A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology

Abstract

Using Richardson and Davidson's model and the sciences of pharmacokinetics and clinical pharmacopsychology, this article reviewed the: (1) poor life expectancy associated with treatment-resistant schizophrenia (TRS), which may be improved in patients who adhere to clozapine; (2) findings that clozapine is the best treatment for TRS (according to efficacy, effectiveness and well-being); and (3) potential for clozapine to cause vulnerabilities, including potentially lethal adverse drug reactions such as agranulocytosis, pneumonia, and myocarditis. Rational use requires: (1) modification of the clozapine package insert worldwide to include lower doses for Asians and to avoid the lethality associated with pneumonia, (2) the use of clozapine levels for personalizing dosing, and (3) the use of slow and personalized titration. This may make clozapine as safe as possible and contribute to increased life expectancy and well-being. In the absence of data on COVID-19 in clozapine patients, clozapine possibly impairs immunological mechanisms and may increase pneumonia risk in infected patients. Psychiatrists should call their clozapine patients and families and explain to them that if the patient develops fever or flu-like symptoms, the psychiatrist should be called and should consider halving the clozapine dose. If the patient is hospitalized with pneumonia, the treating physician needs to assess for symptoms of clozapine intoxication since halving the dose may not be enough for all patients; consider decreasing it to one-third or even stopping it. Once the signs of inflammation and fever have disappeared, the clozapine dose can be slowly increased to the prior dosage level. 46, 48, 52-67] describes the important pharmacokinetic variables for clozapine clearance. Higher clozapine C/D ratios, indicating lower clearance, are associated with females, non-smokers, Asians, genetic poor metabolizers, inhibitors, obesity, inflammation, and possibly with renal impairment and pregnancy. Lower clozapine C/D ratios indicate lack of adherence or higher clearance associated with males, smokers, non-Asians, and inducers.Two prior TDM review articles [68,69] are summarized in online supplementary Box S3 [31, 44, 50, 51, 55, 58-61, 63, 65, 68-91] which also describe our extensive experience with thousands of inpatient clozapine TDMs under standard conditions (trough and steady-state levels) in the US [44] and China [45,65]. Many of these inpatients were followed for months and/or years after changes in important pharmacokinetic variables [31, 44, 50, 58-61, 63, 65, 74, 79, 86-91].Published review articles [92][93][94] usually insist on the wide variability of clozapine TDM among individuals and the difficulty of interpreting a single clozapine level, but they fail to pay attention to findings from these two sciences: pharmacokinetics and clinical pharmacopsychology, which help in interpreting variability in clozapine levels. In inpatients, repeated measures allow the calculation of average clozapine clearance in an individual through a...

A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43

“…The mainstay of therapy for CLZ-induced pneumonia, cardiotoxicity, and seizures is recommended CLZ cessation, specialist review, and instigation of disease modifying treatments [ 27 , 44 , 67 ]. Contrary to the benefit of the abrupt discontinuation of CLZ against several adverse CLZ reactions, there are a few mentions of the risk for the mental status of schizophrenia.…”

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

“…In spite of its complex toxicological profile, when properly used it decreases the mortality of patients with treatment-resistant schizophrenia. 102 The next 3 subsections include a summary of the second author's studies on clozapine non-adherence in reference to clinical relevance, half-life and TDM.…”

“…This relatively short half-life is not compatible with the possibility of single-day administration. 102 As the matter of fact, by using drug discontinuation in the clinical environment, the second author obtained a half-life of 17 hours in one patient and 34 hours in another. 104 Clozapine is lipophilic and deposits in the fat tissue 111 which explains the dramatic increase in clozapine half-life after repeated dosing.…”

Psychopharmakotherapie in Zeiten der COVID-19-Pandemie

“…Benzodiazepine stellen bei vielen psychischen Erkrankungen eine wirkungsvolle Option in der Akutbehandlung dar. Gerade bei Angsterkrankungen, deren Inzidenz ersten Studien zufolge im Rahmen der COVID-19-Pandemie zunimmt [28] [18]. Daher sollten mit Clozapin behan-delte Patienten und ggf.…”