Journal of Affective Disorders Reports

BackgroundNon-suicidal self-injury (NSSI) represents a growing public health concern, particularly in adolescents. Emotion dysregulation is central to prevailing NSSI models, yet it remains unclear whether acceptance-based emotion regulation (ER) and its underlying neural processes are disrupted in naturalistic, dynamic contexts. MethodsPre-registered neuroimaging trial in recently diagnosed and treatment-naive adolescents with NSSI (n=25) and healthy controls (n=25) using an ER paradigm with dynamic video clips and concomitant functional magnetic resonance imaging. Behavioral, neural activity, and connectivity indices during emotion reactivity and acceptance-based regulation were compared between groups. ResultsAdolescents with NSSI experienced elevated negative feelings during neutral clips, reflecting heightened baseline negativity. In comparison to controls, they displayed reduced temporal and ventrolateral prefrontal engagement during emotional reactivity, but increased engagement of regions implicated in both emotion reactivity (right amygdala, insula) and ER (right dlPFC, dmPFC, vlPFC) when utilizing acceptance. Higher activation in the right dlPFC was positively associated with difficulties in accessing ER strategies in everyday life. Adolescents with NSSI showed reduced functional connectivity between the right amygdala and left dlPFC. ConclusionsAdolescents with NSSI exhibited a baseline negativity bias and altered neural engagement during both negative emotional reactivity and acceptance-based regulation, characterized by increased activation and reduced amygdala-dlPFC connectivity. These findings highlight atypical emotion processing in real-life contexts in individuals with NSSI. Targeting acceptance-based regulation and prefrontal-limbic circuitry may represent a promising intervention approach for adolescents with NSSI.

Background: Nursing documentation is an essential component of nursing practice that has a potential to improve patient care outcome. Poor documentation of nursing care activities among nurses has been shown to have negative impacts on the health care quality. The aim of this study was to assess documentation practice and associated factors among nurses working in Felege Hiwot comprehensive specialized hospital from August 1 to August 30, 2025. Method: Institutional based cross sectional study design was employed. The data was checked for completeness, coded and entered in epi -data version 3.1 and analysis was made by STATA version 14. Binary logistic regression analysis was computed to assess associations of factors with documentation practice. Variables with p- value less than 0.25 in Bivariable analysis was entered to final model and P < 0.05 at 95% confidence interval was considered as statistically significant. Odds ratio was used to show strength of association. Result: Out of the 349 respondents, 209 (59.9%) were females. In this study 40.1% of nurses had good documentation practice. Educational level, MSc (AOR, 95%CI; 10.3(3.4-31.8)), attitude (AOR, 95%CI; 2.6(1.5-4.7)), number of patient care (AOR, 95%CI; 5.6(1.9-16.3)) and Knowledge (AOR< 95%CI; 3.7(2.1-6.2)) were statistically associated with documentation practice. Conclusion and recommendation: Poor documentation practice was due to the identified factors. So, it is better to put further effort toward improving documentation practice through providing training on standards of documentation and enhancing the favorable attitude of nurses toward documentation practice. Keywords: Documentation, Nursing care, nursing record of patient care.

Background As lockdown measures was eased, pregnant women faced an elevated risk of COVID-19 infection, potentially impacting their mental health. This study aimed to investigate the prevalence of antenatal depression (AD) post-lockdown and develop predictive models for AD risk using machine learning. Methods A cross-sectional study utilizing the Edinburgh Postnatal Depression Scale was conducted in Beijing and Guizhou, China, from January to August 2023. Data was randomly split into training and test datasets (6:4 ratio), with logistic regression (LR), Support Vector Machine (SVM), K-Nearest Neighbors (KNN), Random Forest (RF), eXtreme Gradient Boosting (XGBoost), and Gradient Boosting Decision Tree (GBDT) models trained and compared. The best model underwent further examination, including SHapley Additive exPlanations (SHAP) for feature importance, calibration curve (CC) for discrimination, and decision curve analysis (DCA) for clinical benefit. Results The effective response rate was 91.07% (459/504), with 25.7% (118/459) testing positive for AD. Multivariate analysis identified "sleep disorders," "family support level," and "COVID-19 symptom severity" as independent predictors. RF model showed the highest area under the curve in both training (0.842) and testing (0.724) datasets, with SHAP emphasizing the greatest impact of "sleep disorders" on AD. The RF model's calibration (P > 0.05) and clinical utility across thresholds (8%-95% and 10%-58%) were confirmed by CC and DCA, respectively. Conclusions AD strongly correlated with "sleep disorders," "family support level," and "COVID-19 symptom severity" post-lockdown, and the EPDS-based RF model effectively predicted AD risk.

BackgroundTranscranial alternating current stimulation (tACS) is a promising non-pharmacological intervention for major depressive disorder (MDD), but its effects on endogenous alpha oscillatory dynamics and their relationship to clinical improvement remain unclear. MethodsIn this double-blind, sham-controlled randomized clinical trial, 20 adults with MDD received five consecutive days of prefrontal 10 Hz tACS or sham. Resting 128-channel EEG was acquired before stimulation on Day 1 (D1), Day 5 (D5), and two-week follow-up. Changes in alpha power spectral density were quantified at the stimulation frequency (10 Hz) and at each participants individual alpha frequency (IAF), using prefrontal regions of interest and whole-head topographical analyses. Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS-17). ResultsBetween-group comparisons revealed no significant differences in prefrontal alpha power changes at either 10 Hz or IAF during the intervention week or at follow-up, although right prefrontal 10 Hz power showed a trend-level reduction with tACS. In contrast, within the tACS group, greater reductions in prefrontal IAF power were associated with greater HDRS-17 improvement from D1 to follow-up, and early IAF power suppression during the intervention week predicted later symptom improvement. Whole-head analyses identified a posterior cluster of reduced 10 Hz power at follow-up in the tACS group relative to sham, whereas clinically relevant correlations were specific to IAF power and distributed across frontal-central and parietal electrodes. Depression scores improved over time in both groups, with greater reductions in HDRS-17 scores observed in the tACS group. ConclusionsFindings suggest that five days of 10 Hz tACS engages depression-relevant alpha mechanisms, with symptom improvement linked specifically to modulation of alpha power at IAF. Results support personalization of tACS in future trials.

IntroductionThere is a growing body of research showing that the menstrual cycle can affect mood, although research in those with an existing depressive disorder is still scarce. Studies estimate that 60% of women with depression experience premenstrual exacerbation (PME) of their depressive symptoms. AimsWith the TIDE study, we aim to 1) examine the feasibility of daily symptom tracking for two consecutive menstrual cycles to track PME, 2) estimate the prevalence of PME in depression in a clinical cohort and 3) examine whether PME is associated with other hormone-related mood symptoms (i.e., hormonal contraceptive side effects, peripartum depression). MethodsWe aim to recruit 60 female participants aged 18 to 45, who are in treatment for a depressive episode and who have a regular natural menstrual cycle. Participants will participate in questionnaires at baseline, inquiring about demographic characteristics and previous experiences with hormonal contraceptives and pregnancy. Participants will complete retrospective menstruation questionnaires on days 1 and 10 of each menstrual cycle, as well as daily diaries for two consecutive menstrual cycles, inquiring about menstruation and mood symptoms. After completion of the diaries, participants will receive a symptom report, as well as a study evaluation questionnaire. Results and conclusionWe expect that providing the menstrual cycle overview of symptom severity will lead to increased symptom course insights in participants with PME, and that participants with PME will find it clinically relevant and significant to gain insight into symptom trajectories across the menstrual cycle. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/26352210v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1d6545eorg.highwire.dtl.DTLVardef@3ceb57org.highwire.dtl.DTLVardef@17ea0faorg.highwire.dtl.DTLVardef@7aa9f6_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundIntermittent theta burst stimulation (iTBS) and H-coil repetitive transcranial magnetic stimulation (rTMS) are FDA-cleared treatments for major depression; yet their comparative effectiveness in treatment-resistant depression (TRD) has not been evaluated in randomized trials. This pilot randomized trial was designed to obtain preliminary comparative estimates and to explore whether baseline cognitive functioning relates to early remission. MethodsTwenty-eight adults with TRD were randomized to six weeks of iTBS delivered to the dorsolateral prefrontal cortex (DLPFC) using a figure-8 coil (n=15) or H-coil rTMS delivered to the dorsomedial prefrontal cortex (DMPFC) using a H7-coil (n=13). The primary outcome was change in 17-item Hamilton Depression Rating Scale (HRSD-17) score from baseline to week 6, analyzed with ANCOVA. Additional outcomes included response, remission, and symptom trajectories through week 18. Exploratory analyses examined the association between baseline cognitive functioning, such as executive functions and memory, and remission. ResultsTwenty-five participants completed all 30 sessions. Adjusted week-6 HRSD-17 scores did not differ between groups (mean difference -0.40, 95% CI -5.23 to 4.43; p=.865). Response rates were 40.0% for iTBS and 50.0% for H-coil (p>.60), and remission rates were identical across groups (20.0%). Remitters showed higher baseline executive functioning than non-remitters in exploratory analyses, although these associations were not confirmed in adjusted models. ConclusionIn this pilot trial, iTBS and H7-coil rTMS showed symptom improvement, with no clear between-group pattern. Exploratory findings suggest a potential signal involving executive functioning that warrants further investigation. These results inform the feasibility and design of larger comparative trials. Trial registrationClinicalTrials.gov (NCT05902312)

Depression remains a major public health concern globally, particularly in low resource settings where access to quality mental health care is limited and treatment outcomes are often suboptimal. In this context, the quality of the clinician patient relationship has been increasingly recognised as a critical determinant of therapeutic success. This study examined the influence of clinician patient therapeutic alliance and relational factors on treatment outcomes among patients with depression in Benue State, Nigeria. A crosssectional correlational design was adopted, involving patients diagnosed with depression and receiving care in selected health facilities. Data were analysed using Structural Equation Modelling to test hypothesised relationships among therapeutic alliance, relational factors, and treatment outcomes. The measurement model demonstrated strong psychometric properties, with all factor loadings exceeding 0.60, composite reliability above 0.90, and adequate convergent and discriminant validity. Results revealed that therapeutic alliance significantly predicted treatment outcomes, while relational factors also had a significant positive effect. Therapeutic alliance further significantly predicted relational factors. The model explained 61 percent of the variance in treatment outcomes. Mediation analysis indicated that relational factors partially mediated the relationship between therapeutic alliance and treatment outcomes, accounting for 29 percent of the total effect. The study concludes that therapeutic alliance, strengthened through trust, empathy, and collaboration, plays a central role in improving depression outcomes. Strengthening relational competencies in clinical practice is therefore essential for enhancing mental health care delivery in Nigeria.

BackgroundHealthcare workers are at increased risk of post-traumatic stress disorder (PTSD) due to prolonged exposure to high-stress clinical environments. Although the Health Belief Model (HBM) has been widely used to explain health behaviors, its application to psychological outcomes such as PTSD remains limited. The role of cognitive-emotional processes, particularly experiential avoidance, in linking health beliefs to trauma symptoms is not well understood. MethodsThis study adopted a quantitative cross-sectional design to collect data from 475 healthcare workers in Ekiti State, Nigeria. Participants completed standardized measures assessing Health Belief Model constructs, experiential avoidance, and PTSD symptoms. Data were analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM), with bootstrapping used to test direct, indirect (mediation), and moderation effects. Cluster analysis was also conducted using SPSS to validate differences in PTSD symptom severity across psychological constructs and demographic variables. ResultsExperiential avoidance significantly predicted PTSD symptoms ({beta} = 0.395, 95% CI [0.231, 0.565]). HBM constructs were negatively associated with experiential avoidance ({beta} = - 0.198, 95% CI [-0.270, -0.108]) and PTSD symptoms ({beta} = -0.119, 95% CI [-0.216, -0.006]). Mediation analysis indicated that experiential avoidance partially mediated the relationship between HBM constructs and PTSD ({beta} = -0.078, 95% CI [-0.132, -0.037]), with a total effect of - 0.197. Age moderated the relationship between HBM and experiential avoidance ({beta} = -0.114, 95% CI [-0.207, -0.025]) as well as the indirect pathway to PTSD. Sex significantly predicted PTSD symptoms ({beta} = 0.358, 95% CI [0.214, 0.501]). Cluster analysis showed that experiential avoidance and perceived barriers significantly differentiated high and low PTSD symptom groups. ConclusionThe findings support a conditional cognitive-emotional model in which Health Belief Model constructs influence PTSD symptoms both directly and indirectly through experiential avoidance. Demographic factors shape the strength of these relationships, while perceived barriers and experiential avoidance emerge as key determinants of trauma-related distress among healthcare workers.

Esketamine is a fast-acting antidepressant drug which induces acute psychoactive effects. The most frequent is a dissociative state which seems unrelated to therapeutic efficacy. Other esketamine-induced effects, including psychedelic-like mystical experiences, have been poorly studied in terms of phenomenology and frequency, and may carry specific therapeutic relevance. In this study, we characterised esketamine-induced mystical experiences in relation with clinical outcomes. We conducted a longitudinal observational study and systematically measured acute subjective effects in patients receiving esketamine for treatment-resistant depression after each administration across the induction phase. A total of 45 patients were included, from two independent centres, totalling 352 esketamine administrations. Principal Component Analysis (PCA) supported the validity of the Mystical Experience Questionnaire (MEQ-30) for assessing esketamine-induced subjective effects, with components recovering dimensions previously validated with classic psychedelics. Mystical experiences (MEQ-30 score above 60) occurred in 58% of patients, with high inter- and intra-individual variability in frequency, intensity, and phenomenology across sessions. Higher mean and peak MEQ scores were associated with greater improvement in Montgomery-Asberg Depression Rating Scale scores from pre- to post-treatment, whereas the intensity of dissociative or other non-mystical effects was not. Positive mood and mystical MEQ dimensions in particular predicted therapeutic outcomes. Baseline spirituality also significantly predicted treatment outcomes and peak MEQ scores in the first week of treatment. These findings add to the growing body of evidence suggesting that psychedelic-like mystical experiences may be associated to therapeutic efficacy, not only in classic psychedelic-assisted therapy, but also in esketamine treatment.

Digital therapeutics for mental health often face low patient engagement, which limits their clinical impact. Interventions that deliver treatment using a video game medium may improve engagement and therapeutic efficacy, but the putative emergence of gaming-related problems remains a concern among clinical stakeholders. We examined whether long-term engagement with Meliora, a video game therapeutic for adult major depressive disorder, was associated with changes in gaming-related problems in a three-arm randomized controlled trial. The intention-to-treat cohort (n = 1,001) had a mean age of 33.4 years (SD 9.3) and 64% were female. The Gaming Addiction Scale (GAS-7) scores decreased from baseline (week 0) to post-intervention (week 12) in the Meliora arm (p = 8.1x10-4) and in the treatment-as-usual arm (p = 6.0x10-6), with no significant change observed in the Sham arm (p = 0.39). Changes in GAS-7 scores were not associated with intervention use hours (Meliora: p = 0.17; Sham: p = 0.28) or with experienced immersion (Meliora: p = 0.93; Sham: p = 0.19). Deterioration analysis found worsening rates from baseline to post-intervention low and comparable across study arms. Analyses in the per-protocol completer cohort ([&ge;]24 h use) corroborated these findings, indicating that even higher use did not lead to increases in gaming-related problems. These results provide evidence that long-term use of a video game therapeutic does not increase gaming-related problems when risks are properly mitigated, suggesting that video games may provide a safe medium for digital therapeutics. Author summaryMany patients use digital therapeutics insufficiently or drop out early, which limits their effectiveness and applicability in healthcare. Video game therapeutics deliver the treatment using an interactive video game as a medium to improve both engagement and therapeutic efficacy. However, extended use of video game therapeutics could inadvertently increase gaming-related problems. We examined whether long-term use of Meliora, a video game therapeutic for adults living with depression, was associated with increased gaming-related problems. We found that using Meliora or a highly similar Sham device did not increase gaming-related problems. Changes in gaming-related problems were not associated with the amount of time participants used the interventions, suggesting that typical use patterns are safe. We also found no relationship between experienced immersion and changes in gaming-related problems, suggesting that subjective immersion is distinct from problematic gaming. This study provides the first clinical evidence that extended engagement with a video game therapeutic does not increase gaming-related problems. These findings suggest that video games can be a safe medium for digital therapeutics in healthcare.

Background: Childhood adversity (CA) is recognized as a distal risk-factor for suicide attempts (SA) in individuals with psychiatric disorders. However, not all individuals with experiences of CA will engage in SA. Contributing to this relationship may be proximal factors such as impulsivity, inward anger and self-aggression. However, these factors are often conceptually blended and measured in different samples. We sought to clarify association among CA and personality factors in persons with SA. Methods: Participants from two studies comprised individuals with a diagnosed psychiatric disorder and history of SA (n= 139) and individuals with depressive disorder (clinical controls, CC; n= 24). We investigated self-reported levels of CA, impulsivity, inward anger, and self-aggression between the SA and CC (pcorr< .012). We tested the relationship among the factors using regression (pcorr<.017) and mediation model (indirect effects, p<.05) within the SA group. Sensitivity models were run controlling for age, gender, symptom severity, trait anger, and externally oriented aggression. Results: SA group had higher impulsivity (pcorr=.067) in a model controlled for age and gender. Other factors did not differ among groups. Within the SA group the analyses revealed positive association among CA and personality factors (pcorr<.06) in basic and model with age and gender, however the association was not specific for internally (self) oriented factors (coefficient comparison, p<.07). Parallel mediation model indicated that CA had indirect effect on self-aggression through impulsivity (p=.001) and to a lesser extent through inward anger (p=.066). Generally, models controlling for cognitive depression symptoms showed less prominent effects (pcorr>.1). Limitations: The study was cross-sectional and did not include behavioral tasks (state) measures of proximal factors. Conclusions: CA and personality factors showed similar severity levels among the SA and CC groups suggesting they may relate to broader psychopathologies, rather than specifically to SA. The association of CA with anger and aggression was unspecific to internally oriented factors indicating the need for more precise measuring instruments developed specifically for individuals with SA. Overall, the study highlights personality factors as being associated with risk in broader vulnerable populations.

Objective: Major depressive episodes frequently show limited response to first-line treatments, motivating the search for objective biomarkers. EEG/ECG-based support tools aggregating electrophysiological predictors may guide treatment selection. We examined whether antidepressant treatments concordant with an EEG/ECG-biomarker report were associated with higher response rates. Methods: We retrospectively analyzed adults with ICD-10 depressive disorder or bipolar depression treated with electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), (es)ketamine, or selective serotonin reuptake inhibitors (SSRIs) between 2022 and 2024. Resting-state EEG with simultaneous ECG generated individualized biomarker reports with modality-specific response likelihoods. Treatment chosen by clinical teams was classified as concordant or non-concordant; response was derived from routinely collected clinical scales. Results: Among 153 patients (ECT n=53, rTMS n=48, (es)ketamine n=36, SSRIs n=16), response rates were higher for concordant vs non-concordant treatments: ECT 70% vs 50%, rTMS 30% vs 13%, (es)ketamine 31% vs 10%, and SSRIs 100% vs 11%. Overall, 46% (42/92) of concordant vs. 26% (14/54) of non-concordant patients responded (absolute difference +20 percentage points; relative increase {approx}77%; number needed to treat {approx}5). Conclusion: Concordance with EEG/ECG biomarkers correlated with higher treatment response, warranting confirmation in prospective trials. Significance: EEG/ECG-based decision support may enhance antidepressant treatment response in everyday clinical practice.

BackgroundEarly adolescence is a common period of onset for depressive symptoms. In part, this may reflect a developmental manifestation of individuals genetic propensities as they undergo physiological and hormonal changes and interact with new environments. Many commonly proposed mechanisms assume direct effects of an individuals own genes on emerging variation in their depressive symptomatology. However, estimates of genetic influence based on analyses in unrelated individuals capture not only direct genetic effects but also genetic effects from parents and other biologically related family members. AimIn data from the Norwegian Mother, Father and Child Cohort (MoBa), we used linear mixed models to distinguish developmentally-stable and adolescence-specific direct and parental indirect genetic effects. We examined effects of polygenic scores for major depressive disorder (MDD), ADHD, anxiety disorders, and educational attainment (EA) on depressive symptoms, which were assessed by maternal reports at ages 8 and 14. ResultsChildrens own MDD polygenic scores showed adolescence-specific effects on depressive symptoms ({beta}PGS*wave=0.041, [95% CI: 0.017, 0.065]). Developmentally-stable direct effects from childrens polygenic scores for MDD ({beta}=0.016, [0.006, 0.039]), ADHD ({beta}=0.024, [0.008, 0.041]) and EA ({beta}=-0.02, [-0.038, -0.002]) were also evident. The only evidence of indirect genetic effects was a stable effect of maternal EA polygenic scores ({beta}=0.04, [0.024, 0.054]). ConclusionDirect genetic effects linked to genetic liability to MDD accounted for emerging variation in depressive symptoms in adolescence. These results imply that specific etiological mechanisms related to MDD may become particularly relevant for depressive symptoms during early adolescence compared to at earlier ages.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder with changes in motivation to work for rewards being a core symptom. Transcutaneous vagus nerve stimulation (tVNS) has emerged as a promising therapy but its effects on the core features of MDD, such as changes in motivation, remained relatively unexplored. In this randomised, single-blind, cross-over, controlled trial, we used a grip strength effort task to investigate how tVNS impacted choices to exert different levels of physical effort for varying monetary rewards in MDD patients (n=53) and a non-depressed control group (n=45). Compared to sham stimulation, tVNS enhanced the efficiency with which participants with severe depressive symptoms allocated physical effort for rewards (reward-effort efficiency). These effects were not seen in participants with less severe symptoms. Specifically, we found that the effect of tVNS on reward-effort efficiency was driven by reduced unnecessary effort, i.e., a reduction in choices to exert additional effort when this was not required to gain a larger reward. These findings suggest a potential motivational mechanism by which tVNS exerts its therapeutic effects in MDD. Determining whether the effects of tVNS are linked to broader changes in executive functioning, such as improvements in cognitive flexibility in MDD, should be a key aim for future work.

Abstract Background Insomnia is a major public health problem affecting an estimated 852 million adults worldwide. Current pharmacological treatments, including benzodiazepines and Z-drugs, carry serious risks of dependency, cognitive impairment, and adverse events. These limitations have driven growing interest in complementary and alternative therapies, particularly herbal sedatives, which are perceived as natural and safer. However, evidence on their safety and efficacy remains insufficient and patchy. Objective: This review evaluated the effectiveness of lesser known herbal sedatives for insomnia. Methods The protocol was registered with PROSPERO (CRD420251101795). Eligibility was defined using the PICO framework: Population: adults aged [&ge;]18 years with insomnia; Interventions: Passiflora incarnata, Hawthorn, Melissa officinalis, Chamomile, Viola odorata, Nelumbo nucifera, Rhodiola rosea, and Eschscholtzia californica. Comparators: placebo or usual care; Primary and Secondary Outcomes: sleep quality (Pittsburgh Sleep Quality Index, Insomnia Severity Index, Epworth Sleepiness Scale), sleep duration, and sleep latency. Databases and registers were searched from January 2005 to July 2025. Randomized controlled trials, nonrandomized controlled trials, clinical trials, and observational studies were included. Five reviewers independently screened studies. Data extraction used a structured Excel spreadsheet. Risk of bias was assessed using RoB 2.0 for randomized trials and ROBINS-I V2 for nonrandomized studies. Random-effects meta-analyses (DerSimonian and Laird) were conducted in RevMan. Narrative synthesis followed SWiM guidelines. Results From 1,294 records, 32 studies met eligibility criteria. Meta-analysis of 23 RCTs demonstrated a statistically significant pooled effect favouring herbal sedatives (SMD -0.77, 95% CI -1.14 to -0.40, p=0.0001), with substantial heterogeneity (I square=92%). Subgroup analysis showed larger effects for chamomile (SMD -1.06) and Melissa officinalis (SMD -0.66). Most RCTs had high overall risk of bias; nonrandomized studies predominantly had critical risk of bias. Conclusions This systematic review provides preliminary evidence that several herbal sedatives, particularly chamomile and Melissa officinalis, may improve insomnia-related outcomes. However, methodological weaknesses, high risk of bias, and substantial heterogeneity limit evidence strength. Future research requires standardized extracts, large multicentre RCTs, and extended follow-up.

ImportanceConventional repetitive transcranial magnetic stimulation (rTMS) can be ineffective in individuals who have previously failed brain stimulation, ketamine and/or multiple lines of therapies. Modern accelerated rTMS protocols using image-guided targets have not been systematically investigated in these individuals. The goal of this study was to assess the feasibility and efficacy of personalized, connectivity-guided, accelerated intermittent theta-burst stimulation (iTBS) in patients with treatment-resistant depression (TRD) of varying refractoriness. ObjectiveTo assess whether connectivity-guided, accelerated iTBS produces significant reductions in depression severity, and to what extent this benefit extends to ultra treatment-resistant depression (UTRD). DesignThis was an open-label feasibility trial of connectivity-guided, accelerated iTBS in patients with TRD. Two distinct groups of participants were recruited from a neurosurgical-psychiatry clinic with UTRD and an interventional psychiatry clinic with TRD. Patients were stratified into a priori treatment-resistance subgroups. Patients received five days of open-label treatment. Outcome measures were collected immediately prior to and after treatment, as well as at 4- and 12-weeks post-treatment. SettingThis trial (NCT05813093) was conducted between November 2023 and July 2025 at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. ParticipantsPatients with major depressive disorder. A total of 96 participants were screened, with 73 meeting eligibility criteria (UTRD=30, TRD=43). One withdrew due to inability to tolerate the baseline MRI, and the other withdrew voluntarily prior to treatment. InterventionParticipants underwent a neuronavigated accelerated iTBS (600 pulses) protocol using personalized left dorsolateral prefrontal cortex (dlPFC) targets derived from functional magnetic resonance imaging (fMRI), comprising eight daily treatments, repeated over five days. Main OutcomesPrimary outcomes were i) change in Hamilton Depression Rating Scale (HAM-D17) from baseline to the end of the fifth day of treatment, and ii) the difference in change in HAM-D17 between UTRD and TRD subgroups. ResultsConnectivity-guided fMRI targeting yielded personalized targets clustered around the anterolateral dlPFC. Accelerated iTBS elicited rapid antidepressant effects ({Delta}HAM-D17 -9.01 [SD 6.06], t = -12.45, p < 0.001) regardless of treatment-resistance group ({Delta}HAM-D17 -9.64 [SD 5.94] vs -8.10 [SD 6.12], t = -1.05, p = 0.299), which were sustained up to 12 weeks after treatment. Overall response and remission rates at the end of treatment were 40.8% and 16.9%. Self-report scales revealed broad symptomatic relief outside of core depressive symptoms. Conclusions & RelevanceThis study demonstrated that fMRI connectivity-guided, accelerated iTBS induces sustained antidepressant effects and broader psychiatric benefits in patients across the spectrum of TRD. In a cohort unlikely to respond to most antidepressant therapies, connectivity-guided, accelerated iTBS offers a safe, well-tolerated option that can achieve benefit, or when ineffective, allow patients to expeditiously proceed with subsequent therapies than conventional rTMS. Trial RegistrationThis clinical trial was registered at clinicaltrials.gov with NCT05813093.

BackgroundMajor depression affects at least 10% of adults, yet evidence-based treatments have modest clinical effectiveness and acceptability. In recent years, outdoor swimming has grown increasingly popular and emerging quantitative and qualitative evidence suggests potential as an intervention for depression, however, there is yet to be a full-scale randomised controlled trial (RCT). This is a protocol to assess the safety and test the clinical- and cost-effectiveness of an 8-session outdoor swimming course (in addition to usual care) on depression symptom severity in adults experiencing major depression, in comparison to usual care alone. MethodsThis study is a pragmatic, parallel group, superiority RCT with 1:1 allocation comparing the outdoor swimming intervention (in addition to treatment as usual) with treatment as usual, aiming to recruit 480 adult participants meeting diagnostic criteria for major depression. Recruitment will take place across 21 sites with blind post treatment and follow up assessments. The primary outcome is depression symptom severity at T1 post-intervention, 12 weeks post-randomisation (the primary end point) using the Patient Health Questionnaire 9 (PHQ-9). Secondary clinical outcomes are anxiety (Generalised Anxiety Disorder 7 at T1 and T2 [38 weeks post-randomisation] and PHQ-9 at T2), mindfulness is measured as a potential mechanism at all timepoints (Five Facet Mindfulness Questionnaire 15). Health economic measures at all time points are: EQ-5D-5L, Recovering Quality of Life (ReQoL), Client Service Receipt Inventory and the Productivity Cost Questionnaire. A qualitative study will examine the experience of participants during and after the swim course. DiscussionIf the 8-session outdoor swim course is safe, clinically- and cost-effective, findings will support national implementation, offering an evidence-based intervention to those affected by depression, while potentially reducing healthcare costs. Furthermore, this may pave the way for other outdoor activities to support people with poor mental health to be developed and evaluated as interventions. Trial registrationControlled trial registration number is ISRCTN registration number 24759023. Registered on 21 February 2024 (https://www.isrctn.com/ISRCTN24759023). Administrative informationNote: Numbers enclosed in braces within this protocol correspond to SPIRIT checklist item numbers. The sequence of items has been adjusted to group related content together. (https://www.consort-spirit.org/). O_TBL View this table: org.highwire.dtl.DTLVardef@7f6ff8org.highwire.dtl.DTLVardef@900309org.highwire.dtl.DTLVardef@b75bc0org.highwire.dtl.DTLVardef@1e8d410org.highwire.dtl.DTLVardef@ba71ac_HPS_FORMAT_FIGEXP M_TBL C_TBL Plain Language Summary BackgroundDepression is very common,with at least 1 in 10 people having an episode of depression during their lifetime. Many people believe that outdoor swimming can improve depression. There is some research that suggests outdoor swimming is helpful for depression, but we do not yet have enough evidence to be sure. OUTSIDE 2 is a large research study that aims to find out whether outdoor swimming can help people with depression. AimThe aim of this study is to find out if taking part in an 8-session outdoor swimming course, along with usual care, is safe, helps improve depression, and is good value for money. We will compare people who do the swimming course (alongside their usual care) with people who only receive their usual care. In our study we will also talk to participants about their experiences. We want to understand how the outdoor swimming course affects their depression, and how the activity itself might help them feel better. Describe your research plan, includingPeople who are interested in taking part in the study can visit our website (outside2.co.uk) to read more information and sign up. Once someone agrees to join, they will be randomly placed into one of two groups available at their location to keep the study fair. One group will take part in eight one-hour outdoor swimming sessions in a small group. They will continue with their usual care for depression, which may include talking therapies, antidepressant medication, or community activities. The other group will continue with usual care only during the study. After the study ends, they will be offered the same outdoor swimming course, so no one misses out. The swimming sessions will be led by experienced swimming coaches who will help participants build confidence in the water and learn important water safety skills. During the study, all participants will complete questionnaires about their symptoms of depression, overall mental health, and use of health services. They will do these before they are put in a group, right after the swimming course or usual care period and six months later. Participants in the swimming group will also be asked to keep a diary about their experiences during the course. Researchers may visit some sessions to ask participants about how they are finding the swimming and how it affects their mood. Swim coaches will record attendance at each session and describe what activities were included. This helps the research team understand exactly what took place during each class. Knowledge mobilisationWe want to make sure that the information we learn from this study reaches many different people, not just scientists. To do this, we will share our findings in several ways. We will create a Podcast mini-series, an animated video as well as research papers. Using these different methods helps us share our findings with many groups, including adults in the community, mental health professionals, people working in the swimming industry, scientists, and policymakers. By sharing the results in several ways, more people can understand if and how outdoor swimming might support recovery from depression and mental health more broadly, and it increases the chance that the study will make a real difference, whatever it finds.

BackgroundHigh-demand sanitary crises, such as the COVID-19 pandemic, impose a high burden on healthcare professionals, increasing their risk of burnout. Healthcare postgraduate (HCP) trainees compound the general healthcare professional workforce and may face unique risks and challenges. This study aimed to evaluate the incidence of burnout and identify its predictors among healthcare postgraduate trainees during a high-demand sanitary crisis. MethodsA longitudinal observational study was conducted during the pandemic among healthcare postgraduate trainees from 67 Brazilian healthcare institutions. Participants were assessed at baseline (July to September 2020) and after an 18-months follow-up. Individuals with burnout at baseline were excluded. Several questionnaires, including the Oldenburg Burnout Inventory (OLBI) and the depressive disorder PHQ-9 scale were applied. Associations between baseline characteristics and the development of burnout were analyzed using chi-squared and t tests, and log-binomial regression. The study received ethical approval (CAAE: 33493920.0.0000.5558). ResultsA total of 313 participants were included; mean (SD) age: 28.2 (4.6) years; 80.1% (n=250) were biological females; 58.5% (n=183) whites; 51.1% (n=160) physicians; 12.5% (n=39) nurses; 36.4% (n=114) other HCP trainees; 47.9% (n=150) had depressed symptoms at baseline. Burnout incidence rate [95% CI] was 202.9 [166.5, 239.3] cases per 1000 person-years. In bivariate analyses, depressive mood at baseline predicted future burnout (relative risk [95% CI] = 2.14 [1.49, 3.08]; p<0.001), while older age (mean difference, MD [95% CI] = 1.10 [0.16, 2.09] years; p=0.029), higher autonomy (MD [95% CI] = 0.57 [0.10, 1.04] on a 10-point visual numerical scale, VNS; p=0.018) and adequate professional training (MD [95% CI] =0.85 [0.30, 1.40] on VNS; p=0.003) showed protective effects. Sex, race and weekly workload could not predict burnout. In multivariate analyses, depressive symptoms at baseline remained independently associated with higher risk of burnout (risk ratio, RR [95% CI] = 1.84 [1.26, 2.71]; p=0.002), while having adequate professional training showed a protective effect (RR [95% CI] = 0.61 [0.43, 0.87]; p=0.007). ConclusionsVery high incidence of burnout among HCP trainees was observed under a global sanitary crisis. Depressed mood at baseline was the most relevant predictor of subsequent burnout. Providing mental health support for HCP trainees in future widespread sanitary crises seems advisable to preserve the workforce.

BackgroundMajor depressive disorder (MDD), a leading cause of disability worldwide, exhibits substantial heterogeneity in treatment outcomes. Patients who do not respond to standard antidepressant therapy account for the majority of MDDs disease burden. Risk factors have been implicated in treatment response, including genes impacting on how antidepressants are metabolised. Yet, despite its clinical importance, risk factors for treatment-resistant depression (TRD) remain unexplored in low- and middle-income countries (LMIC). We used data from the DIVERGE study on MDD to investigate the risk factors of TRD in Pakistan. MethodsDIVERGE is a genetic epidemiological study that recruited adult MDD patients ([&ge;]18 years) between Sep 27,2021 to Jun 30, 2025, from psychiatric care facilities across Pakistan. Detailed phenotypic information was collected by trained interviewers and blood samples taken. Infinium Global Diversity Array with Enhanced PGx-8 from Illumina was used for genotyping followed by DRAGEN calling to infer metaboliser phenotypes for Cytochrome P450 (CYP) enzyme genes. We defined TRD as minimal to no improvement after [&ge;]12 weeks of adherent antidepressant therapy. We conducted multi-level logistic regression to test the association of demographic, clinical and pharmacogenetic variables with TRD. FindingsAmong 3,677 eligible patients, polypharmacy was rampant; 86% were prescribed another psychotropic drug along with an antidepressant. Psychological therapies were uncommon (6%) while 49% of patients had previously visited to a religious leader/faith healer in relation to their mental health problems. TRD was experienced by 34% (95%CI: 32-36%) patients. The TRD group was characterised by more psychotic symptoms and suicidal behaviour (OR=1.39, 95%CI=1.04-1.84, p=0.02; OR=1.03, 95%CI=1.01-1.05, p=0.005). Social support (OR=0.55, 95%CI=0.44-0.69, p=1.4x10-7) and parents being first cousins (OR=0.81, 95%CI=0.69-0.96, p=0.01) were associated with lower odds of TRD. In 1,085 patients with CYP enzyme data, poor (OR=1.85, 95%CI=1.11-3.07, p=0.01) and ultra-rapid (OR=3.11, 95%CI=1.59-6.12, p=0.0009) metabolizers for CYP2C19 had increased risk of TRD compared with normal metabolisers. InterpretationThere was an excessive use of polypharmacy in the treatment of depression while psychological therapies were uncommon highlighting the need for more evidence-based practice. This first large study of MDD from Pakistan uncovered the importance of culture-specific forms of social support in preventing TRD, highlighting opportunities for interventions in low-income settings. Pharmacogenetic markers can be leveraged to predict TRD.

Despite the global prevalence of postpartum depression (PPD), current referral uptake rates are far from satisfactory. While some qualitative studies have investigated factors affecting PPD referrals, a gap in quantitative analysis remains. Addressing this, our study utilized a discrete choice experiment (DCE) to understand the procedural elements influencing PPD referral uptake among diagnosed women. The DCE was conducted via home visits by healthcare providers and a comprehensive mobile app questionnaire. We constructed seven distinct referral attributes to explore participants' preferences, analyzed using mixed logit models and latent class analysis. This analysis identified key determinants and revealed the heterogeneities in referral preferences. A total of 698 individuals completed the DCE questionnaire. All assessed attributes, except for Accompaniment (going to clinic with a family member), were important determinants of preference. Participants generally preferred referrals to psychiatric clinics, face-to-face consultations, lower costs, and shorter waiting times. Significantly, participants' personal and socio-demographic characteristics also played a critical role in their referral preferences. Latent class analysis categorized participants into four distinct groups based on their preferences, with treatment cost and waiting times being the most decisive factors. In conclusion, the preference for PPD referrals is predominantly driven by convenience and access to specialist care. To enhance referral uptake, developing flexible and personalized referral programs that cater to these preferences is crucial.