The American journal of psychiatry最新文献

{"title":"Gray Matter Iron and Neuromelanin in Psychosis: A Systematic Review and Meta-Analysis of MRI Studies.","authors":"Luke James Vano, Jan Sedlacik, Richard Włodzimierz Carr, Bernard Roch Bukala, Oliver David Howes, Robert Ali McCutcheon","doi":"10.1176/appi.ajp.20251257","DOIUrl":"https://doi.org/10.1176/appi.ajp.20251257","url":null,"abstract":"<p><strong>Objective: </strong>The pathophysiology of psychosis remains unclear. Preclinical, postmortem, and imaging evidence implicates iron and neuromelanin abnormalities, but the consistency and magnitude of effects are uncertain. The authors characterized brain iron and neuromelanin alterations in psychosis through a systematic review and meta-analysis of iron-sensitive MRI and neuromelanin-sensitive MRI (NM-MRI) studies.</p><p><strong>Methods: </strong>The authors searched Embase, PubMed, and PsycINFO from inception to October 31, 2025, for case-control studies using iron-sensitive MRI or NM-MRI in patients with psychosis. They used random-effects models to calculate effect sizes (Hedges' g) and meta-regressions to examine clinical confounders. The primary outcomes included effect sizes for NM-MRI and iron-sensitive MRI measures: transverse relaxation rate (R2), effective transverse relaxation rate (R2*), and quantitative susceptibility mapping (QSM).</p><p><strong>Results: </strong>Twenty-seven reports including 879 individuals with psychosis and 813 control subjects were analyzed. Meta-analyses were conducted across the caudate nucleus, putamen, globus pallidus, thalamus, and substantia nigra. Patients with psychosis showed significantly lower R2* across all examined regions (g values, -0.40 to -0.27), lower QSM values in the substantia nigra (g=-0.61, 95% CI=-0.84, -0.38), lower R2 in the caudate nucleus (g=-0.30, 95% CI=-0.56, -0.04), and higher NM-MRI values in the substantia nigra (g=0.39, 95% CI=0.23, 0.55). However, this effect was correlated with antipsychotic dosage (β=0.001, 95% CI=0.0003, 0.0018).</p><p><strong>Conclusions: </strong>Psychosis is associated with lower subcortical iron-sensitive MRI values, most prominently in the substantia nigra, alongside higher nigral NM-MRI values, which index neuromelanin-bound iron in dopamine neurons. Antipsychotic exposure may contribute to higher NM-MRI values, but confounding by indication cannot be excluded, highlighting the need for longitudinal studies. These findings suggest that while subcortical iron is lower overall in psychosis, neuromelanin-bound iron is increased within dopamine neurons. Investigating the mechanisms underlying these iron alterations may provide new treatment targets.</p>","PeriodicalId":520786,"journal":{"name":"The American journal of psychiatry","volume":" ","pages":"appiajp20251257"},"PeriodicalIF":14.7,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148214195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Social Media Use Trajectories and Substance Use Experimentation: A Prospective Cohort Study.","authors":"Jason M Nagata, Jennifer H Wong, Samuel E Benabou, Elizabeth J Li, Kyle T Ganson, Alexander Testa, Glenn-Milo Santos, Claire D Brindis, Fiona C Baker","doi":"10.1176/appi.ajp.20251292","DOIUrl":"10.1176/appi.ajp.20251292","url":null,"abstract":"<p><strong>Objective: </strong>Research on social media use has been largely cross-sectional, with limited longitudinal measurement of social media in relation to substance use. This study examined whether social media time trajectories were prospectively associated with substance use experimentation.</p><p><strong>Methods: </strong>The authors analyzed data from 7,166 adolescents (mean age, 10 years [SD=0.6]; 48.6% female) from the Adolescent Brain Cognitive Development Study, from baseline (2016-2018, ages 9-11) to year 5 (2021-2023, ages 13-16). Group-based trajectory modeling identified patterns of daily social media use from baseline to year 4. Alcohol, cannabis, and nicotine experimentation were assessed at year 5. Multiple logistic regression models estimated the associations between social media time trajectories and substance use experimentation, adjusting for baseline age, sex, race, ethnicity, household income, parental education, externalizing symptoms, internalizing symptoms, non-social-media screen time, study site, and respective substance use experimentation at baseline.</p><p><strong>Results: </strong>Four social media time trajectories were identified: 1) no or very low use, 2) moderate, gradual increasing, 3) mid-onset, rapid increasing, and 4) early-onset, rapid increasing. Compared to the no or very low use trajectory, all increasing social media trajectories were associated with higher odds of alcohol, cannabis, and nicotine experimentation, with the early-onset, rapid increasing use trajectory having the largest magnitude of associations. For example, the early-onset, rapid increasing use trajectory was significantly associated with greater cannabis experimentation (adjusted odds ratio=16.86, 95% CI=10.28, 27.65).</p><p><strong>Conclusions: </strong>Increasing social media time trajectories were prospectively associated with a greater likelihood of substance use experimentation. These findings underscore the need for public health strategies that support healthier digital habits during early adolescence.</p>","PeriodicalId":520786,"journal":{"name":"The American journal of psychiatry","volume":" ","pages":"appiajp20251292"},"PeriodicalIF":14.7,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13321752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148214179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Schizophrenia in Offspring of Holocaust Survivors: Intergenerational Effects of Preconception Parental Trauma Within the Jerusalem Perinatal Study.","authors":"Iaroslav Youssim, Salomon Israel, Ronit Calderon-Margalit, Orly Manor, Ora Paltiel, Ilona Shapiro, David S Siscovick, Yechiel Friedlander, Dolores Malaspina, Hagit Hochner","doi":"10.1176/appi.ajp.20241145","DOIUrl":"https://doi.org/10.1176/appi.ajp.20241145","url":null,"abstract":"<p><strong>Objective: </strong>The role of parental preconception trauma in the pathogenesis of psychiatric disorders remains unclear. The authors investigated whether offspring of Holocaust survivors, born years later, are at increased risk of schizophrenia.</p><p><strong>Methods: </strong>Data from the Jerusalem Perinatal Study (1964-1976) were linked to Israel's National Psychiatric Registry. Parents from European countries under Nazi rule who immigrated to Israel after the anti-Jewish persecutions began were classified as exposed. Parents were further categorized by their own age (≤5 or >5 years) when the persecutions began. Unexposed parents were of European descent not living under Nazi rule. Two offspring subsamples were assembled: 14,759 offspring of 7,316 mothers and 18,085 offspring of 8,833 fathers, of whom 3,913 had exposed mothers and 5,672 had exposed fathers. For each offspring subsample, Cox models were used to analyze time to first schizophrenia hospitalization.</p><p><strong>Results: </strong>In minimally adjusted models, offspring of parents who were older than age 5 at exposure showed elevated schizophrenia rates (maternal exposure: hazard ratio=2.71, 95% CI=1.60-4.61; paternal exposure: hazard ratio=1.52, 95% CI=1.01-2.28). No associations were observed in offspring whose parents were exposed earlier (≤5 years). Adjustments for sociodemographic variables diminished the association of paternal exposure at age >5, whereas association with maternal exposure remained strong (hazard ratio=2.38, 95% CI=1.20-4.70) and withstood further adjustments for mother's psychiatric hospitalization (hazard ratio=3.73, 95% CI=1.87-7.43) and other covariates.</p><p><strong>Conclusions: </strong>Offspring of mothers who were older than age 5 when Nazi persecutions began showed over a twofold increase in schizophrenia risk, underscoring the potential impact of trauma and its timing during the preconception period in the pathogenesis of schizophrenia.</p>","PeriodicalId":520786,"journal":{"name":"The American journal of psychiatry","volume":" ","pages":"appiajp20241145"},"PeriodicalIF":14.7,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148153188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regional Blood Flow Signatures of Opioidergic Modulation of Ketamine in Major Depressive Disorder: A Randomized Crossover Study.","authors":"Luke A Jelen, Owen O'Daly, Fernando O Zelaya, James M Stone, Allan H Young, Mitul A Mehta","doi":"10.1176/appi.ajp.20250903","DOIUrl":"10.1176/appi.ajp.20250903","url":null,"abstract":"<p><strong>Objective: </strong>Accumulating evidence suggests that the opioid system may modulate ketamine's rapid antidepressant effects. The objective of this study was to test whether opioid system modulation via naltrexone alters ketamine's acute effects on regional cerebral blood flow (rCBF) in major depressive disorder (MDD), and whether these changes relate to symptom measures and map onto receptor density profiles.</p><p><strong>Methods: </strong>In a randomized, double-blind, crossover study, 26 adults (18-50 years of age) with MDD completed two treatment sessions: oral naltrexone 50 mg or placebo, each followed by intravenous ketamine (0.5 mg/kg over 40 minutes) during 3-D pseudo-continuous arterial spin labeling MRI to quantify rCBF. Subjective effects were assessed with the Clinician-Administered Dissociative States Scale and the Psychotomimetic States Inventory (PSI), and clinical outcomes with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). Exploratory analyses spatially correlated CBF maps with receptor density profiles (MOR, KOR, NMDA, mGluR5, GABA_A, GABA_Aα5), correcting for spatial autocorrelation.</p><p><strong>Results: </strong>Ketamine significantly increased CBF in subgenual, pregenual, and dorsal anterior cingulate cortices, and the effects were not attenuated by naltrexone. Under placebo pretreatment, baseline-adjusted infusion pregenual relative rCBF was significantly associated with acute subjective effects (PSI delusional score: r=0.56; PSI perceptual distortion score: r=0.64), and baseline subgenual rCBF (adjusted for global CBF) was significantly associated with day 1 antidepressant response (MADRS, r=0.60; QIDS-SR, r=0.67). Naltrexone pretreatment disrupted these associations. Ketamine-induced CBF changes aligned with MOR and mGluR5 receptor profiles; naltrexone's interaction aligned with MOR, mGluR5, and GABA_Aα5.</p><p><strong>Conclusions: </strong>The results suggest that ketamine's effects on CBF in MDD are influenced by complex interactions between glutamatergic, opioidergic, and GABAergic systems. These findings provide mechanistic insights with potential implications for optimizing ketamine-based treatments.</p>","PeriodicalId":520786,"journal":{"name":"The American journal of psychiatry","volume":" ","pages":"420-430"},"PeriodicalIF":14.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147597824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treating Severe Depression and Suicidality.","authors":"Ned H Kalin","doi":"10.1176/appi.ajp.20260382","DOIUrl":"https://doi.org/10.1176/appi.ajp.20260382","url":null,"abstract":"","PeriodicalId":520786,"journal":{"name":"The American journal of psychiatry","volume":"183 6","pages":"367-369"},"PeriodicalIF":14.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148140675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Go With the Flow: MOR(E) to Ketamine Than NMDA Receptor Antagonism.","authors":"Michael Michaelides","doi":"10.1176/appi.ajp.20260275","DOIUrl":"https://doi.org/10.1176/appi.ajp.20260275","url":null,"abstract":"","PeriodicalId":520786,"journal":{"name":"The American journal of psychiatry","volume":"183 6","pages":"376-378"},"PeriodicalIF":14.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148140689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-Dose Buprenorphine Following Ketamine Treatment for Suicidal Ideation in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial.","authors":"Jason M Tucciarone, Igor D Bandeira, Christine Blasey, Ian H Kratter, Jarrod Ehrie, Jennifer Keller, Heather Pankow, Maureen Chang, Jessica Hawkins, Audrey G Evers, Rebecca Bernert, Charles DeBattista, Henry Truong, Carolyn I Rodriguez, Boris D Heifets, Alan F Schatzberg","doi":"10.1176/appi.ajp.20250840","DOIUrl":"10.1176/appi.ajp.20250840","url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 (p<0.001). Depression scores did not differ significantly between groups. No serious treatment-related adverse events occurred.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":520786,"journal":{"name":"The American journal of psychiatry","volume":" ","pages":"409-419"},"PeriodicalIF":14.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147978543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mu-Opioid Signaling Engagement as a Candidate Maintenance Mechanism for Prolonging Ketamine's Antisuicidal Effects.","authors":"Mark D Kvarta, Carlos A Zarate","doi":"10.1176/appi.ajp.20260266","DOIUrl":"https://doi.org/10.1176/appi.ajp.20260266","url":null,"abstract":"","PeriodicalId":520786,"journal":{"name":"The American journal of psychiatry","volume":"183 6","pages":"373-375"},"PeriodicalIF":14.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148140704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Update on Somatic Treatments for Suicide Risk.","authors":"Mina M Rizk, J John Mann","doi":"10.1176/appi.ajp.20260287","DOIUrl":"10.1176/appi.ajp.20260287","url":null,"abstract":"<p><strong>Objective: </strong>Suicide is a major cause of death worldwide and a key public health challenge. Pharmacologic and neuromodulatory interventions are central to suicide prevention. This review summarizes evidence for these interventions with potential antisuicidal effects across major psychiatric disorders and, where possible, distinguishes their direct effects on suicide diathesis from those mediated by psychiatric symptom improvement.</p><p><strong>Methods: </strong>This scoping review synthesized evidence from randomized controlled trials (RCTs), meta-analyses, national registry studies, and large pharmacoepidemiologic and cohort studies to examine associations between pharmacologic and neuromodulatory treatments and suicide deaths, suicide attempts, or suicidal ideation as outcomes. Studies were appraised based on design, sample size, population, and outcome definitions.</p><p><strong>Results: </strong>Lithium and clozapine were associated with reductions in suicidal behavior in bipolar disorder and schizophrenia spectrum disorders, respectively, mediated by mechanisms beyond disease stabilization. Intravenous ketamine rapidly reduced suicidal ideation in RCTs, partially independent of antidepressant effects. Benefit was generally transient, and studies were not powered for suicidal behavior. Antidepressants reduced suicidal ideation primarily through improvement in depressive symptoms in RCTs that were generally underpowered to determine effects on suicidal behavior. Observational and patient-level RCT meta-analyses generally found reduced suicidal behavior risk. Opioid use disorder medications were associated with lowered suicide and overdose mortality in observational studies. Electroconvulsive therapy rapidly reduced suicidal ideation and suicide mortality, and transcranial magnetic stimulation appeared to reduce suicidal ideation primarily via antidepressant effects.</p><p><strong>Conclusions: </strong>Somatic treatments reduce suicidal ideation and, in some cases, suicidal behavior risk, with effects mostly mediated by antidepressant or mood-stabilizing mechanisms. Clozapine and lithium may prevent suicidal behavior, and intravenous ketamine may reduce suicidal ideation through additional effects on suicide diathesis. Targeting the diathesis for suicidal behavior is a largely unexplored therapeutic strategy. Adequately powered RCTs to test somatic treatment effects on suicidal behavior are essential for evidence-based suicide prevention.</p>","PeriodicalId":520786,"journal":{"name":"The American journal of psychiatry","volume":"183 6","pages":"382-400"},"PeriodicalIF":14.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148140696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relapse Prevention After Successful ECT for Depression: The Role of Lithium and Continuation/Maintenance ECT.","authors":"Charles H Kellner, Ana Jelovac, Richard Braithwaite","doi":"10.1176/appi.ajp.20260210","DOIUrl":"https://doi.org/10.1176/appi.ajp.20260210","url":null,"abstract":"","PeriodicalId":520786,"journal":{"name":"The American journal of psychiatry","volume":"183 6","pages":"370-372"},"PeriodicalIF":14.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148140679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}