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Intranasal esketamine has recently come onto the market as an antidepressant. Besides experience from short\u2010term use in anaesthesia and analgesia, the experience with ketamine as long\u2010term medication is rather low. The use of ketamine and esketamine is limited due to potential neurotoxicity, psychotomimetic side effects, potential abuse and interindividual variability in treatment response including cessation of therapy. Therefore, taking a look at individual patient risks and potential underlying variability in pharmacokinetics may improve safety and dosing of these new antidepressant drugs in clinical practice.<\/jats:p><jats:p>Differential drug metabolism due to polymorphic cytochrome P450 (CYP) enzymes and gene\u2010drug interactions are known to influence the efficacy and safety of many drugs. Ketamine and esketamine are metabolized by polymorphic CYP enzymes including CYP2B6, CYP3A4, CYP2C9 and CYP2A6. In antidepressant drug therapy, usually multiple drugs are administered which are substrates of CYP enzymes, increasing the risk for drug\u2013drug interactions. We reviewed the potential impact of polymorphic CYP variants and common drug\u2013drug interactions in antidepressant drug therapy affecting ketamine pharmacokinetics, and the role for dose optimization. The use of ketamine or intranasal esketamine as antidepressants demands a better understanding of the factors that may impact its metabolism and efficacy in long\u2010term use. In addition to other clinical and environmental confounders, prior information on the pharmacodynamic and pharmacokinetic determinants of response variability to ketamine and esketamine may inform on dose optimization and identification of individuals at risk of adverse drug reactions.<\/jats:p>","DOI":"10.1111\/bcp.15467","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T22:03:28Z","timestamp":1658441008000},"page":"5149-5165","source":"Crossref","is-referenced-by-count":38,"title":["Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant \u2010 implications for precision dosing in a global perspective"],"prefix":"10.1111","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5862-708X","authenticated-orcid":false,"given":"Immaculate M.","family":"Langmia","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacology University Hospital of RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6782-8078","authenticated-orcid":false,"given":"Katja S.","family":"Just","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology University Hospital of RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Yamoune","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology University Hospital of RWTH Aachen  Aachen Germany"},{"name":"Federal Institute for Drugs and Medical Devices, BfArM  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian Peter","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology University Hospital of RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia C.","family":"Stingl","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology University Hospital of RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,5]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/NNR.0000000000000164"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010016\u20100383\u20106"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/2045125320916657"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.2019.102"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2017.17020239"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/mhw.32471"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2013.01.007"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12630\u2010011\u20109560\u20100"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.18553\/jmcp.2020.26.1.16"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.117.015198"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010020\u201000953\u20104"},{"key":"e_1_2_13_13_1","unstructured":"FDA.FDA\u2010Approved Drugs New Drug Application (NDA): 016812 (Ketamine Hydrochloride). 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