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Variation in SSRI pharmacokinetics could explain differences in treatment outcomes, but this is often overlooked as a contributing factor to SSRI tolerability. This study evaluated data from 288 escitalopram\u2010treated and 255 sertraline\u2010treated patients \u2264\u200918\u2009years old to develop machine learning models to predict side effects using electronic health record data and Bayesian estimated pharmacokinetic parameters. Trained on a combined cohort of escitalopram\u2010 and sertraline\u2010treated patients, a penalized logistic regression model achieved an area under the receiver operating characteristic curve (AUROC) of 0.77 (95% confidence interval (CI): 0.66\u20130.88), with 0.69 sensitivity (95% CI: 0.54\u20130.86), and 0.82 specificity (95% CI: 0.72\u20130.87). Medication exposure, clearance, and time since the last dose increase were among the top features. Individual escitalopram and sertraline models yielded an AUROC of 0.73 (95% CI: 0.65\u20130.81) and 0.64 (95% CI: 0.55\u20130.73), respectively. <jats:italic>Post hoc<\/jats:italic> analysis showed sertraline\u2010treated patients with activation side effects had slower clearance (<jats:italic>P<\/jats:italic>\u2009=\u20090.01), which attenuated after accounting for age (<jats:italic>P<\/jats:italic>\u2009=\u20090.055). These findings raise the possibility that a machine learning approach leveraging pharmacokinetic data can predict escitalopram\u2010 and sertraline\u2010related side effects. Clinicians may consider differences in medication pharmacokinetics, especially during dose titration and as opposed to relying on dose, when managing side effects. With further validation, application of this model to predict side effects may enhance SSRI precision dosing strategies in youth.<\/jats:p>","DOI":"10.1002\/cpt.3184","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T01:13:48Z","timestamp":1706750028000},"page":"860-870","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Machine Learning\u2010Based Prediction of Escitalopram and Sertraline Side Effects With Pharmacokinetic Data in Children and Adolescents"],"prefix":"10.1002","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6805-2243","authenticated-orcid":false,"given":"Ethan A.","family":"Poweleit","sequence":"first","affiliation":[{"name":"Division of Biomedical Informatics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Biomedical Informatics University of Cincinnati, College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Research in Patient Services, Department of Pediatrics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9280-1953","authenticated-orcid":false,"given":"Samuel E.","family":"Vaughn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati, College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Child and Adolescent Psychiatry Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Psychiatry and Behavioral Neuroscience University of Cincinnati, College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1513-1295","authenticated-orcid":false,"given":"Zeruesenay","family":"Desta","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Indiana University, School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4196-7846","authenticated-orcid":false,"given":"Judith W.","family":"Dexheimer","sequence":"additional","affiliation":[{"name":"Division of Biomedical Informatics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati, College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Emergency Medicine Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7526-2641","authenticated-orcid":false,"given":"Jeffrey R.","family":"Strawn","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati, College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Child and Adolescent Psychiatry Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Psychiatry and Behavioral Neuroscience University of Cincinnati, College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6417-3961","authenticated-orcid":false,"given":"Laura B.","family":"Ramsey","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Neuroscience University of Cincinnati, College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Clinical Pharmacology, Toxicology &amp; 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