|
1
|
Wu HN, Zhu SY, Zhang LN, Shen BH, Xu LL. Association between 5-HTR1A gene C-1019G polymorphism and antidepressant response in patients with major depressive disorder: A meta-analysis. World J Psychiatry 2024; 14:1573-1582. [DOI: 10.5498/wjp.v14.i10.1573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 09/11/2024] [Accepted: 09/23/2024] [Indexed: 10/17/2024] Open
Abstract
BACKGROUND Major depressive disorder (MDD) is a substantial global health concern, and its treatment is complicated by the variability in individual response to antidepressants.
AIM To consolidate research and clarify the impact of genetic variation on MDD treatment outcomes.
METHODS Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search across PubMed, EMBASE, Web of Science, and the Cochrane Library was conducted without date restrictions, utilizing key terms related to MDD, serotonin 1A receptor polymorphism (5-HTR1A), C-1019G polymorphism, and antidepressant response. Studies meeting inclusion criteria were thoroughly screened, and quality assessed using the Newcastle-Ottawa Scale. Statistical analyses, including χ2 and I² values, were used to evaluate heterogeneity and fixed-effect or random-effect models were applied accordingly.
RESULTS The initial search yielded 1216 articles, with 11 studies meeting criteria for inclusion. Analysis of various genetic models showed no significant association between the 5-HTR1A C-1019G polymorphism and antidepressant efficacy. The heterogeneity was low to moderate, and no publication bias was detected through funnel plot symmetry and Egger's and Begg's tests.
CONCLUSION This meta-analysis does not support a significant association between the 5-HTR1A C-1019G polymorphism and the efficacy of antidepressant treatment in MDD. The findings call for further research with larger cohorts to substantiate these results and enhance the understanding of antidepressant pharmacogenetics.
Collapse
Affiliation(s)
- Huai-Neng Wu
- Department of Psychiatry, Affiliated Mental Health Center and Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310013, Zhejiang Province, China
| | - Shuang-Yue Zhu
- Department of Psychiatry, Affiliated Mental Health Center and Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310013, Zhejiang Province, China
| | - Li-Na Zhang
- Department of Psychiatry, Affiliated Mental Health Center and Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310013, Zhejiang Province, China
| | - Bian-Hong Shen
- Department of Psychiatry, Affiliated Mental Health Center and Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310013, Zhejiang Province, China
| | - Lian-Lian Xu
- Department of Psychiatry, Affiliated Mental Health Center and Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310013, Zhejiang Province, China
| |
Collapse
|
|
2
|
Singh P, Srivastava A, Guin D, Thakran S, Yadav J, Chandna P, Sood M, Chadda RK, Kukreti R. Genetic Landscape of Major Depressive Disorder: Assessment of Potential Diagnostic and Antidepressant Response Markers. Int J Neuropsychopharmacol 2023; 26:692-738. [PMID: 36655406 PMCID: PMC10586057 DOI: 10.1093/ijnp/pyad001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 01/18/2023] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND The clinical heterogeneity in major depressive disorder (MDD), variable treatment response, and conflicting findings limit the ability of genomics toward the discovery of evidence-based diagnosis and treatment regimen. This study attempts to curate all genetic association findings to evaluate potential variants for clinical translation. METHODS We systematically reviewed all candidates and genome-wide association studies for both MDD susceptibility and antidepressant response, independently, using MEDLINE, particularly to identify replicated findings. These variants were evaluated for functional consequences using different in silico tools and further estimated their diagnostic predictability by calculating positive predictive values. RESULTS A total of 217 significantly associated studies comprising 1200 variants across 545 genes and 128 studies including 921 variants across 412 genes were included with MDD susceptibility and antidepressant response, respectively. Although the majority of associations were confirmed by a single study, we identified 31 and 18 replicated variants (in at least 2 studies) for MDD and antidepressant response. Functional annotation of these 31 variants predicted 20% coding variants as deleterious/damaging and 80.6% variants with regulatory effect. Similarly, the response-related 18 variants revealed 25% coding variant as damaging and 88.2% with substantial regulatory potential. Finally, we could calculate the diagnostic predictability of 19 and 5 variants whose positive predictive values ranges from 0.49 to 0.66 for MDD and 0.36 to 0.66 for response. CONCLUSIONS The replicated variants presented in our data are promising for disease diagnosis and improved response outcomes. Although these quantitative assessment measures are solely directive of available observational evidence, robust homogenous validation studies are required to strengthen these variants for molecular diagnostic application.
Collapse
Affiliation(s)
- Priyanka Singh
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Ankit Srivastava
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Debleena Guin
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Delhi, India
| | - Sarita Thakran
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Jyoti Yadav
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
| | - Puneet Chandna
- Indian Society of Colposcopy and Cervical Pathology (ISCCP), Safdarjung Hospital, New Delhi, India
| | - Mamta Sood
- Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Rakesh Kumar Chadda
- Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Ritushree Kukreti
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| |
Collapse
|
|
3
|
Serotonergic receptor gene polymorphism and response to selective serotonin reuptake inhibitors in ethnic Malay patients with first episode of major depressive disorder. THE PHARMACOGENOMICS JOURNAL 2021; 21:498-509. [PMID: 33731884 DOI: 10.1038/s41397-021-00228-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 01/29/2021] [Accepted: 02/18/2021] [Indexed: 01/31/2023]
Abstract
The polymorphisms of the 5HTR1A and 5HTR2A receptor genes (rs6295C/G and rs6311G/A) have been evaluated for association with SSRI treatment outcome in various populations with different results. The present study was carried out to determine the association between genotypes of HTR1A-rs6295 and HTR2A-rs6311 with SSRI treatment outcome among the ethnic Malay patients diagnosed with first-episode major depressive disorder (MDD). The patients were recruited from four tertiary hospitals in the Klang Valley region of Malaysia. Predefined efficacy phenotypes based on 25% (partial early response) and 50% (clinical efficacy response) reduction in Montgomery Asberg Depression Rating Scale-self Rated score (MADRS-S) were adopted for assessment of treatment efficacy in this study. Self-reporting for adverse effects (AE) was documented using the Patient Rated Inventory of Side Effect (PRISE) after treatment with SSRI for up to 6 weeks. Adjusted binary logistic regression between genotypes of the polymorphism obtained using sequencing technique with the treatment outcome phenotypes was performed. The 142 patients recruited were made up of 96 females (67.6%) and 46 males (32.4%). Clinical efficacy and Partial early response phenotypes were not significantly associated with genotypes of HTR1A and HTR2A polymorphism. The GG genotype of HTR2A polymorphism has decreased odds for dizziness (CNS) and increased odds for poor concentration. The GA genotype increases the odd for excessive sweating, diarrhoea, constipation and blurred vision. The CC genotype of HTR1A-rs6295 decreases the odd for nausea/vomiting and increases the odd for anxiety. Thus, some genotypes of HTR1A and HTR2A polymorphism were associated with SSRI treatment outcomes in ethnic Malay MDD patients.
Collapse
|
|
4
|
Wan YS, Zhai XJ, Tan HA, Ai YS, Zhao LB. Associations between the 1438A/G, 102T/C, and rs7997012G/A polymorphisms of HTR2A and the safety and efficacy of antidepressants in depression: a meta-analysis. THE PHARMACOGENOMICS JOURNAL 2020; 21:200-215. [PMID: 33097827 DOI: 10.1038/s41397-020-00197-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 09/12/2020] [Accepted: 10/08/2020] [Indexed: 11/10/2022]
Abstract
The correlations between hydroxytryptamine receptor 2A (HTR2A) gene polymorphisms (1438A/G, 102T/C, and rs7997012G/A) and the safety and efficacy of antidepressants in depression patients were constantly reported, but conclusions are debatable. This meta-analysis ascertained forty-two studies on the efficacy (including response and remission) and side-effect issued before February 2020. Pooled analyses indicated significant associations of 1438A/G polymorphism (16 studies, 1931 subjects) and higher response within dominant model (OR: 1.40, 95% CI: 1.12-1.76); rs7997012G/A polymorphism (nine studies, 1434 subjects) and higher remission in overall models (dominant model: OR: 1.30, 95% CI: 1.01-1.66; recessive model: OR: 2.20, 95% CI: 1.53-3.16; homozygote model: OR: 2.73, 95% CI: 1.78-4.17); 102T/C polymorphism (eight studies, 804 subjects) and reduced risk of side-effect within recessive (OR: 0.57, 95% CI: 0.4-0.83) and homozygote models (OR: 0.54, 95% CI: 0.29-0.99). For depression patients, genotyping of HTR2A polymorphisms is a promising tool for estimating the outcome and side-effect of antidepressants.
Collapse
Affiliation(s)
- Yuan-Sheng Wan
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xue-Jia Zhai
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong-Ai Tan
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - You-Sheng Ai
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Li-Bo Zhao
- Beijing Children's Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
|
5
|
Page KC, Anday EK. Dietary Exposure to Excess Saturated Fat During Early Life Alters Hippocampal Gene Expression and Increases Risk for Behavioral Disorders in Adulthood. Front Neurosci 2020; 14:527258. [PMID: 33013310 PMCID: PMC7516040 DOI: 10.3389/fnins.2020.527258] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 08/21/2020] [Indexed: 02/01/2023] Open
Abstract
Purpose Maternal and postnatal diets result in long-term changes in offspring brain and behavior; however, the key mediators of these developmental changes are not well-defined. In this study, we investigated the impact of maternal and post-weaning high-fat diets on gene expression of key components mediating hippocampal synaptic efficacy. In addition, we evaluated the risk for impaired stress-coping and anxiety-like behaviors in adult offspring exposed to obesogenic diets during early life. Methods Dams were fed a control (C) or high-fat (HF) diet prior to mating, pregnancy, and lactation. Male offspring from control chow and high-fat fed dams were weaned to control chow or HF diets. The forced swim test (FST) and the elevated-plus maze (EPM) were used to detect stress-coping and anxiety-like behavior, respectively. Real-time RT-PCR and ELISA were used to analyze hippocampal expression of genes mediating synaptic function. Results Animals fed a HF diet post-weaning spent more time immobile in the FST. Swimming time was reduced in response to both maternal and post-weaning HF diets. Both maternal and post-weaning HF diets contributed to anxiety-like behavior in animals exposed to the EPM. Maternal and post-weaning HF diets were associated with a significant decrease in mRNA and protein expression for hippocampal GDNF, MAP2, SNAP25, and synaptophysin. Hippocampal mRNA expression of key serotonergic and glutamatergic receptors also exhibited differential responses to maternal and post-weaning HF diets. Hippocampal serotonergic receptor 5HT1A mRNA was reduced in response to both the maternal and post-weaning diet, whereas, 5HT2A receptor mRNA expression was increased in response to the maternal HF diet. The glutamate AMPA receptor subunit, GluA1, mRNA expression was significantly reduced in response to both diets, whereas no change was detected in GluA2 subunit mRNA expression. Conclusion These data demonstrate that the expression of genes mediating synaptic function are differentially affected by maternal and post-weaning high-fat diets. The post-weaning high-fat diet clearly disturbs both behavior and gene expression. In addition, although the transition to control diet at weaning partially compensates for the adverse effects of the maternal HF diet, the negative consequence of the maternal HF diet is exacerbated by continuing the high-fat diet post-weaning. We present evidence to support the claim that these dietary influences increase the risk for anxiety and impaired stress-coping abilities in adulthood.
Collapse
Affiliation(s)
- Kathleen C Page
- Department of Biology, Bucknell University, Lewisburg, PA, United States
| | - Endla K Anday
- College of Medicine, Drexel University, Philadelphia, PA, United States
| |
Collapse
|
|
6
|
Du D, Tang Q, Han Q, Zhang J, Liang X, Tan Y, Liu K, Xiang B. Association between genetic polymorphism and antidepressants in major depression: a network meta-analysis. Pharmacogenomics 2020; 21:963-974. [PMID: 32819202 DOI: 10.2217/pgs-2020-0037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
This network meta-analysis was conducted to compare the predictive value of eight SNPs on the efficacy of antidepressants in major depressive disorder (MDD), including 5-HTTLPR, 5HTR2A (rs6311, rs6314, rs7997012 and rs6313), 5HTR2A (rs6295), BDNF (rs6265) and 5HTTSTin2. Databases were searched for related studies published up to December 2019. A total of 16 studies were included in this study. The predictive value were evaluated by the use of the odd ratios (OR) and drawing surface under the cumulative ranking curves (SUCRA). The pairwise meta-analysis indicated that in terms of overall response ratio, the SNPs were not associated with the efficacy of antidepressants in MDD. The result of this network meta-analysis suggested that there was no significant difference in predictive value of eight SNPs on the efficacy of antidepressants in MDD. More research is needed to explore the relationship between SNPs and antidepressant response.
Collapse
Affiliation(s)
- Dan Du
- Department of Psychiatry, Laboratory of Neurological Diseases & Brain Function, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China
| | - Qiong Tang
- Department of Psychiatry, Laboratory of Neurological Diseases & Brain Function, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China
| | - Qiong Han
- Department of Breast Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China
| | - Jin Zhang
- Department of Psychiatry, Laboratory of Neurological Diseases & Brain Function, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China.,Zigong Mental Health Research Center & Institute on Aging at Zigong, Zigong, 643020, Sichuan Province, China
| | - Xuemei Liang
- Geriatrics Department, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China
| | - Youguo Tan
- Zigong Mental Health Center, Zigong, 643020, Sichuan Province, China.,Zigong Mental Health Research Center & Institute on Aging at Zigong, Zigong, 643020, Sichuan Province, China
| | - Kezhi Liu
- Department of Psychiatry, Laboratory of Neurological Diseases & Brain Function, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China
| | - Bo Xiang
- Department of Psychiatry, Laboratory of Neurological Diseases & Brain Function, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China.,Zigong Mental Health Research Center & Institute on Aging at Zigong, Zigong, 643020, Sichuan Province, China
| |
Collapse
|
|
7
|
Zhao L, Wang H, Zhang Y, Wei J, Ni P, Ren H, Li G, Wang Q, Reynolds GP, Yue W, Deng W, Yan H, Tan L, Chen Q, Yang G, Lu T, Wang L, Zhang F, Yang J, Li K, Lv L, Tan Q, Li Y, Yu H, Zhang H, Ma X, Yang F, Li L, Wang C, Wang H, Li X, Guo W, Hu X, Tian Y, Ma X, Coid J, Zhang D, Chen C, Li T. Interaction Between Variations in Dopamine D2 and Serotonin 2A Receptor is Associated with Short-Term Response to Antipsychotics in Schizophrenia. Neurosci Bull 2019; 35:1102-1105. [PMID: 31571100 DOI: 10.1007/s12264-019-00432-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/12/2019] [Indexed: 02/05/2023] Open
Affiliation(s)
- Liansheng Zhao
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Huijuan Wang
- The National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, 710069, China
| | - Yamin Zhang
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Jinxue Wei
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Peiyan Ni
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Hongyan Ren
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Gang Li
- Shaanxi Lifegen Co., Ltd, Xi'an, 712000, China
| | - Qiang Wang
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Gavin P Reynolds
- Biomolecular Science Research Centre, Sheffield Hallam University, Sheffield, S11WB, UK
| | - Weihua Yue
- Peking University Sixth Hospital (Institute of Mental Health), Beijing, 100083, China.,National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, 100871, China
| | - Wei Deng
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Hao Yan
- Peking University Sixth Hospital (Institute of Mental Health), Beijing, 100083, China.,National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, 100871, China
| | - Liwen Tan
- Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Qi Chen
- Beijing Anding Hospital, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100088, China
| | - Guigang Yang
- Beijing HuiLongGuan Hospital, Beijing, 102200, China
| | - Tianlan Lu
- Peking University Sixth Hospital (Institute of Mental Health), Beijing, 100083, China.,National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, 100871, China
| | - Lifang Wang
- Peking University Sixth Hospital (Institute of Mental Health), Beijing, 100083, China.,National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, 100871, China
| | - Fuquan Zhang
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, 214121, China
| | - Jianli Yang
- Institute of Mental Health, Tianjin Anding Hospital, Tianjin, 300222, China.,Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, 300052, China
| | - Keqing Li
- Hebei Mental Health Center, Baoding, 071000, China
| | - Luxian Lv
- Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, China
| | - Qingrong Tan
- Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Yinfei Li
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Hua Yu
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Hongyan Zhang
- Peking University Sixth Hospital (Institute of Mental Health), Beijing, 100083, China.,National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, 100871, China
| | - Xin Ma
- Beijing Anding Hospital, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100088, China
| | - Fude Yang
- Beijing HuiLongGuan Hospital, Beijing, 102200, China
| | - Lingjiang Li
- Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Chuanyue Wang
- Beijing Anding Hospital, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100088, China
| | - Huiyao Wang
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Xiaojing Li
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Wanjun Guo
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Xun Hu
- Huaxi Biobank, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Yang Tian
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Xiaohong Ma
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Jeremy Coid
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Dai Zhang
- Peking University Sixth Hospital (Institute of Mental Health), Beijing, 100083, China.,National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, 100871, China
| | - Chao Chen
- The National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, 710069, China.
| | - Tao Li
- Psychiatric Laboratory and Mental Health Center, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China. .,West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
| | | |
Collapse
|
|
8
|
Bartova L, Dold M, Kautzky A, Fabbri C, Spies M, Serretti A, Souery D, Mendlewicz J, Zohar J, Montgomery S, Schosser A, Kasper S. Results of the European Group for the Study of Resistant Depression (GSRD) - basis for further research and clinical practice. World J Biol Psychiatry 2019; 20:427-448. [PMID: 31340696 DOI: 10.1080/15622975.2019.1635270] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Objectives: The overview outlines two decades of research from the European Group for the Study of Resistant Depression (GSRD) that fundamentally impacted evidence-based algorithms for diagnostics and psychopharmacotherapy of treatment-resistant depression (TRD). Methods: The GSRD staging model characterising response, non-response and resistance to antidepressant (AD) treatment was applied to 2762 patients in eight European countries. Results: In case of non-response, dose escalation and switching between different AD classes did not show superiority over continuation of original AD treatment. Predictors for TRD were symptom severity, duration of the current major depressive episode (MDE), suicidality, psychotic and melancholic features, comorbid anxiety and personality disorders, add-on treatment, non-response to the first AD, adverse effects, high occupational level, recurrent disease course, previous hospitalisations, positive family history of MDD, early age of onset and novel associations of single nucleoid polymorphisms (SNPs) within the PPP3CC, ST8SIA2, CHL1, GAP43 and ITGB3 genes and gene pathways associated with neuroplasticity, intracellular signalling and chromatin silencing. A prediction model reaching accuracy of above 0.7 highlighted symptom severity, suicidality, comorbid anxiety and lifetime MDEs as the most informative predictors for TRD. Applying machine-learning algorithms, a signature of three SNPs of the BDNF, PPP3CC and HTR2A genes and lacking melancholia predicted treatment response. Conclusions: The GSRD findings offer a unique and balanced perspective on TRD representing foundation for further research elaborating on specific clinical and genetic hypotheses and treatment strategies within appropriate study-designs, especially interaction-based models and randomized controlled trials.
Collapse
Affiliation(s)
- Lucie Bartova
- Department of Psychiatry and Psychotherapy, Medical University of Vienna , Vienna , Austria
| | - Markus Dold
- Department of Psychiatry and Psychotherapy, Medical University of Vienna , Vienna , Austria
| | - Alexander Kautzky
- Department of Psychiatry and Psychotherapy, Medical University of Vienna , Vienna , Austria
| | - Chiara Fabbri
- Department of Biomedical and NeuroMotor Sciences, University of Bologna , Bologna , Italy.,Institute of Psychiatry, Psychology and Neuroscience, King's College London , London , United Kingdom
| | - Marie Spies
- Department of Psychiatry and Psychotherapy, Medical University of Vienna , Vienna , Austria
| | - Alessandro Serretti
- Department of Biomedical and NeuroMotor Sciences, University of Bologna , Bologna , Italy
| | | | | | - Joseph Zohar
- Psychiatric Division, Chaim Sheba Medical Center , Tel Hashomer , Israel
| | | | - Alexandra Schosser
- Department of Psychiatry and Psychotherapy, Medical University of Vienna , Vienna , Austria.,Zentrum für seelische Gesundheit Leopoldau, BBRZ-MED , Vienna , Austria
| | - Siegfried Kasper
- Department of Psychiatry and Psychotherapy, Medical University of Vienna , Vienna , Austria
| |
Collapse
|
|
9
|
Gassó P, Blázquez A, Rodríguez N, Boloc D, Torres T, Mas S, Lafuente A, Lázaro L. Further Support for the Involvement of Genetic Variants Related to the Serotonergic Pathway in the Antidepressant Response in Children and Adolescents After a 12-Month Follow-Up: Impact of the HTR2A rs7997012 Polymorphism. J Child Adolesc Psychopharmacol 2018; 28:711-718. [PMID: 29975559 DOI: 10.1089/cap.2018.0004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Objective: Fluoxetine is an effective and well-tolerated pharmacological treatment for children and adolescents with major depressive disorder (MDD). However, a high percentage of patients do not respond. There is a substantial genetic contribution to this variable clinical outcome. Based on previous genetic results of our group and given the lack of pharmacogenetics studies of antidepressant response with a long follow-up period, we evaluated the influence of single nucleotide polymorphisms (SNPs) in genes related to the serotonergic pathway on remission and recovery in children and adolescents diagnosed with MDD after 12 months of initiating fluoxetine treatment. Methods: The assessment was performed in 46 patients. All of them were visited at least once a month during the 12-month follow-up. Psychiatrists interviewed patients and their parents to explore clinical improvement. A total of 75 genotyped SNPs in 10 candidate genes were included in the genetic association analysis with remission and recovery. Bonferroni correction for multiple testing was applied to avoid false positive results. Results: The HTR2A rs7997012 SNP was significantly associated after Bonferroni correction with clinical improvement. Particularly, the homozygotes for the major allele (GG) showed the highest percentage of remitters and the highest score reductions on the Clinical Global Impressions-Severity (CGI-S) scale. Moreover, although the results were on the border of statistical significance, the GG homozygotes also tended to experience fewer readmissions during the follow-up period Conclusions: These results provide more evidence of the involvement of genetic variants related to the serotonergic pathway in the antidepressant response. Studies with larger cohorts are needed to integrate all relevant variants into clinical predictors of antidepressant response.
Collapse
Affiliation(s)
- Patricia Gassó
- Department of Basic Clinical Practice, Unit of Pharmacology, University of Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ana Blázquez
- Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Natalia Rodríguez
- Department of Basic Clinical Practice, Unit of Pharmacology, University of Barcelona, Barcelona, Spain
| | - Daniel Boloc
- Department of Medicine, University of Barcelona, Barcelona, Spain
| | - Teresa Torres
- Department of Basic Clinical Practice, Unit of Pharmacology, University of Barcelona, Barcelona, Spain
| | - Sergi Mas
- Department of Basic Clinical Practice, Unit of Pharmacology, University of Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain
| | - Amalia Lafuente
- Department of Basic Clinical Practice, Unit of Pharmacology, University of Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain
| | - Luisa Lázaro
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic de Barcelona, Barcelona, Spain.,Department of Medicine, University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain
| |
Collapse
|
|
10
|
Pharmacogenetics and Imaging-Pharmacogenetics of Antidepressant Response: Towards Translational Strategies. CNS Drugs 2016; 30:1169-1189. [PMID: 27752945 DOI: 10.1007/s40263-016-0385-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Genetic variation underlies both the response to antidepressant treatment and the occurrence of side effects. Over the past two decades, a number of pharmacogenetic variants, among these the SCL6A4, BDNF, FKBP5, GNB3, GRIK4, and ABCB1 genes, have come to the forefront in this regard. However, small effects sizes, mixed results in independent samples, and conflicting meta-analyses results led to inherent difficulties in the field of pharmacogenetics translating these findings into clinical practice. Nearly all antidepressant pharmacogenetic variants have potentially pleiotropic effects in which they are associated with major depressive disorder, intermediate phenotypes involved in emotional processes, and brain areas affected by antidepressant treatment. The purpose of this article is to provide a comprehensive review of the advances made in the field of pharmacogenetics of antidepressant efficacy and side effects, imaging findings of antidepressant response, and the latest results in the expanding field of imaging-pharmacogenetics studies. We suggest there is mounting evidence that genetic factors exert their impact on treatment response by influencing brain structural and functional changes during antidepressant treatment, and combining neuroimaging and genetic methods may be a more powerful way to detect biological mechanisms of response than either method alone. The most promising imaging-pharmacogenetics findings exist for the SCL6A4 gene, with converging associations with antidepressant response, frontolimbic predictors of affective symptoms, and normalization of frontolimbic activity following antidepressant treatment. More research is required before imaging-pharmacogenetics informed personalized medicine can be applied to antidepressant treatment; nevertheless, inroads have been made towards assessing genetic and neuroanatomical liability and potential clinical application.
Collapse
|
|
11
|
Qesseveur G, Petit AC, Nguyen HT, Dahan L, Colle R, Rotenberg S, Seif I, Robert P, David D, Guilloux JP, Gardier AM, Verstuyft C, Becquemont L, Corruble E, Guiard BP. Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: A translational approach. Neuropharmacology 2016; 105:142-153. [PMID: 26764241 DOI: 10.1016/j.neuropharm.2015.12.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 12/23/2015] [Accepted: 12/24/2015] [Indexed: 01/31/2023]
Abstract
Pharmacological studies have yielded valuable insights into the role of the serotonin 2A (5-HT2A) receptor in major depressive disorder (MDD) and antidepressant drugs (ADs) response. However, it is still unknown whether genetic variants in the HTR2A gene affect the therapeutic outcome of ADs and the mechanism underlying the regulation of such response remains poorly described. In this context, a translational human-mouse study offers a unique opportunity to address the possibility that variations in the HTR2A gene may represent a relevant marker to predict the efficacy of ADs. In a first part of this study, we investigated in depressed patients the effect of three HTR2A single nucleotide polymorphisms (SNPs), selected for their potential functional consequences on 5-HT2A receptor (rs6313, rs6314 and rs7333412), on response and remission rates after 3 months of antidepressant treatments. We also explored the consequences of the constitutive genetic inactivation of the 5-HT2A receptor (i.e. in 5-HT2A(-/-) mice) on the activity of acute and prolonged administration of SSRIs. Our clinical data indicate that GG patients for the rs7333412 SNP were less prone to respond to ADs than AA/AG patients. In the preclinical study, we demonstrated that the 5-HT2A receptor exerts an inhibitory influence on the neuronal activity of the serotonergic system after acute administration of SSRIs. However, while the chronic administration of the SSRIs escitalopram or fluoxetine elicited a progressive increased in the firing rate of 5-HT neurons in 5-HT2A(+/+) mice, it failed to do so in 5-HT2A(-/-) mutants. These electrophysiological impairments were associated with a decreased ability of the chronic administration of fluoxetine to stimulate hippocampal plasticity and to produce antidepressant-like activities. Genetic loss of the 5-HT2A receptor compromised the activity of chronic treatment with SSRIs, making this receptor a putative marker to predict ADs response.
Collapse
Affiliation(s)
- Gaël Qesseveur
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France
| | - Anne Cécile Petit
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, CESP, Fac Médecine Paris Sud, 94275, Le Kremlin Bicêtre, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service de Psychiatrie, Le Kremlin Bicêtre, F-94275, France
| | - Hai Thanh Nguyen
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France
| | - Lionel Dahan
- Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France
| | - Romain Colle
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, CESP, Fac Médecine Paris Sud, 94275, Le Kremlin Bicêtre, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service de Psychiatrie, Le Kremlin Bicêtre, F-94275, France
| | - Samuel Rotenberg
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, CESP, Fac Médecine Paris Sud, 94275, Le Kremlin Bicêtre, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service de Psychiatrie, Le Kremlin Bicêtre, F-94275, France
| | - Isabelle Seif
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France
| | - Pauline Robert
- UMS IPSIT (INST. Paris-Saclay d'innovation Thérapeutique), Paris Sud, France
| | - Denis David
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France
| | - Jean-Philippe Guilloux
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France
| | - Alain M Gardier
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France
| | - Céline Verstuyft
- INSERM U1184, Le Kremlin Bicêtre, F-94276, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service de Génétique moléculaire, Pharmacogénétique et Hormonologie, Le Kremlin Bicêtre, F-94275, France
| | - Laurent Becquemont
- INSERM U1184, Le Kremlin Bicêtre, F-94276, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service de Génétique moléculaire, Pharmacogénétique et Hormonologie, Le Kremlin Bicêtre, F-94275, France
| | - Emmanuelle Corruble
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, CESP, Fac Médecine Paris Sud, 94275, Le Kremlin Bicêtre, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service de Psychiatrie, Le Kremlin Bicêtre, F-94275, France.
| | - Bruno P Guiard
- Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France; Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France
| |
Collapse
|
|
12
|
Höfer P, Schosser A, Calati R, Serretti A, Massat I, Kocabas NA, Konstantinidis A, Mendlewicz J, Souery D, Zohar J, Juven-Wetzler A, Montgomery S, Kasper S. The impact of serotonin receptor 1A and 2A gene polymorphisms and interactions on suicide attempt and suicide risk in depressed patients with insufficient response to treatment--a European multicentre study. Int Clin Psychopharmacol 2016; 31:1-7. [PMID: 26544898 DOI: 10.1097/yic.0000000000000101] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
So far, associations between serotonergic neurotransmission pathways and suicidality have been reported. The aim of our study was to investigate the role of genetic polymorphisms and gene-gene interactions of the 5-HTR1A and the 5-HTR2A gene on suicide risk and/or a personal history of suicide attempts. A total of 374 major depressive disorder patients, adequately treated with antidepressants for at least 4 weeks, were collected in the context of a European multicentre study on treatment-resistant depression. We assessed suicidality using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of adequate antidepressant treatment. The 5-HTR1A rs6295 (C-1019G) single nucleotide polymorphism (SNP) and the 5-HTR2A rs7997012, rs6313, rs643627 and rs17288723 SNPs were selected for genotyping. Using logistic regression analyses, no association (P<0.05) could be found between any SNP and neither suicide risk nor personal history of suicide attempts. Interactions between 5HTR1A rs6295 and 5HTR2A rs6313 in suicide risk, and 5HTR1A rs6295 and 5HTR2A rs643627 in a personal history of suicide attempts have been reported (P=0.027 and 0.036, respectively); however, the results did not survive multiple testing correction. In conclusion, our study shows no association between 5HTR1A or 5HTR2A gene polymorphisms and both current suicide risk and personal history of suicide attempts. In addition, epistatic effects of 5HTR1A and 5HTR2A genes on suicidal behaviour were not significant, although sample size limitations do not allow definitive conclusions.
Collapse
Affiliation(s)
- Peter Höfer
- aDepartment of Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Bern, Bern, Switzerland bDepartment of Psychiatry and Psychotherapy, Medical University of Vienna cZentrum für Seelische Gesundheit Leopoldau, BBRZ-Med, Vienna dZentrum für Seelische Gesundheit Muldenstrasse, BBRZ-Med, Linz, Austria eINSERM U1061, University of Montpellier, FondaMental Foundation, Montpellier, France fDepartment of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy gLaboratory of Experimental Neurology, National Fund of Scientific Research, Université Libre de Bruxelles hUniversité Libre de Bruxelles iLaboratoire de Psychologie Medicale, Université Libre de Bruxelles and Psy Pluriel, Centre Europe en de Psychologie Medicale, Bruxelles, Belgium jDepartment of Toxicology, Faculty of Pharmacy, University of Gazi, Etiler Ankara, Turkey kChaim Sheba Medical Center, Tel-Hashomer, Israel lImperial College, School of Medicine, University of London, UK
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Mast Cell Serotonin Immunoregulatory Effects Impacting on Neuronal Function: Implications for Neurodegenerative and Psychiatric Disorders. Neurotox Res 2015; 28:147-53. [PMID: 26038194 DOI: 10.1007/s12640-015-9533-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 05/15/2015] [Accepted: 05/15/2015] [Indexed: 01/05/2023]
Abstract
Mast cells (MCs) are derived from hemopoietic precursor cells, undergo their maturation in peripheral tissues, and play a significant role in both the innate and adaptive immune response. Cross-linking of the FcεRI on MCs initiates activation of several cytoplasmic protein tyrosine kinases which rapidly lead to phosphorylation and recruitment of adaptor molecules. These effects trigger the release of preformed mediators stored in the cytoplasmic granules, including histamine, serotonin and tryptase, as well as newly synthesized mediators, such as cytokines/chemokines, prostaglandins, leukotrienes, and growth factors. Serotonin (5-HT) is a bioactive monoamine, which has seven specific cell surface membrane bound receptors which are coupled to G-proteins, plays an important role in the central and peripheral nervous system, and is one of the key mediators in signaling between nervous and immune systems. Serotonin is not stored in all MC types but is implicated in MC adhesion, chemotaxis, tumorigenesis, and tissue regeneration through smooth muscle differentiation of stromal cells. Recent evidence indicates that serotonin has immunoregulatory actions that may be important in neuropsychiatric conditions. Chemokines, RANTES/CCL5, MCP-1/CCL2, and related molecules, constitute the C-C class of chemokine supergene family, play a role in regulating T helper-cell cytokine production and MC trafficking, and are involved in histamine and serotonin generation and MC functions. Pro-inflammatory cytokines such as interleukin-1-β and tumor necrosis factor which mediate MC response, are capable of activating p38 MAPK, and might increase serotonin generation through p38 MAPK activation. Here, we review the relationship between MCs and serotonin and its role in inflammatory diseases and neuroimmune interactions.
Collapse
|
|
14
|
Lin JY, Jiang MY, Kan ZM, Chu Y. Influence of 5-HTR2A genetic polymorphisms on the efficacy of antidepressants in the treatment of major depressive disorder: a meta-analysis. J Affect Disord 2014; 168:430-8. [PMID: 25108775 DOI: 10.1016/j.jad.2014.06.012] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 06/03/2014] [Accepted: 06/05/2014] [Indexed: 01/11/2023]
Abstract
OBJECTIVE The aim of the current meta-analysis was to assess the influence of common genetic polymorphisms in the 5-HTR2A gene on the efficacy of antidepressants in the treatment of major depressive disorder (MDD). METHOD MEDLINE (1966-2013), Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982-2013), Web of Science (1945-2013) and Chinese Biomedical Database (CBM) (1982-2013) were searched without language restrictions. Meta-analysis was performed using the STATA statistical software. We calculated the odds ratio (OR) and its 95% confidence interval (95% CI) to estimate the efficacy of antidepressants in the treatment of MDD. RESULTS Eleven studies with a total of 1775 MDD patients met the inclusion criteria of this meta-analysis. Three common polymorphisms in the 5-HTR2A gene were assessed, including rs6311 C>T, rs7997012 G>A, and rs6313 T>C. Our findings suggested that the 5-HTR2A rs6313 T>C polymorphism was significantly correlated with a higher response rate to antidepressants in MDD patients (allele model: OR=1.33, 95% CI=1.05-1.68, P=0.020; dominant model: OR=1.62, 95% CI=1.21-2.18, P=0.001; homozygous model: OR=1.85, 95% CI=1.18-2.90, P=0.008). The rs7997012 G>A polymorphism was also associated with a higher response rate to antidepressants in MDD patients under the dominant model (OR=1.92, 95% CI=1.02-3.61, P=0.044). However, no significant correlation was found for the 5-HTR2A rs6311 C>T polymorphism under five genetic models (all P>0.05). CONCLUSION Our findings provide empirical evidence that the 5-HTR2A rs6313 T>C and rs7997012 G>A polymorphism may be correlated with the efficacy of antidepressants in the treatment of MDD.
Collapse
Affiliation(s)
- Jian-Yang Lin
- Department of Pharmacy, the First Hospital of China Medical University, Nanjing Street No. 155, Heping District, Shenyang 110001, PR China.
| | - Ming-Yan Jiang
- Department of Pharmacy, the First Hospital of China Medical University, Nanjing Street No. 155, Heping District, Shenyang 110001, PR China
| | - Zhou-Mi Kan
- Department of Pharmacy, the First Hospital of China Medical University, Nanjing Street No. 155, Heping District, Shenyang 110001, PR China
| | - Yang Chu
- Department of Pharmacy, the First Hospital of China Medical University, Nanjing Street No. 155, Heping District, Shenyang 110001, PR China
| |
Collapse
|
|
15
|
Ren H, Wey HY, Strebl M, Neelamegam R, Ritter T, Hooker JM. Synthesis and imaging validation of [¹⁸F]MDL100907 enabled by Ni-mediated fluorination. ACS Chem Neurosci 2014; 5:611-5. [PMID: 24845956 DOI: 10.1021/cn500078e] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Several voids exist in reliable positron emission tomography (PET) radioligands for quantification of the serotonin (5HT) receptor system. Even in cases where 5HT radiotracers exist, challenges remain that have limited the utility of 5HT imaging in clinical research. Herein we address an unmet need in 5HT2a imaging using innovative chemistry. We report a scalable and robust synthesis of [(18)F]MDL100907, which was enabled by a Ni-mediated oxidative fluorination using [(18)F]fluoride. This first demonstration of a Ni-mediated fluorination used for PET imaging required development of a new reaction strategy that ultimately provided high specific activity [(18)F]MDL100907. Using the new synthetic strategy and optimized procedure, [(18)F]MDL100907 was evaluated against [(11)C]MDL100907 for reliability to quantify 5HT₂a in the nonhuman primate brain and was found to be superior based on a single scan analysis using the same nonhuman primate. The use of this new 5HT₂a radiotracer will afford clinical neuroscience research the ability to distinguish 5HT₂a receptor abnormalities binding between healthy subjects and patients even when group differences are small.
Collapse
Affiliation(s)
- Hong Ren
- Athinoula A. Martinos
Center for Biomedical Imaging, Massachusetts General Hospital and
Harvard Medical School, 13th Street, Charlestown, Massachusetts 02129, United States
- Department
of Chemistry and Chemical Biology, Harvard University, 12 Oxford
Street, Cambridge, Massachusetts 02138, United States
| | - Hsiao-Ying Wey
- Athinoula A. Martinos
Center for Biomedical Imaging, Massachusetts General Hospital and
Harvard Medical School, 13th Street, Charlestown, Massachusetts 02129, United States
| | - Martin Strebl
- Department
of Chemistry and Chemical Biology, Harvard University, 12 Oxford
Street, Cambridge, Massachusetts 02138, United States
| | - Ramesh Neelamegam
- Athinoula A. Martinos
Center for Biomedical Imaging, Massachusetts General Hospital and
Harvard Medical School, 13th Street, Charlestown, Massachusetts 02129, United States
| | - Tobias Ritter
- Department
of Chemistry and Chemical Biology, Harvard University, 12 Oxford
Street, Cambridge, Massachusetts 02138, United States
| | - Jacob M. Hooker
- Athinoula A. Martinos
Center for Biomedical Imaging, Massachusetts General Hospital and
Harvard Medical School, 13th Street, Charlestown, Massachusetts 02129, United States
| |
Collapse
|
|
16
|
Nasr S, Wendt B, Popli A, Crayton J. Comparing outcomes of adjunctive treatment in depression: aripiprazole versus bupropion. J Affect Disord 2014; 162:50-4. [PMID: 24767005 DOI: 10.1016/j.jad.2014.03.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 03/14/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND Adjunctive therapy in depression is often used in patients with an inadequate response to antidepressant therapy. METHODS Utilizing a chart review from a private, outpatient psychiatric clinic, patients with adjunctive medication added to their antidepressant were reviewed. Demographic information, diagnoses, medication history, and QIDS SR16 depression scores were collected and recorded at each visit and entered into a database. RESULTS Significant reductions were observed in the QIDS score of aripiprazole (n=70) and bupropion (n=83) patients after the first visit. At the first visit, 70% of aripiprazole patients had lower QIDS score compared to baseline visit, with 17% achieving remission, whereas 66% of bupropion users had lower scores at the first visit compared to baseline visit, with 23% achieving remission. At the end of the observation period 50% of patients on aripiprazole achieved remission compared to 33% of bupropion patients. Both groups of patients had significant reductions in their QIDS symptom scores of sadness, concentration, and general interest. In addition, aripiprazole patients had a decrease in the thoughts of death and suicide score while bupropion patients had decreases in the low energy score. None of the differences in QIDS line-item scores between aripiprazole and bupropion patients were statistically significant. LIMITATIONS This study was a small scale, retrospective study that did not have a placebo control group. CONCLUSION Aripiprazole and bupropion were comparable in significantly lowering patients' QIDS SR16 scores and helping over 50% of the patients achieve remission. Differences in line-item QIDS score were also observed.
Collapse
Affiliation(s)
- Suhayl Nasr
- Nasr Psychiatric Services, Michigan City, IN, United States; Indiana University, Department of Psychiatry, Michigan City, IN, United States; University of Notre Dame, Department of Psychology, Notre Dame, IN, United States; Memorial Epworth Center, South Bend, IN 46617, United States.
| | - Burdette Wendt
- Nasr Psychiatric Services, Michigan City, IN, United States
| | - Anand Popli
- Nasr Psychiatric Services, Michigan City, IN, United States; Indiana University, Department of Psychiatry, Michigan City, IN, United States
| | - John Crayton
- Nasr Psychiatric Services, Michigan City, IN, United States
| |
Collapse
|
|
17
|
Fabbri C, Porcelli S, Serretti A. From pharmacogenetics to pharmacogenomics: the way toward the personalization of antidepressant treatment. CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE 2014; 59:62-75. [PMID: 24881125 PMCID: PMC4079233 DOI: 10.1177/070674371405900202] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Major depressive disorder is the most common psychiatric disorder, worldwide, yet response and remission rates are still unsatisfactory. The identification of genetic predictors of antidepressant (AD) response could provide a promising opportunity to improve current AD efficacy through the personalization of treatment. The major steps and findings along this path are reviewed together with their clinical implications and limitations. METHOD We systematically reviewed the literature through MEDLINE and Embase database searches, using any word combination of "antidepressant," "gene," "polymorphism," "pharmacogenetics," "genome-wide association study," "GWAS," "response," and "adverse drug reactions." Experimental works and reviews published until March 2012 were collected and compared. RESULTS Numerous genes pertaining to several functional systems were associated with AD response. The more robust findings were found for the following genes: solute carrier family 6 (neurotransmitter transporter), member 4; serotonin receptor 1A and 2A; brain-derived neurotrophic factor; and catechol-O-methyltransferase. Genome-wide association studies (GWASs) provided many top markers, even if none of them reached genome-wide significance. CONCLUSIONS AD pharmacogenetics have not produced any knowledge applicable to routine clinical practice yet, as results were mainly inconsistent across studies. Despite this, the rising awareness about methodological deficits of past studies could allow for the identication of more suitable strategies, such as the integration of the GWAS approach with the candidate gene approach, and innovative methodologies, such as pathway analysis and study of depressive endophenotypes.
Collapse
Affiliation(s)
- Chiara Fabbri
- Researcher, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Stefano Porcelli
- Researcher, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Alessandro Serretti
- Professor, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| |
Collapse
|
|
18
|
Guo H, Ren Y, Zhao N, Wang Y, Li S, Cui H, Zhang S, Zhang J. Synergistic effect of 5-HT2A receptor gene and MAOA gene on the negative emotion of patients with depression. Clin Physiol Funct Imaging 2013; 34:277-81. [PMID: 24314147 DOI: 10.1111/cpf.12094] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 09/25/2013] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To analyse the synergistic effect of polymorphism of the tandem repeat sequence u-VNTR of 5-hydroxytryptamine 2A (5-HT2A) receptor gene and monoamine oxidase A (MAOA) gene on the negative emotion in frontal lobe of patients with depression through functional magnetic resonance imaging (fMRI) technique. METHODS Functional magnetic resonance imaging scanning was performed for 72 patients with depression and 70 gender, age-matched healthy people with physical examination under negative emotion recognition task. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was adopted to analyse genotype. The superior, middle and inferior gyrus of bilateral frontal lobe was regarded as the brain region of interest, and then the difference of activation intensity in frontal lobe subregion between control groups and patient groups with different genotypes, and the interaction between the two kinds of polymorphism were compared. RESULTS The activation intensity in right frontal middle gyrus of patients with CC genotype increased obviously compared with TT and TC genotype patient groups and TT genotype control group (P<0·01); the activation intensity in right frontal inferior gyrus of patients with CC genotype increased obviously compared with TT and TC genotype patient groups and control groups (P<0·01); the activation intensity in right frontal middle gyrus and left frontal inferior gyrus of patients with MAOA high-activity genotype increased obviously compared with patient and control groups with MAOA low-activity genotype (P<0·01). In sum, there existed synergistic effect of the two genotypes on the activation abnormality of negative emotion recognition in right frontal middle gyrus (F = 6·18, P = 0·029). The negative activation in right frontal middle gyrus of patients with CC+H genotypes increased most obviously (P<0·05). CONCLUSION The frontal abnormality of patients with depression had certain 5-HT genetic basis, and 5-HT2A receptor CC allele and MAOA-H genotype had synergistic effect on the activity abnormality when recognizing negative emotion in right frontal middle gyrus of patients with depression.
Collapse
Affiliation(s)
- Huirong Guo
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Altar CA, Hornberger J, Shewade A, Cruz V, Garrison J, Mrazek D. Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. Int Rev Psychiatry 2013; 25:509-33. [PMID: 24151799 DOI: 10.3109/09540261.2013.825579] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness.
Collapse
|
|
20
|
Variation in the HTR1A and HTR2A genes and social adjustment in depressed patients. J Affect Disord 2013; 150:649-52. [PMID: 23537781 DOI: 10.1016/j.jad.2013.02.036] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2012] [Revised: 02/15/2013] [Accepted: 02/18/2013] [Indexed: 01/27/2023]
Abstract
BACKGROUND Social adjustment is impaired in depressed patients. The difficulty to adjust to social circumstances has been hypothesized to be one of the causes of depression, as well as a consequence of the disorder. Genetic variation in the serotonin transporter gene has been previously associated with social adjustment levels in patients with mood disorders. METHODS We investigated whether variations on the HTR1A (rs6295) and HTR2A (rs7997012) genes were associated with levels of social adjustment using the Social Adjustment Scale in two samples of depressed patients (total n=156). RESULTS Patients carrying the GG genotype of the HTR2A-rs7997012 showed better social adjustment in areas of work and family unit bonding. LIMITATIONS These findings did not survive correction for multiple testing and should be interpreted with caution. CONCLUSION Our finding is in line with previous observations that have associated the G allele of the HTR2A-rs7997012 with higher rate of antidepressant response. The HTR2A-rs7997012 is worthy of further investigation in studies examining factors that are related to depression course and outcome.
Collapse
|
|
21
|
Fabbri C, Di Girolamo G, Serretti A. Pharmacogenetics of antidepressant drugs: an update after almost 20 years of research. Am J Med Genet B Neuropsychiatr Genet 2013; 162B:487-520. [PMID: 23852853 DOI: 10.1002/ajmg.b.32184] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2012] [Accepted: 06/19/2013] [Indexed: 12/12/2022]
Abstract
Major depressive disorder (MDD) is an emergent cause of personal and socio-economic burden, both for the high prevalence of the disorder and the unsatisfying response rate of the available antidepressant treatments. No reliable predictor of treatment efficacy and tolerance in the single patient is available, thus drug choice is based on a trial and error principle with poor clinical efficiency. Among modulators of treatment outcome, genetic polymorphisms are thought to explain a significant share of the inter-individual variability. The present review collected the main pharmacogenetic findings primarily about antidepressant response and secondly about antidepressant induced side effects, and discussed the main strengths and limits of both candidate and genome-wide association studies and the most promising methodological opportunities and challenges of the field. Despite clinical applications of antidepressant pharmacogenetics are not available yet, previous findings suggest that genotyping may be applied in the clinical practice. In order to reach this objective, further rigorous pharmacogenetic studies (adequate sample size, study of better defined clinical subtypes of MDD, adequate covering of the genetic variability), their combination with the results obtained through complementary methodologies (e.g., pathway analysis, epigenetics, transcriptomics, and proteomics), and finally cost-effectiveness trials are required.
Collapse
Affiliation(s)
- Chiara Fabbri
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | | | | |
Collapse
|
|
22
|
Niitsu T, Fabbri C, Bentini F, Serretti A. Pharmacogenetics in major depression: a comprehensive meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2013; 45:183-94. [PMID: 23733030 DOI: 10.1016/j.pnpbp.2013.05.011] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 05/20/2013] [Accepted: 05/26/2013] [Indexed: 10/26/2022]
Abstract
A number of candidate gene studies focused on major depression (MD) and antidepressant (AD) efficacy have been carried out, but results mainly remain inconclusive. We performed a comprehensive meta-analysis of published candidate gene studies focused on AD efficacy in MD to evaluate the cumulative evidence. A random-effect model was applied to study the polymorphisms with genotypic counts available from at least three independent studies. On the base of previous evidence, the analysis was stratified by ethnicity (Caucasian, Asian, and other/mixed), and AD class (SSRIs and mixed/other ADs). Genotypic data were available for 16 polymorphisms in 11 genes. After the exclusion of 5-HTTLPR in SLC6A4 included in another recent meta-analysis, 15 polymorphisms in 11 genes were included in the present meta-analysis (BDNF rs6265, SLC6A4 STin2, HTR1A rs6295, HTR2A rs6311, rs6313 and rs7997012, HTR6 rs1805054, TPH1 rs1800532, SLC6A2 rs5569, COMT rs4680, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs1045642 and rs2032582). Our results suggested that BDNF rs6265 (Val66Met) heterozygous genotype was associated with better SSRIs response compared to the homozygous genotypes, particularly in Asians (OR=1.53, 95%CI 1.12-2.07, p=0.007). SLC6A4 STin2, HTR2A rs6311 and rs7997012, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs2032582 showed associations with AD efficacy, but these results were highly dependent on one or two single studies. In conclusion, our findings suggested the BDNF Val66Met as the best single candidate involved in AD response, with a selective effect on SSRI treatment. Our overall results supported no major effect of any single gene variant on AD efficacy.
Collapse
Affiliation(s)
- Tomihisa Niitsu
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | | | | | | |
Collapse
|
|
23
|
Serretti A, Fabbri C, Pellegrini S, Porcelli S, Politi P, Bellino S, Menchetti M, Mariotti V, Demi C, Martinelli V, Cappucciati M, Bozzatello P, Brignolo E, Brambilla P, Pae CU, Balestrieri M, De Ronchi D. No effect of serotoninergic gene variants on response to interpersonal counseling and antidepressants in major depression. Psychiatry Investig 2013; 10:180-9. [PMID: 23798967 PMCID: PMC3687053 DOI: 10.4306/pi.2013.10.2.180] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Revised: 10/22/2012] [Accepted: 11/06/2012] [Indexed: 01/18/2023] Open
Abstract
OBJECTIVE Gene variants within the serotonin pathway have been associated with major depressive disorder (MDD) treatment outcomes, however a possible different modulation on pharmacological or psychological treatments has never been investigated. METHODS One hundred sixty MDD patients were partially randomized to either inter-personal counseling (IPC) or antidepressants. The primary outcome was remission at week 8. Five serotonergic polymorphisms were investigated (COMT rs4680, HTR1A rs6295, HTR2A rs2224721, HTR2A rs7997012 and SLC6A4 rs421417). RESULTS IPC (n=43) and antidepressant (n=117) treated patients did not show any difference in remission rates at week 8 (corrected for baseline severity, age and center). None of the studied gene variants impacted on response and remission rates at week 8 neither in the IPC nor in the antidepressant group. An analysis of the whole sample showed a trend of association between rs7997012 AA genotype and a better treatment outcome. CONCLUSION Our study confirms that IPC is an effective psychological intervention comparable to antidepressants in mild-moderate MDD. Polymorphisms related to the serotonin system did not exert a major effect on clinical outcomes in none of the treatment groups.
Collapse
Affiliation(s)
- Alessandro Serretti
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Chiara Fabbri
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Silvia Pellegrini
- Department of Experimental Pathology, Medical Biotechnology, Epidemiology and Infectious Diseases, University of Pisa, Pisa, Italy
| | - Stefano Porcelli
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Pierluigi Politi
- Department of Health Sciences, Section of Psychiatry, University of Pavia, Pavia, Italy
| | | | - Marco Menchetti
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Veronica Mariotti
- Department of Experimental Pathology, Medical Biotechnology, Epidemiology and Infectious Diseases, University of Pisa, Pisa, Italy
| | - Cristina Demi
- Department of Experimental Pathology, Medical Biotechnology, Epidemiology and Infectious Diseases, University of Pisa, Pisa, Italy
| | - Valentina Martinelli
- Department of Health Sciences, Section of Psychiatry, University of Pavia, Pavia, Italy
| | - Marco Cappucciati
- Department of Health Sciences, Section of Psychiatry, University of Pavia, Pavia, Italy
| | | | | | - Paolo Brambilla
- Inter-University Centre for Behavioural Neurosciences (ICBN), University of Verona, Verona and DPMSC, Section of Psychiatry, University of Udine, Udine, Italy
| | - Chi-Un Pae
- Department of Psychiatry, Bucheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Bucheon, Republic of Korea
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
| | - Matteo Balestrieri
- Inter-University Centre for Behavioural Neurosciences (ICBN), University of Verona, Verona and DPMSC, Section of Psychiatry, University of Udine, Udine, Italy
| | - Diana De Ronchi
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| |
Collapse
|
|
24
|
Lebe M, Hasenbring MI, Schmieder K, Jetschke K, Harders A, Epplen JT, Hoffjan S, Kötting J. Association of serotonin-1A and -2A receptor promoter polymorphisms with depressive symptoms, functional recovery, and pain in patients 6 months after lumbar disc surgery. Pain 2012; 154:377-384. [PMID: 23318131 DOI: 10.1016/j.pain.2012.11.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Revised: 10/28/2012] [Accepted: 11/20/2012] [Indexed: 02/08/2023]
Abstract
Single nucleotide polymorphisms (SNPs) in the serotonergic (5HT) system seem to have modulatory effects on depression and physical function. Preliminary evidence suggests that gene×environment interactions play a role in the development of depression, with somatic complaints serving as environmental stressors. We hypothesized that pain intensity may serve as a stress factor that modulates the association between SNPs in the 5HT system and depression. We investigated symptoms of pain, depression, physical functioning, and disability in 224 patients 6months after lumbar disc surgery. Associations between these variables and functional promoter SNPs in the serotonin receptor genes 5HTR1A (rs6295) and 5HTR2A (rs6311) were analyzed. For 5HTR2A, we found a significant gene×environment×sex interaction, as female patients carrying at least one A allele of the -1438A/G promoter SNP had significantly higher depression scores when confronted with severe pain compared to women harboring the GG genotype (P=.005). For 5HTR1A, patients homozygous for the -1019 G allele presented higher Beck Depression Inventory scores relative to the CG/CC group, indicating a major effect of this SNP on depression. Furthermore, women homozygous for either the 5HTR1A G allele or the 5HTR2A A allele had lower levels of physical functioning than patients with the other genotypes. These results suggest that 5HTR1A and 5HTR2A promoter variations have gender-dependent modulatory effects on depression and physical function in patients with pain. Furthermore, this study demonstrates that pain after lumbar surgery modulates the association between 5HT gene polymorphisms and depression.
Collapse
Affiliation(s)
- Moritz Lebe
- Department of Medical Psychology and Medical Sociology, Faculty of Medicine, Ruhr University of Bochum, Bochum, Germany Department of Neurosurgery, University of Mannheim, Mannheim, Germany Department of Neurosurgery, Knappschaftskrankenhaus Ruhr University of Bochum, Bochum, Germany Department of Human Genetics, Ruhr University of Bochum, Bochum, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Fluoxetine pharmacogenetics in child and adult populations. Eur Child Adolesc Psychiatry 2012; 21:599-610. [PMID: 22791347 DOI: 10.1007/s00787-012-0305-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 06/24/2012] [Indexed: 01/08/2023]
Abstract
Although fluoxetine is useful in the treatment of major depression, 30-40 % of the patients do not respond to therapy. The response seems to be influenced by certain genes which are involved in the drug's pharmacodynamics and pharmacokinetics. The present study reviews the literature on genetic contributions to fluoxetine response in children and adults, and concludes that the different polymorphisms of CYP2D6 and CYP2C9 may influence the blood concentrations of fluoxetine. If the childhood dose is adjusted for weight, differences between children and adults are unlikely. As regards the genes that influence the drug's pharmacodynamics, polymorphisms of SLC6A4, HTR1A and MAO-A seem to be involved in the response to fluoxetine, while the genes COMT, CRHR1, PDEA1, PDEA11 GSK3B and serpin-1 also seem to play a role. Comparison of different studies reveals that the results are not always consistent, probably due to methodological differences. Other factors such as gender or ethnicity may also influence treatment response.
Collapse
|
|
26
|
Computational exploration of polymorphisms in 5-Hydoxytryptamine 5-HT1A and 5-HT2A receptors associated with psychiatric disease. Gene 2012; 502:16-26. [DOI: 10.1016/j.gene.2012.04.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 02/13/2012] [Accepted: 04/05/2012] [Indexed: 01/12/2023]
|
|
27
|
European Group for the Study of Resistant Depression (GSRD)--where have we gone so far: review of clinical and genetic findings. Eur Neuropsychopharmacol 2012; 22:453-68. [PMID: 22464339 DOI: 10.1016/j.euroneuro.2012.02.006] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 02/22/2012] [Indexed: 12/22/2022]
Abstract
The primary objective of this review is to give an overview of the main findings of the European multicenter project "Patterns of Treatment Resistance and Switching Strategies in Affective Disorder", performed by the Group for the Study of Resistant Depression (GSRD). The aim was to study methodological issues, operational criteria, clinical characteristics, and genetic variables associated with treatment resistant depression (TRD), that is failure to reach response after at least two consecutive adequate antidepressant trials. The primary findings of clinical variables associated with treatment resistance include comorbid anxiety disorders as well as non-response to the first antidepressant received lifetime. Although there is a plethora of hints in textbooks that switching the mechanism of action should be obtained in case of nonresponse to one medication, the results of the GSRD challenge this notion by demonstrating in retrospective and prospective evaluations that staying on the same antidepressant mechanism of action for a longer time is more beneficial than switching, however, when switching is an option there is no benefit to switch across class. The GSRD candidate gene studies found that metabolism status according to cytochrome P450 gene polymorphisms may not be helpful to predict response and remission rates to antidepressants. Significant associations with MDD and antidepressant treatment response were found for COMT SNPs. Investigating the impact of COMT on suicidal behaviour, we found a significant association with suicide risk in MDD patients not responding to antidepressant treatment, but not in responders. Further significant associations with treatment response phenotypes were found with BDNF, 5HTR2A and CREB1. Additional investigated candidate genes were DTNBP1, 5HT1A, PTGS2, GRIK4 and GNB3.
Collapse
|
|
28
|
Narasimhan S, Lohoff FW. Pharmacogenetics of antidepressant drugs: current clinical practice and future directions. Pharmacogenomics 2012; 13:441-64. [PMID: 22380000 PMCID: PMC12046622 DOI: 10.2217/pgs.12.1] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
While antidepressants are widely used to treat mood and anxiety disorders, only half of the patients will respond to antidepressant treatment and only one-third of patients experience a full remission of symptoms. The identification of genetic biomarkers that predict antidepressant-treatment response can improve current clinical practice. This is an emerging field known as pharmacogenetics, which comprises of genetic studies on both the pharmacokinetics and pharmacodynamics of treatment response. Recent studies on antidepressant-treatment response have focused on both aspects of pharmacogenetics research, identifying new candidate genes that may predict better treatment response for patients. This paper reviews recent findings on the pharmacogenetics of antidepressant drugs and future clinical applications. Ultimately, these studies should lead to the use of genetic testing to guide the use of antidepressants in clinical practice.
Collapse
Affiliation(s)
| | - Falk W Lohoff
- Department of Psychiatry , Center for Neurobiology & Behavior, Translational Research Laboratories, 125 South 31st Street, Room 2213, Philadelphia, PA 19104, USA
| |
Collapse
|
|
29
|
Interaction between two HTR2A polymorphisms and gender is associated with treatment response in MDD. Neurosci Lett 2011; 501:20-4. [PMID: 21741447 DOI: 10.1016/j.neulet.2011.06.031] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2011] [Accepted: 06/21/2011] [Indexed: 12/13/2022]
Abstract
The 5HT2A receptor gene (HTR2A) polymorphisms rs7997012 and rs6311 have in some earlier studies been associated with serotonin selective reuptake inhibitor (SSRI) treatment response in major depressive disorder (MDD), but the findings are inconsistent. The aim of the present study was to test for an association between two HTR2A polymorphisms (rs7997012 and rs6311), their interaction and the Montgomery and Åsberg Depression Rating Scale (MADRS) score change after ECT or SSRI treatment. The total number of patients was 218. All were treated in outpatient care. Of these, 119 subjects had treatment-resistant MDD and were treated with ECT and 99 were depressive patients treated with SSRI. Treatment response was assessed by MADRS. Patients scoring <8 on post-treatment MADRS were considered remitters. Neither rs7997012 nor rs6311 HTR2A polymorphism was significantly associated with MADRS score change alone, but the interaction between them and gender explained 14% of the variance in MADRS score change. The finding suggests an association between MADRS score change and interaction of HTR2A polymorphisms, rs7997012 and rs6311 and gender.
Collapse
|
|
30
|
Crisafulli C, Fabbri C, Porcelli S, Drago A, Spina E, De Ronchi D, Serretti A. Pharmacogenetics of antidepressants. Front Pharmacol 2011; 2:6. [PMID: 21687501 PMCID: PMC3108562 DOI: 10.3389/fphar.2011.00006] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 02/04/2011] [Indexed: 12/28/2022] Open
Abstract
Up to 60% of depressed patients do not respond completely to antidepressants (ADs) and up to 30% do not respond at all. Genetic factors contribute for about 50% of the AD response. During the recent years the possible influence of a set of candidate genes as genetic predictors of AD response efficacy was investigated by us and others. They include the cytochrome P450 superfamily, the P-glycoprotein (ABCB1), the tryptophan hydroxylase, the catechol-O-methyltransferase, the monoamine oxidase A, the serotonin transporter (5-HTTLPR), the norepinephrine transporter, the dopamine transporter, variants in the 5-hydroxytryptamine receptors (5-HT1A, 5-HT2A, 5-HT3A, 5-HT3B, and 5-HT6), adrenoreceptor beta-1 and alpha-2, the dopamine receptors (D2), the G protein beta 3 subunit, the corticotropin releasing hormone receptors (CRHR1 and CRHR2), the glucocorticoid receptors, the c-AMP response-element binding, and the brain-derived neurotrophic factor. Marginal associations were reported for angiotensin I converting enzyme, circadian locomotor output cycles kaput protein, glutamatergic system, nitric oxide synthase, and interleukin 1-beta gene. In conclusion, gene variants seem to influence human behavior, liability to disorders and treatment response. Nonetheless, gene × environment interactions have been hypothesized to modulate several of these effects.
Collapse
|