Alterations in the somatostatin (SST) and parvalbumin (PVALB) classes of inhibitory GABAergic interneurons in the dorsolateral prefrontal cortex (DLPFC) are thought to contribute to the core cognitive impairments of schizophrenia. Both classes of interneurons are composed of multiple subtypes, but the distinguishing features and relative proportions of these subtypes have not been determined in the DLPFC. The aim of this study is to provide a comprehensive analysis of these subtypes from young and middle-age adults with no known psychiatric disorders. The authors used single-nucleus RNA sequencing to determine the transcriptional profiles of interneuron subtypes in DLPFC tissue samples from discovery and validation cohorts; fluorescent in situ hybridization to validate selected findings; and comparisons of transcriptome and electrophysiology data from the Allen Brain Atlas to infer functional properties of selected subtypes. The relative proportions of five major interneuron classes and of 37 interneuron subtypes were highly consistent across 19 individuals. Eleven SST subtypes were identified, including two rare subtypes that likely produce dopamine or regulate blood flow, and a subtype derived from the caudal ganglionic eminence. Among the nine PVALB subtypes identified, chandelier cells were transcriptionally distinct from PVALB basket cells (PVBCs) and PVBC subtypes. Moreover, subsets of PVBCs were distinguished by high versus low PVALB expression and had distinctive molecular features consistent with differences in anatomical (i.e., perineuronal nets) and electrophysiological (i.e., firing properties) characteristics. The robust identification of discrete subtypes of SST and PVALB interneurons in the DLPFC from young and middle-age adults with no known psychiatric disorders provides the means to determine which specific subtypes could be altered in proportional representation and/or gene expression in schizophrenia.
The relationship between the endocannabinoid system and the emergence and treatment of schizophrenia-related symptoms continues to be a topic of significant interest within psychiatry. Cannabis is the most widely used recreational drug worldwide, and individuals with schizophrenia use it at a much higher rate than the general population. The shared genetic risk for schizophrenia and cannabis use may partially account for this phenomenon. However, the exposure to cannabis in individuals at risk of schizophrenia appears to not only represent the manifestation of overlapping risks, but also pharmacological exacerbation of an already altered cortical system. Thus, cannabis use dose-dependently increases the likelihood of receiving a schizophrenia diagnosis, acutely exacerbates schizophrenia symptoms, and worsens long-term prognosis for individuals with schizophrenia. The psychoactive substance in cannabis, Δ9-tetrahydrocannabinol, targets the cannabinoid CB1 receptor (CB1R), a G protein-coupled receptor (GPCR). This brief review focuses on recent advances that may enable effective therapeutic targeting of CB1R for the treatment of schizophrenia, especially in individuals with comorbid schizophrenia and cannabis use. The authors summarize the current understanding of CB1R relevant to schizophrenia in sections covering the basic cortical biology and sex differences of CB1R; current knowledge of CB1R alterations in schizophrenia and the potential impact of comorbid cannabis use; recent cell type-specific findings that reconcile past discrepant research in the field; and advances in understanding of GPCR pharmacology and biased ligands that provide new opportunities for CB1R-targeted therapeutics. Derived from this more nuanced understanding of CB1R, the authors propose future directions with the potential to develop a CB1R-targeted treatment of schizophrenia.
The authors of this review aimed to examine the characteristics of published research on the clinical diagnosis of malingering and to critically assess the reporting of data on housing, race-ethnicity, and co-occurring psychiatric disorders. Five databases (Embase, MEDLINE, ProQuest Dissertations and Theses Global, PsycInfo, and Web of Science) were searched from database inception to June 17, 2025. Results were independently screened by two researchers to identify studies of patients given a diagnosis of malingering in a clinical setting. PRISMA guidelines were followed. Of 3,150 records screened, 21 articles were included. Methods of identifying malingering used by these studies included the nonmutually exclusive categories of chart review (N=17 studies, 81%), ICD codes (N=7, 33%), and DSM criteria (N=3, 14%). Only five (24%) articles reported the housing status of individuals given a diagnosis of malingering. The racial-ethnic characteristics of people determined to be malingering were seldom reported (N=6, 29%). Although nine (43%) articles reported the prevalence of co-occurring psychiatric disorders among people determined to be malingering, the focus of reporting was overwhelmingly on personality, mood, psychotic, and substance use-related disorders, with limited coverage of cognitive disorders and anxiety- and trauma-related disorders. Only three (14%) articles reported data on longitudinal mental health outcomes such as overdose and suicide. Limited data are available with regard to how diagnostic decisions about malingering take into consideration patients' housing status and mental health history. Potential racial-ethnic disparities in malingering diagnoses are poorly characterized.
The objective of this study was to assess the efficacy of theta-burst stimulation (TBS) in treating late-life depression. A triple-blind, sham-controlled randomized clinical trial was performed. The study included participants age 60 and older with a diagnosis of moderate to severe major depressive disorder who were not using antidepressants. Exclusion criteria included other psychiatric disorders, neurological disorders, and contraindications to TBS. TBS was administered bilaterally, with intermittent TBS on the left dorsolateral prefrontal cortex (DLPFC) and continuous TBS on the right DLPFC, with 1,800 pulses at each side. Participants underwent 20 daily sessions of active or sham TBS over 20 consecutive weekdays and one additional session during weeks 6, 8, and 12 (totaling 23 sessions). A total of 108 participants (mean age, 67 years) were enrolled and underwent either active or sham TBS. In an intention-to-treat analysis, there was no significant difference between groups at week 6 in mean reduction in Hamilton Depression Rating Scale (HAM-D) score (mean difference, -1.65, 95% CI=-3.38, 0.08). By week 12, active TBS was associated with a significantly greater reduction in HAM-D score compared to sham (mean difference, -1.89, 95% CI=-3.75, -0.03), with response rates of 52% in the active group and 33% in the sham group. Linear mixed models analyzing HAM-D score did not show a statistically significant greater reduction in the active TBS group compared to the sham group at week 6 (Cohen's d=-0.36, 95% CI=-0.74, 0.01). The active TBS group did not have a statistically significant greater reduction in HAM-D scores compared to the sham group at week 6. By week 12, however, active TBS was superior to sham stimulation in reducing depressive symptoms in patients with late-life depression, suggesting TBS as a possible treatment option for this population.
Xanomeline and trospium chloride (X/T) reduced symptoms and was generally well tolerated in two phase 3, 5-week, randomized, double-blind, placebo-controlled trials in adults with schizophrenia. The authors evaluated the long-term safety, tolerability, and efficacy of X/T in an open-label extension of the two phase 3 trials. EMERGENT-4 was a 52-week open-label extension trial of participants who completed the EMERGENT-2 and EMERGENT-3 acute trials. Between February 2021 and October 2023, 152 participants initiated twice-daily oral doses of xanomeline 50 mg/trospium 20 mg and titrated to a maximum dosage of twice-daily oral xanomeline 125 mg/trospium 30 mg. The primary endpoint was the proportion of participants reporting a treatment-emergent adverse event (TEAE). Efficacy measures included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions severity scale (CGI-S). A total of 156 (42.6%) of the 366 participants who completed EMERGENT-2 or EMERGENT-3 enrolled in EMERGENT-4; of these 34 (21.8%) enrolled participants completed the 52-week treatment period. Overall, 81 (53.3%) of 152 treated participants experienced at least one TEAE. Consistent with the acute trials, the most common treatment-related adverse events were gastrointestinal disorders (e.g., nausea, vomiting, dyspepsia, dry mouth) that were mild or moderate in intensity and resolved with continued treatment. No new safety or tolerability issues were observed. X/T was not associated with clinically meaningful motor symptoms, hyperprolactinemia, weight gain, or adverse effects on metabolic parameters. X/T was associated with continued symptom improvement over the trial duration. Mean changes in PANSS total score from acute trial baseline to week 52 were -33.8 and -31.3 in the treatment groups receiving X/T and placebo, respectively, in the acute trials. Similar patterns of continued improvement were observed for scores on the CGI-S, PANSS positive subscale, and PANSS negative subscale. Long-term treatment with X/T over 52 weeks was safe, generally well tolerated, and associated with durable symptom improvement in people with schizophrenia.
Noninvasive brain stimulation (NIBS) holds promise for reducing suicidal ideation (SI), but its cross-diagnostic efficacy remains unexamined. This systematic review and network meta-analysis examined the comparative efficacy of NIBS interventions on SI across psychiatric conditions and the lifespan. The authors searched Embase, MEDLINE, PsycINFO, CINAHL, and the Cochrane CENTRAL Database from inception to March 2023 for randomized controlled trials (RCTs) with at least one NIBS arm and an outcome from the suicide item of a standardized measure or a suicide-specific measure. Studies that focused solely on invasive stimulation or excluded participants with SI were ineligible. Network meta-analyses examined the comparative efficacy of NIBS for treating SI, using standardized mean differences (Hedges' g). Analyses were first restricted to RCTs that recruited participants with SI at baseline (network 1), then were conducted on all identified RCTs (network 2), and, finally, were conducted to examine NIBS plus pharmacotherapy initiation (network 3). Seventy-five studies met inclusion criteria for the systematic review, and 58 were included in meta-analyses. Studies in network 1 (three RCTs) used accelerated transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC); no difference from sham TMS was found. In network 2 (25 RCTs), bitemporal electroconvulsive therapy (ECT) was favorable compared to sham stimulation for reducing SI, and all other NIBS interventions showed no benefit over sham NIBS. In network 3 (five RCTs), left DLPFC repetitive TMS plus escitalopram significantly reduced SI compared to sham TMS plus a selective serotonin reuptake inhibitor (SSRI). Although the findings were limited by small numbers of studies in networks 1 and 3, large heterogeneity in study design and SI outcomes in network 2, and a focus mostly on treating patients with depression in networks 2 and 3, they support bitemporal ECT and high-frequency repetitive TMS combined with SSRIs as effective interventions for improving SI, and nonconvulsive NIBS without pharmacotherapy shows no benefit over sham NIBS.
Studies investigating resting-state functional connectivity of the amygdala and hippocampus have produced inconsistent findings. The authors' objective was to conduct the largest systematic comparison of alterations in functional connectivity of the amygdala and hippocampus in individuals with posttraumatic stress disorder (PTSD) using a multicohort mega-analysis with uniform processing steps and parameters across all cohorts. Resting-state functional MRI data from 1,017 PTSD patients and 1,702 control participants from 32 international sites were centrally preprocessed with HALFpipe and analyzed using the Image-Based Meta- and Mega-Analysis (IBMMA) package for neuroimaging processing. Group-level seed-based whole-brain analyses were completed for the right and left amygdala and hippocampus. Additional correlation analyses were conducted between PTSD norm-severity scores and resting-state functional connectivity (rs-FC). Compared to control participants, individuals with PTSD showed stronger rs-FC between the left amygdala seed and right hippocampus and amygdala and the left and right lingual gyri. Greater PTSD total norm-severity scores were significantly associated with rs-FC between the left amygdala and right hippocampus/amygdala and rs-FC between the right amygdala and left hippocampus/amygdala. Greater connectivity between subcortical threat centers involved in fear processing, memory, and extinction learning characterizes the resting state in PTSD. Future directions include investigating how different interventions, such as brain stimulation, neurofeedback, and psychotherapy, might modulate the aberrant neural networks in PTSD.
The authors compared the risk of mental disorders between patients with cannabis use disorder (CUD) and those with other substance use disorders (SUDs). The TriNetX Research Network was queried to identify patients with SUDs and no preceding mental disorders and compare 1) adult patients with CUD only versus those with other SUDs, 2) pediatric patients with CUD only versus those with other SUDs, and 3) adult patients with CUD plus another SUD versus those with comorbid noncannabis SUDs. Propensity score matching was performed on demographic characteristics and 24 risk factors or comorbidities. Subsequent diagnosis of schizophrenia and other common mental disorders was assessed. Compared to adults with other SUDs, those with noncomorbid CUD (N=345,903 for both cohorts) had a lower risk of schizophrenia (0.34% vs. 0.42%; relative risk [RR]=0.81, 95% CI=0.75, 0.88), depression (1.35% vs. 1.74%; RR=0.78, 95% CI=0.75, 0.81), and psychotic disorders (0.36% vs. 0.52%; RR=0.68, 95% CI=0.63, 0.73). Compared to pediatric patients with other SUDs, those with CUD (N=24,793 for both cohorts) had a higher risk of schizophrenia (0.29% vs. 0.19%; RR=1.52, 95% CI=1.06, 2.19), depression (1.65% vs. 1.27%; RR=1.30, 95% CI=1.13, 1.51), and anxiety disorders (8.13% vs. 6.71%; RR=1.21, 95% CI=1.14, 1.29). Compared to adult patients with other SUDs, those with CUD and a comorbid SUD (N=203,916 for both cohorts) had a decreased risk of schizophrenia (1.94% vs. 2.25%; RR=0.86, 95% CI=0.83, 0.90), depression (3.98% vs. 5.67%; RR=0.70, 95% CI=0.68, 0.72), bipolar disorder (4.23% vs. 5.60%; RR=0.76, 95% CI=0.74, 0.78), and anxiety disorders (16.20% vs. 21.36%; RR=0.76, 95% CI=0.75, 0.77). CUD-associated mental health risks varied by age and comorbid SUDs, possibly due to earlier onset of mental disorders in cannabis users or age-related differences in CUD effects.
Bipolar disorder, major depressive disorder (MDD), and schizophrenia are severe mental disorders and are each associated with poor cardiometabolic health. Mapping genetic relationships of these heritable disorders with blood markers of metabolic activity may uncover biological pathways underlying this important shared clinical feature. The authors charted genetic overlap of the three disorders, type 2 diabetes, coronary artery disease, and body mass index (BMI) with 249 circulating metabolites through linkage disequilibrium score regression and bivariate Gaussian mixture modeling. Causal relationships and functionally annotated shared genetic variants were estimated, and enrichment across brain and body tissues was investigated. All three disorders had extensive overlap with the metabolites. The pattern of genetic correlations was similar between MDD, type 2 diabetes, coronary artery disease, and BMI (Spearman's correlation rs>0.93), opposite in direction to the pattern found for schizophrenia and bipolar disorder (MDD-bipolar disorder rs=-0.74; MDD-schizophrenia rs=-0.83). Notably, this genetic divergence contrasted with phenotypic associations, which were similar across all three disorders. The metabolites had widespread, robust causal effects on the disorders and cardiometabolic traits. The authors mapped 1,056 genes shared between the individual disorders and metabolites to disorder-specific processes related to metabolic activity, mitochondrial function, and synaptic processes. These genes were expressed throughout the brain, heart, and liver. Severe mental disorders have strong associations with metabolites, and MDD has a distinctly different genetic relationship than bipolar disorder and schizophrenia do. The study findings suggest that metabolic pathways are involved in the development of severe mental disorders and can play a central role in disentangling disorder-specific etiologies. The "metabolic psychiatry" approach applied here has high potential to guide development of targeted interventions.
The authors sought to examine substance use patterns across the sexual identity spectrum, particularly among individuals who describe their sexual identity using different terms or express uncertainty about their orientation-groups that remain poorly understood beyond lesbian, gay, or bisexual (LGB) categories. Using data from the 2023 National Survey on Drug Use and Health among individuals ≥12 years of age (N=52,525), the authors examined past-year substance use across five sexual identity groups: heterosexual, gay/lesbian, bisexual, those using a different term to describe their sexual identity, and those unsure of their identity. Associations were examined between sexual identity (overall and disaggregated by sex using sex-specific heterosexual reference groups) and past-year use of cannabis, hallucinogens, cocaine, inhalants, methamphetamine, and misuse of prescription opioids, tranquilizers/sedatives, and stimulants. Substance use was higher across all other sexual identity groups compared with heterosexual individuals. Bisexual and gay/lesbian individuals showed elevated odds across most substances examined, particularly inhalants, hallucinogens, and cannabis. Both individuals using different terms and those unsure of their sexual identity showed elevated odds for inhalants, hallucinogens, cannabis, and prescription tranquilizer/sedative misuse, with those using different terms additionally showing elevated odds for prescription stimulant misuse. In sex-disaggregated analyses, both males and females showed elevated odds across multiple substances, with females generally showing elevations across a greater number of substances, although some estimates for males were suppressed due to small sample sizes. These findings extend our understanding of substance use beyond LGB categories, revealing nuanced patterns among emerging identity groups, underscoring the importance of targeted screening and prevention strategies.
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. 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, GABAA, GABAAα5), correcting for spatial autocorrelation. 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 GABAAα5. 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.
Obsessive-compulsive disorder (OCD) is an impairing mental health condition that affects individuals across the lifespan. Some literature has evaluated mental health stigma in adults with OCD but limited attention has been given to youth, as well as those of Latino ancestry. The present study reported the extent of stigma experiences among Latin American youth with OCD, as well as examined sociodemographic, clinical and psychological correlates. 235 youth with clinician confirmed diagnoses of OCD from 10 North and South American countries completed questionnaires assessing stigma experiences, symptomatology, and functioning. Sociodemographic and clinical variables were also collected. The average OCD stigma response corresponded to a frequency rating of "rarely" (M=16.4 on an 8 to 40 possible range), though 42.1% of the sample endorsed experiencing at least one stigma-related item "often" or greater. Multivariate regression analyses indicated that depressive symptomatology was the strongest predictor of stigma, with no sociodemographic or clinical variables independently associated with stigma. Additional regression analyses revealed that stigma was uniquely associated with higher clinician-rated OCD symptom severity and higher parent-rated impact of OCD, but stigma did not independently associate with youth-rated quality of life. Findings highlight that stigma related concerns affect many Latin American youth with OCD, with links to worse psychological health.
Although mobile health-tracking technologies have burgeoned, offering objective health information to consumers on an unprecedented scale, opportunities to directly test effects of such monitoring have been limited. Low-cost mobile breathalyzers are one tool commonly employed for blood alcohol concentration (BAC) assessment. The authors explored outcomes linked with BAC-tracking technologies, examining effects on alcohol use and self-estimation of BAC levels in a large U.S. sample. Participants (N=32,179) were individuals who voluntarily purchased a mobile breathalyzer and provided at least three ad-lib readings between 2016 and 2022. A paired smartphone application prompted users to enter a BAC self-estimate (a guess) before the measured BAC level was displayed. Analyses included observations collected during active consumption (BAC >0.00%) from breathalyzer users who opted to share anonymized data. Breathalyzer users who displayed inattentive patterns of guessing were excluded from self-estimation analyses. The final dataset comprised 787,393 BAC readings and 387,643 self-estimates. The accuracy of BAC guesses increased by 2.38% over the course of breathalyzer use. Associations between breathalyzer use and BAC levels varied significantly according to participants' initial drinking levels (b=-0.0062, 95% CI=-0.0065, -0.0059). Among heavy-drinking participants, BAC levels decreased on average from 0.106% to 0.096%, whereas the reverse trend was observed for lighter-drinking participants, whose levels increased from 0.058% to 0.067%. A similar interaction emerged for BAC underestimation (b=-0.0058, 95% CI=-0.0066, -0.0049), with odds of underestimation decreasing among heavy-drinking and increasing among light-drinking participants. The results indicate promise for mobile BAC-tracking technologies as a low-impact intervention with the potential to decrease drinking among individuals who drink heavily-a population particularly susceptible to alcohol-related problems. In contrast, inverted trends emerged for light-drinking individuals, highlighting the need for empirical research in the fast-moving landscape of digital health.
Self-harm in childhood and adolescence is associated with a range of adverse outcomes. Limited evidence suggests that these individuals are at elevated risk of experiencing sexual violence in adolescence and young adulthood. This population-based cohort study identified children and adolescents with a first presentation to health services for self-harm and examined their risk of subsequent presentation for sexual abuse or assault. Health administrative data were used to identify all children and adolescents with a first presentation for self-harm over a 10-year period (2013-2022) in the province of Ontario, Canada (population 16 million). Time to first presentation for sexual abuse or assault was compared to that of individuals in a control group matched on age, sex, and area-level socioeconomic status using Cox proportional hazards modeling. The cohort included 139,233 individuals. After a first presentation for self-harm, the 10-year cumulative incidence of presentation for sexual abuse was 9.06% (95% CI=8.55, 9.57), compared to 1.26% (95% CI=1.17, 1.36) for the control group (hazard ratio=8.32, 95% CI=7.68, 9.02). Risk remained elevated after adjustment for factors influencing vulnerability to sexual abuse (hazard ratio=5.06, 95% CI=4.53, 5.65). Results were similar for the outcome of sexual assault (cumulative incidence, 4.14% [95% CI=3.76, 4.51] versus 0.48% [95% CI=0.41, 0.54]; fully adjusted hazard ratio=6.44, 95% CI=5.38, 7.71). Sex-stratified analyses revealed a greater absolute risk for females. Presentation for self-harm during childhood and adolescence, in addition to being concerning for potential sexual abuse history, may be a marker of vulnerability for future sexual abuse or assault. These findings suggest a need for further research and implications for clinical practice.
Transcranial magnetic stimulation (TMS) has shown promise in reducing posttraumatic stress disorder (PTSD) symptoms, with varied clinical results. A mechanistic understanding is needed to personalize treatment and improve response rates. The threat neurocircuitry, specifically the right amygdala, has consistently been implicated in PTSD pathophysiology. This neuroscience-informed trial aimed to modulate the threat neurocircuitry using functional MRI (fMRI)-guided TMS to treat PTSD. In a double-blind clinical trial, 50 adults with PTSD symptoms were randomized to 10 twice-daily sessions of either 1-Hz TMS or sham TMS. TMS was delivered to an fMRI-guided target within the right dorsolateral prefrontal cortex with the strongest functional connection to the right amygdala. The primary outcomes were right amygdala threat reactivity, assessed by fMRI, and skin conductance reactivity during trauma recall, measured pre- and post-TMS. The secondary outcomes were hyperarousal and total PTSD symptoms (based on the PTSD Checklist for DSM-5), measured pre- and post-TMS and at a follow-up assessment between 3 and 6 months after TMS. Active TMS significantly reduced right amygdala threat reactivity compared with sham TMS. No significant effect of TMS was observed on skin conductance reactivity. From pre- to post-TMS, significant reductions in hyperarousal and total PTSD symptoms were observed across groups, but no significant differences between groups were observed. From pre-TMS to follow-up, active TMS compared with sham TMS significantly reduced hyperarousal and total PTSD symptoms. Clinical findings were found to be robust in sensitivity analyses. This is the first clinical trial to demonstrate that personalized fMRI-guided TMS targeting the threat neurocircuitry reduces amygdala threat reactivity and improves long-term PTSD symptoms at follow-up. These findings suggest the potential for a personalized approach to neuromodulation in individuals with PTSD.
Electroconvulsive therapy (ECT) is a highly effective treatment for depression, yet relapse rates up to 50% within a year are reported. Studies have examined ECT, pharmacological, and nonpharmacological relapse prevention strategies, and although current guidelines provide general recommendations, no consensus-based or operationalized guidance exists regarding optimal relapse prevention after successful ECT for major depressive disorder. The aims of this study were to identify relapse prevention strategies commonly implemented after ECT, to evaluate their perceived effectiveness among international ECT experts, and to establish consensus-based personalized clinical recommendations. A multiround Delphi study was conducted with a global panel of 18 ECT experts. Consensus was defined as ≥80% agreement on Likert-scale responses. Consensus was reached on key clinical factors influencing relapse prevention, including treatment resistance, psychiatric comorbidities, and prior ECT response. An essential relapse prevention strategy, namely, pharmacotherapy with lithium and an antidepressant (a tricyclic antidepressant, venlafaxine, or a prior effective antidepressant), was endorsed for all patients. Continuation ECT by means of tapering, rather than abrupt cessation, was recommended for patients at high risk of relapse and with severe or psychotic depression. Psychotherapy was considered beneficial as an adjunctive rather than a standalone treatment. No consensus was reached on the role of repetitive transcranial magnetic stimulation, esketamine, or optimal treatment duration of relapse prevention beyond 6 months. This Delphi study provides expert-based guidance on relapse prevention following successful ECT for major depressive disorder. While pharmacotherapy and continuation ECT are core strategies, personalized adjustments based on clinical risk factors remain essential. Further empirical research is needed to refine guidelines and improve long-term outcomes.
Substance use disorders (SUDs) are associated with risk of psychiatric comorbidities, with inconsistent sex differences across studies. The objective of this study was to determine odds of psychiatric comorbidities based on sex in persons with a primary diagnosis of opioid, alcohol, or cannabis dependence, using a national clinical dataset. This was a cross-sectional study of data from state-funded and state-run mental health programs in 2022 (Mental Health Client-Level Data, from the U.S. Substance Abuse and Mental Health Services Administration). Data were obtained from adults (age ≥18 years) with a primary diagnosis of either opioid (N=28,808), alcohol (N=23,281), or cannabis dependence (N=5,961). Data from individuals with each SUD were examined for psychiatric comorbidity outcomes, based on secondary diagnoses of an anxiety disorder, bipolar disorder, a depressive disorder, schizophrenia or other psychotic disorder, or a trauma- and stressor-related disorder versus no comorbidity. Data were analyzed with multinomial logistic regressions, examining sex, race, ethnicity, and age as predictors. Males with a primary diagnosis of opioid, alcohol, or cannabis dependence had lower adjusted odds of anxiety, bipolar, depressive, and trauma- and stressor-related disorders compared to females. However, males with opioid or cannabis dependence had higher adjusted odds of schizophrenia or other psychotic disorders compared to females. Adjusted analyses also detected associations of race and ethnicity with specific comorbidities. In this recent national clinical dataset, sex-based differences were observed in specific psychiatric comorbidities for each of these three SUDs. Future studies should examine biopsychosocial mechanisms that underlie these differences, with the goal of improving personalized care.
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Transcranial electrical stimulation with temporal interference (TES-TI) is a noninvasive technique that uses multiple high-frequency carrier currents to generate a low-frequency amplitude-modulated envelope, enabling steerable and relatively focal engagement of deep regions with reduced off-target exposure compared to conventional TES approaches. This review outlines the biophysical principles and technical implementation of TES-TI, summarizes safety and feasibility data in humans, and considers potential applications in psychiatry. TES-TI is thought to engage neural circuits by modulating physiologically relevant oscillations (TI between 0.5 and 80 Hz) and is being explored at higher frequencies (TI at ∼130 Hz), as a noninvasive approach inspired by deep brain stimulation to influence pathological network activity. Features relevant to psychiatric application are discussed alongside current evidence for engagement of key targets. TES-TI is rapidly developing, and much remains to be investigated about parameter optimization (frequency, intensity, dose, and dosing schedules) and about the strength, durability, and clinical relevance of its effects. Taken together, current findings position TES-TI as a promising but still exploratory approach for noninvasively probing and modulating deep brain circuits relevant to psychiatric disorders, while underscoring the need for further study before clinical translation.