Preprint Review Version 2 Preserved in Portico This version is not peer-reviewed

Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety—Particularities in the Context of COVID-19

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.

Journal reference: Brain Sci. 2020, 10, 840
DOI: 10.3390/brainsci10110840

Abstract

Background: Clozapine (CLZ) use is precarious due to its neurological, cardiovascular, and hematological side effects; however, it is the gold standard in therapy-resistant schizophrenia (TRS) in adults and is underused. Objective: to examine the most recent CLZ data on (a) side effects concerning (b) recent pharmacological mechanisms, (c) therapy benefits, and (d) the particularities of the COVID-19 pandemic. Data sources: a search was performed in two databases (PubMed and Web of Science) using the specific keywords "clozapine" and "schizophrenia," "side effects," "agranulocytosis," "TRS," or "bipolar affective disorder (BAF)" for the last ten years. Study eligibility criteria: clinical trials on adults with acute symptoms of schizophrenia or related disorders. Results: We selected 37 studies, randomized controlled trials (RCTs), and clinical case series (CCS), centered on six main topics in the search area: (a) CLZ in schizophrenia, (b) CLZ in bipolar disorder, (c) side effects during the clozapine therapy, (d) CLZ in pregnancy, (e) CLZ in early-onset schizophrenia, and (f) CLZ therapy and COVID-19 infection. Limitations: We considered RCTs and CCS from two databases, limited to the search topics. Conclusions and implications of key findings: (a) Clozapine doses should be personalized for each patient based on pharmacogenetics testing when available; the genetic vulnerability postulates predictors of adverse reactions' severity; patients with a lower genetic risk could have less frequent hematological monitoring; (b) CLZ-associated risk of pulmonary embolism imposes prophylactic measures for venous thromboembolism; (c) convulsive episodes are not an indication for stopping treatment; the plasma concentration of clozapine is a better side effect predictor than the dosage; (d) 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 the clozapine dose decreased by half until three days after the fever breaks; psychiatrists and healthcare providers must act together. Background: Clozapine (CLZ) use is precarious due to its neurological, cardiovascular, and hematological side effects; however, it is the gold standard in therapy-resistant schizophrenia (TRS) in adults and is underused. Objective: to examine the most recent CLZ data on (a) side effects concerning (b) recent pharmacological mechanisms, (c) therapy benefits, and (d) the particularities of the COVID-19 pandemic. Data sources: a search was performed in two databases (PubMed and Web of Science) using the specific keywords "clozapine" and "schizophrenia," "side effects," "agranulocytosis," "TRS," or "bipolar affective disorder (BAF)" for the last ten years. Study eligibility criteria: clinical trials on adults with acute symptoms of schizophrenia or related disorders. Results: We selected 37 studies, randomized controlled trials (RCTs), and clinical case series (CCS), centered on six main topics in the search area: (a) CLZ in schizophrenia, (b) CLZ in bipolar disorder, (c) side effects during the clozapine therapy, (d) CLZ in pregnancy, (e) CLZ in early-onset schizophrenia, and (f) CLZ therapy and COVID-19 infection. Limitations: We considered RCTs and CCS from two databases, limited to the search topics. Conclusions and implications of key findings: (a) Clozapine doses should be personalized for each patient based on pharmacogenetics testing when available; the genetic vulnerability postulates predictors of adverse reactions' severity; patients with a lower genetic risk could have less frequent hematological monitoring; (b) CLZ-associated risk of pulmonary embolism imposes prophylactic measures for venous thromboembolism; (c) convulsive episodes are not an indication for stopping treatment; the plasma concentration of clozapine is a better side effect predictor than the dosage; (d) 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 the clozapine dose decreased by half until three days after the fever breaks; psychiatrists and healthcare providers must act together.

Subject Areas

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

Comments (1)

Comment 1
Received: 9 November 2020
Commenter: Anca Pop
Commenter's Conflict of Interests: Author
Comment: Title simplified; abstract reduced 
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