Inflammation, substance use, psychopathology, and cognition in phase 1 of the clinical antipsychotic trials of intervention effectiveness study Brian J. Miller a, ⁎, Peter F. Buckley b , Joseph P. McEvoy a a Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA, United States b School of Medicine, Virginia Commonwealth University, Richmond, VA, United States abstract article info Article history: Received 14 March 2017 Received in revised form 11 August 2017 Accepted 16 August 2017 Available online xxxx Introduction: Schizophrenia has been associated with aberrant blood levels of inflammatory markers. However, patients with comorbid illicit drug use have been inadequately studied with respect to immune function. Furthermore, associations between inflammatory markers, psychopathology, and cognition have been inconsis- tently considered. We investigated relationships between inflammatory markers, comorbid marijuana and cocaine use, and psychopathology and cognition in patients with schizophrenia. Method: For subjects with available fasting data from the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, inflammatory markers were investigated as predictors of psychopathology and cognition in patients with and without comorbid marijuana or cocaine use, using linear regression models controlling for potential confounding factors. Results: Compared to subjects with a negative urine drug screen (UDS), marijuana use was a predictor of higher lymphocytes and E-selectin, and lower leptin (p ≤ 0.04 for each); cocaine use was a predictor of higher adiponectin (p = 0.04). In subjects with marijuana use, lower WBC and higher IL-6 were predictors of higher PANSS total score (p b 0.05 for each). In subjects with cocaine use, lower total and differential WBC were predic- tors of higher PANSS total score (p b 0.04 for each). In younger, non-obese subjects with a negative UDS, higher monocytes and IL-6 were predictors of PANSS total score (p b 0.04 for each). Conclusions: Our findings provide additional evidence that inflammation may be associated with psychopathol- ogy and cognition in some patients with schizophrenia. Furthermore, there is preliminary evidence for differen- tial effects of comorbid marijuana and cocaine use on these relationships. © 2017 Elsevier B.V. All rights reserved. Keywords: Schizophrenia Inflammation Marijuana Cocaine Psychopathology Cognition 1. Introduction The investigation of immune system abnormalities in schizophrenia, though ongoing for decades, has more recently become a popular re- search area. This interest has been partially stimulated by our increased understanding of interactions between the immune system and the brain in other chronic medical disorders. Key replicated findings supporting the hypothesis that immune dysfunction may be involved in the pathophysiology of schizophrenia in some patients includes the following: 1) associations between genes involved in the regulation of the immune system and increased risk of schizophrenia (Psychiatric Genomics Consortium, 2014; Sekar et al., 2016; Shi et al., 2009); 2) pre- natal maternal infection with a variety of different infectious agents is a risk factor for schizophrenia in the offspring (Brown and Derkits, 2010), and may act synergistically with family history of psychosis (Clarke et al., 2009); 3) there is a bidirectional association between psychosis and autoimmune disorders (Benros et al., 2014); 4) patients with schizophrenia have immune abnormalities in the blood, cerebrospinal fluid, and central nervous system, including immune cell numbers, in- flammatory markers, and antibody titers (reviewed in Miller and Goldsmith, 2017); and 5) several trials have found that treatment with agents with anti-inflammatory properties may be associated with significant improvement in psychopathology in schizophrenia (Nitta et al., 2013; Sommer et al., 2014), and baseline blood levels of in- flammatory markers may predict response to these agents (Laan et al., 2010; Muller et al., 2004). Taken together, these findings suggest we need to more systematically and extensively evaluate this hypothesis. Although some associations are well replicated, there is significant het- erogeneity regarding findings for immune markers in schizophrenia, in- cluding negative studies. An important potential explanation for this observed heterogeneity is that immune system dysfunction occurs in only a subset of patients with schizophrenia, which may reflect an in- herent limitation of our phenomenologically-based nosology. Another contributor to between-study heterogeneity is the inconsistent consid- eration of important potential confounding factors. Many previous studies of immune function in schizophrenia also did not explore Schizophrenia Research xxx (2017) xxx–xxx ⁎ Corresponding author at: Department of Psychiatry and Health Behavior, Augusta University, 997 Saint Sebastian Way, Augusta, GA 30912, United States. E-mail address: brmiller@augusta.edu (B.J. Miller). SCHRES-07476; No of Pages 8 http://dx.doi.org/10.1016/j.schres.2017.08.027 0920-9964/© 2017 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Please cite this article as: Miller, B.J., et al., Inflammation, substance use, psychopathology, and cognition in phase 1 of the clinical antipsychotic trials of intervention effect..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.08.027