Blumberger DM, Vila Rodriguez F, McClintock SM
… +12 more, Thorpe KE, Burhan AM, Foley K, Goodman MS, Gregory EC, Kaster TS, Knyahnytska Y, Tham J, Trevizol AP, Voineskos D, Zrenner B, Daskalakis ZJ
Am J Psychiatry
· 2026 May · PMID 42087328
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OBJECTIVE: Despite the established clinical effectiveness of electroconvulsive therapy (ECT) in the treatment of bipolar depression, its acceptance is limited by concerns over cognitive adverse effects. Magnetic seizure...OBJECTIVE: Despite the established clinical effectiveness of electroconvulsive therapy (ECT) in the treatment of bipolar depression, its acceptance is limited by concerns over cognitive adverse effects. Magnetic seizure therapy (MST) has shown promise in treating patients with depression, with fewer cognitive adverse effects. The aim of this pilot study was to assess the clinical efficacy and cognitive adverse effects of MST compared to right unilateral ultrabrief-pulse (RUL-UB) ECT in patients with bipolar depression. METHODS: In this double-blind, randomized, parallel-group pilot clinical trial, participants with bipolar depression received either RUL-UB ECT or MST until they achieved remission, dropped out, or received a maximum of 21 treatments. The primary outcomes were 1) clinical remission as assessed with the 24-item Hamilton Rating Scale for Depression and 2) cognitive adverse effects as assessed with the Autobiographical Memory Test (AMT). RESULTS: Of 55 participants who were randomized, 45 received an adequate trial of treatment, of whom 6/20 (30%) in the ECT group and 5/25 (20%) in the MST group achieved remission. Clinically important worsening in autobiographical memory (≥25% decline in AMT score) occurred in 6/27 (22.2%) participants in the ECT group and 2/28 (7.1%) in the MST group. Secondary clinical outcomes were similar in both groups. CONCLUSIONS: This pilot study demonstrated similar effects on depression symptoms between MST and ECT. MST appeared to have resulted in less worsening of autobiographical memory and was better tolerated, suggesting that it may be a safe clinical application to treat bipolar depression. Given the relatively small sample size of this pilot study, these findings should be considered preliminary.
Enwright JF, Tamburino AM, Tumkaya T
… +10 more, Lovatt D, Pan J, Gunaratna R, Fagegaltier D, Wang X, Marino MJ, Fish K, Arion D, Gonzalez-Burgos G, Lewis DA
OBJECTIVE: Alterations in the somatostatin () and parvalbumin () classes of inhibitory GABAergic interneurons in the dorsolateral prefrontal cortex (DLPFC) are thought to contribute to the core cognitive impairments of s...OBJECTIVE: Alterations in the somatostatin () and parvalbumin () 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. METHODS: 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. RESULTS: The relative proportions of five major interneuron classes and of 37 interneuron subtypes were highly consistent across 19 individuals. Eleven 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 subtypes identified, chandelier cells were transcriptionally distinct from basket cells (PVBCs) and PVBC subtypes. Moreover, subsets of PVBCs were distinguished by high versus low expression and had distinctive molecular features consistent with differences in anatomical (i.e., perineuronal nets) and electrophysiological (i.e., firing properties) characteristics. CONCLUSIONS: The robust identification of discrete subtypes of and 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.
OBJECTIVE: 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 compa...OBJECTIVE: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.
Ku SH, Stringfield SJ, Torregrossa MM
… +2 more, Sweet RA, Chou S
Am J Psychiatry
· 2026 Apr · PMID 41992094
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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 re...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, Δ-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.
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 ste...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.
Hinojosa CA, Sun D, Russell C
… +96 more, Baird CL, Hussain A, Sendi M, Jahanshad N, Salminen LE, Olff M, Frijling JL, Veltman DJ, Koch SBJ, Nawijn L, van Zuiden M, Wang L, Zhu Y, Li G, Stein DJ, Ipser J, Koopowitz SM, Neria Y, Zhu X, Ravid O, Zilcha-Mano S, Lazarov A, Suarez-Jimenez B, Huggins AA, Ressler K, Jovanovic T, Fani N, Mueller SC, Hudson AR, Daniels JK, Sierk A, Manthey A, Walter H, van der Wee NJA, van der Werff SJA, Vermeiren RRJM, Rektor I, Říha P, Kaufman ML, Lebois LAM, Baker JT, King A, Liberzon I, Angstadt M, Davenport ND, Disner SG, Sponheim SR, Straube T, Hofmann D, Lu GM, Qi R, Wang X, Kunch A, Xie H, Quidé Y, El-Hage W, Lissek S, Berg H, Cisler J, Ross M, Herringa RJ, Grupe DW, Nitschke JB, Davidson RJ, Larson CL, deRoon-Cassini TA, Tomas CW, Fitzgerald JM, Feola B, Urbano-Blackford J, Olatunji BO, May G, Nelson SM, Gordon EM, Abdallah CG, Lanius R, Densmore M, Théberge J, Neufeld RWJ, Baugh LA, Simons RM, Simons JS, Magnotta VA, Fercho KA, Elman J, Panizzon M, Franz C, Lyons MJ, Kremen W, McLaughin KA, Peverill M, Sambrook K, Thompson PM, Stevens JS, Morey RA, van Rooij SJH
Am J Psychiatry
· 2026 May · PMID 41922983
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OBJECTIVE: 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 alter...OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
Am J Psychiatry
· 2026 May · PMID 41922982
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OBJECTIVE: 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...OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Jelen LA, O'Daly O, Zelaya FO
… +3 more, Stone JM, Young AH, Mehta MA
Am J Psychiatry
· 2026 Jun · PMID 41922981
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OBJECTIVE: 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 ketami...OBJECTIVE: 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. METHODS: 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, GABAα5), correcting for spatial autocorrelation. RESULTS: 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 GABAα5. CONCLUSIONS: 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.