搜索结果：Journal of psychopharmacology (Oxford, England)

The current era is characterized by the pursuit of novel medications and drug repurposing through innovative mechanisms that modulate systems beyond the monoaminergic, focusing on novel synaptic signaling targets. Against this backdrop, it can be challenging to recall a time when psychopharmacology was in its infancy, and every discovery represented the cutting edge. Nathan S. Kline, a clinician and researcher, was a pivotal figure in introducing the first psychoactive substances into clinical practice. His seminal work on reserpine as a sedative and his evaluation of the antidepressant properties of iproniazid, a monoamine oxidase inhibitor (MAOI), positioned him at the scientific vanguard of pharmacological psychiatry. Kline made multiple substantial contributions to the medical-scientific literature, publishing foundational papers on the use of reserpine in neuropsychiatric hospitals, the application of Rauwolfia serpentina for neuropsychiatric conditions, and comparative studies of iproniazid and other MAOIs, among numerous other manuscripts. Kline's enduring legacy extends beyond psychopharmacology, encompassing early efforts in health informatics to optimize psychiatric logistics and advocacy for the expansion of global mental health care networks, including in low- and middle-income countries.

Brain function is the dynamic output of coordinated excitatory and inhibitory (E-I) activity. E-I alterations, arising from differences in excitatory glutamate and inhibitory GABA pathways, are implicated in the development and heterogeneity of autism, and are consequently targets for pharmacological support options. Existing tools, such as Magnetic Resonance Spectroscopy, are limited in capturing the dynamic nature of E-I regulation. The aperiodic 1/f exponent of the EEG power spectrum has shown sensitivity to E-I perturbations in animals and neurotypical humans, but its applicability to neurodiverse populations remains underexplored. Therefore, as proof-of-concept, this study tested the hypotheses that (i) the aperiodic 1/f exponent of resting-state EEG changes following a pharmacological E-I challenge with arbaclofen (STX209), a GABAB receptor agonist; and (ii) dynamic responsivity to GABAergic challenge is different in autism. Participants were 40 adults, 15 autistic. EEG was recorded at rest after randomised, double-blind administration of a placebo, 15 mg of arbaclofen, and 30 mg of arbaclofen. Aperiodic 1/f exponents were extracted. As predicted, in both groups the aperiodic 1/f exponent significantly increased following a high (30 mg) dose of arbaclofen, replicating the effect observed in animals. Furthermore, a lower (15 mg) dose showed a different response pattern across groups, with aperiodic exponents tending to increase in autistic individuals but decrease in non-autistic individuals, suggesting differences in GABAergic responsivity. These findings support the aperiodic 1/f exponent as a metric for dynamic E-I regulation and provide preliminary evidence of distinct homeostatic E-I dynamics in autism.

Chronic methamphetamine (METH) intake is associated with a high risk of psychosis and high susceptibility to relapse following abstinence. Prelimbic cortex (PLC) extrasynaptic GABAA receptors containing the δ-subunit may be involved in the long-term effects of METH. We therefore investigated the effects of intra-PLC injection of the δ-subunit GABAA receptor agonist 4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridine-3(-ol) (THIP), on METH sensitisation, a model of METH psychosis, or relapse to METH seeking behaviour following extinction of intravenous self-administration. In Experiment 1, male rats received 1 week of chronic treatment with METH (1 mg/kg days 1 and 7, 5 mg/kg days 2-6) or saline, followed by 14 days withdrawal. THIP (0, 0.1, 0.3 or 1.0 μg per hemisphere) was then micro-injected into the PLC prior to challenge with METH (1 mg/kg) or saline. Acute METH challenge enhanced locomotor hyperactivity in METH-pretreated rats, confirming sensitisation. THIP administration into the PLC dose-dependently reduced the effect of acute METH challenge in METH-pretreated rats. In Experiment 2, rats were trained to intravenously self-administer METH, followed by 2 weeks of extinction. Rats were then given a METH priming injection or exposed to cues associated with METH self-administration, both of which reinstated responding on the lever previously paired with METH delivery. At the 0.3 µg dose, injection of THIP into the PLC reduced reinstatement responding in both paradigms. Selective activation of extrasynaptic PLC δ-subunit GABAA receptors reduced METH sensitisation and drug primed or cue-induced METH-seeking behaviour. These findings may aid development of effective pharmacotherapies for treating chronic METH use.

Cognitive impairments are prevalent in schizophrenia and are associated with functional outcomes, yet there are currently no approved treatments to address these deficits. Roflumilast, a phosphodiesterase 4 inhibitor, has previously been shown to improve verbal memory in healthy and schizophrenia populations. This study aimed to investigate the neural changes which occur with roflumilast administration and which may underpin these cognitive effects. Ten participants with schizophrenia were administered 8 days of placebo, 100 and 250 µg of roflumilast in a 3-way crossover design. We present analyses of seed-based functional connectivity (FC) with bilateral hippocampus (HC) and regional cerebral blood flow measured with arterial spin labelling. Results indicated that 250 µg roflumilast was associated with significantly greater FC between HC and prefrontal cortex (PFC) compared to placebo. There was also a significant increase in cerebral blood flow with 250 µg roflumilast relative to placebo in the dorsolateral PFC and HC. These changes provide preliminary support for a cerebral mechanism of action of roflumilast, which includes modulation of brain regions involved in memory known to be impaired in patients with schizophrenia. This data supports existing findings suggesting roflumilast has the potential to be an effective treatment for cognitive impairments in schizophrenia.

This review provides an overview of Roland R. Griffiths' history of research, and his mentoring and collaborating approach to science that contributed to his impact in behavioral and neuropsychopharmacology and psychedelic medicines development. The approach was to summarize studies in his major domains of research, including preclinical and clinical abuse liability assessment science, alcohol, benzodiazepines, caffeine, tobacco, and psychedelics. All the authors of this review were mentored by and collaborated with Griffiths-some over several decades-and were able to provide personal perspectives and insights into Griffiths' approach to science and scientific collaborations, including insights into how major research initiatives were conceived and evolved with personal anecdotes and quotes. Roland Griffiths is widely described as a "scientist's scientist," driven by his powerful curiosity to explore new frontiers in behavioral biology and neuropharmacology, with a passion to pursue humanity-serving science. His methodical approach to research development and then systematic extension and assessment of the generalizability of findings contributed to the evolution of thinking and scientific methods for abuse liability assessment, policy, and regulation of alcohol and other sedatives, tobacco and nicotine, caffeinated products and other stimulants, and in his last 2 decades, psychedelics. His inclusive and collegial approach to science, mentoring, and collaborating fueled his creativity and productivity and a fountain of innovation and research that will go on in perpetuity. Nowhere is this more evident than at the Johns Hopkins Center for Psychedelic and Consciousness Research established in the last few years of his life, in part because of his remarkable scientific life.

Bipolar disorder affects around 2% of the population and is linked with reduced life expectancy and socioeconomic burden. Depressive episodes are difficult to treat and typically more prevalent, enduring and burdensome than manic episodes. The use of antidepressants alone has limited effect and is associated with significant clinical risk through polarity switch. Current National Institute for Health and Care Excellence guidelines recommend quetiapine, olanzapine (with or without fluoxetine) and lamotrigine; however, these medications have limited efficacy, tolerability and acceptability. The ASCEnD study aims to assess the clinical and cost-effectiveness of aripiprazole plus sertraline compared with quetiapine, offering potential improvements for outcomes in bipolar depression. The study is funded by the National Institute for Health and Care Research Health Technology Assessment programme (NIHR132773). ASCEnD is a prospective, two-arm, superiority, individually 1:1 randomised, controlled, pragmatic, parallel group, type A open-label clinical trial of aripiprazole/sertraline medication combination compared with quetiapine for bipolar depression. The study is conducted in the UK National Health Service setting with the aim of recruiting and randomising 270 participants followed-up for 24 weeks. Adults with bipolar disorder self-refer or are recruited through primary and secondary care services. The primary outcome is change in depressive symptoms 12-16 weeks after randomisation. Secondary outcomes include measures of symptom change, treatment satisfaction, tolerability, medication adherence, concomitant medication use, psychosocial functioning, quality of life and cost-effectiveness and informal carer measures of quality of life and costs of caring. The exploratory outcome is change in participant reward and punishment responsiveness. Analysis will follow a prespecified statistical analysis plan. A nested qualitative study is included to examine feasibility and acceptability of the trial design. A Clinical Trial Authorisation from Medicines and Healthcare products Regulatory Agency, and approval from the Health Research Authority (IRAS 1007468) and North East - Newcastle and North Tyneside 1 Research Ethics Committee (23/NE/0132) were obtained. Results will be disseminated through peer-reviewed publications, conference presentations and lay summaries for participants and patient and public groups. ISRCTN63917405.

Amylovis-201 (CNEURO-201) shows strong neuroprotective activity in Alzheimer's disease (AD) models due to its anti-Aβ aggregating properties and sigma-1 receptors (S1R) agonist activity. The drug is neuroprotective in transgenic rodent models of AD that could translate into disease-modifying effects by both protecting neuronal and glial viability and actively decreasing amyloid aggregation. The individual vulnerability to the neurodegenerative process in AD is highly dependent on the "cognitive reserve," understood as the efficacy of brain plasticity throughout lifetime events. We aimed to determine whether Amylovis-201 efficacy in AD could be potentiated through stimulation of cognitive reserve. We combined Amylovis-201 administration with an experimental model of environmental enrichment (EE), using training on the Hamlet device. We analyzed the potentiating effects of the combination on brain plasticity and the development of resilience against memory deficits in a pharmacological AD model. We implemented a combined protocol with repeated per os (PO) administration of Amylovis-201 (0.1 and 1 mg/kg) and EE over 2 weeks (5 days/week), consisting of a 4-hour exploration of the Hamlet, a complex environment mimicking a small village with five functionalized houses. The combination of EE and low dose (0.1 mg/kg PO) of Amylovis-201 had an additive effect on hippocampal neurogenesis. It also protected mice against scopolamine (0.5 mg/kg IP)-induced spatial working memory deficits in the Y-maze and, at 0.1 or 1 mg/kg PO, against Aβ25-35-induced memory deficits. As EE is known to increase S1R expression, the combination of EE and Amylovis-201 had major effects on brain plasticity and neuroprotection.

Psychiatric disorders represent a particularly challenging area of medicine to study using non-human animals. They arise from a complex interaction between genetic and environmental factors and are diagnosed using clinical interviews and diagnostic criteria based largely on self-reported symptoms and with significant heterogeneity seen within patient populations. Anxiety and major depressive disorder are the most diagnosed psychiatric disorders, with prescriptions of antidepressants exceeding 80 million in the UK in 2024. Despite more than 70 years of research, we do not understand how antidepressants achieve their effects on mood. With a resurgence in interest in developing new treatments based on clinical advances in the psychedelic field, there is a pressing need for translational methods to study the underlying mechanisms and provide reliable predictions of clinical effects. Human studies are limited in terms of the resolution of current imaging methods and the depth of mechanistic interrogation which can be achieved. Studies involving non-human animals offer an important avenue to understand how psychedelics alter behaviour and the underlying mechanisms mediating these effects, as well as playing a critical role in the development of new drugs. However, the value of these studies in terms of delivering outcomes for patients will only be achieved if the methods used have clinical relevance. In this perspective article, I consider whether 'behavioural biomarkers', and their translation to animal tasks, could achieve this much-need approach.

Research suggests that a greater perception of hostility in social cues increases aggression, and alcohol influences perception of social cues. Taken together, this could explain some instances of alcohol-related aggression. This study investigated whether social drinkers interpret faces as more hostile following acute alcohol compared to placebo, and whether alcohol influences the tendency to approach or avoid emotional facial expressions. Regular non-dependent drinkers (N = 84) participated in a double-blind placebo-controlled experiment. Participants completed two sessions and were tested following an alcoholic drink (0.4 g/kg), and matched placebo. In each session, they completed tasks measuring hostile attribution bias (HAB) towards emotional faces (happy, sad, angry, disgust, surprise, and fear), and approach/avoidance tendencies towards emotional faces (angry, happy, sad and disgust). Alcohol did not affect global hostility ratings of emotional facial expression (p = 0.342). However, it did increase global hostility ratings of ambiguous emotional faces after alcohol (drink by intensity interaction; p = 0.002). At an emotion-specific level, happy faces were seen as more hostile after alcohol when compared to placebo (p = 0.009; irrespective of emotional intensity). Alcohol did not affect approach/avoidance tendencies when seeing emotional faces following alcohol. These findings suggest that alcohol increases hostile judgements of ambiguous emotional faces. They also suggest that happy faces are perceived to be more hostile following alcohol. As an increased HAB when processing socially relevant information increases aggressive responding, this increased hostile perception of happy faces following alcohol may increase the likelihood of aggressive behaviour.

Current treatments for obsessive-compulsive disorder (OCD), including serotonin reuptake inhibitors and cognitive-behavioral therapy, are often insufficient. Psilocybin, a 5HT2a agonist psychedelic, has shown promise for treating OCD, but rigorous evidence is still needed. This randomized clinical trial evaluated safety, tolerability, and benefit of multiple psilocybin doses in OCD patients. Fifteen participants were randomized to receive 4 weekly sessions of high-dose (300 µg/kg), low-dose (100 µg/kg) psilocybin, or active placebo (lorazepam) in a double-blind Phase 1 (n = 5 per condition), followed by four additional high-dose sessions (single-blind Phase 2). OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale (YBOCS) following each session, and prospectively for 6 months. Safety was evaluated via adverse event systematic assessment, suicide severity rating, and psychosis screening. Psilocybin was generally well-tolerated, with no serious adverse events, or psychotic symptoms, and no significant changes in suicide severity scores. Psilocybin but not placebo significantly reduced YBOCS scores. At the end of 8-week treatment, after participants had received at least four high doses of psilocybin, 73.3% were responders (⩾35% reduction in YBOCS scores), with 40% in remission. These effects diminished but remained substantial at 6 months. Post hoc analysis of cumulative dosing correlated with YBOCS score reductions at the end of treatment. Administration of up to eight doses of psilocybin in a clinical research setting appears to be safe and potentially effective for patients with OCD. Larger trials are needed to further support efficacy and refine treatment protocols. ClinicalTrials.gov ID NCT03300947.

Effective pharmacological treatments for Post-Stroke Cognitive Impairment (PSCI) remain elusive. Preclinical studies have shown that phosphodiesterase 4 (PDE4) inhibition improved cognition, particularly memory, in post-stroke animal models and in healthy young and elderly individuals. This study tested whether the PDE4 inhibitor roflumilast could improve memory in PSCI patients. A double-blind randomized placebo-controlled trial (RCT) included 100 community-dwelling participants receiving roflumilast (100 µg q.d.) or placebo (N = 50 per group). Participants were 41-70 years and had suffered a cerebrovascular accident more than a year ago. They had subjective memory complaints and scored below the normative score on the delayed recall of the verbal learning test (VLT). After the RCT, 42 placebo group participants completed a 3-month open label extension (OLE). The primary outcome was the VLT delayed recall score. Roflumilast efficacy in the RCT was estimated through analysis of covariance (ANCOVA) with (post hoc) and without adjustment for baseline prognostic covariates defined a priori. In the OLE, general linear model repeated measures analyses were used. Secondary outcomes related to cognition, mood, and daily functioning. Of the 97 participants completing the study (roflumilast: 48; placebo: 49), primary ANCOVA indicated a larger response in the roflumilast group on VLT and Rivermead Behavioural Memory Test (stories) at endpoint with non-significant moderate effect sizes (Cohen's d: 0.31-0.36). When post hoc adjusting for prognostic baseline covariates, effect sizes (0.33-0.40) became significant. Adverse events were similar in both groups. In the OLE, all memory test scores improved with medium to large significant effect sizes (Partial η2: 0.079-0.171). Roflumilast appeared to improve memory and was not associated with adverse effects. Results support further clinical studies.

Oral S-ketamine (S-KETPO) is being explored as an alternative to intravenous maintenance treatment (S-KETIV) in treatment-resistant depression (TRD). However, the first-pass effect with S-KETPO significantly alters S-ketamine's bioavailability and the systemic exposure of its active metabolites, raising potential safety and efficacy concerns. This study characterized the pharmacodynamic and safety profiles of S-KETPO related to its pharmacokinetics in healthy participants, compared head-to-head with an S-KETIV dose that had previously demonstrated antidepressant effects in TRD . In a randomized, double-blind, placebo-controlled, double-dummy, four-way cross-over study, 16 healthy participants received a single dose of S-KETPO 0.20 and 0.45 mg/kg, S-KETIV 0.40 mg/kg and placebo. Plasma concentrations of S-KET and its active metabolites norketamine (S-NOR) and S-hydroxynorketamine (S-HNK) were measured, safety assessments were conducted up to 24 hours post-dose, and central nervous system (CNS) effects were evaluated up to 6 hours post-dose. Absolute bioavailability of S-KETPO was poor (9-12%). Peak plasma concentrations for S-KETPO 0.20 mg/kg, 0.45 mg/kg and S-KETIV were 9.81, 22.7 and 146 ng/mL (S-KET); 62.0, 127 and 55.2 ng/mL (S-NOR); and 29.5, 62.1 and 32.2 ng/mL (S-HNK), respectively. S-KET and S-HNK:S-KET metabolite-to-parent compound ratios were 7.52, 6.98 and 0.42, and 3.78, 3.71 and 0.23, for KETPO 0.20 mg/kg, S-KETPO 0.45 mg/kg, and S-KETIV, respectively. S-KETIV produced sedative, psychomotor and psychotomimetic effects coinciding with reductions in quantitative electroencephalography (qEEG) alpha, beta and delta power, whereas S-KETPO 0.45 mg/kg demonstrated inconsistent effects on vigilance and arousal but clear albeit relatively smaller reductions in qEEG alpha, beta and delta power coinciding with limited psychotomimetic effects, and finally, KETPO 0.20 mg/kg lacked effects altogether. Safety was comparable across treatments. Oral administration of S-ketamine alters pharmacokinetic and pharmacodynamic profiles, resulting in poor bioavailability, increased pharmacologically active metabolite exposures, and limited CNS effects relative to intravenous administration. The current findings have implications for S-KETPO dose selection, which may impact safety and/or therapeutic outcomes in future TRD studies. The study was registered in the 'Overview of Medical Research in the Netherlands' (OMON) under NL-OMON55261.

Ketamine has emerged as a promising rapid-acting treatment for mood disorders and suicidality. Notwithstanding its replicated antidepressant efficacy, ketamine-associated risk for abuse, dependence, and misuse remain. We conducted a systematic review of clinical and preclinical studies from database inception to August 2025, including randomized and observational trials, open-label extensions, case reports, and preclinical animal research, assessing ketamine or its enantiomers for outcomes related to abuse potential including craving, drug liking, tolerance, withdrawal, or dependence. A total of 30 studies (25 clinical and 5 preclinical) met the inclusion criteria. Clinical studies consistently reported minimal evidence of craving, dose escalation, misuse, or illicit use when ketamine or esketamine was administered in controlled, clinically supervised settings. Preclinical findings demonstrated that (S)-ketamine produces reward-related behaviors and locomotor sensitization, racemic ketamine shows reinforcing effects at higher doses, whereas (R)-ketamine demonstrates minimal reinforcing effects. Overall, the body of reviewed literature suggests that ketamine and esketamine carry low abuse liability when delivered in a monitored clinical setting while risk of abuse and misuse was identified largely in case reports and series in which appropriate monitoring was often not conducted. These findings support the safe incorporation of ketamine into treatment protocols for mood disorders while emphasizing the importance of structured administration and ongoing patient monitoring both throughout treatment and follow-up. Further research using longitudinal, prospective designs is warranted to assess potential misuse over extended treatment periods and across diverse patient populations, to optimize clinical safety and further inform evidence-based clinical practice guidelines.

Cannabidiol (CBD) is being investigated as a novel antipsychotic treatment, but its effects on psychosis are mainly drawn from pre-clinical studies, leading to uncertainty about its clinical impact. To evaluate the efficacy and tolerability of CBD in patients with schizophrenia spectrum disorders. PubMed, Scopus, Embase, PsycInfo, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and clinicaltrials.gov were searched up to July 2025. Randomized controlled trials (RCTs) of CBD in adults with schizophrenia spectrum disorders were included. Pairwise meta-analyses were conducted using random-effects models. The primary outcome was the standardized mean difference (SMD), with 95% confidence interval (95% CI), between CBD and controls at post-treatment on psychosis symptom severity. Tolerability assessment considered pooled odds ratio (OR, with 95% CI) of trial withdrawal and side effects across treatment groups. A total of eight trials (six published and two unpublished), accounting for 288 participants diagnosed with psychotic disorders, were included. CBD was administered orally, at a median daily dose of 800 mg. Follow-up times ranged from 20 minutes to 12 weeks. Effect size for CBD on psychosis symptom severity was not statistically significant (SMD: -0.194; 95%CI: -0.444 to 0.056), similarly on cognitive, and psychosis positive and negative symptoms. Tolerability assessments were comparable across CBD and controls. Quality of the evidence ranged from low to very low. Despite the limited number of outcomes assessed at the current state of the evidence, CBD did not show a clear benefit for psychosis symptoms in RCTs but was generally well tolerated. Larger, high-quality trials are needed to reach more robust conclusions about CBD efficacy in these disorders.

Benzodiazepines are commonly prescribed psychotropic drugs with anxiolytic, sedating, hypnotic, and anticonvulsant effects. They impair saccadic eye movements in prosaccade tasks, particularly peak velocity, but the extent of the effects on different saccadic parameters remains unclear. Therefore, we conducted a systematic review and meta-analyses on the effects of different benzodiazepines on peak velocity (k (number of included studies) = 30, kES (number of included effect sizes) = 45, N (number of participants) = 444), latency (k = 12, kES = 17, N = 221) and amplitude gain (k = 5, kES = 8, N = 113). Furthermore, we performed meta-analyses and dose-dependent meta-regressions of lorazepam effects on peak velocity (k = 13, kES = 19, N = 257) and latency (k = 8, kES = 12, N = 187). We found a robust and large effect on peak velocity (standardised mean change (SMCC)) = -1.064, 95% CI (confidence intervals) [-1.287, -0.84]), a less consistent, medium sized effect on latency (SMCC = 0.706, 95% CI [0.285, 1.127]), and a medium sized, but non-significant, effect on gain (SMCC = -0.581, 95% CI [-1.226, 0.064]). These findings confirm the sensitivity of saccadic eye movements to modulation of gamma-aminobutyric acid (GABA) through benzodiazepines and point to the peak velocity in particular as a biomarker for sedative effects in pharmacological research in healthy adults.

Patients with chronic cluster headache (CCH) suffer from poor sleep, which may impact their brain microstructure and parenchymal clearance of waste products. Psilocybin has shown promise for the treatment of CCH and has been linked to increased neuroplasticity with possible influences on brain microstructure. To investigate the effects of psilocybin on sleep, brain water diffusivity, and microstructure in CCH. Eleven CCH patients underwent diffusion-weighted MRI and subjective sleep quality assessment with the Pittsburgh Sleep Quality Index (PSQI) before and 1 week after three psilocybin administrations (0.14 mg/kg) spaced 1 week apart. Measures taken prior to intervention were also compared to 24 healthy controls, and subjective sleep quality was related to brain microstructure and diffusivity across groups. We found that sleep was poor in CCH patients, but improved after psilocybin treatment (CCH mean PSQI change (SD) = -2.50 (2.1), pFWER = 0.015). When analyzing brain microstructure and water diffusivity in conjunction, we found differences between CCH patients and controls, which were primarily driven by differences in grey matter. On average, psilocybin intervention in CCH patients was not associated with statistically significant changes in brain microstructure or water diffusivity. However, most patients exhibited lower white matter diffusivity and neurite volume after intervention. Subjective sleep quality showed borderline significant correlations of moderate effect size with brain microstructure and water diffusivity. Subjective sleep quality improved in CCH patients after psilocybin and showed some evidence of an association with measures of brain microstructure and water diffusivity. gov identifiers:Prophylactic Effects of Psilocybin on Chronic Cluster Headache (EPOCH; NCT04280055) and The Neurobiological Effect of 5-HT2AR Modulation (NeuroPharm2; NCT03289949).

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a potential treatment for antipsychotic-induced weight gain. This meta-analysis aimed to investigate the efficacy of GLP-1RAs on weight, body mass index (BMI), waist circumference, and visceral fat in patients receiving antipsychotics. We searched PubMed, Embase, the Cochrane Central, and APA PsycINFO through April 21, 2026, for randomized controlled trials (RCTs) of GLP-1RAs in patients treated with antipsychotics. Outcomes included weight, BMI, waist circumference, and visceral fat. Between-group mean differences (MDs) and their standard errors were used for meta-analyses. The risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. This study is registered with PROSPERO (CRD420251118829). Nine RCTs including 595 participants were identified, of whom 294 received GLP-1RAs and 301 received placebo. Four studies reported visceral fat outcomes. GLP-1RAs significantly reduced body weight (MD -6.82&#x2009;kg (95% confidence interval; CI -9.66 to -3.97), p&#x2009;<&#x2009;0.0001), BMI (-2.23&#x2009;kg/m2 (95% CI -3.15 to -1.30), p&#x2009;<&#x2009;0.0001), waist circumference (-4.94&#x2009;cm (95% CI -6.92 to -2.96), p&#x2009;<&#x2009;0.0001), and visceral fat (-0.37&#x2009;kg (95% CI -0.69 to -0.05), p&#x2009;=&#x2009;0.0255) compared with placebo. The certainty of evidence was rated as moderate across all outcomes. This meta-analysis demonstrates the benefit of GLP-1RAs in reducing body weight, BMI, waist circumference, and visceral fat. These findings support the clinical utility of GLP-1RAs as adjunctive treatments in patients with psychiatric disease and underscore the need for further trials with adiposity endpoints.

Previous systematic reviews and meta-analyses have reported impressive antidepressant effects of ketamine in treatment-resistant depression (TRD). While ketamine has been compared with electroconvulsive therapy (ECT), the gold standard treatment, the extent and durability of its antidepressant effects over longer periods remain unclear. To our knowledge, this is the first systematic review comparing average time-to-relapse between ECT and ketamine in TRD. To compare the average time-to-relapse between ECT and ketamine for TRD. We conducted this systematic review using PubMed, Medline, ScienceDirect, Cochrane Library, Ovid, PsycNET, Embase and Google Scholar, against predetermined criteria. CRD42025643824. Thirteen studies met inclusion criteria: 10 examined ketamine/(s)ketamine, and 3 focused on ECT. Twelve were randomised controlled trials (RCTs), and one was retrospective. Heterogeneity was observed in dosing regimens and administration schedules, with some studies having limited follow-up and small sample sizes. Findings are synthesised narratively. In summary, there is evidence for sustained therapeutic potential of both ECT and ketamine, ECT possibly being associated with longer remission. Increased dose, frequency and use of maintenance ECT/ketamine appear to prolong remission, and continuing oral antidepressants may prolong this further. It should also be noted that this review excluded studies involving psychotic depression, leading to the exclusion of some head-to-head studies, thus limiting the generalisability of the findings in these populations. There is currently a lack of studies within our inclusion criteria that directly compare time-to-relapse after ECT and ketamine, preventing formal statistical analysis. More high-quality, large-scale RCTs directly comparing these treatment modalities with longer follow-up times are needed.

Individuals with schizophrenia experience disproportionately high rates of impaired glucose tolerance and insulin resistance. While pharmacological strategies have demonstrated efficacy, concerns about polypharmacy and drug-drug interactions highlight the need to evaluate alternative approaches. We systematically searched PubMed, EMBASE, Web of Science, and CENTRAL up to February 10, 2025, for randomized controlled trials assessing pharmacological or nutritional interventions on metabolic outcomes in schizophrenia. Eligible trials reported fasting blood glucose, HbA1c, serum insulin, or Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Secondary outcomes included anthropometrics, lipid profiles, and psychopathology (Positive and Negative Syndrome Scale). Data were synthesized using Bayesian network meta-analysis with random-effects, and treatments were ranked using surface under the cumulative ranking curve. Risk of bias was assessed with RoB 2. A total of 102 RCTs including 7278 participants were analyzed. For fasting glucose, topiramate, synbiotic, vitamin E, and probiotic/selenium were beneficial. Metformin improved insulin levels and HOMA-IR, while aripiprazole showed significant improvement in HbA1c. Secondary outcomes revealed reductions in body mass index and body weight with aripiprazole, liraglutide, metformin, nizatidine, sibutramine, topiramate, zonisamide, and berberine. Lipid improvements were observed with aripiprazole, liraglutide, pioglitazone, pravastatin, sitagliptin, topiramate, berberine, synbiotic, and Withania somnifera. Evidence for most nutritional supplements was limited and heterogeneous. This study provides the first integrated comparison of pharmacological and nutritional interventions for glucose dysfunction in schizophrenia. Metformin showed the most consistent benefits, whereas aripiprazole, topiramate, liraglutide, and select supplements demonstrated additional advantages. These findings highlight the importance of targeting glucose dysregulation as a core therapeutic priority and support the cautious but promising role of nutritional agents alongside established pharmacological strategies.