精神药理影像遗传学研究进展及其临床应用前景
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摘要
精神疾病危害严重,其发病机制复杂难解,临床治疗效果不一,且存在明显的个体差异.近期精准医学研究发现精神药物作用于脑神经的生化过程受到遗传多态性的影响.本文从五羟色胺能、去甲肾上腺素能和多巴胺能三大系统入手,系统综述精神药理影像遗传学的相关研究进展,深入探讨精神药理的神经作用机制以及药物-基因-脑之间的交互作用.我们发现:SLC6A4、BDNF、FKBP5、COMT和多巴胺相关受体等基因多态性与多种精神疾病的发生发展及其治疗效果具有一定的相关性,可能成为相关精神疾病诊断的候选基因.杏仁核、海马、眶额叶、扣带回和前额叶等皮层与皮层下脑结构可能是不同神经递质相关的基因多态性影响精神药物生化作用过程的关键靶点脑区.在建立精神药物-基因-脑影像-行为的因果链中,仍然存在很多相互矛盾的结果和一定的局限性.因此,开展同质性强的临床试验、研究表观遗传作用等可以作为未来的研究发展趋势.
Although the harm of mental illness is serious, its pathogenesis remains unclear, clinical treatment is not effective, and there are obvious individual differences. Recent precision medical research has discovered the role of gene polymorphism in the individualized treatment of drugs. Based on the three major systems of serotonin, norepinephrine and dopaminergic, this article systematically reviewed the research progress of psychiatric pharmacogenomics and imaging pharmacogenomics studies, and explored in depth the mechanism of action of the brain, the mechanism of drug action, and gene-drug-brain interactions. We found that genetic polymorphisms such as SLC6A4, BDNF, FKBP5, COMT, and dopamine-related receptors were found to correlate with the occurrence of multiple mental disorders and the efficacy of antidepressant treatment, and consequently may be candidates for the diagnosis of related mental disorders. The cortical and subcortical brain regions including the amygdala, the hippocampus, the orbitofrontal cortex, the anterior cingulate cortex and the prefrontal lobe may be the key targets of the effect of different neurotransmitter gene polymorphisms on the biochemical process of psychotropic drugs. These related important brain areas may become biological markers for the diagnosis and treatment of related mental disorders. However, in the establishment of psychotropic drug-geneneuroimaging-behavior causal chain, there are still many contradictory results and limitations. Therefore, the studies on homogenous clinical trials and epigenetic effects can be recommended as future research trends.
Although the harm of mental illness is serious, its pathogenesis remains unclear, clinical treatment is not effective, and there are obvious individual differences. Recent precision medical research has discovered the role of gene polymorphism in the individualized treatment of drugs. Based on the three major systems of serotonin, norepinephrine and dopaminergic, this article systematically reviewed the research progress of psychiatric pharmacogenomics and imaging pharmacogenomics studies, and explored in depth the mechanism of action of the brain, the mechanism of drug action, and gene-drug-brain interactions. We found that genetic polymorphisms such as SLC6A4, BDNF, FKBP5, COMT, and dopamine-related receptors were found to correlate with the occurrence of multiple mental disorders and the efficacy of antidepressant treatment, and consequently may be candidates for the diagnosis of related mental disorders. The cortical and subcortical brain regions including the amygdala, the hippocampus, the orbitofrontal cortex, the anterior cingulate cortex and the prefrontal lobe may be the key targets of the effect of different neurotransmitter gene polymorphisms on the biochemical process of psychotropic drugs. These related important brain areas may become biological markers for the diagnosis and treatment of related mental disorders. However, in the establishment of psychotropic drug-geneneuroimaging-behavior causal chain, there are still many contradictory results and limitations. Therefore, the studies on homogenous clinical trials and epigenetic effects can be recommended as future research trends.
引文
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[7]Serretti A,Calati R,Mandelli L,et al.Serotonin transporter gene variants and behavior:a comprehensive review.Current Drug Targets,2006,7(12):1659-1669
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[16]Outhred T,Das P,Dobson-Stone C,et al.Impact of 5-HTTLPR on SSRI serotonin transporter blockade during emotion regulation:a preliminary fMRI study.Journal of Affective Disorders,2016,196:11-19
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[18]Eaton K,Sallee F R,Sah R.Relevance of neuropeptide Y(NPY)in psychiatry.Curr Top Med Chem,2007,7(17):1645-1659
[19]Domschke K,Dannlowski U,Hohoff C,et al.Neuropeptide Y(NPY)gene:impact on emotional processing and treatment response in anxious depression.European Neuropsychopharmacology,2010,20(5):301-309
[20]O'brien S M,Scott L V,Dinan T G.Cytokines:abnormalities in major depression and implications for pharmacological treatment.Human Psychopharmacology,2004,19(6):397-403
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[22]Grimes C A,Jope R S.The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling.Prog Neurobiol,2001,65(4):391-426
[23]Luykx J J,Boks M P,Terwindt A P,et al.The involvement of GSK3beta in bipolar disorder:integrating evidence from multiple types of genetic studies.European Neuropsychopharmacology,2010,20(6):357-368
[24]Benedetti F,Bollettini I,Barberi I,et al.Lithium and GSK3-beta promoter gene variants influence white matter microstructure in bipolar disorder.Neuropsychopharmacology,2013,38(2):313-327
[25]Schwarz L A,Luo L.Organization of the locus coeruleusnorepinephrine system.Current Biology,2015,25(21):R1051-R1056
[26]Tank A W,Lee Wong D.Peripheral and central effects of circulating catecholamines.Comprehensive Physiology,2015,5(1):1-15
[27]Sara S J,Bouret S.Orienting and reorienting:the locus coeruleus mediates cognition through arousal.Neuron,2012,76(1):130-141
[28]Sara S J.Locus Coeruleus in time with the making of memories.Current Opinion in Neurobiology,2015,35:87-94
[29]Heal D J,Smith S L,Gosden J,et al.Amphetamine,past and present--a pharmacological and clinical perspective.Journal of Psychopharmacology,2013,27(6):479-496
[30]Castren E,Rantamaki T.The role of BDNF and its receptors in depression and antidepressant drug action:reactivation of developmental plasticity.Dev Neurobiol,2010,70(5):289-297
[31]Bueller J A,Aftab M,Sen S,et al.BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects.Biological Psychiatry,2006,59(9):812-815
[32]Yan T,Wang L,Kuang W,et al.Brain-derived neurotrophic factor Val66Met polymorphism association with antidepressant efficacy:a systematic review and meta-analysis.Asia Pac Psychiatry,2014,6(3):241-251
[33]Alexopoulos G S,Glatt C E,Hoptman M J,et al.BDNF val66met polymorphism,white matter abnormalities and remission of geriatric depression.Journal of Affective Disorders,2010,125(1-3):262-268
[34]Cardoner N,Soria V,Gratacos M,et al.Val66Met BDNFgenotypes in melancholic depression:effects on brain structure and treatment outcome.Depression and Anxiety,2013,30(3):225-233
[35]Notaras M,Hill R,Gogos J A,et al.BDNF Val66Met genotype determines hippocampus-dependent behavior via sensitivity to glucocorticoid signaling.Molecular Psychiatry,2016,21(6):730-732
[36]Willour V L,Chen H,Toolan J,et al.Family-based association of FKBP5 in bipolar disorder.Molecular Psychiatry,2009,14(3):261-268
[37]Tozzi L,Farrell C,Booij L,et al.Epigenetic changes of FKBP5 as a link connecting genetic and environmental risk factors with structural and functional brain changes in major depression.Neuropsychopharmacology,2018,43(5):1138-1145
[38]Gotti C,Clementi F.Neuronal nicotinic receptors:from structure to pathology.Prog Neurobiol,2004,74(6):363-396
[39]Janes A C,Smoller J W,David S P,et al.Association between CHRNA5 genetic variation at rs16969968 and brain reactivity to smoking images in nicotine dependent women.Drug and Alcohol Dependence,2012,120(1-3):7-13
[40]Trossbach S V,De Souza Silva M A,Huston J P,et al.Intranasal dopamine treatment reinstates object-place memory in aged rats.Neurobiology of Learning and Memory,2014,114:231-235
[41]Cachope R,Cheer J F.Local control of striatal dopamine release.Frontiers in Behavioral Neuroscience,2014,8:188
[42]Domschke K.Clinical and molecular genetics of psychotic depression.Schizophr Bull,2013,39(4):766-775
[43]Badner J A,Gershon E S.Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia.Molecular Psychiatry,2002,7(4):405-411
[44]Karayiorgou M,Morris M A,Morrow B,et al.Schizophrenia susceptibility associated with interstitial deletions of chromosome22q11.Proc NatlAcad Sci U SA,1995,92(17):7612-7616
[45]Mattay V S,Goldberg T E,Fera F,et al.Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine.Proc Natl Acad Sci USA,2003,100(10):6186-6191
[46]Bertolino A,Caforio G,Blasi G,et al.Interaction of COMT(Val(108/158)Met)genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia.The American Journal of Psychiatry,2004,161(10):1798-1805
[47]Brody A L,Mandelkern M A,Olmstead R E,et al.Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens.Archives of General Psychiatry,2006,63(7):808-816
[48]Wang Z,Ray R,Faith M,et al.Nicotine abstinence-induced cerebral blood flow changes by genotype.Neuroscience Letters,2008,438(3):275-280
[49]Loughead J,Wileyto E P,Valdez J N,et al.Effect of abstinence challenge on brain function and cognition in smokers differs by COMT genotype.Molecular Psychiatry,2009,14(8):820-826
[50]Giros B,Caron M G.Molecular characterization of the dopamine transporter.Trends Pharmacol Sci,1993,14(2):43-49
[51]Uhl G R.Dopamine transporter:basic science and human variation of a key molecule for dopaminergic function,locomotion,and parkinsonism.Mov Disord,2003,18 Suppl7:S71-80
[52]Rohde L A,Roman T,Szobot C,et al.Dopamine transporter gene,response to methylphenidate and cerebral blood flow in attentiondeficit/hyperactivity disorder:a pilot study.Synapse,2003,48(2):87-89
[53]Cheon K A,Ryu Y H,Kim J W,et al.The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in Korean children with attention deficit hyperactivity disorder:relating to treatment response to methylphenidate.European Neuropsychopharmacology,2005,15(1):95-101
[54]Szobot C M,Roman T,Hutz M H,et al.Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity.Synapse,2011,65(2):154-159
[55]Franklin T R,Lohoff F W,Wang Z,et al.DAT genotype modulates brain and behavioral responses elicited by cigarette cues.Neuropsychopharmacology,2009,34(3):717-728
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