Journal of Psychiatric Research

Abstract Background Ketamine has emerged as an effective rapid-acting treatment for treatment-resistant depression (TRD), producing significant antidepressant effects within hours of administration. Given ketamine's capacity to induce states of heightened neuroplasticity and psychological openness, psychotherapy may represent a meaningful complement to its pharmacological effects - facilitating emotional processing, cognitive restructuring, and the consolidation of therapeutic gains. However, the adjunctive potential of structured psychotherapeutic support in ketamine-based interventions remains largely unexplored. Methods This preliminary, non-randomized, open-label clinical trial evaluated the adjunctive effects of ketamine-assisted psychotherapy (KAP) in an outpatient setting. Forty-six patients with TRD received eight weekly sessions of subcutaneous esketamine (0.5-1.0 mg/kg) and were allocated into two groups: esketamine without psychotherapeutic support (n = 23) and esketamine combined with structured KAP encompassing preparation, dosing accompaniment, and post-session integration (n = 23). Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory-II (BDI-II) at multiple timepoints during treatment and at follow-up assessments up to six months after protocol completion. Results Both groups showed significant reductions in depressive symptoms throughout treatment. The KAP group demonstrated greater clinical improvement by the end of treatment, with between-group differences on the MADRS emerging at sessions 7 and 8. MADRS response and remission rates were 52.2% and 34.8% in the KET group, and 78.3% and 78.3% in the KAP group, respectively. BDI-II scores indicated earlier subjective improvement in the KAP group, with between-group differences emerging as early as the second session and persisting across multiple timepoints. No significant between-group differences were observed during the six-month follow-up, with both groups maintaining symptom reductions comparable to end-of-treatment levels. Conclusions These findings suggest that structured psychotherapeutic support may be associated with early clinical response and remission rates in subcutaneous esketamine treatment for TRD, potentially through facilitation of emotional processing, psychological flexibility, and behavioural change. Further controlled studies are needed to clarify the specific contribution of psychotherapy, investigate the mechanisms underlying this interaction, and optimize integrated treatment approaches for TRD. The trial was registered at https://ensaiosclinicos.gov.br/rg/RBR-1072m6nv . Keywords: esketamine; treatment-resistant depression; ketamine-assisted psychotherapy; innovative therapies.

Structured AbstractO_ST_ABSBackgroundC_ST_ABSPost-Traumatic Stress Disorder (PTSD) is a mental health condition affecting people who experience traumatic events. Trauma-exposed occupational groups report higher rates of PTSD than the general population. Current treatments, and access, often take months and may cause distress when people are required to talk about the trauma. ObjectiveTo determine the proof of concept of FIRST, a brief, non-trauma focussed therapy, in two separate populations with employment-associated PTSD. MethodTwo independent, single-arm, experimental therapy pilot trials were conducted. Trial one recruited 20 military veterans who received FIRST therapy via trained third-sector therapists. Trial two recruited 16 health and social care workers with FIRST therapy delivered by healthcare provider therapists. All participants were adults with PTSD (confirmed via CAPS-5 in trial one, and symptom score of [≥]33 on the PCL5 in trial two). Primary outcomes were recruitment feasibility, retention, data quality and reduction in PTSD symptoms. Secondary outcomes were anxiety and depression symptoms, daily life functioning and perceived health status. Veterans were followed up at 12 weeks post-enrolment and healthcare workers at 8 weeks. ResultsThe veteran trial progression criteria to main trial were met. Seventy-nine people screened eligible, 43 attended a CAPS-5 assessment; 20 had confirmed PTSD and were enrolled. Seventeen completed therapy and 12-week outcome measures. Mean PCL-5 scores decreased from 48.7 (SD = 13.02, n=20) at baseline to 23.5 (SD = 15.30, n=17) at 12-weeks. The healthcare worker trial obtained informed consent from 16 participants, 10 commenced therapy and were included in analysis with eight completing therapy. Mean PCL-5 scores decreased from 42.60 (12.23, (n=10) at baseline to 22.00 (19.92, n=8) at 8-weeks. ConclusionsProof of concept of FIRST was established. PTSD symptom reductions exceeded the PCL-5 minimal clinically important difference. Undertaking a fully powered randomised controlled trial of FIRST therapy is feasible within both healthcare and third sectors. HighlightsO_LIPost-traumatic stress disorder (PTSD) is more common in military veterans and health workers than the general population C_LIO_LITherapy can be challenging to commence and complete when it requires a focus on the trauma incident C_LIO_LIFIRST offers a promising, brief, non-trauma focused therapy for the treatment of PTSD C_LI

Background: Internet-based cognitive behavioral therapy (iCBT) is efficacious for panic disorder (PD), yet the mechanisms of change remain underspecified. Anxiety sensitivity (AS) is theoretically central to PD maintenance, but its role as a mediator has not been formally tested in Spanish-speaking populations using minimal-contact formats. This study evaluates the efficacy of the "Free from Anxiety" iCBT program and examines AS as a mediator of clinical outcomes. Methods: In a randomized controlled trial, 95 adults meeting DSM-IV-TR criteria for PD were assigned to an 8-week iCBT program with optional email support (n = 49) or a waiting-list control (n = 46). Primary outcome was PD severity (PDSS); secondary outcomes included anxiety sensitivity (ASI-3), general anxiety (BAI), and depression (BDI-II). Mediation was assessed via Baron and Kenny's framework with bootstrapping (5,000 resamples) to estimate the indirect effect of ASI-3 change on PDSS reduction. Results: The treatment group showed significant improvements across all measures compared to controls (PDSS: d = 0.76, 95% CI [0.10, 1.42]; mean d = 1.30). Mediation analysis confirmed that ASI-3 change partially mediated the treatment effect on PDSS (indirect effect = 1.85, 95% CI [0.36, 3.70]), accounting for 27.4% of the total effect. The direct effect remained significant (b = 4.89, p < .001). Intent-to-treat (ITT) analyses supported robustness (d = 0.47 to 1.47). Gains were maintained at 6-month follow-up (d = 1.19 to 1.26). Conclusions: iCBT reduces anxiety sensitivity as a partial mechanism of change, aligning with cognitive models of panic. These findings support Free from Anxiety as an evidence-based, viable first-step intervention for Spanish-speaking clinical populations within stepped-care pathways.

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.

Background: Generalized anxiety disorder (GAD) is associated with substantial psychological burden, autonomic dysregulation, and limitations of existing pharmacological and psychotherapeutic treatments. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a promising non-invasive neuromodulation approach, but evidence regarding home-based application in GAD remains limited. Objective: To evaluate the feasibility, safety, and preliminary clinical and physiological outcomes of a home-based taVNS intervention in adults with psychologist-confirmed moderate-to-severe GAD. Methods: In this prospective single-arm feasibility study, 48 participants initiated a 4-week home-based taVNS intervention consisting of two daily stimulation sessions performed five days per week. Clinical assessments were conducted at baseline, Week 2, Week 4, and follow-up visits at Weeks 6 and 8. Ambulatory electrocardiographic monitoring was performed before treatment initiation, at Week 2, and at the end of treatment to assess heart rate variability (HRV) using the root mean square of successive differences (RMSSD). Primary outcomes included feasibility, safety, adherence, and change in clinician-rated anxiety severity (HAM-A). Results: Thirty-four participants completed the study and were included in the primary analyses. HAM-A scores decreased significantly from baseline to Week 4 ([EMD] -6.9, 95% CI -10.4 to -3.4, p = 0.001), with partial maintenance during follow-up. Improvements were also observed in Beck Anxiety Inventory scores, whereas changes in GAD-7, perceived stress, depressive symptoms, and sleep quality were not statistically significant. RMSSD increased significantly from baseline to Week 4 (EMD 6.7 ms, 95% CI 2.1-11.3, p = 0.009). Greater increases in RMSSD were associated with larger reductions in HAM-A (R^2 = 0.18, p = 0.031) and BAI scores (R^2 = 0.21, p = 0.019). No serious adverse events occurred. Mean adherence was 79.8%, and 73.5% of participants completed at least 70% of prescribed stimulation sessions. Conclusions: Home-based taVNS was feasible and generally well tolerated in adults with moderate-to-severe GAD. Preliminary improvements in clinician-rated anxiety severity and autonomic physiological measures were observed; however, the single-arm design precludes causal inference. These findings support further evaluation of home-based taVNS in adequately powered randomized sham-controlled trials.

Separate research has evaluated trajectories of posttraumatic stress symptoms (PTSS) and obsessive-compulsive symptoms (OCS), but no study has evaluated OCS trajectories following trauma exposure nor combined PTSS/OCS trajectories. The present study evaluated combined PTSS/OCS trajectories among 585 survivors of Hurricane Helene, spanning three waves of data collection over 12 months. A 3-class solution was supported, including resilient (i.e., consistently low PTSS and OCS), chronic (i.e., elevated PTSS and OCS with gradual reduction over time), and moderate-yet-diverging (i.e., moderate elevations in PTSS and OCS with gradually declining PTSS and persistent and increasing OCS over time) classes. This study shows both overlap and differentiation in symptom trajectories from earlier research, with the moderate-yet-diverging trajectory suggesting unique OCS pathways distinct from PTSS.

Background Treatment guidelines for borderline personality disorder (BPD) recommend assessment, diagnosis, and psychoeducation. We report on the feasibility and safety of a randomized controlled trial protocol of online psychoeducation, assessment, and personalized feedback as an immediate first step of care for BPD. Methods Newly diagnosed participants were randomized to receive 10 videos about BPD or general mental health for two weeks. Half the participants receiving BPD videos were randomized to receive personalized feedback on changes in symptom ratings and cognitive performance. Ecological momentary assessment (EMA) evaluated interpersonal interactions, emotions, and behaviors for 30 days. BPD symptoms, depression, and personality functioning were assessed at baseline, after videos, after feedback, and one month later. Results Eighty-two participants were randomized into three conditions that did not differ significantly in terms of demographics or baseline variables. Dropout occurred for 32.9% of the sample. No differences in rate of emergency room visits, hospitalizations, or other escalations in level of care were reported among groups. Satisfaction was higher for those receiving psychoeducational videos about BPD. Improvement in BPD knowledge in the psychoeducation conditions was significantly greater than the control condition. No statistically significant differences were found regarding reduction of BPD symptoms. The psychoeducation with feedback arm showed significantly greater improvements in self-impairment compared to controls with medium effect size at the final timepoint. Modeling of the relationship between time spent alone and BPD symptoms showed a positive correlation in the control condition, but in the group receiving both psychoeducation about BPD and feedback, this relationship was negative. Conclusion Online psychoeducational videos and assessment were safe, feasible, and acceptable to participants with newly diagnosed BPD. Psychoeducation with personalized feedback appears to be more effective than either BPD or general psychoeducation alone in improving deficits in self-functioning, which may relate to an increased capacity to be alone with fewer symptoms. The protocol was registered with ClinicalTrials.gov (NCT05358925, https://clinicaltrials.gov/study/NCT05358925) on April 28th, 2022.

Background: Dissociative experiences encompass a variety of discontinuities in awareness and perception that are elevated in the dissociative disorders and associated with extensive comorbid symptomatology. Accumulating evidence points to developmental trauma and trait responsiveness to verbal suggestions (REVS) as factors that confer risk for severe dissociative symptoms, but they have typically been studied in isolation. This study integrated these measures using prediction modelling to better understand their predictive value for the risk of dissociative psychopathology. Method: 1,104 non-clinical participants completed measures of trauma, dissociation and trait REVS. The predictive model was developed using elastic net logistic regression, internally validated with 10-fold cross-validation, and assessed using receiver operating characteristic (ROC) curve and area under the ROC (AUROC). Variables entered into the model were components of REVS, trauma, age, and their interactions. Results: A dissociative psychopathology at-risk group (7%) was characterised by younger age, greater trauma and elevated REVS, particularly involuntariness during cognitive-perceptual suggestions. The prediction model retained nine of ten predictors, with an AUROC of .77 [95% CI: .73, .82], reflecting good discrimination with moderate sensitivity (78%) but modest specificity (67%). Conclusions: These findings reinforce trauma and trait REVS as risk factors for dissociative psychopathology and demonstrate that they can be integrated in a model that can identify at-risk individuals. Further validation and extension of the model is necessary to improve the identification of individuals at risk for severe dissociative symptomatology and the diagnosis of dissociative disorders with implications for outcome trajectories.

Hoarding disorder (HD) affects approximately 2-3% of adults and is associated with substantial functional disability and limited access to evidence-based care. The aim of the current analysis was to examine the naturalistic effectiveness of therapist-delivered video cognitive-behavioral therapy (CBT) for HD in a large real-world sample, and to characterize individual-level treatment response, time-to-response, and moderators of outcome. This retrospective, observational analysis examined clinical data from 305 adults diagnosed with HD who received therapist-delivered video CBT through an online specialty therapy platform between September 2021 and February 2026. Hoarding symptom severity was assessed using the Hoarding Rating Scale-Self Report (HRS-SR). Linear mixed models examined symptom change from baseline to three timepoints: session 10, session 20, and each patient's final session. HRS-SR scores decreased from M = 22.4 (SD = 7.6) at baseline to M = 16.4 (SD = 8.2) at final session (Hedges' g = 0.81, 95% CI: 0.68-0.94). By the final session, median percent improvement was 25.0% [IQR: 3.0-46.7%]. A total of 39.3% of patients achieved [&ge;]35% HRS-SR reduction, 27.4% of patients who began above the clinical threshold achieved remission, 36.4% demonstrated reliable improvement, and 22.9% of eligible patients achieved clinically significant change. Among patients who achieved and maintained [&ge;]35% reduction through their final session (n = 120), median time to first response was session 9, with 54.2% responding within 10 sessions. Analyses of secondary outcomes showed significant improvements in clutter severity, depressive and anxiety symptoms, stress, quality of life, and functional disability (Hedges' g = 0.21-0.47). Greater baseline severity, more sessions, and longer treatment duration significantly moderated outcomes; prior OCD treatment history did not. Findings suggest that therapist-delivered video CBT for HD, delivered remotely in a real-world setting, produces outcomes consistent with controlled trials and may be a clinically effective and scalable approach for a condition historically underserved by mental health systems.

Background: While growing enthusiasm for the therapeutic potential of classic psychedelics has led to a rise in non-clinical use, attention to persisting adverse effects has emerged with delay. A subset of individuals reports persisting complications such as hallucinogen persisting perception disorder (HPPD), depersonalization/derealization disorder (DDD), anxiety and depression. Yet few medical services are equipped to address these complications. Aims: This qualitative study examines how societal, medical, and media discourses shape the experiences of individuals with persisting psychedelic-related complications, focusing on help-seeking trajectories. Methods: Thirteen semi-structured interviews with adults experiencing persisting psychedelic-related psychological symptoms (four women, nine men, age 19-49 years; HPPD (n = 10), DDD (n = 6), depression (n = 1), and anxiety (n = 1)) were conducted within a larger study on these complications. Data were analysed using reflexive thematic analysis. Reporting followed the COREQ guidelines. Results: Three interrelated themes emerged: (1) The dissonance between expectation and harm - idealised media and scientific portrayals of psychedelics shaped initial use and complicated recognition of adverse outcomes; (2) Stigma, silence, and self-blame - prohibitionist discourse and internalised shame significantly inhibited help-seeking; and (3) Between systemic absence and self-organised support - participants encountered clinical unpreparedness and epistemic dismissal, which often led them to rely on online peer communities and self-management strategies. Positive clinical encounters, characterised by professional expertise and nonjudgmental engagement, were experienced as helpful. Conclusions: Adequate clinical and conceptual frameworks for persisting psychedelic-related complications are lacking. An interdisciplinary, experience-informed approach integrating realistic risk communication, clinician training, and destigmatisation is required to support affected individuals.

Objective: Biopsychosocial models recognize multiple determinants of post-trauma mental disorders, but their relative and interactive effects remain unclear. We quantified the independent contribution of traumatic event severity, preexisting vulnerability, social support, and coping capacity, and tested mediation pathways. Methods: In a Brazilian clinical sample reporting traumatic or stressful events (N = 612), constructs were operationalized as composite scores and a dichotomous clinical outcome was derived from intake assessments. Logistic regression (n = 594) and structural equation modeling evaluated prediction and mediation. Results: Vulnerability was the strongest risk factor (OR = 1.46, p < .001) and social support the main protective factor (OR = 0.60, p < .001). Traumatic event severity remained an independent predictor (OR = 1.39, p < .001), whereas coping capacity was not significant (OR = 0.94, p = .410). Discrimination was good (AUC = 0.80). Mediation indicated vulnerability reduced social support and coping capacity, with a significant indirect effect via social support. Conclusions: Findings support a multifactorial model centered on a triad of vulnerability, social support, and traumatic exposure. Risk is shaped primarily by preexisting vulnerability and relational context, alongside a direct trauma effect, providing a clinically relevant framework for assessment and intervention.

Suicidal ideation in obsessive-compulsive disorder (OCD) is common and clinically significant, yet much of the existing literature conceptualizes suicide risk through the lens of comorbid depressive symptomatology. The present study examined whether other clinical features can identify clinically meaningful patterns associated with SI. Participants included 231 individuals with clinically significant OCD symptoms. SI was operationalized using Item 9 of the Beck Depression Inventory-II and binarized to reflect the presence or absence of suicidal thoughts. Depression severity scores were intentionally excluded from the predictive feature set, and three machine learning models (ElasticNet, Random Forest, and Explainable Boosting Machines) were evaluated using repeated nested cross-validation. All three algorithms showed comparable predictive performance. Given this overlap, the EBM was selected for interpretation due to its ability to model nonlinear relationships and interaction effects transparently. The model identified quality of life, obsessive-compulsive trait severity, somatic burden, and conscientiousness as prominent predictors of SI. Risk functions suggested nonlinear increases in estimated suicide risk at elevated levels of obsessive-compulsive traits and reduced quality of life. Additionally, interaction analyses indicated that severe obsessive-compulsive traits combined with elevated somatic burden were associated with higher estimated suicide risk than either factor alone. These findings suggest that interpretable machine learning can support clinically relevant phenotypic hypothesis generation. They also highlight somatic burden, functional impairment, obsessive-compulsive trait severity, and conscientiousness as potentially underappreciated targets for SI risk assessment in OCD, beyond the traditional focus on depressive comorbidity.

Background: Aberrations in neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways are implicated in major depressive disorder (MDD). First-episode simple dysmood disorder (FE-SDMD) without metabolic syndrome offers a unique model to investigate early lipid alterations underlying NIMETOX pathophysiology. Methods: Plasma samples were collected from 88 university students (44 FE-SDMD, 44 healthy controls). Participants underwent comprehensive psychiatric and psychological assessments, including adverse childhood experiences (ACEs), negative life events (NLEs), depression, anxiety, suicidal behaviors, and insomnia. Untargeted lipid profiling was performed using LC-QTOF-MS, while indices of oxidative and nitrosative stress (ONS) and lecithin-cholesterol acyltransferase (LCAT) activity were assessed. Data was analyzed using machine learning approaches with recursive feature elimination and cross-validation. Results: FE-SDMD was characterized by increased ceramides (CER), diacylglycerides (DAG), triacylglycerides (TG), sphingomyelins (SM), bis-monoacylglycerol phosphates (BMP), cholestone, and fatty-acyl amino acids (FAAA). DAG, CER, and BMP were the strongest predictors of depression severity and physiosomatic symptoms, whereas cholestone, CER, and SM predicted suicidal behaviors. These lipid modules, together with lowered LCAT and increased ONS, explained substantial variance in depression severity (46.4%), physiosomatic symptoms (42.4%), cognitive-affective symptoms (37.9%), suicidal behaviors (30.1%), insomnia (32%), and anxiety (19.5%). ACEs and NLEs were strongly associated with CER (p<0.001), DAG (p<0.01), and cholestone (p<0.01). Conclusion: Early-stage MDD is characterized by distinct lipid dysregulations linked to psychosocial stress exposure, oxidative and nitrosative stress, and an indicant of impaired reverse cholesterol transport. These lipid modules may serve as early biomarkers and therapeutic targets in vulnerable populations.

BackgroundDeep brain stimulation (DBS) is effective for approximately two-thirds of patients with treatment-resistant obsessive-compulsive disorder (OCD). While prior work has emphasized the engagement of specific white matter tracts in mediating outcomes, the contribution of region-specific white matter integrity to clinical response remains unclear. MethodsTwelve patients with treatment-resistant OCD underwent preoperative neuroimaging and DBS at our center. We assessed OCD severity preoperatively and at [~]18 months postoperatively. We extracted mean fractional anisotropy (FA) for the anterior limb of the internal capsule (ALIC) and a control tract and used Spearmans rank correlations to evaluate associations between FA and symptom improvement. We additionally evaluated this relationship for 49 white matter bundles. Finally, we used diffusion tractography to determine endpoints connected with ALIC voxels most predictive of symptom improvement. ResultsHigher preoperative ALIC FA was associated with greater clinical improvement following DBS (p=0.002). This effect was specific to the ALIC and not the control tract. Hemispheric asymmetry (right>left) in ALIC FA was moderately correlated with clinical improvement. Among all 49 bundles, the right ALIC demonstrated the strongest association with clinical improvement. Streamlines passing through the ALIC voxels that most strongly correlated with outcome ended in the diencephalon and superior frontal cortex. ConclusionsBaseline structural integrity of the ALIC was associated with the magnitude of clinical improvement following DBS for OCD. These findings suggest that regional variation in white matter integrity may reflect an underlying circuit disruption amenable to DBS, supporting the use of neuroimaging-based metrics as potential biomarkers in DBS treatment.

Background Multimorbidity is increasingly prevalent, and associated with worse clinical and psychosocial burdens. Interoception, the brain's ability to sense and interpret internal bodily signals, may contribute to multimorbidity, through its link with health behaviors, stress regulation, and mental health. This study examines whether self-reported interoceptive accuracy and attention is associated with multimorbidity, by identifying multimorbid subgroups and their interoceptive profiles. Methods Morbidity classes were identified through latent class analyses in two Dutch survey datasets, focusing on depression and alexithymia (DA-dataset; N = 671) and lifestyle factors (L-dataset; N = 1022). Linear regression analyses were used to assess interoceptive accuracy and attention (by the Interoceptive Accuracy Scale and Interoceptive Attention Scale respectively) among different subgroups. Results Multimorbid subgroups were characterized by older age, low socioeconomic position, and elevated physical, psychological, and behavioral problems. Multimorbid classes exhibited lower interoceptive accuracy (DA-dataset: B = -1.14, 95% CI = [-2.89, 0.62]; L-dataset: B = -2.36, 95% CI = [-3.83, -0.89]) and higher attention (DA-dataset: B = 3.62, 95% CI = [0.97, 6.27]; L-dataset: B = 1.07, 95% CI = [-1.42, 3.56]) compared to healthier classes. Conclusion Multimorbid populations demonstrated lower interoceptive accuracy and higher interoceptive attention. This highlights the psychosocial complexity of multimorbid populations which may impact their self-management and health behavior. These findings underscore the need to expand treatments to include psychosocial domains for multimorbid patients.

Forensic patients often have complex and costly healthcare needs, even following discharge from secure care. However, little is known about their health and justice outcomes after community reintegration. To address this gap in the literature, we conducted a systematic review and meta-analysis to estimate the incidence of key post-discharge outcomes among community-discharged forensic patients, including any reoffending, violent reoffending, reconvictions, readmissions, all-cause mortality, and suicide. We systematically searched PsycINFO, Embase, CINAHL, Medline, PubMed, and ProQuest Dissertations from database inception to May 2025 (PROSPERO CRD42024529265). Random-effect meta-analyses were used to generate pooled incidence estimates, with heterogeneity quantified using prediction intervals. A total of 49 studies met inclusion criteria (total patient n = 18,871) and contributed to the meta-analyses. The pooled incidence rate per 100,000 person-years was: any reoffending 3,889 (95% CI 2,055, 7,359; 95% PI 290, 52,136); violent reoffending 1,851 (95% CI 1,229, 2,789; 95% PI 201, 17,068); reconvictions 3,291 (95% CI 2,591, 4,179; 95% PI 950, 11,394); readmissions 7,945 (95% CI 5,507, 11,463; 95% PI 1,225, 51,548); all-cause mortality 1,789 (95% CI 1,341, 2,388; 95% PI 673, 4,756); and suicide 407 (95% CI 319, 519; 95% PI 225, 735). Overall, the reoffending rate for forensic patients discharged to the community was lower than that reported for other cohorts of people charged with general and violent offences. However, despite typically receiving long admission periods, discharged forensic patients continue to experience high rates of readmission, all-cause mortality, and suicide relative to other psychiatric patient groups in the community. Together, our findings highlight a need for enhanced post-discharge suicide support for forensic patients living in the community to better facilitate successful, long-term reintegration.

Importance: The menopausal transition is associated with an increased risk of depression. Prior depression is a well-established risk factor, but studies do not distinguish between prior reproductive and non-reproductive depression. Objective: To compare the associations of reproductive (i.e., premenstrual mood disorder and perinatal depression) and non-reproductive (i.e., not related to hormonal transitions) histories of depression with depressive symptoms during the menopausal transition. Design: Cross-sectional analysis of questionnaire data from the Multidisciplinary Menopausal Outpatient Care Project (MOPP) collected between February 2023 and October 2025. Setting: Menopause outpatient clinics Amsterdam, the Netherlands, including a specialized multidisciplinary menopause clinic. Participants: In total 364 individuals were approached; 244 enrolled at baseline. After exclusions for age <40 (n=3), premature ovarian insufficiency (n=2), premenopausal status (n=1), age >58 with final menstruation >10 years earlier (n=12), bipolar disorder (n=5), and missing survey data (n=41), 180 participants were included. Exposures: Premenstrual mood disorder measured with Premenstrual Symptom Screening Tool, perinatal depression with Edinburgh Postnatal Depression Scale Lifetime version, and reported prior non-reproductive depression in medical records. Main outcome and measures: Depressive symptom severity measured with Inventory of Depressive Symptomatology-Self Rated. We used univariable and multivariable linear regressions; multivariable models accounted for overlap between exposures. Results: Among 180 participants (median age 51; 61% perimenopausal and 39% postmenopausal), premenstrual mood disorder showed the strongest association with depressive symptom severity (B = 9.0, 95% CI 5.1-12.9, p < 0.001), followed by perinatal depression (B = 7.8, 95% CI 3.4-12.1, p < 0.001) and prior non-reproductive depression (B = 4.7, 95% CI 0.7-8.7, p = 0.021). In multivariable analysis, only premenstrual mood disorder (B = 7.2, 95% CI 2.4-12.1, p = 0.0037) and perinatal depression (B = 5.7, 95% CI 1.2-10.1, p = 0.013) remained associated with depressive symptom severity. Conclusions and Relevance: Prior reproductive depression, but not prior non-reproductive depression, was associated with greater depressive symptom severity during the menopausal transition. A history of premenstrual mood disorder and/or perinatal depression may therefore help identify individuals at increased vulnerability to depressive symptoms during this period. Future studies should replicate these findings in population-based samples.

Background and PurposeWhile inflammation has been generally considered to exacerbate symptoms of schizophrenia, some clinical observations suggest that acute inflammation may alleviate positive symptoms. However, animal models often use excessive inflammatory stimuli, and the effects of acute inflammation--comparable to levels observed in patients--remain unknown. Experimental ApproachTo address this, we examined whether acute inflammation induced under relatively mild, clinically relevant conditions suppresses behavioural sensitization in methamphetamine (METH)-sensitized mice, a model of psychostimulant-induced psychosis with relevance to certain aspects of positive symptoms of schizophrenia. We used a repeated METH (1 mg/kg) sensitized model to evaluate the effects of acute inflammation on behavioural sensitization. Acute inflammation was induced via two methods using either lipopolysaccharides (LPS; 1 g/kg) to mimic peripheral immune activation or restraint stress (RS; single 2-h exposure) to model the neuroinflammation induced by psychological stress. LPS doses were adjusted with reference to the magnitude of peripheral cytokine elevation reported in patients, and RS was applied in short single sessions to avoid excessive inflammation. Key ResultsBoth LPS and RS significantly suppressed behavioural sensitization, without inducing other behavioural abnormalities. This suppression was dependent on toll-like receptor-4 activation. LPS-mediated suppression involved cyclooxygenase-2, whereas RS-mediated suppression was linked to the microglia-derived tumour necrosis factor-. LPS did not alter, whereas RS significantly reduced the striatal extracellular dopamine levels. Conclusion and ImplicationsThese findings suggest that acute inflammation suppresses behavioural sensitization through distinct mechanisms depending on the inflammatory trigger, providing a framework for understanding how inflammation may influence psychosis-related processes, with potential relevance to schizophrenia.

Background: The incidence of antidepressant withdrawal reactions in longer-term users and the influence of dosage is insufficiently understood. Objectives: Informed by neuropharmacological models and user surveys, this study examined symptom change during tapering and if increases were specifically associated with reductions below 75% of the minimum effective dose. Design: This was a prospective longitudinal cohort study with seven assessments over six months. Methods: Altogether 32 Swiss adult primary care patients who were on antidepressants for at least six months and in stable remission were assessed at baseline (week 0) before they started tapering and after 2, 4, 6, 8, 16, and 26 weeks. Withdrawal symptoms were measured repeatedly using an adapted version of the Discontinuation-Emergent Signs and Symptoms Scale (DESS) and the main outcome was intra-individual symptom change during intervals. Antidepressant dose was standardized relative to the minimum effective dose in the treatment of depressive and anxiety disorders. Results: Across intervals, reductions below 75% of the minimum effective dose were associated with symptom increases, while reductions above that threshold or no reductions were associated with symptom decreases. After adjusting for potential confounders, the rate of clinically relevant symptom increases contingent on dose reductions below 75% of the minimum effective dose was 33%, as compared to 13% during intervals with no dose reductions (OR=3.2, 1.4 to 7.4). We thus estimated that 60% of the risk of clinically relevant symptom increases was attributable to pharmacological withdrawal effects. The adjusted incidence rates for clinically relevant and severe withdrawal reactions were 32% and 11%, respectively. Conclusions: Consistent with neuropharmacological research findings, we found that antidepressant withdrawal symptoms emerge mostly following reductions below 75% of the minimum effective dose, affecting about one-third of patients. Even small reductions may trigger clinically relevant withdrawal reactions in this lowest dose-range, stressing the need for personalized tapering plans.

Aim: Schema Therapy (ST) is an evidence-based treatment for complex mental health problems rooted in early Adverse Childhood Experiences (ACEs). Although both individual and group formats have shown effectiveness, little is known about which format works best for whom. This question is particularly relevant for adolescents given their unique developmental needs. Despite over a decade of clinical experience with ST in adolescents, current research offers limited guidance on how to tailor the format to individual needs - resulting in a persistent gap between research and practice. This study aims to develop practice-based indication criteria for individual versus group schema therapy by integrating therapists expertise with experiences from adolescents who underwent ST. Methods: This qualitative study employs a constructivist Grounded Theory approach. Data will be gathered through focus group discussions with schema therapists and individual interviews with adolescents. Therapists will be purposively selected based on experience with both therapy formats and with traumatized adolescents. Adolescents are eligible if they have experienced ACEs and have completed at least 20 sessions of ST. Results: The analysis will result in a theoretical model that integrates therapists clinical reasoning and adolescents preferences. Conclusions: This study integrates schema therapists expertise and adolescents lived experiences to develop actionable indication criteria for choosing between individual and group ST. By supporting informed clinical decision-making, the findings contribute to treatment personalization in adolescent ST and address key challenges such as suboptimal outcomes and treatment dropout. Moreover, the identified criteria provide a foundation for future quantitative validation.