International Journal of Neuropsychopharmacology最新文献

{"title":"Correction to: Inflammation and Blood-Brain Barrier in Depression: Interaction of CLDN5 and IL6 Gene Variants in Stress-Induced Depression.","authors":"","doi":"10.1093/ijnp/pyaf054","DOIUrl":"10.1093/ijnp/pyaf054","url":null,"abstract":"","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":"28 7","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12289547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707447","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":"N6-methyladenosine methylation: a novel key to unlocking mental disorders.","authors":"Yinuo Wang, Xiaobing Li, Min Liu, Xiaoxu Xu, Yue Ma, Yang Luo, Yue Wang","doi":"10.1093/ijnp/pyaf044","DOIUrl":"10.1093/ijnp/pyaf044","url":null,"abstract":"<p><p>More than 100 types of RNA modifications have been identified in mammalian cells, among which N6-methyladenosine (m6A) is the most prevalent. This reversible and dynamic modification involves methyltransferases, demethylases, and reader proteins. Aberrant expression of m6A-related regulatory proteins in the nervous system significantly impacts neuronal physiology, contributing to mental disorders such as depression, autism spectrum disorder, and schizophrenia. This review summarizes the role of m6A methylation in the pathogenesis of mental disorders and highlights its potential as a biomarker and therapeutic target, providing a comprehensive reference for future research and clinical interventions.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540103","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":"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 Nazli Khatib, R Roopashree, Mandeep Kaur, Manish Srivastava, Amit Barwal, G V Siva Prasad, Pranchal Rajput, Vinamra Mittal, Muhammed Shabil, Amit Kumar, Ganesh Bushi, Rachana Mehta, Prakasini Satapathy, Sanjit Sah","doi":"10.1093/ijnp/pyaf045","DOIUrl":"https://doi.org/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, 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 (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":4.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NMDA receptor involvement in dopaminergic modulation of neuroplasticity induced by paired associative stimulation.","authors":"Marie C Beaupain, Elham Ghanavati, Amba M Frese, Lorena Melo, Min-Fang Kuo, Michael A Nitsche","doi":"10.1093/ijnp/pyaf038","DOIUrl":"10.1093/ijnp/pyaf038","url":null,"abstract":"<p><strong>Background: </strong>Dopamine (DA) modulates long-term potentiation (LTP)-like neuroplasticity. While particularly D1 and D2 receptors are thought to influence neuroplasticity through glutamatergic N-methyl-D-aspartate (NMDA) receptor and gamma-aminobutyric acid (GABA) modulation, the exact mechanisms are not completely clarified.</p><p><strong>Objective: </strong>We aimed to explore the relevance of NMDA receptor activity for DAergic modulation of focal LTP-like plasticity induced by excitatory paired associative stimulation (ePAS).</p><p><strong>Methods: </strong>In a double-blinded, randomized, and placebo-controlled design, 17 healthy participants received DAergic agents (100 mg L-Dopa for general DAergic enhancement, 10 mg bromocriptine for selective D2 receptor activation, or placebo) with different doses of the partial NMDA receptor agonist D-cycloserine (CYC; 50, 100, 200 mg, or placebo) and underwent ePAS. Cortical excitability was monitored via motor-evoked potentials induced by TMS over the left motor cortex for up to 2 hours post-stimulation.</p><p><strong>Results: </strong>We did not find significant interactions between DAergic agents, CYC, and time across the entire sample, but significant group differences depending on sensitivity to ePAS. In high-sensitivity, but not low-sensitivity participants, ePAS induced LTP-like effects. CYC produced nonlinear, dose-dependent effects on plasticity in both groups. In the high-sensitivity group, LTP-like effects persisted under both DAergic agents, but were significantly reduced under bromocriptine. CYC had a nonlinear effect when combined with bromocriptine. In the low-sensitivity group, ePAS under DAergic agents did not induce LTP-like effects, and only additional intervention with medium-dose CYC restored facilitatory effects under L-Dopa.</p><p><strong>Conclusions: </strong>These findings suggest that optimal NMDA receptor activation is necessary for ePAS-induced neuroplasticity and that D2 receptor activity may reduce LTP-like effects by downregulating NMDA receptor function.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181809","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":"Role of endogenous serotonin in psychedelic-like effects of psilocybin in mice.","authors":"Ines Erkizia-Santamaría, Nerea Martínez-Álvarez, Leyre Salinas-Novoa, Jose Javier Meana, Jorge Emilio Ortega","doi":"10.1093/ijnp/pyaf035","DOIUrl":"10.1093/ijnp/pyaf035","url":null,"abstract":"<p><strong>Background: </strong>The psychedelic psilocybin has been posited as efficacious for the treatment of depression. However, the potential link between the intensity of acute psychedelic effects and long-term therapeutic outcomes remains undiscovered. Moreover, the impact of classical antidepressant drugs that modulate serotonergic activity on psilocybin's effects is a clinically relevant concern. The aim of the present study was to assess serotonergic mechanisms implicated in the regulation of the intensity of the psilocybin-induced acute effects.</p><p><strong>Methods: </strong>The head-twitch response (HTR), the most translational behavioral assay to characterize the psychedelic-like effect in rodents was performed. Moreover, the role of endogenous serotonin (5-HT) on psilocybin-induced HTR was studied by in vivo brain microdialysis technique.</p><p><strong>Results: </strong>Maximally effective psilocybin dose (1 mg/kg) induced progressively lower HTR in heterozygous and homozygous knockout mice for serotonin 2A receptor (5HT2AR), compared to wild type. Synaptic increase of 5-HT by citalopram dose-dependently attenuated psilocybin-induced HTR after both acute and chronic dosing regimens. Conversely, depletion of 5-HT by p-chlorophenylalanine potentiated psilocybin-evoked HTR. Serotonin 1A receptor (5HT1AR) agonist 8-OH-DPAT dose-dependently decreased psilocybin-induced HTR, demonstrating functional interaction between 5HT2AR and 5HT1AR for psychedelic effects.</p><p><strong>Conclusions: </strong>The present findings reveal an inverse correlation between cortical 5-HT levels and the acute psychedelic-like effects of psilocybin. Consequently, the enhancement of serotonergic activity induced by prior antidepressant treatment may underlie interindividual variability in the acute response to psychedelics. Investigating these mechanisms in relation to the sustained therapeutic outcomes of psilocybin could contribute to optimizing the efficacy of psychedelic-based therapies.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142490","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":"Acute inflammation induced by the Escherichia coli lipopolysaccharide considerably increases the systemic and brain exposure of olanzapine after oral administration in mice.","authors":"Jan Hubeňák, Martin Mžik, Hana Laštůvková, David Bayer, Lenka Jandová, Jolana Schreiberová, Ctirad Andrýs, Stanislav Mičuda, Jiří Masopust, Jaroslav Chládek","doi":"10.1093/ijnp/pyaf036","DOIUrl":"10.1093/ijnp/pyaf036","url":null,"abstract":"<p><strong>Background: </strong>A detailed understanding of alterations in olanzapine pharmacokinetics during acute inflammatory states, associated with infections, remains lacking. This study aimed to investigate the impact of endotoxemia on the pharmacokinetics of olanzapine and desmethylolanzapine (DMO) in mice.</p><p><strong>Methods: </strong>C57BL/6N mice received an intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) or saline (controls), followed 24 hours later by single oral or intravenous doses of olanzapine or intravenous DMO. Concentrations and unbound fractions of olanzapine and DMO were measured in the plasma and brain homogenates.</p><p><strong>Results: </strong>In LPS-injected mice, the area under the concentration-time curve (AUCs) for olanzapine increased 3.8-fold in the plasma and 5.2-fold in brain homogenates, in consequence of a higher absolute bioavailability of olanzapine (+200%), a lower plasma clearance (-34%), and a higher brain penetration ratio for the unbound drug relative to controls (Kp,uu,brain 6.2 vs. 4.1). LPS attenuated the hepatic mRNA expression of cytochrome P450 1A2 and the metabolism of olanzapine to DMO. However, the AUC of plasma DMO increased by 140% due to a 4.8-fold decrease in the plasma clearance of DMO. The brain penetration of DMO was minimal (Kp,uu,brain ≤ 0.051). The LPS-injected mice exhibited a downregulation of the hepatic and ileal mRNA expression of P-glycoprotein (Abcb1a), whereas the expression of Abcb1a and Abcb1b in the brain was upregulated.</p><p><strong>Conclusions: </strong>Endotoxemia notably increases olanzapine concentrations in the plasma and brain following oral administration in mice. Further studies should clarify whether altered pharmacokinetics results in adverse effects in acutely infected patients taking oral olanzapine.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136162","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":"Activating group II metabotropic glutamate receptors in the basolateral amygdala inhibits increases in reward seeking triggered by discriminative stimuli in rats.","authors":"Mandy Rita LeCocq, Amélie Mainville-Berthiaume, Isabel Laplante, Anne-Noël Samaha","doi":"10.1093/ijnp/pyaf030","DOIUrl":"10.1093/ijnp/pyaf030","url":null,"abstract":"<p><strong>Background: </strong>Reward-associated cues guide reward-seeking behaviors. These cues include conditioned stimuli (CSs), which occur following seeking actions and predict reward delivery, and discriminative stimuli (DSs), which occur response-independently and signal that a seeking action will produce reward. Metabotropic group II glutamate (mGlu2/3) receptors in the basolateral amygdala (BLA) modulate CS-guided reward seeking; however, their role in DS effects is unknown.</p><p><strong>Methods: </strong>We developed a procedure to assess DS and CS effects on reward seeking in the same subjects within the same test session. Female and male rats self-administered sucrose where DSs signaled periods of sucrose availability (DS+) and unavailability (DS-). During DS+ trials, lever presses produced sucrose paired with a CS+. During DS- trials, lever presses produced a CS- and no sucrose. Across 14 sessions, rats learned to load up on sucrose during DS+ trials and inhibit responding during DS- trials. We then determined the effects of intra-BLA microinfusions of the mGlu2/3 receptor agonist LY379268 on cue-evoked sucrose seeking during a test where the DSs and CSs were presented response-independently, without sucrose. Before testing, rats received intra-BLA microinjections of artificial cerebrospinal fluid (aCSF) or LY379268.</p><p><strong>Results: </strong>Under aCSF, only the DS+ and DS+CS+ combination triggered increases in reward-seeking behavior. The CS+ alone was ineffective. Intra-BLA LY379268 suppressed the increases in sucrose seeking triggered by the DS+ and DS+CS+ combination.</p><p><strong>Conclusions: </strong>Using a new procedure to test reward seeking induced by DSs and CSs, we show that BLA mGlu2/3 receptor activity mediates the incentive motivational effects of reward-predictive DSs.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964627","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":"Acute effects of intranasal esketamine application on thalamic structures in healthy individuals.","authors":"Benjamin Spurny-Dworak, Thomas Liebe, Samantha Graf, Gregor Dörl, Peter Stöhrmann, Elisa Briem, Manfred Klöbl, Clemens Schmidt, Marie Spies, Rupert Lanzenberger","doi":"10.1093/ijnp/pyaf037","DOIUrl":"10.1093/ijnp/pyaf037","url":null,"abstract":"<p><strong>Background: </strong>The N-methyl-D-aspartate receptor antagonist ketamine has found broad application in the field of psychiatry. Due to its rapid antidepressant and anti-suicidal properties, it is used as a treatment for major depressive disorder. Furthermore, ketamine evokes dissociative and psychotropic states, which allows the modeling of schizophrenic symptoms. The thalamus, a main target for ketamine's actions, consists of different nuclei responsible for sensory gating, attention, and consciousness. Thus, we here examine the effects of intranasally applied ketamine on thalamic structures in healthy individuals in a cross-over placebo-controlled study.</p><p><strong>Methods: </strong>Twenty-six subjects (14 female, mean age ± SD = 24.3 ± 3 years) underwent two magnetic resonance imaging scans on a 3T system immediately after receiving a subanesthetic dose of 56 mg esketamine (2x Spravato 28mg nasal sprays) or placebo in a cross-over study design. FreeSurfer was used for morphological analysis of the thalamus and its distinct nuclei based on derived T1-weighted MPRAGE images. Repeated measure analyses of covariance across the whole group, regardless of measurement order, and the subgroup, receiving placebo in the first scan, were performed for the thalamus and all its nuclei, for each hemisphere, separately. Post hoc tests on thalamic nuclei were done in an exploratory manner.</p><p><strong>Results: </strong>We found a significant volume increase in the right thalamus (pcorr. = .048), the pulvinar anterior nucleus (p = .048), and the right mediodorsal lateral parvocellular (p = .034) after esketamine in the subsample receiving placebo application in the first scan.</p><p><strong>Conclusion: </strong>Our results suggest rapid structural adaptations in right thalamic structures which serve as relay stations for the visual cortex. This emphasizes the thalamus' role in visual perception after esketamine and its importance as a target to model schizophrenic symptoms.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136190","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 hippocampal or thalamic inputs to the nucleus accumbens reverses stress-induced alterations in dopamine system function.","authors":"Hannah B Elam, Alexandra M McCoy, Angela M Boley, Olivia J Yang, Natalie I Belle, Daniel J Lodge","doi":"10.1093/ijnp/pyaf034","DOIUrl":"10.1093/ijnp/pyaf034","url":null,"abstract":"<p><strong>Background: </strong>Symptoms of psychosis are often observed in patients with post-traumatic stress disorder (PTSD) and are driven by aberrant regulation of the mesolimbic dopamine system. We have previously shown that targeting upstream brain regions that regulate dopamine neuron activity, the ventral hippocampus (vHipp), and paraventricular nucleus of the thalamus (PVT) maybe a novel approach to restore dopamine system function. The vHipp and PVT work in concert to regulate ventral tegmental area (VTA) dopamine neuron activity through a multisynaptic circuit that begins with inputs to the nucleus accumbens (NAc). Therefore, we hypothesized that inhibition of projections from either the vHipp or PVT to the NAc would reverse stress-induced alterations in dopamine system function.</p><p><strong>Methods: </strong>In this study, we induced stress-related pathophysiology in rats using a 2-day inescapable foot shock procedure. We then examined if foot shock stress altered the firing patterns and coordinated neuronal activity within vHipp and PVT circuits. Finally, we examined if chemogenetic inhibition of NAc afferents could reverse stress-induced alterations in dopamine system function.</p><p><strong>Results: </strong>We observed a significant increase in coherence between the PVT and NAc up to 48 hours after foot shock stress. In addition, stress increased VTA dopamine neuron population activity, which was reversed following chemogenetic inhibition of either vHipp-NAc or PVT-NAc projections.</p><p><strong>Conclusions: </strong>Taken together, these results suggest that increased coherence between the PVT and NAc, following stress, may contribute to psychosis-like symptoms but targeting either the PVT or vHipp may be viable options for the treatment of comorbid psychosis related to PTSD.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132387","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":"Safety and efficacy with esketamine in treatment-resistant depression: long-term extension study.","authors":"Naim Zaki, Li Nancy Chen, Rosanne Lane, Teodora Doherty, Wayne C Drevets, Randall L Morrison, Gerard Sanacora, Samuel T Wilkinson, Allan H Young, Acioly L T Lacerda, Jong-Woo Paik, Vanina Popova, Dong-Jing Fu","doi":"10.1093/ijnp/pyaf027","DOIUrl":"10.1093/ijnp/pyaf027","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;The rates of relapse and suicide risk are higher in treatment-resistant depression (TRD) vs non-treatment-resistant major depressive disorder. Even among patients with TRD who initially respond, the majority (70%) relapse within 6 months.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To evaluate the long-term safety and efficacy of esketamine nasal spray, combined with an oral antidepressant, in patients with TRD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;Phase 3, open-label, single-arm long-term extension study (SUSTAIN-3) conducted from June 2016 to December 2022.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Setting: &lt;/strong&gt;Outpatient.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants: &lt;/strong&gt;Adults with TRD who participated in ≥1 of 6 phase 3 \"parent\" studies continued esketamine by either entering a 4-week induction phase followed by an optimization/maintenance phase of variable duration (n = 458) or directly entering the optimization/maintenance phase of SUSTAIN-3 (n = 690), based on their individual response to study drug at the endpoint of the parent study.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interventions: &lt;/strong&gt;Intranasal esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance (weekly, every-other-week, or every-4-weeks), under direct supervision by site staff.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main outcomes and measures: &lt;/strong&gt;To assess the long-term safety of esketamine. Efficacy endpoints included the change in depressive symptoms, assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A total of 1148 patients were enrolled. Total exposure to esketamine was 3777 cumulative patient-years. Mean (median, range) exposure to esketamine in SUSTAIN-3 was 42.9 (45.8, range 0-79) months. The most common adverse events were headache (36.9%), dizziness (33.9%), nausea (33.6%), dissociation (25.5%), nasopharyngitis (23.8%), somnolence (23.1%), dysgeusia (20.2%), and back pain (20.0%). During the study, 5.3% and 6.4% of participants discontinued due to lack of efficacy or adverse event, respectively. Nine participants died: COVID-19-related (n = 3), pneumonia (n = 2), and completed suicide, myocardial infarction, multiple injuries, unknown cause (n = 1 each). The mean MADRS total score decreased during induction, and this reduction persisted during optimization/maintenance (mean [SD] change from baseline-to-phase endpoint of each phase: induction: -12.8 [9.73]; optimization/maintenance: + 0.2 [9.93]). A total of 35.6% of participants were in remission at the induction endpoint, and 48.5% and 49.6% at week 112 and optimization/maintenance endpoint, respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions and relevance: &lt;/strong&gt;In the SUSTAIN-3 final dataset, no new safety signals were identified during long-term treatment with intermittently-dosed esketamine, combined with oral antidepressant, and improvement in depression generally persisted among participants who remained on maintenance treatment. These results add ","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964811","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}