September 2025

Importance: Research has consistently shown links between parent and child depression. The prevailing assumption is that parent depression precedes the onset, persistence, and even exacerbation of child depression. However, it is plausible, albeit infrequently tested, that child depression triggers subsequent parent depression. Clarifying the direction and developmental timing of these associations is critical for designing and advocating for family-centered approaches to pediatric care. Objective: To estimate the longitudinal bidirectional associations between maternal and child depression from middle childhood through emerging adolescence during a period that coincided with the COVID-19 pandemic, and to assess whether these associations are moderated by key sociodemographic factors. Design, setting, and participants: This study used data from the All Our Families (Calgary, Alberta, Canada) cohort across multiple waves during and beyond the COVID-19 pandemic when children were aged 10.3 (May 20 to July 15, 2020), 10.9 (March 4 to April 30, 2021), 11.6 (November 22, 2021 to January 17, 2022), and 12.8 (January 16 to July 7, 2024) years. Data were analyzed between March 1 and August 31, 2024, using random-intercept cross-lagged panel models. Exposures: Maternal and child report of depressive symptoms. Main outcomes and measures: The Behavior Assessment System for Children for child depression and the Center for Epidemiologic Studies Depression Scale-10 for maternal depression. Results: The sample included 1801 mother-child dyads (52% boys, 48% girls). Mothers were a mean (SD) 41.6 (4.4) years old at study entry and most had completed postsecondary education (80%), had an annual income more than CAD $100 000 (75%), and were married or in common-law relationships (71.4%). Consistent cross-sectional correlations were observed, reflecting stable between-participant associations for maternal depression and child depression throughout the study period. Within-participant increases in child depression scores at ages 10.3 and 10.9 years were associated with subsequent increases in maternal depression scores at child ages 10.9 (standardized coefficient 0.12; 95% CI, 0.02-0.22) and 11.6 (0.17; 95% CI, 0.07-0.26) years; however, this was not present for maternal depression. These patterns of associations were moderated by household income (difference test for χ212 = 23.0; P = .03) and within-participant increases in child depression were consistently associated with subsequent increases in maternal depression for the higher income group. Conclusions and relevance: Contrary to prevailing assumptions, these findings suggest that children's depression over time may have contributed to worsening maternal depression, rather than the other way around. While these results should be replicated in nonpandemic contexts to confirm their generalizability, they highlight the need for family-centered approaches to mental health care.

Background and objectives: Consumption of low- and no-calorie sweeteners (LNCSs) has been associated with adverse health outcomes. However, little is known about the association between consumption of LNCSs and cognition. The aim of this study was to investigate the association between consumption of LNCSs and cognitive decline. Methods: We conducted a longitudinal observational study using data from civil servants aged 35+ years at baseline who were enrolled in the Brazilian Longitudinal Study of Adult Health and evaluated across 3 study waves (2008-10, 2012-14, and 2017-19). Participants with incomplete dietary data, extreme caloric intake (<1st percentile or >99th percentile), and incomplete data for cognitive tests and covariates at baseline were excluded. A Food Frequency Questionnaire was used to calculate combined and individual consumption of 7 LNCSs (aspartame, saccharin, acesulfame k, erythritol, xylitol, sorbitol, and tagatose). We estimated z-scores across 6 cognitive tests. The association of LNCSs with cognitive decline was evaluated using linear mixed-effects models. Results: Among 12,772 participants (mean age 51.9 ± 9.0 years, 54.8% women, 43.2% Black/mixed race), the mean consumption of LNCSs was 92.1 ± 90.1 mg/d. Among participants aged younger than 60 years, consumption of combined LNCSs in the highest tertiles was associated with a faster decline in verbal fluency (second tertile: β = -0.016, 95% CI -0.040 to -0.008; third tertile: β = -0.040, 95% CI -0.064 to -0.016) and global cognition (second tertile: β = -0.008, 95% CI -0.024 to 0.008; third tertile: β = -0.024, 95% CI -0.040 to -0.008). There was no association between tertiles of LNCSs and cognitive decline in participants aged 60+ years. Consumption of aspartame, saccharin, acesulfame k, erythritol, sorbitol, and xylitol was associated with a faster decline in global cognition, particularly in memory and verbal fluency domains. Consumption of combined LNCSs in the highest tertiles was associated with a faster decline in verbal fluency and global cognition in participants without diabetes and faster decline in memory and global cognition in participants with diabetes. Discussion: Consumption of LNCSs was associated with an accelerated rate of cognitive decline during 8 years of follow-up. Our findings suggest the possibility of long-term harm from LNCS consumption, particularly artificial LNCSs and sugar alcohols, on cognitive function. Study limitations include self-reported dietary data, selection bias from attrition, and residual confounding from co-occurring health behaviors.

Obesity is one of the most prevalent somatic comorbidities in individuals with major depressive disorder and greatly affects the course and prognosis of that disorder. The bidirectional relationship between major depressive disorder and obesity often creates a feedback cycle that challenges both patients and health-care providers. Gaps in interdisciplinary collaboration and limitations in knowledge transfer hinder the effective management of this patient population. This narrative Review synthesises current evidence from obesity and major depressive disorder research, offering a comprehensive risk stratification and monitoring framework that integrates psychological and metabolic parameters to enhance clinical decision making. We examine the latest evidence on pharmacological and psychotherapeutic interventions as well as lifestyle-based strategies-such as exercise, dietary modifications, and weight-loss medications-with the aim of alleviating depressive symptoms while supporting weight management and improving metabolic health. Bariatric surgery, which is a key component in obesity management, is not covered in this Review. Finally, we highlight the crucial need for an integrated, interdisciplinary treatment approach and provide practical guidance for optimising care to improve outcomes for individuals with major depressive disorder and comorbid obesity.

Objective: Neuroimaging studies have independently associated schizophrenia with low iron and elevated dopamine synthesis. While preclinical research demonstrates that midbrain iron deficiency leads to striatal hyperdopaminergia, this relationship has not been studied in schizophrenia. The authors conducted a case-control study to examine differences in tissue magnetic susceptibility, a marker of brain iron, and correlated these with striatal dopamine synthesis capacity. Methods: Magnetic susceptibility in the substantia nigra and ventral tegmental area (SN-VTA) was measured using quantitative susceptibility mapping (QSM) MRI in 159 participants (control subjects, N=80; early-course schizophrenia, N=79, including patients who were antipsychotic-naïve or antipsychotic-free). Because magnetic susceptibility is increased by neuromelanin and reduced by myelin, neuromelanin-sensitive MRI (NM-MRI) and diffusion tensor imaging (DTI) were employed to investigate the influence of neuromelanin and myelin on the QSM findings in 99 participants (control subjects, N=38; schizophrenia patients, N=61). Dopamine synthesis capacity (Ki cer) was then assessed with [18F]-DOPA positron emission tomography in 40 people from the schizophrenia group to test whether low SN-VTA magnetic susceptibility was related to high striatal Ki cer. Results: SN-VTA magnetic susceptibility was lower in patients with schizophrenia than in control subjects (d=-0.66, 95% CI=-0.98, -0.34). This difference remained significant in analyses controlling for mean diffusivity (a DTI measure inversely correlating with myelin concentration) and NM-MRI contrast-to-noise ratios. SN-VTA magnetic susceptibility was significantly inversely correlated with striatal Ki cer, independent of mean diffusivity and NM-MRI contrast-to-noise ratios (r=-0.44). In both analyses, the strongest effects were observed in the ventral SN-VTA. Conclusions: These findings suggest that lower levels of non-neuromelanin-bound iron in the SN-VTA contribute to striatal hyperdopaminergia in schizophrenia. Further investigation is warranted to understand the role of low iron in schizophrenia and its potential as a treatment target.

Objective: The study aim was to identify ethnoracial disparities in the prevalence of schizophrenia spectrum disorders (SSDs) and positive psychotic symptoms in the United States and examine the role of social neighborhood inequities. Methods: Participants in the Mental and Substance Use Disorders Prevalence Study, a national household sample of nonelderly adults (N=4,764), were assessed by clinicians with the Structured Clinical Interview for DSM-5 (SCID-5) for SSDs (past year and lifetime), including schizophrenia, schizoaffective disorder, and schizophreniform disorder, and for psychotic symptoms. Weighted logistic regression models estimated ethnoracial differences in the prevalence of SSDs and psychotic symptoms in unadjusted models, age- and sex-adjusted models, and models further adjusted for a neighborhood Social Vulnerability Metric (SVM) score, a composite index of five social determinants of health domains. Results: Compared to non-Hispanic White individuals, non-Hispanic Black individuals had a significantly higher prevalence of SSDs (4.1% vs. 1.2%; adjusted odds ratio=3.49, 95% CI=1.37, 8.91) and psychotic symptoms (9.3% vs. 4.9%; adjusted odds ratio=2.04, 95% CI=1.15, 3.63), and non-Hispanic multiracial individuals had a significantly higher prevalence of SSDs (5.6%; adjusted odds ratio=4.59, 95% CI=1.53, 13.76). Further adjustment for SVM score lowered the Black-White group difference for SSDs (adjusted odds ratio=2.49, 95% CI=0.63, 9.90) and psychotic symptoms (adjusted odds ratio=1.69, 95% CI=0.83, 3.44), and the associations were no longer statistically significant. The difference in SSDs between the non-Hispanic multiracial and White groups was attenuated after SVM score adjustment (adjusted odds ratio=3.95, 95% CI=1.30, 12.00) but remained significant. Conclusions: This national U.S. household study found ethnoracial differences in the prevalence of clinician-assessed SCID-based schizophrenia spectrum disorders and positive psychotic symptoms. The higher prevalence among minoritized groups, particularly Black individuals, was connected to social inequities and community-level vulnerabilities embedded in neighborhoods and associated with structural racism.

Importance: The incidence and nature of discontinuation symptoms following antidepressant cessation remain unclear. Objective: To examine the presence of discontinuation symptoms using standardized scales (eg, Discontinuation-Emergent Signs and Symptoms [DESS]) and the incidence of individual discontinuation symptoms in individuals who stop taking antidepressants. Data sources: The databases Embase, PsycINFO, Ovid MEDLINE, and Cochrane Library were systematically searched from inception until November 7, 2023. Study selection: Randomized clinical trials (RCTs) reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation were included. Data extraction and synthesis: Data extracted were cross-checked by 2 reviewers. Additional unpublished data from 11 RCTs were included. A random-effects meta-analysis was conducted to calculate standardized mean difference between individuals who discontinued an antidepressant vs those who continued an antidepressant or discontinued placebo. A proportion and odds ratio (OR) meta-analysis was performed to assess incidence of individual discontinuation symptoms compared to placebo. Subgroup analyses were conducted to compare different antidepressants. Data analysis was conducted between September 2024 and December 2024. Main outcomes and measures: The primary outcomes were incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales. Results: A total of 50 studies were included, 49 of which were included in meta-analyses. The 50 studies included 17 828 participants in total, with 66.9% female participants and mean participant age of 44 years. Follow-up was between 1 day and 52 weeks. The DESS meta-analysis indicated increased discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31; 95% CI, 0.23-0.39; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more symptom on the DESS. Discontinuation of antidepressants was associated with increased odds of dizziness (OR, 5.52; 95% CI, 3.81-8.01), nausea (OR, 3.16; 95% CI, 2.01-4.96), vertigo (OR, 6.40; 95% CI, 1.20-34.19), and nervousness (OR, 3.15; 95% CI, 1.29-7.64) compared to placebo discontinuation. Dizziness was the most prevalent discontinuation symptom (risk difference, 6.24%). Discontinuation was not associated with depression symptoms, despite being measured in people with major depressive disorder (k = 5). Conclusions and relevance: This systematic review and meta-analysis indicated that the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome. Mood worsening was not associated with discontinuation; therefore, later presentation of depression after discontinuation is indicative of depression relapse.

Importance: Insomnia and inflammation are prevalent in older adults, and both are risk factors for late-life depression. Older adults with insomnia who are exposed to inflammatory challenge may be more vulnerable to depression. Objective: To determine whether inflammatory exposure induces greater increases in depressive mood and symptoms in older adults with insomnia disorder compared to those without insomnia. Design, setting, and participants: This assessor-blinded, parallel-condition randomized clinical trial was conducted from August 2017 to November 2022 at a single site in Los Angeles, California, among a community-based sample of 160 nondepressed adults aged 60 years or older (53 with insomnia disorder and 107 without insomnia, or control). Data analysis occurred from July 2023 to August 2024. Interventions: Participant groups stratified by insomnia status were randomized to 2 conditions: endotoxin or placebo. Main outcomes and measures: The primary outcome was depressed mood, assessed by the Profiles of Mood States depression subscale (POMS-D). Secondary outcomes were depressive symptom severity and inflammatory cytokines. Results: Among 160 randomized participants eligible for the study (mean [SD] age, 65.9 [4.6] years; 84 female participants [52.5%]), 79 participants (26 with insomnia, 53 control participants) were randomized to endotoxin and 81 (27 with insomnia, 54 control participants) to placebo. All randomized participants completed the protocol. Compared to placebo, endotoxin induced increases in POMS-D to a significantly greater extent in those with insomnia than controls (condition × group interaction, F10,1478 = 4.7; P < .001), with a similar effect for observer-rated POMS-D mood (condition × group interaction, F3,450 = 5.5; P = .001), as well as clinically meaningful increases in observer-rated measures of depressive symptoms. Endotoxin induced similar increases in inflammatory cytokines in both groups. Moderation analyses found that the inflammatory response was associated with increases in POMS-D in the insomnia group (β = 0.33; 95% CI, 0.26-0.41; P < .001) but not in control participants. Conclusions and relevance: In this randomized clinical trial, older adults with insomnia showed an exaggerated vulnerability to depressive mood and symptoms in response to inflammatory challenge. Older adults with insomnia should undergo vigilant depression monitoring during periods of inflammatory exposure; selective depression prevention strategies that target both insomnia and inflammatory phenotypes are needed.

Importance: Esketamine nasal spray, administered in conjunction with an oral antidepressant, is approved for treatment-resistant depression (TRD). However, the efficacy of esketamine nasal spray administered as monotherapy for patients with TRD has not yet been evaluated. Objective: To assess the efficacy and safety of esketamine monotherapy compared to placebo in reducing depressive symptoms in patients with TRD. Design, setting, and participants: This phase 4, double-blind, placebo-controlled randomized clinical trial was conducted from November 2020 to January 2024 at 51 outpatient centers in the US. Adults with major depressive disorder (DSM-5 criteria) without psychotic features who experienced inadequate response (≤25% improvement) to 2 or more oral antidepressants during the current depressive episode were eligible for inclusion. Data analyses were conducted from March 1, 2024, to July 8, 2024. Interventions: After a 2-week or longer antidepressant-free period, participants were randomized at a 1:1:2 ratio to fixed-dose intranasal esketamine (56 mg or 84 mg) or matching intranasal placebo, administered twice weekly for 4 weeks. Main outcomes and measures: Change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 28 (primary efficacy end point) and to 24 hours post-first dose (day 2; key secondary efficacy end point) were analyzed by a mixed-effects model using repeated measures. Results: In this multicenter randomized clinical trial, 378 participants who met prerandomization MADRS severity criteria received 1 or more study drug doses (esketamine, 56 mg [n = 86]; esketamine, 84 mg [n = 95]; or placebo [n = 197]). Mean (SD) participant age was 45.4 (14.1) years, 231 participants (61.1%) were female, and baseline mean (range) MADRS total score was 37.3 (28-50). At day 28, the least-square (LS) mean difference (SE) between esketamine and placebo was -5.1 (1.42) (95% CI, -7.91 to -2.33) for the 56-mg dose and -6.8 (1.38) (95% CI, -9.48 to -4.07) for the 84-mg dose (for each, 2-sided P < .001). Observed effect sizes were 0.48 and 0.63 for the 56-mg and 84-mg dose groups, respectively. At day 2 (approximately 24 hours post-first dose), the between-group difference was significant for both esketamine doses: -3.8 (1.29) (95% CI, -6.29 to -1.22; 2-sided P = .004) for 56 mg and -3.4 (1.24) (95% CI, -5.89 to -1.00; 2-sided P = .006) for 84 mg. The most common treatment-emergent adverse events reported for esketamine (combined doses) were nausea (56 participants [24.8%]), dissociation (55 [24.3%]), dizziness (49 [21.7%]), and headache (43 [19.0%]). Conclusions and relevance: According to results of this multicenter, double-blind randomized clinical trial, esketamine monotherapy may expand treatment options for adult patients with TRD by addressing an unmet need of patients experiencing treatment-limiting tolerability concerns and nonresponse with oral antidepressants.

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 32 354 individuals receiving GLP-1 RAs and 27 042 treated with placebo, over 69 653 and 63 853 person-years of exposure, respectively. Event incidence was very low in the GLP-1 RA (0.047 per 100 person-years) and placebo (0.042 per 100 person-years) groups, with no statistically significant difference (rate ratio [RR], 0.76; 95% CI, 0.48-1.21; P = .25). 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.

Ketamine, introduced as an anesthetic drug, is now used for many indications beyond anesthesia; it is also increasingly a drug of abuse. Long-term recreational use and abuse of ketamine are associated with urological risks. This article discusses ketamine-associated uropathy from the perspective of prevalence, clinical features, mechanisms, and strategies for risk reduction in patients who require long term maintenance therapy with the drug for psychiatric indications. A systematic review and meta-analysis of 37 studies of uropathy in recreational (ab)users obtained prevalences of 44% to 77% for lower urinary tract symptoms and 8% to 30% for upper urinary tract disease; for reasons explained, these findings are potentially misleading and cannot be extrapolated to therapeutic contexts. More recent studies, using different methods of case ascertainment, present lower risks (2% to 27%). A systematic review of 27 studies of ketamine used to treat psychiatric disorders, mainly depression, found urological symptoms in 0% to 24% of patients; however, in 14 randomized controlled trials, urological symptom prevalences differed little between ketamine and comparison arms. The review presented no convincing evidence of ketamine-associated uropathy arising in therapeutic contexts. The literature on ketamine-associated uropathy is critically examined; reasons for false positive uropathy findings are considered. Ketamine pharmacokinetics are described to assist the understanding of how ketamine and its metabolites may predispose to uropathy. Mechanisms of uropathy, arising from exposure to ketamine and its metabolites in urine (rather than in circulation), are summarized. A reasonable conclusion is that higher doses of ketamine, more frequent dosing with ketamine, longer duration of treatment with ketamine, and oral administration of ketamine are all potential risk factors for ketamine-associated uropathy during maintenance therapy. High hydration and frequent voiding of urine on treatment days can reduce exposure of the bladder to ketamine and its metabolites, reducing urological risks. Fortnightly or monthly urine testing is also advisable.

A ketogenic diet (KD) has shown promise as an adjunctive therapy for neurological and neuropsychiatric disorders, including bipolar disorder and major depressive disorder (MDD). We examined tolerance for a KD in young adults with MDD and assessed symptoms of depression and metabolic health. Students (n = 24) with a confirmed diagnosis of MDD at baseline receiving standard of care counseling and/or medication treatment were enrolled in a 10-12 week KD intervention that included partial provision of ketogenic-appropriate food items, frequent dietary counseling, and daily morning tracking of capillary R-beta-hydroxybutyrate (R-BHB). Primary outcome measures for mood symptoms included the Patient Health Questionnaire (PHQ-9) and Hamilton Rating Scale for Depression (HRSD). Additional outcomes included body composition, neurocognitive function, and blood hormonal and inflammatory markers. Sixteen students (10 women, 6 men, mean age 24 yr) completed the intervention. Nutritional ketosis (R-BHB > 0.5 mM) was achieved 73% of the time. Depressive symptoms decreased by 69% (PHQ-9) and 71% (HRSD) post-intervention (p < 0.001), with improvement occurring within 2-6 weeks. Global well-being increased nearly 3-fold (p < 0.001). Participants lost body mass (-6.2%; p = 0.002) and fat mass (-13.0%; p < 0.001). Serum leptin decreased (-52%; p = 0.009) and brain-derived neurotropic factor increased (+32%; p = 0.029). Performance improved on several cognitive tasks. In students with mild to moderate depression based on PHQ-9 and HRSD, implementation of a WFKD for 10-12 weeks is a feasible adjunctive therapy and may be associated with improvements in depression symptoms, well-being, body composition, and cognition.

Importance: Individuals with attention-deficit/hyperactivity disorder (ADHD) may present with psychosis or bipolar disorder (BD) following treatment with stimulants. The extent to which this occurs is currently unclear. Objective: To meta-analytically quantify the occurrence of psychosis or BD after exposure to stimulants in individuals with ADHD and assess possible moderating factors. Data sources: PubMed, Web of Science, Ovid/PsycINFO, and Cochrane Central Register of Reviews were searched from inception until October 1, 2024, without language restrictions. Study selection: Studies of any design with DSM or International Classification of Diseases-defined ADHD populations exposed to stimulants, where psychosis or BD outcomes were evaluated. Data extraction and synthesis: PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses and MOOSE Meta-analysis of Observational Studies in Epidemiology guidelines were followed, the protocol was registered, and the Newcastle-Ottawa scale and Cochrane risk of bias-2 tool were used for quality appraisal. Random-effects meta-analysis, subgroup analyses, and meta-regressions were conducted. Main outcomes and measures: For the proportion of individuals developing psychotic symptoms, psychotic disorders, and BD, effect sizes are reported as percentages with 95% CIs. For the comparison between amphetamines and methylphenidate, effect sizes are presented as odds ratios with 95% CIs. Results: Sixteen studies (N = 391 043; mean [range] age, 12.6 [8.5-31.1] years; 288 199 [73.7%] male) were eligible. Among individuals with ADHD prescribed stimulants, 2.76% (95% CI, 0.73-9.88; k = 10; n = 237 035), 2.29% (95% CI, 1.52-3.40; k = 4; n = 91 437), and 3.72% (95% CI, 0.77-16.05; k = 4; n = 92 945) developed psychotic symptoms, a psychotic disorder, and BD, respectively. Heterogeneity across the studies was significant (I2 > 95%). Psychosis occurrence risk was significantly higher in individuals exposed to amphetamines than to methylphenidate (odds ratio [OR], 1.57, 95% CI, 1.15-2.16; k = 3, n = 231 325). Subgroup analyses showed significantly higher prevalence of psychotic symptoms in studies from North America and in those with longer follow-up periods. Increased psychosis occurrence was associated with a higher proportion of female participants, smaller sample sizes, and higher dose of stimulants. Conclusions and relevance: This systematic review and meta-analysis found a nonnegligible occurrence of psychotic symptoms, psychotic disorders, or BD in individuals with ADHD treated with stimulants. Amphetamines were associated with higher occurrence compared to methylphenidate. The included studies cannot establish causality, highlighting the need for further research, including randomized clinical trials and mirror-image studies comparing individuals exposed and not exposed to stimulants. Nonetheless, clinicians should inform patients about the increased occurrence of psychosis or BD when discussing stimulant pharmacotherapy and systematically monitor for these conditions throughout treatment. New Episodes and Suicidal Risks in Bipolar and Major Depressive Disorder Patients During Versus Before Long‐Term Treatment With Lithium Lithium treatment reduces the risk of recurring episodes in bipolar disorder (BD) and probably also in major depressive disorder (MDD) and has evidence of antisuicidal effects. Study objectives were to test for effects of adding lithium treatment for one year to a year of other treatments on risks of illness recurrence, suicidal ideation, and suicide attempts. We compared 296 major mood disorder outpatients for 12 months with treatment that did not include lithium versus 12 months with lithium included. We considered differences in the recurrence of new episodes of illness, new suicidal ideation and suicide attempts, and estimated time to these outcomes with survival analyses. With lithium treatment included, there were marked reductions in episode recurrences (3.12‐fold), suicidal ideation (4.78‐fold), and suicide attempts (6.54‐fold) in both BD and MDD patients, with corresponding delays to these outcomes. Conclusions Adding lithium treatment was strongly associated with reduced risk and delay of clinical recurrence, suicidal ideation and suicide attempts in both BD and MDD outpatients.

Introduction: Clozapine is the only truly effective treatment for refractory schizophrenia, but its use is constrained by the requirements for frequent monitoring of neutrophil counts. In the UK during the COVID-19 pandemic, the frequency of clozapine blood monitoring was reduced in some units from 4-weekly to 12-weekly. We aimed to investigate the outcomes of reduced monitoring in long-term clozapine patients. Methods: This was an anonymous, retrospective, observational cohort study. No restrictions were applied regarding care setting (i.e., outpatients or inpatients). All patients who registered for reduced frequency haematological monitoring from 1 March 2020 to 1 November 2022 were included and followed up till 1 August 2024. The primary outcome was death resulting from clozapine-induced agranulocytosis (CIA). Secondary outcomes were the proportion of patients with mild to moderate neutropenia during the follow-up period and the proportion of patients who reverted to standard monitoring during the study period. Results: Amongst 1025 patients, there were no cases of agranulocytosis over 3365.9 patient-years of 12-weekly blood monitoring (incident rate 0.0 per 100 person-years). There were 43 episodes of mild neutropenia (so-called amber results-1.5-2.0 × 109/L) or neutropenia (red results < 1.5 × 109/L), an overall incident rate of 1.28 per 100 person-years. During follow-up, 41 patients (4%) reverted permanently to standard 4-weekly monitoring, and 157 patients (15%) temporarily interrupted reduced frequency monitoring but restarted 12-weekly monitoring before the end of the follow-up period. In total, 42 patients (4%) died during the observation period-no death was related to agranulocytosis. Conclusion: Reducing the frequency of clozapine haematological monitoring to 12-weekly was safe in a group of long-term patients. No cases of agranulocytosis occurred and no deaths due to agranulocytosis were recorded. Most patients remained on extended-interval monitoring.

Introduction: ADHD is often associated with comorbid psychiatric conditions. Differential diagnosis between other conditions and ADHD is not always clear, and patients are sometimes initially treated for another disorder instead. ADHD diagnosis and appropriate ADHD treatment potentially reduce the need for medication of the other disorder. Reaching high adherence to and persistence with ADHD medication is challenging. This nationwide cohort study aimed to describe not only ADHD medication use but also the use of other drugs in ADHD patients compared to controls. Methods: Nationwide care and prescription registers were used to identify incident ADHD patients of any age between 2015 and 2020. Four controls were matched to each ADHD patient by age, gender, and residence. Analyses included data from 1.1.2010 to 31.12.2021. Results: Study cohort included 66,146 ADHD patients and 256,270 controls, with a total follow-up of 1,123,412 years. Sustained and extended-release methylphenidate were the two most commonly used first-line ADHD drugs across all age groups. Simultaneous use of different ADHD drugs was rare. Primary adherence was very high, with 95% of the patients purchasing their prescribed medication in general and 80% doing so within 10 days. Persistence with medication was the highest among the youngest patients. A decrease in purchases was observed during the summer holidays in school-age children and adolescents. In adults, antidepressant use often preceded ADHD diagnosis and decreased after ADHD treatment initiation, unlike in controls at the same time. In young children, antibiotics and anti-inflammatory drug use was higher in ADHD patients than in controls, especially before ADHD identification. Conclusion: As far as we know, this is the first study to describe changes in the use of non-ADHD medications in relation to ADHD identification. In adults, antidepressant use decreased after ADHD treatment initiation, and in children, antibiotic and anti-inflammatory use showed more prominent decrease compared to controls of the same age. The data indicated high primary adherence to ADHD medication, and the youngest children remained on continuous ADHD medication the longest. The effect of summer holidays was visible in the purchase data.

Lamotrigine is beneficial in bipolar disorder and is often prescribed to patients during their period of reproductive potential. We summarise aspects of the pharmacology of lamotrigine, highlight its uses in psychiatric practice, drawing attention to recent findings relating to potential hazards arising from lamotrigine exposure in utero, and make some suggestions for clinical management.

Objective: The aim of this study was to determine whether advanced puberty at age 9 and 10 years, relative to that in same-aged peers, predicts current and/or new-onset self-injurious thoughts and behaviors (SITBs). New predictors of SITBs in preadolescence are urgently needed to address this escalating public health crisis of youth self-harm and suicidality. Method: Data from the baseline, 1-year, and 2-year waves of the Adolescent Brain and Cognitive Development Study were used. Bayesian mixed-effects models were estimated for test and replication split halves, and tested whether relatively advanced youth-reported pubertal development at 9 or 10 years predicted SITBs (suicidal ideation, suicide attempts, and nonsuicidal self-injury) as reported by preadolescents (each wave) and their caregiver (baseline, 2-year follow-up) in a computerized version of the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS). Preadolescents with baseline self-reported puberty, KSADS (N = 8,708; 44.6% female; 60.8% White non-Hispanic), and demographic information were included. Results: Baseline preadolescent-reported puberty predicted the presence of any SITB before or at baseline (odds ratio = 1.50, 95% credible interval = 1.23-1.85) and the new-onset SITBs between baseline and 2-year follow-up in preadolescents SITB-naive at baseline (odds ratio = 2.26, 95% credible interval = 1.66-3.21). Conclusion: Preadolescents reporting relatively advanced puberty were more likely to have experienced SITBs and, if SITB naive, were more likely to experience the onset of SITBs across the following 2 years. Findings were not explained by child psychopathology or other familial and psychosocial factors known to predict SITBs. Screening preadolescents for advanced puberty at ages 9 and 10 years and applying targeted suicide screening for those youth showing advanced puberty should be considered in primary care and mental health settings. Plain language summary: Analyzing data from the Adolescent Brain and Cognitive Development (ABCD) study, the authors found that adolescents reporting advanced puberty at age 9 to 10 were more likely to have experienced self-injurious thoughts and behaviors (SITB) and, if SITB naive, were more likely to experience the onset of SITBs over the following 2 years. These findings were not explained by other child mental health problems or familial or social factors known to predict these behaviors. The authors recommend screening preadolescents for advanced puberty and applying targeted suicide screening for those youth showing advanced puberty in primary care and mental health settings.

No abstract available

Clinicians across medical disciplines are intimately familiar with an unusual feature of descriptive diagnoses. The diagnostic terms, despite their non-aetiological nature, seem to offer an explanatory lens to many patients, at times with profound effects. These experiences highlight a striking, neglected and unchristened medical phenomenon: the therapeutic effect of a clinical diagnosis, independent of any other intervention, where clinical diagnosis refers to situating the person's experiences into a clinical category by either a clinician or the patient. We call this the Rumpelstiltskin effect. This article describes this phenomenon and highlights its importance as a topic of empirical investigation.

No abstract available

This Medical News article is an interview with epidemiologist Brian Lee, PhD, about his study on acetaminophen use during pregnancy and children’s risk of autism and other neurodevelopmental disorders.

Twenty years ago Shitij Kapur's "Psychosis as a state of aberrant salience" captured the attention of clinicians and cognitive and behavioral neuroscientists. It has become the de facto way of talking about delusion formation in labs and clinics. Here, evidence for this theory is critically evaluated in consideration of evolving data since its publication. A particular focus is placed on its specific predictions regarding the neural and behavioral loci of dopamine dysfunction in psychosis and finds them lacking. This examination is informed by recent advances in the understanding of the function of the dopamine system and its impacts on behavior following the explosion of new tools and probes for precise measurement and manipulation of dopaminergic circuits. Contemporary theories that have developed since Kapur-which suggest a role for dopamine in belief formation, belief updating under uncertainty, and abductive inference to the best explanation for some set of circumstances-are argued to form a more cogent theory that fits better with the work in patients with delusions and hallucinations, how they behave, and what is known about the function of their dopamine system. The original salience hypothesis has been influential as it attempted to unite neurochemical dysfunction with clinical phenomenology through computational cognitive neuroscience, which has led to the development of novel predictions that the authors highlight as future directions for the field.