The serotonin transporter and the activity regulated cytoskeleton-associated protein genes in antidepressant response and resistance: 5-HTTLPR and other variants
Marco Calabrò
Department of Biomedical and Dental Sciences and Morphofunctional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy
Search for more papers by this authorChiara Fabbri
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Search for more papers by this authorConcetta Crisafulli
Department of Biomedical and Dental Sciences and Morphofunctional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy
Search for more papers by this authorDiego Albani
Laboratory of Biology of Neurodegenerative Disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
Search for more papers by this authorGianluigi Forloni
Laboratory of Biology of Neurodegenerative Disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
Search for more papers by this authorSiegfried Kasper
Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria
Search for more papers by this authorAntonina Sidoti
Department of Biomedical and Dental Sciences and Morphofunctional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy
Search for more papers by this authorElvira Velardi
Department of Biomedical and Dental Sciences and Morphofunctional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy
Search for more papers by this authorJoseph Zohar
Department of Psychiatry, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Search for more papers by this authorAlzbeta Juven-Wetzler
Department of Psychiatry, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Search for more papers by this authorDaniel Souery
Laboratoire de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels, Belgium
Search for more papers by this authorStuart Montgomery
Imperial College, University of London, London, UK
Search for more papers by this authorJulien Mendlewicz
School of Medicine, Free University of Brussels, Brussels, Belgium
Search for more papers by this authorCorresponding Author
Alessandro Serretti
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Correspondence
Alessandro Serretti, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna 40123, Italy.
Email: [email protected]
Search for more papers by this authorMarco Calabrò
Department of Biomedical and Dental Sciences and Morphofunctional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy
Search for more papers by this authorChiara Fabbri
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Search for more papers by this authorConcetta Crisafulli
Department of Biomedical and Dental Sciences and Morphofunctional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy
Search for more papers by this authorDiego Albani
Laboratory of Biology of Neurodegenerative Disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
Search for more papers by this authorGianluigi Forloni
Laboratory of Biology of Neurodegenerative Disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
Search for more papers by this authorSiegfried Kasper
Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria
Search for more papers by this authorAntonina Sidoti
Department of Biomedical and Dental Sciences and Morphofunctional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy
Search for more papers by this authorElvira Velardi
Department of Biomedical and Dental Sciences and Morphofunctional Images, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, Messina, Italy
Search for more papers by this authorJoseph Zohar
Department of Psychiatry, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Search for more papers by this authorAlzbeta Juven-Wetzler
Department of Psychiatry, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Search for more papers by this authorDaniel Souery
Laboratoire de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels, Belgium
Search for more papers by this authorStuart Montgomery
Imperial College, University of London, London, UK
Search for more papers by this authorJulien Mendlewicz
School of Medicine, Free University of Brussels, Brussels, Belgium
Search for more papers by this authorCorresponding Author
Alessandro Serretti
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Correspondence
Alessandro Serretti, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna 40123, Italy.
Email: [email protected]
Search for more papers by this authorAbstract
Objective
Previous evidence suggested the involvement of serotonin transporter (SLC6A4) and activity regulated cytoskeleton-associated protein (ARC) in antidepressant action. This study investigated their role in antidepressant efficacy and treatment-resistant depression (TRD).
Methods
Three samples (n total = 648) were investigated to test the association between treatment outcomes (response, remission, symptom improvement, and TRD) and 11 polymorphisms within SLC6A4 and ARC genes. The possible modulating effect of age and gender was considered. Response and remission were also investigated using a fixed-effects meta-analysis of the three samples.
Results
SLC6A4 5-HTTLPR/rs25531 effects on symptom improvement were modulated by age (better improvement in L/LA carriers in older subjects) and gender (better improvement in L/LA female carriers). SLC6A4 STin2 long alleles were associated with remission and lower risk of TRD. Preliminary evidence of association between ARC rs11167152/rs10110456 and different outcomes was found.
Conclusions
5-HTTLPR/rs25531 effect on antidepressant efficacy was modulated by age, in line with previous literature data. STin2 effect on antidepressant efficacy was in line with previous meta-analyses. A new possible effect of ARC variants on antidepressant efficacy was observed; however, further studies in larger samples are needed to confirm their role.
CONFLICT OF INTEREST
Dr. Souery has received grant/research support from GlaxoSmithKline and Lundbeck and has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen and Lundbeck.
Prof. Montgomery has been a consultant or served on Advisory boards: AstraZeneca, Bionevia, Bristol Myers Squibb, Forest, GlaxoSmithKline, Grunenthal, Intellect Pharma, Johnson & Johnson, Lilly, Lundbeck, Merck, Merz, M's Science, Neurim, Otsuka, Pierre Fabre, Pfizer, Pharmaneuroboost, Richter, Roche, Sanofi, Sepracor, Servier, Shire, Synosis, Takeda, Theracos, Targacept, Transcept, UBC, Xytis, and Wyeth.
Prof. Kasper has received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Eli Lilly, Janssen, KRKA-Pharma, Lundbeck, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe, and Servier.
Prof. Zohar has received grant/research support from Lundbeck, Servier, and Pfizer, has served as a consultant or on advisory boards for Servier, Pfizer, Solvay and Actelion, and has served on speakers' bureaus for Lundbeck, GSK, Jazz, and Solvay.
Prof. Mendlewicz is a member of the Board of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier.
Prof. Serretti is or has been consultant/speaker for Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier.
All other authors declare no conflict of interest.
Supporting Information
| Filename | Description |
|---|---|
| hup2682-sup-0001-Table_S1.docxWord 2007 document , 686.2 KB |
Table S1. Clinical-demographic characteristics of EU-TRD1 (Supplementary Table 1a), EU-TRD2 (Supplementary Table 1b) and IT-D sample (Supplementary Table 1c). Table S2. SNPs analyzed with Hardy–Weinberg (HW) test. Minor allele frequency (MAF). observed and predicted heterozygosity (ObsHET. PredHET). Table S3a. Results of primary analyses in EU-TRD1 (whole sample). Anxiety and suicide risk were used as covariates because of their impact on phenotypes. Table S3b. Results of primary analyses in EU-TRD1 (NoCh*) subsample. Table S3c. Results of primary analyses in EU-TRD1 (MDD subsample). Anxiety and suicide risk were used as covariates because of their impact on phenotypes. Table S4a. Results of primary analyses in EU-TRD2. Anxiety and suicide risk were used as covariates because of their impact on phenotypes. Table S4b. Results of primary analysis in EU-TRD2 after exclusion of subjects with chronic depression (defined as the 25% of subjects with the longest duration of the current episode). Table S5a. Results of primary analyses in IT-D sample. Suicide risk was used as covariate. Table S5b. Results of analysis in IT-D sample after exclusion of subjects with chronic depression (defined as the 25% of subjects with the longest duration of the current episode). Table S6a. Results of secondary analyses in EU-TRD1. Table S6b. Results of secondary analyses in EU-TRD2. HDRS=Hamilton Depression Rating Scale. MADRS = Montgomery-Åsberg Depression Rating Scale. Table S6c. results of secondary analyses in IT-D sample. HDRS=Hamilton Depression Rating Scale. Table S7. Significant results of a fixed-effects meta-analysis including the three investigated samples. Table S8. Best models including 2, 3, 4 and 5 SNPs in EU-TRD2. Phenotype was remission to venlafaxine. Figure S1: results of repeated-measure analyses in the longitudinal samples (EU-TRD2 and IT-D). Only comparisons showing evidence of association with binary phenotypes were tested also using this approach. The significance of each model was estimated comparing it with the corresponding null-model using ANOVA. Figure S2: Forest plots representing the results of the meta-analysis of the three investigated samples. Only the MDD subjects of EU-TRD1 sample were considered for the meta-analyses. The significant genotype-based comparisons are shown. Figure S3: the strongest epistatic interaction came from ARC (rs10097505) and SLC6A4 (rs2066713). High and low risk genotypes are represented in the figure below. Figure S4: all genotypic combinations were reported for the significant model including ARC (rs7465272), ARC (rs10097505) and SLC6A4(rs2066713). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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