Identifying Aging and Alzheimer Disease-Associated Somatic Variations in Excitatory Neurons From the Human Frontal Cortex
The results show that combining scRNA-seq and WGS data can successfully detect putative somatic mutations. The putative somatic mutations detected from ROSMAP data set have provided new insights into the association of AD and aging with brain somatic mutagenesis.
KEY FINDINGS: The results show that combining scRNA-seq and WGS data can successfully detect putative somatic mutations. The putative somatic mutations detected from ROSMAP data set have provided new insights into the association of AD and aging with brain somatic mutagenesis.
BACKGROUND: With age, somatic mutations accumulated in human brain cells can lead to various neurologic disorders and brain tumors. Because the incidence rate of Alzheimer disease (AD) increases exponentially with age, investigating the association between AD and the accumulation of somatic mutation can help understand the etiology of AD.
DETAILS: Authors designed a somatic mutation detection workflow by contrasting genotypes derived from whole-genome sequencing (WGS) data with genotypes derived from scRNA-seq data and applied this workflow to 76 participants from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP) cohort. We focused only on excitatory neurons, the dominant cell type in the scRNA-seq data. 196 sites were identified that harbored at least 1 individual with an excitatory neuron–specific somatic mutation (ENSM), and these 196 sites were mapped to 127 genes. The single base substitution (SBS) pattern of the putative ENSMs was best explained by signature SBS5 from the Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, a clock-like pattern correlating with the age of the individual. The count of ENSMs per individual also showed an increasing trend with age. Among the mutated sites, we found 2 sites tend to have more mutations in older individuals (16:6899517 [RBFOX1], p = 0.04; 4:21788463 [KCNIP4], p < lt; 0.05). In addition, 2 sites were found to have a higher odds ratio to detect a somatic mutation in AD samples (6:73374221 [KCNQ5], p = 0.01 and 13:36667102 [DCLK1], p = 0.02). Thirty-two genes that harbor somatic mutations unique to AD and the KCNQ5 and DCLK1 genes were used for gene ontology (GO)–term enrichment analysis. We found the AD-specific ENSMs enriched in the GO-term "vocalization behavior" and "intraspecies interaction between organisms." Of interest we observed both age-specific and AD-specific ENSMs enriched in the K+ channel–associated genes.
Our Most Popular Resources
Copyright © American Academy of Neurology. All Rights Reserved.
Source: Zhang, M., Bouland, G. A., Holstege, H., et al. (2023). Identifying Aging and Alzheimer Disease-Associated Somatic Variations in Excitatory Neurons From the Human Frontal Cortex. Neuro Genetics. 2023; 9(3): e200066. Published: June, 2023. DOI: 10.1212/NXG.0000000000200066.
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 6574 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.
Our Most Popular Resources
Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts
Early initiation of a 5-day oral ensitrelvir regimen within 72 hours after symptom onset in an index patient significantly reduced the risk of developing Covid-19 among household contacts while maintaining a safety profile comparable to placebo. Clinical benefit was observed across major patient subgroups, including individuals at increased risk for severe disease, and treatment was associated with reduced household transmission. These findings support ensitrelvir as an effective postexposure prophylactic option for household contacts and suggest potential utility in other high-risk exposure settings where rapid outbreak control is needed.
KEY FINDINGS: Early initiation of a 5-day oral ensitrelvir regimen within 72 hours after symptom onset in an index patient significantly reduced the risk of developing Covid-19 among household contacts while maintaining a safety profile comparable to placebo. Clinical benefit was observed across major patient subgroups, including individuals at increased risk for severe disease, and treatment was associated with reduced household transmission. These findings support ensitrelvir as an effective postexposure prophylactic option for household contacts and suggest potential utility in other high-risk exposure settings where rapid outbreak control is needed.
BACKGROUND: Household transmission remains a major contributor to the spread of SARS-CoV-2, particularly among individuals at increased risk for severe Covid-19. Although vaccination and prior infection have reduced disease severity, waning immunity and emerging variants continue to sustain transmission. Previous trials evaluating oral antiviral agents for postexposure prophylaxis in household contacts have not demonstrated significant protection, highlighting the need for effective preventive therapies. This phase 3 trial evaluated whether oral ensitrelvir, a SARS-CoV-2 3C-like protease inhibitor, could prevent Covid-19 among household contacts exposed to an infected index patient.
DETAILS: This phase 3, double-blind, randomized, placebo-controlled trial was conducted between June 2023 and mid-September 2024 across the United States, Argentina, Japan, South Africa, and Vietnam. Eligible household contacts were 12 years of age or older, had a negative SARS-CoV-2 test at enrollment, and were randomized within 72 hours after symptom onset in the index patient. Participants received either ensitrelvir 375 mg on day 1 followed by 125 mg once daily on days 2-5 or matching placebo. The primary endpoint was laboratory-confirmed Covid-19 by day 10 in the modified intention-to-treat population, defined as RT-PCR positivity accompanied by at least one prespecified Covid-19 symptom lasting 48 hours or longer. Secondary endpoints included laboratory-confirmed SARS-CoV-2 infection regardless of symptoms, subgroup analyses, and safety outcomes. Overall, 2,387 household contacts were randomized, including 1,030 participants in the ensitrelvir group and 1,011 in the placebo group within the modified intention-to-treat population. The mean participant age was 42.4 years, 71.1% were enrolled within 48 hours after symptom onset in the index patient, and 37.0% had at least one risk factor for severe Covid-19. By day 10, laboratory-confirmed Covid-19 occurred in 2.9% of participants receiving ensitrelvir compared with 9.0% receiving placebo, corresponding to a risk ratio of 0.33 (95% CI, 0.22-0.49; P<0.001) and an approximate 67% relative risk reduction in the modified intention-to-treat population. In the intention-to-treat population, Covid-19 developed in 4.4% and 10.2% of participants, respectively (risk ratio, 0.43; 95% CI, 0.32-0.59; P<0.001). Laboratory-confirmed SARS-CoV-2 infection irrespective of symptoms was also lower with ensitrelvir (14.0% vs. 21.5%; risk ratio, 0.66; 95% CI, 0.55-0.79). Subgroup analyses demonstrated generally consistent efficacy across age groups and participants with risk factors for severe disease. Among participants with risk factors, Covid-19 developed in 2.4% of the ensitrelvir group compared with 9.9% of the placebo group. Ensitrelvir was also associated with a 34% relative reduction in household SARS-CoV-2 transmission. Adverse events occurred at similar frequencies in the ensitrelvir and placebo groups (15.1% vs. 15.5%), with serious adverse events reported in 0.2% of participants in each group. No Covid-19-related hospitalizations or deaths occurred. Transient reductions in high-density lipoprotein concentrations were observed with ensitrelvir but returned toward baseline by day 15 and were not associated with clinical events.
Our Most Popular Resources
Pharmacogenomic-Informed Antidepressant Prescribing in Australian Primary Care
In this pragmatic double-blind randomized controlled trial conducted in Australian primary care, pharmacogenomic-informed antidepressant prescribing did not improve depressive symptoms compared with prescribing guided by national therapeutic guidelines. Clinical outcomes, medication tolerability, adherence, and quality of life were similar between groups, while cost-effectiveness analyses did not support routine implementation of pharmacogenomic testing in this setting. These findings suggest that broad pharmacogenomic-guided antidepressant prescribing in general practice does not provide additional clinical benefit over guideline-based management, although targeted evaluation in carefully selected patient populations may warrant further investigation.
Summary
Findings from the PRESIDE Double-Blind Randomized Controlled Trial
[Posted 7/Jul/2026]
AUDIENCE: Family Medicine, Psychiatry
KEY FINDINGS: In this pragmatic double-blind randomized controlled trial conducted in Australian primary care, pharmacogenomic-informed antidepressant prescribing did not improve depressive symptoms compared with prescribing guided by national therapeutic guidelines. Clinical outcomes, medication tolerability, adherence, and quality of life were similar between groups, while cost-effectiveness analyses did not support routine implementation of pharmacogenomic testing in this setting. These findings suggest that broad pharmacogenomic-guided antidepressant prescribing in general practice does not provide additional clinical benefit over guideline-based management, although targeted evaluation in carefully selected patient populations may warrant further investigation.
BACKGROUND: Pharmacogenomic testing has been proposed as a strategy to individualize antidepressant selection by identifying CYP2D6 and CYP2C19 variants that influence drug metabolism. Although previous studies have suggested potential clinical benefits, evidence from pragmatic primary care settings remains limited. The Pharmacogenomic-Informed Antidepressant Prescribing for Moderate-to-Severe Depressive Symptoms in Australian General Practice (PRESIDE) trial evaluated whether pharmacogenomic-guided prescribing improves depression outcomes compared with guideline-based prescribing in routine general practice.
DETAILS: PRESIDE was a multicenter, double-blind, randomized controlled trial conducted in Australian general practice between May 26, 2021, and September 28, 2023. Of 5185 patients approached, 552 were randomized, and 550 participants (275 per group) were included in the intention-to-treat analysis. Participants with moderate-to-severe depressive symptoms were assigned in a 1:1 ratio to receive antidepressant prescribing recommendations based either on pharmacogenomic testing combined with Australian Therapeutic Guidelines or on Australian Therapeutic Guidelines alone. Pharmacogenomic reports incorporated CYP2D6 and CYP2C19 metabolizer phenotypes derived from saliva-based genotyping. The primary endpoint was change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 12 weeks after the prescribing report was received. Secondary outcomes included remission, treatment response, antidepressant-related adverse effects, medication adherence, prescribing congruence, quality of life, and cost-effectiveness. A total of 479 participants (87%) completed the primary 12-week outcome assessment. Depressive symptoms improved over time in both groups. At 12 weeks, the adjusted between-group difference in PHQ-9 change was 0.90 (95% CI, 0.06-1.75; standardized mean difference 0.23 [95% CI, 0.02-0.45]; p=0.036), indicating a small but greater improvement in depressive symptoms in the guideline-based control group. No significant between-group differences were observed at 4, 8, or 26 weeks. Remission at 12 weeks occurred in 11% of participants receiving pharmacogenomic-guided prescribing compared with 18% in the control group, corresponding to an adjusted difference of -7.22% (95% CI, -13.25 to -1.19) and an odds ratio of 0.530 (95% CI, 0.311-0.903; p=0.020). Treatment response rates did not differ significantly between groups (29% vs 32%; OR 0.874; 95% CI, 0.581-1.315; p=0.518). Approximately two-thirds of participants had an actionable CYP2D6 or CYP2C19 phenotype, yet subgroup analyses demonstrated no differential treatment benefit based on genotype. Antidepressant adherence, side-effect burden, health-related quality of life, and health-care utilization were comparable between groups. Economic analyses indicated that pharmacogenomic-guided prescribing was more costly and less effective than standard guideline-based care, although differences in costs and quality-adjusted life years were not statistically significant. No grade 2-5 adverse events occurred, and only one grade 1 adverse event related to an administrative reporting error was documented.
Our Most Popular Resources
Source: Saya, S., Chondros, P., Abela, A., et al. Pharmacogenomic-informed antidepressant prescribing for moderate-to-severe depressive symptoms in Australian general practice (PRESIDE): a double-blind, randomised controlled trial. The Lancet Primary Care. 2026; Published: June 25, 2026. DOI: 10.1016/j.lanprc.2026.100158
Low-Dose Buprenorphine Following Ketamine Treatment for Suicidal Ideation in Major Depressive Disorder
The Randomized Controlled Trial (RCT) provides the first evidence that low-dose buprenorphine can effectively extend the antisuicidal effects of a single intravenous ketamine infusion over 4 weeks in individuals with MDD. These findings offer a potentially scalable and safe therapeutic option for a population at risk of suicide.
Summary
A Randomized, Double-Blind, Placebo-Controlled Trial
[Posted 1/Jul/2026]
AUDIENCE: Psychiatry, Neurology
KEY FINDINGS: This randomized controlled trial provides the first evidence that a pharmacological intervention, buprenorphine, significantly sustains and enhances the antisuicidal effects of ketamine in MDD. These findings offer a potentially scalable and safe therapeutic option for a population at risk of suicide.
BACKGROUND: Ketamine rapidly reduces suicidal ideation in major depressive disorder (MDD), but its effects are transient. Preclinical and clinical studies suggest that ketamine’s antidepressant and antisuicidal effects may be partly mediated by mu-opioid receptor (MOR) modulation. The authors investigated the efficacy and safety of low-dose sublingual buprenorphine, a partial MOR agonist, as a follow-on treatment to prolong the effects of intravenous ketamine.
DETAILS: This was a randomized, double-blind, placebo-controlled trial conducted at a single outpatient center in the United States. Adults with MDD and a total score >=6 on the Scale for Suicide Ideation (SSI) were randomly assigned in a 1:1 ratio to receive either sublingual buprenorphine (0.2 to 0.8 mg/day) or a matched placebo for 4 weeks, beginning 48 hours after a single open-label intravenous ketamine infusion (0.5 mg/kg over 40 minutes). The primary outcome was the change in SSI total score, assessed weekly from day 1 through day 31. From November 2020 to March 2025, 50 participants (68% female) received ketamine, of whom 45 completed at least 1 week of follow-on treatment. Both groups showed significant reductions in SSI total scores, with greater improvement in the buprenorphine group (mean change, -11.6, SD=5.8; N=23) than the placebo group (mean change, -6.3, SD=7; N=22) (Glass delta=0.76, 95% CI=0.11, 1.39). Mixed-effects modeling showed a significant time-by-treatment interaction (p0.001). Depression scores did not differ significantly between groups. No serious treatment-related adverse events occurred.
Our Most Popular Resources
Copyright © American Psychiatric Association. All rights reserved.
Source: Tucciarone, J. M., Bandeira, I. D., Blasey, C., et al. Low-Dose Buprenorphine Following Ketamine Treatment for Suicidal Ideation in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial. American Journal of Psychiatry. 2026; 183(6): 409-419. Published: June, 2026. DOI: 10.1176/appi.ajp.202508
FDA Approves First Single-Dose Generic Treatment for Influenza
FDA approved the first generic single-dose baloxavir marboxil tablet for influenza in patients aged 5 years and above, ahead of the 20262027 flu season. Approved for both acute uncomplicated influenza treatment (within 48 hours of symptom onset) and post-exposure prophylaxis, this milestone may improve access, affordability, and ease of antiviral use in clinical practice.
KEY FINDINGS:
- FDA approved the first generic form of baloxavir marboxil tablets.
- Approved for patients aged 5 years and older.
- Indications include acute uncomplicated influenza treatment and post-exposure prophylaxis.
- Treatment eligibility requires symptom duration of no more than 48 hours.
- Contraindicated in patients with hypersensitivity to baloxavir marboxil or formulation ingredients.
- Common adverse effects: diarrhea, bronchitis, nausea, sinusitis, and headache.
- In the U.S., nine out of 10 prescriptions filled are for generic drugs.
- Approval granted to Norwich Pharmaceuticals, Inc.
BACKGROUND: The U.S. Food and Drug Administration (FDA) announced approval of the first generic version of baloxavir marboxil tablets, previously marketed as Xofluza. This approval introduces the first single-dose generic option for both treatment and post-exposure prophylaxis of influenza. The approval was issued ahead of the 2026–2027 influenza season with the objective of expanding access to generic medications and supporting public health preparedness.
DETAILS: Generic baloxavir marboxil tablets are approved for use in patients aged 5 years and older. Indications include treatment of acute uncomplicated influenza in individuals who have experienced symptoms for no more than 48 hours and who are either otherwise healthy or at elevated risk for influenza-related complications. The medication is also approved for post-exposure prophylaxis following contact with an infected individual.
Our Most Popular Resources
The drug is contraindicated in patients with known hypersensitivity to baloxavir marboxil or any formulation components. Safety considerations include warnings regarding increased incidence of treatment-emergent resistance in patients younger than 5 years of age.
Common adverse effects reported include diarrhea, bronchitis, nausea, sinusitis, and headache.
FDA approval of generic baloxavir marboxil provides an additional therapeutic option for influenza management through a single-dose regimen. Increased availability of generic alternatives may support broader patient access and affordability while maintaining treatment availability before the upcoming flu season.
Copyright © Skyscape Editorial Team. All rights reserved.
Source: News Release: FDA Approves First Single-Dose Generic Treatment for Influenza.. FDA. Published: June 17, 2026.
Specialty: