{"title":"重度抑郁症患者度洛西汀治疗后脑去甲肾上腺素转运体有效性变化的纵向PET研究。","authors":"Sho Moriguchi, Keisuke Takahata, Harumasa Takano, Hironobu Endo, Kenji Tagai, Soichiro Kitamura, Hiroyuki Uchida, Masaru Mimura, Manabu Kubota, Ming-Rong Zhang, Makoto Higuchi","doi":"10.1093/ijnp/pyaf064","DOIUrl":null,"url":null,"abstract":"<p><strong>Importance: </strong>The norepinephrine transporter (NET) plays a crucial role in major depressive disorder (MDD). Serotonin and norepinephrine reuptake inhibitors, such as duloxetine, are first-line treatments for MDD. Duloxetine inhibits the reuptake of both serotonin and norepinephrine. However, its precise mechanism, particularly regarding NET occupancy and changes in transporter availability, remains unclear. Norepinephrine transmission, mediated by NET, may be instrumental in treating MDD. Therefore, NET occupancy could serve as a potential biomarker to evaluate treatment efficacy.</p><p><strong>Objective: </strong>This study evaluated duloxetine's impact on brain NET availability in patients with MDD using positron emission tomography (PET) with (S,S)-[18F]FMeNER-D2 and its correlation with clinical symptoms using the Hamilton Depression Rating Scale (HAM-D).</p><p><strong>Design: </strong>Longitudinal study.</p><p><strong>Setting: </strong>Psychiatric hospitals and clinics.</p><p><strong>Participants: </strong>Fifteen patients with MDD.</p><p><strong>Interventions: </strong>Duloxetine (20-60 mg daily).</p><p><strong>Main outcomes and measures: </strong>Baseline PET examinations were conducted for all patients, followed by treatment with duloxetine (20-60 mg daily). After 4-6 weeks of duloxetine administration, a second PET examination was performed, and plasma concentrations of duloxetine were measured immediately before and after the second examination using gas chromatography-mass spectrometry. Seven patients showing symptom improvement over the course of time discontinued duloxetine and underwent a third PET examination after a 2-month washout period.</p><p><strong>Results: </strong>Norepinephrine transporter occupancy by duloxetine was 30%-40% across the doses studied. A paired t-test comparing NET availability before and after duloxetine treatment showed no significant differences, suggesting that duloxetine did not significantly alter NET availability in the short term. Further analysis revealed a significant positive correlation between the change in NET availability and HAM-D scores after treatment. Patients with greater reductions in HAM-D scores exhibited more pronounced reductions in NET availability.</p><p><strong>Conclusions: </strong>These findings underscore the potential role of NET occupancy by duloxetine in the treatment of MDD and its relationship with clinical outcomes.</p><p><strong>Relevance: </strong>Understanding changes in NET and their implications enhances our comprehension of the complex mechanisms behind antidepressants and may reveal new therapeutic targets for MDD and other neuropsychiatric disorders.</p><p><strong>Clinical trial registration number: </strong>UMIN000008251.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":"28 10","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489337/pdf/","citationCount":"0","resultStr":"{\"title\":\"A longitudinal PET study on changes in brain norepinephrine transporter availability following duloxetine treatment in major depressive disorder.\",\"authors\":\"Sho Moriguchi, Keisuke Takahata, Harumasa Takano, Hironobu Endo, Kenji Tagai, Soichiro Kitamura, Hiroyuki Uchida, Masaru Mimura, Manabu Kubota, Ming-Rong Zhang, Makoto Higuchi\",\"doi\":\"10.1093/ijnp/pyaf064\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Importance: </strong>The norepinephrine transporter (NET) plays a crucial role in major depressive disorder (MDD). Serotonin and norepinephrine reuptake inhibitors, such as duloxetine, are first-line treatments for MDD. Duloxetine inhibits the reuptake of both serotonin and norepinephrine. However, its precise mechanism, particularly regarding NET occupancy and changes in transporter availability, remains unclear. Norepinephrine transmission, mediated by NET, may be instrumental in treating MDD. Therefore, NET occupancy could serve as a potential biomarker to evaluate treatment efficacy.</p><p><strong>Objective: </strong>This study evaluated duloxetine's impact on brain NET availability in patients with MDD using positron emission tomography (PET) with (S,S)-[18F]FMeNER-D2 and its correlation with clinical symptoms using the Hamilton Depression Rating Scale (HAM-D).</p><p><strong>Design: </strong>Longitudinal study.</p><p><strong>Setting: </strong>Psychiatric hospitals and clinics.</p><p><strong>Participants: </strong>Fifteen patients with MDD.</p><p><strong>Interventions: </strong>Duloxetine (20-60 mg daily).</p><p><strong>Main outcomes and measures: </strong>Baseline PET examinations were conducted for all patients, followed by treatment with duloxetine (20-60 mg daily). After 4-6 weeks of duloxetine administration, a second PET examination was performed, and plasma concentrations of duloxetine were measured immediately before and after the second examination using gas chromatography-mass spectrometry. Seven patients showing symptom improvement over the course of time discontinued duloxetine and underwent a third PET examination after a 2-month washout period.</p><p><strong>Results: </strong>Norepinephrine transporter occupancy by duloxetine was 30%-40% across the doses studied. A paired t-test comparing NET availability before and after duloxetine treatment showed no significant differences, suggesting that duloxetine did not significantly alter NET availability in the short term. Further analysis revealed a significant positive correlation between the change in NET availability and HAM-D scores after treatment. Patients with greater reductions in HAM-D scores exhibited more pronounced reductions in NET availability.</p><p><strong>Conclusions: </strong>These findings underscore the potential role of NET occupancy by duloxetine in the treatment of MDD and its relationship with clinical outcomes.</p><p><strong>Relevance: </strong>Understanding changes in NET and their implications enhances our comprehension of the complex mechanisms behind antidepressants and may reveal new therapeutic targets for MDD and other neuropsychiatric disorders.</p><p><strong>Clinical trial registration number: </strong>UMIN000008251.</p>\",\"PeriodicalId\":14134,\"journal\":{\"name\":\"International Journal of Neuropsychopharmacology\",\"volume\":\"28 10\",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489337/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Neuropsychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/ijnp/pyaf064\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Neuropsychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ijnp/pyaf064","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
A longitudinal PET study on changes in brain norepinephrine transporter availability following duloxetine treatment in major depressive disorder.
Importance: The norepinephrine transporter (NET) plays a crucial role in major depressive disorder (MDD). Serotonin and norepinephrine reuptake inhibitors, such as duloxetine, are first-line treatments for MDD. Duloxetine inhibits the reuptake of both serotonin and norepinephrine. However, its precise mechanism, particularly regarding NET occupancy and changes in transporter availability, remains unclear. Norepinephrine transmission, mediated by NET, may be instrumental in treating MDD. Therefore, NET occupancy could serve as a potential biomarker to evaluate treatment efficacy.
Objective: This study evaluated duloxetine's impact on brain NET availability in patients with MDD using positron emission tomography (PET) with (S,S)-[18F]FMeNER-D2 and its correlation with clinical symptoms using the Hamilton Depression Rating Scale (HAM-D).
Design: Longitudinal study.
Setting: Psychiatric hospitals and clinics.
Participants: Fifteen patients with MDD.
Interventions: Duloxetine (20-60 mg daily).
Main outcomes and measures: Baseline PET examinations were conducted for all patients, followed by treatment with duloxetine (20-60 mg daily). After 4-6 weeks of duloxetine administration, a second PET examination was performed, and plasma concentrations of duloxetine were measured immediately before and after the second examination using gas chromatography-mass spectrometry. Seven patients showing symptom improvement over the course of time discontinued duloxetine and underwent a third PET examination after a 2-month washout period.
Results: Norepinephrine transporter occupancy by duloxetine was 30%-40% across the doses studied. A paired t-test comparing NET availability before and after duloxetine treatment showed no significant differences, suggesting that duloxetine did not significantly alter NET availability in the short term. Further analysis revealed a significant positive correlation between the change in NET availability and HAM-D scores after treatment. Patients with greater reductions in HAM-D scores exhibited more pronounced reductions in NET availability.
Conclusions: These findings underscore the potential role of NET occupancy by duloxetine in the treatment of MDD and its relationship with clinical outcomes.
Relevance: Understanding changes in NET and their implications enhances our comprehension of the complex mechanisms behind antidepressants and may reveal new therapeutic targets for MDD and other neuropsychiatric disorders.
期刊介绍：
The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.
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