Maju Mathew Koola, MD Sheppard Pratt Health System Baltimore, Maryland Associate Professor Department of Psychiatry and Behavioral Sciences George Washington University School of Medicine and Health Sciences Washington, DC
Jeffrey K. Raines, MD, PhD Emeritus Professor Department of Surgery University of Miami Miami, Florida Department of Surgery Harvard Medical School Cambridge, Massachusetts
Robert G. Hamilton, PhD, D(ABMLI) Professor Departments of Medicine and Pathology Johns Hopkins University School of Medicine Baltimore, Maryland
Robert P. McMahon, PhD Professor of Psychiatry University of Maryland School of Medicine Baltimore, Maryland
The overlap of cytokine abnormalities linked to schizophrenia and to arterial compliance is depicted in theFigure.
Anti-inflammatory medications and arterial compliance Evidence suggests that anti-inflammatory medications increase arterial compliance:
In 10 patients who had coronary artery disease or diabetes, or both, simvastatin (40 mg/d) was administered for 4 months. Arterial compliance improved in all 10 after 2 months of treatment and increased by 34% after 4 months.27
Evidence also suggests that the use of omega-3 fatty acids was associated with increased arterial compliance in people with dyslipidemia.50
Last, in people with rheumatoid arthritis, infliximab, a monoclonal antibody against TNF-Symbol Stdα, reduced aortic inflammation; this effect correlated with an increase in aortic compliance.51
Anti-inflammatory medications in schizophrenia Two studies have yielded notable findings:
A meta-analysis of 5 randomized controlled trials (RCTs) involving 264 subjects, comprising 4 studies of celecoxib and 1 of acetylsalicylic acid, had an effect size of 0.43 on total symptom severity. Investigators argued that acetylsalicylic acid might have the additional benefit of decreasing the risk of cardiac death in schizophrenia.52
A review of 26 RCTs examined the efficacy of anti-inflammatory medications on symptom severity in schizophrenia. Acetylsalicylic acid, N-acetylcysteine, and estrogens had an effect size of 0.3, 0.45, and 0.51, respectively.53
Significance of these findings A revelation that cytokine abnormalities are associated with schizophrenia symptoms and co-occurring somatic illness might offer an important new avenue of therapeutic discovery. On average, people with schizophrenia die 20 to 25 years earlier than the general population; CVD is the major cause of their death. Measuring arterial compliance, a novel noninvasive technology in psychiatry, as well as metabolic parameters, could serve as an early biomarker for assessing risk of CVD.
Implications for psychiatric practice. If inflammation plays a role in CVD in schizophrenia—either independently of factors such as metabolic syndrome, obesity, and smoking, or on the causal pathway linking these factors to reduced arterial compliance and to CVD—treatment with anti-inflammatory medications might reduce the alarming disparity of mortality that accompanies schizophrenia. In short, anti-inflammatory medications may offer a double benefit in this setting. Furthermore, success in this approach could spur clarification of the role of abnormal cytokines in other psychiatric disorders.
At this time, for your patients, consider that anti-inflammatory medications routinely used in medical practice, such as nonsteroidal anti-inflammatory drugs, omega-3 fatty acids, and statins, might alleviate psychiatric symptoms and might reduce cardiovascular mortality in schizophrenia.
Future directions Perhaps only a limited number of cytokines are common to schizophrenia and reduced arterial compliance. Targeting those specific cytokines might, however, provide the dual benefit in schizophrenia of:
alleviating symptoms
reducing the rate of CVD-related mortality.
Studies are warranted to determine the value of (1) anti-inflammatory medications, such as N-acetylcysteine and infliximab and (2) anti-inflammatory combination therapy for this dual purpose. In fact, recruitment of subjects is underway for a study, Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia, at the University of Maryland (ClinicalTrials.gov Identifier: NCT01514682).
Bottom Line An emerging hypothesis posits a common inflammatory process involving cytokine imbalance that is associated with schizophrenia symptoms, reduced arterial compliance, and cardiovascular disease. Anti-inflammatory medications routinely used in medical practice, such as nonsteroidal anti-inflammatory drugs, omega-3 fatty acids, and statins, might alleviate psychiatric symptoms and reduce cardiac mortality in people with schizophrenia.
Related Resources
Müller N, Weidinger E, Leitner B, et al. The role of inflammation in schizophrenia. Front Neurosci. 2015;21(9):372. doi: 10.3389/fnins.2015.00372. eCollection 2015.
Xiong GL, Kenedi, CA. Aspirin to prevent cardiovascular events: Weighing risks and benefits. Current Psychiatry. 2010;9(2):55,56,62,63.
Disclosures Dr. Koola’s work is underwritten by the American Psychiatric Association’s Kempf Fund Award for Research Development in Psychobiological Psychiatry and by National Institute of Mental Health-funded T32 Grant MH067533-07.
Drs. Raines and Hamilton report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. McMahon is a statistical consultant for Amgen, Inc.
