Clozapine is associated with secondary antibody deficiency

Ponsford, Mark; Castle, Daniel; Tahir, Tayyeb A.; Robinson, Rebecca; Wade, Wendy; Steven, Rachael; Bramhall, Kathryn; Moody, Mo; Carne, Emily; Ford, Catherine; Farewell, Daniel; Williams, Paul; El‐Shanawany, Tariq; Jolles, Stephen

doi:10.1192/bjp.2018.152

Cited by 64 publications

(97 citation statements)

References 27 publications

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“…25 In a British case-control study, a higher proportion of the clozapine-treated group reported taking more than five courses of antibiotics in the preceding year, 5.3% (5/123) vs 1% (1/111) in controls taking other antipsychotics, and this was associated with an increased percentage of patients with low values for all immunoglobulins. 26 In an vitro study, clozapine increased the production of the interleukin-1 receptor antagonist. 27 Regarding possible increased infection risk in the absence of agranulocytosis, we only recommend that clinicians tell clozapine patients to avoid close contact with contagious people.…”

Section: Inflammation Can Increase Clozapine Levelsmentioning

confidence: 99%

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: Inflammation Can Increase Clozapine Levelsmentioning

confidence: 99%

Clozapine is strongly associated with the risk of pneumonia and inflammation

et al. 2020

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“…The lethality of pneumonia in clozapine patients is explained in that clozapine can contribute to pneumonia, and once pneumonia develops it can cause a clozapine intoxication; therefore, the combination of pneumonia and clozapine intoxication is highly lethal. This complex bidirectional association [162] is described in detail in online supplementary Box S7 [157,[163][164][165][166][167][168][169]. Our recommendations for decreasing the risk and lethality of pneumonia in clozapine patients are described in online supplementary Box S8 [65,162,170,171].…”

Section: Pneumoniamentioning

confidence: 99%

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

Leon

Ruan

Schoretsanitis

et al. 2020

Psychother Psychosom

114

118

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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...

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“…Various mechanisms have been proposed for the rise in pneumonia, including sedation, sialorrhoea and aspiration, agranulocytosis, and smoking 910. Following the introduction of calculated globulin screening in Wales,11 we found a novel and striking association between use of the antipsychotic clozapine and antibody deficiency 12. Patients taking clozapine follow an intensive regimen of blood testing for the rare risk of agranulocytosis (with cumulative incidence of <1% cases), but antibody testing is not included in existing clozapine monitoring programmes.…”

mentioning

confidence: 90%