Journal of Psychopharmacology最新文献

{"title":"Mitochondrial dysfunction in schizophrenia and its modulation by atypical antipsychotic drugs: A randomized controlled trial.","authors":"Amiya Shaju, Biswa Ranjan Mishra, Debadatta Mohapatra, Archana Mishra, Anand Srinivasan, Rituparna Maiti","doi":"10.1177/02698811261453937","DOIUrl":"https://doi.org/10.1177/02698811261453937","url":null,"abstract":"<p><p>BackgroundRecent evidence increasingly links schizophrenia to mitochondrial dysfunction, implicating altered mitochondrial respiratory and metabolic processes in its pathophysiology. Preclinical data suggest that atypical antipsychotics may inhibit mitochondrial respiratory chain complex I (MRCC I), raising concerns regarding mitochondrial impairment despite clinical efficacy. Hence, this study was conducted to evaluate mitochondrial dysfunction associated with schizophrenia and to compare changes during treatment with risperidone and aripiprazole.MethodsIn this randomized, open-label, clinical trial, 60 patients with schizophrenia were allocated to either risperidone or aripiprazole for 12 weeks. A healthy control group (<i>n</i> = 30) was recruited for baseline biochemical comparisons. The outcome measures were the change in platelet MRCC I, serum lactate, pyruvate, lactate:pyruvate (L:P) ratio, creatine kinase, Positive and Negative Syndrome Scale (PANSS), Newcastle Mitochondrial Disease Adult Scale (NMDAS), responder rate, and treatment-emergent adverse events (TEAEs).ResultsAt baseline, schizophrenia patients exhibited significantly higher levels of MRCC I, lactate, pyruvate, and L:P ratio compared to healthy controls, consistent with underlying mitochondrial dysregulation. After 12 weeks of therapy, both risperidone and aripiprazole significantly reduced MRCC I concentration (-2.66 vs -3.13 nmol/10⁸ platelets), with no inter-group difference (<i>p</i> = 0.508). Serum lactate and L:P ratio increased significantly, while serum pyruvate remained unchanged. PANSS scores improved significantly in both groups, with comparable responder rates. NMDAS scores showed no significant change. TEAEs were mostly mild and more frequent with risperidone, though not statistically significant.ConclusionSchizophrenia is associated with alterations in mitochondrial-related biochemical markers suggestive of disrupted cellular bioenergetics. Treatment with risperidone and aripiprazole was associated with changes in these markers, without differences between groups. These findings reflect altered bioenergetic status and warrant further investigation using functional assays.Trial registrationClinicalTrials.gov identifier: NCT06236451.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261453937"},"PeriodicalIF":5.3,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and pharmacodynamics of orally administered S-ketamine in healthy participants.","authors":"Joost C van Mechelen, Tobias A Wieles, Laura G J M Borghans, Marije E Otto, Maria J Juachon, Amy L Gillespie, Martijn S van Noorden, Catherine J Harmer, Albert M van Hemert, Joop M A van Gerven, Gabriël E Jacobs","doi":"10.1177/02698811261456187","DOIUrl":"https://doi.org/10.1177/02698811261456187","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Aims: </strong>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 .</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>S-ketpo s-nor: </strong>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.</p><p><strong>Discussion and conclusion: </strong>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.</p><p><strong>Trial registration: </strong>The study was registered in the 'Overview of Medical Research in the Netherlands' (OMON) under NL-OMON55261.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261456187"},"PeriodicalIF":5.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of pimavanserin, xanomeline and highly-purified plant-derived cannabidiol on MK-801-induced behaviours in mice relevant to psychosis.","authors":"Jackie Cilia, Oriane Guillermin-Escobar, Andrew C McCreary, David Virley, Jennifer Li","doi":"10.1177/02698811261456216","DOIUrl":"10.1177/02698811261456216","url":null,"abstract":"<p><strong>Background: </strong>Psychosis, as a comorbidity, is seen in many neuropsychiatric and neurodegenerative disorders and is often treated with dopamine D₂ receptor (D₂R) antagonists, which could aggravate Alzheimer's disease and Parkinson's disease (PD) symptoms. Hence, there is a need for new treatments with a non-D₂R antagonist-related mechanism of action. Recently approved drugs for psychosis in PD, including pimavanserin (PIM), and for schizophrenia, xanomeline-trospium, offer advances since they lack D₂R antagonism but both carry associated risks. The highly-purified, plant-derived form of cannabidiol (hpCBD; Epidiolex^®) has a different safety profile, does not inhibit D₂R and has demonstrated antipsychotic effects in patients with psychosis.</p><p><strong>Aims: </strong>To systematically assess the potential antipsychotic-like effects of hpCBD, alongside newer non-D₂ antagonist drugs approved for PD psychosis (PIM) and schizophrenia psychosis (xanomeline oxalate (XAN)) in the same set of standardised preclinical assays.</p><p><strong>Methods: </strong>MK-801-induced hyperlocomotion and pre-pulse inhibition (PPI) deficits in male C57BL/6J mice were assessed following PIM (0.1, 0.3, 1 mg/kg s.c.), XAN (1, 3, 10 mg/kg s.c.) or hpCBD (50, 100, 200 mg/kg i.p.) administration. Locomotor activity was measured by infrared photobeams and Laboratory Animal Behaviour Observation Registration and Analysis System, and PPI was measured in acoustic startle chambers using a variable pre-pulse intensity protocol.</p><p><strong>Results: </strong>PIM, XAN (all doses) and hpCBD (200 mg/kg) attenuated MK-801 hyperlocomotion (<i>p</i> < 0.01). PPI deficits, at various pre-pulse intensities, were attenuated by PIM (all doses), XAN 10 mg/kg and hpCBD 200 mg/kg (<i>p</i> < 0.05).</p><p><strong>Conclusion: </strong>These results suggest that hpCBD, like PIM and XAN, demonstrates putative antipsychotic-like activity in classic mouse assays relevant to psychosis, consistent with positive clinical data in patients with psychosis.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261456216"},"PeriodicalIF":5.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiotensin II and angiotensin-(1-7) neurotransmissions in the medial amygdala differently control cardiovascular and anxiogenic-like responses to stress in rats.","authors":"Willian Costa-Ferreira, Lucas Gomes-de-Souza, Paula C Bianchi, Fernanda F Evangelista, Fábio C Cruz, Maria V S Ferronato, Carlos C Crestani","doi":"10.1177/02698811261453873","DOIUrl":"https://doi.org/10.1177/02698811261453873","url":null,"abstract":"<p><p>BackgroundThe medial amygdala nucleus (MeA) has been implicated in stress responses. However, the local neurochemical mechanisms involved are not completely understood.AimsThis study examined how angiotensin II and angiotensin-(1-7) neurotransmissions within the MeA contribute to cardiovascular, autonomic, and anxiogenic-like responses to acute restraint stress (ARS) and repeated restraint stress (RRS) in rats.MethodsSelective angiotensinergic receptor antagonists and agonists were microinjected into the MeA, and physiological and behavioral responses were evaluated during ARS and the 10th restraint session (i.e., RRS).ResultsDuring ARS, tachycardia was potentiated by angiotensin II, the AT₁ receptor antagonist losartan, and angiotensin-(1-7), whereas antagonism of AT₂ receptors with PD123319 or Mas receptors with A-779 attenuated this effect. AT₂ receptor antagonism also reduced the pressor response and sympathetically mediated cutaneous vasoconstriction. In addition, angiotensin II, losartan, and angiotensin-(1-7) reduced the anxiogenic-like behavior in the elevated plus maze following ARS. RRS did not affect gene expression of angiotensinergic receptors in the MeA. Consistently, angiotensin-(1-7) produced similar effects during ARS and the 10th restraint session. However, contrary to findings obtained in acutely stressed animals, angiotensin II and losartan failed to influence responses during the 10th restraint session. Interestingly, AT₂ receptor antagonism, which reduced tachycardia in ARS, enhanced it under chronic stress.ConclusionsThese findings indicate that angiotensin II/AT₁-AT₂ receptors and angiotensin-(1-7)/Mas receptor axes within the MeA regulate cardiovascular and anxiety-related responses to acute stress, and their roles are influenced by repeated stress exposure.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261453873"},"PeriodicalIF":5.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A noninvasive approach to modeling cocaine self-administration in mice.","authors":"Yanzuo Liu, Qiaochu Wang, George F Koob, Leandro F Vendruscolo, Nora D Volkow, Congwu Du, Yingtian Pan","doi":"10.1177/02698811261453842","DOIUrl":"10.1177/02698811261453842","url":null,"abstract":"<p><strong>Background: </strong>Intravenous self-administration (SA) in rodents is widely regarded as the standard approach for studying the neurobiological mechanisms of drug addiction. However, its use in mice is limited by the frequent complications of intravenous catheterization, including catheter failure or occlusion.</p><p><strong>Aims: </strong>To overcome these challenges, we developed and validated a noninvasive vapor approach for cocaine SA in mice.</p><p><strong>Methods: </strong>In this study, mice were trained to self-administer cocaine vapor under fixed-ratio schedules (FR1 and FR3) and exposure to cocaine SA in both short-access (1 hour/day) and long-access (3 hours/day) sessions.</p><p><strong>Results: </strong>Our findings show that the vaporized cocaine SA model induces robust behavioral and physiological effects consistent with cocaine use disorder. Our results demonstrated increased operant responding under higher reinforcement schedules, and the escalation of vaporized cocaine intake during extended access sessions (3 hours/day) emulates features of compulsive drug use in humans.</p><p><strong>Conclusions: </strong>Our findings show that the vaporized cocaine SA model offers a translational model to advance preclinical research and develop effective treatments. This vapor-based approach circumvents the need for catheterization, reduces animal stress, and is suitable for longitudinal studies and compatible for use with various modern neurogenetic techniques that require a tether for imaging free-moving, behaving animals (e.g., optogenetics and brain imaging).</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261453842"},"PeriodicalIF":5.3,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced cognitive protection through the combination of Amylovis-201, an anti-amyloidogenic agent with sigma-1 receptor agonist activity, and environmental enrichment in mice.","authors":"Roberto Menéndez Soto Del Valle, Charlyne Barry-Simonnet, Lison Verjus, Lucie Crouzier, Sairys Peña Alcolea, Marquiza Sablón Carrazana, Tangui Maurice, Chryslaine Rodríguez-Tanty","doi":"10.1177/02698811261458343","DOIUrl":"https://doi.org/10.1177/02698811261458343","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 Aβ_25-35-induced memory deficits.</p><p><strong>Conclusion: </strong>As EE is known to increase S1R expression, the combination of EE and Amylovis-201 had major effects on brain plasticity and neuroprotection.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261458343"},"PeriodicalIF":5.3,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the abuse liability of ketamine in the treatment of mood disorders: A systematic review.","authors":"Shreya Vasudeva, Gabrielle F M Lovell, Sabrina Wong, Gia Han Le, Diana K Orsini, Sara Di Luch, Roger S McIntyre, Joshua D Rosenblat","doi":"10.1177/02698811261453814","DOIUrl":"https://doi.org/10.1177/02698811261453814","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261453814"},"PeriodicalIF":5.3,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking 5-HT2B receptors abolishes psilocybin's efficacy in the rat forced swim test.","authors":"Lenka Seillier, Alexandre Seillier, Morgan A Zvolska, Romana Šlamberová","doi":"10.1177/02698811261458349","DOIUrl":"https://doi.org/10.1177/02698811261458349","url":null,"abstract":"<p><strong>Background: </strong>Major depressive disorder is one of the most debilitating psychiatric disorders worldwide. First-line treatments such as selective serotonin reuptake inhibitors have significant limitations, including delayed onset of therapeutic effects and treatment resistance in about 30% of patients. Increasing evidence suggests that acute administration of serotonergic psychedelics, such as psilocybin, produces rapid and long-lasting antidepressant effects, including in treatment-resistant patients. However, it remains unknown which specific 5-HT receptor subtype mediates psilocybin's antidepressant activity.</p><p><strong>Methods: </strong>We examined in Wistar rats whether pretreatment with the 5-HT2B receptor (5-HT2BR) antagonist RS-127445 (0.32, 1.0, or 3.2 mg/kg) blocked the rapid (day 1) and sustained (day 21) behavioral effects of a single psilocybin administration (0.32 mg/kg) in the forced swim test (FST), a test with predictive validity for antidepressant efficacy. We also measured the impact of RS-127445 on psilocybin-induced head-twitch response (HTR), a behavioral proxy in rodents for psychedelic properties.</p><p><strong>Results: </strong>Our data showed that psilocybin produced both a rapid and sustained decrease in immobility and an increase in climbing behavior in the FST and significantly increased HTR counts. Although RS-127445 did not affect HTR counts at any tested dose, it dose-dependently reversed both the rapid and sustained psilocybin-induced reductions in immobility and increases in climbing behavior.</p><p><strong>Conclusion: </strong>These findings indicate that 5-HT2BRs are required for psilocybin's behavioral effects in the FST, but are not required for its HTR. The results add to evidence that psilocybin's predictive validity in the FST can be dissociated from its 5-HT2A-mediated psychedelic effects.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261458349"},"PeriodicalIF":5.3,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148302091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of glucagon-like peptide-1 receptor agonists on anthropometric and adiposity measures in patients with antipsychotic-induced weight gain: A systematic review and meta-analysis.","authors":"Songmin Lee, Min-Gul Kim, Mike Trott, Dan Siskind, Jae Hyun Kim","doi":"10.1177/02698811261456190","DOIUrl":"https://doi.org/10.1177/02698811261456190","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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 kg (95% confidence interval; CI -9.66 to -3.97), <i>p</i> < 0.0001), BMI (-2.23 kg/m² (95% CI -3.15 to -1.30), <i>p</i> < 0.0001), waist circumference (-4.94 cm (95% CI -6.92 to -2.96), <i>p</i> < 0.0001), and visceral fat (-0.37 kg (95% CI -0.69 to -0.05), <i>p</i> = 0.0255) compared with placebo. The certainty of evidence was rated as moderate across all outcomes.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261456190"},"PeriodicalIF":5.3,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The renin angiotensin system in cognitive flexibility: Effects of single-dose losartan on task-switching in healthy volunteers.","authors":"Divya Prasad, Georgia Feltham, Riccardo De Giorgi, Sara Costi, Elaine Fox, Amy L Gillespie, Andrea Reinecke","doi":"10.1177/02698811261456198","DOIUrl":"10.1177/02698811261456198","url":null,"abstract":"<p><strong>Introduction: </strong>Cognitive flexibility, defined as the ability to shift mental strategies when environmental demands change, may influence psychological well-being and psychiatric treatment outcomes. Research increasingly implicates the renin angiotensin system (RAS) in cognition, yet its role in cognitive flexibility is inadequately understood.</p><p><strong>Methods: </strong>We conducted a double-masked trial with <i>N</i> = 60 healthy adults aged 18-50. Participants were randomly assigned a single 50 mg dose of losartan, an angiotensin type 1 receptor blocker, or placebo. Following a waiting period, participants completed a task-switching paradigm as a measure of cognitive flexibility, which required dynamically categorizing arrows based on location or direction. Statistical analyses were conducted to determine group (losartan vs placebo), task (location vs direction), and switch (switching vs repeating a task) effects on reaction time (RT) and accuracy independently. A composite bin score was also computed, integrating both RT and accuracy data.</p><p><strong>Results: </strong>All participants displayed the expected switch costs. While participants on losartan exhibited numerically superior RTs and accuracy, losartan did not significantly improve task-switching relative to placebo. This was confirmed by composite bin scoring, which indicated no benefit of losartan when RT and accuracy were integrated. An exploratory probe suggested that losartan improved accuracy on direction-switch trials, indicating a potential drug effect under specific cognitive conditions.</p><p><strong>Conclusion: </strong>Overall, we found no significant benefits of losartan on task-switching in healthy adults. Our results may be explained by ceiling effects, which could have hindered the detection of group differences, or possibly reflect a negligible role for the RAS in cognitive flexibility.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811261456198"},"PeriodicalIF":5.3,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}