Neuropsychopharmacology最新文献

{"title":"Quantifying VMAT2 target occupancy at effective valbenazine doses and comparing to a novel VMAT2 inhibitor: a translational PET study.","authors":"Ryan Terry-Lorenzo, Daniel Albrecht, Sabrinia Crouch, Richard Wong, Gordon Loewen, Nagdeep Giri, Heather Skor, Kelly Lin, Christine M Sandiego, Meghan Pajonas, Eugenii A Rabiner, Roger N Gunn, David S Russell, Dietrich Haubenberger","doi":"10.1038/s41386-024-02046-3","DOIUrl":"10.1038/s41386-024-02046-3","url":null,"abstract":"<p><p>Positron emission tomography (PET) is frequently used to obtain target occupancy (%TO) of central nervous system (CNS) drug candidates during clinical development. Obtaining %TO with PET can be particularly powerful when the %TO associated with efficacy is known for a protein target. Using the radiotracer [¹⁸F]AV-133, the relationship between plasma concentration (PK) and %TO of NBI-750142, an experimental inhibitor of the vesicular monoamine transporter type 2 (VMAT2) was obtained in both nonhuman primate (NHP) and human. This work established [¹⁸F]AV-133 PET as capable of providing a VMAT2 inhibitor PK-%TO relationship that translated from NHP to human. To establish the VMAT2%TO benchmark, PET was performed in NHP with NBI-98782, the main active metabolite of valbenazine, and this PK-%TO relationship was used to estimate VMAT2%TO at NBI-98782 exposures associated with valbenazine therapeutic effects in the treatment of tardive dyskinesia (TD). This work defined 85-90% as the VMAT2%TO achieved by exposures associated with daily dosing with 80 mg valbenazine, a dosing regimen known to exhibit a large effect size in the treatment of TD and in the treatment of chorea associated with Huntington's Disease. NBI-750142 was estimated to achieve 36-78% VMAT2 target occupancy at acceptable doses, indicating potential inferiority in conferring clinical benefit compared to valbenazine. It is recommended that the %TO benchmark of valbenazine derived from [¹⁸F]AV-133 PET serve as a gold standard biomarker to evaluate novel VMAT2 inhibitors undergoing clinical development.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In remembrance of Herbert Pardes, M.D. July 7, 1934-April 30, 2024.","authors":"Peter J Tarr, Judith M Ford","doi":"10.1038/s41386-024-02037-4","DOIUrl":"https://doi.org/10.1038/s41386-024-02037-4","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cigarette smoking is associated with reduced neuroinflammation and better cognitive control in people living with HIV.","authors":"Arthur L Brody, Anna K Mischel, Andre Y Sanavi, Alvin Wong, Ji Hye Bahn, Arpi Minassian, Erin E Morgan, Brinda Rana, Carl K Hoh, David R Vera, Kishore K Kotta, Alannah H Miranda, Nina Pocuca, Thomas J Walter, Natalie Guggino, Renee Beverly-Aylwin, Jeffrey H Meyer, Neil Vasdev, Jared W Young","doi":"10.1038/s41386-024-02035-6","DOIUrl":"10.1038/s41386-024-02035-6","url":null,"abstract":"<p><p>People living with HIV (HIV+) are roughly twice as likely to smoke cigarettes (Smok+) as the general population. With the advent of effective antiretroviral therapies, it is increasingly important to understand the effects of chronic HIV infection and cigarette smoking on brain function and cognition since HIV+ individuals have heightened neuroinflammation and cognitive deficits even with such therapies. Based on prior studies demonstrating that smoking reduces a marker for neuroinflammation in HIV- individuals, we hypothesized that HIV+/Smok+ individuals would have less neuroinflammation and better cognitive control than HIV+/Smok- individuals. Fifty-nine participants (HIV-/Smok- [n = 16], HIV-/Smok+ [n=14], HIV+/Smok- [n = 18], and HIV+/Smok+ [n = 11]) underwent baseline eligibility tests, positron emission tomography (PET) scanning to determine levels of a marker for neuroinflammation, and assessment of cognitive control with the reverse-translated 5-choice continuous performance test (5C-CPT), with smokers having smoked to satiety prior to testing. For the PET data, a significant effect of smoking status on whole brain (WB) standardized uptake value (SUV) was found between HIV+/Smok+ and HIV+/Smok- participants (due to 18.8% lower WB SUV in the HIV+/Smok+ group). HIV+/Smok- participants exhibited a mean 13.5% higher WB SUV than HIV-/Smok- participants. For the 5C-CPT, HIV+/Smok+ participants performed significantly better than HIV+/Smok- participants (d prime), and HIV+/Smok- participants performed worse than HIV-/Smok- participants. Thus, HIV+/Smok+ individuals demonstrated lower levels of the neuroinflammation marker and better cognitive control than HIV+/Smok- individuals. Given that HIV+ individuals whose HIV is well-controlled can still have chronic neurocognitive complications, study results suggest possible paths for future research into nicotine-related treatments to prevent such complications.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relative effectiveness of antidepressant treatments in treatment-resistant depression: a systematic review and network meta-analysis of randomized controlled trials.","authors":"Johan Saelens, Anna Gramser, Victoria Watzal, Carlos A Zarate, Rupert Lanzenberger, Christoph Kraus","doi":"10.1038/s41386-024-02044-5","DOIUrl":"https://doi.org/10.1038/s41386-024-02044-5","url":null,"abstract":"<p><p>This systematic review and network meta-analysis (NMA) sought to compare different antidepressant treatments for treatment-resistant depression (TRD) in order to facilitate evidence-based choices. A literature search of PubMed, Cochrane Library, and Embase from inception until April 13th, 2023 identified randomized, controlled trials (RCTs) of adults with depression who had not responded to at least two antidepressant trials; all RCTs had ≥10 participants per study arm, and participants with bipolar or psychotic depression were excluded. The Cochrane Risk of Bias Tool-2 was used to assess study quality. Response rate was the primary outcome measure. Odds ratios (ORs) using a random effects NMA are reported. From 8234 records, 69 RCTs were included in this analysis, encompassing 10,285 participants (5662 F/4623 M) and 25 separate treatments. Six of the 25 treatments demonstrated a higher response rate versus placebo or sham treatment: electroconvulsive therapy (ECT), minocycline, theta-burst stimulation (TBS), repetitive transcranial magnetic stimulation (rTMS), ketamine, and aripiprazole. ORs ranged from 1.9 (95%CI = [1.25; 2.91]) for aripiprazole to 12.86 (95%CI = [4.07; 40.63]) for ECT. Moderate heterogeneity of the model was observed (I² = 47.3% (95%CI [26.8-62%]). Of the included studies, 12.5% were rated as having high risk of bias, 28.13% as having low risk, and 59.38% as showing some concerns. Several effective treatments for TRD showed robust treatment effects across outcomes (ECT, TBS, rTMS, and ketamine), and others showed promising results for some, but not all, outcomes (minocycline, aripiprazole). These findings may help guide evidence-based treatment choices for TRD. Study Registration: PROSPERO (#CRD42023420584).</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and cognitive pharmacodynamics following dose escalations with 3-methylmethcathinone (3-MMC): a first in human, designer drug study.","authors":"Johannes G Ramaekers, Johannes T Reckweg, Natasha L Mason, Kim P C Kuypers, Stefan W Toennes, Eef L Theunissen","doi":"10.1038/s41386-024-02042-7","DOIUrl":"https://doi.org/10.1038/s41386-024-02042-7","url":null,"abstract":"<p><p>3-Methylmethcathinone (3-MMC) is a designer drug that belongs to the group of synthetic cathinones. The compound has been scheduled in many jurisdictions because of public health concerns associated with excessive use. To date, there are no clinical studies that have evaluated the risk profile of 3-MMC in the recreational range of low to moderate doses. The current, first-in-human study (N = 14) assessed the impact of three escalating doses of 3-MMC (25, 50 and 100 mg) on vital signs, neurocognitive function, state of consciousness, appetite and drug desire, in a cross-over, placebo-controlled trial. A battery of neurocognitive tests and questionnaires as well as measures of vital signs were repeatedly administered up to 5 h after dosing. Overall, 3-MMC caused dose-dependent increases in heart rate and blood pressure, though not of clinical significance, and feelings of subjective high. Additionally, 3-MMC induced dose-related enhancement of task performance across several neurocognitive domains, including processing speed, cognitive flexibility, psychomotor function, attention and memory. Impulse control was not affected by 3-MMC. Participants also reported mild increases in dissociative and psychedelic effects, decreased appetite, and gave greater ratings of liking and wanting for 3-MMC that were transient over time. Overall, the cardiovascular, psychostimulant and psychotomimetic profile of 3-MMC appears consistent with that of compounds structurally related to amphetamine. It is concluded that low to moderate doses of 3-MMC were well tolerated and safe and that potential health risks might only occur at high or excessive doses of 3-MMC.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute dose-dependent effects and self-guided titration of continuous N,N-dimethyltryptamine infusions in a double-blind placebo-controlled study in healthy participants.","authors":"Livio Erne, Severin B Vogt, Lorenz Müller, Albiona Nuraj, Anna Becker, Aaron Klaiber, Melani Zuparic, Nimmy Varghese, Anne Eckert, Deborah Rudin, Dino Luethi, Matthias E Liechti","doi":"10.1038/s41386-024-02041-8","DOIUrl":"https://doi.org/10.1038/s41386-024-02041-8","url":null,"abstract":"<p><p>N,N-dimethyltryptamine (DMT) is a serotonergic psychedelic that is known for its short-lasting effects when administered intravenously. Several studies have investigated the administration of intravenous boluses or combinations of a bolus and a subsequent continuous infusion. However, data on dose-dependent acute effects and pharmacokinetics of continuous DMT infusions are lacking. We used a double-blind, randomized, placebo-controlled, crossover design in 22 healthy participants (11 women, 11 men) who received placebo and DMT (0.6, 1.2, 1.8, and 2.4 mg/min) over an infusion duration of 120 min. We also tested a self-guided titration scheme that allowed participants to adjust the DMT dose rate at prespecified time points to achieve their desired level of subjective effects. Outcome measures included subjective effects, autonomic effects, adverse effects, plasma hormone concentrations, and pharmacokinetics up to 3 h after starting the infusion. DMT infusions exhibited dose-proportional pharmacokinetics and rapidly induced dose-dependent subjective effects that reached a plateau after 30 min. A ceiling effect was observed for \"good drug effect\" at 1.8 mg/min. The 2.4 mg/min dose of DMT induced greater anxious ego dissolution than the 1.8 mg/min dose and induced significant anxiety compared with placebo. We observed moderate acute tolerance to acute effects of DMT. In the self-guided titration session, the participants opted for moderate to strong psychedelic effects, comparable in intensity to the 1.8 mg/min DMT dose rate in the randomized dosing sessions. These results may assist with dose finding for future DMT research and demonstrate that acute subjective effects of DMT can be rapidly adjusted through dose titration.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epac2-mediated synaptic insertion of Ca²⁺-permeable AMPARs in the nucleus accumbens contributes to incubation of cocaine craving.","authors":"Xiaojie Liu, Yao Huang, Lianwei Mu, Vladislav Friedman, Thomas J Kelly, Ying Hu, Dong Yuan, Qing-Song Liu","doi":"10.1038/s41386-024-02030-x","DOIUrl":"https://doi.org/10.1038/s41386-024-02030-x","url":null,"abstract":"<p><p>The accumulation of GluA2-lacking Ca²⁺-permeable AMPARs (CP-AMPARs) in the medium spiny neurons (MSNs) of the nucleus accumbens (NAc) is required for the expression of incubation of cocaine craving. The exchange protein directly activated by cAMP (Epac) is an intracellular effector of cAMP and a guanine nucleotide exchange factor for the small GTPase Rap1. Epac2 has been implicated in the trafficking of AMPA receptors at central synapses. We tested the hypothesis that Epac2 activation contributes to the accumulation of CP-AMPARs in NAc MSNs and incubation of cocaine craving. Here we demonstrate that the selective Epac2 agonist S-220 facilitated the synaptic insertion of GluA2-lacking CP-AMPARs at excitatory synapses onto NAc MSNs. In addition, prolonged abstinence from cocaine self-administration in rats resulted in elevated Rap1-GTP levels in the NAc, implying that Epac2 is activated during incubation. Importantly, we show that AAV-mediated shRNA knockdown of Epac2 in the NAc core attenuated the accumulation of CP-AMPARs and cue-induced drug-seeking behavior after prolonged abstinence from cocaine self-administration. In contrast, acute pharmacological inhibition of Epac2 with the selective Epac2 inhibitor ESI-05 did not alter CP-AMPARs that had already accumulated during incubation, and intra-NAc application of ESI-05 did not significantly affect cue-induced drug seeking following prolonged abstinence. Taken together, these results suggest that Epac2 activation during the period of incubation, but not during cue-induced drug seeking, leads to the accumulation of CP-AMPARs in NAc MSNs, which in turn contributes to incubation of cocaine craving.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural basis of adolescent THC-induced potentiation of opioid responses later in life.","authors":"Elizabeth Hubbard, Pieter Derdeyn, Vivienne Mae Galinato, Andrew Wu, Katrina Bartas, Stephen V Mahler, Kevin T Beier","doi":"10.1038/s41386-024-02033-8","DOIUrl":"10.1038/s41386-024-02033-8","url":null,"abstract":"<p><p>Use of one addictive drug typically influences the behavioral response to other drugs, either administered at the same time or a subsequent time point. The nature of the drugs being used, as well as the timing and dosing, also influence how these drugs interact. Here, we tested the effects of adolescent THC exposure on the development of morphine-induced behavioral adaptations following repeated morphine exposure during adulthood. We found that adolescent THC administration paradoxically prevented the development of anxiety-related behaviors that emerge during a forced abstinence period following morphine administration but facilitated reinstatement of morphine CPP. Following forced abstinence, we then mapped the whole-brain response to a moderate dose of morphine and found that adolescent THC administration led to an overall increase in brain-wide neuronal activity and increased the functional connectivity between frontal cortical regions and the ventral tegmental area. Last, we show using rabies virus-based circuit mapping that adolescent THC exposure triggers a long-lasting elevation in connectivity from the frontal cortex regions onto ventral tegmental dopamine cells. Our study adds to the rich literature on the interaction between drugs, including THC and opioids, and provides potential neural substates by which adolescent THC exposure influences responses to morphine later in life.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: The might of light for revealing neuropsychiatric mechanisms","authors":"Kutlu Kaya,&nbsp;Hilary P. Blumberg","doi":"10.1038/s41386-024-02032-9","DOIUrl":"10.1038/s41386-024-02032-9","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 3","pages":"607-607"},"PeriodicalIF":6.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The efficacy and cerebral mechanism of intradermal acupuncture for major depressive disorder: a multicenter randomized controlled trial.","authors":"Xiaoting Wu, Mingqi Tu, Zelin Yu, Zhijian Cao, Siying Qu, Nisang Chen, Junyan Jin, Sangsang Xiong, Jiajia Yang, Shuangyi Pei, Maosheng Xu, Jia Wang, Yan Shi, Lishu Gao, Jian Xie, Xinwei Li, Jianqiao Fang, Xiaomei Shao","doi":"10.1038/s41386-024-02036-5","DOIUrl":"https://doi.org/10.1038/s41386-024-02036-5","url":null,"abstract":"<p><p>New combinations or alternative therapies for major depressive disorder (MDD) are necessary. Intradermal acupuncture (IA) shows promise but requires further investigation regarding its efficacy, safety, and mechanisms. Conducted across 3 centers from November 2022 to January 2024, our randomized controlled trial included 120 participants with moderate to severe MDD, divided into the selective serotonin reuptake inhibitors (SSRIs), SSRIs plus sham IA (SSRIs + SIA), and SSRIs plus active IA (SSRIs + AIA) groups. Acupuncture groups received 10 sessions over 6 weeks at Shenmen (HT7), Neiguan (PC6), Sanyinjiao (SP6) and Taichong (LR3) bilaterally, followed by a 4-week follow-up. The primary outcome was changes in Hamilton Depression Rating Scale-17 (HAMD-17) scores at week 6. Furthermore, healthy controls (HCs) and MDD patients underwent magnetic resonance imaging (MRI) scans for functional connectivity (FC) analysis. After 6 weeks of treatment, the SSRIs + AIA group showed a greater reduction in HAMD-17 score than the SSRIs + SIA group (MD, -4.9 [CI, -7.6 to -2.2], P < 0.001) and SSRIs group (MD, -5.1 [CI, -7.8 to -2.3], P < 0.001). No serious adverse events occurred. SSRIs + AIA resulted in lower incidences of palpitations (vs.SSRIs + SIA: OR, 0.1% [CI, 0.0-1.0%]; vs. SSRIs: OR, 0.1% [CI, 0.0-0.7%]; P < 0.05), somnolence (vs.SSRIs + SIA: OR, 0.1% [CI, 0.0-0.9%]; vs.SSRIs: OR, 0.1% [CI, 0.0-0.7%]; P < 0.05), and nausea (vs.SSRIs + SIA: OR, 0.1% [CI, 0.0-1.0%]; vs. SSRIs: OR, 0.1% [CI, 0.0-0.9%]; P < 0.05). MDD patients showed abnormal FCs, and IA enhanced FCs between striatum and frontal_inf_tri, and striatum and cerebellum in the MRI study. Overall, IA as adjunctive therapy provides clinical efficacy and safety for MDD, and it may exert antidepressant effects by modulating striatal FCs.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}