International Journal of Neuropsychopharmacology最新文献

{"title":"Neurotoxic biomarkers of ethanol exposure: from adolescent vulnerability to adult voluntary intake in rats of both sexes.","authors":"Carles Colom-Rocha, M Julia García-Fuster","doi":"10.1093/ijnp/pyaf061","DOIUrl":"10.1093/ijnp/pyaf061","url":null,"abstract":"<p><strong>Background: </strong>Ethanol use is frequently initiated during adolescence, a vulnerable developmental period with a great deal of neuro-remodeling, specially affecting hippocampal integrity, and with a unique sensitivity to drug abuse. Previous data evaluated the neurochemical effects exerted by either ethanol or cocaine alone in the adolescent brain, but few studies measured the combined negative impact of both drugs immediate during adolescence and later following withdrawal and drug re-exposure in adulthood and therefore will be the aim of this study.</p><p><strong>Methods: </strong>Male and female Sprague-Dawley rats were treated in adolescence with non-contingent paradigms of ethanol, cocaine, their combination, or vehicle. Hippocampal samples were collected in adolescence, during forced withdrawal and following voluntary exposure to ethanol in adulthood to evaluate signs of neurotoxicity by western blot (Fas-Associated protein with Death Domain [FADD], and the ratio between Neurofilament light chain protein, NF-L, and Brain-Derived Neurotrophic Factor, BDNF) or neurogenesis by immunohistochemistry (Ki-67, NeuroD).</p><p><strong>Results: </strong>Adolescent ethanol induced hippocampal neurotoxicity by decreasing FADD and increasing NF-L/BDNF ratio, paired with decreased neuronal differentiation as labeled by NeuroD. These effects reverted to normal in adulthood during withdrawal. NeuroD was decreased after adult voluntary ethanol consumption, but exclusively in rats previously exposed to adolescent ethanol. Adolescent cocaine alone did not induce any changes at any time-points examined. The neurochemical effects were observed independently of sex. Interestingly, NeuroD emerged as a biomarker of ethanol toxicity both in adolescence and adulthood.</p><p><strong>Conclusions: </strong>Ethanol is a neurotoxic agent, and its toxicity is exacerbated by an early initiation during adolescence. Our conclusions reinforce the recommendation of avoiding and/or delaying the age of initial ethanol exposure, since it poses a prior vulnerability to its later impact in life.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953378","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":"Five-factor personality traits in patients with schizophrenia and bipolar disorder: a systematic review and meta-analysis.","authors":"Mayuka Hashimoto, Kazutaka Ohi, Daisuke Fujikane, Kentaro Takai, Ayumi Kuramitsu, Yukimasa Muto, Shunsuke Sugiyama, Toshiki Shioiri","doi":"10.1093/ijnp/pyaf060","DOIUrl":"10.1093/ijnp/pyaf060","url":null,"abstract":"<p><strong>Background: </strong>Personality traits play crucial roles in the onset, manifestation, and course of schizophrenia and bipolar disorder (BD). Previous meta-analyses focusing on NEO personality traits in patients with schizophrenia and BD revealed distinct differences in specific personality traits between patients with schizophrenia and healthy controls and between patients with BD and healthy controls. However, direct comparisons of personality profiles between schizophrenia patients and BD patients have been limited, with existing studies often limited by relatively small sample sizes.</p><p><strong>Methods: </strong>Two online databases (PubMed and Scopus) were searched systematically to identify relevant articles, including publications up to April 2024. A meta-analysis of five personality traits, namely, neuroticism (N), extraversion (E), openness (O), agreeableness (A), and conscientiousness (C), assessed by the NEO five-factor inventory, was performed in seven cohorts, including our patient samples, consisting of 768 patients with schizophrenia and 555 patients with BD.</p><p><strong>Results: </strong>There was no significant heterogeneity in the five personality traits among the seven studies (I2 = 0-53.8, P > .05), except for C (I2 = 77.1, P = 5.65 × 10-4). Our meta-analyses revealed significant differences in three personality traits (E, O, and A) between patients with schizophrenia and patients with BD (E: Hedges' g = -0.40, P = 1.34 × 10-11; O: g = -0.22, P = 1.76 × 10-4; and A: g = -0.24, P = 3.73 × 10-5). Patients with schizophrenia had lower scores on E, O, and A than those with BD did. No significant differences in the other two traits, N and C, were observed between the groups (P > .05).</p><p><strong>Conclusions: </strong>Our findings suggest that schizophrenia patients and BD patients have distinct personality profiles and that schizophrenia patients have more pronounced personality profiles than BD do, despite their overlapping symptoms and genetic predispositions.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12418928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835057","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":"Stress-induced altered expression of hippocampal nuclear and mitochondrial encoded genes in rats and cross-species genetic associations reveal molecular links to depression.","authors":"Ellie Hulwi, Qingzhong Wang, Aleena Francis, Anuj K Verma, Yogesh Dwivedi","doi":"10.1093/ijnp/pyaf057","DOIUrl":"10.1093/ijnp/pyaf057","url":null,"abstract":"<p><strong>Background: </strong>Mitochondria play a pivotal role in energy production, and their dysfunction not only hampers cells' ability to meet energy requirements but also contributes to the impairment of neural plasticity, a critical feature of depressive disorders. In this study, mitochondrial cross-omics analysis was carried out in the hippocampus of restraint rats to understand the role of mitochondria in depression pathophysiology.</p><p><strong>Methods: </strong>The expression profiles of hippocampal mitochondrial and nuclear-encoded genes in mitochondrial fractions from restraint and handled control rats were obtained using high-throughput RNA sequencing. Weighted gene co-expression network analysis (WGCNA) was used to identify the gene co-expression and pathways associated with the restraint phenotype. Mutual Information Network algorithm tools Arance, CLR, and MRNET were additionally used to screen the functional modules and hub genes and their similarity with the WGCNA-based network analysis. Finally, cross-species homology followed by gene association analysis was conducted to obtain SNPs and haplotypes related to depression phenotype.</p><p><strong>Results: </strong>A significant proportion of mitochondrial and nuclear-encoded genes showed differential regulation in the hippocampus of restraint rats. WGCNA and Mutual Information Network analysis yielded distinct functional modules significantly related to restraint phenotype. Further network analysis revealed distinct co-expression patterns associated with differentially expressed genes associated with these modules. Cross-species analysis showed 39 significantly associated SNPs with the depression phenotype, where the most significant SNP, rs10899570, was located within the TENM4 gene. Further, rs1573529 and rs10899570 were distributed into the linkage disequilibrium block where SNPs were highly correlated. Subsequent haplotype analysis showed that rs1573529 and rs10899570 were significantly associated with depressive behavior.</p><p><strong>Conclusions: </strong>The study demonstrates a significant impact of restraint stress on mitochondrial functions and genetic association, suggesting their critical role in depression pathophysiology.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12418956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835059","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":"Pemafibrate treatment produces antidepressant-like effects in CUMS and CRS models through activation of hippocampal PPARα and BDNF signaling.","authors":"Jin Zhou, Wei Zhao, Hua Fan, Si-Yi Zhou, Xiao-Li Zhang, Hui Xu, Bo Jiang, Wei Liu, Zhi-Ming Cui, Da-Wei Xu","doi":"10.1093/ijnp/pyaf063","DOIUrl":"10.1093/ijnp/pyaf063","url":null,"abstract":"<p><strong>Background: </strong>It is well established that peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the pathogenesis of depression. Several PPARα agonists, including WY14643, fenofibrate, and gemfibrozil, have been reported to produce antidepressant-like effects in mouse models through PPARα-mediated enhancement of hippocampal brain-derived neurotrophic factor (BDNF) signaling and neurogenesis. Pemafibrate is a novel and highly selective modulator of PPARα; we therefore hypothesized that it might also exhibit antidepressant-like efficacy.</p><p><strong>Methods: </strong>We employed 2 established mouse models of depression, chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS), to evaluate the potential antidepressant effects of pemafibrate. Western blotting and immunofluorescence were used to assess whether pemafibrate treatment counteracts chronic stress-induced suppression of hippocampal PPARα, BDNF signaling, and neurogenesis. To investigate the mechanism of action, we utilized pharmacological inhibitors (GW6471 for PPARα and K252a for BDNF signaling) combined with adeno-associated virus-mediated genetic knockdown approaches.</p><p><strong>Results: </strong>Repeated pemafibrate administration significantly ameliorated chronic stress-induced depressive-like behaviors and restored hippocampal PPARα levels, BDNF signaling, and neurogenesis in both models. These antidepressant effects were markedly attenuated by co-administration of GW6471 or K252a. Similarly, genetic knockdown of either hippocampal PPARα or BDNF abolished pemafibrate's antidepressant-like actions.</p><p><strong>Conclusions: </strong>Pemafibrate exerts antidepressant-like effects in both CUMS and CRS mouse models by promoting hippocampal PPARα and BDNF signaling.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12452276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953356","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 role of affective states in computational psychiatry.","authors":"David Benrimoh, Ryan Smith, Andreea O Diaconescu, Timothy Friesen, Sara Jalali, Nace Mikus, Laura Gschwandtner, Jay Gandhi, Guillermo Horga, Albert Powers","doi":"10.1093/ijnp/pyaf049","DOIUrl":"10.1093/ijnp/pyaf049","url":null,"abstract":"<p><p>Studying psychiatric illness has often been limited by difficulties in connecting symptoms and behavior to neurobiology. Computational psychiatry approaches promise to bridge this gap by providing formal accounts of the latent information processing changes that underlie the development and maintenance of psychiatric phenomena. Models based on these theories generate individual-level parameter estimates which can then be tested for relationships to neurobiology. In this review, we explore computational modelling approaches to one key aspect of health and illness: affect. We discuss strengths and limitations of key approaches to modelling affect, with a focus on reinforcement learning, active inference, the hierarchical gaussian filter, and drift-diffusion models. We find that, in this literature, affect is an important source of modulation in decision making, and has a bidirectional influence on how individuals infer both internal and external states. Highlighting the potential role of affect in information processing changes underlying symptom development, we extend an existing model of psychosis, where affective changes are influenced by increasing cortical noise and consequent increases in either perceived environmental instability or expected noise in sensory input, becoming part of a self-reinforcing process generating negatively valenced, over-weighted priors underlying positive symptom development. We then provide testable predictions from this model at computational, neurobiological, and phenomenological levels of description.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12315682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540104","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":"Sleep deprivation engages the orexin/hypocretin system to regulate food reward seeking.","authors":"Ana L Almeida Rojo, Tyler R Barnhardt, Thien Quy Pham, Benjamin Heim, Li Cai, George C Tseng, Yanhua H Huang","doi":"10.1093/ijnp/pyaf047","DOIUrl":"10.1093/ijnp/pyaf047","url":null,"abstract":"<p><strong>Background: </strong>Inadequate sleep is a prevalent health issue in modern society, with unintended consequences in dysregulation of the reward system. For example, acute sleep deprivation (SD) in humans increases craving for and intake of calorie-dense foods, which lead to further health concerns. The circuit and molecular mechanisms underlying sleep regulation of reward, however, remain poorly understood. The hypothalamic orexin (also called hypocretin) system is phylogenetically conserved to dually regulate sleep/arousal and reward. Here, we tested the hypothesis that acute SD engages the orexin (OX) system to modulate food reward seeking.</p><p><strong>Methods: </strong>We used sucrose self-administration (SA) model in male and female mice to test how acute SD by gentle handling regulates sucrose reward seeking. We then administered specific OX receptor antagonists systemically (Ox1R antagonist SB-334867 10 mg/kg or Ox2R antagonist seltorexant 10 mg/kg) or in selective brain regions (up to 100 μm) to assess their respective roles.</p><p><strong>Results: </strong>We found that under normal sleep conditions the OX system is minimally involved in sucrose reward seeking. By contrast, SD increased sucrose SA in both male and female mice, and preferentially engaged orexin receptor 2 (Ox2R) signaling in females to mediate this effect. Moreover, in nucleus accumbens or paraventricular nucleus of hypothalamus, key reward regulatory regions enriched in Ox2Rs, blocking Ox2R signaling in each individually did not counteract the SD effects in females. Finally, c-Fos analysis showed highly correlative activity levels between diverse cortical and subcortical regions during sucrose SA in females, revealing differential network engagement following SD, which was partially restored by systemic Ox2R antagonism following SD in females.</p><p><strong>Conclusion: </strong>These results highlight Ox2R signaling in counteracting the acute SD effects on food reward seeking in females.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12982918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560050","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":"Antidepressant efficacy of ketamine plus naltrexone for major depression comorbid with alcohol use disorder: a randomized controlled trial.","authors":"Gihyun Yoon, Brian Pittman, Elizabeth Ralevski, Ismene L Petrakis, John H Krystal","doi":"10.1093/ijnp/pyaf056","DOIUrl":"10.1093/ijnp/pyaf056","url":null,"abstract":"<p><strong>Importance: </strong>The comorbidity of major depressive disorder (MDD) and alcohol use disorder (AUD) is often treated inadequately. This study evaluated the impact of adding the opioid receptor blocker, naltrexone, to the NMDA glutamate receptor antagonist, ketamine, for the treatment of MDD comorbid with AUD. In so doing, it also attempted to shed light on the contribution of opioid receptor stimulation to the antidepressant effects of ketamine in this population.</p><p><strong>Objective: </strong>To compare the efficacy of ketamine plus naltrexone to ketamine plus saline and midazolam plus saline for reducing depression and decreasing alcohol consumption in outpatients with comorbid MDD and AUD.</p><p><strong>Design, setting, and participants: </strong>A 3-arm, randomized, double-blind, parallel-group study was conducted. Participants were 65 adults with current MDD and AUD, with Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 20 or higher and heavy drinking at least 4 times in the month prior to randomization.</p><p><strong>Interventions: </strong>Randomized (1:1:1) to receive (1) intravenous (IV) ketamine (0.5 mg/kg) once a week for 4 weeks (a total of 4 infusions) plus intramuscular (IM) naltrexone (380 mg), (2) IV ketamine plus IM saline, or (3) IV midazolam (0.045 mg/kg) plus IM saline.</p><p><strong>Main outcomes and measures: </strong>Co-primary: MADRS; complete alcohol abstinence. Secondary: alcohol craving, anxiety, quality of life, safety.</p><p><strong>Results: </strong>Of 65 participants, 58 received at least 1 ketamine/midazolam infusion: 20 in ketamine-naltrexone, 19 in ketamine-saline, 19 in midazolam-saline. All groups improved significantly (>80% depression remission). No group differences were observed in MADRS changes during treatment (primary outcome), although antidepressant effects persisted longer in ketamine groups compared to midazolam. There were no significant group differences in alcohol-related outcomes. Ketamine groups showed greater improvement in anxiety and quality of life (secondary outcomes) than midazolam, with the ketamine-naltrexone group showing greater improvement in anxiety than ketamine-saline. No study-related serious adverse events.</p><p><strong>Conclusions and relevance: </strong>This study found similar antidepressant and anti-alcohol effects across 3 groups. Compared to midazolam, the ketamine groups showed longer-lasting antidepressant effects and greater improvements in anxiety and quality of life. Comparable outcomes between the 2 ketamine groups suggest opioid receptor antagonism did not alter ketamine's therapeutic effects.</p><p><strong>Clinical trial registration: </strong>The study was registered at ClinicalTrials.gov (Identifier: NCT02461927).</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835055","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":"Cariprazine and clozapine: a systematic review of a promising antipsychotic combination for treatment-resistant schizophrenia.","authors":"Sofia Pappa, Réka Csehi, Ellice Caldwell-Dunn, Zsófia Borbála Dombi, Stephan Hjorth","doi":"10.1093/ijnp/pyaf053","DOIUrl":"10.1093/ijnp/pyaf053","url":null,"abstract":"<p><p>Treatment-resistant schizophrenia affects over half of individuals with schizophrenia. Clozapine is the only approved treatment in the United States but often provides limited relief. Augmenting clozapine with cariprazine (CAR) (a D3-preferring dopamine D2-D3 partial agonist) may improve outcomes. This systematic review evaluated the efficacy and safety of this combination in patients with sub-optimal response. A search of PubMed, Embase, and Cochrane Library yielded 52 cases from 21 eligible studies to be included in the analysis. Patient and treatment characteristics and clinical outcomes were synthesized. Cariprazine replaced another antipsychotic or was added to clozapine monotherapy in 44.2% and 34.6% of cases, respectively. Before treatment, 90% of patients had positive and 81% had negative symptoms. Combination therapy improved these symptoms in 66% and 83% of cases, respectively. In 19 patients with Positive and Negative Symptom Scale scores available before and after treatment, total scores decreased by 43.4%, with positive and negative subscale reductions of 23.0% and 59.1%. The combination was generally well tolerated; some patients experienced weight loss and reduced clozapine-related side effects. New adverse events occurred in 19% (most commonly akathisia at 6%). Cariprazine was discontinued in 17% of cases due to side effects or lack of efficacy. Overall, the combination appears safe and promising, especially for persistent negative symptoms, likely due to complementary neuroreceptor effects. Larger controlled trials are needed to confirm these findings.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659193","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":"Adjunctive brexpiprazole in patients with unresolved symptoms of depression on antidepressant treatment who are early in the disease course: post hoc analysis of randomized controlled trials.","authors":"Shivani Kapadia, Zhen Zhang, Csilla Csoboth, Mehul Patel, Michael E Thase, George I Papakostas","doi":"10.1093/ijnp/pyaf050","DOIUrl":"10.1093/ijnp/pyaf050","url":null,"abstract":"<p><strong>Background: </strong>Treatment for major depressive disorder (MDD) should be optimized as early as possible in the disease course to minimize patient suffering and maximize clinical benefits. This post hoc analysis aimed to investigate the efficacy and safety of adjunctive brexpiprazole in patients who were earlier and later in the disease course.</p><p><strong>Methods: </strong>Data were pooled from three 6-week, randomized, double-blind, placebo-controlled trials of adjunctive brexpiprazole in adult outpatients with MDD and inadequate response to antidepressant treatment. \"Earlier\" and \"later\" disease course subgroups were defined based on the proxies of median age, age at diagnosis, number of episodes, episode duration, and number of prior antidepressants. Efficacy was assessed by changes in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and safety by treatment-emergent adverse events.</p><p><strong>Results: </strong>Greater improvement in MADRS total score at week 6 (P < .05) was observed for antidepressant + brexpiprazole 2-3 mg/day (n = 579) versus antidepressant + placebo (n = 583) in all subgroups representing earlier and later disease course, with treatment effects (least-squares mean differences in score change) ranging from -1.79 to -2.92 points. The incidence of treatment-emergent adverse events across subgroups was 53.1%-67.2% for antidepressant + brexpiprazole 2-3 mg/day and 43.0%-51.8% for antidepressant + placebo, with no consistent differences in patients who were earlier or later in the disease course.</p><p><strong>Conclusions: </strong>Adjunctive brexpiprazole improved depressive symptoms earlier in the disease course, when benefits to patients and healthcare systems can be maximized. Adjunctive brexpiprazole also improved depressive symptoms later in the disease course; there was no advantage of delaying brexpiprazole treatment.</p><p><strong>Trial registration: </strong>Post hoc analysis of NCT01360645, NCT01360632, NCT02196506 (ClinicalTrials.gov).</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12982916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553469","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":"Hexahydrocannabinol: pharmacokinetics, systemic toxicity, and acute behavioral effects in Wistar rats.","authors":"Klára Šíchová, Barbara Mallarino, Lucie Janečková, Petr Palivec, Magdaléna Vágnerová, Čestmír Vejmola, Marek Nikolič, Lucie Ladislavová, Kristýna Mazochová, Pavel Ryšánek, Martin Šíma, Adam Šafanda, Bui Quang Hiep, Isis Rita Anzel Koutrouli, Martin Kuchař, Tomáš Páleníček","doi":"10.1093/ijnp/pyaf041","DOIUrl":"10.1093/ijnp/pyaf041","url":null,"abstract":"<p><strong>Background: </strong>Hexahydrocannabinol (HHC) is a new psychoactive substance known for its mind-altering effects and temporary legal status. It is widely used in parts of the Europe and United Kingdom as a legal alternative to ∆9-tetrahydrocannabinol, yet little research has explored its effects and safety. This study examined how HHC is processed in the body, its toxicity, and its impact on behavior in male Wistar rats.</p><p><strong>Methods: </strong>A 1:1 mixture of (9R)-HHC and (9S)-HHC was administered via intragastric gavage at doses of 1, 5, and 10 mg/kg. Behavioral effects were assessed using the open field test and the prepulse inhibition of acoustic startle response.</p><p><strong>Results: </strong>Two hours after the highest dose (10 mg/kg), peak concentrations of HHC were detected in blood and brain tissue. The Organization for Economic Co-operation and Development 423 toxicity test classified HHC as a Category 4 substance, estimating a lethal dose of 1000 mg/kg. Compared to controls (administered by sunflower oil), 10 mg/kg HHC reduced movement, increased anxiety, and impaired sensory processing.</p><p><strong>Conclusions: </strong>Overall, HHC crosses the blood-brain barrier, exhibits mild toxicity, and induces behavioral effects similar to tetrahydrocannabinol. Its dose-dependent anxiogenic properties and impact on information processing highlight the importance of the appropriate dosing in any potential therapeutic use.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608315","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}