Converging Evidence for Frontopolar Cortex as a Target for Neuromodulation in Addiction Treatment
The review highlights the importance of targeting the frontopolar area and tailoring the treatment according to interindividual variations in brain state and trait and electric field distribution patterns. This converging evidence supports the potential for treatment optimization through context, target, dose, and timing dimensions to improve clinical outcomes of transcranial brain stimulation in people with substance use disorders in future clinical trials.
KEY FINDINGS: This review highlights the importance of targeting the frontopolar area and tailoring the treatment according to interindividual variations in brain state and trait and electric field distribution patterns. This converging evidence supports the potential for treatment optimization through context, target, dose, and timing dimensions to improve clinical outcomes of transcranial brain stimulation in people with substance use disorders in future clinical trials.
BACKGROUND: Noninvasive brain stimulation technologies such as transcranial electrical and magnetic stimulation (tES and TMS) are emerging neuromodulation therapies that are being used to target the neural substrates of substance use disorders.
DETAILS: By the end of 2022, 205 trials of tES or TMS in the treatment of substance use disorders had been published, with heterogeneous results, and there is still no consensus on the optimal target brain region. Recent work may help clarify where and how to apply stimulation, owing to expanding databases of neuroimaging studies, new systematic reviews, and improved methods for causal brain mapping. Whereas most previous clinical trials targeted the dorsolateral prefrontal cortex, accumulating data highlight the frontopolar cortex as a promising therapeutic target for transcranial brain stimulation in substance use disorders. This approach is supported by converging multimodal evidence, including lesion-based maps, functional MRI-based maps, tES studies, TMS studies, and dose-response relationships.
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Copyright © American Psychiatric Association. All rights reserved.
Source: Soleimani, G., Joutsa, J., Moussawi, K., et al. (2024). Converging Evidence for Frontopolar Cortex as a Target for Neuromodulation in Addiction Treatment. American Journal of Psychiatry. 2024; 181(2): 100-114. Published: February, 2024. DOI: 10.1176/appi.ajp.20221022.
Paternal Valproate Use During Spermatogenesis Not Linked to Neurodevelopmental Disorders in Offspring
A large Swedish-Norwegian cohort found no significant association between paternal valproate use during spermatogenesis and neurodevelopmental disorders in offspring compared with paternal lamotrigine or levetiracetam use. Findings were consistent across dose-response analyses and among fathers with epilepsy, supporting reassessment of paternal valproate restrictions.
Summary
A population-based cohort study in Sweden and Norway.
[Posted 17/Aug/2026]
AUDIENCE: Neurology, Psychiatry
KEY FINDINGS: In this large Nordic population-based cohort, paternal valproate monotherapy during spermatogenesis was not significantly associated with neurodevelopmental disorders in offspring compared with paternal lamotrigine or levetiracetam monotherapy. Findings were consistent across dose-response analyses and among fathers with epilepsy. The results do not support an increased neurodevelopmental risk from paternal valproate exposure, although limitations inherent to registry-based observational research remain.
BACKGROUND: Valproate is an effective antiseizure medication, but its established teratogenic effects with maternal exposure have led to regulatory restrictions for women of reproductive potential. Concerns about possible paternal effects on offspring neurodevelopment have also prompted precautionary recommendations for men. This study evaluated whether paternal valproate use during spermatogenesis was associated with neurodevelopmental disorders (NDDs) in offspring.
DETAILS: This population-based cohort study used nationwide Swedish and Norwegian health registries. It included singleton live births at >=22 completed gestational weeks between 1 January 2007 and 31 December 2020 in Sweden and between 1 January 2010 and 31 December 2018 in Norway. After exclusions, 4681 children in Sweden and 1572 children in Norway were included for analysis.
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The analysis compared children whose fathers received valproate monotherapy during spermatogenesis with children whose fathers received lamotrigine or levetiracetam monotherapy. Outcomes included NDDs, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability (ID), and disorders of psychological development. Analyses were adjusted for relevant parental and child characteristics, including parental age, psychiatric diagnoses, psychotropic medication use, epilepsy diagnosis, and, in Sweden, parental education and maternal cohabitation/marital status.
The study specifically examined paternal antiseizure medication exposure during spermatogenesis, corresponding to the approximately 3 months before conception. Dose-response analyses and analyses restricted to fathers with epilepsy were also conducted.
Among the children included in the primary comparison, 2051 were born to fathers who used valproate monotherapy during spermatogenesis. No significant association was identified between paternal valproate exposure and NDDs compared with paternal lamotrigine or levetiracetam exposure. The findings remained consistent in dose-response analyses and when the analysis was restricted to fathers with epilepsy.
During follow-up in Sweden, 406 children were diagnosed with an NDD, including 287 with ADHD, 140 with ASD, 55 with ID, and 79 with disorders of psychological development. In Norway, 60 children were diagnosed with an NDD, including 35 with ADHD, 13 with ASD, 5 with ID, and 26 with disorders of psychological development.
For ASD, the pooled adjusted hazard ratio was 1.29 (95% CI 0.89 to 1.85). The study authors noted that point estimates were slightly above 1.0 in some analyses but did not reach statistical significance.
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Source: Razaz, N., Soderling, J., Tomson, T., et al. Risk of Neurodevelopmental Disorders Associated With Paternal Use of Valproate During Spermatogenesis. Journal of Neurology, Neurosurgery & Psychiatry. 2026; 97-8: 671-679. Published: August, 2026. DOI: 10.1136/jnnp-2025-337441.
Gut Microbiome Dysbiosis Promotes Breast Cancer Dissemination Through Altered Bile Acid Signaling
Gut microbiome dysbiosis increases primary bile acids, triggering mammary inflammation and promoting HR+ breast tumor dissemination through PGE2 signaling. Bile acid, insulin resistance, and PGE2 gene signatures were associated with reduced survival, while bile acid sequestrant use correlated with longer restricted mean survival time in metastatic disease.
KEY FINDINGS: This study demonstrates that gut microbiome imbalance may contribute to HR+ breast cancer progression through systemic metabolic and inflammatory mechanisms. Dysbiosis-associated elevation of primary bile acids was shown to promote mammary inflammation and tumor dissemination through PGE2 signaling. Clinical database analyses further suggested that bile acid pathway modulation, including bile acid sequestrant use, may be associated with improved survival outcomes in metastatic disease. These findings highlight the potential importance of microbiome-derived metabolites in cancer biology and future precision oncology strategies.
BACKGROUND: Breast cancer metastasis remains a major clinical challenge, particularly in hormone receptor-positive (HR+) tumors, which represent the most common metastatic breast cancer subtype. Emerging evidence suggests that alterations in the gut microbiome may influence systemic inflammation and cancer progression. This study investigated whether commensal dysbiosis alters bile acid metabolism and contributes to mammary gland inflammation and HR+ breast tumor dissemination.
DETAILS: Researchers evaluated the relationship between gut microbiome alterations, bile acid signaling, inflammation, and breast cancer progression using experimental models and human genomic and clinical datasets. Metabolomic profiling demonstrated increased primary bile acids in dysbiotic microbiomes. Additional mechanistic studies using bile acid sequestration and supplementation approaches examined how altered bile acid levels influenced mammary inflammation and tumor dissemination.
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The investigators further analyzed The Cancer Genome Atlas (TCGA) data to evaluate associations between bile acid-related signatures, insulin resistance, prostaglandin E2 (PGE2) signaling, and survival outcomes in patients with HR+ breast tumors. Electronic health record data from the Epic Cosmos database were also examined to assess associations between bile acid sequestrant use and outcomes among patients with metastatic disease.
Commensal dysbiosis increased primary bile acid levels by disrupting microbial bile acid metabolism. Elevated primary bile acids promoted mammary gland inflammation and enhanced HR+ breast tumor dissemination through a prostaglandin E2 (PGE2)-dependent pathway.
TCGA analysis demonstrated that gene signatures related to bile acids, insulin resistance, and PGE2 signaling were associated with reduced survival in patients with HR+ tumors. In complementary clinical data analysis, bile acid sequestrant use was associated with longer restricted mean survival time among patients with metastatic disease.
These findings identify gut microbiome–bile acid signaling as a potential biological pathway linking intestinal dysbiosis with breast cancer progression and suggest that modulation of bile acid pathways may represent an area for future therapeutic investigation.
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Source: Putelo, A. M., Bajgai, S., Poblete, M. K., et al. Commensal Dysbiosis Alters Primary Bile Acid Signaling to Drive Mammary Gland Inflammation and Breast Tumor Dissemination. Cancer Research. 2026; Published: June 2, 2026. DOI: 10.1158/0008-5472.CAN-25-4466
Obesity, Rather Than High Body Surface Area Alone, Predicts Clinically Significant Asparaginase Toxicity During Induction Therapy for Acute Lymphoblastic Leukemia
Among 4,925 children and young adults with ALL, obesity—not high BSA alone—was the strongest predictor of clinically significant asparaginase toxicity. Patients with obesity and high BSA had the highest risk of hepatic toxicity and thromboembolism, whereas induction toxicities were not associated with increased end-of-induction MRD positivity.
KEY FINDINGS: This large multicenter analysis demonstrates that obesity-not elevated BSA alone-is the principal patient-related risk factor for clinically significant asparaginase toxicity during induction therapy for ALL. The greatest excess risk occurred in patients with both obesity and high BSA, particularly for hepatic toxicity and thromboembolic events, while pancreatitis risk was unaffected. Older age independently increased toxicity risk, especially hyperbilirubinemia. Notably, induction-phase AAT did not compromise early treatment response, as measured by EOI MRD. These findings suggest that obesity should be prioritized when identifying patients for enhanced toxicity surveillance and future preventive strategies, whereas high BSA in the absence of obesity does not appear to justify dose modification based solely on body size.
BACKGROUND: Asparaginase remains a cornerstone of induction therapy for acute lymphoblastic leukemia (ALL), but treatment-limiting toxicities frequently interrupt therapy and may compromise long-term outcomes. Previous studies have produced conflicting evidence regarding whether older age, obesity, or high body surface area (BSA) independently increase the risk of asparaginase-associated toxicities (AAT). This large Children’s Oncology Group analysis evaluated the relative contributions of these risk factors and examined whether induction-phase AAT affected early treatment response measured by end-of-induction (EOI) minimal residual disease (MRD).
DETAILS: This retrospective analysis included 4,925 patients aged 1-30 years enrolled in the Children’s Oncology Group trials AALL0232 and AALL0434. All patients received a single induction dose of pegaspargase 2500 IU/m² without dose capping. Investigators assessed grade >=3 hyperbilirubinemia, grade >=4 alanine aminotransferase (ALT) elevation, grade >=2 thromboembolism, and grade >=3 acute pancreatitis. Multivariable analyses evaluated the independent effects of age, obesity, and BSA, while EOI MRD positivity (>=0.01%) was analyzed to determine whether AAT adversely influenced early leukemia response. Among 4,925 patients, 290 (6%) experienced at least one clinically significant AAT during induction. Toxicity rates increased with advancing age and obesity. After adjustment for confounding variables, obesity independently increased the likelihood of AAT (OR 2.5; 95% CI 1.88-3.24), whereas high BSA alone was not an independent predictor. Patients with both obesity and high BSA had the greatest risk of overall AAT (OR 3.3; 95% CI 2.22-4.77), while high BSA without obesity was not associated with increased risk (OR 1.4; 95% CI 0.94-2.04). Older patients (>=10 years) demonstrated more than a twofold increase in AAT risk compared with younger children.
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Obesity combined with high BSA significantly increased the risk of hyperbilirubinemia (OR 3.5; 95% CI 2.2-5.7), severe ALT elevation (OR 3.3; 95% CI 1.7-6.6), and thromboembolism (OR 3.1; 95% CI 1.5-6.5). Acute pancreatitis showed no significant association with obesity or BSA. Importantly, development of AAT did not increase the likelihood of EOI MRD positivity (36.6% vs 33.5%; Ps= .318), suggesting that induction toxicities did not adversely affect early disease response.
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Source: Orgel, E., Maese, L. D., Devidas, M., et al. Toxicity From Asparaginase During Acute Lymphoblastic Leukemia Induction: A Report From the Children's Oncology Group. Blood Advances. 2026; 10(14):4923-4930. Published: July 28, 2026. DOI: 10.1182/bloodadvances.2026019870
Suicide Risk Peaks During the First Year After Dementia Diagnosis in Older Adults
Among 2,667,987 older adults with newly diagnosed dementia, suicide risk during the first year was significantly higher than in the general population (SMR 1.53), peaking within 90 days of diagnosis. Adults aged 65–74 years, patients with frontotemporal dementia, and those with mental illness, substance use disorders, or chronic pain had the greatest risk.
KEY FINDINGS: Older adults experience a significantly elevated risk of suicide during the first year after receiving a dementia diagnosis, particularly within the first 90 days. Individuals aged 65-74 years and those diagnosed with frontotemporal dementia represent the highest-risk groups. Coexisting mental illness, substance use disorders, chronic pain, rural residence, and recent mental health service utilization further increase suicide risk. These findings support routine suicide risk assessment, early psychiatric evaluation when appropriate, caregiver support, and discussions regarding restriction of access to lethal means immediately after a dementia diagnosis.
BACKGROUND: A new diagnosis of Alzheimer's disease or related dementias (ADRD) can be psychologically distressing and may increase vulnerability to suicidal behavior. Previous studies have reported inconsistent findings regarding suicide risk after dementia diagnosis. This nationwide U.S. cohort study evaluated suicide mortality and non-fatal suicidal events during the first year following a new ADRD diagnosis and identified patient characteristics associated with increased risk.
DETAILS: This retrospective cohort study included 2,667,987 Medicare fee-for-service beneficiaries aged >=65 years with newly diagnosed ADRD identified between 2012 and 2015. Patients were followed for up to 12 months after the initial dementia diagnosis or until death. Suicide deaths were identified through linkage with the National Death Index, while non-fatal suicidal events were captured using hospital claims. Standardized mortality ratios (SMRs) compared suicide risk with that of the general U.S. older adult population. Adjusted hazard ratios (AHRs) were calculated after controlling for age, sex, and race/ethnicity. During the first year after diagnosis, 705 suicide deaths occurred, corresponding to a suicide rate of 26.42 per 100,000 person-years, with an overall SMR of 1.53 (95% CI 1.42-1.65) compared with the general older adult population. The highest relative risk was observed among adults aged 65-74 years (SMR 3.40; 95% CI 2.94-3.86), and approximately half of all suicides occurred within the first 90 days after diagnosis. Patients with frontotemporal dementia had the highest suicide rate (124.63 per 100,000 person-years) and a significantly increased risk of suicide compared with unspecified dementia (AHR 2.91; 95% CI 1.67-5.05). Rural residence, recent mental health disorders, substance use disorders, chronic pain, and recent mental health-related healthcare utilization were independently associated with higher suicide risk. Non-fatal suicidal events were more frequent among patients with vascular dementia, personality disorders, bipolar disorder, anxiety disorders, substance use disorders, and chronic pain.
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Comparative Effectiveness and Safety of Pharmacological Treatments for Rapid Tranquilisation in Emergency Settings
This IPD network meta-analysis suggests that antipsychotic–benzodiazepine combinations may offer the greatest efficacy for rapid tranquilisation in emergency settings. However, the very low certainty of evidence and study heterogeneity underscore the need for individualized treatment decisions and further high-quality randomized trials.
Summary
An Individual Participant Data Network Meta-analysis
[Posted 17/Jul/2026]
AUDIENCE: Emergency Medicine, Psychiatry
KEY FINDINGS: This IPD network meta-analysis suggests that antipsychotic–benzodiazepine combinations may provide the most effective pharmacologic option for rapid tranquilisation in emergency settings, particularly compared with haloperidol monotherapy. While other antipsychotics and benzodiazepines also demonstrated favorable efficacy, haloperidol alone appeared less effective and was associated with extrapyramidal adverse effects. Given the very low certainty of evidence and the heterogeneity across studies, treatment selection should be individualized, and additional large pragmatic randomized trials are needed to strengthen the evidence base.
BACKGROUND: Psychomotor agitation is a frequent medical emergency requiring rapid pharmacologic intervention when nonpharmacologic de-escalation is insufficient. Although multiple parenteral agents are available, including antipsychotics, benzodiazepines, and combination regimens, treatment recommendations vary across clinical guidelines and practice settings. This systematic review and individual participant data (IPD) network meta-analysis evaluated the comparative effectiveness and safety of pharmacologic agents used for rapid tranquilisation in psychiatric and general emergency settings.
DETAILS: This systematic review included randomized controlled trials comparing intramuscular or intravenous pharmacologic treatments for rapid tranquilisation in patients with psychomotor agitation. Literature searches were conducted from database inception through November 14, 2025. A total of 18 trials involving 3,411 participants across eight regions met the inclusion criteria, with 13 trials (2,705 participants) providing individual participant data for the primary analysis. Participants had a mean age of 36.0 years (SD 11.7), 58.3% were men, and 68.2% presented with severe agitation at baseline. The primary outcome was achievement of sedation within 15-30 minutes after treatment. Bayesian one-stage random-effects IPD network meta-regression was used to compare treatment classes while accounting for agitation severity and other prognostic factors. Safety outcomes were assessed using aggregate data. Baseline agitation severity significantly influenced treatment response. In patients with moderate agitation, the likelihood of achieving sedation within 15-30 minutes, compared with haloperidol monotherapy, was greatest with antipsychotic-benzodiazepine combinations (OR 12.93, 95% CrI 3.00-50.91; RR 1.58), followed by benzodiazepines (OR 5.52, 95% CrI 1.37-21.02; RR 1.49) and other antipsychotics (OR 4.54, 95% CrI 1.35-14.45; RR 1.45). Among patients with severe agitation, antipsychotic-benzodiazepine combinations remained more effective than haloperidol monotherapy (OR 4.86, 95% CrI 1.28-17.54; RR 1.73), whereas the comparative effectiveness of benzodiazepines (OR 2.09, 95% CrI 0.58-6.99; RR 1.38) and other antipsychotics (OR 1.70, 95% CrI 0.62-4.59; RR 1.28) was less certain. Most participants (>90%) achieved sedation within 45-240 minutes irrespective of treatment. Antipsychotic-benzodiazepine combinations demonstrated the greatest advantage during the first 10 minutes after administration, although early time-point data were limited. Haloperidol monotherapy was associated with extrapyramidal adverse effects, whereas benzodiazepines were linked to cardiorespiratory depression. Sensitivity analyses suggested ketamine ranked as the most effective treatment; however, this finding was derived from a single study without individual participant data. Overall confidence in the evidence for the primary outcome was rated as very low.
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Source: Siafis, S., Philipona, F., Nomura, N., et al. Comparative Effectiveness and Safety of Pharmacological Treatments for Rapid Tranquilisation in Emergency Settings: A Systematic Review and Individual Participant Data Network Meta-Analysis. The Lancet Psychiatry. 2026; 13(7): 567-580. Published: July, 2026. DOI: 10.1016/S2215-0366(26)00097-0.
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