Pub Date : 2025-12-16DOI: 10.1038/s41386-025-02302-0
Nakul Aggarwal, Logan France, Rachel Puralewski, Karen J. Parker, Ned Kalin
The US biomedical research enterprise has led the world in driving medicine forward but now faces unprecedented threats. Systematic efforts to defund and dismantle the academic research infrastructure, compounded by misinformation and questionable public support for science, have already impeded innovation and discouraged students from pursuing careers in research and healthcare, which ultimately will harm patients. This moment calls on us, as scientists and physicians, to effectively communicate the relevance of our research to the public and elected officials and ensure that the value of basic, translational, and clinical scientific inquiry in developing novel treatments for debilitating medical and psychiatric conditions is fully appreciated. In this Perspective, we highlight concrete, actionable steps to robustly engage in science communication, grassroots advocacy, and early education efforts to rejuvenate the vigorous research environment that is essential to the health and well-being of the public.
{"title":"When the science alone is not enough: embracing our responsibility as science communicators","authors":"Nakul Aggarwal, Logan France, Rachel Puralewski, Karen J. Parker, Ned Kalin","doi":"10.1038/s41386-025-02302-0","DOIUrl":"10.1038/s41386-025-02302-0","url":null,"abstract":"The US biomedical research enterprise has led the world in driving medicine forward but now faces unprecedented threats. Systematic efforts to defund and dismantle the academic research infrastructure, compounded by misinformation and questionable public support for science, have already impeded innovation and discouraged students from pursuing careers in research and healthcare, which ultimately will harm patients. This moment calls on us, as scientists and physicians, to effectively communicate the relevance of our research to the public and elected officials and ensure that the value of basic, translational, and clinical scientific inquiry in developing novel treatments for debilitating medical and psychiatric conditions is fully appreciated. In this Perspective, we highlight concrete, actionable steps to robustly engage in science communication, grassroots advocacy, and early education efforts to rejuvenate the vigorous research environment that is essential to the health and well-being of the public.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 3","pages":"548-549"},"PeriodicalIF":6.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770391","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}
Pub Date : 2025-12-15DOI: 10.1038/s41386-025-02291-0
Kamilla W. Miskowiak, Brice Ozenne, Hanne L. Kjærstad, Patrick M. Fisher, Emily E. Beaman, Vibeke H. Dam, Alexander T. Ysbæk-Nielsen, Gitte M. Knudsen, Lars V. Kessing, Julian Macoveanu, Vibe G. Frøkjær, Anjali Sankar
Biased neural and behavioral responses to emotional information, specifically threat-related amygdala and fusiform hyperactivity and negative bias in the recognition of facial expressions, have emerged as potential biomarkers of responses to short-term intervention outcomes in major depressive disorder (MDD) and bipolar disorder (BD). However, investigating the influence of these biomarkers on the risk of longer-term adverse outcomes, over at least a year, may provide valuable insights for developing tailored interventions to improve outcomes in these often recurrent and persistent disorders. Thus, we examined whether threat-related amygdala and fusiform responses, and negative biases in facial expression recognition were associated with a one-year risk of psychiatric hospitalizations. The study participants were 112 individuals diagnosed with either BD (n = 62) or MDD (n = 50), who underwent functional magnetic resonance imaging during an emotion face processing task and behavioral assessments of negative emotional biases. Longitudinal data on psychiatric hospitalizations for up to one-year after the participants’ study inclusion were obtained using the Danish registers. The analyses were conducted using a Cox regression model, adjusting for demographics, and clinical variables such as prior hospitalizations, diagnoses, illness chronicity, baseline symptoms, and medication. The results showed that left amygdala hyperactivity to fearful vs. happy faces (HR = 14.05, 95% CI: 1.17–168.26, p = 0.037), and increased speed in recognizing negative vs. positive facial expressions (HR = 20.75, 95% CI: 4.13–104.11, p = 0.0002), were significantly associated with subsequent psychiatric hospitalizations. Future studies are needed to explore whether targeting negative threat biases, such as through psychotherapeutic interventions, might help reduce overall disease burden, and potentially decrease societal costs associated with hospitalizations in these conditions.
{"title":"Amygdala reactivity to threat, negative facial perception, and risk of future psychiatric hospitalizations: a longitudinal study in major depressive and bipolar disorders","authors":"Kamilla W. Miskowiak, Brice Ozenne, Hanne L. Kjærstad, Patrick M. Fisher, Emily E. Beaman, Vibeke H. Dam, Alexander T. Ysbæk-Nielsen, Gitte M. Knudsen, Lars V. Kessing, Julian Macoveanu, Vibe G. Frøkjær, Anjali Sankar","doi":"10.1038/s41386-025-02291-0","DOIUrl":"10.1038/s41386-025-02291-0","url":null,"abstract":"Biased neural and behavioral responses to emotional information, specifically threat-related amygdala and fusiform hyperactivity and negative bias in the recognition of facial expressions, have emerged as potential biomarkers of responses to short-term intervention outcomes in major depressive disorder (MDD) and bipolar disorder (BD). However, investigating the influence of these biomarkers on the risk of longer-term adverse outcomes, over at least a year, may provide valuable insights for developing tailored interventions to improve outcomes in these often recurrent and persistent disorders. Thus, we examined whether threat-related amygdala and fusiform responses, and negative biases in facial expression recognition were associated with a one-year risk of psychiatric hospitalizations. The study participants were 112 individuals diagnosed with either BD (n = 62) or MDD (n = 50), who underwent functional magnetic resonance imaging during an emotion face processing task and behavioral assessments of negative emotional biases. Longitudinal data on psychiatric hospitalizations for up to one-year after the participants’ study inclusion were obtained using the Danish registers. The analyses were conducted using a Cox regression model, adjusting for demographics, and clinical variables such as prior hospitalizations, diagnoses, illness chronicity, baseline symptoms, and medication. The results showed that left amygdala hyperactivity to fearful vs. happy faces (HR = 14.05, 95% CI: 1.17–168.26, p = 0.037), and increased speed in recognizing negative vs. positive facial expressions (HR = 20.75, 95% CI: 4.13–104.11, p = 0.0002), were significantly associated with subsequent psychiatric hospitalizations. Future studies are needed to explore whether targeting negative threat biases, such as through psychotherapeutic interventions, might help reduce overall disease burden, and potentially decrease societal costs associated with hospitalizations in these conditions.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 3","pages":"604-611"},"PeriodicalIF":6.6,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02291-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764957","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}
Pub Date : 2025-12-09DOI: 10.1038/s41386-025-02293-y
Michael D. Murphy, Keegan S. Krick, Shuo Zhang, Elizabeth A. Heller
Behavioral flexibility allows organisms to modify actions based on new information, such as shifts in reward value or availability, and is promoted by the dorsomedial striatum (DMS). In contrast, behavioral inflexibility provides efficiency and automaticity in familiar contexts, and is promoted by the dorsolateral striatum (DLS). Importantly, chronic elevation of the primary stress hormone, corticosterone (CORT) in rodents or cortisol in humans, impairs behavioral flexibility through dendritic atrophy in the DMS, and promotes inflexible behavioral response strategies through dendritic outgrowth in the DLS. However, understanding of changes in gene expression underlying behavioral inflexibility is lacking. We used a food-motivated operant task in male and female mice to define gene changes that accompany the shift to inflexible behavior with CORT. We discovered that CORT-accelerated loss of behavioral flexibility is accompanied by decreased DMS- and increased DLS-specific synaptic plasticity gene expression, and that distinct genes are either differentially expressed or spliced in the transition to inflexible behavior. Splicing analysis suggests that repressed activity in the DMS during the transition to inflexible behavior may reflect both reduced expression and increased degradation of plasticity-related mRNA transcripts. Finally, given the ability of CORT to influence histone acetylation, we defined CORT-mediated H3K9ac enrichment profiles associated with synaptic plasticity gene regulation stratified by sex and striatal subregion. This study is the first to define CORT-driven epigenetic regulation in the DMS and DLS during the CORT-accelerated transition from flexible to inflexible behavior in male and female mice.
{"title":"Corticosterone accelerates behavioral inflexibility via plasticity-related gene expression in the dorsal striatum","authors":"Michael D. Murphy, Keegan S. Krick, Shuo Zhang, Elizabeth A. Heller","doi":"10.1038/s41386-025-02293-y","DOIUrl":"10.1038/s41386-025-02293-y","url":null,"abstract":"Behavioral flexibility allows organisms to modify actions based on new information, such as shifts in reward value or availability, and is promoted by the dorsomedial striatum (DMS). In contrast, behavioral inflexibility provides efficiency and automaticity in familiar contexts, and is promoted by the dorsolateral striatum (DLS). Importantly, chronic elevation of the primary stress hormone, corticosterone (CORT) in rodents or cortisol in humans, impairs behavioral flexibility through dendritic atrophy in the DMS, and promotes inflexible behavioral response strategies through dendritic outgrowth in the DLS. However, understanding of changes in gene expression underlying behavioral inflexibility is lacking. We used a food-motivated operant task in male and female mice to define gene changes that accompany the shift to inflexible behavior with CORT. We discovered that CORT-accelerated loss of behavioral flexibility is accompanied by decreased DMS- and increased DLS-specific synaptic plasticity gene expression, and that distinct genes are either differentially expressed or spliced in the transition to inflexible behavior. Splicing analysis suggests that repressed activity in the DMS during the transition to inflexible behavior may reflect both reduced expression and increased degradation of plasticity-related mRNA transcripts. Finally, given the ability of CORT to influence histone acetylation, we defined CORT-mediated H3K9ac enrichment profiles associated with synaptic plasticity gene regulation stratified by sex and striatal subregion. This study is the first to define CORT-driven epigenetic regulation in the DMS and DLS during the CORT-accelerated transition from flexible to inflexible behavior in male and female mice.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 3","pages":"588-603"},"PeriodicalIF":6.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02293-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717182","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}
Pub Date : 2025-12-02DOI: 10.1038/s41386-025-02294-x
Arpana Agrawal
{"title":"Getting into the weed—the genetics of cannabis use in modern America","authors":"Arpana Agrawal","doi":"10.1038/s41386-025-02294-x","DOIUrl":"10.1038/s41386-025-02294-x","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 3","pages":"550-551"},"PeriodicalIF":6.6,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663639","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}
Pub Date : 2025-11-26DOI: 10.1038/s41386-025-02288-9
Dongsun Park, Gwangho Lee, Bokyum Kim, Minjoo Seong, Ji-Woon Kim
Ketamine has emerged as a rapid-acting antidepressant that challenges classical monoaminergic frameworks and highlights the importance of synaptic and circuit-level plasticity in mood regulation. This review examines the hippocampus as a key site through which ketamine exerts both rapid and sustained antidepressant effects. We synthesize evidence showing that ketamine enhances hippocampal synaptic plasticity via mechanisms including NMDAR blockade of spontaneous neurotransmission, BDNF–TrkB signaling, MeCP2-dependent transcriptional priming, and adult neurogenesis. Molecular modulators such as Reelin, which influence NMDAR signaling and synaptic function, may also shape the efficacy of ketamine in a subset of individuals. Importantly, these hippocampal effects occur in coordination with broader network interactions, particularly with the medial prefrontal cortex and lateral habenula, allowing for circuit-level integration of antidepressant responses. Notably, ketamine’s therapeutic actions are dissociable from normalization of hypothalamic–pituitary–adrenal (HPA) axis function, underscoring a shift away from neuroendocrine-based models. By integrating molecular, synaptic, and systems-level findings, this review provides a hippocampus-centered framework for understanding ketamine’s antidepressant mechanisms and outlines novel strategies for circuit-informed, fast-acting antidepressant development.
{"title":"The hippocampus as a central hub in ketamine’s antidepressant action: from molecules to circuit rewiring","authors":"Dongsun Park, Gwangho Lee, Bokyum Kim, Minjoo Seong, Ji-Woon Kim","doi":"10.1038/s41386-025-02288-9","DOIUrl":"10.1038/s41386-025-02288-9","url":null,"abstract":"Ketamine has emerged as a rapid-acting antidepressant that challenges classical monoaminergic frameworks and highlights the importance of synaptic and circuit-level plasticity in mood regulation. This review examines the hippocampus as a key site through which ketamine exerts both rapid and sustained antidepressant effects. We synthesize evidence showing that ketamine enhances hippocampal synaptic plasticity via mechanisms including NMDAR blockade of spontaneous neurotransmission, BDNF–TrkB signaling, MeCP2-dependent transcriptional priming, and adult neurogenesis. Molecular modulators such as Reelin, which influence NMDAR signaling and synaptic function, may also shape the efficacy of ketamine in a subset of individuals. Importantly, these hippocampal effects occur in coordination with broader network interactions, particularly with the medial prefrontal cortex and lateral habenula, allowing for circuit-level integration of antidepressant responses. Notably, ketamine’s therapeutic actions are dissociable from normalization of hypothalamic–pituitary–adrenal (HPA) axis function, underscoring a shift away from neuroendocrine-based models. By integrating molecular, synaptic, and systems-level findings, this review provides a hippocampus-centered framework for understanding ketamine’s antidepressant mechanisms and outlines novel strategies for circuit-informed, fast-acting antidepressant development.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 3","pages":"537-547"},"PeriodicalIF":6.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644751","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}
Pub Date : 2025-11-25DOI: 10.1038/s41386-025-02290-1
Jacqueline F. McGinty
{"title":"Orbitofrontal BDNF puts the brakes on alcohol intake and relapse","authors":"Jacqueline F. McGinty","doi":"10.1038/s41386-025-02290-1","DOIUrl":"10.1038/s41386-025-02290-1","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 3","pages":"552-553"},"PeriodicalIF":6.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145608557","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}
Pub Date : 2025-11-21DOI: 10.1038/s41386-025-02285-y
Amna Asim, Yuan Yang, PsyCourse Study, Urs Heilbronner, Thomas Schulze, Todd Lencz, Evangelos Vassos, Sean A. P. Clouston, Roman Kotov, Katherine Jonas
Polygenic risk scores (PRS) have potential utility as biomarkers of psychiatric disorders. However, the potential utility of some PRS has been much clearer than others. The schizophrenia PRS has been consistently associated with diagnosis, symptom severity, and other correlates of schizophrenia. Yet despite the close genetic correlation (rg = 0.69) between bipolar disorder and schizophrenia, the bipolar (BP) PRS has been inconstantly associated with clinical course and outcomes. We hypothesize that common sample selection strategies induce collider bias between the SZ and BP PRS, in turn moderating the association between the BP PRS and clinical outcomes. Collider bias is illustrated in three effects. First, it is shown that clinical characteristics used in sample ascertainment (i.e. case status, treatment history) are a function of the SZ and BP PRSs. Second, selecting on these clinical characteristics biases the correlation between the BP and SZ PRSs. Third, selection on these clinical characteristics in turn moderates the association between the BP PRS and clinical outcomes. Effects were tested in three samples: UK Biobank (N = 337,420), a population-based sample; PsyCourse (N = 1,594), a case-control cohort of individuals with mood and psychotic disorders; and the Suffolk County Mental Health Cohort (N = 378), a first-admission psychosis cohort. In all three samples, SZ and BP PRSs were significantly correlated with case status or treatment history. In addition, correlations between SZ and BP PRS were biased in samples selected by case status or treatment history. Finally, conditioning analyses on case status moderated, and in some cases reversed, associations between the BP PRS and clinical outcomes. It is important to understand the impact of this and other forms of selection bias in evaluating PRS as biomarkers of psychiatric disorders, particularly when the intended application is populations enriched for high genetic risk.
{"title":"The impact of collider bias on genetic prediction in psychotic disorders","authors":"Amna Asim, Yuan Yang, PsyCourse Study, Urs Heilbronner, Thomas Schulze, Todd Lencz, Evangelos Vassos, Sean A. P. Clouston, Roman Kotov, Katherine Jonas","doi":"10.1038/s41386-025-02285-y","DOIUrl":"10.1038/s41386-025-02285-y","url":null,"abstract":"Polygenic risk scores (PRS) have potential utility as biomarkers of psychiatric disorders. However, the potential utility of some PRS has been much clearer than others. The schizophrenia PRS has been consistently associated with diagnosis, symptom severity, and other correlates of schizophrenia. Yet despite the close genetic correlation (rg = 0.69) between bipolar disorder and schizophrenia, the bipolar (BP) PRS has been inconstantly associated with clinical course and outcomes. We hypothesize that common sample selection strategies induce collider bias between the SZ and BP PRS, in turn moderating the association between the BP PRS and clinical outcomes. Collider bias is illustrated in three effects. First, it is shown that clinical characteristics used in sample ascertainment (i.e. case status, treatment history) are a function of the SZ and BP PRSs. Second, selecting on these clinical characteristics biases the correlation between the BP and SZ PRSs. Third, selection on these clinical characteristics in turn moderates the association between the BP PRS and clinical outcomes. Effects were tested in three samples: UK Biobank (N = 337,420), a population-based sample; PsyCourse (N = 1,594), a case-control cohort of individuals with mood and psychotic disorders; and the Suffolk County Mental Health Cohort (N = 378), a first-admission psychosis cohort. In all three samples, SZ and BP PRSs were significantly correlated with case status or treatment history. In addition, correlations between SZ and BP PRS were biased in samples selected by case status or treatment history. Finally, conditioning analyses on case status moderated, and in some cases reversed, associations between the BP PRS and clinical outcomes. It is important to understand the impact of this and other forms of selection bias in evaluating PRS as biomarkers of psychiatric disorders, particularly when the intended application is populations enriched for high genetic risk.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 2","pages":"430-439"},"PeriodicalIF":6.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566679","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}
Pub Date : 2025-11-18DOI: 10.1038/s41386-025-02271-4
Jennifer D. Ellis, Eleanor Blair Towers, Kelly E. Dunn, Siny Tsang, Traci Speed, Sheera F. Lerman, Michelle Mei, Wendy Lynch, Eric C. Strain, Michael T. Smith, Patrick H. Finan
A subset of individuals without a history of prolonged or problematic opioid use demonstrate attenuated subjective responses to orally administered opioids despite physiological and analgesic responses. This phenotype may confer elevated risk for greater analgesic requests and physiologic dependence, but it is unclear if this is driven by differences in route of administration. This study evaluated responses to cumulative dosing of parenteral hydromorphone, versus placebo, in persons without a history of significant opioid use to further identify and characterize this subgroup. Individuals without opioid use disorder (N = 82) were exposed to a cumulative hydromorphone dosing procedure, during which they completed measures of subjective effects and were assessed for physiological opioid responses. Linear mixed effects regressions were used to examine changes in subjective and physiological measures as a function of responder phenotype, drug condition, and time. Approximately 31.7% of the sample were classified as Opioid Non-Responders. These individuals had attenuated changes in subjective responses to hydromorphone relative to other participants, despite equivalent physiological responses. Race and sex did not predict Opioid Responder status. These findings confirm the presence of a “Opioid Non-Responder” phenotype for the first time in the context of a cumulative, parenteral dosing paradigm. Further research is warranted to elucidate the clinical implications and potential risk or protective factors underlying this phenotype.
{"title":"Reliable variability in subjective responses to parenteral hydromorphone administration: empirical confirmation of an opioid non-responder phenotype","authors":"Jennifer D. Ellis, Eleanor Blair Towers, Kelly E. Dunn, Siny Tsang, Traci Speed, Sheera F. Lerman, Michelle Mei, Wendy Lynch, Eric C. Strain, Michael T. Smith, Patrick H. Finan","doi":"10.1038/s41386-025-02271-4","DOIUrl":"10.1038/s41386-025-02271-4","url":null,"abstract":"A subset of individuals without a history of prolonged or problematic opioid use demonstrate attenuated subjective responses to orally administered opioids despite physiological and analgesic responses. This phenotype may confer elevated risk for greater analgesic requests and physiologic dependence, but it is unclear if this is driven by differences in route of administration. This study evaluated responses to cumulative dosing of parenteral hydromorphone, versus placebo, in persons without a history of significant opioid use to further identify and characterize this subgroup. Individuals without opioid use disorder (N = 82) were exposed to a cumulative hydromorphone dosing procedure, during which they completed measures of subjective effects and were assessed for physiological opioid responses. Linear mixed effects regressions were used to examine changes in subjective and physiological measures as a function of responder phenotype, drug condition, and time. Approximately 31.7% of the sample were classified as Opioid Non-Responders. These individuals had attenuated changes in subjective responses to hydromorphone relative to other participants, despite equivalent physiological responses. Race and sex did not predict Opioid Responder status. These findings confirm the presence of a “Opioid Non-Responder” phenotype for the first time in the context of a cumulative, parenteral dosing paradigm. Further research is warranted to elucidate the clinical implications and potential risk or protective factors underlying this phenotype.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 2","pages":"455-463"},"PeriodicalIF":6.6,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02271-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553045","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}
Pub Date : 2025-11-15DOI: 10.1038/s41386-025-02277-y
Mark S. George, Harold A. Sackeim
{"title":"IN MEMORIAM: Nolan R. Williams, MD","authors":"Mark S. George, Harold A. Sackeim","doi":"10.1038/s41386-025-02277-y","DOIUrl":"10.1038/s41386-025-02277-y","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 2","pages":"534-535"},"PeriodicalIF":6.6,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02277-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531067","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}
Pub Date : 2025-11-13DOI: 10.1038/s41386-025-02249-2
Jeremy J. Watts, Xavier Navarri, Patricia J. Conrod
There is an accumulation of evidence linking adolescent cannabis use with variations in brain structure and function, however it remains poorly understood whether cannabis-associated variations in brain structure represent pre-existing risk factors or consequences of cannabis use. We investigated whether cannabis use propensity and within-person variations of cannabis use were associated with cortical thickness during adolescence. Adolescents (n = 136, 74 female) completed three neuroimaging sessions and annual assessments from 12 until 17 years of age (with 90% follow-up). Cannabis use was disaggregated into between- (vulnerability) and within-person (time-varying) components using longitudinal multi-level modelling, controlling for age, sex and alcohol use. Across the whole sample, cortical thickness was lower in years when participants’ cannabis use exceeded their own average level of cannabis use (F1,25663.3 = 3.96, p = 0.047; mean: −0.0023 mm/once-per-week increase). This effect was stronger in males (F1,11447.7 = 9.83, p = 0.0017), such that each once-per-week increase in cannabis use was associated with a 0.005 mm reduction in cortical thickness, comparable to 17.9% of the annual rate of cortical thinning (−0.028 mm/year). The strongest within-person effects of cannabis were observed in regions with the greatest expression of CNR1, the gene that codes for the CB1 receptor (sample: rho = −0.33, pspin = .025; males: rho = −0.5, pspin = .005). At the between-person level, males (but not females) also exhibited a stable cortical thickness signature associated with propensity towards cannabis use and this signature was present before cannabis exposure. These results highlight the importance of longitudinal analyses using multi-level modelling to disaggregate potential risk factors from potential consequences of substance use.
{"title":"Independent brain cortical signatures of risk for adolescent cannabis use and consequences of such use are moderated by sex","authors":"Jeremy J. Watts, Xavier Navarri, Patricia J. Conrod","doi":"10.1038/s41386-025-02249-2","DOIUrl":"10.1038/s41386-025-02249-2","url":null,"abstract":"There is an accumulation of evidence linking adolescent cannabis use with variations in brain structure and function, however it remains poorly understood whether cannabis-associated variations in brain structure represent pre-existing risk factors or consequences of cannabis use. We investigated whether cannabis use propensity and within-person variations of cannabis use were associated with cortical thickness during adolescence. Adolescents (n = 136, 74 female) completed three neuroimaging sessions and annual assessments from 12 until 17 years of age (with 90% follow-up). Cannabis use was disaggregated into between- (vulnerability) and within-person (time-varying) components using longitudinal multi-level modelling, controlling for age, sex and alcohol use. Across the whole sample, cortical thickness was lower in years when participants’ cannabis use exceeded their own average level of cannabis use (F1,25663.3 = 3.96, p = 0.047; mean: −0.0023 mm/once-per-week increase). This effect was stronger in males (F1,11447.7 = 9.83, p = 0.0017), such that each once-per-week increase in cannabis use was associated with a 0.005 mm reduction in cortical thickness, comparable to 17.9% of the annual rate of cortical thinning (−0.028 mm/year). The strongest within-person effects of cannabis were observed in regions with the greatest expression of CNR1, the gene that codes for the CB1 receptor (sample: rho = −0.33, pspin = .025; males: rho = −0.5, pspin = .005). At the between-person level, males (but not females) also exhibited a stable cortical thickness signature associated with propensity towards cannabis use and this signature was present before cannabis exposure. These results highlight the importance of longitudinal analyses using multi-level modelling to disaggregate potential risk factors from potential consequences of substance use.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 2","pages":"497-505"},"PeriodicalIF":6.6,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02249-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515535","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}
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