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

Abstract

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.

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

“…The studies of changes in BDNF levels during treatment are controversial; only relapse schizophrenic males patients showed elevated BDNF after 4 weeks of risperidone consumption (3-6 mg/day), a result that suggests gender should be considered when choosing the pharmacological treatment (167)(168)(169). However, other studies reported no alteration whatsoever after risperidone consumption (170,171).…”

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

“…Further, baseline levels are free of diurnal variations and, according to Pfuhlmann et al [237], independent of sex. Although a positive correlation between CRP and the leukocyte/white blood cell (WBC) count has previously been reported [257], Scherf-Clavel et al discourage the use of WBC count as a measure of inflammation [238]. In their study sample, CRP levels and WBC counts were not significantly associated, and-in contrast to CRP-none of the studied antipsychotic drugs seemed to correlate with the number of leukocytes.…”

“…Hefner et al analyzed intraindividual drug and CRP levels (>5 mg/L) of 105 patients and revealed a significant association for the C/D ratio of clozapine and risperidone, but only a trend for quetiapine [40]. Instead, a correlation between pathological CRP concentrations and increases of quetiapine's C/D ratio (n = 166) was shown by Scherf-Clavel et al [238]: the C/D ratio rose by 0.11 (ng/mL)/(mg/day) with each increase of 5 mg/L CRP. A trend was detected for olanzapine (n = 24) while no association to CRP was found for aripiprazole (n = 30) and risperidone (n = 45).…”

“…Especially large-scale prospective studies that systematically assess drug levels (including their respective C/D and metabolic ratios), inflammatory markers, and the clinical consequences, i.e., the presence of any infection-associated ADRs, are required. Regarding the laboratory inflammation markers, CRP (which is mainly expressed under transcriptional control of IL-6 [40,251] with contribution of IL-1 [238,252,253]) was suggested to be appropriate, as it rises and declines rapidly following infection or tissue injury and its subsequent resolution [40,236]. Age, smoking status, weight, lipid levels, and blood pressure were reported to modulate CRP levels.…”

“…Age, smoking status, weight, lipid levels, and blood pressure were reported to modulate CRP levels. However, keeping the immense increase during an APR in mind (from baseline levels of less than 1 mg/L to 500 mg/L within 24-72 h following severe tissue injury) [238,[254][255][256], these factors may be of limited clinical relevance. Further, baseline levels are free of diurnal variations and, according to Pfuhlmann et al [237], independent of sex.…”