March 2025

Background: Despite affecting 2-4% of the population worldwide, fibromyalgia often remains refractory to treatment. Here we report the first international randomised double-blind, sham-controlled trial developed to assess the efficacy of repetitive transcranial magnetic stimulation (rTMS) as an add-on therapy for fibromyalgia. Methods: Women aged ≥18 yr with fibromyalgia refractory to best available treatment were enrolled in Brazil, France, and Japan, and randomised to 10 Hz motor cortex (M1) rTMS, 3000 pulses day-1, or sham stimulation. This included 10 induction sessions over 2 weeks, followed by weekly maintenance (6 weeks), and fortnightly extended maintenance (8 weeks). Primary outcome was ≥50% pain reduction at week 8 compared with baseline. Secondary outcomes included pain interference, mood, global impression of change, and Fibromyalgia Impact Questionnaire (FIQ) scores at weeks 8 and 16. Results: We randomised 101 women (mean age 48 [range 25-83] yr) into active (n=52) or sham (n=49) arms. Bayesian analysis revealed a 99.4% probability of ≥50% pain reduction at week 8 in the active group vs sham (odds ratio [OR] 3.04; 95% credible interval [95% CrI] 1.26-8.06), with a number needed to treat of 4.54. Frequentist analysis confirmed that relative pain reduction was higher in the active than in the sham group (40.4% vs 18.4%, P=0.028). At week 16, this probability reduced to 34.2% (OR 0.815; 95% CrI 0.313-2.1), but the likelihood of FIQ score reduction was 79.1%. The intervention appeared safe. Conclusions: Add-on M1-repetitive transcranial magnetic stimulation reduced pain intensity up to 8 weeks in women with fibromyalgia. Although analgesic effects waned, functional improvements remained during extended maintenance at week 16.

Background: Depression in older adults is often undertreated. A 2011 systematic review of treatments for treatment-resistant depression (TRD) in older adults identified one placebo-controlled randomised controlled trial (RCT). We aimed to update this review, synthesising evidence for the effectiveness of treatments for TRD in older people. Methods: We systematically searched electronic databases (PubMed, Cochrane, Web of Science) from 9 January 2011 through 10 December 2023 (updating our search on 7 January 2024 for RCTs investigating TRD therapies in adults aged ≥55 years, defining treatment resistance as ≥1 unsuccessful treatment. We assessed bias with the Cochrane Risk of Bias (RoB) 2 tool, meta-analysed remission rates and evaluated evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Results: 14 studies (11 newly identified, 3 from previous review) involving 1196 participants (mean age 65.0, male/female 548/648) met the inclusion criteria; 10 were placebo controlled and 4 were rated as low RoB. The pooled proportion of participants in intervention arms remitting was 0.35 (17 arms; 95% CI=0.26; 0.45). Relative to placebo, intervention participants were more likely to remit (9 studies; OR 2.42 (95% CI=1.49; 3.92)). Relative to controls, remission rates favoured ketamine (n=3; OR 2.91 (1.11; 7.65)), with a trend towards transcranial magnetic stimulation (TMS) (n=3; 1.99 (0.71; 5.61)), and in single placebo-controlled studies, selegiline, aripiprazole augmentation, pharmacogenetic-guided prescribing (PGP) and cognitive remediation favoured interventions. Conclusions: We identified weak evidence that ketamine therapy and aripiprazole augmentation, and very weak evidence that TMS, PGP and cognitive remediation increased remission. Lack of evidence regarding routinely prescribed antidepressants and psychosocial treatments is problematic, requiring clinicians to extend evidence from younger populations.

Background: Despite the promising therapeutic effects of psilocybin, its efficacy in preventing relapse after withdrawal treatment for alcohol use disorder (AUD) remains unknown. This study aims to assess whether a single dose of psilocybin combined with brief psychotherapy could reduce relapse rates and alcohol use in AUD patients. Methods: This single-center, double-blind, randomized clinical trial was conducted in Switzerland. We recruited participants with AUD between June 8, 2020, and August 16, 2023 who completed withdrawal treatment within six weeks prior to enrollment. Participants were randomized (1:1) to receive either a single oral dose of psilocybin (25 mg) or placebo (mannitol), combined with brief psychotherapy. The primary outcomes were abstinence and mean alcohol use at 4-week follow-up. Participants completed the timeline followback to assess daily alcohol use. The trial is registered on ClinicalTrials.gov (NCT04141501). Findings: We included 37 participants who completed the 4-week follow-up (female:male = 14:23; psilocybin = 18, placebo = 19) in the analysis. There were no significant differences between groups in abstinence duration (p = 0.55, psilocybin mean = 16.80 days, 95% CI: 14.31-19.29; placebo mean = 13.80 days, 95% CI: 10.97-16.63; Cohen's d = 0.151) or mean alcohol use per day (p = 0.51, psilocybin: median = 0.48 standard alcohol units, range: 0-3.99, placebo: median = 0.54 standard alcohol units, range: 0-5.96; Cohen's d = 0.11) at 4-week or 6-month follow-up (abstinence: Cohen's d = 0.10, alcohol use: Cohen's d = 0.075). Participants in both groups reported reduced craving and temptation to drink alcohol after the dosing visit, with an additional reduction observed in the psilocybin group. Thirteen adverse events occurred in the psilocybin and seven in the placebo group. One serious adverse event occurred in the psilocybin and four in the placebo group, all related to inpatient withdrawal treatments. Interpretation: A single dose of psilocybin combined with five psychotherapy sessions may not be sufficient to reduce relapse rates and alcohol use in severely affected AUD patients following withdrawal treatment. However, given the limited sample size of our study, larger trials are needed in the future to confirm these findings.

Importance: Stimulants are increasingly prescribed for US adults. Whether such prescribing is associated with misuse and prescription stimulant use disorder (PSUD) is less understood. Objectives: To examine (1) sex- and age-specific trends in the number of persons dispensed stimulants and trends in dispensed prescription stimulants by prescriber specialty in 2019 through 2022; (2) prevalence of misuse and PSUD by use of prescription amphetamine-type stimulants (hereafter referred to as amphetamines) and methylphenidate; and (3) PSUD prevalence and sociodemographic and behavioral health correlates among persons using prescription stimulants with and without prescription stimulant misuse. Design, setting, and participants: This cross-sectional survey study used the 2019-2022 IQVIA Total Patient Tracker and National Prescription Audit New to Brand databases and the 2021-2022 National Surveys on Drug Use and Health (NSDUH) (community-dwelling 18- to 64-year-old individuals). Data analysis was performed from March to April 2024. Exposure: Past-year use of prescription stimulants. Main outcomes and measures: PSUD using DSM-5 criteria. Results: Of the sampled 83 762 adults aged 18 to 64 years, 33.8% (unweighted) were aged 18 to 25 years, 53.0% (unweighted) were aged 26 to 49 years, and 56.0% (unweighted) were women. Among those using prescription stimulants, 25.3% (95% CI, 23.8%-26.8%) reported misuse, and 9.0% (95% CI, 8.0%-10.0%) had PSUD. Among those with PSUD, 72.9% (95% CI, 68.3%-77.6%) solely used their own prescribed stimulants, 87.1% (95% CI, 82.3%-90.8%) used amphetamines, 42.5% (95% CI, 36.6%-48.5%) reported no misuse, and 63.6% (95% CI, 56.8%-69.8%) had mild PSUD. Individuals using amphetamines, compared with those using methylphenidate, had higher prevalence ratios of misuse (3.1 [95% CI, 2.2-4.3]) and PSUD (2.2 [95% CI, 1.3-3.8]). The largest increase in the number of individuals dispensed prescription stimulants was among women aged 35 to 64 years, from 1.2 million in quarter 1 of 2019 to 1.7 million in quarter 4 of 2022 (average quarterly percentage change, 2.6% [95% CI, 2.1%-3.1%]). The prevalence of prescription stimulant misuse was lower among women aged 35 to 64 years using these medications (13.7% [95% CI, 11.1%-16.8%]) than other sex- and age-specific subgroups (ranging from 22.0% [95% CI, 17.9%-26.7%] for men aged 35-64 years to 36.8% [95% CI, 32.6%-41.2%] for women aged 18-25 years). Conclusions and relevance: High prevalence of prescription stimulant misuse and PSUD (regardless of misuse status) suggests the importance of ensuring clinically appropriate use and of screening for and treating PSUD among all adults prescribed stimulants, especially those using amphetamines. Findings may suggest potential progress in addressing the mental health care gap for middle-aged women and the need for evidence-based clinical guidance and training on benefits and risks of prescription stimulants for adults.

Importance: Bariatric surgery, once the criterion standard in obesity treatment, has a small but concerning association with increased suicidality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed to treat diabetes, now provide substantial efficacy in the treatment of obesity. However, concerns of risk of suicidality with these medicines have been raised. Objective: To evaluate the risk of suicidality and self-harm in randomized, placebo-controlled trials of GLP-1 RAs in adults with diabetes or obesity. Data sources: MEDLINE, Embase, ClinicalTrials.gov, and Cochrane databases were systematically searched from inception to August 29, 2023. Study selection: Reports of randomized clinical trials (RCTs) lasting 6 or more months comparing GLP-1 RAs with placebo for the treatment of diabetes or obesity published in peer-reviewed journals were identified. Two independent reviewers screened all search-identified studies for inclusion. Records of outcomes were queried from primary papers, ClinicalTrials.gov entries, and corresponding authors. Data extraction and synthesis: Two independent researchers abstracted data and assessed data quality and validity using PRISMA guidelines. Data were pooled using random-effects models. Main outcomes and measures: Pooled incidence of completed or attempted suicide, occurrences of suicidal ideation, or self-harm. Results: A total of 27 of 144 RCTs meeting inclusion criteria systematically recorded suicide and/or self-harm-related events and included 32 357 individuals receiving GLP-1 RAs and 27 046 treated with placebo, over 74 740 and 68 095 person-years of follow-up, respectively. Event incidence was very low in the GLP-1 RA (0.044 per 100 person-years) and placebo (0.040 per 100 person-years) groups, with no statistically significant difference (rate ratio [RR], 0.76; 95% CI, 0.48-1.21; P = .24). Subgroup analyses did not suggest differences in outcomes based on diabetes status or GLP-1 RA used. Five studies were considered at risk of bias due to the loss of more than 5% of participants to follow-up. Otherwise, studies were not found to be heterogeneous nor at high risk of bias. Conclusions and relevance: There is unlikely to be an increase in the very low incidence of suicide-related adverse events among individuals receiving GLP-1 RAs within the context of RCTs. While these findings may further ease concerns about these adverse effects, continued monitoring is warranted to identify particular patients who may be at risk as extended use of GLP-1 RAs expands.

Importance: In the Netherlands, a growing group of young people request medical assistance in dying based on psychiatric suffering (MAID-PS). Little is known about this group, their characteristics, and outcomes. Objective: To assess the proportion of requests for and deaths by MAID-PS among young patients, outcomes of their application and assessment procedures, and characteristics of those patients who died by either MAID or suicide. Design, setting, and participants: This retrospective cohort study included Dutch individuals younger than 24 years requesting MAID-PS between January 1, 2012, and June 30, 2021, whose patient file had been closed by December 1, 2022, at the Expertisecentrum Euthanasie, a specialized health care facility providing MAID consultation and care. Main outcomes and measures: Outcomes of the MAID-PS assessment procedure (discontinued, rejected, or MAID-PS) and clinical characteristics of patients who died by MAID or suicide. Results: The study included 397 processed applications submitted by 353 individuals (73.4% female; mean [SD] age, 20.84 [1.90] years). Between 2012 and the first half of 2021, the number of MAID-PS applications by young patients increased from 10 to 39. The most likely outcome was application retracted by the patient (188 [47.3%]) followed by application rejected (178 [44.8%]). For 12 applications (3.0%), patients died by MAID. Seventeen applications (4.3%) were stopped because the patient died by suicide during the application process and 2 (0.5%) because the patient died after they voluntarily stopped eating and drinking. All patients who died by suicide or MAID (n = 29) had multiple psychiatric diagnoses (most frequently major depression, autism spectrum disorder, personality disorders, eating disorder, and/or trauma-related disorder) and extensive treatment histories. Twenty-eight of these patients (96.5%) had a history of suicidality that included multiple suicide attempts prior to the MAID application. Among 17 patients who died by suicide, 13 of 14 (92.9%) had a history of crisis-related hospital admission, and 9 of 12 patients who died by MAID (75.0%) had a history of self-harm. Conclusions and relevance: This cohort study found that the number of young psychiatric patients in the Netherlands who requested MAID-PS increased between 2012 and 2021 and that applications were retracted or rejected for most. Those who died by MAID or suicide were mostly female and had long treatment histories and prominent suicidality. These findings suggest that there is an urgent need for more knowledge about persistent death wishes and effective suicide prevention strategies for this high-risk group.

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) trials targeting the anterior limb of the internal capsule have shown promising results. We evaluated the long-term safety and efficacy of MRgFUS capsulotomy in patients with obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Methods: This phase 1, single-center, open-label study recruited patients with treatment-resistant OCD and MDD. Outcomes were measured 6 months, 12 months, and 18 to 24 months (long term) after MRgFUS capsulotomy. Neuropsychological testing and neuroimaging were conducted at baseline and 12 months postoperatively. The primary outcome was safety. The secondary outcome was clinical response, defined for OCD as a ≥35% improvement in Yale-Brown Obsessive Compulsive Scale scores and for MDD as a ≥50% reduction in Hamilton Depression Rating Scale scores compared with baseline. Results: No serious adverse effects were registered. In patients with OCD (n= 15), baseline Yale-Brown Obsessive Compulsive Scale scores (31.9 ± 1.2) were significantly reduced by 23% (p = .01) at 6 months and 35% (p < .0001) at 12 months. In patients with MDD (n = 12), a 26% and 25% nonsignificant reduction in Hamilton Depression Rating Scale scores (baseline 24.3 ± 1.2) was observed at 6 months and 12 months, respectively. Neuropsychological testing revealed no negative effects of capsulotomy. In the OCD and MDD cohorts, we found a correlation between clinical outcome and lesion laterality, with more medial left-placed lesions (OCD, p = .08) and more lateral right-placed lesions (MDD, p < .05) being respectively associated with a stronger response. In the MDD cohort, more ventral tracts appeared to be associated with a poorer response. Conclusions: MRgFUS capsulotomy is safe in patients with OCD and MDD and particularly effective in the former population.

Background: Lithium and quetiapine are first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. We aimed to assess whether quetiapine augmentation therapy is more clinically effective and cost-effective than lithium for patients with treatment-resistant depression over 12 months. Methods: We did this pragmatic, open-label, parallel-group, randomised controlled superiority trial at six National Health Service trusts in England. Eligible participants were adults (aged ≥18 years) with a current episode of major depressive disorder meeting DSM-5 criteria, with a score of 14 or higher on the 17-item Hamilton Depression Rating Scale at screening who had responded inadequately to two or more therapeutic antidepressant trials. Exclusion criteria included having a diagnosis of bipolar disorder or current psychosis. Participants were randomly assigned (1:1) to the decision to prescribe lithium or quetiapine, stratified by site, depression severity, and treatment resistance, using block randomisation with randomly varying block sizes. After randomisation, pre-prescribing safety checks were undertaken as per standard care before proceeding to trial medication initiation. The coprimary outcomes were depressive symptom severity over 12 months, measured weekly using the Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation. Economic analyses compared the cost-effectiveness of the two treatments from both an NHS and personal social services perspective, and a societal perspective. Primary analyses were done in the intention-to-treat population, which included all randomly assigned participants. People with lived experience were involved in the trial. The trial is completed and registered with the International Standard Randomised Controlled Trial registry, ISRCTN16387615. Findings: Between Dec 5, 2016, and July 26, 2021, 212 participants (97 [46%] male gender and 115 [54%] female gender) were randomly assigned to the decision to prescribe quetiapine (n=107) or lithium (n=105). The mean age of participants was 42·4 years (SD 14·0 years) and 188 (89%) of 212 participants were White, seven (3%) were of mixed ethnicity, nine (4%) participants were Asian, four (2%) were Black, three (1%) were of Other ethnicity, and ethnicity was not recorded for one (1%) participant. Participants in the quetiapine group had a significantly lower overall burden of depressive symptom severity than participants in the lithium group (area under the between-group differences curve -68·36 [95% CI -129·95 to -6·76; p=0·0296). Time to discontinuation did not significantly differ between the two groups. Quetiapine was more cost-effective than lithium. 32 serious adverse events were recorded in 18 participants, one of which was deemed possibly related to the trial medication in a female participant in the lithium group. The most common serious adverse event was overdose, occurring in three (3%) of 107 participants in the quetiapine group (seven events) and three (3%) of 105 participants in the lithium group (five events). Interpretation: Results of the trial suggest that quetiapine is more clinically effective than lithium as a first-line augmentation option for reducing symptoms of depression in the long-term management of treatment-resistant depression, and is probably more cost-effective than lithium

Background: Clozapine is recommended by national and international guidelines for people with treatment-resistant schizophrenia. However, available meta-analyses of randomised controlled trials have not shown superior efficacy of clozapine when compared with other second-generation antipsychotics, with heterogeneity identified between the original studies. We aimed to use individual patient data (IPD) to account for potential reasons of variability and to synthesise an adjusted estimate for the difference in efficacy between clozapine and other second-generation antipsychotics for treatment-resistant schizophrenia. Methods: In this systematic review and IPD meta-analysis, we searched the Cochrane Schizophrenia Group's Study-Based Register from inception to Jan 24, 2024, and previous reviews for blinded randomised controlled trials comparing clozapine with other second-generation antipsychotics in participants with treatment-resistant schizophrenia. Trials were eligible if they included patients with treatment-resistant schizophrenia and had a duration of at least 6 weeks. IPD were requested from trial investigators. The primary outcome was change in overall schizophrenia symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) between clozapine and other second-generation antipsychotics after 6-8 weeks of treatment. The effect size measure for the primary outcome was mean difference with 95% credible interval (CrI). We fitted a Bayesian random-effects IPD meta-regression model that included duration of illness, baseline severity, and sex as potential prognostic factors or treatment effect modifiers. Confidence in the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). People with lived experience of mental illness were involved in this study. This study is registered with PROSPERO, CRD42021254986. Findings: We screened 13 876 references and included 19 studies with data for 1599 participants; IPD were available for 12 of 19 trials (n=1052; mean age 37·67 years [SD 11·24; range 10-66]; 348 [33·08%] women and 704 [66·92%] men). Data on ethnicity were not available. The estimated mean difference in change from baseline PANSS total score was -0·64 points (95% CrI -3·97 to 2·63; τ=2·68) in favour of other second-generation antipsychotics. Shorter duration of illness and higher baseline severity were prognostic factors associated with a larger reduction in symptoms, but neither those factors nor sex were found to modify the relative effect between clozapine and other second-generation antipsychotics. The confidence in the evidence was graded as very low. Interpretation: This IPD meta-analysis found a small and uncertain advantage of other second-generation antipsychotics, mainly olanzapine and risperidone, and so did not provide evidence for superior efficacy of clozapine compared with other second-generation antipsychotics in treatment-resistant schizophrenia. It is limited by unavailability of IPD for some studies, uncaptured sources of variance, and uncertainty due to premature study discontinuation. Given the side-effects of clozapine, the observed uncertainty regarding clozapine's superiority warrants prudent use and further research.

Background: Although repetitive transcranial magnetic stimulation (rTMS) is an effective and commonly used treatment option for treatment-resistant depression, its cost-effectiveness remains much less studied. In particular, the comparative cost-effectiveness of rTMS and other treatment options, such as antidepressant medication, has not been investigated. Methods: An economic evaluation with 12 months follow-up was conducted in the Dutch care setting as part of a pragmatic multicenter randomized controlled trial, in which patients with treatment-resistant depression were randomized to treatment with rTMS or treatment with the next pharmacological step according to the treatment algorithm. Missing data were handled with single imputations using predictive mean matching (PMM) nested in bootstraps. Incremental cost-effectiveness and cost-utility ratios (ICERs/ICURs) were calculated, as well as cost-effectiveness planes and cost-effectiveness acceptability curves (CEACs). Results: Higher QALYs, response, and remission rates were found for lower costs when comparing the rTMS group to the medication group. After 12 months, QALYs were 0.618 in the rTMS group and 0.545 in the medication group. The response was 27.1% and 24.4% and remission was 25.0% and 17.1%, respectively. Incremental costs for rTMS were -€2.280, resulting in a dominant ICUR for QALYs and ICER for response and remission. Conclusion: rTMS appears to be a cost-effective treatment option for treatment-resistant depression when compared to the next pharmacological treatment step. The results support the implementation of rTMS as a step in the treatment algorithm for depression.

Importance: New pharmacotherapy options are needed for posttraumatic stress disorder (PTSD). Objective: To investigate the efficacy, safety, and tolerability of brexpiprazole and sertraline combination treatment (brexpiprazole + sertraline) compared with sertraline + placebo for PTSD. Design, setting, and participants: This was a parallel-design, double-blind, randomized clinical trial conducted from October 2019 to August 2023. The study had a 1-week, placebo run-in period followed by an 11-week, double-blind, randomized, active-controlled, parallel-arm period (with 21-day follow-up) and took place at 86 clinical trial sites in the US. Adult outpatients with PTSD were enrolled (volunteer sample). Interventions: Oral brexpiprazole 2 to 3 mg per day (flexible dose) + sertraline 150 mg per day or sertraline 150 mg per day + placebo (1:1 ratio) for 11 weeks. Main outcomes and measures: The primary end point was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score (which measures the severity of 20 PTSD symptoms) from randomization (week 1) to week 10 for brexpiprazole + sertraline vs sertraline + placebo. Safety assessments included adverse events. Results: A total of 1327 individuals were assessed for eligibility. After 878 screen failures, 416 participants (mean [SD] age, 37.4 [11.9] years; 310 female [74.5%]) were randomized. Completion rates were 137 of 214 participants (64.0%) for brexpiprazole + sertraline and 113 of 202 participants (55.9%) for sertraline + placebo. At week 10, brexpiprazole + sertraline demonstrated statistically significant greater improvement in CAPS-5 total score (mean [SD] at randomization, 38.4 [7.2]; LS mean [SE] change, -19.2 [1.2]; n = 148) than sertraline + placebo (randomization, 38.7 [7.8]; change, -13.6 [1.2]; n = 134), with LS mean difference, -5.59 (95% CI, -8.79 to -2.38; P < .001). All key secondary and other efficacy end points were also met. Treatment-emergent adverse events with incidence of 5% or greater for brexpiprazole + sertraline (and corresponding incidences for sertraline + placebo) were nausea (25 of 205 [12.2%] and 23 of 196 [11.7%]), fatigue (14 of 205 [6.8%] and 8 of 196 [4.1%]), weight increase (12 of 205 [5.9%] and 3 of 196 [1.5%]), and somnolence (11 of 205 [5.4%] and 5 of 196 [2.6%]). Discontinuation rates due to adverse events were 8 of 205 participants (3.9%) for brexpiprazole + sertraline and 20 of 196 participants (10.2%) for sertraline + placebo. Conclusions and relevance: Results of this randomized clinical trial show that brexpiprazole + sertraline combination treatment statistically significantly improved PTSD symptoms vs sertraline + placebo, indicating its potential as a new efficacious treatment for PTSD. Brexpiprazole + sertraline was tolerated by most participants, with a safety profile consistent with that of brexpiprazole in approved indications.

To examine the associations of serotonergic antidepressant exposure during pregnancy with the risk of depression and anxiety disorders in offspring. The Mayo Clinic Rochester Epidemiology Project medical records-linkage system was used to study offspring born to mothers who were prescribed selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors (S/NRI users, n=837) during pregnancy (1997-2010). Cox regression models were used to calculate hazard ratios (HRs) to examine associations of S/NRIs with diagnosed depression and anxiety, defined based on a review of medical records by two board-certified psychiatrists, using no maternal antidepressant use during pregnancy (non-users, n=863) and maternal antidepressant use in the year prior to pregnancy (former users, n=399) as control groups. After all adjustments for covariates, children born to S/NRI users during pregnancy did not differ in onset of depression or anxiety than the children of non-users (Adjusted Hazard Ratios, (aHR [95% CI]=1.00 [0.74, 1.85]) or former users (aHR=0.94 [0.69, 1.27]). The above associations were similar when exposure was limited only to SSRIs. Our results suggest that the higher rates of childhood and adolescent depression or anxiety conditioned on maternal S/NRI use in pregnancy are more likely to be driven by maternal depression or underlying propensity for depression rather than direct pharmacological effects of in utero S/NRI exposure.

The use of Attention-Deficit/Hyperactivity Disorder (ADHD) medications during pregnancy is increasing, raising concerns about potential long-term effects on offspring. This study investigates in utero exposure to methylphenidate, amphetamines and atomoxetine and risk of offspring neurodevelopmental disorders (NDDs). The population-based cohort study identified from Swedish registers included 861,650 children born by 572,731 mothers from 2008-2017. We categorized exposure based on redeemed medication during pregnancy and compared exposed children to those whose mothers discontinued medication before conception. Main outcomes were any NDD, including ADHD and autism spectrum disorder (ASD). Cox proportional hazards regression estimated hazard ratios (HRs), adjusting for maternal psychiatric and sociodemographic factors. Sensitivity analyses included stratifications by medication type, timing, and duration of exposure, and sibling comparisons. We also performed a meta-analysis combining data from the present study with those from a previous Danish study. Results showed no increased risk for any NDD (HRadjusted 0.95, 95% CI 0.82-1.11), ADHD (HRadjusted 0.92, 95% CI 0.78-1.08), or ASD (HRadjusted 0.86, 95% CI 0.63-1.18). Sensitivity analyses showed consistent patterns of no increased risks across different exposure durations, medication types and between siblings. Meta-analyses further supported the findings (pooled HR for any NDD 1.00, 95% CI 0.83;1.20). Our study provides evidence that in utero exposure to ADHD medications does not increase the risk of long-term NDDs in offspring. This study replicates safety data for methylphenidate and extends it with new safety data on amphetamines and atomoxetine. These findings are crucial for informing clinical guidelines and helping healthcare providers and expectant mothers make informed decisions.

Agitation and aggression are challenging behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD), which is diagnosed based on NINCDS-ADRDA criteria. Limited efficacy and safety of existing pharmacotherapies complicate treatment. Agomelatine, a melatonergic agonist and serotonergic antagonist, may provide a safer and more effective alternative. The primary outcome is to evaluate the efficacy of agomelatine as an add-on therapy to non-pharmacological treatment in reducing agitation and aggression in patients with AD, with secondary outcomes assessing its safety and potential neuroprotective effects. In a randomized, triple-blind, placebo-controlled trial, 56 patients with AD (aged ≥65) experiencing agitation and aggression received 12.5 mg agomelatine (n = 28) or placebo (n = 28) daily for six weeks. The primary outcome was the Cohen-Mansfield Agitation Inventory (CMAI) score change. Secondary outcomes included serum brain-derived neurotrophic factor (BDNF) levels and safety. At six weeks, the agomelatine group showed a greater reduction in CMAI scores than placebo (mean difference: –12.39, 95% CI: –19.37 to –5.42; P = 0.001). No significant BDNF changes were detected (P = 0.848). Total adverse events (AEs) were more common in the agomelatine group (50.0% vs. 21.4%, P = 0.050), but no serious AEs or liver enzyme abnormalities were reported. A daily dose of 12.5 mg agomelatine may effectively and safely reduce agitation and aggression in patients with AD when used as an add-on therapy. However, further studies with larger samples and extended durations are needed to definitively confirm agomelatine's role in managing BPSD in AD.

This editorial examines the rise of attention-deficit hyperactivity disorder (ADHD) in the digital age, suggesting that excessive digital media use may mimic or exacerbate ADHD symptoms. We propose examining ADHD through the lens of a spectrum condition, highlighting the importance of considering both genetic and environmental factors in its diagnosis and treatment.

No abstract available

The p-value, introduced by Fisher in the early 20th century [1], remains a dominant feature of null hypothesis significance testing (NHST) in psychological research. Despite its utility as a measure of data compatibility with a null hypothesis, its misinterpretation has fostered flawed practices that undermine the reliability of scientific findings. This issue has far-reaching consequences in psychology, including within mental health research, where statistical errors can affect therapeutic practices and policy decisions. Misinterpretations of p-values perpetuate overconfidence in research findings, often leading to oversights in clinical trials, misallocation of resources, and misguided interventions in mental health [2]. Historical Roots of Misinterpretations Fisher’s original intent for the p-value was as a heuristic tool rather than a definitive decision-making criterion [1]. Its integration with Neyman-Pearson’s decision framework in the mid-20th century created conflicting interpretations. While Fisher viewed the p-value as a continuum of evidence, Neyman-Pearson’s dichotomous thresholds for decision-making fostered binary thinking [3]. This historical duality has left researchers with a fractured understanding of statistical significance, particularly in psychology, where education often overlooks these nuances. Misinterpretations have thus become embedded in research culture, exacerbated by pressures to produce significant findings

This Viewpoint discusses social health, which refers to the quality and quantity of social interactions, relationships, and support networks, as an important independent component of overall health alongside physical and mental health.

Understanding the disparate outcomes of those who have experienced historical trauma is critical to developing interventions for individuals, families, and communities. The authors1 suggest that population health approaches that incorporate traditional knowledge and practices is one powerful approach for Indigenous communities. Efforts at narrative change at the population level will be key to understanding the impact of the past, dealing with current realities, and empowering for the future. There is much to learn from Indigenous peoples about not only the impact of historical trauma, but the response to that and current traumas, as well as the role of empowering narratives of resilience to offset the demoralization of Indigenous peoples and to address health disparities.