治疗难治性精神分裂症的遗传风险及健康个体多巴胺合成能力和D2/3受体可用性的相应变异

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Psychiatry Pub Date : 2024-12-27 DOI:10.1038/s41380-024-02873-2
Daniel Paul Eisenberg, Rachael Keir Blackman, Maria G. Tietcheu, Philip D. Kohn, Jasmin S. Bettina, Bhaskar Kolachana, Michael D. Gregory, Karen F. Berman
{"title":"治疗难治性精神分裂症的遗传风险及健康个体多巴胺合成能力和D2/3受体可用性的相应变异","authors":"Daniel Paul Eisenberg, Rachael Keir Blackman, Maria G. Tietcheu, Philip D. Kohn, Jasmin S. Bettina, Bhaskar Kolachana, Michael D. Gregory, Karen F. Berman","doi":"10.1038/s41380-024-02873-2","DOIUrl":null,"url":null,"abstract":"<p>Dysfunction of dopamine systems has long been considered a hallmark of schizophrenia, and nearly all current first-line medication treatments block dopamine D<sub>2</sub> receptors. However, approximately a quarter of patients will not adequately respond to these agents and are considered treatment-resistant. Whereas abnormally high striatal presynaptic dopamine synthesis capacity has been observed in people with schizophrenia, studies of treatment-resistant patients have not shown this pattern and have even found the opposite – i.e., <i>reductions</i> in striatal presynaptic dopamine synthesis capacity. Whether such reductions in fact represent clinical epiphenomena such as medication or other treatment effects or whether they rather represent neurobiological differences related to etiology has been unclear. To understand the dopaminergic implications of genetic liability for treatment-resistant schizophrenia without the confound of clinical epiphenomena, we studied a cohort of healthy individuals without neuropsychiatric illness using [<sup>18</sup>F]-FDOPA positron emission tomography (PET) and found that striatal presynaptic dopamine synthesis capacity showed an expected direct association with cumulative genetic risk burden for general schizophrenia but an <i>inverse</i> association with specific polygenic risk for treatment-resistant schizophrenia. Subsequent evaluation of D<sub>2/3</sub> dopamine receptor availability in an overlapping cohort using [<sup>18</sup>F]-fallypride PET did not identify any effects of genetic risk in the striatum but found an association with treatment-resistant schizophrenia polygenic risk in the thalamus. Overall, these results align with prior PET studies in patients and implicate, at least with respect to the dopamine system, fundamentally distinct molecular mechanisms in the unique genetic liability for treatment-resistant schizophrenia.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"s3-2 1","pages":""},"PeriodicalIF":9.6000,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genetic risk for treatment resistant schizophrenia and corresponding variation in dopamine synthesis capacity and D2/3 receptor availability in healthy individuals\",\"authors\":\"Daniel Paul Eisenberg, Rachael Keir Blackman, Maria G. Tietcheu, Philip D. Kohn, Jasmin S. Bettina, Bhaskar Kolachana, Michael D. Gregory, Karen F. Berman\",\"doi\":\"10.1038/s41380-024-02873-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Dysfunction of dopamine systems has long been considered a hallmark of schizophrenia, and nearly all current first-line medication treatments block dopamine D<sub>2</sub> receptors. However, approximately a quarter of patients will not adequately respond to these agents and are considered treatment-resistant. Whereas abnormally high striatal presynaptic dopamine synthesis capacity has been observed in people with schizophrenia, studies of treatment-resistant patients have not shown this pattern and have even found the opposite – i.e., <i>reductions</i> in striatal presynaptic dopamine synthesis capacity. Whether such reductions in fact represent clinical epiphenomena such as medication or other treatment effects or whether they rather represent neurobiological differences related to etiology has been unclear. To understand the dopaminergic implications of genetic liability for treatment-resistant schizophrenia without the confound of clinical epiphenomena, we studied a cohort of healthy individuals without neuropsychiatric illness using [<sup>18</sup>F]-FDOPA positron emission tomography (PET) and found that striatal presynaptic dopamine synthesis capacity showed an expected direct association with cumulative genetic risk burden for general schizophrenia but an <i>inverse</i> association with specific polygenic risk for treatment-resistant schizophrenia. Subsequent evaluation of D<sub>2/3</sub> dopamine receptor availability in an overlapping cohort using [<sup>18</sup>F]-fallypride PET did not identify any effects of genetic risk in the striatum but found an association with treatment-resistant schizophrenia polygenic risk in the thalamus. Overall, these results align with prior PET studies in patients and implicate, at least with respect to the dopamine system, fundamentally distinct molecular mechanisms in the unique genetic liability for treatment-resistant schizophrenia.</p>\",\"PeriodicalId\":19008,\"journal\":{\"name\":\"Molecular Psychiatry\",\"volume\":\"s3-2 1\",\"pages\":\"\"},\"PeriodicalIF\":9.6000,\"publicationDate\":\"2024-12-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Psychiatry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41380-024-02873-2\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41380-024-02873-2","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

长期以来,多巴胺系统功能障碍一直被认为是精神分裂症的一个标志,目前几乎所有的一线药物治疗都会阻断多巴胺D2受体。然而,大约四分之一的患者对这些药物没有充分的反应,被认为是治疗耐药。虽然在精神分裂症患者中观察到异常高的纹状体突触前多巴胺合成能力,但对治疗抵抗患者的研究并未显示出这种模式,甚至发现了相反的情况-即纹状体突触前多巴胺合成能力降低。这种减少实际上是否代表临床现象,如药物或其他治疗效果,或者它们是否代表与病因相关的神经生物学差异,目前尚不清楚。为了在不混淆临床现象的情况下理解难治性精神分裂症遗传倾向的多巴胺能含义,我们使用[18F]-FDOPA正电子发射断层扫描(PET)研究了一组没有神经精神疾病的健康个体,发现纹状体突触前多巴胺合成能力与一般精神分裂症的累积遗传风险负担有预期的直接关联,但与治疗抵抗性精神分裂症的特定多基因风险呈负相关。随后使用[18F]-fallypride PET对重叠队列中D2/3多巴胺受体可用性进行评估,未发现纹状体中遗传风险的任何影响,但发现丘脑与治疗抵抗性精神分裂症多基因风险相关。总的来说,这些结果与之前对患者的PET研究一致,至少在多巴胺系统方面,从根本上不同的分子机制在治疗难治性精神分裂症的独特遗传责任中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Genetic risk for treatment resistant schizophrenia and corresponding variation in dopamine synthesis capacity and D2/3 receptor availability in healthy individuals

Dysfunction of dopamine systems has long been considered a hallmark of schizophrenia, and nearly all current first-line medication treatments block dopamine D2 receptors. However, approximately a quarter of patients will not adequately respond to these agents and are considered treatment-resistant. Whereas abnormally high striatal presynaptic dopamine synthesis capacity has been observed in people with schizophrenia, studies of treatment-resistant patients have not shown this pattern and have even found the opposite – i.e., reductions in striatal presynaptic dopamine synthesis capacity. Whether such reductions in fact represent clinical epiphenomena such as medication or other treatment effects or whether they rather represent neurobiological differences related to etiology has been unclear. To understand the dopaminergic implications of genetic liability for treatment-resistant schizophrenia without the confound of clinical epiphenomena, we studied a cohort of healthy individuals without neuropsychiatric illness using [18F]-FDOPA positron emission tomography (PET) and found that striatal presynaptic dopamine synthesis capacity showed an expected direct association with cumulative genetic risk burden for general schizophrenia but an inverse association with specific polygenic risk for treatment-resistant schizophrenia. Subsequent evaluation of D2/3 dopamine receptor availability in an overlapping cohort using [18F]-fallypride PET did not identify any effects of genetic risk in the striatum but found an association with treatment-resistant schizophrenia polygenic risk in the thalamus. Overall, these results align with prior PET studies in patients and implicate, at least with respect to the dopamine system, fundamentally distinct molecular mechanisms in the unique genetic liability for treatment-resistant schizophrenia.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
期刊最新文献
Shank3 modulates Rpl3 expression and protein synthesis via mGlu5: implications for Phelan McDermid syndrome Neuroimaging changes in major depression with brief computer-assisted cognitive behavioral therapy compared to waitlist S-ketamine exposure in early postnatal period induces social deficit mediated by excessive microglial synaptic pruning Bidirectional emotional regulation through prefrontal innervation of the locus coeruleus Neuroinflammatory fluid biomarkers in patients with Alzheimer’s disease: a systematic literature review
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1