{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T22:18:01Z","timestamp":1792534681322,"version":"4.5.0"},"reference-count":113,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"INSPIRED","award":["MIS 5002550"],"award-info":[{"award-number":["MIS 5002550"]}]},{"name":"INSPIRED","award":["NSRF 2014\u20132020"],"award-info":[{"award-number":["NSRF 2014\u20132020"]}]},{"name":"Competitiveness, Entrepreneurship and Innovation","award":["MIS 5002550"],"award-info":[{"award-number":["MIS 5002550"]}]},{"name":"Competitiveness, Entrepreneurship and Innovation","award":["NSRF 2014\u20132020"],"award-info":[{"award-number":["NSRF 2014\u20132020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Clozapine is the gold standard for treatment-resistant schizophrenia. Serious and even life-threatening adverse effects, mostly granulocytopenia, myocarditis, and constipation, are of great clinical concern and constitute a barrier to prescribing clozapine, thus depriving many eligible patients of a lifesaving treatment option. Interestingly, clozapine presents variable pharmacokinetics affected by numerous parameters, leading to significant inter- and intra-individual variation. Therefore, therapeutic drug monitoring of plasma clozapine levels confers a significant benefit in everyday clinical practice by increasing the confidence of the prescribing doctor to the drug and the adherence of the patient to the treatment, mainly by ensuring effective treatment and limited dose-related side effects. In the present systematic review, we aimed at identifying how a full range of adverse effects relates to plasma clozapine levels, using the Jadad grading system for assessing the quality of the available clinical evidence. Our findings indicate that EEG slowing, obsessive-compulsive symptoms, heart rate variability, hyperinsulinemia, metabolic syndrome, and constipation correlate to plasma clozapine levels, whereas QTc, myocarditis, sudden death, leucopenia, neutropenia, sialorrhea, are rather unrelated. Rapid dose escalation at the initiation of treatment might contribute to the emergence of myocarditis, or leucopenia. Strategies for managing adverse effects are different in these conditions and are discussed accordingly.<\/jats:p>","DOI":"10.3390\/ph15070817","type":"journal-article","created":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T20:59:18Z","timestamp":1656968358000},"page":"817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Adverse Drug Reactions in Relation to Clozapine Plasma Levels: A Systematic Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8579-8933","authenticated-orcid":false,"given":"Maria","family":"Skokou","sequence":"first","affiliation":[{"name":"Department of Psychiatry, General University Hospital of Patras, School of Medicine, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni A.","family":"Karavia","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoi","family":"Drakou","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, General University Hospital of Patras, School of Medicine, University of Patras, 26504 Patras, Greece"},{"name":"Department of Pharmacology, School of Medicine, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassiliki","family":"Konstantinopoulou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina-Anna","family":"Kavakioti","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, General University Hospital of Patras, School of Medicine, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippos","family":"Gourzis","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, General University Hospital of Patras, School of Medicine, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6784-2710","authenticated-orcid":false,"given":"Kyriakos E.","family":"Kypreos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Patras, 26504 Patras, Greece"},{"name":"Department of Life Sciences, School of Sciences, European University of Cyprus, Nicosia 2404, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ourania","family":"Andreopoulou","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, General University Hospital of Patras, School of Medicine, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,1]]},"reference":[{"key":"ref_1","unstructured":"Miles, S.H. 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