International Journal of Neuropsychopharmacology最新文献

{"title":"Predicting Antidepressant Responsiveness in MDD patients via EEG Gamma-Band Dynamic Functional Connectivity in Response to Salient Auditory Stimuli.","authors":"Kang-Min Choi, Taegyeong Lee, Seung-Hwan Lee, Chang-Hwan Im","doi":"10.1093/ijnp/pyaf042","DOIUrl":"https://doi.org/10.1093/ijnp/pyaf042","url":null,"abstract":"<p><strong>Background: </strong>Heterogeneous pathophysiological characteristics in patients with major depressive disorder (MDD) lead to individually differentiated sensitivities to antidepressants. Based on the hypothesis that gamma-band dynamic fluctuations in cortical functional connectivity (FC) in response to salient stimuli are linked to pathophysiological characteristics, we conducted a classification analysis for antidepressant responsiveness prediction.</p><p><strong>Methods: </strong>Biosignals and psychological measures were acquired from 47 patients with MDD prior to treatment. After eight weeks of vortioxetine therapy, patients were divided into non-remitted MDD (nrMDD; aged 42.55±11.52 years; n = 20) and remitted MDD (rMDD; aged 47.22±11.59 years; n = 27) groups based on their depressive symptom reduction. Electroencephalography (EEG) signals were acquired during the duration-variant auditory mismatch negativity (MMN) paradigm. From the deviant condition, gamma-band weighted phase-lag index-based dynamic fluctuations were evaluated using a template generated from 21 demography-matched healthy control (HC, aged 43.81±14.10 years) data.</p><p><strong>Results: </strong>Using these dynamic FC (dFC) features, a machine-learning-based classification analysis was performed for nrMDD and rMDD. Using leave-one-out cross-validation, the linear discriminant analysis classifier achieved the best accuracy (82.98%) for classifying nrMDD and rMDD. Further simple effect analyses identified three core dFC features for nrMDD: (i) relatively intact time-dependent FC between the left frontal and right temporal regions; (ii) disrupted right frontoparietal FC; and (iii) disrupted left fronto-temporal FC. These dFC features commonly exhibit transient hyperconnections in patients with nrMDD.</p><p><strong>Conclusions: </strong>We demonstrated that gamma-band dynamic FC responses to salient stimuli could serve as potential biomarkers for antidepressant responsiveness prediction in patients with MDD.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511906","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":"Frequent Vocalizations and DBS-Responsive Hyperkinesia in a Striatal Disinhibition Rat Model for Tourette Syndrome.","authors":"Boriss Sagalajev, Lina Lennartz, Niloofar Mokhtari, Mikolaj Szpak, Meryem Sinem Uyar, Thomas Schüller, Juan Carlos Baldermann, Pablo Andrade, Veerle Visser-Vandewalle, Thibaut Sesia","doi":"10.1093/ijnp/pyaf039","DOIUrl":"https://doi.org/10.1093/ijnp/pyaf039","url":null,"abstract":"<p><strong>Background: </strong>The lack of a rodent model for both motor and phonic tics hinders research on deep brain stimulation (DBS) for refractory Tourette syndrome (TS). Striatal disinhibition with a GABA-A antagonist (bicuculline) was previously shown to induce hyperkinesia and vocalizations in monkeys, indicating its potential as a TS model. In rats, however, only hyperkinesia was validated, prompting us to investigate whether they can also develop abnormal vocalizations and whether both conditions respond to thalamic DBS.</p><p><strong>Methods: </strong>Rats underwent surgical implantation of a unilateral guide cannula targeting the caudate putamen (CPu) or nucleus accumbens (NAc). Additionally, they were implanted with an ipsilateral stimulation electrode targeting the border between the central medial (CM) and ventrolateral (VL) thalamic nuclei. Motor changes and ultrasound vocalizations were recorded and characterized offline.</p><p><strong>Results: </strong>CPu bicuculline elicited arrhythmic shoulder jerks that tend to appear in fading bursts and sporadically alternate with sustained generalized hyperextension. NAc bicuculline elicited similar hyperkinesia, but at a much lower dose to prevent convulsions. DBS of CM/VL, but not adjacent regions, attenuated hyperkinesia with lower intensity showing stronger effects. In addition, bicuculline in NAc, but not CPu, elicited nonsensical vocalizations. However, the effect of CM/VL DBS on vocalizations remained inconclusive.</p><p><strong>Conclusions: </strong>Hyperkinesia temporal features, co-development with vocalizations, and responsiveness to CM/VL DBS suggest striatal disinhibition may serve as a TS rat model. Yet, other movement disorders with vocal complications cannot be excluded, given the challenge of validating key tic indicators in animals, such as premonitory urge and suppressibility.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144283862","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":"Exploring the Influence of Synaptic Density and Anxiety on Pain Perception: Evidence from a [11C]UCB-J PET Imaging Study.","authors":"Karina Moisieienko, Ruth H Asch, Margaret T Davis, Robert H Pietrzak, Irina Esterlis","doi":"10.1093/ijnp/pyaf040","DOIUrl":"https://doi.org/10.1093/ijnp/pyaf040","url":null,"abstract":"<p><strong>Background: </strong>Structural and functional brain alterations may be associated with pain and anxiety. We hypothesized that synaptic density (measured in vivo with [11C]UCB-J and positron emission tomography quantification of synaptic vesicle SV2A) alterations may play a role in higher pain sensitivity, and that this relationship may be mediated by anxiety symptoms.</p><p><strong>Methods: </strong>Twenty-one mentally and medically healthy subjects (11 males, 10 females; age 45.1 ± 16.9 years) participated in imaging, acute pain [cold pressor test (CPT)] and anxiety (State-Trait Anxiety Inventory) assessments. SV2A density was quantified as regional volumes of distribution (VT) using a one-tissue compartment model with a plasma input function. SV2A density was assessed in five regions of interest (ROIs) that were previously shown to be associated with pain: dorsolateral prefrontal cortex (DLPFC), amygdala, anterior cingulate cortex (ACC), fusiform gyrus, and cerebellum.</p><p><strong>Results: </strong>State anxiety was positively correlated with pain sensitivity (r = 0.60, p=.004). Significant negative correlations were observed between pain sensitivity and SV2A density in cerebellum (r = -0.67, p=.001), fusiform gyrus (r = -0.66, p=.001), DLPFC (r = -0.63, p=.002), and ACC (r = -0.58, p=.006). Mediation analysis revealed a significant indirect effect of cerebellar synaptic density on pain sensitivity through state anxiety symptoms (B = -0.77, 95% CI [-1.89, -0.04]), accounting for 33% of the total effect. For the fusiform gyrus, the direct effect on pain sensitivity remained significant after controlling for anxiety symptoms (B = -1.67, p=.020), while the indirect effect through anxiety symptoms was not significant (B = -0.43, 95% CI [-1.44, 0.37]).</p><p><strong>Conclusion: </strong>Results provide the first known in vivo evidence that lower synaptic (SV2A) density is associated with greater pain sensitivity, particularly in the fusiform gyrus and cerebellum. Mediation analyses revealed that state anxiety partially mediated the relationship between cerebellar synaptic density and pain sensitivity, while having an additive - but not mediating - effect on the relationship between fusiform synaptic density and pain sensitivity.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144283861","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":"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":4.5,"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":"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":4.5,"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":"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":4.5,"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":"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":4.5,"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":"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":4.5,"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":"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":4.5,"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":4.5,"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}