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Combining clozapine and the selective serotonin reuptake inhibitor (SSRI) sertraline represents a clinically important strategy in patients with therapy\u2010resistant schizophrenia, but there is limited knowledge about mutual pharmacokinetic interactions. In the present study, we assessed the impact of clozapine on sertraline plasma concentrations. Based on a therapeutic drug monitoring (TDM) database, sertraline plasma concentrations were compared between two groups: patients receiving a combined treatment with sertraline and clozapine (<jats:italic>N<\/jats:italic>\u00a0=\u200915) and a matched control group receiving sertraline but no clozapine (<jats:italic>N<\/jats:italic>\u00a0=\u200917). Group differences with respect to raw and dose\u2010adjusted concentrations were assessed using nonparametric tests. Comedication with clozapine was associated with 67% lower median sertraline plasma concentrations (16 vs. 48\u2009ng\/mL; <jats:italic>p<\/jats:italic>\u00a0=\u2009.022) and 28% lower median dose\u2010adjusted plasma concentrations (C\/D; 0.21 vs. 0.29 (ng\/mL)\/(mg\/day); <jats:italic>p<\/jats:italic>\u00a0=\u2009.049) as compared to the control group. Scatter plots revealed a complex relationship between the dosage of clozapine and dose\u2010adjusted sertraline concentrations composed of an initial decrease at clozapine doses below 300\u2009mg, an increase between 300 and 600\u2009mg and a final decrease at 800\u2009mg which was best modeled by a third order polynomial term. Cotreatment with clozapine may lead to reduced sertraline plasma concentrations which may be explained by clozapine\u2010induced gastrointestinal hypo\u2010mobility already present at low doses and cytochrome P450 3A4 inducing properties at high clozapine doses. For this drug combination, clinicians should consider TDM to confirm therapeutically effective plasma concentrations of sertraline.<\/jats:p>","DOI":"10.1002\/prp2.1065","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T09:10:40Z","timestamp":1677229840000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Lower sertraline plasma concentration in patients co\u2010medicated with clozapine\u2014Implications for pharmacological augmentation strategies in schizophrenia"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8816-3415","authenticated-orcid":false,"given":"Arnim Johannes","family":"Gaebler","sequence":"first","affiliation":[{"name":"Department of Psychiatry Psychotherapy and Psychosomatics, Medical Faculty  Aachen Germany"},{"name":"JARA \u2010 Translational Brain Medicine  Aachen Germany"},{"name":"Institute of Physiology, Medical Faculty  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