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Neuroplasticity and second messenger pathways in antidepressant efficacy: pharmacogenetic results from a prospective trial investigating treatment resistance

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Abstract

Genes belonging to neuroplasticity, monoamine, circadian rhythm, and transcription factor pathways were investigated as modulators of antidepressant efficacy. The present study aimed (1) to replicate previous findings in an independent sample with treatment-resistant depression (TRD), and (2) to perform a pathway analysis to investigate the possible molecular mechanisms involved. 220 patients with major depressive disorder who were non-responders to a previous antidepressant were treated with venlafaxine for 4–6 weeks and in case of non-response with escitalopram for 4–6 weeks. Symptoms were assessed using the Montgomery Asberg Depression Rating Scale. The phenotypes were response and remission to venlafaxine, non-response (TRDA) and non-remission (TRDB) to neither venlafaxine nor escitalopram. 50 tag SNPs in 14 genes belonging to the pathways of interest were tested for association with phenotypes. Molecular pathways (KEGG database) that included one or more of the genes associated with the phenotypes were investigated also in the STAR*D sample. The associations between ZNF804A rs7603001 and response, CREB1 rs2254137 and remission were replicated, as well as CHL1 rs2133402 and lower risk of TRD. Other CHL1 SNPs were potential predictors of TRD (rs1516340, rs2272522, rs1516338, rs2133402). The MAPK1 rs6928 SNP was consistently associated with all the phenotypes. The protein processing in endoplasmic reticulum pathway (hsa04141) was the best pathway that may explain the mechanisms of MAPK1 involvement in antidepressant response. Signals in genes previously associated with antidepressant efficacy were confirmed for CREB1, ZNF804A and CHL1. These genes play pivotal roles in synaptic plasticity, neural activity and connectivity.

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Acknowledgements

We thank the NIMH for having had the possibility of analyzing their data on the STAR*D sample. We also thank the authors of previous publications in this dataset, and foremost, we thank the patients and their families who accepted to be enrolled in the study. Data and biomaterials were obtained from the limited access datasets distributed from the NIH-supported “Sequenced Treatment Alternatives to Relieve Depression” (STAR*D). The study was supported by NIMH Contract No. N01MH90003 to the University of Texas Southwestern Medical Center. The ClinicalTrials.gov identifier is NCT00021528.

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Authors and Affiliations

  1. Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123, Bologna, Italy

    Chiara Fabbri, Rosalba Martines & Alessandro Serretti

  2. Department of Biomedical Science, Odontoiatric and Morphological and Functional Images, University of Messina, Messina, Italy

    Concetta Crisafulli & Marco Calabrò

  3. INSERM U1061, France and FondaMental Foundation, University of Montpellier UM1, Montpellier, France

    Raffaella Calati

  4. Laboratory of Biology of Neurodegenerative Disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy

    Diego Albani, Gianluigi Forloni & Rosalba Martines

  5. Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria

    Siegfried Kasper

  6. Department of Psychiatry, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Joseph Zohar & Alzbeta Juven-Wetzler

  7. Laboratoire de Psychologie Medicale, Centre Européen de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Brussels, Belgium

    Daniel Souery

  8. lmperial College School of Medicine, London, UK

    Stuart Montgomery

  9. Université Libre de Bruxelles, Brussels, Belgium

    Julien Mendlewicz

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  1. Chiara Fabbri
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  14. Alessandro Serretti
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Corresponding author

Correspondence to Alessandro Serretti.

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Conflict of interest

Dr. Souery D. has received grant/research support from GlaxoSmithKline and Lundbeck; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen and Lundbeck. Prof. Montgomery S. 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 S. has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen, and Novartis; and has served on speakers’ bureaus for AstraZeneca, Eli Lily, Lundbeck, Schwabe, Sepracor, Servier, Pierre Fabre, Janssen and Neuraxpharm. Prof. Zohar J. 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 J. is a member of the Board of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier. Prof. Serretti A. 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.

Role of the funding source

This study was supported by an unrestricted grant from Lundbeck for the Group for the Study of Resistant Depression (GSRD). Lundbeck had no further role in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication. All authors were actively involved in the design of the study, the analytical method of the study, the selection and review of all scientific content. All authors had full editorial control during the writing of the manuscript and finally approved it. Trial registry name: Australian New Zealand Clinical Trials Registry. (ANZCTR). Registration identification number: ACTRN12613000256774. URL for the registry: http://www.ANZCTR.org.au/ACTRN12613000256774.aspx.

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Fabbri, C., Crisafulli, C., Calati, R. et al. Neuroplasticity and second messenger pathways in antidepressant efficacy: pharmacogenetic results from a prospective trial investigating treatment resistance. Eur Arch Psychiatry Clin Neurosci 267, 723–735 (2017). https://doi.org/10.1007/s00406-017-0766-1

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