Chieh-Hsin Lin, Tin-May Li, Yu-Jhen Huang, Shaw-Ji Chen, Hsien-Yuan Lane
Background: Impaired antioxidant defense is implicated in the pathophysiology of schizophrenia, and superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) are 3 first-line endogenous antioxidants. Various cognitive functions decline differently during the schizophrenia course. The characteristic roles of the 3 antioxidants in clinical and cognitive profiles in acute and chronic phases of schizophrenia require study.
Methods: We recruited 311 patients with schizophrenia, including 92 acutely exacerbated patients who had been off antipsychotics for at least 2 weeks and 219 chronic patients who had been stable on medication for at least 2 months. Blood SOD, CAT, and GSH levels; clinical symptoms; and 9 cognitive test scores were measured.
Results: Blood CAT levels were higher in the acute patients than in the chronic patients, whereas SOD and GSH levels were similar to one another. Higher CAT levels were correlated with less positive symptoms, better working memory and problem solving in the acute phase, and less negative symptoms, less general psychopathology, better global assessment of function, and better cognitive function (in speed of processing, attention, problem solving) in the chronic period. Higher SOD levels were correlated with better global assessment of function in the acute phase and better speed of processing, working memory, and verbal learning and memory in the chronic period. GSH influenced neither clinical nor cognitive manifestations.
Conclusions: This study showed that blood CAT affected different clinical and cognitive domains between acute and chronic stages of schizophrenia, SOD influenced cognitive functions in chronic state, but GSH affected none. Further studies are needed to explore the underlying mechanisms.
{"title":"Differential Impacts of Endogenous Antioxidants on Clinical Symptoms and Cognitive Function in Acute and Chronic Schizophrenia Patients.","authors":"Chieh-Hsin Lin, Tin-May Li, Yu-Jhen Huang, Shaw-Ji Chen, Hsien-Yuan Lane","doi":"10.1093/ijnp/pyad040","DOIUrl":"https://doi.org/10.1093/ijnp/pyad040","url":null,"abstract":"<p><strong>Background: </strong>Impaired antioxidant defense is implicated in the pathophysiology of schizophrenia, and superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) are 3 first-line endogenous antioxidants. Various cognitive functions decline differently during the schizophrenia course. The characteristic roles of the 3 antioxidants in clinical and cognitive profiles in acute and chronic phases of schizophrenia require study.</p><p><strong>Methods: </strong>We recruited 311 patients with schizophrenia, including 92 acutely exacerbated patients who had been off antipsychotics for at least 2 weeks and 219 chronic patients who had been stable on medication for at least 2 months. Blood SOD, CAT, and GSH levels; clinical symptoms; and 9 cognitive test scores were measured.</p><p><strong>Results: </strong>Blood CAT levels were higher in the acute patients than in the chronic patients, whereas SOD and GSH levels were similar to one another. Higher CAT levels were correlated with less positive symptoms, better working memory and problem solving in the acute phase, and less negative symptoms, less general psychopathology, better global assessment of function, and better cognitive function (in speed of processing, attention, problem solving) in the chronic period. Higher SOD levels were correlated with better global assessment of function in the acute phase and better speed of processing, working memory, and verbal learning and memory in the chronic period. GSH influenced neither clinical nor cognitive manifestations.</p><p><strong>Conclusions: </strong>This study showed that blood CAT affected different clinical and cognitive domains between acute and chronic stages of schizophrenia, SOD influenced cognitive functions in chronic state, but GSH affected none. Further studies are needed to explore the underlying mechanisms.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/26/c9/pyad040.PMC10464923.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10157586","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}
Berta Escudero, Marta Moya, Leticia López-Valencia, Francisco Arias, Laura Orio
Background: Apolipoprotein E (APOE)-4 isoform, reelin, and clusterin share very-low-density liporeceptor and apolipoprotein E receptor 2 receptors and are related to cognition in neuropsychiatric disorders. These proteins are expressed in plasma and brain, but studies involving plasma expression and cognition are scarce.
Methods: We studied the peripheral expression (plasma and peripheral blood mononuclear cells) of these proteins in 24 middle-aged patients with alcohol use disorder (AUD) diagnosed at 4 to 12 weeks of abstinence (t = 0) and 34 controls. Cognition was assessed using the Test of Detection of Cognitive Impairment in Alcoholism. In a follow-up study (t = 1), we measured reelin levels and evaluated cognitive improvement at 6 months of abstinence.
Results: APOE4 isoform was present in 37.5% and 58.8% of patients and controls, respectively, reaching similar plasma levels in ε4 carriers regardless of whether they were patients with AUD or controls. Plasma reelin and clusterin were higher in the AUD group, and reelin levels peaked in patients expressing APOE4 (P < .05, η2 = 0.09), who showed reduced very-low-density liporeceptor and apolipoprotein E receptor 2 expression in peripheral blood mononuclear cells. APOE4 had a negative effect on memory/learning mainly in the AUD group (P < .01, η2 = 0.15). Multivariate logistic regression analyses identified plasma reelin as a good indicator of AUD cognitive impairment at t = 0. At t = 1, patients with AUD showed lower reelin levels vs controls along with some cognitive improvement.
Conclusions: Reelin plasma levels are elevated during early abstinence in patients with AUD who express the APOE4 isoform, identifying cognitive deterioration to a great extent, and it may participate as a homeostatic signal for cognitive recovery in the long term.
{"title":"Reelin Plasma Levels Identify Cognitive Decline in Alcohol Use Disorder Patients During Early Abstinence: The Influence of APOE4 Expression.","authors":"Berta Escudero, Marta Moya, Leticia López-Valencia, Francisco Arias, Laura Orio","doi":"10.1093/ijnp/pyad034","DOIUrl":"https://doi.org/10.1093/ijnp/pyad034","url":null,"abstract":"<p><strong>Background: </strong>Apolipoprotein E (APOE)-4 isoform, reelin, and clusterin share very-low-density liporeceptor and apolipoprotein E receptor 2 receptors and are related to cognition in neuropsychiatric disorders. These proteins are expressed in plasma and brain, but studies involving plasma expression and cognition are scarce.</p><p><strong>Methods: </strong>We studied the peripheral expression (plasma and peripheral blood mononuclear cells) of these proteins in 24 middle-aged patients with alcohol use disorder (AUD) diagnosed at 4 to 12 weeks of abstinence (t = 0) and 34 controls. Cognition was assessed using the Test of Detection of Cognitive Impairment in Alcoholism. In a follow-up study (t = 1), we measured reelin levels and evaluated cognitive improvement at 6 months of abstinence.</p><p><strong>Results: </strong>APOE4 isoform was present in 37.5% and 58.8% of patients and controls, respectively, reaching similar plasma levels in ε4 carriers regardless of whether they were patients with AUD or controls. Plasma reelin and clusterin were higher in the AUD group, and reelin levels peaked in patients expressing APOE4 (P < .05, η2 = 0.09), who showed reduced very-low-density liporeceptor and apolipoprotein E receptor 2 expression in peripheral blood mononuclear cells. APOE4 had a negative effect on memory/learning mainly in the AUD group (P < .01, η2 = 0.15). Multivariate logistic regression analyses identified plasma reelin as a good indicator of AUD cognitive impairment at t = 0. At t = 1, patients with AUD showed lower reelin levels vs controls along with some cognitive improvement.</p><p><strong>Conclusions: </strong>Reelin plasma levels are elevated during early abstinence in patients with AUD who express the APOE4 isoform, identifying cognitive deterioration to a great extent, and it may participate as a homeostatic signal for cognitive recovery in the long term.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/68/50/pyad034.PMC10464928.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10228292","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}
Background: Central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission has been implicated in the etiology of depression. Most antidepressants ameliorate depressive symptoms by increasing 5-HT at synaptic clefts, but their effect on 5-HT receptors has yet to be clarified. 11C-WAY-100635 and 18F-MPPF are positron emission tomography (PET) radioligands for 5-HT1A receptors. While binding of both ligands reflects 5-HT1A receptor density, 18F-MPPF biding may also be affected by extracellular 5-HT concentrations. This dual-tracer PET study explored the neurochemical substrates underlying antidepressant effects in patients with depression.
Methods: Eleven patients with depression, including 9 treated with antidepressants, and 16 age- and sex-matched healthy individuals underwent PET scans with 11C-WAY-100635 and 18F-MPPF. Radioligand binding was determined by calculating the nondisplaceable binding potential (BPND).
Results: Patients treated with antidepressants showed significantly lower 18F-MPPF BPND in neocortical regions and raphe nuclei, but not in limbic regions, than controls. No significant group differences in 11C-WAY-100635 BPND were found in any of the regions. Significant correlations of BPND between 11C-WAY-100635 and 18F-MPPF were observed in limbic regions and raphe nuclei of healthy controls, but no such associations were found in antidepressant-treated patients. Moreover, 18F-MPPF BPND in limbic regions was significantly correlated with the severity of depressive symptoms.
Conclusions: These results suggest a diversity of antidepressant-induced extracellular 5-HT elevations in the limbic system among depressive patients, which is associated with the individual variability of clinical symptoms following the treatment.
{"title":"Serotonergic Neurotransmission in Limbic Regions May Reflect Therapeutic Response of Depressive Patients: A PET Study With 11C-WAY-100635 and 18F-MPPF.","authors":"Soichiro Kitamura, Yasuyuki Kimura, Keisuke Takahata, Sho Moriguchi, Manabu Kubota, Hitoshi Shimada, Hironobu Endo, Yuhei Takado, Kazunori Kawamura, Ming-Rong Zhang, Tetsuya Suhara, Makoto Higuchi","doi":"10.1093/ijnp/pyad026","DOIUrl":"https://doi.org/10.1093/ijnp/pyad026","url":null,"abstract":"<p><strong>Background: </strong>Central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission has been implicated in the etiology of depression. Most antidepressants ameliorate depressive symptoms by increasing 5-HT at synaptic clefts, but their effect on 5-HT receptors has yet to be clarified. 11C-WAY-100635 and 18F-MPPF are positron emission tomography (PET) radioligands for 5-HT1A receptors. While binding of both ligands reflects 5-HT1A receptor density, 18F-MPPF biding may also be affected by extracellular 5-HT concentrations. This dual-tracer PET study explored the neurochemical substrates underlying antidepressant effects in patients with depression.</p><p><strong>Methods: </strong>Eleven patients with depression, including 9 treated with antidepressants, and 16 age- and sex-matched healthy individuals underwent PET scans with 11C-WAY-100635 and 18F-MPPF. Radioligand binding was determined by calculating the nondisplaceable binding potential (BPND).</p><p><strong>Results: </strong>Patients treated with antidepressants showed significantly lower 18F-MPPF BPND in neocortical regions and raphe nuclei, but not in limbic regions, than controls. No significant group differences in 11C-WAY-100635 BPND were found in any of the regions. Significant correlations of BPND between 11C-WAY-100635 and 18F-MPPF were observed in limbic regions and raphe nuclei of healthy controls, but no such associations were found in antidepressant-treated patients. Moreover, 18F-MPPF BPND in limbic regions was significantly correlated with the severity of depressive symptoms.</p><p><strong>Conclusions: </strong>These results suggest a diversity of antidepressant-induced extracellular 5-HT elevations in the limbic system among depressive patients, which is associated with the individual variability of clinical symptoms following the treatment.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10388381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10300241","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}
Haili Li, Ze Zhang, Huixin Li, Xinyu Pan, Yue Wang
The transcription factor p53, a widely accepted tumor suppressor, regulates the expression of many oncogenes and their downstream signaling pathways, resulting in a series of biological outcomes. Mutations and deletions of the p53 gene often occur in tumor tissues and are involved in their development. In addition to its role in tumors, p53 has a widespread expression in the brain and participates in most cell processes, such as dendrite formation, oxidative stress, apoptosis, autophagy, DNA repair, and cell cycle arrest. Therefore, abnormalities in p53 and its related signaling pathways play an important role in the diagnosis and treatment of central nervous system diseases. This review mainly discusses the latest findings regarding the role of p53 in some central nervous system diseases, such as brain tumors, Alzheimer disease, Parkinson disease, autism, epilepsy, spinocerebellar ataxia, and so on, to provide a comprehensive interpretation of the treatment of neurological diseases from a new perspective.
{"title":"New Insights into the Roles of p53 in Central Nervous System Diseases.","authors":"Haili Li, Ze Zhang, Huixin Li, Xinyu Pan, Yue Wang","doi":"10.1093/ijnp/pyad030","DOIUrl":"https://doi.org/10.1093/ijnp/pyad030","url":null,"abstract":"<p><p>The transcription factor p53, a widely accepted tumor suppressor, regulates the expression of many oncogenes and their downstream signaling pathways, resulting in a series of biological outcomes. Mutations and deletions of the p53 gene often occur in tumor tissues and are involved in their development. In addition to its role in tumors, p53 has a widespread expression in the brain and participates in most cell processes, such as dendrite formation, oxidative stress, apoptosis, autophagy, DNA repair, and cell cycle arrest. Therefore, abnormalities in p53 and its related signaling pathways play an important role in the diagnosis and treatment of central nervous system diseases. This review mainly discusses the latest findings regarding the role of p53 in some central nervous system diseases, such as brain tumors, Alzheimer disease, Parkinson disease, autism, epilepsy, spinocerebellar ataxia, and so on, to provide a comprehensive interpretation of the treatment of neurological diseases from a new perspective.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10388388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9914618","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}
Ann M Iturra-Mena, Brian D Kangas, Diego A Pizzagalli
Using in vivo electrophysiology and a reward-learning task reverse-translated from humans, this study tested the hypothesis that a nociceptin (NOP) receptor antagonist (J-113397) would potentiate behavioral and electrophysiological markers of reward learning in rats. Relative to vehicle, the NOP antagonist modulated electrophysiological markers of reward processing but did not affect response bias toward a more frequently rewarded stimulus. This proof-of-concept study provides initial insights into the effects of NOP receptor antagonism on reward learning, which are consistent with previous findings suggesting that such mechanism is a promising antidepressant target.
{"title":"Nociceptin Receptor Antagonism Modulates Electrophysiological Markers of Reward Learning.","authors":"Ann M Iturra-Mena, Brian D Kangas, Diego A Pizzagalli","doi":"10.1093/ijnp/pyad031","DOIUrl":"https://doi.org/10.1093/ijnp/pyad031","url":null,"abstract":"Using in vivo electrophysiology and a reward-learning task reverse-translated from humans, this study tested the hypothesis that a nociceptin (NOP) receptor antagonist (J-113397) would potentiate behavioral and electrophysiological markers of reward learning in rats. Relative to vehicle, the NOP antagonist modulated electrophysiological markers of reward processing but did not affect response bias toward a more frequently rewarded stimulus. This proof-of-concept study provides initial insights into the effects of NOP receptor antagonism on reward learning, which are consistent with previous findings suggesting that such mechanism is a promising antidepressant target.","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10388382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9914619","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}
Christoph U Correll, Mikkel Højlund, Christine Graham, Mark S Todtenkopf, David McDonnell, Adam Simmons
Background: Patients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population.
Methods: PubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5.
Results: Of 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42-8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies >13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05-12.65) vs 5.51 (4.73-6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and >13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration.
Conclusions: In RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting >13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered.
{"title":"Weight Gain and Metabolic Changes in Patients With First-Episode Psychosis or Early-Phase Schizophrenia Treated With Olanzapine: A Meta-Analysis.","authors":"Christoph U Correll, Mikkel Højlund, Christine Graham, Mark S Todtenkopf, David McDonnell, Adam Simmons","doi":"10.1093/ijnp/pyad029","DOIUrl":"https://doi.org/10.1093/ijnp/pyad029","url":null,"abstract":"<p><strong>Background: </strong>Patients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population.</p><p><strong>Methods: </strong>PubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5.</p><p><strong>Results: </strong>Of 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42-8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies >13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05-12.65) vs 5.51 (4.73-6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and >13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration.</p><p><strong>Conclusions: </strong>In RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting >13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10388390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9940762","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}
Background: BTRX-246040, a nociceptin/orphanin FQ peptide receptor antagonist, is being developed for the treatment of depressive patients. However, the underlying mechanism of this potential antidepressant is still largely unclear. Here, we studied the antidepressant-related actions of BTRX-246040 in the ventrolateral periaqueductal gray (vlPAG).
Methods: The tail suspension test, forced swim test, female urine sniffing test, sucrose preference test, and learned helplessness (LH) combined with pharmacological approaches were employed to examine the antidepressant-like effects and drug effects on LH-induced depressive-like behavior in C57BL/6J mice. Electrophysiological recordings in vlPAG neurons were used to study synaptic activity.
Results: Intraperitoneal administration of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Systemic BTRX-246040 (10 mg/kg) resulted in an increased frequency and amplitude of miniature excitatory postsynaptic currents (EPSCs) in the vlPAG. Moreover, slice perfusion of BTRX-246040 directly elevated the frequency and amplitude of miniature EPSCs and enhanced the evoked EPSCs in the vlPAG, which were blocked by pretreatment with the nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198. In addition, intra-vlPAG application of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Moreover, intra-vlPAG pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione reversed both systemic and local BTRX-246040-mediated antidepressant-like behavioral effects. Furthermore, both systemic and local BTRX-246040 decreased the LH phenotype and reduced LH-induced depressive-like behavior.
Conclusions: The results suggested that BTRX-246040 may act through the vlPAG to exert antidepressant-relevant actions. The present study provides new insight into a vlPAG-dependent mechanism underlying the antidepressant-like actions of BTRX-246040.
{"title":"BTRX-246040 Acts Through the Ventrolateral Periaqueductal Gray to Exert Antidepressant-Relevant Actions in Mice.","authors":"Zhenlong Li, Yuanyuan Xu, Rourou Li, Zhenyu Sheng, Xinya Chen, Xueman Liu, Chau-Shoun Lee, Hsien-Yu Peng, Tzer-Bin Lin, Ming-Chun Hsieh, Cheng-Yuan Lai, Han-Fang Wu, Dylan Chou","doi":"10.1093/ijnp/pyad027","DOIUrl":"https://doi.org/10.1093/ijnp/pyad027","url":null,"abstract":"<p><strong>Background: </strong>BTRX-246040, a nociceptin/orphanin FQ peptide receptor antagonist, is being developed for the treatment of depressive patients. However, the underlying mechanism of this potential antidepressant is still largely unclear. Here, we studied the antidepressant-related actions of BTRX-246040 in the ventrolateral periaqueductal gray (vlPAG).</p><p><strong>Methods: </strong>The tail suspension test, forced swim test, female urine sniffing test, sucrose preference test, and learned helplessness (LH) combined with pharmacological approaches were employed to examine the antidepressant-like effects and drug effects on LH-induced depressive-like behavior in C57BL/6J mice. Electrophysiological recordings in vlPAG neurons were used to study synaptic activity.</p><p><strong>Results: </strong>Intraperitoneal administration of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Systemic BTRX-246040 (10 mg/kg) resulted in an increased frequency and amplitude of miniature excitatory postsynaptic currents (EPSCs) in the vlPAG. Moreover, slice perfusion of BTRX-246040 directly elevated the frequency and amplitude of miniature EPSCs and enhanced the evoked EPSCs in the vlPAG, which were blocked by pretreatment with the nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198. In addition, intra-vlPAG application of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Moreover, intra-vlPAG pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione reversed both systemic and local BTRX-246040-mediated antidepressant-like behavioral effects. Furthermore, both systemic and local BTRX-246040 decreased the LH phenotype and reduced LH-induced depressive-like behavior.</p><p><strong>Conclusions: </strong>The results suggested that BTRX-246040 may act through the vlPAG to exert antidepressant-relevant actions. The present study provides new insight into a vlPAG-dependent mechanism underlying the antidepressant-like actions of BTRX-246040.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fc/4f/pyad027.PMC10388391.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10300244","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}
Mark D Underwood, Hanga Galfalvy, Shu-Chi Hsiung, Yan Liu, Norman R Simpson, Mihran J Bakalian, Gorazd B Rosoklija, Andrew J Dwork, Victoria Arango, J John Mann
Background: The hypothalamic-pituitary-adrenal (HPA) axis is a major stress response system, and excessive HPA responses can impact major depressive disorder and suicide. We examined relationships between reported early-life adversity (ELA), recent-life stress (RLS), suicide, and corticotropin-releasing hormone (CRH), CRH binding protein, FK506-binding protein (FKBP5), glucocorticoid receptor (GR), and brain-derived neurotrophic factor (BDNF) in postmortem human prefrontal cortex (BA9), and anterior cingulate cortex (BA24).
Methods: Thirteen quadruplets, matched for sex, age, and postmortem interval and consisting of suicide decedents and healthy controls, were divided equally into those with and without ELA. ELA, RLS, and psychiatric diagnoses were determined by psychological autopsy. Protein levels were determined by western blots.
Results: There were no suicide- or ELA-related differences in CRH, CRH binding protein, GR, or FKBP5 in BA9 or BA24 and no interaction between suicide and ELA (P > .05). For BDNF, there was an interaction between suicide and ELA in BA24; suicides without ELA had less BDNF than controls without ELA, and controls with ELA had less BDNF than controls without ELA. CRH in BA9 and FKBP5 in anterior cingulate cortex correlated negatively with RLS. Least Absolute Shrinkage and Selection Operator logistic regression with cross-validation found combining BDNF, GR, and FKBP5 BA24 levels predicted suicide, but ELA did not contribute. A calculated "suicide risk score" using these measures had 71% sensitivity and 71% specificity.
Conclusion: A dysregulated HPA axis is related to suicide but not with ELA. RLS was related to select HPA axis proteins in specific brain regions. BDNF appears to be dysregulated in a region-specific way with ELA and suicide.
{"title":"A Stress Protein-Based Suicide Prediction Score and Relationship to Reported Early-Life Adversity and Recent Life Stress.","authors":"Mark D Underwood, Hanga Galfalvy, Shu-Chi Hsiung, Yan Liu, Norman R Simpson, Mihran J Bakalian, Gorazd B Rosoklija, Andrew J Dwork, Victoria Arango, J John Mann","doi":"10.1093/ijnp/pyad025","DOIUrl":"https://doi.org/10.1093/ijnp/pyad025","url":null,"abstract":"<p><strong>Background: </strong>The hypothalamic-pituitary-adrenal (HPA) axis is a major stress response system, and excessive HPA responses can impact major depressive disorder and suicide. We examined relationships between reported early-life adversity (ELA), recent-life stress (RLS), suicide, and corticotropin-releasing hormone (CRH), CRH binding protein, FK506-binding protein (FKBP5), glucocorticoid receptor (GR), and brain-derived neurotrophic factor (BDNF) in postmortem human prefrontal cortex (BA9), and anterior cingulate cortex (BA24).</p><p><strong>Methods: </strong>Thirteen quadruplets, matched for sex, age, and postmortem interval and consisting of suicide decedents and healthy controls, were divided equally into those with and without ELA. ELA, RLS, and psychiatric diagnoses were determined by psychological autopsy. Protein levels were determined by western blots.</p><p><strong>Results: </strong>There were no suicide- or ELA-related differences in CRH, CRH binding protein, GR, or FKBP5 in BA9 or BA24 and no interaction between suicide and ELA (P > .05). For BDNF, there was an interaction between suicide and ELA in BA24; suicides without ELA had less BDNF than controls without ELA, and controls with ELA had less BDNF than controls without ELA. CRH in BA9 and FKBP5 in anterior cingulate cortex correlated negatively with RLS. Least Absolute Shrinkage and Selection Operator logistic regression with cross-validation found combining BDNF, GR, and FKBP5 BA24 levels predicted suicide, but ELA did not contribute. A calculated \"suicide risk score\" using these measures had 71% sensitivity and 71% specificity.</p><p><strong>Conclusion: </strong>A dysregulated HPA axis is related to suicide but not with ELA. RLS was related to select HPA axis proteins in specific brain regions. BDNF appears to be dysregulated in a region-specific way with ELA and suicide.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/39/47/pyad025.PMC10388383.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9934612","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}
Ariadna Requana Aradas, Youssra Djaboub, Isabelle McCort-Tranchepain, Zuzana Hajasova, Loïc Clémenceau, Corinne Canestrelli, Anika Mann, Stefan Schulz, Angélique Delaval, Francine Acher, Dominique Massotte, Florence Noble, Nicolas Marie
Background: Evidence has accumulated demonstrating the existence of opioid receptor heteromers, and recent data suggest that targeting these heteromers could reduce opioid side effects while retaining therapeutic effects. Indeed, CYM51010 characterized as a MOR (mu opioid receptor)/DOR (delta opioid receptor) heteromer-preferring agonist promoted antinociception comparable with morphine but with less tolerance. In the perspective of developing these new classes of pharmacological agents, data on their putative side effects are mandatory.
Methods: Therefore, in this study, we investigated the effects of CYM51010 in different models related to drug addiction in mice, including behavioral sensitization, conditioned place preference and withdrawal.
Results: We found that, like morphine, CYM51010 promoted acute locomotor activity as well as psychomotor sensitization and rewarding effect. However, it induced less physical dependence than morphine. We also investigated the ability of CYM51010 to modulate some morphine-induced behavior. Whereas CYM51010 was unable to block morphine-induced physical dependence, it blocked reinstatement of an extinguished morphine induced-conditioned place preference.
Conclusions: Altogether, our results reveal that targeting MOR-DOR heteromers could represent a promising strategy to block morphine reward.
{"title":"Activation of the Mu-Delta Opioid Receptor Heteromers Blocks Morphine Rewarding Effects.","authors":"Ariadna Requana Aradas, Youssra Djaboub, Isabelle McCort-Tranchepain, Zuzana Hajasova, Loïc Clémenceau, Corinne Canestrelli, Anika Mann, Stefan Schulz, Angélique Delaval, Francine Acher, Dominique Massotte, Florence Noble, Nicolas Marie","doi":"10.1093/ijnp/pyad032","DOIUrl":"https://doi.org/10.1093/ijnp/pyad032","url":null,"abstract":"<p><strong>Background: </strong>Evidence has accumulated demonstrating the existence of opioid receptor heteromers, and recent data suggest that targeting these heteromers could reduce opioid side effects while retaining therapeutic effects. Indeed, CYM51010 characterized as a MOR (mu opioid receptor)/DOR (delta opioid receptor) heteromer-preferring agonist promoted antinociception comparable with morphine but with less tolerance. In the perspective of developing these new classes of pharmacological agents, data on their putative side effects are mandatory.</p><p><strong>Methods: </strong>Therefore, in this study, we investigated the effects of CYM51010 in different models related to drug addiction in mice, including behavioral sensitization, conditioned place preference and withdrawal.</p><p><strong>Results: </strong>We found that, like morphine, CYM51010 promoted acute locomotor activity as well as psychomotor sensitization and rewarding effect. However, it induced less physical dependence than morphine. We also investigated the ability of CYM51010 to modulate some morphine-induced behavior. Whereas CYM51010 was unable to block morphine-induced physical dependence, it blocked reinstatement of an extinguished morphine induced-conditioned place preference.</p><p><strong>Conclusions: </strong>Altogether, our results reveal that targeting MOR-DOR heteromers could represent a promising strategy to block morphine reward.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/eb/8d/pyad032.PMC10388387.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10293139","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}
Introduction: Major depressive disorder (MDD) is a highly prevalent and burdensome condition. This study aims to evaluate the effectiveness, tolerability, and safety of vortioxetine in treating MDD based on real-world data.
Methods: A systematic search of 8 electronic databases was performed from inception until October 2022 to identify real-world studies, excluding randomized controlled trials. We conducted subgroup, meta-regression, sensitivity analyses, publication bias, and quality assessments using the random-effects model. The effects were summarized by rates or standardized mean difference (SMD) with 95% confidence interval (CI).
Results: Of the 870 records identified, 11 studies (3139 participants) and 10 case reports or series were eligible for inclusion. Vortioxetine significantly relieved depression symptoms as assessed by both patients (SMD = 2.25, 95% CI = 1.60-2.89) and physicians (SMD = 3.73, 95% CI = 2.78-4.69). Cognitive function (SMD =1.86, 95% CI = 1.11-2.62) and functional disability (SMD =1.71, 95% CI = 1.14-2.29) were similarly markedly improved. Subgroup and meta-regression analyses showed that geographic location and medication regimen (whether combined with other antidepressants) were crucial factors influencing effectiveness (in terms of depression severity and cognitive function), potentially contributing to significant heterogeneity. The estimated response and remission rates were 66.4% (95% CI = 51.2%-81.5%) and 58.0% (95% CI = 48.9%-67.1%), respectively. Vortioxetine was well tolerated, with a pooled dropout rate of 3.5% (95% CI = 1.8%-5.8%), and the most common adverse event was nausea, with an estimated rate of 8.9% (95% CI = 3.8%-15.8%).
Limitations: The study has some limitations, including significant heterogeneity and limited evidence for some outcomes.
Conclusions: Vortioxetine is effective, well tolerated, and safe for treating MDD in clinical practice, with significant improvements observed in depressive severity, cognitive function, and functioning. Future studies should directly compare vortioxetine with other antidepressants in real-world settings to further evaluate its clinical utility.
简介:重度抑郁障碍(MDD)是一种非常普遍和沉重的疾病。本研究旨在基于真实数据评估沃替西汀治疗重度抑郁症的有效性、耐受性和安全性。方法:系统检索8个电子数据库,从成立到2022年10月,以确定真实世界的研究,不包括随机对照试验。我们使用随机效应模型进行了亚组、meta回归、敏感性分析、发表偏倚和质量评估。用95%可信区间(CI)的比率或标准化平均差(SMD)来总结效果。结果:在确定的870条记录中,11项研究(3139名参与者)和10例病例报告或系列符合纳入条件。沃替西汀显著缓解了患者(SMD = 2.25, 95% CI = 1.60-2.89)和医生(SMD = 3.73, 95% CI = 2.78-4.69)的抑郁症状。认知功能(SMD =1.86, 95% CI = 1.11-2.62)和功能障碍(SMD =1.71, 95% CI = 1.14-2.29)同样显著改善。亚组和荟萃回归分析显示,地理位置和用药方案(是否与其他抗抑郁药联合使用)是影响疗效(就抑郁严重程度和认知功能而言)的关键因素,可能导致显著的异质性。估计缓解率和缓解率分别为66.4% (95% CI = 51.2%-81.5%)和58.0% (95% CI = 48.9%-67.1%)。Vortioxetine耐受性良好,总退出率为3.5% (95% CI = 1.8%-5.8%),最常见的不良事件是恶心,估计发生率为8.9% (95% CI = 3.8%-15.8%)。局限性:该研究有一些局限性,包括显著的异质性和一些结果的证据有限。结论:Vortioxetine在临床实践中治疗重度抑郁症是有效的,耐受性良好且安全的,在抑郁严重程度,认知功能和功能方面观察到显着改善。未来的研究应直接比较沃替西汀与其他抗抑郁药在现实世界的设置,以进一步评估其临床效用。
{"title":"Effectiveness and Safety of Vortioxetine for the Treatment of Major Depressive Disorder in the Real World: A Systematic Review and Meta-Analysis.","authors":"Zejun Li, Shouhuan Liu, Qiuxia Wu, Jing Li, Qian Yang, Xin Wang, Pu Peng, Qianjin Wang, Yueheng Liu, Manyun Li, Yuzhu Hao, Huixue Xu, Li He, Yunfei Wang, Shubao Chen, Tieqiao Liu","doi":"10.1093/ijnp/pyad018","DOIUrl":"https://doi.org/10.1093/ijnp/pyad018","url":null,"abstract":"<p><strong>Introduction: </strong>Major depressive disorder (MDD) is a highly prevalent and burdensome condition. This study aims to evaluate the effectiveness, tolerability, and safety of vortioxetine in treating MDD based on real-world data.</p><p><strong>Methods: </strong>A systematic search of 8 electronic databases was performed from inception until October 2022 to identify real-world studies, excluding randomized controlled trials. We conducted subgroup, meta-regression, sensitivity analyses, publication bias, and quality assessments using the random-effects model. The effects were summarized by rates or standardized mean difference (SMD) with 95% confidence interval (CI).</p><p><strong>Results: </strong>Of the 870 records identified, 11 studies (3139 participants) and 10 case reports or series were eligible for inclusion. Vortioxetine significantly relieved depression symptoms as assessed by both patients (SMD = 2.25, 95% CI = 1.60-2.89) and physicians (SMD = 3.73, 95% CI = 2.78-4.69). Cognitive function (SMD =1.86, 95% CI = 1.11-2.62) and functional disability (SMD =1.71, 95% CI = 1.14-2.29) were similarly markedly improved. Subgroup and meta-regression analyses showed that geographic location and medication regimen (whether combined with other antidepressants) were crucial factors influencing effectiveness (in terms of depression severity and cognitive function), potentially contributing to significant heterogeneity. The estimated response and remission rates were 66.4% (95% CI = 51.2%-81.5%) and 58.0% (95% CI = 48.9%-67.1%), respectively. Vortioxetine was well tolerated, with a pooled dropout rate of 3.5% (95% CI = 1.8%-5.8%), and the most common adverse event was nausea, with an estimated rate of 8.9% (95% CI = 3.8%-15.8%).</p><p><strong>Limitations: </strong>The study has some limitations, including significant heterogeneity and limited evidence for some outcomes.</p><p><strong>Conclusions: </strong>Vortioxetine is effective, well tolerated, and safe for treating MDD in clinical practice, with significant improvements observed in depressive severity, cognitive function, and functioning. Future studies should directly compare vortioxetine with other antidepressants in real-world settings to further evaluate its clinical utility.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2023-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/35/ef/pyad018.PMC10289145.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9705631","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}