Pharmacogenomics-Driven Prediction of Antidepressant Treatment Outcomes: A Machine-Learning Approach With Multi-trial Replication

Arjun P. Athreya, Drew Neavin, Tania Carrillo-Roa, Michelle Skime, Joanna Biernacka, Mark A. Frye, A. John Rush, Liewei Wang, Elisabeth B. Binder, Ravishankar K. Iyer, Richard M. Weinshilboum, William V. Bobo

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

We set out to determine whether machine learning–based algorithms that included functionally validated pharmacogenomic biomarkers joined with clinical measures could predict selective serotonin reuptake inhibitor (SSRI) remission/response in patients with major depressive disorder (MDD). We studied 1,030 white outpatients with MDD treated with citalopram/escitalopram in the Mayo Clinic Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS; n = 398), Sequenced Treatment Alternatives to Relieve Depression (STAR*D; n = 467), and International SSRI Pharmacogenomics Consortium (ISPC; n = 165) trials. A genomewide association study for PGRN-AMPS plasma metabolites associated with SSRI response (serotonin) and baseline MDD severity (kynurenine) identified single nucleotide polymorphisms (SNPs) in DEFB1, ERICH3, AHR, and TSPAN5 that we tested as predictors. Supervised machine-learning methods trained using SNPs and total baseline depression scores predicted remission and response at 8 weeks with area under the receiver operating curve (AUC) > 0.7 (P < 0.04) in PGRN-AMPS patients, with comparable prediction accuracies > 69% (P ≤ 0.07) in STAR*D and ISPC. These results demonstrate that machine learning can achieve accurate and, importantly, replicable prediction of SSRI therapy response using total baseline depression severity combined with pharmacogenomic biomarkers.

Original languageEnglish (US)
Pages (from-to)855-865
Number of pages11
JournalClinical pharmacology and therapeutics
Volume106
Issue number4
DOIs
StatePublished - Oct 1 2019

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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