February 2025

Background: Few treatments are available for individuals with marked treatment-resistant depression (TRD). Objective: Evaluate the safety and effectiveness of FDA-approved adjunctive vagus nerve stimulation (VNS) in patients with marked TRD. Methods: This 12-month, multicenter, double-blind, sham-controlled trial included 493 adults with marked treatment-resistant major depression who were randomized to active or no-stimulation sham VNS for 12 months. The primary outcome was percent time in response across months 3-12, with response defined as a ≥50 % change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS). Several secondary endpoints were evaluated. Results: Overall, 88.4 % of participants completed the trial. Percent time in MADRS response did not distinguish active from sham VNS. However, ratings from on-site clinicians (Clinical Global Inventory-Impression [CGI-I]), patients (Quick Inventory of Depressive Symptomology-Self Report [QIDS-SR]), and offsite masked raters (Quick Inventory of Depressive Symptomology-Clinician [QIDS-C]) revealed antidepressant benefits significantly favoring active VNS. Active VNS demonstrated significantly more percent time in response on the CGI-I (P = 0.004) and QIDS-SR (P = 0.049), and significantly more percent time in partial response (PR; symptom improvement ≥30 %) on the CGI-I (P < 0.001) and QIDS-C (P = 0.006) versus sham VNS. Active VNS exceeded sham VNS in rate of dyspnea (P = 0.035), a known side effect of VNS. No new adverse events were identified. Conclusions: Percent time in MADRS response did not distinguish the treatment groups, but on multiple instruments time in response and PR showed a positive treatment effect. VNS was found safe and effective in participants with marked TRD.

Cannabis has been consumed for centuries, but global regulatory changes over the past three decades have increased the availability and consumption of cannabis. Cannabinoids are touted to have therapeutic potential for many diseases and could be a replacement for opioids for analgesia and sedation. However, cannabinoids can cause substantial adverse cardiovascular events that would mitigate any potential benefit. The endocannabinoid system regulates mood, satiety and memory, and modulates the cardiovascular system. The link between cannabinoids and cardiovascular disease, which used to be limited to evidence from preclinical studies, case reports and case series, is now evident in epidemiological studies. Cannabinoids adversely affect the cardiovascular system, causing myocardial infarction, cerebrovascular accidents, arrhythmia and heart failure. The effects of novel cannabinoids are unknown, and synthetic cannabinoids have the potential to cause even more substantial harm than traditional cannabinoids. Therefore, with the increasing availability and use of cannabis, the acute and chronic effects of this drug are becoming apparent.

Objective: Intranasal esketamine has been approved as an adjunctive therapy for treatment-resistant major depressive disorder with acute suicidal ideation and behavior. The authors conducted a systematic review and meta-analysis of the available data on its efficacy against depression and suicidality as well as its side effects. Methods: MEDLINE was searched with the keyword "esketamine" on March 24, 2024, using the PRISMA method. Data processing and statistical analysis were performed with R, version 4.3.3, and the meta-analysis was performed with the METAFOR package. Results: Of 1,115 articles initially identified, 87 were included for analysis and discussion. At weeks 2-4, randomized controlled trials were mostly negative or failed; however, the meta-analysis returned a weak but significant positive effect for depression (effect size range, 0.15-0.23 at weeks 2-4), similar to augmentation strategies with atypical antipsychotics for treatment-resistant depression. The effect size concerning suicidality was not significant at any time point. The sensitivity analysis produced the same results. Conclusions: The study findings suggest that esketamine's efficacy as an add-on to antidepressants is modest in treatment-resistant depression (similar to augmentation strategies with atypical antipsychotics) and is absent against suicidality itself. These findings need to be considered in light of esketamine's abuse potential and the fact that long-term effects are still not fully known. Some alarming signs concerning deaths and emerging suicidality during the testing phase are discussed, along with other regulatory issues.

Can machines be therapists?” is a question receiving increased attention given the relative ease of working with generative artificial intelligence. Although recent (and decades-old) research has found that humans struggle to tell the difference between responses from machines and humans, recent findings suggest that artificial intelligence can write empathically and the generated content is rated highly by therapists and outperforms professionals. It is uncertain whether, in a preregistered competition where therapists and ChatGPT respond to therapeutic vignettes about couple therapy, a) a panel of participants can tell which responses are ChatGPT-generated and which are written by therapists (N = 13), b) the generated responses or the therapist-written responses fall more in line with key therapy principles, and c) linguistic differences between conditions are present. In a large sample (N = 830), we showed that a) participants could rarely tell the difference between responses written by ChatGPT and responses written by a therapist, b) the responses written by ChatGPT were generally rated higher in key psychotherapy principles, and c) the language patterns between ChatGPT and therapists were different. Using different measures, we then confirmed that responses written by ChatGPT were rated higher than the therapist’s responses suggesting these differences may be explained by part-of-speech and response sentiment. This may be an early indication that ChatGPT has the potential to improve psychotherapeutic processes. We anticipate that this work may lead to the development of different methods of testing and creating psychotherapeutic interventions. Further, we discuss limitations (including the lack of the therapeutic context), and how continued research in this area may lead to improved efficacy of psychotherapeutic interventions allowing such interventions to be placed in the hands of individuals who need them the most.

Background: Long-term add-on antidepressant use for bipolar depression remains controversial. This study aimed to investigate primarily the association between psychopharmacological treatments and hospitalisation (ie, hospital admission) for bipolar depression, and secondarily the association between psychopharmacological treatments and hospitalisation for bipolar mania and somatic reasons in a registry-based national Swedish cohort. Methods: In this within-subject analysis, people diagnosed with bipolar disorder were identified from Swedish nationwide registers of inpatient and specialised outpatient care, sickness absence, and disability pension between Jan 1, 2006, and Dec 31, 2021. Data for hospitalisations, and antidepressant, antipsychotic, and mood stabiliser medication use were also retrieved from national databases. Treatment periods were modelled using the PRE2DUP method. Data were analysed with a within-individual design with stratified Cox Regression models, to eliminate selection bias when calculating adjusted hazard ratios (aHRs) and 95% CIs. The main outcome was hospitalisation due to depression and secondary outcomes were mania-related and somatic hospitalisations to address the risk-benefit ratio of antidepressant treatment. The reference was non-use of antidepressant, antipsychotic, and mood stabiliser medications. We also did head-to-head comparisons (ie, comparing different drug use periods within the same individual against each other) between medications to obtain results on comparative effectiveness while minimising confounding by indication. Ethnicity data were not available. People with related lived experience were involved in the research and writing process. Findings: The study cohort included 105 495 individuals (mean age 44·2 years, SD 18·8; 65 607 [62·2%] women and 39 888 [37·8%] men). In medication class-based analyses, a higher risk of depression-related hospitalisation was associated with the use of antidepressant only (aHR 1·25, 95% CI 1·16-1·34), antipsychotic only (1·39, 1·24-1·55), antidepressant-antipsychotic combination (1·28, 1·18-1·39), and antipsychotic-mood stabiliser combination treatment (1·13, 1·03-1·24). By contrast, use of mood stabilisers only (0·89, 0·81-0·98) was associated with lower risk. For specific monotherapies, only lithium was associated with lower depression-related hospitalisation risk (0·75, 0·67-0·85). No specific antidepressant monotherapy was associated with reduced depression-related hospitalisation, while several antidepressants and antipsychotics were related to an increased risk. In head-to-head comparisons, lithium monotherapy was associated with a superior outcome compared with antidepressant monotherapy (0·59, 0·51-0·68), antipsychotic monotherapy (0·54, 0·44-0·66), lamotrigine monotherapy (0·69, 0·53-0·91), and quetiapine monotherapy (0·54, 0·41-0·71). Lithium was associated with the lowest risk of somatic hospitalisation (0·86, 0·80-0·93) when compared with non-use of antidepressants, antipsychotics, and mood stabilisers. Finally, antidepressant-only treatment (1·22, 1·03-1·44) was associated with increased risk of mania-related hospitalisation and other monotherapies and combinations were associated with a lower risk. Interpretation: Since medications are typically started when depressive symptoms re-emerge, all treatments might appear less effective than they actually are when the reference is non-use of medication. Lithium was the only specific monotherapy with significantly reduced risk of depression-related hospitalisations when compared with non-use of antidepressants, antipsychotics, and mood stabilisers, and with more than 30% lower risk than any antidepressant, any antipsychotic, quetiapine, or lamotrigine monotherapy in the head-to-head analysis. Lithium was also associated with the lowest risk of somatic hospitalisation. Our findings supported the use of lithium as the mainstay of treatment in bipolar disorder.

Purpose: To evaluate the risk of bleeding associated with the simultaneous administration of antidepressants (ADs) and direct oral anticoagulants (DOACs). Methods: PubMed, Embase, and Scopus databases were searched for papers that focused on the concomitant administration of ADs and DOACs and presented data on the bleeding outcomes. The comparator group of interest was subjects who received only DOACs. Besides the overall pooled analysis, irrespective of the primary disease condition, we were also interested in studies involving patients with atrial fibrillation (AF). We therefore included studies with relevant comparisons (AD with DOACs, compared to DOACs alone), regardless of the reported underlying condition. Thereafter, we conducted a sensitivity analysis to refine estimates specific to AF. Clinical trials and observational studies were eligible. Pooled effect sizes were reported as relative risk (RR) for studies with cohort design and as odds ratio (OR) for case-control studies. Results: Ten studies were included. Overall pooled analysis showed that treatment with both DOAC and selective serotonin reuptake inhibitor and serotonin and norepinephrine reuptake inhibitor (SSRI/SNRI) was associated with significantly higher risk of major bleeding (cohort: RR 1.25, 95% CI: 1.07-1.47; case-control: OR 1.40, 95% CI: 1.15-1.69). The risk of intracranial bleeding was found to be increased when cohort studies were pooled (RR 1.44, 95% CI: 1.24-1.66), but not with pooling of case-control studies (OR 1.58, 95% CI: 0.43-5.75). The risk of gastrointestinal bleeding and transient ischemic attack (TIA)/ischemic stroke was comparable between the 2 groups (DOAC + SSRI/SNRI vs DOAC only group). Conclusions: Our results indicate that combined SSRIs/SNRIs and DOAC treatment may be associated with increased incidence of major and intracranial bleeding, further emphasizing the importance of caution when considering their concomitant use.

Introduction: Comorbidity between posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD) is prevalent. Despite evidence-based therapies, high rates of non-response and dropout persist. This study therefore aimed to examine whether the concurrent application of eye movement desensitization and reprocessing (EMDR) for PTSD and dialectical behavior therapy (DBT) for BPD yields better results than EMDR alone. Methods: Patients with a PTSD diagnosis and at least four BPD symptoms were randomly assigned to EMDR (n = 63) or concurrent EMDR-DBT (n = 61). Over one year, changes in PTSD symptoms were measured using the Clinician-Administered PTSD Scale for DSM-5. Secondary outcomes included BPD symptoms, global functioning and quality of life. Results: Both treatments led to large reductions in PTSD symptoms, without significant differences after one year (p = .312, d = -0.23, 95% CI = -0.6, 0.1). Both treatments also yielded large and comparable reductions in BPD symptoms and improved quality of life. Global functioning improved only in the EMDR condition according to one measure (WHODAS 2.0), while the other measure (OQ-45) showed improvements in both groups. Additionally, patients in the EMDR-DBT condition were twice as likely to drop out from EMDR treatment compared to those in the EMDR-only condition. Conclusion: Stand-alone EMDR demonstrated safety and efficacy in alleviating PTSD and BPD symptoms, as well as enhancing quality of life. These findings support the use of EMDR as a strong therapeutic option for patients with PTSD and comorbid BPD symptoms. Further research is needed to assess longer-term outcomes beyond one year.

Within precision psychiatry, there is a growing interest in normative models given their ability to parse heterogeneity. While they are intuitive and informative, the technical expertise and resources required to develop normative models may not be accessible to most researchers. Here we present Neurofind, a new freely available tool that bridges this gap by wrapping sound and previously tested methods on data harmonisation and advanced normative models into a web-based platform that requires minimal input from the user. We explain how Neurofind was developed, how to use the Neurofind website in four simple steps ( www.neurofind.ai ), and provide exemplar applications. Neurofind takes as input structural MRI images and outputs two main metrics derived from independent normative models: (1) Outlier Index Score, a deviation score from the normative brain morphology, and (2) Brain Age, the predicted age based on an individual's brain morphometry. The tool was trained on 3362 images of healthy controls aged 20-80 from publicly available datasets. The volume of 101 cortical and subcortical regions was extracted and modelled with an adversarial autoencoder for the Outlier index model and a support vector regression for the Brain age model. To illustrate potential applications, we applied Neurofind to 364 images from three independent datasets of patients diagnosed with Alzheimer's disease and schizophrenia. In Alzheimer's disease, 55.2% of patients had very extreme Outlier Index Scores, mostly driven by larger deviations in temporal-limbic structures and ventricles. Patients were also homogeneous in how they deviated from the norm. Conversely, only 30.1% of schizophrenia patients were extreme outliers, due to deviations in the hippocampus and pallidum, and patients tended to be more heterogeneous than controls. Both groups showed signs of accelerated brain ageing.

Objective: To examine the association between newer generation antidepressants and insomnia as an adverse event (AE) in the treatment of children and adolescents with major depressive disorder (MDD). Method: A systematic search was performed in major databases (inception to August 31, 2023) to retrieve double-blind, placebo-controlled, randomized controlled trials (RCTs) evaluating the safety of 19 antidepressants in the acute treatment (initial 6-12 weeks) of children and adolescents ≤18 years of age with MDD (primary analyses). RCTs in anxiety disorders and obsessive-compulsive disorder (OCD) were retrieved from a recent meta-analysis and included in complementary analyses. A mixed-effects logistic regression model was used to compare the frequency of insomnia in the antidepressant relative to the placebo group. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Results: In total, 20 trials in MDD (N = 5,357) and 8 trials in anxiety disorders and OCD (N = 1,271) evaluating selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) were included. In MDD, antidepressant treatment was associated with a modest increase in the odds of insomnia compared with placebo (odds ratio [OR] = 1.65, 95% CI = 1.21-2.27, p = .002), with no significant difference between SSRIs and SNRIs. The RCTs showed low risk of bias or minor concerns for the assessment of insomnia. The odds of treatment-emergent insomnia were significantly lower in MDD (OR = 1.62; 95% CI = 1.21-2.15) compared to anxiety disorders and OCD (OR = 2.89; 95% CI = 1.83-4.57) for treatment with SSRIs (p = .03). Among individual antidepressants with evidence from ≥3 studies, sertraline had the highest OR (3.45; 95% CI = 1.91-6.24), whereas duloxetine had the lowest OR (1.38; 95% CI = 0.79-2.43). Conclusion: Children and adolescents are at a modestly increased risk for experiencing insomnia during the first 6 to 12 weeks of treatment with SSRIs and SNRIs. Antidepressant- and disorder-specific variability in the risk of treatment-emergent insomnia may be relevant to consider in clinical decision making.

Objective: To evaluate the efficacy, safety, and tolerability of esketamine nasal spray versus psychoactive placebo (oral midazolam) in rapidly reducing depressive symptoms in adolescents with major depressive disorder at imminent risk for suicide. Method: This double-blind, double-dummy, phase 2b study randomized (1:1:1:2) 147 adolescents (12 to <18 years old) to esketamine (28, 56, or 84 mg) or midazolam twice-weekly for 4 weeks. Participants concomitantly received comprehensive standard-of-care (SOC), including initial hospitalization, oral antidepressant, and evidenced-based psychotherapy. The primary efficacy endpoint - change in Children's Depression Rating Scale-Revised (CDRS-R) total score from baseline to 24 hours post-first dose was analyzed using ANCOVA, according to a pooled sequential multiple-testing procedure. Results: All participants were moderately-to-severely depressed at enrollment; approximately 95% were moderately-to-extremely suicidal. Pooled esketamine doses (56 and 84 mg) showed superiority over midazolam in reducing CDRS-R total score at 24 hours post-first dose (between-group difference of LS means [95% CI]: -5.8 [-11.19, -0.35]; p=0.037). The between-group differences for individual 84 mg and 56 mg esketamine doses versus midazolam were -5.7 ([-12.91, 1.55], p=0.123) and -5.9 ([-12.25, 0.53], p=0.072), respectively. Severity of suicidality, per Clinical Global Impression-Severity of Suicidality Revised, improved in all 4 groups (between-group difference of LS means [95% CI]: -0.2 [-0.90, 0.41], -0.3 [-0.93, 0.31], 0.0 [-0.69, 0.72] for esketamine 28, 56, and 84 mg, respectively, at 24 hours post-first dose). Common adverse events (incidence ≥20%) reported for esketamine were dizziness, nausea, dissociation, headache, dysgeusia, somnolence, vomiting, hypoesthesia, and intentional self-injury. Conclusion: The primary efficacy endpoint of the study was met for the pooled esketamine doses (56 and 84 mg): Esketamine in conjunction with comprehensive SOC rapidly improved depressive symptoms among adolescents at imminent risk for suicide.

Objective: Selective serotonin reuptake inhibitors (SSRIs) are the first choice in pharmacotherapy for children and adolescents with obsessive-compulsive disorder (OCD). SSRI trials for pediatric OCD have not been investigated using individual participant data (IPD), which is crucial for detecting patient-level effect modifiers. This study performed an IPD meta-analysis of efficacy of SSRIs compared with placebo and a meta-regression on baseline patient characteristics that might modify efficacy. Method: Crude participant data from short-term, randomized, placebo-controlled SSRI trials for pediatric OCD were obtained from the registry of the Dutch regulatory authority. A systematic literature search was also performed, and authors were approached to provide IPD. A 1- and 2-stage analysis was conducted, with change on Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) as the primary outcome. Odds ratio (OR) with ≥35% CY-BOCS reduction was used as the responder outcome measure. Modifying effect of age, sex, weight, duration of illness, family history, and baseline symptom severity was examined. The Cochrane RoB 2.0 tool was used to examine methodological rigor, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to examine certainty of evidence. Results: Data were obtained from 4 studies comprising 614 patients. The sample represented 86% of all participants ever included in double-blind placebo-controlled SSRI trials for pediatric OCD. Meta-analysis showed reduction of 3.0 CY-BOCS points compared with placebo (95% CI 2.5-3.5), corresponding to a small effect size (0.38 Hedges' g). Analysis of response showed an odds ratio of 1.89 (95% CI 1.45-2.45). Of all possible modifiers, severity was correlated negatively with odds ratio for response (β = -0.92, p = .0074). Risk of bias was generally low. All studies were performed in North America with an overrepresentation of White participants. Findings were limited by inability to include data on additional variables such as socioeconomic status and comorbidities. Conclusion: This IPD meta-analysis showed a small effect size of SSRIs in pediatric OCD, with baseline severity as a negative modifier of response. Generalizability of findings might be limited by selective inclusion of White, North American participants.

Importance: Neurofeedback has been proposed for the treatment of attention-deficit/hyperactivity disorder (ADHD) but the efficacy of this intervention remains unclear. Objective: To conduct a meta-analysis of randomized clinical trials (RCTs) using probably blinded (ie, rated by individuals probably or certainly unaware of treatment allocation) or neuropsychological outcomes to test the efficacy of neurofeedback as a treatment for ADHD in terms of core symptom reduction and improved neuropsychological outcomes. Data sources: PubMed (MEDLINE), Ovid (PsycInfo, MEDLINE, Embase + Embase Classic), and Web of Science, as well as the reference lists of eligible records and relevant systematic reviews, were searched until July 25, 2023, with no language limits. Study selection: Parallel-arm RCTs investigating neurofeedback in participants of any age with a clinical ADHD or hyperkinetic syndrome diagnosis were included. Data extraction and synthesis: Standardized mean differences (SMDs) with Hedges g correction were pooled in random effects meta-analyses for all eligible outcomes. Main outcomes and measures: The primary outcome was ADHD total symptom severity assessed at the first postintervention time point, focusing on reports by individuals judged probably or certainly unaware of treatment allocation (probably blinded). Secondary outcomes were inattention and/or hyperactivity-impulsivity symptoms and neuropsychological outcomes postintervention and at a longer-term follow-up (ie, after the last follow-up time point). RCTs were assessed with the Cochrane risk of bias tool version 2.0. Results: A total of 38 RCTs (2472 participants aged 5 to 40 years) were included. Probably blinded reports of ADHD total symptoms showed no significant improvement with neurofeedback (k = 20; n = 1214; SMD, 0.04; 95% CI, -0.10 to 0.18). A small significant improvement was seen when analyses were restricted to RCTs using established standard protocols (k = 9; n = 681; SMD, 0.21; 95% CI, 0.02 to 0.40). Results remained similar with adults excluded or when analyses were restricted to RCTs where cortical learning or self-regulation was established. Of the 5 neuropsychological outcomes analyzed, a significant but small improvement was observed only for processing speed (k = 15; n = 909; SMD, 0.35; 95% CI, 0.01 to 0.69). Heterogeneity was generally low to moderate. Conclusions and relevance: Overall, neurofeedback did not appear to meaningfully benefit individuals with ADHD, clinically or neuropsychologically, at the group level. Future studies seeking to identify individuals with ADHD who may benefit from neurofeedback could focus on using standard neurofeedback protocols, measuring processing speed, and leveraging advances in precision medicine, including neuroimaging technology.

Importance: Pediatric posttraumatic stress disorder (PTSD) is a common and debilitating mental disorder, yet a comprehensive network meta-analysis examining psychological interventions is lacking. Objective: To synthesize all available evidence on psychological interventions for pediatric PTSD in a comprehensive systematic review and network meta-analysis. Data sources: PsycINFO, MEDLINE, Web of Science, and PTSDpubs were searched from inception to January 2, 2024, and 74 related systematic reviews were screened. Study selection: Two independent raters screened publications for eligibility. Inclusion criteria were randomized clinical trial (RCT) with at least 10 patients per arm examining a psychological intervention for pediatric PTSD compared to a control group in children and adolescents (19 years and younger) with full or subthreshold PTSD. Data extraction and synthesis: PRISMA guidelines were followed to synthesize and present evidence. Two independent raters extracted data and assessed risk of bias with Cochrane criteria. Random-effects network meta-analyses were run. Main outcome and measures: Standardized mean differences (Hedges g) in PTSD severity. Results: In total, 70 RCTs (N = 5528 patients) were included. Most RCTs (n = 52 [74%]) examined trauma-focused cognitive behavior therapies (TF-CBTs). At treatment end point, TF-CBTs (g, 1.06; 95% CI, 0.86-1.26; P < .001), eye movement desensitization and reprocessing (EMDR; g, 0.86; 95% CI, 0.54-1.18; P < .001), multidisciplinary treatments (MDTs) (g, 0.88; 95% CI, 0.53-1.23; P < .001), and non-trauma-focused interventions (g, 0.95; 95% CI, 0.62-1.28; P < .001) were all associated with significantly larger reductions in pediatric PTSD than passive control conditions. TF-CBTs were associated with the largest short-term reductions in pediatric PTSD relative to both passive and active control conditions and across all sensitivity analyses. In a sensitivity analysis including only trials with parent involvement, TF-CBTs were associated with significantly larger reductions in pediatric PTSD than non-trauma-focused interventions (g, 0.35; 95% CI, 0.04-0.66; P = .03). Results for midterm (up to 5 months posttreatment) and long-term data (6-24 months posttreatment) were similar. Conclusions and relevance: Results from this systematic review and network meta-analysis indicate that TF-CBTs were associated with significant reductions in pediatric PTSD in the short, mid, and long term. More long-term data are needed for EMDR, MDTs, and non-trauma-focused interventions. Results of TF-CBTs are encouraging, and disseminating these results may help reduce common treatment barriers by counteracting common misconceptions, such as the notion that TF-CBTs are harmful rather than helpful.

Importance: Interest in and use of hallucinogens has been increasing rapidly. While a frequently raised concern is that hallucinogens may be associated with an increased risk of psychosis, there are limited data on this association. Objectives: To examine whether individuals with an emergency department (ED) visit involving hallucinogen use have an increased risk of developing a schizophrenia spectrum disorder (SSD). Design, settings, and participants: This population-based, retrospective cohort study (January 2008 to December 2021) included all individuals aged 14 to 65 years in Ontario, Canada, with no history of psychosis (SSD or substance induced). Data were analyzed from May to August 2024. Exposure: An incident ED visit involving hallucinogen use. Main outcomes and measures: Diagnosis of SSD using a medical record-validated algorithm. Associations between ED visits involving hallucinogens and SSD were estimated using cause-specific adjusted hazard models. Individuals with an incident ED visit involving hallucinogens were compared with members of the general population (primary analysis) or individuals with ED visits involving alcohol or cannabis (secondary analysis). Results: The study included 9 244 292 individuals (mean [SD] age, 40.4 [14.7] years; 50.2% female) without a history of psychosis, with a median follow-up of 5.1 years (IQR, 2.3-8.6 years); 5217 (0.1%) had an incident ED visit involving hallucinogen use. Annual rates of incident ED visits involving hallucinogens were stable between 2008 and 2012 and then increased by 86.4% between 2013 and 2021 (3.4 vs 6.4 per 100 000 individuals). Individuals with ED visits involving hallucinogens had a greater risk of being diagnosed with an SSD within 3 years compared with the general population (age- and sex-adjusted hazard ratio [HR], 21.32 [95% CI, 18.58-24.47]; absolute proportion with SSD at 3 years, 208 of 5217 with hallucinogen use [3.99%] vs 13 639 of 9 239 075 in the general population [0.15%]). After adjustment for comorbid substance use and mental health conditions, individuals with hallucinogen ED visits had a greater risk of SSD compared with the general population (HR, 3.53; 95% CI, 3.05-4.09). Emergency department visits involving hallucinogens were associated with an increased risk of SSD within 3 years compared with ED visits involving alcohol (HR, 4.66; 95% CI, 3.82-5.68) and cannabis (HR, 1.47; 95% CI, 1.21-1.80) in the fully adjusted model. Conclusions and relevance: In this cohort study, individuals with an ED visit involving hallucinogen use had a greater risk of developing an SSD compared with both the general population and with individuals with ED visits for other types of substances. These findings have important clinical and policy implications given the increasing use of hallucinogens and associated ED visits.

Importance: Adolescent cannabis use has been consistently posited to contribute to the onset and progression of psychosis. However, alternative causal models may account for observed associations between cannabis use and psychosis risk, including shared vulnerability for both cannabis use and psychosis or efforts to self-medicate distress from psychosis spectrum symptomology. Objective: To test 3 hypotheses that may explain cannabis-psychosis risk associations by modeling psychosis spectrum symptom trajectories prior to and after cannabis initiation across adolescent development (approximately 10-15 years of age). Design, setting, and participants: This cohort study used data from 5 waves across 4 years of follow-up from the Adolescent Brain Cognitive Development (ABCD) Study. The ABCD study is an ongoing large-scale, longitudinal study of brain development and mental and physical health of children in the US launched in June 2016. Data are collected from 21 research sites. The study included data from 11 868 adolescents aged 9 to 10 years at baseline. Three participants were excluded from the present analysis owing to missing data. Data analysis was performed from September 2023 to July 2024. Main outcomes and measures: Discontinuous growth curve modeling was used to assess trajectories of psychosis spectrum symptoms before and after cannabis initiation. Control variables considered for this investigation were age, sex, internalizing and externalizing symptoms, socioeconomic status, parental mental health, and other substance use. Results: Among the 11 858 participants at wave 1, the mean (SD) age was 9.5 (0.5) years; 6182 (52%) participants were male. Consistent with a shared vulnerability hypothesis, adolescents who used cannabis at any point during the study period reported a greater number of psychosis spectrum symptoms (B, 0.86; 95% CI, 0.68-1.04) and more distress (B, 1.17; 95% CI, 0.96-1.39) from psychosis spectrum symptoms relative to those who never used cannabis. Additionally, consistent with a self-medication hypothesis, the number of psychosis spectrum symptoms (B, 0.16; 95% CI, 0.12-0.20) and distress (B, 0.23; 95% CI, 0.21-0.26) from psychosis spectrum symptoms increased in the time leading up to cannabis initiation. We observed mixed evidence for an increase in psychosis symptoms after cannabis initiation (ie, contributing risk hypothesis). Conclusion and relevance: The findings underscore the importance of accounting for shared vulnerability and self-medication effects when modeling cannabis-psychosis risk associations.

Background: The association between delirium and dementia has been suggested, but mostly in the postoperative setting. This study aims to explore this relationship in a broader inpatient population, leveraging extensive real-world data to provide a more generalized understanding. Methods: In this retrospective cohort study, electronic health records of 11,970,475 hospitalized patients aged over 60 from nine institutions in South Korea were analyzed. Patients with and without delirium were identified, and propensity score matching (PSM) was used to create comparable groups. A 10-year longitudinal analysis was conducted using the Cox proportional hazards model, which calculated the hazard ratio (HR) and 95% confidence interval (CI). Additionally, a meta-analysis was performed, aggregating results from all nine medical institutions. Lastly, we conducted various subgroup and sensitivity analyses to demonstrate the consistency of our study results across diverse conditions. Results: After 1:1 PSM, a total of 47,306 patients were matched in both the delirium and nondelirium groups. Both groups had a median age group of 75-79 years, with 43.1% being female. The delirium group showed a significantly higher risk of all dementia compared with the nondelirium group (HR: 2.70 [95% CI: 2.27-3.20]). The incidence risk for different types of dementia was also notably higher in the delirium group (all dementia or mild cognitive impairment, HR: 2.46 [95% CI: 2.10-2.88]; Alzheimer's disease, HR: 2.74 [95% CI: 2.40-3.13]; vascular dementia, HR: 2.55 [95% CI: 2.07-3.13]). This pattern was consistent across all subgroup and sensitivity analyses. Conclusions: Delirium significantly increases the risk of onset for all types of dementia. These findings highlight the importance of early detection of delirium and prompt intervention. Further research studies are warranted to investigate the mechanisms linking delirium and dementia.

Introduction: The rising prevalence of Alzheimer's disease (AD) and related dementia worldwide underscores the urgent need for effective interventions, particularly for managing neuropsychiatric symptoms (NPS) such as sleep disturbance. This review explores the emerging role of Dual Orexin Receptor Antagonists (DORA) in addressing sleep disturbance in patients with Alzheimer's disease dementia. Methods: A comprehensive literature search identified four relevant publications between 2014 and 2024, detailing the use of DORA medications, including suvorexant and lemborexant, in patients with Alzheimer's disease. Results: Findings suggest that suvorexant may improve total sleep time (TST), wakefulness after sleep onset (WASO), and sleep efficiency (SE) in Alzheimer's patients with insomnia. Lemborexant demonstrated potential in improving circadian rhythm parameters, particularly in patients with irregular sleep-wake rhythm disorder (ISWRD). Safety profiles of DORA medications appeared favorable, with mild to moderate adverse events reported. However, concerns over potential adverse events, such as falls, underscore the need for careful monitoring. Conclusion: While the evidence suggests promise for DORA medications in addressing sleep disturbance in Alzheimer's disease, limitations in study populations and duration highlight the need for further investigation. Future clinical trials should aim for broader inclusion criteria, encompassing diverse dementia subtypes and severity levels, to enhance generalizability. Additionally, longer-term trials are essential to assess the sustained efficacy and safety of DORA interventions in this vulnerable population.

This article explores the potential of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy to enhance exposure and response prevention in obsessive-compulsive disorder treatment. We discuss the mechanisms of MDMA, including fear extinction, psychological flexibility, and empathogenic effects that may improve adherence and efficacy, as well as highlighting important safety considerations for further research.