April 2025

Schizophrenia is a mental illness involving multiple symptom domains and is often associated with substantial physical health comorbidities. Guidelines exist, but these tend to be country-specific and are often missing a concise yet comprehensive algorithmic approach. From May 1, 2023, to Jan 1, 2025, International Guidelines for Algorithmic Treatment (INTEGRATE) authors from all UN regions collaborated to develop a consensus guideline focused on the pharmacological treatment of schizophrenia. Following an umbrella review of the literature, input from expert workshops, a consensus survey, and lived experience focus groups, a consensus algorithmic guideline and associated digital tool were developed. Key recommendations include a focus on metabolic health from treatment initiation, timely assessment and management of non-response, symptom domain-specific interventions, mitigation of side-effects, and the prompt use of clozapine in cases of treatment resistance.

Importance: Hormonal contraceptive (HC) use is associated with depression. It is, however, unknown whether this is also true in the postpartum period when women have a heightened depression risk and are routinely offered HC treatment. Objective: To examine whether HC initiation post partum is associated with the development of depression within 12 months post partum. Design, setting, and participants: A population-based cohort study based on nationwide Danish register data was conducted including all primiparous women who gave birth from January 1, 1997, through December 31, 2022. Women were excluded if they had depression within 24 months before delivery, multiple births or stillbirth, or a diagnosis of breast cancer or liver tumor. Data analysis was conducted between March 20, 2023, and January 17, 2025. Exposure: Hormonal contraceptive initiation within 12 months post partum was treated as a time-varying exposure. Hormonal contraceptive types were categorized as combined oral contraceptives (COCs), combined nonoral contraceptives (CNOCs), progestogen-only pills (POPs), and progestogen-only nonoral contraceptives (PNOCs). Main outcomes and measures: Depression within 12 months post partum, defined as filling an antidepressant prescription or receiving a hospital diagnosis of depression, was the main outcome. Adjusted hazard ratios (AHRs) and average absolute risks of depression within 12 months post partum were estimated using Cox proportional hazards regression and a G-formula estimator. Results: Of 610 038 first-time mothers, 248 274 (40.7%) initiated HCs within 12 months post partum (mean [SD] age, 27.6 [4.3] years for HC users vs 29.6 [4.8] years for nonusers). Hormonal contraceptive initiation was associated with subsequent depression, with an AHR of 1.49 (95% CI, 1.42-1.56) compared with no use, resulting in an increase in the 12-month absolute risk from 1.36% (95% CI, 1.32%-1.39%) to 1.54% (95% CI, 1.50%-1.57%). The AHR for COC was 1.72 (95% CI, 1.63-1.82); CNOC, 1.97 (95% CI, 1.64-2.36); and PNOC, 1.40 (95% CI, 1.25-1.56). Progestogen-only pill exposure was associated with an instantaneously reduced risk in the early study period, but it was increased late post partum. The earlier COCs were initiated post partum the higher the associated rate ratio of depression. Conclusions and relevance: In this cohort study, HC initiation post partum was associated with an instantaneous increased risk of developing depression. The associated risk was higher the earlier it was initiated post partum, at least for COC. This finding raises the issue of whether the incidence of depression post partum is increased by routine HC initiation after childbirth.

Purpose: Describe xanomeline and trospium chloride efficacy and safety/tolerability for the treatment of schizophrenia using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Methods: Categorical data were extracted from the three 5-week, randomized, double blind, placebo controlled EMERGENT-1, EMERGENT-2, and EMERGENT-3 clinical trials of xanomeline/trospium in adults with schizophrenia experiencing acute psychosis. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and categorical response criteria. Safety and tolerability were assessed using rates of discontinuation and treatment-emergent adverse events (TEAEs). NNT, NNH, and LHH values were calculated for each individual study as well as pooled. Results: In data from the acute EMERGENT trials, NNT estimates were significant for xanomeline/trospium vs placebo for the pre-specified treatment response threshold of ≥30% reduction from baseline in PANSS total score at Week 5 (NNT=5 [95% CI, 4-8]). NNT estimates for response thresholds of ≥20% and ≥40% reduction from baseline in PANSS total score and ≥1- and ≥2-point decrease from baseline in CGI-S score were <10, indicating a clinically relevant therapeutic benefit of xanomeline/trospium over placebo. Estimates of NNH vs placebo for the most common TEAEs were >10, with the exception of nausea and vomiting; however, rates of discontinuations due to TEAEs of nausea, dyspepsia, or vomiting were low (NNH=49 [95% CI, 28-182]). LHH indicated an overall benefit of xanomeline/trospium vs placebo for all assessed outcomes. In indirect comparisons based on published data from trials of available antipsychotics approved for schizophrenia, xanomeline/trospium exhibited comparable or more robust NNT estimates vs placebo and was the least likely agent to be associated with weight gain or somnolence/sedation. Conclusion: In the 5-week EMERGENT clinical trials, NNT, NNH, and LHH assessments demonstrated a favorable benefit-risk profile for xanomeline/trospium.

Introduction: Previous studies have shown patient preference can have large effects on treatment adherence and patient satisfaction. However, the direct effects of matching treatment with patient preference on efficacy and safety outcomes remain unclear. We aimed to evaluate the effects of patient preference and preference-matching on efficacy, adverse events, and adherence to electroconvulsive therapy (ECT) and intravenous (IV) ketamine treatments in a randomized clinical trial. Methods: Data were collected during the Patient-Centered Outcomes Research Institute (PCORI) funded ECT vs. Ketamine in Patients with Treatment Resistant Depression (ELEKT-D) study, which randomized patients to treatment with either ECT or IV ketamine across five U.S. sites. We performed post hoc-analyses on 255 patients who provided responses to a patient preference survey following treatment phase completion, which allowed us to explore the relationships between treatment preference and several treatment outcome measures. Results: Our analysis showed that (1) Ketamine was preferred by more trial participants than ECT; (2) Preference for ketamine was associated with higher likelihood of treatment response for all patients regardless of treatment assignment; (3) Preference-matching (patients receiving the treatment they indicated a moderate or strong preference for on the survey) was associated with greater likelihood of treatment response to ketamine but not ECT; (4) Preference-matching was associated with reduced rates of adverse events in ECT-treated patients. There was a trend for preference-matching potentially influencing treatment adherence. Conclusions: Our findings suggest treatment preference-matching affects treatment effectiveness, adverse event reporting and possibly adherence. However, these associations may be contextual, modality dependent, and complex.

Introduction: Up to 50% of individuals fail to respond to current depression treatments. Repetitive negative thought and default mode network hyperconnectivity are central in depression and can potentially be targeted using novel neuromodulation techniques. This community-based study assessed whether a treatment using non-invasive transcranial focused ultrasound targeting the default mode network can decrease depression symptoms and repetitive negative thought, and improve quality of life. Methods: Study recruitment began in August 2023 and ended in February 2024. Twenty individuals aged 18 - 50 were enrolled from among 247 screened. Exclusion criteria included history of psychosis/mania, acute suicidality, MRI contraindications, pregnancy, and medical and neurological factors that may complicate diagnosis or brain function. Participants completed up to three weeks of transcranial ultrasound (11 sessions) targeting the anterior medial prefrontal cortex; ten minutes per session. Depression severity (Beck Depression Inventory - II and the Hamilton Depression Rating Scale), repetitive negative thought (Perseverative Thinking Questionnaire), and quality of life (World Health Organization Quality of Life Scale) were outcomes. Results: This sample was young (mean 30.4 years ± 10.0), predominantly female (75%), with moderate to severe depression and high comorbidity. Fifty percent of participants endorsed current psychiatric medication use. Ten percent of subjects dropped out of the study due to time constraints. Significant decreases in depression were observed over the course of treatment on self-report, 10.9 (p < 0.001, CI = -13.55, -7.92) and interview depression ratings, 4.2 (p < 0.001, CI = -5.85, -2.62), as well as significant decreases in repetitive negative thought, 8.4 (p <0.001, CI = -10.55, -6.03). Improvements in physical and psychological well-being were also observed over the course of treatment, 7.2 (p < 0.001, CI = 3.64, 10.63) and 11.2 (p < 0.001, CI = 7.79, 14.49), respectively, as well as improvements in environment satisfaction, 5.0 (p =0.001, CI = 2.24, 7.56). Discussion: Non-invasive transcranial focused ultrasound holds promise as a treatment for depression holds promise as a treatment for depression, however, future work including control arms is required to ascertain its causal role in depression.

Interoception is the awareness of bodily sensations, conveyed by both hormonal and neural signals. The vagus nerve is the primary neural interoceptive conduit, responsible for transmitting information from peripheral organs to the brain. It is widely accepted that vagal signals are essential for purely physiological functions like blood pressure maintenance, or nutrient intake homeostasis. However, a growing body of evidence, taking advantage of new technological advances, suggests that the vagus nerve also orchestrates or tunes emotions. Disruption of vagal interoceptive feedback prevents normal emotional control in rodents. Importantly, accumulating evidence indicates that pathological disruption of vagal afferent signals also occurs in humans and may constitute an important risk factor for emotional disorders. Hence, alleviating vagal interoceptive deficits may constitute a new therapeutic avenue for neurotic and affective disorders. Considering the technical and safety challenges for direct stimulation of brain regions relevant to emotionality disorders, the vagus nerve offers a safer and more practical route of potentially achieving similar outcomes. Here we will highlight the earliest studies which examined the consequences of manipulations of the vagal afferent neurons on anxiety, fear, and mood, and integrate these older findings with new research investigating the necessity of vagal afferent neurons in mediating the anxiety or mood-altering effects of physiological signals. We will also discuss the evolutionary significance of vagal control over emotional states within the boundaries of "normal" physiology and conclude by discussing the challenges of engaging the vagal interoception as novel therapeutics in mental health disorders.

Background: People with dementia (PwD) and their carers often consider maintaining good quality of life (QoL) more important than improvements in cognition or other symptoms of dementia. There is a clinical need for identifying interventions that can improve QoL of PwD. There are currently no evidence-based guidelines to help clinicians, patients and policy makers to make informed decisions regarding QoL in dementia. Aims: To conduct the first comprehensive systematic review of all studies that investigated efficacy of any pharmacological or non-pharmacological intervention for improving QoL of PwD. Method: Our review team identified eligible studies by comprehensively searching nine databases. We completed quality assessment, extracted relevant data and performed GRADE assessment of eligible studies. We conducted meta-analyses when three or more studies investigated an intervention for improving QoL of PwD. Results: We screened 14 389 abstracts and included 324 eligible studies. Our meta-analysis confirmed level 1 evidence supporting the use of group cognitive stimulation therapy for improving QoL (standardised mean difference 0.25; P = 0.003) of PwD. Our narrative data synthesis revealed level 2 evidence supporting 42 non-pharmacological interventions, including those based on cognitive rehabilitation, reminiscence, occupational therapy, robots, exercise or music therapy. Current evidence supporting the use of any pharmacological intervention for improving QoL in dementia is limited. Conclusions: Current evidence highlights the importance of non-pharmacological interventions and multidisciplinary care for supporting QoL of PwD. QoL should be prioritised when agreeing care plans. Further research focusing on QoL outcomes and investigating combined pharmacological and non-pharmacological interventions is urgently needed.

The global prevalence of autism spectrum disorder (ASD) has quadrupled during the past 3 decades; the reasons for this are many and include broadening of the diagnostic concept, increased awareness of the disorder, increased screening (including of adults and of girl children), and, possibly, increased exposure to environmental risk factors. This article examines genetic and especially environmental risk factors for ASD. Unsurprisingly, hundreds of potential genes have been identified, many of which overlap between ASD, schizophrenia, depression, and cardiometabolic disorders. Likewise, over a hundred environmental exposures have been associated with ASD risk. These include exposure to parental and family characteristics, exposure to maternal disorders arising during pregnancy, exposure to chronic maternal disorders present during pregnancy, exposure to fetal and other pregnancy-related problems/events, exposure to neonatal problems/events, exposure to maternal nutritional deficiencies during pregnancy, maternal exposure to substances during pregnancy, maternal exposure to pharmacological agents during pregnancy, in utero exposure to toxic substances, and early life exposure to toxic substances. Some of the risk factors identified may be causal, some may be markers of intermediary mechanisms, and some may be unrelated markers. About 40 of these risk factors have been confirmed in meta-analysis for association with ASD. Nearly 70 maternal diagnoses have also been associated with ASD, but, after correcting for false discovery error and shared risk, only 30 remain; and, of these 30, almost all may be explained by genetic and environmental risk factors shared between mother and child, judging from findings in discordant sibling pair and paternal negative control analyses. Caveats and nuances in the interpretation of risks are briefly discussed.

Background: In recent years, there has been a significant focus on exploring the potential therapeutic impact of altered states of consciousness on treatment outcomes for mental illness, with the goal of enhancing therapeutic strategies and patient results. Methods: This meta-analysis was designed to investigate the potential link between the psychomimetic effects of ketamine and clinical outcomes in mental health, which adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Eleven studies were selected for meta-analysis, and the main result did not find a significant correlation between the psychoactive effects of ketamine and clinical outcomes either in mental illness (n = 11; n's = 27; r = 0.06 [-0.05, 0.17]; P = 0.268) or depression exclusively (n = 10; n's = 25; r = 0.03 [-0.07, 0.13]; P = 0.561). High heterogeneity was found for general analysis ( I2 = 80.78). Egger's regression did not indicate publication bias (intercept = 1.57; SE = 1.49, P = 0.30). No significant Kendall's rank correlation coefficient was observed ( τ = 0.02, P = 0.88) indicating funnel plot symmetry. The sub-analyses, aimed at minimizing study variability by specifically examining factors such as patient disorders (limited to depression), methods of administration (exclusively intravenous), types of assessment instruments, and the timing of evaluations, also yielded no significant findings. Conclusion: This meta-analysis suggests that the altered states of consciousness experienced during ketamine sessions are not directly linked to clinical outcomes. However, it is important to acknowledge that the limited number of studies and their heterogeneity render this conclusion preliminary, warranting further investigation over time.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for obsessive-compulsive disorder (OCD). The neurobiological mechanisms of rTMS in OCD have been incompletely characterized. We compared clinical outcomes and changes in task-based brain activation following 3 different rTMS protocols, all combined with exposure and response prevention. Methods: In this 3-arm proof-of-concept randomized trial, 61 treatment-refractory adult patients with OCD received 16 sessions of rTMS immediately before exposure and response prevention over 8 weeks, with task-based functional magnetic resonance imaging scans and clinical assessments before and after treatment. Patients received high-frequency rTMS to the left dorsolateral prefrontal cortex (n = 19 [13 women/6 men]), high-frequency rTMS to the left presupplementary motor area (preSMA) (n = 23 [13 women/10 men]), or control rTMS to the vertex (n = 19 [13 women/6 men]). Changes in task-based functional magnetic resonance imaging activation before/after treatment were compared using both a Bayesian region of interest and a general linear model whole-brain approach. Results: Mean OCD symptom severity decreased significantly in all treatment groups (Δ = -10.836, p < .001, 95% CI -12.504 to -9.168), with no differences between groups. Response rate in the entire sample was 57.4%. The dorsolateral prefrontal cortex rTMS group showed decreased planning-related activation after treatment that was associated with greater symptom improvement. No group-level activation changes were observed for the preSMA and vertex rTMS groups. Participants in the preSMA group with greater symptom improvement showed decreased error-related activation, and symptom improvement in the vertex group was associated with increased inhibition-related activation. Conclusions: rTMS to preSMA and dorsolateral prefrontal cortex combined with exposure and response prevention led to activation decreases in targeted task networks in individuals showing greater symptom improvement, although we observed no differences in symptom reduction between groups.

Background: Caregivers of autistic children experience particularly poor levels of mental health and increased caregiving complexities. Proactive post-diagnostic family support is recommended but is inconsistently implemented, largely not evidence based, and does not directly address caregiver mental health. This study aimed to test the clinical effectiveness of the Empower-Autism programme plus treatment as usual versus the usual local post-diagnostic psychoeducation offer plus treatment as usual on caregiver mental health at the 52-week follow-up. Methods: We did a prospective, multicentre, two-parallel-group, randomised controlled superiority trial of the Empower-Autism programme. Empower-Autism is a group-based, manualised, post-diagnostic programme designed to improve the mental health of caregivers of newly diagnosed autistic children. The programme combines autism psychoeducation and psychotherapeutic components based on Acceptance and Commitment Therapy and was delivered online via videoconferencing. Participants were recruited from 11 North-West England autism diagnostic or intervention centres and were parents or primary caregivers of children aged 2-15 years given an autism diagnosis within the past 12 months. Exclusion criteria were insufficient English language skills, significant learning disability, hearing or visual impairment, or psychiatric condition in caregiver and significant current family safeguarding concerns. Participants were randomly assigned to the intervention or treatment as usual (2:1), stratified by centre. Assessors were masked to group assignment but participants were not. The primary outcome was caregiver mental health assessed by the General Health Questionnaire-30 at 52 weeks. All outcomes were analysed following an intention-to-treat approach using linear mixed models on available cases in the first instance, which resulted in a modified intention-to-treat set due to missing data. Sensitivity analyses on multiply imputed data reflected the full intention-to-treat set. People with lived experience were involved in the trial across all stages. The trial was prospectively registered (ISRCTN 45412843) on Sept 11, 2019, and is complete. Findings: Between Sept 16, 2020 and April 14, 2022, 835 potential participants were referred and screened, 384 provided consent, and 379 caregivers were recruited, 255 of whom were randomly assigned to the intervention group and 124 to the treatment as usual group. 333 (88%) participants were female and 46 (12%) were male, with a mean age of 40·6 years (SD 7·3; range 23-69). 294 (78%) of the 379 caregivers were White British, 18 (5%) were White Other, 12 (3%) were Mixed or of multiple ethnicity, 32 (8%) were Asian or Asian British, 16 (4%) were Black or Black British, six (2%) were from any other ethnic group, and one (<1%) had missing ethnicity data. 267 (70%) index children were male, 111 (29%) were female, and one (<1%) was non-binary or other, with a mean age 8·9 years (SD 3·5; range 2·0-16·0). In the available case analysis set (n=319) reflecting a modified intention-to-treat set due to missing data, participants randomly assigned to Empower-Autism had improved mental health at 52 weeks compared with those randomly assigned to treatment as usual (General Health Questionnaire-30 mean difference -4·95 [95% CI -8·21 to -1·68], p=0·0030). 181 adverse events (116 in the Empower-Autism group and 65 in the treatment as usual group) and 15 serious adverse events (nine in the Empower-Autism group and six in the treatment as usual group) were reported; none were deemed to be related to the study intervention. The most common adverse events concerned significant deteriorations in the mental health of caregiver participants or index children and other serious personal issues potentially affecting caregiver mental health. Interpretation: To our knowledge, this is the first fully powered trial to show a statistically and clinically significant sustained effect on mental health in caregivers of newly diagnosed autistic children. In the context of the considerable clinical need in this area, we recommend the use of the Empower-Autism programme to clinicians and policy makers.

Importance: Cognitive behavior therapy (CBT) is a first-line treatment for most mental disorders. However, no meta-analytic study has yet integrated the results of randomized clinical trials on CBT across different disorders, using uniform methodologies and providing a complete overview of the field. Objective: To examine the effect sizes of CBT for 4 anxiety disorders, 2 eating disorders, major depression, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and psychotic and bipolar disorders on symptoms of the respective disorders using uniform methodologies for data extraction, risk of bias (RoB) assessment, and meta-analytic techniques. Data sources: Major bibliographical databases (PubMed, PsycINFO, and Embase for all disorders) were searched up to January 1, 2024, for each disorder separately. Data analysis was performed from August 2024 to January 2025. Study selection: Randomized clinical trials comparing CBT with inactive control conditions in adults with 1 of the mental disorders established through a clinical interview were included. Data extraction and synthesis: Basic characteristics of patients, CBT, and studies were extracted. RoB was assessed with the Cochrane RoB tool 2. Meta-analyses were conducted using random-effects models. Main outcomes and measures: The primary outcome was the standardized mean difference (Hedges g) indicating the difference between CBT and controls at posttreatment on symptoms of the respective disorders. Results: A total of 375 trials (423 comparisons) between CBT and controls were included among 32 968 patients. The overall mean (SD) patient age was 43.4 (13.7) years, and the mean (SD) proportion of women was 0.68 (0.24). Effect sizes for CBT compared to all control conditions (g) were lower than 0.5 for bipolar and psychotic disorder; between 0.5 and 1.0 for panic, social anxiety, and generalized anxiety disorders, bulimia nervosa, binge eating disorders, depression, and OCD; and larger than 1.0 for PTSD and specific phobias (range of effect sizes: 0.31 for bipolar disorder to 1.27 for PTSD). Large effect sizes (g > 0.94) were observed in waitlist-controlled trials, a control condition mostly used in anxiety and eating disorders, PTSD, and OCD. Trials using care as usual showed more modest effect sizes (0.22-1.13). Study dropout rates within the CBT conditions ranged from 8% for specific phobia to 24% for PTSD. Conclusions and relevance: In this unified series of meta-analyses, CBT was probably effective in the treatment of mental disorders, including major depression, anxiety disorders, PTSD, OCD, and eating disorders, and possibly effective in psychotic and bipolar disorders. However, the effect sizes depended on the type of control condition.

Recent evidence from clinical and animal studies with anti-inflammatory agents in depression is conflicting. One possible reason is the heterogeneity of baseline inflammation levels. Since older adults are generally associated with chronic low-grade inflammation and depression is one of the most common mental disorders in this population, this meta-analysis aimed to evaluate the therapeutic and preventative effects of anti-inflammatory interventions for depression among older adults. PubMed, Cochrane Library, Embase, and PsycINFO were searched for randomized controlled trials (RCTs) up to November 18, 2024. The primary outcomes were mean change scores of depression scores and incidences of depression after treatment. Pooled standard mean differences (SMDs) and odds ratios (ORs) including 95% confidence intervals (95% CI) were calculated. Of 3116 screened articles, 31 RCTs met the inclusion criteria, with 25 studies investigating efficacy and 7 studies investigating the incidence following anti-inflammatory treatment. Anti-inflammatory interventions were statistically significantly more effective than placebo in reducing depressive scores for older adults with depression (SMD = -0.57, 95% CI = -0.98 to -0.15, p = 0.008). Sub-group analyses supported the use of omega-3 fatty acids (SMD = -0.14, 95% CI = -0.27 to -0.02, p = 0.03) and botanical drug or dietary intervention (SMD = -0.86, 95% CI = -1.58 to -0.13, p = 0.02) among older participants. While limited by substantial heterogeneity among included studies, these results reveal the moderate beneficial effects of anti-inflammatory interventions for the treatment and prevention of depression among older adults. Future high-quality RCTs are warranted to determine which anti-inflammatory interventions are most preferential for older patients with depression.

Objective: The authors synthesized evidence from studies quantifying the relationship between anticholinergic medication and cognitive function in psychosis, and additionally explored studies that investigated whether reducing anticholinergic medications affects cognitive function in individuals with psychosis. Methods: A database search was conducted in MEDLINE, Embase, and PsycINFO, from database inception to October 2023, for studies reporting objective cognitive assessment and quantification of anticholinergic burden using clinical scales, serological anticholinergic activity, or tapering of anticholinergic medications. Analyses were carried out in R using the metafor package. Random-effects meta-analysis models were employed, along with assessment of heterogeneity, study quality, and meta-regressions (age, sex, and antipsychotic dosage in chlorpromazine equivalents). Results: Of 1,337 citations retrieved, 40 met inclusion criteria, comprising 25 anticholinergic burden studies (4,620 patients), six serological anticholinergic activity studies (382 patients), and nine tapering studies (186 patients). A negative correlation was identified between anticholinergic burden and global cognition (r=-0.37, 95% CI=-0.48, -0.25), verbal learning (r=-0.28, 95% CI=-0.36, -0.21), visual learning (r=-0.17, 95% CI=-0.28, -0.06), working memory (r=-0.22, 95% CI=-0.29, -0.14), processing speed (r=-0.24, 95% CI=-0.35, -0.13), attention (r=-0.19, 95% CI=-0.29, -0.08), executive functions (r=-0.17, 95% CI=-0.27, -0.06), and social cognition (r=-0.12, 95% CI=-0.19, -0.05), and between serological anticholinergic activity and verbal learning (r=-0.26, 95% CI=-0.38, -0.14), working memory (r=-0.19, 95% CI=-0.35, -0.03), and executive functions (r=-0.16, 95% CI=-0.27, -0.04). Finally, tapering off anticholinergic medication improved the scores in verbal learning (d=0.77, 95% CI=0.44, 1.1), working memory (d=0.94, 95% CI=0.63, 1.26), and executive functions (d=0.44, 95% CI=0.26, 0.62). Conclusions: Anticholinergic burden is associated with the cognitive impairments observed in psychosis. From a clinical perspective, tapering off anticholinergic medication in patients with psychosis may improve cognition. However, randomized clinical trials are needed for an unbiased quantification of benefit.

Objective: It is not known what proportion of patients experience relapse in first-episode schizophrenia despite continuous dopamine D2 receptor blockade and whether breakthrough psychosis is attributable to long-term use of D2-blocking antipsychotics. Using data from a Finnish nationwide cohort, the authors sought to test the hypothesis that the incidence of breakthrough psychosis is accelerated among previously relapse-free patients receiving continuous D2 antagonist treatment beyond 5 years. Methods: All persons age 45 years or younger with first-episode schizophrenia were identified from the nationwide registry of inpatient care for the years 1996-2014. The primary outcome was a severe relapse leading to hospitalization among those treated continuously with long-acting injectable (LAI) antipsychotics. The secondary outcome was the incidence rate ratio (IRR) of relapse during years 2-10, using year 1 as the reference. Results: A total of 305 patients initiated ensured LAI use during the first 30 days of follow-up. Kaplan-Meier analysis showed that during the 10-year follow-up, their cumulative probability of relapse was 45% (95% CI=35-57). The annual relapse incidence per person-year decreased from 0.26 (95% CI=0.20-0.35) during the first year to 0.05 (95% CI=0.01-0.19) during the fifth year, corresponding to an IRR of 0.18 (95% CI=0.04-0.74). During years 6-10, only four relapses occurred during 128 person-years, corresponding to an IRR of 0.12 (95% CI=0.03-0.33) compared with year 1. Conclusions: About 40%-50% of patients with first-episode schizophrenia will relapse despite continuous D2 blockade, apparently due to non-dopaminergic elements of the pathophysiology of the illness, as the results show that long-term dopamine receptor blockade is not associated with an increased risk of breakthrough psychosis.

Objectives: To evaluate cariprazine in adults with older- and younger-age bipolar I disorder (OABD-I and YABD-I) and compare treatment effects between them. Design and setting: Pooled post-hoc analysis of studies in depressive or acute manic/mixed episodes associated with bipolar I disorder. Participants: 475/1383 patients (34.3%) in 3 depression trials and 238/1037 patients (23.0%) in 3 manic/mixed trials were OABD-I. Interventions: Depression: placebo, cariprazine 1.5 mg/day, 3.0 mg/day, pooled 1.5-3.0 mg/day. Manic/mixed: placebo, cariprazine 3.0-6.0 mg/day, and 9.0-12.0 mg/day. Measurements: Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression of Severity (CGI-S), and Young Mania Rating Scale (YMRS). Results: In bipolar I depression, mean change from baseline in MADRS was significantly greater for the pooled cariprazine group vs. placebo in OABD-I (-13.72 vs. -11.98; p < 0.05) and for each cariprazine group vs. placebo among YABD-I. There was no significant difference in treatment effect between OABD-I and YABD-I for either individual cariprazine group vs. placebo. For mania/mixed states, mean change in YMRS was significantly greater for cariprazine 3.0-6.0 mg/day vs. placebo in OABD-I (-19.04 vs. -12.45; p < 0.001) and for both cariprazine groups in YABD-I (-12.49, -19.66 and -18.05 for placebo, cariprazine 3.0-6.0 mg/day and 9.0-12.0 mg/day, respectively [both p < 0.0001 vs. placebo]). There was no significant difference in treatment effect between OABD-I and YABD-I for cariprazine 3.0-6.0 mg/day vs. placebo; there was a significantly higher treatment effect for cariprazine 9.0-12.0 mg/day vs. placebo in the YABD-I subpopulation vs. OABD-I (4.20; p < 0.05).

Objective: Adolescent offspring of parents with bipolar disorder (BD) are at high risk to develop BD and other psychopathology, yet how this risk continues into middle adulthood remains unknown. This study aimed to determine the window of risk for BD and other psychopathology in offspring of parents with BD followed from adolescence into adulthood. Method: This study reported on the 22-year follow-up assessment of the Dutch Bipolar Offspring Study, a fixed cohort study of 140 participants established in 1997. Offspring (n = 100; mean [SD] age = 38.28 [2.74] years) of parents with bipolar I disorder or bipolar II disorder were assessed at baseline and 1-, 5-, 12-, and 22-year follow-up. Results: No new BD onsets occurred since the 12-year follow-up (lifetime prevalence = 11%-13%; bipolar I disorder = 4%; bipolar II disorder = 7%). Lifetime prevalence of any mood disorder was 65%; for major depressive disorder, prevalence was 36%; and for recurrent mood episodes, prevalence was 37%. Prevalence of major depressive disorder more than doubled in the past decade. Point prevalence of any psychopathology peaked between 20 and 25 years (38%-46%), subsiding to 29% to 35% per year after age 30. Overall, 71% of offspring contacted mental health services since the last assessment. Conclusion: The risk for homotypic transmission of BD in offspring of parents with BD is highest during adolescence. The heterotypic risk for mood disorder onset and recurrences continues over the life course. Severe mood disorders are often preceded by milder psychopathology, emphasizing the need for early identification and interventions. This study allows for better understanding of the onset and course of mood disorders and specific windows of risk in a familial high-risk population.

Objective: Psychiatric disorders are highly prevalent in adults with childhood-onset attention-deficit/hyperactivity disorder (ADHD). Currently, little is known about childhood predictors for these outcomes. Method: PubMed, PsychInfo, WoS, and EMBASE were searched until June 2024. Eligible studies investigated childhood predictors of persistent ADHD, substance use disorders (SUD), conduct disorder, antisocial personality disorder, major depressive disorder (MDD), and/or anxiety disorders in adults diagnosed with childhood ADHD (PROSPERO #CRD42022320887). Meta-analytic models were tested when N ≥3 for a predictor with similar effect measures, otherwise predictors were discussed narratively when N ≥2. Newcastle-Ottawa scale was used to assess study quality. Results: The selected 36 studies included 119 predictors, with 10 predictors eligible for meta-analyses. History of stimulant treatment (OR = 1.88, 95% CI 1.28-2.75, p = .001) was associated with increased, and higher childhood IQ with decreased (OR = 0.99, 95% CI 0.98-1.00, p =.039), risk of ADHD persistence in adulthood. ADHD persistence was associated with increased risk of SUDs (OR = 2.12, 95% CI 1.53-3.17, p =.004) and MDD (OR = 3.19, 95% CI 1.71-5.95, p <.001). Narratively reviewed predictors of fair/good quality studies showed potential predictors for ADHD persistence (i.e., ADHD combined type, hyperactive/impulsive symptoms, anxiety disorders, externalizing problems, social dysfunctioning, and socioeconomic status). Conclusion: We confirmed earlier reported childhood predictors (i.e., stimulant treatment history, ADHD persistence) and identified potential new predictors (i.e., childhood anxiety disorders, social problems, socioeconomic status) for psychiatric outcomes of ADHD. However, the available literature is hampered by methodological shortcomings. Future studies should focus on studying combined effects of potential predictors.