Exploring the Prevalence of Clozapine Phenotypic Poor Metabolizers in 4 Asian Samples

Ruan, Can Jun; Wang, Chuanyue; Tang, Yi-Lang; Lin, Shih Ku; Lee, Seung Tae; Hong, Kyung Sue; Rajkumar, Anto P.; Jacob, K. S.; León, José de

doi:10.1097/jcp.0000000000001125

Cited by 42 publications

(47 citation statements)

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“…In five Asian samples, around 7% of the patients (2%-13%) were phenotypic PMs, with no known cause, but four of the five studies were limited by not ruling out current inflammation, which can make a patient look temporarily like a clozapine PM. 7 Thus, it is possible that around 7% (2%-13%) of Asians may have unknown genetic mutations possibly at the CYP1A2 gene associated with being a clozapine PM. 7 Until there is a better definition of clozapine PMs, we recommend considering Asian clozapine PMs as those who reach concentrations of 350 ng/mL with clozapine doses <150 mg/day.…”

Section: Clozapine Metabolismmentioning

confidence: 99%

“…7 Thus, it is possible that around 7% (2%-13%) of Asians may have unknown genetic mutations possibly at the CYP1A2 gene associated with being a clozapine PM. 7 Until there is a better definition of clozapine PMs, we recommend considering Asian clozapine PMs as those who reach concentrations of 350 ng/mL with clozapine doses <150 mg/day. A more precise definition, including smoking and gender stratification, is provided in a review article.…”

Section: Clozapine Metabolismmentioning

confidence: 99%

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Clozapine is strongly associated with the risk of pneumonia and inflammation

et al. 2020

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Clinicians need to remember that (1) systemic inflammations can increase clozapine level; (2) clozapine, by itself, can cause inflammation, particularly during titration that is too rapid for that patient; (3) clozapine may increase the risk of infection; and (4) more specifically, clozapine may be particularly strongly associated with the risk of pneumonia. Pneumonia appears to be associated with high mortality in clozapine patients around the world. Clinicians who are alert to the risk of pneumonia in clozapine patients may significantly decrease mortality in clozapine patients. There is no data on COVID-19 infections in clozapine patients, but based on what we know about clozapine pharmacology, we can hypothesise that clozapine, possibly by impairing immunological mechanisms, may increase the risk of pneumonia in infected patients. More importantly, once fever and/or pneumonia develops, the clozapine dose should be cut in half to decrease the risk of clozapine intoxication. If there is any doubt that in spite of halving the dose there are still signs of clozapine intoxication, completely stopping clozapine may be indicated. Once the signs of inflammation and fever have disappeared, the clozapine dose can be increased to the prior dosage level.

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Section: Clozapine Metabolismmentioning

confidence: 99%

Section: Clozapine Metabolismmentioning

confidence: 99%

Clozapine is strongly associated with the risk of pneumonia and inflammation

et al. 2020

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“…Box describes the most important CLO inhibitors: estrogens, fluvoxamine and some other antidepressants, first‐generation antipsychotics, ciprofloxacin, caffeine, and valproic acid (Augustin et al, ; Cooke & de Leon, ; de Leon, , ; de Leon et al, ; Diaz et al, ; Lu et al, , ; Odom‐White & de Leon, ; Pinninti & de Leon, ; Rajkumar et al, ; Ruan, Wang, et al, ; Spina et al, ; Wagner & Kluge, ; Wong et al, ).…”

Section: Personalizing Clo Dosing With Tdmmentioning

confidence: 99%

Using therapeutic drug monitoring to personalize clozapine dosing in Asians

Leon

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Kane

et al. 2020

Asia-Pacific Psychiatry

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This narrative review on clozapine blood levels or therapeutic drug monitoring (TDM) includes sections focused on drug clearance and TDM, personalized dosing with TDM, clinical applications of TDM in Asians, and areas needing further study. Asian patients need half the clozapine dose (D) used in the United States to get the same blood concentrations (C). The concentration-to-dose (C/D) ratio measures drug clearance. In the United States, the average clozapine patient usually needs from 300 to 600 mg/day to reach 350 ng/mL. US male smokers reach this therapeutic C with a D of 600 mg/day (C/D ratio of 0.60 = 600/350), whereas US female nonsmokers usually need a D of 300 mg/day (C/D ratio of 1.17 = 300/350). While in the United States, average CLO C/D ratios typically are 0.6-1.2 ng/mL per mg/day, in Asian populations they range from 1.20 in male smokers to 2.40 in female smokers, requiring Ds of 300 to 150 mg/day to obtain 350 ng/mL. Asian patients can become clozapine poor metabolizers (PMs), needing very low Ds (50-150 mg/day) to get therapeutic Cs, by taking inhibitors (fluvoxamine, oral contraceptives and valproic acid), due to obesity, or duringinflammations with systemic effects. In 573 Asian patients from five samples, around 1% were PMs due to taking inhibitors, 1% due to inflammation, 1% due to obesity, and 7% were potential genetic PMs. The potential genetic PMs ranged between 3% and 13%, but this prevalence will have to be better established in future studies including genetic testing for possible CYP1A2 mutations, which may explain PM status. K E Y W O R D Sclozapine blood, drug interactions, inflammation, sex, smoking

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“…112 As a general principle, any very low clozapine C/D ratio compatible with being a UM in the absence of inducers (eg, carbamazepine or valproate) is likely to be explained by non-adherence. 114 In summary, despite 25 years of research on clozapine TDM, the second author cannot provide any simple advice on how to use clozapine TDM to identify non-adherent patients. Furthermore, as will be discussed in the section on future studies, the use of TDM to predict the effects of or to identify non-adherence for other psychiatric drugs appears much more complicated.…”

Section: Clozapine Non-adherence and Clinical Relevancementioning

confidence: 99%

“…We have started to explore non-adherence in clozapine outpatients through the use of large databases of repeated samples by collaborating with some of the leaders in outpatient TDM. 122 Regarding the use of single clozapine TDM to establish non-adherence, the first step is to further extend the criteria of low clozapine C/D ratios after stratification by gender and smoking from Asians 114 to Caucasians. In a second step, we think that there is potential for using the metabolite norclozapine, 123 which appears to have a longer half-life than clozapine.…”

Section: Future Studies Of Clozapine Tdm and Non-adherencementioning

confidence: 99%

<p>Self-Report for Measuring and Predicting Medication Adherence: Experts’ Experience in Predicting Adherence in Stable Psychiatric Outpatients and in Pharmacokinetics</p>

Cuevas

Leon

2020

PPA

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Poor adherence to appropriately prescribed medication is a global challenge for psychiatrists. Prior Studies: Measuring adherence is complicated. In our recent three-country naturalistic study including more than 1000 patients and their adherence to multiple medication prescriptions at the same time, patients' self-report of adherence to each specific drug was the only practical option for measuring adherence. Systematic literature reviews provide inconsistent results for sociodemographic, clinical and medication variables as predictors of adherence to psychiatric drugs. Our studies over the last 10 years in relatively stable psychiatric outpatients have shown that some self-reported health beliefs had consistent, strong effects and a better predictive role. Three dimensions of these health beliefs are characteristics of the individual: 1) attitudes toward psychiatric medication such as pharmacophobia (fear of taking drugs or medicines), 2) health locus of control (the belief patients have about who or what agent determines the state of their health), 3) psychological reactance (an emotional reaction in direct contradiction to rules or regulations that threaten or suppress certain freedoms in behavior). They can be measured by the Patient Health Beliefs Questionnaire on Psychiatric Treatment. The attitude toward each specific medication can be measured by the necessity-concern framework and summarized as the presence or absence of skepticism about that drug. After 25 years conducting pharmacokinetic studies in psychiatric drugs, particularly antipsychotics, we have limited understanding of how to use blood levels to predict the effects of non-adherence or to establish it. Expert Opinion on Future Studies: Future studies to predict adherence should include the inpatient setting and explore insight. Studying the pharmacokinetics associated with nonadherence in each psychiatric drug is a major challenge. Medication adherence is a complex and dynamic process changing over time in the same patient. Personalizing adherence using psychological or pharmacological variables are in their initial stages.

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Exploring the Prevalence of Clozapine Phenotypic Poor Metabolizers in 4 Asian Samples

Abstract: Ruan is supported by a grant to the Beijing Anding Hospital (Beijing Science and Technology Plan Project Z171100001017074). See four original articles for the support that led to completion and publication of the four studies.

Cited by 42 publications

References 27 publications

Clozapine is strongly associated with the risk of pneumonia and inflammation

Clozapine is strongly associated with the risk of pneumonia and inflammation

Using therapeutic drug monitoring to personalize clozapine dosing in Asians

<p>Self-Report for Measuring and Predicting Medication Adherence: Experts’ Experience in Predicting Adherence in Stable Psychiatric Outpatients and in Pharmacokinetics</p>

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