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

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) a 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 the 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.

Evaluation of Dissolution Profiles of a Newly Developed Solid Oral Immediate-Release Formula Containing Alpha-Lipoic Acid

“…LA supplementation significantly reduces TBARS, AOPP, improves TAS levels in healthy subjects, but it showed significant differences in bipolar or schizophrenic patients group [42][43][44] a need for well-designed clinical trials to enhance the clinical evidence of ALA effects [45].…”

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“…Consequently, psychopharmacology has focused on the discovery of new therapeutic classes that facilitate the efficient drainage of interstitial fluid, for a proper elimination of soluble metabolites (13). Although the option for clozapine is surprising, it is beneficial in such patients (14), as clozapine does not in itself act on the drainage of interstitial fluid, but is a facilitator that allows improved efficacy of acetylcholinesterase inhibitors. Clozapine is thus retained as a backup medication when resistance to antidementia treatment appears to have set in.…”

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