International Journal of Neuropsychopharmacology最新文献

{"title":"From theory to therapy: unlocking the potential of muscarinic receptor activation in schizophrenia with the dual M1/M4 muscarinic receptor agonist xanomeline and trospium chloride and insights from clinical trials.","authors":"Jonathan M Meyer, Ken Kramer, Scott Vuocolo, Inder Kaul, Andrew C Miller","doi":"10.1093/ijnp/pyaf015","DOIUrl":"10.1093/ijnp/pyaf015","url":null,"abstract":"<p><p>Since the 1950s, understanding of antipsychotic activity in schizophrenia has been largely grounded in the dopamine (DA) hypothesis. Most antipsychotics approved for schizophrenia interact with D2 DA receptors as an important part of their mechanism of action. While antipsychotics blocking D2 DA receptors can be effective for positive symptoms of schizophrenia, none are approved by regulatory authorities for predominant negative or cognitive symptoms. Moreover, many of these agents induce a range of problematic side effects related to D2 DA receptor blockade (eg, drug-induced parkinsonism, akathisia, tardive dyskinesia, hyperprolactinemia and related sexual side effects, sedation). This has prompted the search for novel mechanisms with improved efficacy and tolerability based on evidence supporting involvement of other neurotransmitter systems in schizophrenia pathophysiology, including acetylcholine, gamma-aminobutyric acid, and glutamate. Among these options, targeting muscarinic receptors emerged as a promising treatment strategy. In September 2024, the U.S. Food and Drug Administration approved xanomeline and trospium chloride for treatment of adults with schizophrenia based on results from three 5-week, randomized, double-blind, placebo-controlled trials and two 52-week open-label trials. In the placebo-controlled trials, xanomeline/trospium reduced symptoms of schizophrenia, was generally well tolerated, and was not associated with clinically meaningful motor symptoms, hyperprolactinemia, sexual side effects, or weight gain compared with placebo. The long-term safety of xanomeline/trospium was also confirmed in two 52-week, open-label trials. This paper reviews the preclinical and clinical rationale for muscarinic receptor activation as a treatment for schizophrenia and the efficacy, safety, and tolerability profile of xanomeline/trospium.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582247","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":"Antidepressants in the treatment of bipolar depression: commentary.","authors":"Gustavo H Vázquez, Ross J Baldessarini","doi":"10.1093/ijnp/pyaf013","DOIUrl":"10.1093/ijnp/pyaf013","url":null,"abstract":"<p><strong>Background: </strong>Depression is a therapeutic challenge with bipolar disorder (BD) patients and remains a major contributor to disability, comorbidity, and premature mortality. The efficacy and safety of antidepressants (ADs) for this indication remain particularly controversial, and optimally safe and effective treatment of bipolar (BP) depression remains uncertain.</p><p><strong>Method: </strong>We summarized selected research findings on the treatment of depression in BD aimed at supporting practical guidelines for clinical treatment involving ADs.</p><p><strong>Results: </strong>Growing research evidence indicates that ADs are probably effective in BP depression and possibly not less than in major depressive disorder. Tolerability of antidepressant (AD) treatment is greater with type II BD (BD-2) than with type I (BD-1), particularly when ADs are combined with a mood stabilizer or antipsychotic. For BP depression, preferred ADs are serotonin-reuptake inhibitors and bupropion given in moderate doses for limited times.</p><p><strong>Conclusions: </strong>Optimal treatment of depression requires further investigation, particularly for long-term maintenance. Nevertheless, treatment for acute depressive episodes can usefully and safely include some ADs in moderate doses for limited duration, best combined with lithium, some anticonvulsants, or certain atypical antipsychotics, and more safely with BD-2 than BD-1 with close clinical supervision.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440931","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 PDE4B ameliorates cognitive defects in the model of alcoholic dementia in 3xTg-AD mice via PDE4B/cAMP/PKA signaling.","authors":"Rongzhen Sun, Mei Han, Yuanyuan Lin, Shengyao Ma, Huan Tu, Xueliang Yang, Fang Zhang, Han-Ting Zhang","doi":"10.1093/ijnp/pyaf009","DOIUrl":"10.1093/ijnp/pyaf009","url":null,"abstract":"<p><strong>Background: </strong>Chronic, heavy alcohol use may lead to permanent brain damage, cognitive impairment, and dementia. One of the most serious consequences is alcoholic dementia (AlD). Phosphodiesterase-4 (PDE4) inhibitors have been shown to exhibit beneficial effects on cognition deficits and alcoholism. However, it is not known whether PDE4 inhibitors can be used to treat AlD. A33, a relatively selective PDE4B inhibitor, is absent of the emetic effect associated with PDE4D. The effect of A33 on memory and cognition in AlD remains unclear.</p><p><strong>Methods: </strong>We investigated the effects of A33 and the PDE4 inhibitor rolipram on memory and cognition using an AlD animal model, that is, APP/PS1/Tau mice drinking alcohol in the 2-bottle choice test, with or without A33 or rolipram treatment for 3 weeks. The animal groups were compared in behavioral tests related to learning and memory. Neurochemical measures were conducted to explore the underlying mechanism of A33.</p><p><strong>Results: </strong>Compared to wild-type controls, AlD mice showed impairments of learning ability and memory in the behavior tests; this was attenuated by treatment of rolipram or A33. In addition, administration of rolipram or A33 in AlD mice further alleviated neuropathological alterations in the hippocampus, including Aβ expression and deposition; rolipram or A33 also decreased the levels of inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), as well as nuclear factor kappa-B (NF-κB). Further, rolipram or A33 decreased the activation of microglia while increased cyclic adenosine monophosphate (cAMP) levels in the hippocampus of AlD mice.</p><p><strong>Conclusions: </strong>These results revealed that the alleviation of the cognitive impairment of AlD in APP/PS1/Tau triple transgenic mice by rolipram or A33 was linked to the action of the PDE4B/cAMP/PKA signaling pathway. A33 can be a promising therapeutic agent for AlD-related cognitive dysfunction.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374106","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":"Synergistic effects of memantine and alpha7 nicotinic acetylcholine receptor agonist PHA-543613 to improve memory of aged rats.","authors":"Nóra Bruszt, Zsolt Kristóf Bali, Lili Veronika Nagy, Kornélia Bodó, Péter Engelmann, István Hernádi","doi":"10.1093/ijnp/pyaf014","DOIUrl":"10.1093/ijnp/pyaf014","url":null,"abstract":"<p><strong>Background: </strong>Combination treatments based on pharmacological interactions at α7 nicotinic acetylcholine receptors (nAChRs) are promising therapeutic approaches for neurocognitive disorders.</p><p><strong>Methods: </strong>Here, we tested the cognitive efficacy of combinations of memantine with an α7 nAChR-selective agonist (PHA-543613) in naturally aged rats. Age-related changes in the expression of some key genes and proteins were also measured using quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).</p><p><strong>Results: </strong>Aged rats showed marked cognitive decline in the novel object recognition test, and they also exhibited cholinergic changes such as mRNA upregulation of α7 nAChRs. Upregulation of interleukin-1β, macrophage inflammatory protein 1α, CX3CL1, intercellular adhesion molecule 1, and ciliary neurotrophic factor mRNA was also detected in aged rats. Combination treatment of memantine and PHA-543613 successfully alleviated the age-related decline of recognition memory of rats by exceeding the effects of the corresponding monotreatments.</p><p><strong>Conclusions: </strong>Results indicate a positive interaction between memantine and PHA-543613, which also reflects a putative role of α7 nAChRs in the cognitive enhancer effects of memantine. These findings may facilitate the development of combination therapies for age-related neurocognitive disorders.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476604","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":"Neurofilament light chain level is associated with lifetime suicidal behaviors.","authors":"Ying-Chih Cheng, Yu-Li Liu, Wen-Yin Chen, Chih-Chiang Chiu, Ming-Chyi Huang, Po-Hsiu Kuo","doi":"10.1093/ijnp/pyaf003","DOIUrl":"10.1093/ijnp/pyaf003","url":null,"abstract":"<p><strong>Background: </strong>Suicide is among the severe outcomes of mental illness and has been reported to be associated with neurodegeneration and cognitive impairment. The blood neurofilament light chain (NfL) level is a biomarker of neuronal damage in neuropsychiatric disorders. This study investigated whether the NfL levels are associated with lifetime suicidal behaviors and whether this level is higher in patients with major depressive disorder (MDD) compared with healthy controls.</p><p><strong>Methods: </strong>In this cross-sectional study, we included 73 patients with MDD and 40 age- and sex-matched controls. The blood NfL levels were measured using an enzyme-linked immunosorbent assay. We compared the NfL levels between patients with MDD and controls and performed regression analysis to evaluate the association between the NfL levels and suicidal behaviors.</p><p><strong>Results: </strong>Nearly half of the patients with MDD (43.80%) reported lifetime suicide attempts. Those with MDD had higher blood NfL levels, but their levels did not significantly differ from those of the healthy controls. Logistic regression results revealed higher risks of lifetime suicide planning (Odds ratio [OR] = 1.64) and suicide attempts (OR = 1.94) with every 10 pg/mL increase in the NfL levels.</p><p><strong>Conclusions: </strong>Our results demonstrate that higher serum NfL levels were associated with lifetime suicidal behavior.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983532","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":"Neurobiological influences on event perception: the role of catecholamines.","authors":"Foroogh Ghorbani, Xianzhen Zhou, Veit Roessner, Bernhard Hommel, Astrid Prochnow, Christian Beste","doi":"10.1093/ijnp/pyaf008","DOIUrl":"10.1093/ijnp/pyaf008","url":null,"abstract":"<p><strong>Background: </strong>Event segmentation, the cognitive process of parsing continuous experiences into discrete events, plays a fundamental role in how humans perceive and interact with their environment. Guided by Event Segmentation Theory, this study investigates the modulation of event segmentation by the catecholaminergic system by methylphenidate (MPH).</p><p><strong>Methods: </strong>Healthy adult participants (N = 52) engaged in a double-blind, counter-balanced, placebo-controlled experiment in which they watched a movie and identified event boundaries under placebo and MPH conditions.</p><p><strong>Results: </strong>With the same information given, MPH increased the likelihood that the information was considered meaningful. Crucially, the number of situational changes and participant's prior experience had an interactive effect on the probability of event segmentation. There was a stronger relationship between environmental information and segmentation probability when catecholaminergic levels were elevated by MPH in addition to previous experience.</p><p><strong>Conclusions: </strong>The catecholaminergic system modulates how incoming information is segmented to build meaningful episodes. Prior experience supports the effects of MPH to unfold. These findings underscore the complex interplay between neurochemical modulation and cognitive processes involved in event perception.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467918","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":"Investigation of the mesencephalic astrocyte-derived neurotrophic factor-endoplasmic reticulum stress pathway in mood disorders.","authors":"Mohammad Ali, Bianca Wollenhaupt-Aguiar, Yifan Wang, Fahed Abu-Hijleh, Nicolette Rigg, Taiane de Azevedo Cardoso, Imran Ahmed, Ridhi Gopalakrishnan, Karen Jansen, Luciano Dias de Mattos Souza, Ricardo Azevedo da Silva, Thaise Campos Mondin, Flavio Kapczinski, Fernanda Pedrotti Moreira, Andrew Lofts, William D Gwynne, Todd Hoare, Ram Mishra, Benicio N Frey","doi":"10.1093/ijnp/pyaf004","DOIUrl":"10.1093/ijnp/pyaf004","url":null,"abstract":"<p><strong>Background: </strong>Bipolar disorder (BD) has been associated with impaired cellular resilience. Recent studies have shown abnormalities in the unfolded protein response (UPR) in BD. The UPR is the cellular response to endoplasmic reticulum (ER) stress. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a trophic factor, decreases ER stress by modulating the UPR. The objective of this study is to investigate the MANF-ER stress pathway in BD and major depressive disorder (MDD) compared to healthy controls (HC).</p><p><strong>Methods: </strong>MANF protein concentration and MANF and GRP78 gene expression were assessed in peripheral blood from individuals with BD, MDD, and HC (protein: 40 BD, 55 MDD, 55 HC; gene expression: 52 BD, 61 MDD, 69 HC). MANF protein and gene expression along with GRP78 gene expression were also analyzed in postmortem brain tissue (20 BD, 20 MDD, 19 HC). MANF protein was quantified using an ELISA assay while quantitative polymerase chain reaction was used for MANF and GRP78 gene expression.</p><p><strong>Results: </strong>Peripheral MANF protein levels were reduced in individuals with BD in a depressive state compared to controls (P = .031) and euthymic BD participants (P = .013). No significant differences in MANF or GRP78 gene expression were observed in BD irrespective of mood state, or MDD compared to HC (all P > .05). No differences were observed regarding MANF/GRP78 protein or gene expression levels in postmortem tissue (P > .05).</p><p><strong>Conclusions: </strong>Individuals with BD who were in an acute depressive phase were found to have reduced peripheral MANF levels potentially signifying abnormal UPR and supporting the notion that BD is associated with increased ER stress.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11808195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970704","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":"Retraction of: Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate M1 Microglial Activation in Brain Injury of Mice With Subarachnoid Hemorrhage via microRNA-140-5p Delivery.","authors":"","doi":"10.1093/ijnp/pyaf006","DOIUrl":"10.1093/ijnp/pyaf006","url":null,"abstract":"","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":"28 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414093","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 development of opioid vaccines as a novel strategy for the treatment of opioid use disorder and overdose prevention.","authors":"Mustafa Tuncturk, Shikha Kushwaha, Robin M Heider, Tyler Oesterle, Richard Weinshilboum, Ming-Fen Ho","doi":"10.1093/ijnp/pyaf005","DOIUrl":"10.1093/ijnp/pyaf005","url":null,"abstract":"<p><p>Opioid use disorder (OUD) affects over 40 million people worldwide, creating significant social and economic burdens. Medication for opioid use disorder (MOUD) is often considered the primary treatment approach for OUD. MOUD, including methadone, buprenorphine, and naltrexone, is effective for some, but its benefits may be limited by poor adherence to treatment recommendations. Immunopharmacotherapy offers an innovative approach by using vaccines to generate antibodies that neutralize opioids, blocking them from crossing the blood-brain barrier and reducing their psychoactive effects. To date, only 3 clinical trials for opioid vaccines have been published. While these studies demonstrated the potential of opioid vaccines for relapse prevention, there is currently no standardized protocol for evaluating their effectiveness. We have reviewed recent preclinical studies that demonstrated the efficacy of vaccines targeting opioids, including heroin, morphine, oxycodone, hydrocodone, and fentanyl. These studies showed that vaccines against opioids reduced drug reinforcement, decreased opioid-induced antinociception, and increased survival rates against lethal opioid doses. These studies also demonstrated the importance of vaccine formulation and the use of adjuvants in enhancing antibody production and specificity. Finally, we highlighted the strengths and concerns associated with the opioid vaccine treatment, including ethical considerations.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005126","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":"A novel insight into the antidepressant effect of cannabidiol: possible involvement of the 5-HT1A, CB1, GPR55, and PPARγ receptors.","authors":"Yang Miao, Fei Zhao, Wei Guan","doi":"10.1093/ijnp/pyae064","DOIUrl":"10.1093/ijnp/pyae064","url":null,"abstract":"<p><strong>Background: </strong>Depression is a prevalent and disabling disorder that poses serious problems in mental health care, and rapid antidepressants are novel treatments for this disorder. Cannabidiol (CBD), a nonintoxicating phytocannabinoid, is thought to have therapeutic potential due to its important neurological and anti-inflammatory properties. Despite major advances in pharmacotherapy in experimental animals, the exact mechanism of antidepressant-like effects remains to be elucidated.</p><p><strong>Methods: </strong>In this paper, we review the current state of knowledge on the antidepressant properties of CBD in numerous experimental and clinical studies.</p><p><strong>Results: </strong>Accumulating evidence suggests that CBD has antidepressant properties in humans and animals with few side effects, suggesting that CBD may be a potential antidepressant. Furthermore, we discuss that CBD may therefore provide a potential treatment to exert antidepressant-like effects through various molecular targets, reducing inflammation, and enhancing neurogenesis.</p><p><strong>Conclusions: </strong>Taken together with the growing popularity of CBD as a medicine, these findings extend the limited knowledge on the antidepressant effects of CBD. This potentially opens up new therapeutic means for the patients with depression.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828260","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}