July/August 2025

The earliest molecular changes in Alzheimer's disease (AD) are poorly understood1-5. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.

Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC cessation thresholds to 1·0 × 109 cells per L (0·5 × 109 cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years. Comprehensive ADR monitoring every 3 months should address the metabolic syndrome, constipation, gastro-oesophageal reflux, sialorrhea, nocturnal enuresis, tachycardia, sleep apnoea, sedation, and other ADRs. Consumer representatives underscored the need for shared decision-making, streamlined monitoring, and accessible patient education. Although barriers persist, these findings support updating global policies to reduce burden on patients, enhance adherence, and optimise clinical outcomes. Incorporating evidence-based guidelines into practice could transform clozapine care, balancing safety with practicality to improve the lives of those with treatment-resistant schizophrenia.

In patients with schizophrenia, cannabis use exacerbates symptoms and can lead to a relapse of psychosis. Some experimental studies in healthy volunteers suggest that pre-treatment with cannabidiol (CBD) may reduce these effects, but others do not. Here, we investigated whether pre-treatment with CBD ameliorates the acute adverse effects of cannabis in patients with schizophrenia. Participants (n = 30) had schizophrenia or schizoaffective disorder plus a comorbid cannabis use disorder. In a double-blind, randomised, placebo-controlled, crossover trial, participants received oral CBD 1000 mg or placebo three hours before inhaling vaporised cannabis (containing Δ9-tetrahydrocannabinol (THC) 20-60 mg). The primary outcome was delayed verbal recall measured with the Hopkins Verbal Learning Test-Revised. We also measured psychotic symptoms with the Positive and Negative Syndrome Scale (PANSS) - positive subscale. Delayed verbal recall after cannabis administration was 3.5 words (95% confidence interval [CI]: 2.5-4.5) following pre-treatment with CBD, compared to 4.8 words (95% CI: 3.9 to 5.8) following pre-treatment with placebo (mean difference [MD] = -1.3 [95% CI: -2.0 to -0.6]; p = 0.001). After CBD pre-treatment, inhalation of cannabis was associated with an increase in PANSS-P score of 5.0 (95% CI: 3.6 to 6.5), compared to 2.9 (95% CI: 1.5 to 4.3) following pre-treatment with placebo (MD = 2.2 [95% CI: 0.6 to 3.7]; p = 0.01). Administration of CBD did not have a significant effect on plasma concentration of THC or its active metabolite, 11-hydroxy-THC. In patients with schizophrenia and a comorbid cannabis use disorder, pre-treatment with CBD did not attenuate the acute effects of cannabis on memory impairment or psychotic symptoms, but appeared to exacerbate them.

Anxiety disorders are prevalent psychiatric conditions that frequently emerge during adolescence. Among the neurobiological systems implicated in these disorders, the endocannabinoid (eCB) signaling system plays a crucial role, making it a promising target for therapeutic interventions. In addition to its direct effects on anxiety regulation, eCBs may also influence response to first-line pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs). However, little is known about developmental changes in eCB lipids-N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG)-or their relationship to anxiety symptoms and treatment response. Circulating AEA and 2-AG concentrations were measured in youth (aged 9-17, N = 199) with varying anxiety symptoms, assessed using the Screen for Child Anxiety-Related Disorders (SCARED). We evaluated how eCBs relate to developmental factors (e.g., demographics, biological variables) and anxiety symptoms (SCARED total). Additionally, we examined how eCB concentrations change in response to acute SSRI treatment in a subsample of adolescents (age 12-17, N = 41) with generalized anxiety disorder (GAD), who participated in an 8-week randomized placebo-controlled trial of escitalopram (15 mg/day, titrated to 20 mg/day). Body mass index (BMI) was positively correlated with circulating AEA, while 2-AG showed negative associations with age, female sex, and time-of-day. After adjusting for these variables, more severe anxiety symptoms were associated with higher AEA and lower 2-AG. Greater increases in 2-AG from baseline (without changes in AEA) were linked to improved treatment response in adolescents with GAD. Our study suggests that circulating eCBs may serve as biomarkers for anxiety severity and predictors of treatment response in youth.

Background: Nitrous oxide ("laughing gas") is an NMDA receptor antagonist. In the current study, our aim was to investigate the efficacy, safety, and likely optimal dose of nitrous oxide in adults with major depressive disorder (MDD). Methods: In this phase 2b randomized, double-blind trial, 81 patients with MDD were allocated on a 1:1 basis to receive nitrous oxide or oxygen/air (control); the nitrous group was further randomized to either 50% or 25% inspired nitrous oxide. All participants received four 1-hour-long treatment sessions at 1-week intervals and were followed for an additional 4 weeks. The primary outcome was the change in the 21-item Hamilton Depression Rating Scale (HAM-D) over the 4 treatment sessions. Secondary outcomes included remission (HAM-D ≤7 points), the Computerized Adaptive Test-Depression Inventory (CAT-DI) and Computerized Adaptive Test-Suicide Scale (CAT-SS). Results: The mean averaged change in HAM-D scores over the 4 weeks of treatment was lower with nitrous oxide than with control (-1.9 [95% CI, -3.9 to 0.0], p = .051). In the first week, 15 of 39 (38%) in the nitrous oxide group and 5 of 39 (13%) in the control group were remitted (p = .031). The mean averaged change in CAT-DI scores was -7.7 (95% CI, -14.1 to -1.4), p = .017; the mean averaged change in CAT-SS scores was -8.3 (95% CI, -14.4 to -2.1), p = .008, both favoring nitrous oxide. Conclusions: In this study, we confirmed that nitrous oxide has likely beneficial antidepressant effects in people with MDD.

Background: Although workplace mental health screening is often implemented to aid early identification of mental health symptoms and facilitate access to treatment, supporting evidence is limited. Aims: We aimed to evaluate the effect of independently conducted, confidential, online mental health screening, paired with automated tailored feedback recommending referral services, on help-seeking and psychological distress. Method: We conducted a cluster-randomised controlled trial with firefighters from an Australian fire and rescue service. Randomisation occurred by station (N = 264). Firefighters at stations allocated to the intervention group received tailored information detailing suitable mental health services based on their Kessler-6 psychological distress score (K6). The control group received generic feedback on services irrespective of K6 score. The primary outcome was help-seeking at 3-months post-intervention for those with at least moderate levels of psychological distress at baseline (K6 ≥14). The study was registered with Australian New Zealand Clinical Trials Registry (no. ANZCTR 12621001457831). Results: Of the 459 firefighters screened, 141 (30.72%) scored ≥14 on K6. Among this subgroup at 3 months, no differences were observed in rates of overall help-seeking between the intervention and control groups (P = 0.31). In contrast, levels of psychological distress remained high in the intervention group but declined in the control group (t[111] = 2.29, 95% CI: 0.24, 3.23, P = 0.024). The difference in psychological distress associated with workplace mental health screening equated to an effect size of -0.42 (95% CI: -0.04, -0.79). Conclusions: Our findings suggest that independent, confidential online mental health screening, paired with tailored online feedback and information on available treatment, does not significantly increase help-seeking and may sustain psychological distress over time compared with receiving generic information. As such, it should not be implemented to promote help-seeking and reduce levels of psychological distress. These findings are relevant for workplaces, mental health researchers and practitioners alike, highlighting the potential risk and potential harm of mental health screening conducted in this way on individuals.

Background: About 30% of patients with depression treated with antidepressant medication do not respond sufficiently to the first agents used. Pramipexole might usefully augment antidepressant medication in such cases of treatment-resistant depression, but data on its effects and tolerability are scarce. We aimed to assess the efficacy and tolerability of pramipexole augmentation of ongoing antidepressant treatment, over 48 weeks, in patients with treatment-resistant depression. Methods: We did a multicentre, double-blind, placebo-controlled randomised trial in which adults with resistant major depressive disorder were randomly assigned (1:1; using an online randomisation system) to 48 weeks of pramipexole (titrated to 2·5 mg) or placebo added to their ongoing antidepressant medication. The study was conducted in nine National Health Service Trusts in England. Participants, investigators, and researchers involved in recruitment and assessment were masked to group allocation, and the central pharmacy team dispensing the medication was not masked. The primary outcome was change from baseline to week 12 in the total score of the 16-item Quick Inventory of Depressive Symptomology self-report version (QIDS-SR16). The primary analysis was performed on the intention-to-treat population that included all eligible, randomly assigned participants. People with lived experience were involved in the design, oversight, and interpretation of the study. The trial was registered with ISCTRN (ISRCTN84666271) and EudraCT (2019-001023-13) and is complete. Findings: Between Feb 16 and May 29, 2024, 217 participants attended a screening visit, of whom 66 were excluded due to ineligibility. 151 participants were randomly assigned (75 to the pramipexole group and 75 to the placebo group, after one participant was found to be ineligible after randomisation). 84 (56%) participants were female and 66 (44%) were male and the mean age of participants was 44·9 years (SD 14·0). Ethnicity data were not available. The mean QIDS-SR16 total score at baseline was 16·4 (SD 3·4) in the pramipexole group and 16·2 (3·5) in the placebo group. The mean dose of pramipexole received at week 12 was 2·3 mg (SD 0·45). Adjusted mean decrease from baseline to week 12 of the QIDS-SR16 total score was 6·4 (SD 4·9) for the pramipexole group and 2·4 (4·0) for the placebo group; the mean difference between groups was -3·91 (95% CI -5·37 to -2·45; p<0·0001). Termination of trial treatment due to adverse events was more frequent in the pramipexole group (15 participants [20%]) than in the placebo group (four participants [5%]), with reported adverse events consistent with known side-effects of pramipexole, in particular nausea, headache, and sleep disturbance or somnolence. Interpretation: In this trial involving participants with treatment-resistant depression, pramipexole augmentation of antidepressant treatment, at a target dose of 2·5 mg, demonstrated a reduction in symptoms relative to placebo at 12 weeks but was associated with some adverse effects. These results suggest that pramipexole is a clinically effective option for reducing symptoms in patients with treatment-resistant depression. Future trials directly comparing pramipexole with existing treatments for this disorder are needed.

Background: Previous studies investigating the association between pubertal timing and depression in girls primarily use self-reported age at menarche (AAM). This study examines a range of pubertal timing indicators, including anthropometric and self-reported measures. Aims: Compare associations of multiple indicators of pubertal timing with depressive symptoms and depression in girls and explore whether these associations persist into early adulthood. Method: The sample comprised 4607 girls from UK-based Avon Longitudinal Study of Parents and Children. Seven measures of pubertal timing were assessed between ages 7 and 17 (age at: peak height velocity (aPHV); peak weight velocity; peak bone mineral content velocity; Tanner pubic hair and breast development stage 3; axillary hair; and AAM). Depressive symptoms were measured at 14, 17, 18 and 24 years using the Short Mood and Feelings Questionnaire. Depression was assessed at 15, 18 and 24 years using the Development and Well-Being Assessment and Clinical Interview Schedule-Revised. Multivariable logistic regression models were adjusted for socioeconomic status and pre-pubertal body mass index. Results: Later pubertal timing was associated with lower odds of depressive symptoms at age 14 across six measures, including aPHV (adjusted odds ratio (AOR): 0.82; 95% CI 0.72, 0.95) and AAM (AOR: 0.84; 95% CI 0.76, 0.92). Later AAM and Tanner breast stage 3 were associated with lower odds of depression at age 18 (AOR: 0.85; 95% CI 0.75, 0.97 and AOR: 0.83; 95% CI 0.72, 0.95, respectively). Associations attenuated by age 24. Conclusions: Later pubertal timing was associated with reduced odds of depressive symptoms during mid-adolescence, with associations attenuating by adulthood.

Background: Innovative treatments for paranoia, which significantly impairs social functioning in schizophrenia spectrum disorders (SSDs), are urgently needed. The pathophysiology of paranoia implicates the amygdala-prefrontal cortex (PFC) circuits; thus, in this study, we systematically investigated whether transcranial direct current stimulation (tDCS) to the ventrolateral PFC can attenuate paranoia and improve social functioning in SSDs. Methods: A double-blind, within-subjects, crossover design was used to compare active versus sham tDCS effects in 50 participants with SSDs (ClinicalTrials.gov identifier: NCT05746494). Participants completed 2 stimulation visits, each including 2 tDCS sessions about 1 week apart, with active (2 mA for 20 minutes) and sham conditions counterbalanced across the 2 visits. Alongside laboratory-based measurements of state paranoia and its associated social cognitive biases, ecological momentary assessment (EMA) was used. This involved daily evaluations of paranoia and social functioning administered 3 times per day for 7 days during each EMA period (EMA-baseline, EMA-active, EMA-sham). Results: For laboratory-based assessments, participants showed greater reductions in state paranoia and improvements in paranoia-related social cognitive biases after active stimulation compared with sham, including lower self-reported hostility and hostile attributions in ambiguous situations post active versus post sham. Similarly, in the EMA-active period, participants had lower daily paranoia than in the EMA-sham period and higher social interaction motivation with better attitudes compared with baseline and the EMA-sham period. Conclusions: Extending our pilot study, the current findings further supported the efficacy of tDCS in mitigating paranoia and enhancing social functioning in patients with SSDs. This work sheds light on the neuropathology of paranoia and identifies a promising avenue for future large-scale interventions.

Background: Auditory verbal hallucinations are a major burden for patients with schizophrenia spectrum disorder and are often resistant to pharmacological and psychotherapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS) of the temporo-parietal cortex has been proposed as a treatment for persistent auditory verbal hallucinations. We aimed to compare the efficacy and safety of bilateral continuous theta burst stimulation (cTBS), a brief and efficient form of rTMS, in adults with auditory verbal hallucinations versus sham cTBS. Methods: This multicentre, randomised, sham-controlled, triple-blind phase 3 clinical trial was conducted at seven German psychiatric university hospitals and followed a planned two-stage adaptive design. Eligible patients were aged 18-65 years, had experienced persistent auditory verbal hallucinations at least once per week for a minimum of 3 months, and scored 3 points or higher on item P3 (hallucinatory behaviour) of the clinician-rated Positive Scale of the Positive and Negative Syndrome Scale (PANSS). 138 adults with treatment-persistent auditory verbal hallucinations and schizophrenia spectrum disorder were randomly assigned (1:1) to receive 15 sessions of active (n=70) or sham cTBS (n=68) administered sequentially as 600 pulses to the left and 600 pulses to the right temporo-parietal cortex over a 3-week period. The primary outcome was the change in the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS-AH) from baseline to the end of treatment at 3 weeks, analysed in the intention-to-treat population, which included all randomly assigned patients who received at least one stimulation session. Safety was assessed in all patients who received at least one stimulation session. Follow-up assessments were performed at 1, 3, and 6 months after the end of treatment. People with lived experience were not involved in the study. Findings: Between Oct 24, 2015, and May 1, 2023, 2583 patients were screened for eligibility, of whom 138 patients were randomly assigned to active cTBS (n=70; 32 [46%] females and 38 [54%] males) or sham treatment (n=68; 24 [35%] females and 44 [65%] males). Race and ethnicity data were not collected. The primary intention-to-treat analysis (66 patients in the active cTBS group; 64 patients in the sham cTBS group), combining stages 1 and 2, showed patients in the active cTBS group had a significantly greater decrease in the PSYRATS-AH score at end of treatment than did patients in the sham cTBS group (-6·36 [SD 7·97] vs -3·74 [SD 5·79]; adjusted difference -2·36 [95% CI -4·71 to -0·01]; p=0·042). Overall, 85 adverse events (43 in the active cTBS group; 42 in the sham cTBS group) were reported in 22 (33%) of 66 patients in the active cTBS group and 21 (33%) of 64 patients in the sham cTBS group. Headache was the most common adverse event in both groups (n=13 active cTBS group vs n=17 sham cTBS group). One serious adverse event occurred in the active group. Interpretation: Sequential bilateral temporo-parietal cTBS over 3 weeks was safe and effective for reducing auditory verbal hallucinations in adults with schizophrenia spectrum disorder. This trial establishes cTBS as a treatment option for the care of these patients. Further research is needed to evaluate maintenance strategies, identify treatment predictors, and assess long-term efficacy.

Importance: Treatment-resistant depression (TRD) remains a critical challenge in psychiatry, with limited effective options. Esketamine, a rapid-acting antidepressant, is usually combined with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), but comparative evidence of these combinations' effectiveness in real-world settings is sparse. Objective: To determine whether the combination of esketamine + SNRI shows differences in clinical outcomes compared to esketamine + SSRI in patients with TRD. Design, setting, and participants: This retrospective cohort study was conducted in September 2024 using data from the TriNetX global health research network, with a 5-year time window from the first esketamine trial. TriNetX data are drawn from real-world clinical settings and use electronic medical records from more than 90 health care centers across 20 countries. Adults with TRD who were treated with esketamine combined with either an SSRI or an SNRI were eligible for inclusion. Exposure: Treatment with esketamine combined with an SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone) or an SNRI (desvenlafaxine, duloxetine, levomilnacipran, milnacipran, or venlafaxine). Main outcomes and measures: The primary outcomes were all-cause mortality, hospitalization, depression relapse, and suicide attempts. Kaplan-Meier survival analysis was used to estimate survival probabilities, while risk ratios and odds ratios were calculated for all outcomes. Results: In a population-based sample of 61 882 adult participants with TRD who were treated with esketamine combined with either an SSRI or an SNRI, 55 480 participants were selected after applying propensity score matching for age and sex. These patients were divided into 2 matched cohorts: 27 740 patients treated with esketamine + SSRI (16 007 female participants [57.7%]; mean [SD] age, 46.0 [21.3] years) and 27 740 treated with esketamine + SNRI (16 242 female participants [58.6%]; mean [SD] age, 45.9 [21.9] years). In the entire study population, the incidence of mortality, hospitalizations, depressive relapses, and suicide attempts was low throughout the study period. Patients in the esketamine + SNRI group had significantly lower all-cause mortality (5.3% vs 9.1%; P < .001), hospitalization rates (0.1% vs 0.2%; P < .001), and depression relapses (14.8% vs 21.2%; P < .001) compared to the esketamine + SSRI group, which instead showed a lower incidence of suicidal attempts (0.3% vs 0.5%; P = .04). Conclusions and relevance: In this retrospective comparative effectiveness study, among the study sample, incidence of mortality, hospitalizations, depressive relapses, and suicide attempts was low. The esketamine + SNRI group showed lower incidence of mortality, hospitalizations, and depressive relapses, while the esketamine + SSRI group showed a slightly lower incidence of suicidal attempts.

Background and aims: Dispensing of prescription stimulants to adults has risen dramatically over the past decade. Examining trends in nonprescribed use of prescription stimulants can inform public health responses. Most studies in the United States (U.S.) have faced challenges in assessing trends over time due to changes in survey methodologies and variation in populations assessed. We examined data from the Population Assessment of Tobacco and Health (PATH) Study to assess changes in nonprescribed use of prescription stimulants in the U.S. from 2013 to 2022. Design: The PATH Study is an ongoing longitudinal study of U.S. youth and adults, representative of the civilian noninstitutionalized population. Repeated cross-sectional estimates at each wave were used (8 total waves). Trends from Wave (W) 1 (September 2013-December 2014) to W7 (January 2022-April 2023) were assessed. Full-sample and replicate weights were used; joinpoint analyses and wave-to-wave comparisons were applied to test trends. Setting: Civilian noninstitutionalized U.S. youth and adults. Participants/cases: Youth aged 12-17 and adults aged 18 + were assessed, with a total of 45 727 participants at wave 1 (Ns vary by wave). Measurements: Past 12-month (P12M) prevalence of nonprescribed use of Ritalin or Adderall was assessed. Nonprescribed use of stimulants was assessed across subgroups according to age (12-17, 18-24, 25-39, ≥40) and sex (male, female). Findings: While wave-to-wave comparisons showed fluctuations across certain waves, overall, there were no statistically significant changes in P12M prevalence of Ritalin or Adderall nonprescribed use (1.3% at W1 and 1.5% at W7) across the study period. However, statistically significant differences in trends existed across age groups. Among 12-17 year-olds, nonprescribed use prevalence remained stable (1.4% in W1 and 1.5% in W7). Nonprescribed use prevalence also remained stable for 18-24-year-olds from W1 to W3, but then significantly declined (p = 0.016) from W3 (5.3%) to W7 (2.6%). There were no significant changes in nonprescribed use prevalence among 25-39-year-olds (1.7% in W1 and 2.4% in W7) and those aged ≥40 (0.3% in W1 and 0.9% in W7). Across most waves, young adults aged 18-24 had a statistically significantly higher prevalence of nonprescribed use. Neither sex had significant trends in P12M nonprescribed use prevalence. Conclusions: Despite an increase in dispensing of prescription stimulant medications in the United States, the prevalence of nonprescribed Ritalin or Adderall use does not appear to have increased, as assessed in the nationally representative Population Assessment of Tobacco and Health (PATH) Study. The prevalence of nonprescribed Ritalin or Adderall use among young adults aged 18-24, the age group with the highest nonprescribed use prevalence, declined 2013 to 2022.

Importance: The prescription of attention-deficit/hyperactivity disorder (ADHD) medications has risen substantially in many countries over the last 20 years. However, whether the real-world benefits of ADHD medications change with increased prescription rates within a society remains unknown. Objective: To examine whether the associations between ADHD medications and real-world outcomes (self-harm, unintentional injury, traffic crashes, and crime) change as prescription rates rise. Design, setting, and participants: This study used a self-controlled case series design. It was a population-based study using Swedish National Registers that included individuals who used ADHD medications in Sweden between 2006 and 2020. Data were analyzed from October 2023 to November 2024. Exposure: ADHD medication use. Main outcomes and measures: Rates of self-harm, unintentional injury, traffic crashes, and crime during medicated vs nonmedicated periods. The associations between ADHD medication and these real-world outcomes were examined across 3 time periods, 2006 to 2010, 2011 to 2015, and 2016 to 2020, during which ADHD medication prevalence increased from 0.6% to 2.8%. Results: There were 247 420 individuals identified (99 361 females [40.2%] and 148 059 males [59.8%]) aged 4 to 64 years in Sweden who used ADHD medications between 2006 and 2020. ADHD medication was consistently associated with lower risks for self-harm (incidence rate ratio [IRR] ranged from 0.77; 95% CI, 0.73-0.81 to 0.85; 95% CI, 0.82-0.88), unintentional injury (IRR ranged from 0.87; 95% CI, 0.84-0.89 to 0.93, 95% CI, 0.91-0.95), traffic crashes (IRR ranged from 0.71; 95% CI, 0.67-0.77 to 0.87; 95% CI, 0.83-0.91), and crime (IRR ranged from 0.73; 95% CI, 0.71-0.75 to 0.84; 95% CI, 0.82-0.85) across different age groups, sexes, and over time. However, the associations between ADHD medication use and lower risks of unintentional injury (P value for trend < .01), traffic crashes (P value for trend < .01), and crime (P value for trend < .01) appear to weaken over time as prescription rates increased. Changes in age and sex distribution of individuals receiving ADHD medication did not fully explain the weakening trend for unintentional injury and traffic crashes. Conclusions and relevance: In this study, ADHD medication remained associated with reduced risks of several serious real-world outcomes. However, the magnitude of these associations appears to have decreased alongside rising prescription rates over time. Thus, it is important to regularly evaluate medication use in different patient populations.

Objective: The authors sought to determine 1) whether receiving an initial stimulant prescription for attention deficit hyperactivity disorder (ADHD) from a provider whom a patient has never seen in person is associated with increased risk for stimulant use disorder (stimUD) or other substance use disorders (SUDs), and 2) whether receiving an initial stimulant prescription during a telehealth versus in-person appointment is associated with increased risk for stimUD or SUD. Methods: This was a retrospective cohort study using electronic health record data from March 1, 2020, to August 25, 2023, from a not-for-profit, academically affiliated medical system in the Northeastern United States. Eligible study subjects were ≥12 years old with ADHD and initial receipt of any stimulant prescription during the study period. Exclusion criteria included a non-nicotine SUD diagnosis at the time of initial stimulant prescription. Results: The sample included 7,944 patients. After adjustment for covariates, a purely telehealth-based relationship versus any in-person relationship did not significantly alter risk for SUD (adjusted odds ratio=0.85, 95% CI=0.60, 1.20) or stimUD (adjusted odds ratio=1.28, 95% CI=0.34, 4.85). A telehealth versus in-person appointment at the time of the initial stimulant prescription did not significantly alter risk for subsequent SUD (adjusted odds ratio=1.15, 95% CI=0.92, 1.44) but was associated with significantly higher risk for stimUD (adjusted odds ratio=6.18, 95% CI=1.34, 28.46). Conclusions: The results suggest that receipt of a stimulant prescription for ADHD via telehealth does not alter the risk for SUD, but receipt of an initial stimulant prescription via telehealth may signal increased risk of subsequent stimUD. The results, particularly for stimUD, require replication in other health care settings.

Objective: Previous studies have shown that parental factors are associated with an increased risk for attention deficit hyperactivity disorder (ADHD). However, the pathways by which parental factors are associated with risk of ADHD in offspring are not well understood. These associations can arise directly from parental genotypes inherited by offspring, and/or via environmental effects, some of which may themselves be influenced by the parental genotype (i.e., parental genetic nurture). This study specifically examined the impact of the maternal phenotype on offspring ADHD risk, above and beyond the direct genetic effect of maternally inherited genes. Methods: The study population consisted of 982,544 individuals from the Swedish Medical Birth Register. The authors partitioned the liability of ADHD into direct additive genetic effect, maternal genetic nurture effect, and maternal common environment effect. Results: A total of 66,707 (7%) individuals with an ADHD diagnosis were identified in the birth cohort. Maternal half-siblings were associated with a higher ADHD risk compared to paternal half-siblings, suggesting maternal effect. Estimates indicated 66.1% direct additive genetic effect (95% credible interval=0.647, 0.676) and 14.3% maternal genetic nurture effect (95% credible interval=0.136, 0.151). Additionally, evidence for substantial assortative mating among individuals with ADHD was observed. Conclusions: The findings indicate that maternal genotypes influence offspring's risk of ADHD through environmental pathways beyond the effects of direct genetic transmission. Exploring the impact of the genetics of the mother beyond the maternally inherited genes can lead to new insights into ADHD risk. Future studies should also investigate paternal effects to provide a more comprehensive understanding of the ADHD risk architecture.

Objective: The authors sought to determine whether genetic predispositions to cognitive ability or psychiatric conditions interact with anticholinergic burden (AChB) to impact cognition and brain structure in individuals with psychotic disorders. Methods: Participants with psychosis spectrum disorders (N=1,704) from the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium, 18-65 years of age and representing diverse ancestries, underwent cognitive assessments, structural neuroimaging, genotyping, and a comprehensive medication review. The primary cognitive outcome was the Brief Assessment of Cognition in Schizophrenia (BACS) composite score, and the primary brain structural phenotype was total gray matter volume. AChB scores for scheduled medications were quantified using the CRIDECO Anticholinergic Load Scale. Polygenic scores (PGSs) for cognition, schizophrenia, bipolar disorder, and depression were constructed, and a composite psychiatric PGS was subsequently generated. Linear regression models were used to examine AChB-PGS interactions and their associations with cognitive and brain structure outcomes, adjusting for clinical covariates and multiple testing with false discovery rate. Hypothesis-driven moderated mediation models were used to explore potential association pathways. Results: Higher AChB was significantly associated with lower BACS performance and reduced gray matter volume. Individuals with higher cognitive PGS values exhibited greater adverse effects of AChB on BACS, while those with lower composite psychiatric PGS values showed more pronounced gray matter volume reductions from AChB. AChB associations with cognitive impairment were partially mediated by reduced gray matter volume and were moderated by composite psychiatric PGS. Conclusions: Anticholinergic-polygenic interactions significantly impact cognition and brain structure in individuals with psychotic disorders, highlighting a novel gene-by-environment interaction that advances our mechanistic understanding of cognitive impairments in this population.

Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age. It has been linked to a range of psychiatric disorders. Although premenstrual disorders (PMDs) are characterized by psychiatric symptoms in tandem with hormone changes controlled by the endocrine system, the association between PCOS and PMDs remains unknown. Methods: We conducted a nationwide register-based cohort study including 2,965,178 females during 2001-2018 in Sweden. Individuals with PCOS were identified from clinical diagnoses recorded in the Swedish national registers (n = 41,515) and PMDs were identified based on clinical diagnoses and prescriptions with a clear indication of PMDs during follow-up. Using multivariable Cox regression, hazard ratio (HRs) of PMDs were estimated by comparing individuals with PCOS to those without. To account for confounders such as genetics or family environment, we conducted sibling comparison (N = 160,566). Results: During a median follow-up of 15.3 years, 1308 (1.9%) individuals with PCOS had a premenstrual disorder (PMD) (4.67/1000 person-years). Compared to individuals without PCOS they had more than doubled risk of PMDs (age-adjusted HR: 2.26, 95% CI 2.14- 2.39). The association was attenuated after adjustment for demographic and socioeconomic factors as well as for comorbid psychiatric disorders and obesity yet remained significant (HR: 1.54, 95% CI 1.46-1.63). The sibling comparison showed similar findings (full-adjusted HR: 1.61, 95% CI 1.36-1.92). The association between PCOS and PMDs remained statistically significant regardless of the presence of psychiatric comorbidities, with HR of 1.33 (95% CI 1.20-1.47) for individuals with psychiatric comorbidities and 1.55 (95% CI 1.45-1.65) for those without. Conclusions: Our findings suggest that individuals diagnosed with PCOS were at increased risk for PMDs. This association could not be entirely explained by shared risk factors, including such that sisters share.

Objective: Atypical depression is a depression subtype characterized by atypical and energy-related symptoms such as hypersomnia, weight gain, fatigue, and leaden paralysis. Limited research has examined its clinical characteristics in youth. This study investigates the prevalence, sociodemographic and clinical correlates, and six-month depression trajectories of atypical depression in a statewide youth depression registry. Method: Data from the Texas Youth Depression and Suicide Research Network (TX-YDSRN), a registry of youth aged 11-20 years with depression or suicidal ideation, were analyzed. Atypical depression was defined using the Atypical Energy-Related Symptom Scale (AES) score of ≥6. Sociodemographic data, Body Mass Index (BMI), depression and anxiety severity, suicidality, trauma history, and physical functioning were compared between individuals with atypical and non-atypical depression. Mixed-effects models were used to assess depressive symptom trajectories over six months. Results: Of 1,445 participants (mean age 15.8 years, 72.8% female), 22.4% had atypical depression. Atypical depression was associated with greater baseline depression, anxiety, suicidality, and suicide attempts compared to non-atypical depression. Atypical depression was associated with female sex, trauma history, and obesity. Youth with atypical depression also had poorer physical functioning. Over six months, individuals with atypical depression exhibited persistently higher depressive severity compared to those with non-atypical depression. Conclusion: Atypical depression in youth is associated with more severe clinical profiles and worse depression trajectories relative to non-atypical depression. Future studies should investigate the temporal relationships between variables such as trauma, obesity, and the onset of atypical depression to better understand how these factors may precede or exacerbate atypical depression.

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