Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Clozapine. Pharmacodynamic Mechanisms, Potential Pharmacogenetic Biomarkers, and Risks in Schizophrenia. Particularities in the Context of Covid-19. An Updated Overview

Version 1 : Received: 29 September 2020 / Approved: 30 September 2020 / Online: 30 September 2020 (08:06:26 CEST)
Version 2 : Received: 8 November 2020 / Approved: 9 November 2020 / Online: 9 November 2020 (11:48:29 CET)

A peer-reviewed article of this Preprint also exists.

Dragoi, A.M.; Radulescu, I.; Năsui, B.A.; Pop, A.L.; Varlas, V.N.; Trifu, S. Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety—Particularities in the Context of COVID-19. Brain Sci. 2020, 10, 840. Dragoi, A.M.; Radulescu, I.; Năsui, B.A.; Pop, A.L.; Varlas, V.N.; Trifu, S. Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety—Particularities in the Context of COVID-19. Brain Sci. 2020, 10, 840.


Background: Clozapine use is precarious due to its side effects - neurological, cardiovascular, and hematological; however, it is the gold standard in the therapy of resistant schizophrenia (TRS) in adults and harshly underused. Objective: Our purpose is to systematically examine the most recent data regarding clozapine in order to update the knowledge in pharmacological mechanisms, therapy benefits versus side effects to optimize its use in the context of a narrow and scarce of resources pathology, with particularities in the COVID-19 pandemic. (2) Data sources: We performed an accurate search in the primary sources of Databases (PubMed, BMC Public Health, Global Health, Cross Ref, Scopus, Web of Science, and Google Scholar) with specific keywords: “clozapine” and “schizophrenia,” “risks” agranulocytosis” “TRS” “bipolar affective disorder” “pregnancy” “early-onset schizophrenia” “resistance”. Study eligibility criteria: we extracted information regarding drug treatment, side effects profile, and efficacy for each trial; (3) Results: Of all the searched data we selected RCT’s, C.T.’s, reviews, systematic reviews, and meta-analyses; Data were converted and analyzed in a random-effects model. We included 45 studies, centered on six main topics in the search area: (a) treatment-resistant schizophrenia, (b) use in bipolar disorder, (c) side effects during the clozapine therapy - agranulocytosis, metabolic side effects, pharmacogenetic severity markers, dysmetabolic side effects, pulmonary embolism, seizure risk – (d) safety of clozapine in pregnancy, (e) clozapine resistance and ECT augmentation, (f) clozapine therapy and COVID-19 infection. Limitations: _______(4) Conclusions and implications of key findings: (a) The genetic vulnerability postulates predictors of severity so clozapine doses should be personalises for each patient based on pharmacogenetic testing; patients with a lower genetic risk may benefit from a more relaxed hematological monitoring schedule; (b) Pulmonary embolism associated with clozapine has a mortality rate of 36.36%, prophylactic measures for venous thromboembolism for six months after initiating therapy is mandatory; (c) Convulsive episodes are not an indication for stopping the treatment, side effect (s.e.) incidence increases with the dose, the plasma concentration of clozapine (1300 ng/ml) it is a better s. e. predictor than the dosage; (d) clozapine refractory improves up to 69% early-onset schizophrenia, assesed by the Brief Psychiatric Rating Scale (BPRS) (e) more pharmacogenetic studies of the Romanian schizophrenic patients are needed in relation with the clozapine therapy in order to define more precise safety margins; (f) COVID-19 infection may enhance clozapine toxicity generating an increased risk of pneumonia therapy must be continued with proper monitoring of the white blood count and with the decrease of the clozapine dose by half until three days after the subside of the fever; psychiatrists and healthcare providers must act togheder. As in the past four decades, research has failed to generate effective novel psycho-pharmaceuticals, there is an urgent need to enhance the access to clozapine for people with TRS at the worldwide level. The progress of pharmacogenetic researches, endocrinology, genetic testing - offer the psychiatrists nowadays the chance to use this drug at its highest potential in a personalized manner for every patient - minimizing the adverse side-effects.


clozapine; schizophrenia; early-onset; pregnancy; bipolar affective disorder; agranulocytosis; COVID-19; pharmacogenetic


Medicine and Pharmacology, Immunology and Allergy

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