International Journal of Neuropsychopharmacology最新文献

{"title":"Efficacy and safety of the muscarinic receptor agonist KarXT (Xanomeline-Trospium) in schizophrenia: a systematic review, meta-analysis and Bayesian sensitivity analysis.","authors":"Nikhil Sharma, Mahalaqua N Khatib, Roopashree R, Mandeep Kaur, Manish Srivastava, Amit Barwal, Garbham Venkata Siva Prasad, Pranchal Rajput, Vinamra Mittal, Muhammed Shabil, Amit Kumar, Ganesh Bushi, Rachana Mehta, Prakasini Satapathy, Sanjit Sah","doi":"10.1093/ijnp/pyaf045","DOIUrl":"10.1093/ijnp/pyaf045","url":null,"abstract":"<p><strong>Background: </strong>Schizophrenia significantly impacts global health, with existing treatments primarily focusing on positive symptoms and often causing considerable side effects. KarXT (Xanomeline-Trospium), a novel treatment combining xanomeline, a muscarinic M1/M4 receptor agonist, and trospium, targets a broader range of symptoms including negative and cognitive deficits, potentially with fewer side effects. This systematic review and meta-analysis evaluates the efficacy and safety of KarXT in treating schizophrenia, assessing symptom reduction and safety profiles compared to placebo.</p><p><strong>Methods: </strong>We searched PubMed, Embase, and Web of Science up to November 10, 2024, for randomized controlled trials (RCTs) assessing the efficacy and safety of KarXT in schizophrenia. Data were pooled using a random-effects model, assessing outcomes like Positive and Negative Syndrome Scale (PANSS) scores and incidence of treatment-emergent adverse events (TEAEs). R software (Version 4.4.) was used for meta-analysis.</p><p><strong>Results: </strong>Three RCTs involving 674 participants were included. KarXT significantly reduced total PANSS scores of mean difference (MD) -9.707 (95% CI: -12.329 to -7.085), with notable improvements in both negative (MD = -1.623; 95% CI: -2.461 to -0.785) and positive symptom subscales (MD = -3.213; 95% CI: -4.033 to -2.393). The treatment was associated with a higher incidence of TEAEs, predominantly constipation [risk ratio (RR): 2.77; 95% CI: 1.72-4.45] and nausea (RR: 4.87; 95% CI: 2.73-8.68) compared to placebo. Bayesian meta-analysis confirmed the results.</p><p><strong>Conclusion: </strong>KarXT offers significant improvements in both negative and positive symptoms of schizophrenia with a manageable safety profile. Its potential as a transformative treatment for schizophrenia highlights the need for further research to confirm these findings and to fully understand its long-term efficacy and safety.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13278781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Negative allosteric modulator of the metabotropic glutamate receptor 7 ADX71743 increases wakefulness, reduces sleep, and alters stress-induced changes in the brain neurotransmitter levels.","authors":"Mikhail Kalinichev, John A Gruner, Gunnar Flik, Mariette Heins, Hasnaa Haddouk, Isabelle Royer-Urios, Simon T Bate, Sonia Poli, Robert Lütjens","doi":"10.1093/ijnp/pyag025","DOIUrl":"10.1093/ijnp/pyag025","url":null,"abstract":"<p><strong>Objective: </strong>Converging evidence suggests that metabotropic glutamate receptor 7 (mGlu7) contributes to sleep-wake regulation and stress reactivity. We used the selective negative allosteric modulator (NAM) ADX71743 to examine the role of mGlu7 in sleep-wake control and in basal and stress-evoked neurotransmitter release in freely moving rats.</p><p><strong>Method: </strong>Rats were implanted with electrodes and telemetry devices to record electroencephalogram (EEG), neck muscle electromyogram (EMG), motor activity (MA), and body temperature (BT) at baseline and for 9 h after subcutaneous (sc) administration of ADX71743 (50, 100, or 150 mg/kg) or vehicle (50% cyclodextrin in water), given 2 h after lights on. In a separate cohort, rats were implanted with microdialysis probes in the prefrontal cortex (PFC) and ventral hippocampus (vHipp). Samples were collected at baseline, followed by sc ADX71743 (100 mg/kg) or vehicle and 10 min of light handling, 60 min later. Extracellular glutamate (Glu), GABA, glycine (Gly), serotonin (5-HT), norepinephrine (NE), and dopamine (DA) were quantified over the 180 min sampling period.</p><p><strong>Results: </strong>ADX71743 increased wakefulness by up to 100% and reduced rapid eye-movement (REM) sleep by up to 100% and non-REM (NREM) sleep by up to 75% (all P < .05), with comparable effects across doses. ADX71743 also delayed NREM and REM sleep onset by nearly 2-fold (P < .05) for 2 h after dosing, without altering MA or BT. Basal neurotransmitter concentrations were unchanged. However, ADX71743 attenuated stress-related changes in GABA and 5-HT, maintaining higher levels in the vHipp than in vehicle-treated controls. Stress-evoked NE and DA increases tended to be greater after ADX71743 than after vehicle. Neither treatment nor stress markedly affected Glu or Gly in the PFC or vHipp.</p><p><strong>Conclusions: </strong>These findings support an important role for mGlu7 in regulating sleep and wakefulness. The ADX71743-associated maintenance of higher vHipp 5-HT and GABA levels after stress may contribute to reduced stress- and anxiety-like reactivity produced by mGlu7 inhibition.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The introduction of measurement-based care for patients with schizophrenia may improve psychiatric symptoms and guideline adherence rate.","authors":"Keisuke Mori, Junya Matsumoto, Satsuki Ito, Kentaro Fukumoto, Ken Inada, Fumitoshi Kodaka, Harumasa Takano, Shinsuke Kito, Ryota Hashimoto","doi":"10.1093/ijnp/pyag026","DOIUrl":"10.1093/ijnp/pyag026","url":null,"abstract":"<p><strong>Introduction: </strong>Measurement-based care (MBC) is a clinical approach that uses objective measurements to quantitatively assess patients' symptoms and conditions as the basis for treatment, with the assessments shared with patients and used in practice. One indicator of MBC, the guideline adherence rate (GAR), provides a comprehensive evaluation of the extent to which psychiatrists' prescribing practices conform to clinical practice guidelines. Although the practice of MBC has been reported to improve clinical outcomes in depressive disorders, improvements in clinical outcomes with MBC have not been reported in schizophrenia. We examined longitudinal changes in psychiatric symptoms and the GAR among patients with schizophrenia receiving MBC.</p><p><strong>Methods: </strong>Sixty-five patients with schizophrenia were included. The Positive and Negative Syndrome Scale (PANSS) total score and the GAR were compared longitudinally between time point 1 (T1) and time point 2 (T2).</p><p><strong>Results: </strong>The PANSS total score was significantly lower at T2 than at T1. The GAR was significantly higher at T2 than at T1.</p><p><strong>Conclusion: </strong>Improvements in psychiatric symptoms were consistent with previous findings on MBC reported in depressive disorders. In addition, improvements in the GAR indicated that psychiatrists' prescribing practices aligned more closely with the guideline over time within an MBC environment. These findings suggest that the MBC framework may also be clinically useful in the treatment of schizophrenia. The results were obtained from a specialized schizophrenia outpatient clinic in a national center, which represents a best-case environment for guideline adherence and monitoring. Therefore, further studies are needed to examine the generalizability of these findings.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13245167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three-week effect of amisulpride, aripiprazole, and olanzapine on gene expression in peripheral blood in individuals with schizophrenia spectrum disorders.","authors":"Anja Torsvik, Andrea Trentani, Tomasz K Stokowy, Silje Skrede, Inge Joa, Solveig M Klæbo Reitan, Maria Rettenbacher, Rune A Kroken, Erik Johnsen, Vidar M Steen","doi":"10.1093/ijnp/pyag019","DOIUrl":"10.1093/ijnp/pyag019","url":null,"abstract":"<p><strong>Objective: </strong>Antipsychotic drugs are to varying degrees associated with hematological side-effects and peripheral metabolic and immunological changes. Here, we aimed to characterize the initial transcriptional changes in peripheral leukocytes from individuals with schizophrenia spectrum disorder (SSD) after starting antipsychotic treatment with amisulpride, aripiprazole, or olanzapine.</p><p><strong>Methods: </strong>We analyzed RNA sequencing data obtained from peripheral whole blood samples from 100 individuals with SSD (41 antipsychotic-naïve [AP-naïve], 10 AP-free, and 49 AP-switching at inclusion) collected at baseline and after 1 and 3 weeks of antipsychotic drug use. Data from 36 healthy controls (HC) collected at baseline and after 3 weeks without any intervention were included. We analyzed age- and sex-adjusted differentially expressed genes between SSD and HC before and after treatment and stratified by previous antipsychotic use. A linear mixed model was applied to study longitudinal gene expression changes associated with the antipsychotic drug that was used.</p><p><strong>Results: </strong>After 3 weeks of antipsychotic use, the AP-switching group had the most significant transcriptional changes, characterized by increased expression of genes typically transcribed by immature erythroid cells and immature neutrophil cells. This gene profile showed no correlation with symptoms score. Interestingly, the immature neutrophil-associated gene signature was more pronounced in participants receiving olanzapine, and partly also amisulpride, but not aripiprazole. In contrast, only minor transcriptional changes were observed in the AP-naïve participants.</p><p><strong>Conclusions: </strong>These findings suggest that prior antipsychotic exposure may have a priming effect on leukocyte gene expression, which results in a transcriptional response indicative of stress erythropoiesis and neutropoiesis when switching to a new antipsychotic drug. This response appears to be independent of psychosis symptom severity.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13228996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trials, trips, and tribulations: pathways for implementing psychedelic therapy in Ireland.","authors":"John R Kelly, Christopher Sheridan, Patricia Iusan, Lisa Coakley, Lisa Burke, Christine Brennan, Annie MacDonald, Jo-Hanna Ivers, Dominic Trepel, Garrath Tormey, Martha Finnegan, Gareth W Young, Andrew Harkin","doi":"10.1093/ijnp/pyag028","DOIUrl":"10.1093/ijnp/pyag028","url":null,"abstract":"<p><p>Classical serotonergic psychedelics, such as psilocybin, show emerging evidence of therapeutic potential across a range of mental health disorders, including depression, anxiety, and substance use disorders, with indications of transdiagnostic efficacy. While early-phase studies yielded encouraging results, recent larger-scale phase 3 trials, such as those evaluating psilocybin for treatment-resistant depression, have shown more modest effects, and further findings from ongoing trials are awaited. Despite the absence of regulatory approvals from the U.S. Food and Drug Administration and European Medicines Agency, a small but growing number of countries have permitted psychedelic therapies within regulated clinical settings. Across these divergent international approaches, the long-term trajectory and real-world impact of these therapies within public health systems remain uncertain. In anticipation of potential future approval, Ireland has an opportunity to draw on international experience and proactively plan for the integration of psychedelic therapies. Building on emerging evidence, international frameworks, and Ireland-specific policy and health system features, this paper examines the challenges of integrating psychedelic therapies into the Irish public healthcare system. These challenges span regulatory approval, Health Technology Assessment, service implementation, workforce capacity, and the evaluation of long-term patient outcomes. The aim is to inform policymakers, practitioners, and researchers about key system-level considerations.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13248946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Life engagement improvements with cariprazine in schizophrenia: a post-hoc analysis of PANSS data from short-term studies.","authors":"Réka Csehi, Péter Szabó, Zsófia Borbála Dombi, Thomas Brevig, Balázs Szatmári, Ágota Barabássy","doi":"10.1093/ijnp/pyag027","DOIUrl":"10.1093/ijnp/pyag027","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Patient life engagement (PLE) is increasingly recognized as a meaningful treatment goal in schizophrenia, yet it remains under-researched, partly due to the lack of validated PLE measures. This post-hoc analysis evaluated the effect of cariprazine on PLE using a 14-item subset of the Positive and Negative Syndrome Scale (PANSS).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Data from three 6-week, randomized, double-blind, placebo-controlled trials were pooled and analyzed post-hoc. The 14-item PANSS subset measured PLE across four domains: Cognitive, Social, Emotional, and Physical. Changes from baseline to Week 6 in PLE Total Score and domain scores were analyzed using mixed models for repeated measures. Responder rates (≥5- and ≥ 10-point reductions) were further assessed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Cariprazine (n = 880; 1.5-6.0 mg/day) showed significantly greater improvements than placebo (n = 446) on PLE Total Score (LS mean difference [LSMD] = -3.23; 95% CI: -4.59 to -1.87; Cohen's d = 0.79, P &lt; .001) and across Emotional (LSMD: -0.59; 95% CI: -0.97 to -0.22; Cohen's d = 0.49, P &lt; .001), Social (LSMD: -1.13; 95% CI: -1.65 to -0.6; Cohen's d = 0.71, P &lt; .001), and Cognitive (LSMD: -1.34; 95% CI: -1.91 to -0.76; Cohen's d = 0.77, P &lt; .001) domains, and numerically greater improvement on the Physical (LSMD: -0.25; 95% CI: -0.5 to 0.01; Cohen's d = 0.30, P = .071) domain. Statistically significant improvements emerged by Week 2 on the PLE Total and were sustained through Week 6. Responder analyses showed that 81% and 57% of cariprazine-treated patients met the ≥5- and ≥ 10-point thresholds, respectively, versus 64% and 43% with placebo (both P &lt; .001).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The results suggest that cariprazine is associated with significant improvements in patient life engagement in schizophrenia based on the 14-item subset of the PANSS, with early and clinically meaningful benefits across domains. These findings support the value of cariprazine in addressing patient-centered treatment goals. Significant outcomes Cariprazine produced significantly greater overall symptom and illness-severity improvements than placebo, with large effect sizes on both PANSS Total (LSMD -7.44) and CGI-S (LSMD -0.41). Cariprazine showed consistently superior reductions in PLE Total and domain scores - especially Social, Cognitive, and Emotional domains - and demonstrated significantly faster and larger weekly improvements from Week 2 onward in PLE Total. Clinically meaningful response rates were higher with cariprazine, with 81% achieving ≥5-point improvement and 57% achieving ≥10-point improvement, both significantly outperforming placebo. Limitations As a post-hoc analysis, it is inherently exploratory and subject to limitations of the original study designs. While recently validated through a robust process, this 14-item subset of the PANSS is a new tool. Its performance over longer time periods, ability to predict functional ","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increase of the AMPA-evoked response of pyramidal neurons in the rat medial prefrontal cortex following acute administration of ketamine and S-ketamine, but not R-ketamine.","authors":"Mostafa El Mansari, Naomichi Okamoto, Pierre Blier","doi":"10.1093/ijnp/pyag020","DOIUrl":"10.1093/ijnp/pyag020","url":null,"abstract":"<p><strong>Background: </strong>In preclinical studies, an increase in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to N-methyl-D-aspartate (NMDA) receptor throughput is the predominant hypothesis posited to explain the rapid antidepressant effect of ketamine and S-ketamine. Several lines of evidence show that this AMPA increase takes place in the medial prefrontal cortex (mPFC), which activation has been shown to induce antidepressant-like effects. The present electrophysiological study was aimed at investigating whether a single dose of drugs with antidepressant-like effects that act on glutamate receptors as a primary target induce an increase of evoked AMPA-induced response of pyramidal neurons in the mPFC.</p><p><strong>Methods: </strong>Microiontophoretic applications of AMPA and NMDA were carried out in male anesthetized rats, following acute administration racemic ketamine, S-ketamine, R-ketamine, and ifenprodil to first assess their effects on their evoked response of mPFC pyramidal neurons. In a second series of experiments, the effects of these drugs were also assessed on the spontaneous firing activity of these neurons.</p><p><strong>Results: </strong>An increase in the AMPA-, but not NMDA-evoked response was observed following a single acute injection of ketamine and S-ketamine, when compared to saline treated rats. However, R-ketamine and the NMDA receptor GluN2B subunit antagonist ifenprodil had no effect on AMPA- and NMDA-induced responses of mPFC pyramidal neurons. The spontaneous firing activity of pyramidal neurons was enhanced by S-ketamine and ifenprodil.</p><p><strong>Conclusion: </strong>An increase in the AMPA-induced response appears to constitute a common factor underlying the antidepressant-like effects of ketamine and S-ketamine. This increase did not correlate with change in mPFC pyramidal neurons firing activity. Significance statement An increase in AMPA receptors throughput has emerged as common effect in response to drugs aiming at glutamate receptors as a primary target. This study investigated the effects of 4 such drugs on AMPA- and NMDA-evoked responses and the spontaneous firing activity of pyramidal neurons in medial prefrontal cortex. While racemic ketamine and its enantiomer S-ketamine augmented the AMPA-evoked responses, R-ketamine and ifenprodil did not. Evoked NMDA responses were not altered by these drugs. Only S-ketamine and ifenprodil increased the spontaneous firing activity of pyramidal neurons. Thus, only S-ketamine administration resulted in a simultaneous increase in AMPA response and pyramidal neurons firing activity. An increase in AMPA responsiveness in the rat mPFC correlates with the clinical antidepressant effect of racemic ketamine and S-ketamine.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13198725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct therapeutic profiles of ketamine in treatment-resistant depression: an exploratory analysis.","authors":"Kuan-I Liu, Wei-Chen Lin, Cheng-Ta Li, Ya-Mei Bai, Tung-Ping Su, Mu-Hong Chen","doi":"10.1093/ijnp/pyag021","DOIUrl":"10.1093/ijnp/pyag021","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Intravenous ketamine demonstrates rapid efficacy for treatment-resistant depression (TRD). However, its impact on individual depressive symptoms and whether the degree of treatment resistance moderates these effects remain unclear. This study aimed to dissect symptom-specific trajectories and examine the moderating role of the degree of treatment resistance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We conducted a post-hoc analysis of pooled data from two randomized, double-blind, controlled trials involving 154 adults with TRD receiving subanesthetic ketamine or control. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) over 15 days. Linear mixed-effect models (LMM) analyzed total scores, while generalized estimating equations (GEE) assessed item-level improvement. The Maudsley Staging Method (MSM) was used to quantify the degree of treatment resistance and evaluate its moderating effect.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Ketamine elicited a significant reduction in MADRS total scores (P &lt; .001). Item-level analysis revealed significant improvements in seven symptoms, including apparent sadness, inner tension, and suicidal thoughts (P &lt; .05). Crucially, a significant treatment × MSM interaction was found for apparent sadness (P = .002) and inner tension (P = .024), indicating attenuated efficacy in patients with higher resistance. Conversely, anti-suicidal efficacy was robust and not significantly moderated by resistance severity (P = .083).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Ketamine demonstrates broad efficacy in TRD but may exhibit symptom-specific divergence: anti-suicidal effects appear robust across resistance levels, whereas improvements in apparent sadness and inner tension may be attenuated by greater resistance severity. These exploratory findings warrant confirmation in prospective studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Trial registration: &lt;/strong&gt;UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000016985 (registered June 30, 2016), UMIN000023581 (registered December 31, 2018), and UMIN000033916 (registered November 30, 2021). Significant outcomes 1) Intravenous ketamine showed rapid anti-suicidal efficacy in patients with treatment-resistant depression (TRD), which was not significantly moderated by the baseline severity of treatment resistance. 2) Improvement in apparent sadness and inner tension was significantly moderated by the degree of treatment resistance, with attenuated efficacy observed in patients with higher Maudsley Staging Method (MSM) scores. 3) These exploratory findings raise the hypothesis that a symptom-specific stratified therapeutic approach may be warranted. Future research should examine whether ketamine could serve as an acute intervention for suicidal crises across the resistance spectrum, and whether improvements in specific affective symptoms may require augmentation strategies in highly refractory cases. Limitations 1) Limited generalizabil","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13192412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and functional neuroimaging correlates of suicidal ideation in treatment-resistant major depressive disorder.","authors":"Patricia Burhunduli, Katie L Vandeloo, Zhuo Fang, Pierre Blier, Jennifer L Phillips","doi":"10.1093/ijnp/pyag016","DOIUrl":"10.1093/ijnp/pyag016","url":null,"abstract":"<p><strong>Background: </strong>Treatment-resistant depression (TRD) is a severe form of major depressive disorder associated with elevated suicide risk. Identifying neurobiological correlates of suicidal ideation (SI), a key modifiable risk factor, has important clinical implications. This study examined structural and functional magnetic resonance imaging (MRI) correlates of SI severity in individuals with TRD.</p><p><strong>Methods: </strong>Structural and resting-state functional MRI data were collected from 41 participants with TRD and a history of SI. Investigator-rated past-week depression and SI severity was evaluated using the Montgomery-Åsberg Depression Rating Scale and the Columbia Scale of Suicide Severity Rating Scale, respectively. Cortical thickness and subcortical gray matter volumes were measured using FreeSurfer, and resting-state functional connectivity measures were determined using the CONN functional connectivity toolbox. Associations between SI severity and cortical thickness, subcortical gray matter volume, and resting-state functional connectivity were assessed.</p><p><strong>Results: </strong>Whole-brain vertex-wise surface-based structural analyses revealed a significant negative correlation between right lateral occipital cortical thickness and past-week SI severity, covaried for age, sex, and depression severity (P = .03, cluster-corrected). Network-based statistics analyses among 58 preselected regions of interest revealed a significant association between SI severity and resting-state functional connectivity between the right posterior parietal cortex and the left anterior insula, bilateral temporooccipital middle temporal gyrus and left frontal orbital cortex (pFDR = 0.017), covaried for depression severity. Post-hoc analyses further characterized effects, revealing negative associations between SI and functional connectivity measures (pFDR < 0.0001).</p><p><strong>Conclusions: </strong>This multimodal imaging study identified distinct structural and functional correlates of SI severity in TRD. These findings highlight the need to further investigate neurobiological underpinnings of SI to better inform suicide risk assessments and intervention strategies in this high-risk population.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147591875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of FKBP51 alleviates depressive-like behaviors via AKT/mTOR-dependent autophagy and synaptic plasticity.","authors":"Chen Li, Junjie Huang, Hailong Ge, Lujia Si, Lan Wu, Yinping Xie, Ling Xiao, Gaohua Wang","doi":"10.1093/ijnp/pyag018","DOIUrl":"10.1093/ijnp/pyag018","url":null,"abstract":"<p><strong>Background: </strong>Depression is a major global health problem, the pathogenesis of which remains to be elucidated, and current antidepressants exhibit limited efficacy. FK506-binding protein 51 (FKBP51) has been identified as a key modulator of stress-related psychiatric disorders, yet further research is required in depression.</p><p><strong>Methods: </strong>We investigated the role of hippocampal FKBP51 using a chronic unpredictable mild stress rat model and stereotaxic FKBP5 overexpression. The antidepressant effect of the FKBP51 inhibitor, selective antagonist of FKBP51 by induced fit 2 (SAFit2), was evaluated in corticosterone-induced depression model both in vivo and in vitro. Molecular and structural changes were analyzed using quantitative polymerase chain reaction, Western blotting, Golgi-Cox staining, transmission electron microscopy, and immunofluorescence. SH-SY5Y cells were utilized to examine autophagic flux and dissect downstream pathways.</p><p><strong>Results: </strong>Hippocampal FKBP51 was upregulated in chronic unpredictable mild stress-susceptible rats and correlated with depressive-like behaviors. Functionally, FKBP5 overexpression mimicked stress pathologies, inducing autophagic hyperactivation and suppressing AKT/mTOR signaling. Mechanistically, corticosterone enhanced the recruitment of the phosphatase PHLPP to FKBP51, thereby inhibiting the AKT/mTOR pathway. SAFit2 treatment disrupted the FKBP51-PHLPP interaction, reactivated the AKT/mTOR pathway, normalized autophagic flux, restored neuroplasticity, and attenuated depressive-like behaviors.</p><p><strong>Conclusions: </strong>Stress-induced FKBP51 upregulation drives depressive-like behaviors in male rats by impairing neuroplasticity and inducing autophagic hyperactivation via the PHLPP-AKT-mTOR pathway. SAFit2 exhibited antidepressant-like effects by targeting this axis, highlighting FKBP51 as a potential target for depression.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}