Elevated clozapine plasma concentration secondary to a urinary tract infection: proposed mechanisms

Lee, Lik Hang N.; White, Ralph de Vere; Barr, Alasdair M.; Honer, William G.; Procyshyn, Ric M.

doi:10.1503/jpn.150156

Cited by 11 publications

(7 citation statements)

References 14 publications

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“…Any therapeutic benefit from CLZ treatment, however, must take into consideration the high incidence of non-EPS side-effects associated with the drug (Andreazza et al, 2015 ; Thornton et al, 2015 ; Tse et al, 2015 ; Lee et al, 2016 ). An estimated 10–20% of eligible patients are prescribed with CLZ in the U.S., a number indicative that CLZ is vastly underutilized due to concern for its side effects (Meltzer, 2012 ; Kar et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Clozapine-Induced Cardiovascular Side Effects and Autonomic Dysfunction: A Systematic Review

et al. 2018

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Background: Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and has minimal risk for extrapyramidal symptoms. Therapeutic benefits, however, are accompanied by a myriad of cardiometabolic side-effects. The specific reasons for clozapine's high propensity to cause adverse cardiometabolic events remain unknown, but it is believed that autonomic dysfunction may play a role in many of these.Objective: This systematic review summarizes the literature on autonomic dysfunction and related cardiovascular side effects associated with clozapine treatment.Method: A search of the EMBASE, MEDLINE, and EBM Cochrane databases was conducted using the search terms antipsychotic agents, antipsychotic drug*, antipsychotic*, schizophrenia, schizophren*, psychos*, psychotic*, mental ill*, mental disorder*, neuroleptic*, cardiovascular*, cardiovascular diseases, clozapine*, clozaril*, autonomic*, sympathetic*, catecholamine*, norepinephrine, noradrenaline, epinephrine, adrenaline.Results: The search yielded 37 studies that were reviewed, of which only 16 studies have used interventions to manage cardiovascular side effects. Side effects reported in the studies include myocarditis, orthostatic hypotension and tachycardia. These were attributed to sympathetic hyperactivity, decreased vagal contribution, blockade of cholinergic and adrenergic receptors, reduced heart rate variability and elevated catecholamines with clozapine use. Autonomic neuropathy was identified by monitoring blood pressure and heart rate changes in response to stimuli and by spectral analysis of heart rate variability. Metoprolol, lorazepam, atenolol, propranolol, amlodipine, vasopressin and norepinephrine infusion were used to treat tachycardia and fluctuations in blood pressure, yet results were limited to case reports.Conclusion: The results indicate there is a lack of clinical studies investigating autonomic dysfunction and a limited use of interventions to manage cardiovascular side effects associated with clozapine. As there is often no alternative treatment for refractory schizophrenia, the current review highlights the need for better designed studies, use of autonomic tests for prevention of cardiovascular disease and development of novel interventions for clozapine-induced side effects.

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Section: Introductionmentioning

confidence: 99%

Clozapine-Induced Cardiovascular Side Effects and Autonomic Dysfunction: A Systematic Review

et al. 2018

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“…Presumably, the unbound clozapine is measured electrochemically which may explain the diminished sensitivities when buffered solutions are compared against clozapine-spiked serum samples (Kim et al, 2015). It has also been suggested that only the unbound form of clozapine is biologically active (Lee et al, 2016), yet standard centralized laboratory analyses measure the total clozapine (protein bound plus unbound). While we acknowledge the limitations of this standard analytical method, these measurements are currently used by clinicians to adjust dosages and thus we use this standard to develop our electrochemical method.…”

Section: Introductionmentioning

confidence: 99%

Reliable clinical serum analysis with reusable electrochemical sensor: Toward point-of-care measurement of the antipsychotic medication clozapine

Kang

Kim

Winkler

et al. 2017

Biosensors and Bioelectronics

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Clozapine is one of the most promising medications for managing schizophrenia but it is under-utilized because of the challenges of maintaining serum levels in a safe therapeutic range (1–3 μM). Timely measurement of serum clozapine levels has been identified as a barrier to the broader use of clozapine, which is however challenging due to the complexity of serum samples. We demonstrate a robust and reusable electrochemical sensor with graphene-chitosan composite for rapidly measuring serum levels of clozapine. Our electrochemical measurements in clinical serum from clozapine-treated and clozapine-untreated schizophrenia groups are well correlated to centralized laboratory analysis for the readily detected uric acid and for the clozapine which is present at 100-fold lower concentration. The benefits of our electrochemical measurement approach for serum clozapine monitoring are: (i) rapid measurement (≈ 20 min) without serum pretreatment; (ii) appropriate selectivity and sensitivity (limit of detection 0.7 μM); (iii) reusability of an electrode over several weeks; and (iv) rapid reliability testing to detect common error-causing problems. This simple and rapid electrochemical approach for serum clozapine measurements should provide clinicians with the timely point-of-care information required to adjust dosages and personalize the management of schizophrenia.

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“…On the other hand, smoking cessation or stopping carbamazepine treatment increases clozapine serum concentrations and has the potential to cause clozapine toxicity unless the dosage of clozapine is reduced. 5 Serious infections [6][7][8][9][10][11][12] including respiratory or urinary tract infections, pyelonephritis, appendicitis, or even major inflammations, including a lamotrigineinduced rash, 11 behave like inhibitors and have been associated with clozapine concentration increases and sometimes with clozapine toxicity. Cytokine releases during infection and/or inflammation decrease the expression of CYP1A2, CYP2C19, and/or CYP3A4 leading to an increase in the serum concentrations of clozapine.…”

Section: Introductionmentioning

confidence: 99%

Two cases of high serum clozapine concentrations occurring during inflammation in Chinese patients

Ruan

Xiao-ling

Guo

et al. 2018

Int J Psychiatry Med

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Objective Serious infections or inflammations have been associated with serum clozapine concentration increases and sometimes with clozapine toxicity. Method These two cases describe Chinese patients (Case 1: a 57-year-old female nonsmoker with severe dermatitis and Case 2: a 47-year-old male nonsmoker with influenza and secondary infection). Results In both cases, the Drug Interaction Probability Scale established the presence of a probable drug-drug interaction. In both cases, the clozapine and the total clozapine concentration-to-dose ratios followed a temporal pattern (normal-high-normal), consistent with an inhibition of clozapine metabolism during peak inflammation. In the first case, the total clozapine concentration-to-dose ratio (8 with no/low inflammation: median of 3.10 and 2 at peak inflammation: median of 3.90) provided a significant difference (P = 0.044). In the second patient, because of the smaller sample size and reduced statistical power (4 with no infection: a median of 1.59 and 2 at peak infection: 3.46), the increase did not reach significance (P = 0.13). In the first case, the median baseline clozapine concentration-to-dose ratio increased by a factor of 1.45 from 2.00 to a peak of 2.89. To compensate for the inhibition of clozapine metabolism, the dose correction factor was 0.69 (1/1.45) or a decrease in dose of approximately one-third. In the second case, the median baseline clozapine concentration-to-dose ratio increased by a factor of 2.56 from 1.15 to a peak of 2.94. Conclusion This provided a dose correction factor of 0.40 (1/2.56) or approximately half the dose, similar to published cases in Caucasians with serious respiratory infections.

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Elevated clozapine plasma concentration secondary to a urinary tract infection: proposed mechanisms

Cited by 11 publications

References 14 publications

Clozapine-Induced Cardiovascular Side Effects and Autonomic Dysfunction: A Systematic Review

Clozapine-Induced Cardiovascular Side Effects and Autonomic Dysfunction: A Systematic Review

Reliable clinical serum analysis with reusable electrochemical sensor: Toward point-of-care measurement of the antipsychotic medication clozapine

Two cases of high serum clozapine concentrations occurring during inflammation in Chinese patients

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