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Can anti-inflammatory medications improve symptoms and reduce mortality in schizophrenia?
Author(s)
Maju Mathew Koola, MD
Jeffrey K. Raines, MD, PhD

Consider 3 observations:

  • Evidence is mounting that cytokine abnormalities are present in schizophrenia (Box1-8).
  • Reduced arterial compliance (change in volume divided by change in pressure [ΔV/ΔP] in an artery during the cardiac cycle) is an early marker of cardiovascular disease (CVD) and a robust predictor of mortality, and is associated with cytokine abnormalities.
  • People with schizophrenia experience increased mortality from CVD.

Taken together, the 3 statements hint at a hypothesis: a common inflammatory process involving cytokine imbalance is associated with symptoms of schizophrenia, reduced arterial compliance, and CVD.

Anti-inflammatory therapeutics that target specific cytokines might both decrease psychiatric symptoms and reduce cardiac mortality in people with schizophrenia. In this article, we (1) highlight the potential role of anti-inflammatory medications in reducing both psychiatric symptoms and cardiac mortality in people with schizophrenia and (2) review the pathophysiological basis of this inflammatory commonality and the evidence for its presence in schizophrenia.


The ‘membrane hypothesis’ of schizophrenia
In this hypothesis, a disturbance in the synthesis and structure of membrane phospholipids results in a subsequent disturbance in the function of neuronal membrane proteins, which might be associated with symptoms and mortality in schizophrenia.9-12 The synaptic vesicle protein synaptophysin, a marker for synaptic density, was found to be decreased in postmortem tissue from the gyrus cinguli in 11 patients with schizophrenia, compared with 13 controls.10 Intracellular phospholipases A2 (inPLA2) act as key enzymes in cell membrane repair and remodeling and in neuroplasticity, neurodevelopment, apoptosis, synaptic pruning, neurodegenerative processes, and neuroinflammation.

In a study, people with first-episode schizophrenia (n = 24) who were drug-naïve or off antipsychotic medication were compared with 25 healthy controls using voxel-based morphometry analysis of T1 high-resolution MRI. inPLA2 activity was increased in the patient group compared with controls; the analysis revealed abnormalities of the frontal and medial temporal cortices, hippocampus, and left-middle and superior temporal gyri in first-episode patients.11 In another study, inPLA2 activity was increased in 35 people with first-episode schizophrenia, compared with 22 controls, and was associated with symptom severity and outcome after 12 weeks of antipsychotic treatment.12


Early CVD mortality in schizophrenia
People with schizophrenia have an elevated rate of CVD compared with the general population; in part, this elevation is linked to magnified risk factors for CVD, including obesity, metabolic syndrome, cigarette smoking, and diabetes13-17; furthermore, most antipsychotics can cause or worsen metabolic syndrome.17

CVD is one of the most common causes of death among people with schizophrenia.17,18 Their life expectancy is reported to be 51 to 61 years—20 to 25 years less than what is seen in the general population.19-21


Arterial compliance in schizophrenia
Reduced arterial compliance has been found to be a robust predictor of athero­sclerosis, stroke, and myocardial infarction22-29:

  • In 376 subjects who had routine diagnostic coronary angiography associated with coronary stenosis, arterial compliance was reduced significantly—even after controlling for age, sex, smoking, diabetes, hypertension, hyperlipidemia, and obesity.24

In a cross-sectional study, 63 male U.S. veterans age 18 to 70 who had a psychiatric diagnosis (16 taking quetiapine, 19 taking risperidone, and 28 treated in the past but off antipsychotics for 2 months) had significantly reduced compliance in thigh- and calf-level arteries than male controls (n = 111), adjusting for body mass index and Framingham Risk Score (FRS). Of the 63 patients, 23 had a diagnosis of schizophrenia or schizoaffective disorder.30 (The FRS is an estimate of a person’s 10-year cardiovascular risk, calculated using age, sex, total cholesterol, high-density lipoprotein, smoker or not, systolic blood pressure, and whether taking an antihypertensive or not. Compliance was measured using computerized plethysmography). Although not statistically significant, secondary analyses from this data set (n = 77, including men for whom factors for metabolic syndrome were available) showed that calf-level compliance (1.82 vs 2.06 mL) and thigh-level compliance (3.6 vs 4.26 mL; P = .06) were reduced in subjects with schizophrenia, compared with those who had another psychiatric diagnosis.31

  • In another study, arterial compliance was significantly reduced in 10 subjects with schizophrenia, compared with 10 healthy controls.32
  • Last, reduced total arterial compliance has been shown to be a robust predictor of mortality in older people, compared with reduced local or regional arterial compliance.33


Cytokine abnormalities in arterial compliance
The mechanism by which reduced arterial compliance is associated with cardiovascular pathology is not entirely clear. Arterial compliance is a predictor of cardiovascular disorders independent of hypertension.34 Two studies show that vascular inflammation is associated with reduced arterial compliance.35,36 Reduced arterial compliance is associated with increased angiotensin II activity; increased nicotinamide adenine dinucleotide phosphate oxidase activity; reduced nitric oxide activity; and increased reactive oxygen species.37-39 Angiotensin-II signaling activates transforming growth factor-β, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-17, IL-6, and C-reactive protein (CRP)—all of which are associated with reduced arterial compliance.39-46 In addition, high-sensitivity CRP is significantly associated with reduced arterial compliance.47-49

 

 

The overlap of cytokine abnormalities linked to schizophrenia and to arterial compliance is depicted in the Figure.


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.


Drug Brand Names
Celecoxib • Celebrex
Infliximab • Remicade
Omega-3 fatty acids • Lovaza
Quetiapine • Seroquel
Simvastatin • Zocor
Risperidone • Risperdal


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.

References


1. Potvin S, Stip E, Sepehry AA, et al. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63(8):801-808.
2. Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663-671.
3. Frydecka D, Misiak B, Pawlak-Adamska E, et al. Interleukin-6: the missing element of the neurocognitive deterioration in schizophrenia? The focus on genetic underpinnings, cognitive impairment and clinical manifestation. Eur Arch Psychiatry Clin Neurosci. 2015;265(6):449-459.
4. Dickerson F, Stallings C, Origoni A, et al. Additive effects of elevated C-reactive protein and exposure to herpes simplex virus type 1 on cognitive impairment in individuals with schizophrenia. Schizophr Res. 2012;134(1):83-88.
5. Dickerson F, Stallings C, Origoni A, et al. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res. 2007;93(1-3):261-265.
6. Asevedo E, Rizzo LB, Gadelha A, et al. Peripheral interleukin-2 level is associated with negative symptoms and cognitive performance in schizophrenia. Physiol Behav. 2014;129:194-198.
7. Miller BJ, Culpepper N, Rapaport MH. C-reactive protein levels in schizophrenia: a review and meta-analysis. Clin Schizophr Relat Psychoses. 2014;7(4):223-230.
8. Micoulaud-Franchi JA, Faugere M, Boyer L, et al. Elevated C-reactive protein is associated with sensory gating deficit in schizophrenia. Schizophr Res. 2015;165(1):94-96.
9. Horrobin DF. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res. 1998;30(3):193-208.
10. Landén M, Davidsson P, Gottfries CG, et al. Reduction of the synaptophysin level but normal levels of glycerophospholipids in the gyrus cinguli in schizophrenia. Schizophr Res. 2002;55(1-2):83-98.
11. Smesny S, Milleit B, Nenadic I, et al. Phospholipase A2 activity is associated with structural brain changes in schizophrenia. Neuroimage. 2010;52(4):1314-1327.
12. Smesny S, Kunstmann C, Kunstmann S, et al. Phospholipase A2 activity in first episode schizophrenia: associations with symptom severity and outcome at week 12. World J Biol Psychiatry. 2011;12(8):598-607.
13. Fontaine KR, Heo M, Harrigan EP, et al. Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate. Psychiatry Res. 2001;101(3):277-288.
14. Homel P, Casey D, Allison DB. Changes in body mass index for individuals with and without schizophrenia, 1987-1996. Schizophr Res. 2002;55(3):277-284.
15. Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002. JAMA. 2004;291(23):2847-2850.
16. Dickerson FB, Brown CH, Kreyenbuhl JA, et al. Obesity among individuals with serious mental illness. Acta Psychiatr Scand. 2006;113(4):306-313.
17. Newcomer JW. Metabolic syndrome and mental illness. Am J Manag Care. 2007;13(suppl 7):S170-S177.
18. Healy D, Le Noury J, Harris M, et al. Mortality in schizophrenia and related psychoses: data from two cohorts, 1875-1924 and 1994-2010. BMJ Open. 2012;2(5). doi: 10.1136/bmjopen-2012-001810.
19. Newman SC, Bland RC. Mortality in a cohort of patients with schizophrenia: a record linkage study. Can J Psychiatry. 1991;36(4):239-245.
20. Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173:11-53.
21. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42.
22. Farrar DJ, Bond MG, Riley WA, et al. Anatomic correlates of aortic pulse wave velocity and carotid artery elasticity during atherosclerosis progression and regression in monkeys. Circulation. 1991;83(5):1754-1763.
23. Wada T, Kodaira K, Fujishiro K, et al. Correlation of ultrasound-measured common carotid artery stiffness with pathological findings. Arterioscler Thromb. 1994;14(3):479-482.
24. Herrington DM, Kesler K, Reiber JH, et al. Arterial compliance adds to conventional risk factors for prediction of angiographic coronary artery disease. Am Heart J. 2013;146(4):662-667.
25. Willens HJ, Davis W, Herrington DM, et al. Relationship of peripheral arterial compliance and standard cardiovascular risk factors. Vasc Endovascular Surg. 2003;37(3):197-206.
26. Herrington DM, Brown WV, Mosca L, et al. Relationship between arterial stiffness and subclinical aortic atherosclerosis. Circulation. 2004;110(4):432-437.
27. Saliashvili G, Davis WW, Harris MT, et al. Simvastatin improved arterial compliance in high-risk patients. Vasc Endovascular Surg. 2004;38(6):519-523.
28. Le NA, Brown WV, Davis WW, et al. Comparison of the relation of triglyceride-rich lipoproteins and muscular artery compliance in healthy women versus healthy men. Am J Cardiol. 2005;95(9):1049-1054.
29. Willens HJ, Chirinos JA, Brown WV, et al. Usefulness of arterial compliance in the thigh in predicting exercise capacity in individuals without coronary heart disease. Am J Cardiol. 2005;96(2):306-310.
30. Koola MM, Brown WV, Qualls C, et al. Reduced arterial compliance in patients with psychiatric diagnoses. Schizophr Res. 2012;137(1-3):251-253.
31. Koola MM, Sorkin JD, Fargotstein M, et al. Predictors of calf arterial compliance in male veterans with psychiatric diagnoses. The Primary Care Companion for CNS Disorders. In press.
32. Phillips AA, Warburton DE, Flynn SW, et al. Assessment of arterial stiffness among schizophrenia-spectrum disorders using aortic pulse wave velocity and arterial compliance: a pilot study. Psychiatry Res. 2014;215(1):14-19.
33. Papaioannou TG, Protogerou AD, Stergiopulos N, et al. Total arterial compliance estimated by a novel method and all-cause mortality in the elderly: the PROTEGER study. Age (Dordr). 2014;36(3):9661.
34. Park S, Lakatta EG. Role of inflammation in the pathogenesis of arterial stiffness. Yonsei Med J. 2012;53(2):258-261.
35. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation. 2003;107(2):346-354.
36. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(5):932-943.
37. van der Loo B, Labugger R, Skepper JN, et al. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med. 2000;192(12):1731-1744.
38. Csiszar A, Ungvari Z, Edwards JG, et al. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res. 2002;90(11):1159-1166.
39. Wang MC, Tsai WC, Chen JY, et al. Arterial stiffness correlated with cardiac remodelling in patients with chronic kidney disease. Nephrology (Carlton). 2007;12(6):591-597.
40. Belmin J, Bernard C, Corman B, et al. Increased production of tumor necrosis factor and interleukin-6 by arterial wall of aged rats. Am J Physiol. 1995;268(6 pt 2):H2288-2293.
41. Gerli R, Monti D, Bistoni O, et al. Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech Ageing Dev. 2000;121(1-3):37-46.
42. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102(18):2165-2168.
43. Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol. 2000;20(9):2094-2099.
44. Venugopal SK, Devaraj S, Yuhanna I, et al. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002;106(12):1439-1441.
45. Csiszar A, Ungvari Z, Koller A, et al. Aging-induced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J. 2003;17(9):1183-1185.
46. Spinetti G, Wang M, Monticone R, et al. Rat aortic MCP-1 and its receptor CCR2 increase with age and alter vascular smooth muscle cell function. Arterioscler Thromb Vasc Biol. 2004;24(8):1397-1402.
47. Mattace-Raso FU, van der Cammen TJ, van der Meer IM, et al. C-reactive protein and arterial stiffness in older adults: the Rotterdam Study. Atherosclerosis. 2004;176(1):111-116.
48. Mahmud A, Feely J. Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension. 2005;46(5):1118-1122.
49. Nagano M, Nakamura M, Sato K, et al. Association between serum C-reactive protein levels and pulse wave velocity: a population-based cross-sectional study in a general population. Atherosclerosis. 2005;180(1):189-195.
50. Nestel P, Shige H, Pomeroy S, et al. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. Am J Clin Nutr. 2002;76(2):326-330.
51. Mäki-Petäjä KM, Elkhawad M, Cheriyan J, et al. Anti-tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation. 2012;126(21):2473-2480.
52. Sommer IE, de Witte L, Begemann M, et al. Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012;73(4):414-419.
53. Sommer IE, van Westrhenen R, Begemann MJ, et al. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014;40(1):181-191.

Article PDF
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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

Issue
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Current Psychiatry
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anti-inflammatory medications, schizophrenia, psychosis, psychotic disorder, psychotic disorders, cardiovascular disease, mortality, cytokine
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Author(s)
Maju Mathew Koola, MD
Jeffrey K. Raines, MD, PhD
Author(s)
Maju Mathew Koola, MD
Jeffrey K. Raines, MD, PhD
Author and Disclosure Information

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

Author and Disclosure Information

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

Article PDF
0516CP_Koola.pdf
Article PDF
0516CP_Koola.pdf

Consider 3 observations:

  • Evidence is mounting that cytokine abnormalities are present in schizophrenia (Box1-8).
  • Reduced arterial compliance (change in volume divided by change in pressure [ΔV/ΔP] in an artery during the cardiac cycle) is an early marker of cardiovascular disease (CVD) and a robust predictor of mortality, and is associated with cytokine abnormalities.
  • People with schizophrenia experience increased mortality from CVD.

Taken together, the 3 statements hint at a hypothesis: a common inflammatory process involving cytokine imbalance is associated with symptoms of schizophrenia, reduced arterial compliance, and CVD.

Anti-inflammatory therapeutics that target specific cytokines might both decrease psychiatric symptoms and reduce cardiac mortality in people with schizophrenia. In this article, we (1) highlight the potential role of anti-inflammatory medications in reducing both psychiatric symptoms and cardiac mortality in people with schizophrenia and (2) review the pathophysiological basis of this inflammatory commonality and the evidence for its presence in schizophrenia.


The ‘membrane hypothesis’ of schizophrenia
In this hypothesis, a disturbance in the synthesis and structure of membrane phospholipids results in a subsequent disturbance in the function of neuronal membrane proteins, which might be associated with symptoms and mortality in schizophrenia.9-12 The synaptic vesicle protein synaptophysin, a marker for synaptic density, was found to be decreased in postmortem tissue from the gyrus cinguli in 11 patients with schizophrenia, compared with 13 controls.10 Intracellular phospholipases A2 (inPLA2) act as key enzymes in cell membrane repair and remodeling and in neuroplasticity, neurodevelopment, apoptosis, synaptic pruning, neurodegenerative processes, and neuroinflammation.

In a study, people with first-episode schizophrenia (n = 24) who were drug-naïve or off antipsychotic medication were compared with 25 healthy controls using voxel-based morphometry analysis of T1 high-resolution MRI. inPLA2 activity was increased in the patient group compared with controls; the analysis revealed abnormalities of the frontal and medial temporal cortices, hippocampus, and left-middle and superior temporal gyri in first-episode patients.11 In another study, inPLA2 activity was increased in 35 people with first-episode schizophrenia, compared with 22 controls, and was associated with symptom severity and outcome after 12 weeks of antipsychotic treatment.12


Early CVD mortality in schizophrenia
People with schizophrenia have an elevated rate of CVD compared with the general population; in part, this elevation is linked to magnified risk factors for CVD, including obesity, metabolic syndrome, cigarette smoking, and diabetes13-17; furthermore, most antipsychotics can cause or worsen metabolic syndrome.17

CVD is one of the most common causes of death among people with schizophrenia.17,18 Their life expectancy is reported to be 51 to 61 years—20 to 25 years less than what is seen in the general population.19-21


Arterial compliance in schizophrenia
Reduced arterial compliance has been found to be a robust predictor of athero­sclerosis, stroke, and myocardial infarction22-29:

  • In 376 subjects who had routine diagnostic coronary angiography associated with coronary stenosis, arterial compliance was reduced significantly—even after controlling for age, sex, smoking, diabetes, hypertension, hyperlipidemia, and obesity.24

In a cross-sectional study, 63 male U.S. veterans age 18 to 70 who had a psychiatric diagnosis (16 taking quetiapine, 19 taking risperidone, and 28 treated in the past but off antipsychotics for 2 months) had significantly reduced compliance in thigh- and calf-level arteries than male controls (n = 111), adjusting for body mass index and Framingham Risk Score (FRS). Of the 63 patients, 23 had a diagnosis of schizophrenia or schizoaffective disorder.30 (The FRS is an estimate of a person’s 10-year cardiovascular risk, calculated using age, sex, total cholesterol, high-density lipoprotein, smoker or not, systolic blood pressure, and whether taking an antihypertensive or not. Compliance was measured using computerized plethysmography). Although not statistically significant, secondary analyses from this data set (n = 77, including men for whom factors for metabolic syndrome were available) showed that calf-level compliance (1.82 vs 2.06 mL) and thigh-level compliance (3.6 vs 4.26 mL; P = .06) were reduced in subjects with schizophrenia, compared with those who had another psychiatric diagnosis.31

  • In another study, arterial compliance was significantly reduced in 10 subjects with schizophrenia, compared with 10 healthy controls.32
  • Last, reduced total arterial compliance has been shown to be a robust predictor of mortality in older people, compared with reduced local or regional arterial compliance.33


Cytokine abnormalities in arterial compliance
The mechanism by which reduced arterial compliance is associated with cardiovascular pathology is not entirely clear. Arterial compliance is a predictor of cardiovascular disorders independent of hypertension.34 Two studies show that vascular inflammation is associated with reduced arterial compliance.35,36 Reduced arterial compliance is associated with increased angiotensin II activity; increased nicotinamide adenine dinucleotide phosphate oxidase activity; reduced nitric oxide activity; and increased reactive oxygen species.37-39 Angiotensin-II signaling activates transforming growth factor-β, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-17, IL-6, and C-reactive protein (CRP)—all of which are associated with reduced arterial compliance.39-46 In addition, high-sensitivity CRP is significantly associated with reduced arterial compliance.47-49

 

 

The overlap of cytokine abnormalities linked to schizophrenia and to arterial compliance is depicted in the Figure.


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.


Drug Brand Names
Celecoxib • Celebrex
Infliximab • Remicade
Omega-3 fatty acids • Lovaza
Quetiapine • Seroquel
Simvastatin • Zocor
Risperidone • Risperdal


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.

Consider 3 observations:

  • Evidence is mounting that cytokine abnormalities are present in schizophrenia (Box1-8).
  • Reduced arterial compliance (change in volume divided by change in pressure [ΔV/ΔP] in an artery during the cardiac cycle) is an early marker of cardiovascular disease (CVD) and a robust predictor of mortality, and is associated with cytokine abnormalities.
  • People with schizophrenia experience increased mortality from CVD.

Taken together, the 3 statements hint at a hypothesis: a common inflammatory process involving cytokine imbalance is associated with symptoms of schizophrenia, reduced arterial compliance, and CVD.

Anti-inflammatory therapeutics that target specific cytokines might both decrease psychiatric symptoms and reduce cardiac mortality in people with schizophrenia. In this article, we (1) highlight the potential role of anti-inflammatory medications in reducing both psychiatric symptoms and cardiac mortality in people with schizophrenia and (2) review the pathophysiological basis of this inflammatory commonality and the evidence for its presence in schizophrenia.


The ‘membrane hypothesis’ of schizophrenia
In this hypothesis, a disturbance in the synthesis and structure of membrane phospholipids results in a subsequent disturbance in the function of neuronal membrane proteins, which might be associated with symptoms and mortality in schizophrenia.9-12 The synaptic vesicle protein synaptophysin, a marker for synaptic density, was found to be decreased in postmortem tissue from the gyrus cinguli in 11 patients with schizophrenia, compared with 13 controls.10 Intracellular phospholipases A2 (inPLA2) act as key enzymes in cell membrane repair and remodeling and in neuroplasticity, neurodevelopment, apoptosis, synaptic pruning, neurodegenerative processes, and neuroinflammation.

In a study, people with first-episode schizophrenia (n = 24) who were drug-naïve or off antipsychotic medication were compared with 25 healthy controls using voxel-based morphometry analysis of T1 high-resolution MRI. inPLA2 activity was increased in the patient group compared with controls; the analysis revealed abnormalities of the frontal and medial temporal cortices, hippocampus, and left-middle and superior temporal gyri in first-episode patients.11 In another study, inPLA2 activity was increased in 35 people with first-episode schizophrenia, compared with 22 controls, and was associated with symptom severity and outcome after 12 weeks of antipsychotic treatment.12


Early CVD mortality in schizophrenia
People with schizophrenia have an elevated rate of CVD compared with the general population; in part, this elevation is linked to magnified risk factors for CVD, including obesity, metabolic syndrome, cigarette smoking, and diabetes13-17; furthermore, most antipsychotics can cause or worsen metabolic syndrome.17

CVD is one of the most common causes of death among people with schizophrenia.17,18 Their life expectancy is reported to be 51 to 61 years—20 to 25 years less than what is seen in the general population.19-21


Arterial compliance in schizophrenia
Reduced arterial compliance has been found to be a robust predictor of athero­sclerosis, stroke, and myocardial infarction22-29:

  • In 376 subjects who had routine diagnostic coronary angiography associated with coronary stenosis, arterial compliance was reduced significantly—even after controlling for age, sex, smoking, diabetes, hypertension, hyperlipidemia, and obesity.24

In a cross-sectional study, 63 male U.S. veterans age 18 to 70 who had a psychiatric diagnosis (16 taking quetiapine, 19 taking risperidone, and 28 treated in the past but off antipsychotics for 2 months) had significantly reduced compliance in thigh- and calf-level arteries than male controls (n = 111), adjusting for body mass index and Framingham Risk Score (FRS). Of the 63 patients, 23 had a diagnosis of schizophrenia or schizoaffective disorder.30 (The FRS is an estimate of a person’s 10-year cardiovascular risk, calculated using age, sex, total cholesterol, high-density lipoprotein, smoker or not, systolic blood pressure, and whether taking an antihypertensive or not. Compliance was measured using computerized plethysmography). Although not statistically significant, secondary analyses from this data set (n = 77, including men for whom factors for metabolic syndrome were available) showed that calf-level compliance (1.82 vs 2.06 mL) and thigh-level compliance (3.6 vs 4.26 mL; P = .06) were reduced in subjects with schizophrenia, compared with those who had another psychiatric diagnosis.31

  • In another study, arterial compliance was significantly reduced in 10 subjects with schizophrenia, compared with 10 healthy controls.32
  • Last, reduced total arterial compliance has been shown to be a robust predictor of mortality in older people, compared with reduced local or regional arterial compliance.33


Cytokine abnormalities in arterial compliance
The mechanism by which reduced arterial compliance is associated with cardiovascular pathology is not entirely clear. Arterial compliance is a predictor of cardiovascular disorders independent of hypertension.34 Two studies show that vascular inflammation is associated with reduced arterial compliance.35,36 Reduced arterial compliance is associated with increased angiotensin II activity; increased nicotinamide adenine dinucleotide phosphate oxidase activity; reduced nitric oxide activity; and increased reactive oxygen species.37-39 Angiotensin-II signaling activates transforming growth factor-β, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-17, IL-6, and C-reactive protein (CRP)—all of which are associated with reduced arterial compliance.39-46 In addition, high-sensitivity CRP is significantly associated with reduced arterial compliance.47-49

 

 

The overlap of cytokine abnormalities linked to schizophrenia and to arterial compliance is depicted in the Figure.


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.


Drug Brand Names
Celecoxib • Celebrex
Infliximab • Remicade
Omega-3 fatty acids • Lovaza
Quetiapine • Seroquel
Simvastatin • Zocor
Risperidone • Risperdal


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.

References


1. Potvin S, Stip E, Sepehry AA, et al. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63(8):801-808.
2. Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663-671.
3. Frydecka D, Misiak B, Pawlak-Adamska E, et al. Interleukin-6: the missing element of the neurocognitive deterioration in schizophrenia? The focus on genetic underpinnings, cognitive impairment and clinical manifestation. Eur Arch Psychiatry Clin Neurosci. 2015;265(6):449-459.
4. Dickerson F, Stallings C, Origoni A, et al. Additive effects of elevated C-reactive protein and exposure to herpes simplex virus type 1 on cognitive impairment in individuals with schizophrenia. Schizophr Res. 2012;134(1):83-88.
5. Dickerson F, Stallings C, Origoni A, et al. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res. 2007;93(1-3):261-265.
6. Asevedo E, Rizzo LB, Gadelha A, et al. Peripheral interleukin-2 level is associated with negative symptoms and cognitive performance in schizophrenia. Physiol Behav. 2014;129:194-198.
7. Miller BJ, Culpepper N, Rapaport MH. C-reactive protein levels in schizophrenia: a review and meta-analysis. Clin Schizophr Relat Psychoses. 2014;7(4):223-230.
8. Micoulaud-Franchi JA, Faugere M, Boyer L, et al. Elevated C-reactive protein is associated with sensory gating deficit in schizophrenia. Schizophr Res. 2015;165(1):94-96.
9. Horrobin DF. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res. 1998;30(3):193-208.
10. Landén M, Davidsson P, Gottfries CG, et al. Reduction of the synaptophysin level but normal levels of glycerophospholipids in the gyrus cinguli in schizophrenia. Schizophr Res. 2002;55(1-2):83-98.
11. Smesny S, Milleit B, Nenadic I, et al. Phospholipase A2 activity is associated with structural brain changes in schizophrenia. Neuroimage. 2010;52(4):1314-1327.
12. Smesny S, Kunstmann C, Kunstmann S, et al. Phospholipase A2 activity in first episode schizophrenia: associations with symptom severity and outcome at week 12. World J Biol Psychiatry. 2011;12(8):598-607.
13. Fontaine KR, Heo M, Harrigan EP, et al. Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate. Psychiatry Res. 2001;101(3):277-288.
14. Homel P, Casey D, Allison DB. Changes in body mass index for individuals with and without schizophrenia, 1987-1996. Schizophr Res. 2002;55(3):277-284.
15. Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002. JAMA. 2004;291(23):2847-2850.
16. Dickerson FB, Brown CH, Kreyenbuhl JA, et al. Obesity among individuals with serious mental illness. Acta Psychiatr Scand. 2006;113(4):306-313.
17. Newcomer JW. Metabolic syndrome and mental illness. Am J Manag Care. 2007;13(suppl 7):S170-S177.
18. Healy D, Le Noury J, Harris M, et al. Mortality in schizophrenia and related psychoses: data from two cohorts, 1875-1924 and 1994-2010. BMJ Open. 2012;2(5). doi: 10.1136/bmjopen-2012-001810.
19. Newman SC, Bland RC. Mortality in a cohort of patients with schizophrenia: a record linkage study. Can J Psychiatry. 1991;36(4):239-245.
20. Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173:11-53.
21. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42.
22. Farrar DJ, Bond MG, Riley WA, et al. Anatomic correlates of aortic pulse wave velocity and carotid artery elasticity during atherosclerosis progression and regression in monkeys. Circulation. 1991;83(5):1754-1763.
23. Wada T, Kodaira K, Fujishiro K, et al. Correlation of ultrasound-measured common carotid artery stiffness with pathological findings. Arterioscler Thromb. 1994;14(3):479-482.
24. Herrington DM, Kesler K, Reiber JH, et al. Arterial compliance adds to conventional risk factors for prediction of angiographic coronary artery disease. Am Heart J. 2013;146(4):662-667.
25. Willens HJ, Davis W, Herrington DM, et al. Relationship of peripheral arterial compliance and standard cardiovascular risk factors. Vasc Endovascular Surg. 2003;37(3):197-206.
26. Herrington DM, Brown WV, Mosca L, et al. Relationship between arterial stiffness and subclinical aortic atherosclerosis. Circulation. 2004;110(4):432-437.
27. Saliashvili G, Davis WW, Harris MT, et al. Simvastatin improved arterial compliance in high-risk patients. Vasc Endovascular Surg. 2004;38(6):519-523.
28. Le NA, Brown WV, Davis WW, et al. Comparison of the relation of triglyceride-rich lipoproteins and muscular artery compliance in healthy women versus healthy men. Am J Cardiol. 2005;95(9):1049-1054.
29. Willens HJ, Chirinos JA, Brown WV, et al. Usefulness of arterial compliance in the thigh in predicting exercise capacity in individuals without coronary heart disease. Am J Cardiol. 2005;96(2):306-310.
30. Koola MM, Brown WV, Qualls C, et al. Reduced arterial compliance in patients with psychiatric diagnoses. Schizophr Res. 2012;137(1-3):251-253.
31. Koola MM, Sorkin JD, Fargotstein M, et al. Predictors of calf arterial compliance in male veterans with psychiatric diagnoses. The Primary Care Companion for CNS Disorders. In press.
32. Phillips AA, Warburton DE, Flynn SW, et al. Assessment of arterial stiffness among schizophrenia-spectrum disorders using aortic pulse wave velocity and arterial compliance: a pilot study. Psychiatry Res. 2014;215(1):14-19.
33. Papaioannou TG, Protogerou AD, Stergiopulos N, et al. Total arterial compliance estimated by a novel method and all-cause mortality in the elderly: the PROTEGER study. Age (Dordr). 2014;36(3):9661.
34. Park S, Lakatta EG. Role of inflammation in the pathogenesis of arterial stiffness. Yonsei Med J. 2012;53(2):258-261.
35. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation. 2003;107(2):346-354.
36. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(5):932-943.
37. van der Loo B, Labugger R, Skepper JN, et al. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med. 2000;192(12):1731-1744.
38. Csiszar A, Ungvari Z, Edwards JG, et al. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res. 2002;90(11):1159-1166.
39. Wang MC, Tsai WC, Chen JY, et al. Arterial stiffness correlated with cardiac remodelling in patients with chronic kidney disease. Nephrology (Carlton). 2007;12(6):591-597.
40. Belmin J, Bernard C, Corman B, et al. Increased production of tumor necrosis factor and interleukin-6 by arterial wall of aged rats. Am J Physiol. 1995;268(6 pt 2):H2288-2293.
41. Gerli R, Monti D, Bistoni O, et al. Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech Ageing Dev. 2000;121(1-3):37-46.
42. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102(18):2165-2168.
43. Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol. 2000;20(9):2094-2099.
44. Venugopal SK, Devaraj S, Yuhanna I, et al. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002;106(12):1439-1441.
45. Csiszar A, Ungvari Z, Koller A, et al. Aging-induced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J. 2003;17(9):1183-1185.
46. Spinetti G, Wang M, Monticone R, et al. Rat aortic MCP-1 and its receptor CCR2 increase with age and alter vascular smooth muscle cell function. Arterioscler Thromb Vasc Biol. 2004;24(8):1397-1402.
47. Mattace-Raso FU, van der Cammen TJ, van der Meer IM, et al. C-reactive protein and arterial stiffness in older adults: the Rotterdam Study. Atherosclerosis. 2004;176(1):111-116.
48. Mahmud A, Feely J. Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension. 2005;46(5):1118-1122.
49. Nagano M, Nakamura M, Sato K, et al. Association between serum C-reactive protein levels and pulse wave velocity: a population-based cross-sectional study in a general population. Atherosclerosis. 2005;180(1):189-195.
50. Nestel P, Shige H, Pomeroy S, et al. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. Am J Clin Nutr. 2002;76(2):326-330.
51. Mäki-Petäjä KM, Elkhawad M, Cheriyan J, et al. Anti-tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation. 2012;126(21):2473-2480.
52. Sommer IE, de Witte L, Begemann M, et al. Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012;73(4):414-419.
53. Sommer IE, van Westrhenen R, Begemann MJ, et al. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014;40(1):181-191.

References


1. Potvin S, Stip E, Sepehry AA, et al. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63(8):801-808.
2. Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663-671.
3. Frydecka D, Misiak B, Pawlak-Adamska E, et al. Interleukin-6: the missing element of the neurocognitive deterioration in schizophrenia? The focus on genetic underpinnings, cognitive impairment and clinical manifestation. Eur Arch Psychiatry Clin Neurosci. 2015;265(6):449-459.
4. Dickerson F, Stallings C, Origoni A, et al. Additive effects of elevated C-reactive protein and exposure to herpes simplex virus type 1 on cognitive impairment in individuals with schizophrenia. Schizophr Res. 2012;134(1):83-88.
5. Dickerson F, Stallings C, Origoni A, et al. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res. 2007;93(1-3):261-265.
6. Asevedo E, Rizzo LB, Gadelha A, et al. Peripheral interleukin-2 level is associated with negative symptoms and cognitive performance in schizophrenia. Physiol Behav. 2014;129:194-198.
7. Miller BJ, Culpepper N, Rapaport MH. C-reactive protein levels in schizophrenia: a review and meta-analysis. Clin Schizophr Relat Psychoses. 2014;7(4):223-230.
8. Micoulaud-Franchi JA, Faugere M, Boyer L, et al. Elevated C-reactive protein is associated with sensory gating deficit in schizophrenia. Schizophr Res. 2015;165(1):94-96.
9. Horrobin DF. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res. 1998;30(3):193-208.
10. Landén M, Davidsson P, Gottfries CG, et al. Reduction of the synaptophysin level but normal levels of glycerophospholipids in the gyrus cinguli in schizophrenia. Schizophr Res. 2002;55(1-2):83-98.
11. Smesny S, Milleit B, Nenadic I, et al. Phospholipase A2 activity is associated with structural brain changes in schizophrenia. Neuroimage. 2010;52(4):1314-1327.
12. Smesny S, Kunstmann C, Kunstmann S, et al. Phospholipase A2 activity in first episode schizophrenia: associations with symptom severity and outcome at week 12. World J Biol Psychiatry. 2011;12(8):598-607.
13. Fontaine KR, Heo M, Harrigan EP, et al. Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate. Psychiatry Res. 2001;101(3):277-288.
14. Homel P, Casey D, Allison DB. Changes in body mass index for individuals with and without schizophrenia, 1987-1996. Schizophr Res. 2002;55(3):277-284.
15. Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002. JAMA. 2004;291(23):2847-2850.
16. Dickerson FB, Brown CH, Kreyenbuhl JA, et al. Obesity among individuals with serious mental illness. Acta Psychiatr Scand. 2006;113(4):306-313.
17. Newcomer JW. Metabolic syndrome and mental illness. Am J Manag Care. 2007;13(suppl 7):S170-S177.
18. Healy D, Le Noury J, Harris M, et al. Mortality in schizophrenia and related psychoses: data from two cohorts, 1875-1924 and 1994-2010. BMJ Open. 2012;2(5). doi: 10.1136/bmjopen-2012-001810.
19. Newman SC, Bland RC. Mortality in a cohort of patients with schizophrenia: a record linkage study. Can J Psychiatry. 1991;36(4):239-245.
20. Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173:11-53.
21. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42.
22. Farrar DJ, Bond MG, Riley WA, et al. Anatomic correlates of aortic pulse wave velocity and carotid artery elasticity during atherosclerosis progression and regression in monkeys. Circulation. 1991;83(5):1754-1763.
23. Wada T, Kodaira K, Fujishiro K, et al. Correlation of ultrasound-measured common carotid artery stiffness with pathological findings. Arterioscler Thromb. 1994;14(3):479-482.
24. Herrington DM, Kesler K, Reiber JH, et al. Arterial compliance adds to conventional risk factors for prediction of angiographic coronary artery disease. Am Heart J. 2013;146(4):662-667.
25. Willens HJ, Davis W, Herrington DM, et al. Relationship of peripheral arterial compliance and standard cardiovascular risk factors. Vasc Endovascular Surg. 2003;37(3):197-206.
26. Herrington DM, Brown WV, Mosca L, et al. Relationship between arterial stiffness and subclinical aortic atherosclerosis. Circulation. 2004;110(4):432-437.
27. Saliashvili G, Davis WW, Harris MT, et al. Simvastatin improved arterial compliance in high-risk patients. Vasc Endovascular Surg. 2004;38(6):519-523.
28. Le NA, Brown WV, Davis WW, et al. Comparison of the relation of triglyceride-rich lipoproteins and muscular artery compliance in healthy women versus healthy men. Am J Cardiol. 2005;95(9):1049-1054.
29. Willens HJ, Chirinos JA, Brown WV, et al. Usefulness of arterial compliance in the thigh in predicting exercise capacity in individuals without coronary heart disease. Am J Cardiol. 2005;96(2):306-310.
30. Koola MM, Brown WV, Qualls C, et al. Reduced arterial compliance in patients with psychiatric diagnoses. Schizophr Res. 2012;137(1-3):251-253.
31. Koola MM, Sorkin JD, Fargotstein M, et al. Predictors of calf arterial compliance in male veterans with psychiatric diagnoses. The Primary Care Companion for CNS Disorders. In press.
32. Phillips AA, Warburton DE, Flynn SW, et al. Assessment of arterial stiffness among schizophrenia-spectrum disorders using aortic pulse wave velocity and arterial compliance: a pilot study. Psychiatry Res. 2014;215(1):14-19.
33. Papaioannou TG, Protogerou AD, Stergiopulos N, et al. Total arterial compliance estimated by a novel method and all-cause mortality in the elderly: the PROTEGER study. Age (Dordr). 2014;36(3):9661.
34. Park S, Lakatta EG. Role of inflammation in the pathogenesis of arterial stiffness. Yonsei Med J. 2012;53(2):258-261.
35. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation. 2003;107(2):346-354.
36. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(5):932-943.
37. van der Loo B, Labugger R, Skepper JN, et al. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med. 2000;192(12):1731-1744.
38. Csiszar A, Ungvari Z, Edwards JG, et al. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res. 2002;90(11):1159-1166.
39. Wang MC, Tsai WC, Chen JY, et al. Arterial stiffness correlated with cardiac remodelling in patients with chronic kidney disease. Nephrology (Carlton). 2007;12(6):591-597.
40. Belmin J, Bernard C, Corman B, et al. Increased production of tumor necrosis factor and interleukin-6 by arterial wall of aged rats. Am J Physiol. 1995;268(6 pt 2):H2288-2293.
41. Gerli R, Monti D, Bistoni O, et al. Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech Ageing Dev. 2000;121(1-3):37-46.
42. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102(18):2165-2168.
43. Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol. 2000;20(9):2094-2099.
44. Venugopal SK, Devaraj S, Yuhanna I, et al. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002;106(12):1439-1441.
45. Csiszar A, Ungvari Z, Koller A, et al. Aging-induced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J. 2003;17(9):1183-1185.
46. Spinetti G, Wang M, Monticone R, et al. Rat aortic MCP-1 and its receptor CCR2 increase with age and alter vascular smooth muscle cell function. Arterioscler Thromb Vasc Biol. 2004;24(8):1397-1402.
47. Mattace-Raso FU, van der Cammen TJ, van der Meer IM, et al. C-reactive protein and arterial stiffness in older adults: the Rotterdam Study. Atherosclerosis. 2004;176(1):111-116.
48. Mahmud A, Feely J. Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension. 2005;46(5):1118-1122.
49. Nagano M, Nakamura M, Sato K, et al. Association between serum C-reactive protein levels and pulse wave velocity: a population-based cross-sectional study in a general population. Atherosclerosis. 2005;180(1):189-195.
50. Nestel P, Shige H, Pomeroy S, et al. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. Am J Clin Nutr. 2002;76(2):326-330.
51. Mäki-Petäjä KM, Elkhawad M, Cheriyan J, et al. Anti-tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation. 2012;126(21):2473-2480.
52. Sommer IE, de Witte L, Begemann M, et al. Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012;73(4):414-419.
53. Sommer IE, van Westrhenen R, Begemann MJ, et al. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014;40(1):181-191.

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