BackgroundExtended-release injectable naltrexone (XR-NTX), a long-acting opioid antagonist, is an effective relapse prevention strategy in the treatment of opioid use disorder (OUD). However, standard XR-NTX initiation requires completion of opioid withdrawal management and a 1–2 week opioid-free period. This interval is associated with heightened vulnerability to lapse and relapse, and many patients fail to initiate XR-NTX treatment successfully. Therefore, alternative strategies that enable rapid XR-NTX initiation are needed. This study aimed to compare the effectiveness and safety of naltrexone-accelerated (NA) versus sublingual buprenorphine (SB) withdrawal management in facilitating XR-NTX initiation among patients with OUD.MethodsThis single-center, open-label, randomized controlled trial uses a parallel-group design. Eligible patients aged 18–60 years with moderate to severe OUD who are actively using opioids and are not receiving regular maintenance treatment with methadone or buprenorphine are randomly assigned to one of two groups: (1) NA withdrawal management, comprising one day of adjunctive non-opioid medications, one day of buprenorphine administration, one day of washout, and four days of gradual oral naltrexone titration (1, 3, 12, and 25 mg/day); or (2) SB withdrawal management, comprising one day of adjunctive non-opioid medications, six days of buprenorphine tapering (up to 8 mg on Day 2, 6 mg on Day 3, 4 mg on Days 4–5, 2 mg on Day 6, and 1 mg on Day 7), and a seven-day washout period. Adjunctive non-opioid medications in both groups comprised clonidine, clonazepam, gabapentin, and trazodone. The primary outcomes are the proportions of participants who (1) achieve a negative urine drug test for the assessed opioids and (2) receive XR-NTX at the end of the withdrawal management period. Secondary outcomes include severity of withdrawal symptoms, opioid craving intensity, and adverse effects. All analyses are conducted according to the intention-to-treat principle.DiscussionThe findings of this trial may provide clinically relevant evidence to support rapid initiation of XR-NTX treatment in patients with OUD and inform clinical practice.Clinical trial registrationhttps://en.irct.ir/trial/81525, Iranian Registry of Clinical Trials IRCT20250123064499N1.
Bilateral Theta-Burst Stimulation of Dorsolateral Prefrontal Cortex Regions for Late-Life Depression: A Randomized, Sham-Controlled Clinical Trial
American Journal of Psychiatry, Volume 183, Issue 10, Page 797-805, October 01, 2026.
Individualized Connectivity-Guided Versus Conventional Targeting of Accelerated Theta-Burst Stimulation in Depression: A Randomized, Double-Blind, Parallel-Design Trial
American Journal of Psychiatry, Volume 183, Issue 10, Page 775-784, October 01, 2026.
Acceptability and Feasibility of a Virtual Family-Based Single-Session Intervention for Young Teens at High Risk for Substance Use Disorder: Single-Arm Pilot Trial
<strong>Background:</strong> Preventive interventions to delay substance use disorder (SUD) are ideally delivered during early adolescence, a critical period for exposure to substance use (SU) risk factors. Young teens (aged 12-14 years) engaging in occasional use of alcohol, cannabis, or tobacco use, or with a family history of SUD, are at increased risk for SUD. Although behavioral-ecological family therapy is effective for prevention, many families face access barriers. Single-session interventions (SSIs) may offer an accessible, low-intensity alternative. <strong>Objective:</strong> This open pilot trial aimed to evaluate the acceptability, feasibility, and potential usefulness of a family-based SSI targeting improvements in family practices that prevent SUD. <strong>Methods:</strong> Participants were 9 young teens engaging in occasional SU or with a family history of SUD and their parent. The SSI involved a virtual 2-hour family consultation with a trained family coach. Acceptability was measured via Program Feedback Scale, feasibility via SSI completion rate, and potential usefulness via pre-post changes in parenting self-efficacy. <strong>Results:</strong> The SSI was acceptable to parents and teens (mean Program Feedback Scale scores ≥3) and feasible (8/9, 88.89% of parent-teen dyads completed the SSI). Among the 8 completing dyads, most participants (13/16, 81.25%) selected Communication and Problem Solving as their primary target for change. Parents reported increases in parenting self-efficacy from pre- to post-SSI. <strong>Conclusions:</strong> Findings support the SSI’s acceptability and feasibility for young teens at high risk for SUD. A randomized clinical trial is needed to confirm the SSI’s acceptability, feasibility, and efficacy, as well as to address potential for delivery by a lay workforce. <strong>Trial Registration:</strong> ClinicalTrials.gov NCT06538922; https://clinicaltrials.gov/study/NCT06538922
Factors associated with school absenteeism in adolescents with mental illness: a multivariate analysis
Backgroundschool absenteeism is a common functional impairment among adolescents with mental disorders, yet its associated factors remain limited. This study aimed to identify key demographic, clinical, and social factors associated with school absenteeism in this population.MethodsA retrospective cohort study was conducted among 217 adolescents (12–18 years) with mental illness, categorized into school-attending (n=163) and school-suspended (n=54) groups. Baseline data on demographics, clinical characteristics, social support, and family factors were collected. Univariate analyses were used to compare group differences, followed by multivariate logistic regression and restricted cubic spline (RCS) analysis to identify independent predictors of school absenteeism.ResultsIn univariate analysis, school-suspended adolescents had significantly lower social support scores (36.2 ± 10.9 vs. 45.5 ± 12.2, p<0.001), higher rates of parental divorce (46.3% vs. 22.1%, p<0.001), and a higher proportion of pre-hospitalization school absenteeism (51.9% vs. 31.3%, p=0.006). Multivariate logistic regression revealed that parental divorce (OR = 3.04, 95%CI=1.59–5.83, p=0.001), pre-hospitalization school absenteeism (OR = 2.37, 95%CI=1.26–4.43, p=0.007), and longer disease course (OR = 1.02, 95%CI=1.00–1.04, p=0.022) were independent risk factors for school absenteeism. Conversely, higher social support was a strong protective factor: compared to the low social support group (score 17–34), the medium (35–51) and high (52–85) support groups had markedly lower odds of school absenteeism (OR = 0.24, 95%CI=0.08–0.74, p=0.013; OR = 0.05, 95%CI=0.01–0.24, p<0.001, respectively). RCS analysis confirmed a linear negative association (P for non-linearity=0.189), with higher social support scores correlating with progressively lower suspension risk.ConclusionsParental divorce, pre-hospitalization school absenteeism, and longer disease course are independent risk factors for school absenteeism in adolescents with mental illness, while higher social support acts as a robust protective factor. These findings highlight the need for targeted interventions addressing family stability, social support enhancement, and early intervention for pre-existing school impairment to reduce school absenteeism and promote functional recovery in this vulnerable population.Clinical trial registrationhttps://clinicaltrials.gov/, identifier ChiCTR2100046396.
Effect of transcranial alternating current stimulation (NET Device™) on psychostimulant withdrawal severity and time course: a real-world data analysis
BackgroundPsychostimulant use disorder is a life-threatening condition with no FDA-approved treatment. Stimulant withdrawal symptoms impede treatment engagement and are unaddressed by standard of care. The NET Device, a non-invasive transcranial alternating current stimulator, is FDA-cleared for opioid withdrawal suppression. No studies have evaluated whether NET Device use attenuates psychostimulant withdrawal.MethodsElectronic health record and device utilization data were collected from 109 stimulant-only users and 112 stimulant/opioid co-users (N = 221 adults total; Mage=39.2, SDage=10.7; 119M) entering residential addiction treatment (n = 168) or detention centers (n = 53). The Amphetamine Cessation Symptom Assessment (ACSA) was administered at baseline and 1 hour (day 1), and twice daily on days 1–7. A linear mixed model (LMM) with random intercepts and slopes was used to analyze the trajectory of ACSA scores.ResultsACSA severity and time course were similar across settings (residential vs. detention). A two-phase LMM separated acute (baseline to 1 hour) and post-acute withdrawal symptom reductions. Relative to baseline ACSA scores, stimulant-only and co-user groups each reported significant reductions at 1 hour (46% and 33%), day 2 morning (59% and 42%), and decelerating log-time trajectory through day 4 (79 hours), the primary analysis window. Estimates beyond day 4 rest on 6.9% of observations and are reported as exploratory only.ConclusionNET Device monotherapy was associated with rapid reduction in psychostimulant withdrawal severity regardless of setting and opioid co-use. No device-related adverse events were reported. These real-world data support initiation of a sham-controlled randomized trial to evaluate NET Device efficacy for stimulant use disorder.
Beyond dopamine: KarXT and emerging mechanism-based therapies in schizophrenia
KarXT (marketed as Cobenfy™), a fixed-dose combination of xanomeline and trospium chloride, represents the first new mechanism of action of an antipsychotic used for adult schizophrenia approved by the US Food and Drug Administration (FDA) in over 30 years. While mainstream drugs (e.g. haloperidol, chlorpromazine, risperidone, olanzapine, quetiapine, aripiprazole) mainly antagonize dopamine D2 or serotonin 5-HT2A receptors, KarXT acts through transient activation of muscarinic M1 and M4 receptors. M4 stimulation influences the functioning of mesolimbic dopaminergic pathways, providing an indirect means of regulating dopamine release that bypasses D2 blockade. Trospium, a peripherally acting muscarinic receptor antagonist, was used to reduce anticholinergic adverse effects (AEs). It does not cross the blood–brain barrier and therefore minimizes central adverse events. In a series of randomized placebo-controlled phase 2 and 3 studies, the KarXT significantly and clinically meaningfully reduced Positive and Negative Syndrome Scale (PANSS) total scores. The effect sizes were moderate to large with few extrapyramidal symptoms (EPS), minimal metabolic disturbances and no significant prolactin level increases. In this narrative review, we discuss in detail the pharmacological mechanism, basis of preclinical development, and clinical outcomes of KarXT. We also contextualize this drug within the development of a new wave of non-D2 antipsychotics, highlighting cholinergic dysfunction as one important mechanistic pathway within the broader multidimensional neurobiology of schizophrenia.
Pilot evaluation of an educational and lived experience training program on ketogenic metabolic therapy in mental health care for health care professionals
BackgroundSerious mental illness imposes a substantial burden. Pharmacologic treatments remain only partially effective and are associated with significant side effects, highlighting the need for novel treatment approaches. Ketogenic metabolic therapy (KMT) is emerging as an intervention for serious mental illness, with a growing evidence base and strong patient interest. A critical barrier to KMT implementation is the lack of health care professional (HCP) competence and readiness to discuss KMT with patients with serious mental illness. Existing training does not adequately address HCP competence in presenting KMT as a treatment option. This study describes the pilot-testing of “Live It, Launch It” (LI-LI), the first KMT training program designed to build self-reported competence to discuss KMT in psychiatric care for HCPs.MethodsLI-LI combines a 4-hour asynchronous educational course on KMT with a 4-week experiential group KMT intervention during which participants adhered to a ketogenic diet. LI-LI aimed to improve self-reported competence to utilize KMT and perceived ability to engage in shared decision-making with patients about incorporating KMT into their treatment plan.ResultsForty HCPs participated in the education course: 10 psychiatrists, 10 psychiatric pharmacists, 8 psychologists/therapists, and 12 other HCPs (e.g., nurse practitioners, physician assistants). Twenty-five initiated the diet intervention. Baseline competence scores (visual analog scale 0-100) were low, M(SE) = 17.40 (2.68), increasing to M(SE) = 68.08 (2.47) after education (d = 2.88, p <0.0001), and to M(SE) = 86.62 (1.82) post-diet (d = 1.08), with a very large whole-study effect (d = 3.49, p < 0.0001). Shared decision-making scores at baseline were M(SE) = 53.64 (2.89), increasing to M(SE) = 83.35 (1.83) after the educational course (d = 1.74, p <0.0001), and to M(SE) = 91.23 (2.05) after the diet phase (d = 0.73, p = 0.009), with a very large whole-study effect (d = 2.53, p < 0.0001). Feedback indicated that lived experience with KMT was helpful for implementation-readiness.DiscussionThe educational course on KMT was associated with increased self-reported competence and perceived shared decision-making in HCPs, and this was enhanced with combined education and lived experience. Implementation of this approach could accelerate KMT into clinical care. Results should be interpreted with caution as this was a small uncontrolled study with self-reported main outcomes.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT07116226, identifier NCT07116226.
Supporting the Primary Outcomes of the Mirai Trial for the Adjunctive Digital Therapeutic Rejoyn (CT-152) in the Treatment of Major Depressive Disorder: Meaningful Change Analysis in the Montgomery-Åsberg Depression Rating Scale
Background: Rejoyn (CT-152) is a prescription digital therapeutic (DTx) adjunct to antidepressive medication authorized for patients with major depressive disorder. To better understand the patient benefit of DTx and other treatment modalities, current regulatory standards support the use of modern psychometric methods to interpret the clinical meaningfulness of treatment effects for patients. In the primary analysis of Rejoyn from the pivotal phase 3 Mirai trial (NCT04770285), Rejoyn showed a broad risk-to-benefit profile as demonstrated on multiple clinician- and patient-rated scales, including the primary efficacy outcome measure, the Montgomery-Åsberg Depression Rating Scale (MADRS). These findings supported US Food and Drug Administration authorization of Rejoyn as a prescription DTx. However, the clinical relevance of these changes in the MADRS score is not immediately interpretable in clinical practice. Here, we present the results from several post hoc analyses of the Mirai trial data to support the interpretation of clinically meaningful treatment differences on clinician- and patient-reported change in depressive symptoms. Objective: This study had two main objectives: (1) establish threshold parameters that allow for clinically meaningful interpretation of the Mirai results in clinical practice, based on the clinical trial end points of change from baseline in depressive symptoms, and (2) apply this threshold in a responder and sensitivity analysis in the intent-to-treat (ITT) population (which is more frequently reported in pharmacological trials) to further support the interpretation of change in unblinded analysis of the Mirai results. Methods: For the Mirai meaningful within-patient change (MWPC) analysis, anchor-based methods were used to define an MWPC threshold by exploring the associations between the MADRS and the clinician-rated Clinical Global Impression-Severity Scale (CGI-S) and the patient-reported Patient Health Questionnaire 9-Item Scale (PHQ-9). Additional post hoc efficacy analyses (including that of responders) are reported for the ITT population. Results: Using the MWPC thresholds of 8 and 10 points (derived with the CGI-S and PHQ-9 as anchor measures, respectively), the distribution of MADRS responders favored the Rejoyn group over the sham group, and the Rejoyn group had 24%‐47% higher odds of meaningful improvement on the MADRS. Post hoc ITT analyses also favored the Rejoyn group over the sham group for response rates and PHQ-9 and CGI-S score change from baseline. Conclusions: Results are consistent with the primary findings of the Mirai trial, supporting the efficacy of Rejoyn as an adjunctive treatment to antidepressive medication monotherapy for adults with major depressive disorder. The MWPC analyses offered a measure of meaningful change on the MADRS, providing a framework of clinical meaningfulness for the Mirai trial findings.
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Efficacy of a personalized, response-based transdiagnostic intervention for emotional disorders delivered via the Internet: a protocol for an adaptive randomized controlled trial
One of the main challenges in clinical psychotherapy is disseminating effective psychological treatments to the millions who need them but lack access. Transdiagnostic interventions, particularly those delivered online, can help bridge this treatment gap. However, these interventions, often provided as a “one-size-fits-all” approach, do not tailor to individual patient needs. Therefore, it is essential to identify which patients benefit from these treatments and who require more intensive interventions. This randomized controlled trial (RCT) aims to evaluate the effects of an Internet-based transdiagnostic intervention (UJI Online Transdiagnostic Protocol/Transversal) for emotional disorders, adapted to patients’ response. Three hundred sixty-six adults with clinically significant symptoms of anxiety and depression (ODSIS ≥ 7 and/or OASIS ≥ 8) and without suicidal ideation or a severe mental disorder participated. After having completed the first three modules, patients will be randomized based on their symptomatic response. Early responders will either continue with the original intervention—12 self-administered modules—or discontinue treatment. Non-early responders will receive a blended format—including two therapist-led videoconference sessions—or continue with the original intervention. Multilevel models will be used to analyze the data. The primary expected result is that the blended format will improve treatment outcomes for non-early responders compared to the self-applied format. Moreover, it is expected that discontinuing treatment for early responders will be as effective as continuing it until completion. The findings are expected to inform clinical practice by highlighting the importance of assessing symptomatic response throughout treatment, especially in its early phases, to better tailor interventions to the needs of different patient groups.Clinical trial registrationhttp://www.chictr.org.cn, identifier NCT07051148.