. MADRS means: 44.1 (baseline) → 35.1 (wk-2) → 32.3 (wk-4) → 26.4 (wk-8) → 24.4 (wk-12); last-observation mean 19.0; mean absolute change −25.1 (≈−56.6%). Response 4/7 (57.1%); remission 2/7 (28.6%). SDS mean: 28.1 (baseline) → 16.0 (last); mean change −12.1. C-SSRS median: 4 (baseline) → 0 (last). Mean exposure 4.9 months; at cut-off: 5/7 in treatment, 1/7 suspended for lack of efficacy, 1/7 discharged with 4-month post-discharge stability. No discontinuations for safety recorded; adverse-event monitoring ongoing.

Early real-world signals indicate that near-patient outpatient delivery yields rapid, clinically meaningful improvements in symptoms, functioning and suicidality with good feasibility and retention. Findings support the hypothesis that proximity and relational continuity act as outcome amplifiers in TRD, aligning with Spanish implementation experience and expert recommendations on practical delivery and adequate duration (Molero et al. XLI Congr Nac Enferm Salud Ment 2024; — —; Ramos-Quiroga et al. Eur J Psychiatry 2025; 39(3) 100313; Young et al. Neurosci Appl 2024; 3 105240).

None Declared

Esketamine nasal spray (ESK-NS) in combination with a selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor is indicated for treatment of adults with treatment resistant depression (TRD) lacking response to ≥2 pharmacological treatments in the current moderate to severe depressive episode (Spravato SmPC; EMA). The ECHO study investigated ESK-NS efficacy and safety in real-world clinical settings.

To present the first results of the ECHO study, which included patients (pts) with TRD initiating ESK-NS treatment in 7 participating countries.

ECHO was a prospective, international, non-interventional phase IV study. Eligible pts were adults diagnosed with TRD and prescribed ESK-NS independent of the study. The study comprised a screening/baseline period, an on-treatment period (variable duration) and a 6- month post-treatment follow-up (Fig 1). Data were collected from routine clinical practice for clinical, social and economic outcomes, dosing, frequency and duration of treatment in clinical settings and pt outcomes. According to local regulations/clinical practice, pt-reported outcomes were also obtained.

Data collected at every visit included ESK-NS dosing/frequency, blood pressure before/after ESK-NS administration, concomitant medication/non-pharmacological treatments, time of and reasons for discontinuation (if applicable), and adverse events. At Weeks (Wks) 4, 8 and 12 (± 7 days), and then every 12 wks (± 15 days), data collection included various measures of depressive symptoms, clinical response, and pt-reported outcomes, including the Columbia Suicide Severity Rating Scale (C-SSRS). Montgomery-Åsberg Depression Rating Scale (MADRS) was assessed every 2 wks for 8 wks, then every 12 wks. Clinical management was reflective of local practice and at the sole discretion of the treating physician.

Statistical analyses will be descriptive (continuous variables) or summarised using frequencies and percentages (categorical variables).

571 pts were enrolled in the ECHO study (Germany: 145; Italy: 124; Israel: 101; Belgium: 89; Spain: 59; Sweden: 42; Netherlands: 11). Baseline characteristics were representative of a broad pt population with TRD (Constant et al. ECNP 2025 [PS02-1216]). Analysis is ongoing; preliminary study results regarding effectiveness and safety of ESK-NS in a real-world setting will be reported in the poster, in addition to comorbidities and post- treatment follow-up outcomes.Image 1:

ECHO is the first large prospective real-world evidence study of ESK-NS in TRD, with a broader pt population than previously studied. Data will enhance understanding of real- world ESK-NS use, which may improve guidance and treatment strategies for pts with TRD.

Acknowledgements. We thank the pts who participated. Funding: J&J; medical writing: Costello Medical.

G. Rosso Consultant of: Angelini, Johnson & Johnson, Lundbeck, Neuraxpharm, Otsuka and Rovi., Speakers bureau of: Angelini, Johnson & Johnson, Lundbeck, Neuraxpharm, Otsuka and Rovi., E. Constant Grant / Research support from: AstraZeneca, BMS, Eli Lilly and Company, Janssen-Cilag, Lundbeck, Pfizer, Servier, Teva, Viatris and Wyeth., Consultant of: AstraZeneca, BMS, Eli Lilly and Company, Janssen-Cilag, Lundbeck, Pfizer, Servier, Teva, Viatris and Wyeth., Speakers bureau of: AstraZeneca, BMS, Eli Lilly and Company, Janssen-Cilag, Lundbeck, Pfizer, Servier, Teva, Viatris and Wyeth., S. De Filippis Grant / Research support from: Angelini, Lundbeck, Johnson & Johnson, Otsuka, Viatris, Molteni and Rovi, Consultant of: Angelini, Lundbeck, Johnson & Johnson, Otsuka, Viatris, Molteni and Rovi, Speakers bureau of: Angelini, Lundbeck, Johnson & Johnson, Otsuka, Viatris, Molteni and Rovi, Y. Godinov Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson, L. Häggström Grant / Research support from: Participated in clinical studies on esketamine, Consultant of: Johnson & Johnson and Lundbeck, Speakers bureau of: Johnson & Johnson and Lundbeck, A. Ibañez Grant / Research support from: Alter, Casen Recordati, Janssen-Cilag, Lundbeck, Otsuka Pharmaceutical SA, Rovi and Viatris, Consultant of: Alter, Casen Recordati, Janssen-Cilag, Lundbeck, Otsuka Pharmaceutical SA, Rovi and Viatris, Speakers bureau of: Alter, Casen Recordati, Janssen-Cilag, Lundbeck, Otsuka Pharmaceutical SA, Rovi and Viatris, Y. Kambarov Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson, E. Olivier Shareholder of: Author declared no conflicts of interest., J. M. Olivares Grant / Research support from: AstraZeneca, BMS, Eli Lilly and Company, Glaxo-Smith-Kline, Johnson & Johnson, Lundbeck, Novartis, Otsuka, Pfizer and Sanofi-Aventis, Consultant of: AstraZeneca, BMS, Eli Lilly and Company, Glaxo-Smith-Kline, Johnson & Johnson, Lundbeck, Novartis, Otsuka, Pfizer and Sanofi-Aventis, Speakers bureau of: AstraZeneca, BMS, Eli Lilly and Company, Glaxo-Smith-Kline, Johnson & Johnson, Lundbeck, Novartis, Otsuka, Pfizer and Sanofi-Aventis, C. Reif-Leonhard Consultant of: CAMPUS, Johnson & Johnson, LivaNova and Medice, Speakers bureau of: CAMPUS, Johnson & Johnson, LivaNova and Medice, B. Rive Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson, I. Turkoz Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson, C. von Holt Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson, D. Zeeuws Grant / Research support from: Participated in clinical trials on esketamine, Consultant of: Johnson & Johnson and Lundbeck, Speakers bureau of: Johnson & Johnson and Lundbeck, S. Köhler Grant / Research support from: Participated in clinical studies on esketamine, Consultant of: ARISTO Pharma, Johnson & Johnson, Medice and Otsuka, Speakers bureau of: ARISTO Pharma, Johnson & Johnson, Medice and Otsuka.

Major depressive disorder (MDD) is a leading cause of global disability, often resistant to standard treatments. Increasing evidence implicates the gut–brain axis in its pathophysiology. Probiotics, especially Lactobacillus and Bifidobacterium strains, may exert antidepressant effects by modulating inflammation, neurotransmission, and the hypothalamic–pituitary–adrenal axis through their interaction with the gut microbiota.

This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the efficacy of Lactobacillus- and Bifidobacterium-based probiotic supplementation in reducing depressive symptoms in individuals with MDD.

We searched PubMed, Embase, and the Cochrane Library for RCTs comparing probiotic supplementation to placebo or standard therapy in adults with MDD. Included studies used validated depression scales such as the Hamilton Depression Rating Scale (HAMD), Beck Depression Inventory (BDI), or Depression Anxiety Stress Scales (DASS). The primary outcome was change in depressive symptom severity. A random-effects model (Hartung-Knapp-Sidik-Jonkman method) was used to compute standardized mean differences (SMDs) with 95% confidence intervals (CIs). Exploratory subgroup analyses were conducted based on probiotic formulation, dosage, and strain composition.

Eight RCTs with 539 participants were included. Of these, 279 patients (51.8%) received probiotic supplementation and 260 (48.2%) received placebo or standard therapy alone. Probiotic use was associated with a greater, though non-significant, reduction in depressive symptoms (SMD –0.34; 95% CI: –0.76 to 0.09; I² = 75%; Image 1). Subgroup analysis suggested larger effects with multistrain formulations and capsule-based delivery.Image 1:

Probiotic supplementation with Lactobacillus and Bifidobacterium may modestly reduce depressive symptoms in MDD. Subgroup trends favor multistrain, capsule-based products. Given their safety, low cost, and accessibility, probiotics represent a promising adjunctive strategy. Further trials are warranted.

None Declared

Sexual dysfunction (SD) is a frequent comorbidity and a potential adverse consequence of treatment in depression. Antidepressants - particularly those with serotonergic effects - are known to contribute to sexual side effects, yet SD often remains underrecognized in clinical settings. Despite high self-reported rates in survey-based studies, large-scale data on clinically recorded SD and associated treatment patterns in depressed populations remain limited. Understanding predictors of SD at the population level is crucial for improving detection, guiding therapeutic decisions, and informing patient care.

To identify pharmacological and clinical predictors of SD in men with depression using Swedish nationwide registers.

In a cohort of 73,566 men aged 18–65 with incident depression (ICD-10: F32/F33) in Sweden, we identified 1,483 SD cases (ICD-10: F52.0–52.3 or ATC: G04BE) within one year from the depression diagnosis, matched 1:5 to 6,704 controls by age, time since depression diagnosis, and region of residence. Predictors were prescriptions of antidepressants (serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, bupropion, mirtazapine), atypical antipsychotics (quetiapine, olanzapine, aripiprazole), and clinical variables (e.g., depression severity, psychiatric comorbidities, suicide attempts). Conditional logistic regression models were used to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CI).

The use of SSRIs (aOR 1.37, 95% CI 1.17–1.61), SNRIs (aOR 1.81, 95% CI 1.47–2.23), and multiple antidepressants (aOR 1.71, 95% CI 1.44–2.04) was statistically significantly associated with SD. In contrast, the use of mirtazapine (aOR 1.01, 95% CI 0.79–1.29), bupropion (aOR 1.56, 95% CI 0.91–2.69), and TCAs (aOR 1.34, 95% CI 0.85–2.09) showed no statistically significant association. Among antipsychotics, only quetiapine was statistically associated with SD (aOR 1.57, 95% CI 1.07–2.31). No statistically significant associations were found for depression severity, psychiatric comorbidities, or recent suicide attempts.

This national case-control study found that serotonergic antidepressants were associated with higher odds of recorded SD in men with depression, whereas bupropion and mirtazapine showed no significant associations. No clear associations were observed with baseline clinical characteristics. While causality cannot be inferred, findings suggest pharmacological factors may influence SD risk and underscore the importance of addressing sexual health in depression management.

J. Isung Grant / Research support from: Research support from: Affiliated with/employed at the center for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies., P. Karlsson Employee of: Research support from: Affiliated with/employed at the center for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies., O. Tankaya Employee of: Employee of J&J Innovation. The work on this study was part of the employment., V. Johansson Grant / Research support from: Research support from: Affiliated with/employed at the center for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies., K. Gembert Employee of: Research support from: Affiliated with/employed at the center for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies., J. Reutfors Grant / Research support from: Research support from: Affiliated with/employed at the center for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies.

Treatment-resistant depression (TRD) is highly prevalent and can affect one in three patients with unipolar depressive disorders. Lithium is an established option in the treatment of TRD. However, real-world data on how this recommendation is perceived by prescribers, as well as psychopharmacological and diagnostic correlates, remain scarce.

To investigate the frequency, diagnostic predictors, and prescribing patterns of lithium in patients diagnosed with unipolar depressive disorders in Greece, with a focus on polypharmacy and potential drug interactions.

We analysed a large Greek nationwide prescription database covering all ICD-10 unipolar depression codes for one calendar year. Logistic regression models were used to identify diagnostic predictors of lithium prescription, adjusting for age, sex, and psychiatrist involvement. We examined co-prescription patterns and potentially interacting drugs. Sensitivity analyses were conducted to exclude patients with coexisting psychiatric disorders during the observation period.

A total of 9,218,025 prescriptions were retrieved for 753,142 patients who received at least one unipolar depressive disorder diagnosis. Of these, 1,314 patients (0.174%) were prescribed lithium (people prescribed lithium, PPL). PPL were younger, with males overrepresented, and were more likely to have been treated by a psychiatrist. Disorder severity markers such as psychotic symptoms (adjusted odds ratio (aOR) 6.05 (5.21, 6.81)) and mixed presentations (aOR 7.12 (5.11, 9.08)) were predictive of lithium prescription. The most commonly prescribed primary agent was venlafaxine (38% of PPL), while atypical antipsychotics were the most frequently co-prescribed drug class (51%). The historically first described effective combination of lithium + tricyclic antidepressant was prescribed to 7% of PPL.

One in thirteen PPL received a potentially interacting drug, predominantly in the class of antihypertensives.

In sensitivity analyses, the proportion of PPL among those that consistently received only a unipolar depression was even lower (0.08%).

Lithium prescription in unipolar depressive disorders remains unpopular and is predominantly given in those with severe depression. Newer antidepressants are favoured against the classical combinations of lithium and tricyclic antidepressants. Despite proven efficacy and a sustained positioning in the treatment algorithms for treatment-resistant depression, other alternatives are preferred.

None Declared

Thyroid hormones regulate mood, brain development and neurotransmitter systems. The association between thyroid dysfunction and major mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD) has been extensively studied, but it is unknown whether these associations are causal or not. Thyroid dysfunction, both hypothyroidism and hyperthyroidism, is strongly linked to developing mood disorders. Thyroid hormones show potential as biomarkers in mood disorders by predicting treatment outcomes.

We performed a literature review on the association between thyroid hormones, thyroid dysfunction and developing mood disorders, as well as on the role of thyroid hormones as a biomarker of treatment response in mood disorders.

We searched the electronic databases PubMed, PsycINFO and EMBASE to identify appropriate studies. All relevant articles over the last 20 years were included. Search terms included thyroid hormones, thyroid dysfunction, mood disorders, depression, bipolar disorder, and biomarkers.

Many studies have shown that thyroid dysfunction is associated with depression. Hypothyroidism has been considered a strong risk factor for developing depression. However, newer studies have shown that the association between hypothyroidism and clinical depression is considerably lower than previously assumed. Several studies have proposed that thyroid hormones may have a role in the etiology of bipolar disorder. Increased prevalence of thyroid autoantibodies in bipolar patients indicates that a thyroid autoimmunity present in 20-30% of patients with BD might be a genetic marker of vulnerability for bipolar disorder. It is also important to recognize the thyroid hormone mechanisms beyond the HPT axis and the role of deiodination, the conversion of T4 to biologically active T3, and the genetic variation of thyroid deiodinase enzymes in patients with depression. Injection of T3 increases neurogenesis by upregulating BDNF. With respect to thyroid function and treatment response in mood disorders, in some cross-sectional studies of patients with MDD, higher FT4 concentrations were associated with more severe depression, while a significant decrease in T4 was associated with treatment and clinical improvement. T3 augmentation in MDD with partial response to antidepressants is usually effective with a 50% improvement rate. T4 augmentation is effective in patients with bipolar disorder. Higher doses of T4 are helpful in rapid cycling bipolar disorder. Finally, brain-targeted thyromimetic ABX-002, as a CNS-directed thyroid hormone receptor beta agonist, is currently studied as an adjunctive treatment for MDD and BD.

Although there is no definite answer about the causal relationship between thyroid dysfunction and mood disorders, the role of thyroid hormones in mood regulation and response to antidepressant treatments is significant.

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Behavioral health outcome measures often emphasize symptoms, while overlooking other important outcomes, such as recovery and feeling positive. Little is known about what outcomes patients with major depressive disorder (MDD) prioritize and few studies have characterized “positive” outcome measures, such as personal recovery and flourishing.

In a sample of patients treated for MDD in an outpatient psychiatry clinic, we aim to 1) describe personal recovery outcomes most important to patients and 2) describe the relationship between measures of personal recovery, and measures of flourishing, and psychiatric symptoms and functioning.

The sample included 43 patients aged 18-35 with a diagnosis of MDD receiving outpatient treatment in an urban safety net psychiatry department in Massachusetts. Participants completed an electronic survey rating outcomes most important in their recovery and to complete standardized measures of flourishing, personal recovery, functioning, and symptoms of depression and anxiety.

Mean age of the sample was 27.7 (SD = 5.2), most participants were female (n = 23; 53.3%), identified as non-white (n = 25; 59.4%), and were single (n = 28; 65.1%). A majority of participants had high symptoms of depression (61.9%; PHQ-8 ≥ 10), a minority had high symptoms of anxiety (37.5%; GAD-7 ≥ 10), and a minority were classified as flourishing (16.7%; Flourishing Scale ≥ 48). The top three outcomes participants ranked as “most important” in recovery were coping well with stressful events (39.5%), functioning well (34.9%), and having hopes and dreams for the future (30.2%). Flourishing and recovery questionnaires were all strongly positively correlated with one another (correlation coefficients each ≥ 0.73), and negatively correlated with symptom scales. Notably, among individuals with low depressive symptoms, 60.0% had low levels of flourishing and 31.3% had low levels of personal recovery.Image 1:

Individuals with MDD value a diverse range of outcomes. These findings may suggest the need to personalize treatment toward patient-defined goals, which include more positive outcomes. Incorporating measures of flourishing and personal recovery alongside measurement of symptoms may yield a more comprehensive understanding of overall mental health.

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Postpartum depression has emerged as one of the most socially significant medical concerns, exerting a profound impact on maternal health, family relations, and child development (McNab et al. BMC Pregnancy and Childbirth 2022, 22(1):342; Slomian et al., Women’s Health 2019, 15:55). Exploring associations between the prevalence of depressive symptoms and various clinical and sociodemographic factors may provide valuable insights for the development of targeted screening strategies, thereby ensuring appropriate care and support for women in fulfilling their role as mothers.

Our study aimed to provide the first systematic assessment of postpartum depressive symptom prevalence, associated sociodemographic and clinical characteristics of women in outpatient care in Latvia.

All women aged 18 years and older who consecutively attended the country’s largest Riga Maternity Hospital’s outpatient unit 4-6 weeks postpartum were screened with the Patient Health Questionnaire-9 (PHQ-9). Based on sensitivity and specificity analysis, a cut-off score of 8 was identified as the optimal threshold for the PHQ-9. Sociodemographic data were collected via self-administered questionnaires; clinical data were extracted from medical records. Group differences in PHQ-9 score distributions were analyzed using chi-square tests.

Over one year, 272 women aged 18-49 (mean 30.66 ± 5.59) were assessed. Depressive symptoms (PHQ-9 ≥8) were observed in 18.01%. Birth complications were significantly associated with higher PHQ-9 scores (p=0.031), and self-reported sleep problems showed a strong association (p=0.010). Mode of delivery (p=0.184), infant health problems (p=0.172), difficult infant temperament (p=0.124), and stressful events during pregnancy (p=0.100) showed non-significant trends. No significant differences were observed with respect to age, residence, ethnicity, education, marital and employment status, income, or other clinical factors (all p>0.05).

Postpartum depressive symptoms were present in nearly one-fifth of women, underscoring the relevance of mental health in perinatal care. Birth complications and sleep problems emerged as significant associated factors, while other perinatal and psychosocial variables showed non-significant trends. These findings underscore the importance of systematic screening and early identification of women at risk, as well as the need for further studies to elucidate causal pathways and inform effective prevention and intervention strategies.

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Post-stroke depression, a prevalent and persistent neuropsychiatric complication, adversely affects stroke recovery outcomes. Almost half of stroke survivors experience social isolation. Yet the contribution of social isolation to post- stroke depression development remains unclear.

We investigate the association between social isolation and incident depression in stroke survivors.

We included 7,267 UK Biobank participants with prior stroke (mean±SD age =60.5 ±6.9 years, 55.6% male) without baseline depression. Degree of social isolation was assessed with three questions: 1) “Including yourself, how many people are living together in your household? (Include those who usually live in the house such as students living away from home during term, partners in the armed forces, or professions such as pilots)” (1 point for living alone); 2) “How often do you visit friends or family or have them visit you?” (1 point for answering rarely, never, or monthly); and 3) “Which of the following [leisure/social activities] do you engage in once a week or more often? You may select more than one” (1 point for none of the above). Incident post-stroke depression was ascertained from hospital records and death registries. We used Cox cause-specific hazards models to estimate hazard ratios (HRs) adjusted for demographics, socioeconomic status, comorbidities, health behaviours and physiological covariates. We also performed a relative importance analysis to rank risk factors. We calculated the Percentage of Excess Risk Mediated (PERM) by grouping explanatory covariates into categories, such as medication, behaviors, and comorbidities.

Over a median 10.2-year follow-up, 591 stroke survivors developed depression. Compared with the least isolated participants, the most isolated group showed a significantly higher risk of depression (HR: 1.35, 95% CI: 1.07-1.70). In a risk-factor ranking, social isolation ranks higher than traditional risk factors, including hypertension and obesity, as a predictor of post-stroke depression. Health behaviors mediated the association between social isolation and elevated depression risk most strongly, accounting for 32-44% (PERM) of the effect. This mediating effect was significantly greater than that explained by medication, comorbidities, and other covariates.

In this population-based cohort study of UK Biobank participants with stroke, social isolation was significantly associated with an increased risk of post-stroke depression. These findings suggest that interventions targeting social connectivity may improve clinical outcomes in stroke survivors.

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Treatment-resistant depression (TRD) poses a significant clinical challenge, with limited evidence guiding long-term pharmacological strategies. Esketamine, a glutamatergic modulator, has demonstrated short-term efficacy in TRD, but data on its extended use in real-world settings remains scarce

This study aimed to evaluate the long-term effectiveness and tolerability of intranasal esketamine in adults with TRD over more than 100 treatment sessions.

We conducted a retrospective, single-arm pre-post study of 20 patients with TRD at a private psychiatric clinic in the United Arab Emirates. All participants received ≥100 sessions of intranasal esketamine alongside oral antidepressants. Depression and anxiety symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scales. Tolerability was monitored through blood pressure, sedation, dissociation, urinary symptoms, and psychiatric side effects.

After an average of 129 esketamine sessions (mean duration 2.5 years), PHQ-9 and GAD-7 scores significantly decreased (p<0.001). 85% of patients improved in depressive severity, with 25% achieving remission. 65% improved in anxiety severity, and 20% reached remission. Esketamine was generally well-tolerated; side effects were mild and transient, with no serious adverse events. No clinical or demographic factors significantly predicted response.

Intranasal esketamine demonstrated sustained effectiveness and acceptable tolerability in a real-world TRD cohort with extensive psychiatric comorbidity. These findings support its long-term use in complex clinical populations and underscore the need for further prospective, multi-site studies.

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Major depressive disorder (MDD) is one of the most prevalent psychiatric conditions worldwide and is strongly associated with early adverse experiences. While the impact of childhood abuse has been extensively studied, the specific contribution of neglect, encompassing physical, emotional, and unspecified subtypes, has historically received less attention. Given its potential to disrupt attachment and emotion regulation, quantifying its association with MDD is crucial.

This study aimed to investigate the association between childhood neglect and MDD by estimating pooled Odds Ratios (ORs) for unspecified, physical, and emotional neglect. A secondary objective was to examine moderators of these associations through meta-regression analyses.

Following PRISMA guidelines, PubMed, Scopus, and Web of Science were systematically searched in September 2024. Eligible studies included adults with a diagnosis of MDD and documented exposure to childhood neglect assessed with validated instruments.

Random-effects model based on the inverse variance method was applied to calculate pooled ORs and between-study heterogeneity was quantified using Cochran’s Q and I² statistics. Meta-regression models were performed to explore potential moderators influencing the outcomes across studies.

Twenty-two studies were included. Childhood neglect was significantly associated with MDD across all subtypes: unspecified neglect (OR = 4.14, 95% CI [1.73–9.89]; I² = 67.7%, p = 0.015), emotional neglect (OR = 3.71, 95% CI [2.33–5.88]; I² = 85.1%, p < 0.001), and physical neglect (OR = 3.30, 95% CI [2.22–4.91]; I² = 79.7%, p < 0.001). High heterogeneity was observed, particularly for emotional and physical neglect, reflecting variability across studies.

These results are consistent with previous meta-analyses reporting strong associations between neglect and depression (Mandelli et al. Eur Psychiatry 2015; 30:665–680; Nelson et al. Br J Psychiatry 2017; 210:96–104; Norman et al. PLoS Med 2012; 9:e1001349), although the ORs in the present study were higher. Prior evidence indicates that neglect, especially emotional neglect, is more strongly linked to depressive outcomes than other forms of maltreatment (Humphreys et al. Child Abuse Negl 2020; 102:104361; Infurna et al. J Affect Disord 2016; 190:47–55).

The consistency and strength of these associations support the role of childhood neglect as a key vulnerability factor for MDD and underscore the importance of systematic screening and trauma-informed therapeutic strategies in clinical practice.

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Long-term treatment is crucial for achieving favorable outcomes in mood disorders. However, the prolonged treatment process can be stressful, and the ways in which patients cope with stress may influence whether they adhere to or discontinue treatment.

This study aimed to investigate the associations between stress-coping strategies and treatment discontinuation in patients with mood disorders.

A total of 321 patients diagnosed with mood disorders were included. Dropout rates were estimated at 1, 2, and 3 years. The associations between stress-coping strategies and treatment discontinuation were analyzed using a Cox regression model.

The cumulative discontinuation rates were 31.2%, 40.5%, and 47.0% at 1, 2, and 3 years, respectively. Younger age (p = 0.043), emotional coping (p = 0.020), and compulsive coping behaviors (p = 0.043) were significantly associated with treatment discontinuation.

Despite the clinical importance of sustained treatment in mood disorders, nearly half of patients discontinued care within three years. The findings suggest that specific stress-coping strategies may contribute to treatment discontinuation, and that addressing maladaptive coping behaviors could improve adherence and long-term treatment outcomes.

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The role of dissociation in mediating antidepressant response to intranasal esketamine remains debated. While dissociative experiences are often observed during treatment, their predictive value for clinical outcomes is uncertain.

We aimed to assess whether (i) baseline dissociative traits (DES-II) and (ii) early changes in dissociation (ΔDES T0→T2) predict short-term antidepressant response, and to explore whether dissociation mediates depressive symptom improvement across 6 months of follow-up.

This multicenter naturalistic cohort included 31 patients with treatment-resistant depression (mean age 44.7±11.6) treated at academic community clinics in Pavia and Milan. Clinical assessments included MADRS at baseline (T0), 2 weeks (T1), 1 month (T2), 2 months (T3), 3 months (T4), and 6 months (T5) (Montgomery & Åsberg, Br J Psychiatry 1979). Dissociation was measured with DES-II at T0 and T2 (Carlson & Putnam, Dissociation 1993). Outcomes: % MADRS change and responder status (≥50% reduction). Predictors: DES-II at baseline and ΔDES T0→T2. Covariates: baseline MADRS, age, RMET (Baron-Cohen et al., J Child Psychol Psychiatry 2001), Psychache . Analyses included linear/logistic regressions and exploratory mediation (Preacher & Hayes, Behav Res Methods 2008).

Mean MADRS decreased from 31.9±7.9 to 16.7±9.6 at T2 (−47%, responders 48%). Baseline DES-II (mean 0.185±0.12) showed no independent association with response (OR 0.18; 95%CI 0.00–15.5; p = 0.38). ΔDES T0→T2 did not predict response (OR 0.01; 95%CI 0.00–80.5; p = 0.36) nor % improvement (β = 12.7; p = 0.33). Mediation analysis revealed no significant indirect effect (a*b ≈ 10.7%; 95%CI −21.7–79.9). By DES tertiles, % improvement was comparable (Low 42.6%; Mid 51.0%; High 46.5%). Longitudinal follow-up (T1–T5) confirmed sustained MADRS reduction independent of dissociation. (Figure 1 Madrs reduction across timepoints, Figure 2 %madrs improvement by baseline DES, Figure 3 mediation model)Image 1:

In this real-world cohort, dissociative traits and early changes in dissociation did not predict or mediate antidepressant response to intranasal esketamine. However, in clinical practice patients frequently report intense dissociative experiences, and psychotherapists describe esketamine as facilitating emotional processing of unelaborated traumatic memories (DeCou et al., Behav Ther 2019). This suggests that standard trait-based measures such as DES-II may introduce bias and fail to capture clinically meaningful dissociative phenomena. Future studies should employ session-level state measures (e.g., CADSS, ASC-5), cumulative dosing parameters, and longitudinal mixed-effects models to disentangle trait versus state contributions and clarify the therapeutic relevance of dissociation.

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Forced migration is a traumatic experience that heightens vulnerability to depression, with refugee women being particularly susceptible due to multiple stressors. Psychiatric assessment in this population is often constrained by language and cultural barriers, underscoring the need for accessible diagnostic tools. Voice analysis offers a promising approach, as depression is associated with measurable changes in acoustic features such as pitch, intensity, and timing.

To evaluate whether acoustic analysis of free speech can distinguish depressed refugee women from healthy controls, and to explore the potential of voice-based models as tools for mental health assessment of migrants. This pilot study also aimed to generate early evidence to guide future large-scale and validated research.

Thirty-second free speech samples were recorded from 72 Arabic-speaking refugee women, including 31 with depression and 41 healthy controls, all aged 18–65 years and not using psychiatric medication. Recordings were acquired at 16 kHz and pre-processed with silence removal and data augmentation. The acoustic parameters included energy measures, spectral features (spectral centroid, bandwidth, roll-off, flatness, contrast), prosodic markers (pitch, voiced frame ratio, tempo), Mel-Frequency Cepstral Coefficients with derivatives, and chroma features. High-level embeddings were obtained using YAMNet and combined with acoustic features through feature-level fusion. Classification was conducted using support vector machines with radial basis kernel and XGBoost classifiers. Model performance was assessed with 10-fold cross-validation, reporting accuracy, recall, precision, F1 score, ROC-AUC, and precision–recall metrics.

The ensemble model achieved an accuracy of 0.594 (±0.174), precision of 0.618 (±0.135), recall of 0.755 (±0.204), and F1 score of 0.674 (±0.149). The overall discrimination performance was reflected by an ROC-AUC of 0.599 (±0.195) and an average precision of 0.726 (±0.127), based on 10-fold cross-validation.

This pilot study focuses on Arabic-speaking refugee women, a population that is difficult to reach and relatively underrepresented in mental health research, and uses short free speech samples for the detection of depression. The findings highlight the feasibility and potential of voice-based assessment, which is non-invasive and scalable and can potentially overcome cultural and linguistic barriers inherent to traditional approaches. Nonetheless, our findings are preliminary, and larger, externally validated datasets, potentially incorporating multimodal features, are required prior to any clinical application.

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Major depression is one of the leading causes of disability worldwide and is closely associated with physical comorbidities such as cardiometabolic diseases. Comorbidity with type 2 diabetes mellitus (T2DM) is particularly significant. Analysis of the literature shows that adult patients with depression have a 37-60% higher risk of developing T2DM than patients without depressive disorder and that depression in people with T2DM is associated with a more chronic course and a higher frequency of relapses. Insulin resistance (IR), the pathophysiological mechanism underlying T2DM, has been found to be associated with the severity of depressive symptoms in individuals with major depressive episodes. To date, no study has investigated whether the presence of IR/T2DM is associated with a poorer response to psychopharmacological treatment.

The aim of the study, therefore, was to identify the impact of IR/DM2 on the response to drug therapy for major depression.

Patients diagnosed with current major depressive episode not undergoing drug treatment with antidepressants were recruited, and the presence of IR/DM2 was assessed based on HOMA index values. The prospective study lasted 6 months, and all patients recruited in the cross-sectional study were offered SSRI antidepressant therapy. The change in depressive symptoms was assessed after 4, 8, 12, and 18 weeks of drug therapy using the Montgomery Asberg Depression Rating Scale (MADRS). In order to assess the remission rate (MADRS score < 10), Cox regression was used, including IR, gender, age, and severity of depressive symptoms as covariates.

Fifty patients diagnosed with current major depressive episode were recruited, 28 of whom had IR/DM2. The groups did not differ significantly in terms of age, gender, and severity of depressive symptoms. The median remission time was 12 weeks for the control group and 24 weeks for the IR/DM2 group. The results suggest that the presence of IR/DM2 is associated with a longer remission time in response to first-line drug treatment (p = 0.003).

In accordance with the initial hypothesis, it emerged that the presence of dysmetabolic conditions, represented by IR/DM2, negatively influences the response to antidepressant drug treatment. These results could support the existence of an immuno-metabolic subtype of major depression, related to the presence of IR/DM2.

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