Total and differential white blood cell counts, inflammatory markers, adipokines, and the metabolic syndrome in phase 1 of the clinical antipsychotic trials of intervention effectiveness study
Introduction
The metabolic syndrome is a constellation of metabolic risk factors associated with the development of atherosclerotic cardiovascular disease (Galassi et al., 2006, Grundy et al., 2005) and cardiovascular disease mortality (Galassi et al., 2006) — the leading cause of death in patients with schizophrenia (Saha et al., 2007). The metabolic syndrome is common in patients with schizophrenia, with a prevalence of 43% — based on American Heart Association criteria (Grundy et al., 2005) — in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE; McEvoy et al., 2005).
The metabolic syndrome is also associated with a state of chronic, low-grade inflammation (Devaraj et al., 2010). A meta-analysis found that high-sensitivity CRP (hsCRP) was an independent predictor of cardiovascular disease (Kaptoge et al., 2010). Schizophrenia is also associated with increased inflammation, including aberrant blood levels of pro-inflammatory cytokines (Miller et al., 2011), lymphocytes (Miller et al., 2013a) and CRP (Miller et al., 2014), including studies in patients with first-episode psychosis and minimal exposure to antipsychotics. The adverse metabolic effects of atypical antipsychotics, which increase metabolic syndrome risk, may potentiate aberrant blood levels of inflammatory markers (Beumer et al., 2012).
Several large population-based samples found that total and differential white blood cell (WBC) counts were associated with metabolic syndrome risk and individual metabolic syndrome criteria (Kim et al., 2008, Lao et al., 2008). Within schizophrenia, one study found that higher total WBC counts are associated with increased risk of the metabolic syndrome and more severe psychopathology (Fan et al., 2010). We previously found that total WBC count, monocytes, and hsCRP were significant predictors of metabolic syndrome in patients with schizophrenia, and hsCRP was also a significant predictor of increased waist circumference and triglycerides (Miller et al., 2013b). In a subsequent study, we found that total WBC count was a significant predictor of an elevated 10-year estimated risk of myocardial infraction and cardiovascular disease, using Framingham risk scores (Miller et al., 2015).
In the CATIE study, effects of antipsychotics on changes in blood CRP, E-Selectin, intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) levels between screening and 3 months have been previously reported (Meyer et al., 2009). At 3 months, median CRP and E-Selectin levels were significantly greater in patients with versus without metabolic syndrome. Furthermore, median CRP, E-Selectin, and ICAM-1 levels were significantly greater for subjects positive (versus negative) for some individual metabolic syndrome criteria. However, this study focused on changes in inflammatory markers over time, and thus included a smaller subset of subjects in the CATIE study with available blood samples at multiple time points, explored categorical, but not continuous, relationships between inflammatory markers and components of the metabolic syndrome, and did not investigate relationships between total and differential WBC counts and the metabolic syndrome.
The purpose of this study is to investigate the relationship between total and differential WBC counts, inflammatory markers, and the metabolic syndrome in a large sample of patients with schizophrenia from the CATIE study. We hypothesize that total and differential WBC counts, as well as inflammatory markers, are associated with metabolic syndrome risk and individual metabolic syndrome criteria in these subjects. We also explore which of these blood markers is the strongest predictor of current metabolic abnormalities.
Section snippets
Material and methods
Data were obtained from the publicly available limited access CATIE schizophrenia trial dataset. A full description of the CATIE schizophrenia trial has been previously described (Lieberman et al., 2005). The study was deemed exempt by the Georgia Regents University IRB. Blood for total and differential WBC, inflammatory markers (CRP, interleukin-6 [IL-6], E-Selectin, ICAM-1, and VCAM-1), and adipokines (adiponectin and leptin) were collected at baseline/screening. Plasma was CRP levels were
Results
Table 1 presents the demographic and clinical characteristics of the study sample. The number of subjects with available data on blood markers ranged from 1194 (for adiponectin) to 1416 (for ICAM-1), with a mean of 1363 subjects per marker. Data on smoking were available for 1401 subjects, alcohol and drug use for 1439 subjects, and fasting status for 1357 subjects.
Patients with the metabolic syndrome were older, more likely to be female, more likely to be abstinent from alcohol and illicit
Discussion
Subjects with schizophrenia and the metabolic syndrome had significantly higher total and differential WBC counts, and levels of inflammatory markers and adipokines than patients without the metabolic syndrome. After controlling for potential confounding effects of age, sex, race, sex, smoking, alcohol and illicit drug use, and fasting status, these blood markers – most notably total WBC count, CRP, IL-6, leptin, and adiponectin – were significantly predictors of the metabolic syndrome and its
Role of funding source
Not applicable.
Contributors
Dr. Miller designed the study. Drs. Mori and Miller managed the literature searches. Dr. Miller managed the analyses. Drs. Mori and Miller wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
Dr. Mori has nothing to disclose.
Dr. McEvoy has nothing to disclose for the work under consideration. In the past 12 months, Dr. McEvoy participated in Advisory Boards for Ameritox, Forum, Merck, and Otsuk, and has received research grants from Alkermes, Auspex, Avenir, and Otsuka.
Dr. Miller has nothing to disclose for the work under consideration. In the past 12 months, Dr. Miller has received grant support from the National Institute of Mental Health (K23MH098014), the American Psychiatric
Acknowledgments
The authors wish to thank Dr. Jonathan Meyer for his input and assistance.
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