Genetic Determinants of Clozapine-Induced Metabolic Side Effects

Vasudev, Kamini; Choi, Yunhee; Norman, Ross; Kim, Richard B.; Schwarz, Ute I.

doi:10.1177/0706743716670128

Cited by 36 publications

(32 citation statements)

References 52 publications

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“…2013). Klozapin kullanımına bağlı BKİ değişiminde klozapinin hedefi olan 5HT2C reseptör polimorfizmlerinin rolü olduğunu bildiren çalışmalar da mevcuttur (Vasudev ve ark. 2017, Zhang ve ark.…”

Section: Discussionunclassified

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Weight Loss Associated with Clozapine: A Case Report

Mutlu¹,

Eroğlu²,

Ayhan³

et al. 2020

Turkish Journal of Psychiatry

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Section: Discussionunclassified

“…2014). Başka bir çalışmada da LEP-2548A/G polimorfizminin yanı sıra LEPR c.668A>G polimorfizminin de klozapin kullanımına bağlı BKİ değişiminin genetik yordayıcısı olduğu belirtilmiştir (Vasudev ve ark. 2017).…”

Section: Discussionunclassified

Weight Loss Associated with Clozapine: A Case Report

Mutlu¹,

Eroğlu²,

Ayhan³

et al. 2020

Turkish Journal of Psychiatry

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“…Among clozapine-treated patients, elevated levels of CRP were known to be associated with a significant increase in C/D [13,14,17,19]. Clozapine is mainly metabolized via CYP1A2 [28][29][30]. CYP1A2 has been shown to be downregulated during inflammation [1].…”

Section: Discussionmentioning

confidence: 99%

Pathological Concentration of C-reactive Protein is Correlated to Increased Concentrations of Quetiapine, But Not of Risperidone, Olanzapine and Aripiprazole in a Naturalistic Setting

et al. 2019

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Introduction Infections can alter drug clearance, but the impact of inflammation-induced changes is still not well known. The aim of the investigation was to examine the effect of pathological C-reactive protein (CRP) values (≥0.5 mg/dL) and leukocyte count on the metabolism of 4 different atypical antipsychotics. Methods Steady-state serum concentrations of individual patients under therapy with risperidone (n=45), aripiprazole (n=30), olanzapine (n=24), and quetiapine (n=166) were retrospectively analyzed during a period of inflammation by Spearman’s Rho correlation analysis. Mann-Whitney U test was applied for comparison of patients with serum concentrations above and below the upper limit of the therapeutic reference range of each target drug with regard to CRP concentration and leukocyte count. Linear regression analysis was applied to correct for confounding parameters age and sex. Results Pathological concentrations of CRP were significantly associated with elevated values of C/D of quetiapine (n=166, Spearman’s Rho: r=0.269, p<0.001; linear regression: p<0.001). Among patients with quetiapine serum concentrations below 500 ng/mL, CRP concentrations were significantly (p=0.006) lower compared to patients with quetiapine concentrations above 500 ng/mL. A trend for a positive correlation between CRP and serum concentration was found for olanzapine (n=24, Spearman’s Rho: r=0.385, p=0.063; linear regression: p=0.086). Conclusion During a period of inflammation in patients taking quetiapine, according to our results, attention in dosing strategies is required to prevent toxic plasma concentrations.

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“…Two hundred and four studies were published on clozapine and pharmacogenetics topics in the PubMed ® database starting in 1994, with 57 reviews, three systematic reviews or meta-analyses, and 12 clinical trials or RCTs. The genetic vulnerability is correlated with metabolic side effects with a higher prevalence of adverse metabolic reactions in clozapine-treated patients and postulates predictors of severitypharmacogenetics markers such as receptors CYP2C19, LEP, LEPR, and HTR2C [32]. Clozapine's metabolism, elimination, and response were evaluated by genotyping specific enzymes, such as CYP1A2 and CYO2C19, and measuring HTR2C serotonin receptors leptin receptor, taking into account concomitant medication if present.…”

Section: Pharmacogenetic Severity Markers As Potential Biomarkers In mentioning

confidence: 99%

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

Drăgoi¹,

Rădulescu²,

Pop³

et al. 2020

Preprint

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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.

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Genetic Determinants of Clozapine-Induced Metabolic Side Effects

Cited by 36 publications

References 52 publications

Weight Loss Associated with Clozapine: A Case Report

Weight Loss Associated with Clozapine: A Case Report

Pathological Concentration of C-reactive Protein is Correlated to Increased Concentrations of Quetiapine, But Not of Risperidone, Olanzapine and Aripiprazole in a Naturalistic Setting

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

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