SCHRES-06368; No of Pages 2 Schizophrenia Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Cytokines in schizophrenia: Methodological Issues
Dear Editors 1. Introduction Although the etiology of schizophrenia remains unclear, there is evidence that increase in pro-inflammatory and decrease in antiinflammatory cytokine signaling and receptors are factors in the pathophysiology of schizophrenia (Potvin et al., 2008). A metaanalysis of 62 studies with 2298 people with schizophrenia and 1858 controls verified the presence of cytokine abnormalities in schizophrenia (Potvin et al., 2008). In a meta-analysis of 40 studies, 19 of which were also in the Potvin et al. study (2008), similar effect sizes in patients compared to controls were seen in patients with acute relapse of schizophrenia and in first episode psychosis (Miller et al., 2011). These two meta-analyses are summarized in Table 1. The purpose of this letter is to shed light on methodological issues that need to be addressed in order to advance the study of cytokines in schizophrenia. 2. Are cytokine abnormalities independent of body mass index and smoking? The metabolic syndrome is widespread in schizophrenia. Cytokines, such as IL-1, IL-1RA, IL-6, IL-8, IL-10, TNF-α, and C-reactive protein (CRP) are elevated in people with the metabolic syndrome and obesity (Balistreri et al., 2010). Hence, the metabolic syndrome and/or obesity could be a confounding factor in cytokine studies. Similarly, cigarette smoking is widely prevalent in people with schizophrenia, and smoking may increase concentrations of CRP, IL-1β, IL-6, IL-8, and decrease concentrations of IL-1RA, IL-1β, IL-2, IL-6, IL-12, TNF-α, and IFN-γ (Gonçalves et al., 2011). Therefore, smoking is also a potential confound in cytokine studies in schizophrenia. Out of the 83 studies included in the meta-analyses (Potvin et al., 2008; Miller et al., 2011), only three studies controlled for smoking and only two studies controlled for both body mass index (BMI) and smoking (Haack et al., 1999; Fernandez-Egea et al., 2009). 3. Cytokines in blood versus cerebrospinal fluid Another methodological issue relates to the tissue used to measure cytokine concentrations. Blood may not be the most informative source for studying cytokines in schizophrenia, since the association between peripheral and central cytokine concentrations is poorly understood. However, obtaining cerebrospinal fluid (CSF) is very difficult in this population. Only seven out of 40 studies included in the metaanalysis (Miller et al., 2011) used CSF as the tissue source; all 62 studies included in the Potvin meta-analysis used blood at the tissue source
(Potvin et al., 2008). To our knowledge, there are only four studies that have compared CSF and blood cytokine concentrations (Katila et al., 1994; Barak et al., 1995; McAllister et al., 1995; Müller et al., 1997). Based on the four studies conducted to date, there appear to be important similarities and differences between CSF and blood cytokine measurements. Because of the small sample size, we cannot draw any firm conclusions on the correlations between blood and CSF cytokines.
4. Conclusions and future directions In sum, there is considerable evidence for a role of inflammation in the pathophysiology of schizophrenia. However, cytokine findings would be strengthened by the inclusion of the potential confounds of waist circumference, obesity and smoking in future studies. Understanding the association of cytokines and symptoms in schizophrenia independent of obesity and smoking is critical to understanding the role of inflammation in this illness. A better understanding of the association between cytokine concentrations in blood and the central nervous system is an important methodological issue. More research is needed to examine the association between CSF and blood cytokine concentrations. Studies with large sample size are warranted to examine whether CSF cytokines are associated with schizophrenia independent of obesity and smoking. Attention to these issues in future studies will advance the field and allow for potential integration of pathophysiology with novel therapeutic discovery targeting inflammatory mechanisms.
Table 1 Findings from meta-analysis on cytokines in schizophrenia versus controls in blood and cerebrospinal fluid. Meta-analysis
Studies included
Blood cytokines
CSF cytokines
Potvin et al. (2008)
62 studies, all in blood
–
Miller et al. (2011)
33 studies in blood, 7 in CSF
↑ IL-1RA ↑ sIL-2R ↑ IL-6 ↓ IL-2 State markers: ↑ IL-1β ↑ IL-6 ↑ TGF-β Trait markers: ↑ IL-12 ↑ IFN-γ ↑ TNF-α ↑ sIL-2R
↓IL-1βa
IL = interleukin; TGF = Transforming Growth Factor; IFN = Interferon; TNF = Tumor Necrosis Factor; sIL-2R = soluble IL-2 receptor; CSF = cerebrospinal fluid. a Includes two studies (Katila et al., 1994; Barak et al., 1995) (N = 30) done in medicated inpatients.
http://dx.doi.org/10.1016/j.schres.2015.05.005 0920-9964/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Koola, M.M., Duncan, E.J., Cytokines in schizophrenia: Methodological Issues, Schizophr. Res. (2015), http://dx.doi.org/ 10.1016/j.schres.2015.05.005
2
Letter to the Editor
Contributors Koola wrote the first draft of the manuscript with significant intellectual contributions from Duncan. We thank Drs. Robert Buchanan and Robert McMahon for editing the manuscript. Conflict of interest Dr. Duncan is a full time attending psychiatrist in the Mental Health Service Line of the Atlanta Veterans Affairs Medical Center, Decatur, Georgia, and receives grant support from Posit Science Corporation and Auspex Pharmaceuticals, Inc. Dr. Koola has no conflict of interest. Acknowledgments N/A.
References Balistreri, C.R., Caruso, C., Candore, G., 2010. The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediat. Inflamm. 802078. Barak, V., Barak, Y., Levine, J., Nisman, B., Roisman, I., 1995. Changes in interleukin-1 beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic patients. J. Basic Clin. Physiol. Pharmacol. 6 (1), 61–69. Fernandez-Egea, E., Bernardo, M., Donner, T., Conget, I., Parellada, E., Justicia, A., Esmatjes, E., Garcia-Rizo, C., Kirkpatrick, B., 2009. Metabolic profile of antipsychotic-naive individuals with non-affective psychosis. Br. J. Psychiatry 194 (5), 434–438. Gonçalves, R.B., Coletta, R.D., Silvério, K.G., Benevides, L., Casati, M.Z., da Silva, J.S., Nociti Jr., F.H., 2011. Impact of smoking on inflammation: overview of molecular mechanisms. Inflamm. Res. 60 (5), 409–424. Haack, M., Hinze-Selch, D., Fenzel, T., Kraus, T., Kühn, M., Schuld, A., Pollmächer, T., 1999. Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J. Psychiatr. Res. 33 (5), 407–418. Katila, H., Hurme, M., Wahlbeck, K., Appelberg, B., Rimón, R., 1994. Plasma and cerebrospinal fluid interleukin-1 beta and interleukin-6 in hospitalized schizophrenic patients. Neuropsychobiology 30 (1), 20–23.
McAllister, C.G., van Kammen, D.P., Rehn, T.J., Miller, A.L., Gurklis, J., Kelley, M.E., Yao, J., Peters, J.L., 1995. Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am. J. Psychiatry 152 (9), 1291–1297. Miller, B.J., Buckley, P., Seabolt, W., Mellor, A., Kirkpatrick, B., 2011. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol. Psychiatry 70 (7), 663–671. Müller, N., Empl, M., Riedel, M., Schwarz, M., Ackenheil, M., 1997. Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 247 (6), 308–313. Potvin, S., Stip, E., Sepehry, A.A., Gendron, A., Bah, R., Kouassi, E., 2008. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol. Psychiatry 63 (8), 801–808.
Maju Mathew Koola Sheppard Pratt Health System, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA Corresponding author at: Clinical Research Program, Sheppard Pratt Health System, 6501 N Charles St, Baltimore, MD 21204, USA. Tel.: +1 410 938 5429; fax: +1 410 938 3111. E-mail address: [email protected]. Erica J. Duncan Mental Health Service, Atlanta Veterans Affairs Medical Center, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA 28 April 2015 Available online xxxx
Please cite this article as: Koola, M.M., Duncan, E.J., Cytokines in schizophrenia: Methodological Issues, Schizophr. Res. (2015), http://dx.doi.org/ 10.1016/j.schres.2015.05.005
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Cytokines in schizophrenia: Methodological Issues
Dear Editors 1. Introduction Although the etiology of schizophrenia remains unclear, there is evidence that increase in pro-inflammatory and decrease in antiinflammatory cytokine signaling and receptors are factors in the pathophysiology of schizophrenia (Potvin et al., 2008). A metaanalysis of 62 studies with 2298 people with schizophrenia and 1858 controls verified the presence of cytokine abnormalities in schizophrenia (Potvin et al., 2008). In a meta-analysis of 40 studies, 19 of which were also in the Potvin et al. study (2008), similar effect sizes in patients compared to controls were seen in patients with acute relapse of schizophrenia and in first episode psychosis (Miller et al., 2011). These two meta-analyses are summarized in Table 1. The purpose of this letter is to shed light on methodological issues that need to be addressed in order to advance the study of cytokines in schizophrenia. 2. Are cytokine abnormalities independent of body mass index and smoking? The metabolic syndrome is widespread in schizophrenia. Cytokines, such as IL-1, IL-1RA, IL-6, IL-8, IL-10, TNF-α, and C-reactive protein (CRP) are elevated in people with the metabolic syndrome and obesity (Balistreri et al., 2010). Hence, the metabolic syndrome and/or obesity could be a confounding factor in cytokine studies. Similarly, cigarette smoking is widely prevalent in people with schizophrenia, and smoking may increase concentrations of CRP, IL-1β, IL-6, IL-8, and decrease concentrations of IL-1RA, IL-1β, IL-2, IL-6, IL-12, TNF-α, and IFN-γ (Gonçalves et al., 2011). Therefore, smoking is also a potential confound in cytokine studies in schizophrenia. Out of the 83 studies included in the meta-analyses (Potvin et al., 2008; Miller et al., 2011), only three studies controlled for smoking and only two studies controlled for both body mass index (BMI) and smoking (Haack et al., 1999; Fernandez-Egea et al., 2009). 3. Cytokines in blood versus cerebrospinal fluid Another methodological issue relates to the tissue used to measure cytokine concentrations. Blood may not be the most informative source for studying cytokines in schizophrenia, since the association between peripheral and central cytokine concentrations is poorly understood. However, obtaining cerebrospinal fluid (CSF) is very difficult in this population. Only seven out of 40 studies included in the metaanalysis (Miller et al., 2011) used CSF as the tissue source; all 62 studies included in the Potvin meta-analysis used blood at the tissue source
(Potvin et al., 2008). To our knowledge, there are only four studies that have compared CSF and blood cytokine concentrations (Katila et al., 1994; Barak et al., 1995; McAllister et al., 1995; Müller et al., 1997). Based on the four studies conducted to date, there appear to be important similarities and differences between CSF and blood cytokine measurements. Because of the small sample size, we cannot draw any firm conclusions on the correlations between blood and CSF cytokines.
4. Conclusions and future directions In sum, there is considerable evidence for a role of inflammation in the pathophysiology of schizophrenia. However, cytokine findings would be strengthened by the inclusion of the potential confounds of waist circumference, obesity and smoking in future studies. Understanding the association of cytokines and symptoms in schizophrenia independent of obesity and smoking is critical to understanding the role of inflammation in this illness. A better understanding of the association between cytokine concentrations in blood and the central nervous system is an important methodological issue. More research is needed to examine the association between CSF and blood cytokine concentrations. Studies with large sample size are warranted to examine whether CSF cytokines are associated with schizophrenia independent of obesity and smoking. Attention to these issues in future studies will advance the field and allow for potential integration of pathophysiology with novel therapeutic discovery targeting inflammatory mechanisms.
Table 1 Findings from meta-analysis on cytokines in schizophrenia versus controls in blood and cerebrospinal fluid. Meta-analysis
Studies included
Blood cytokines
CSF cytokines
Potvin et al. (2008)
62 studies, all in blood
–
Miller et al. (2011)
33 studies in blood, 7 in CSF
↑ IL-1RA ↑ sIL-2R ↑ IL-6 ↓ IL-2 State markers: ↑ IL-1β ↑ IL-6 ↑ TGF-β Trait markers: ↑ IL-12 ↑ IFN-γ ↑ TNF-α ↑ sIL-2R
↓IL-1βa
IL = interleukin; TGF = Transforming Growth Factor; IFN = Interferon; TNF = Tumor Necrosis Factor; sIL-2R = soluble IL-2 receptor; CSF = cerebrospinal fluid. a Includes two studies (Katila et al., 1994; Barak et al., 1995) (N = 30) done in medicated inpatients.
http://dx.doi.org/10.1016/j.schres.2015.05.005 0920-9964/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Koola, M.M., Duncan, E.J., Cytokines in schizophrenia: Methodological Issues, Schizophr. Res. (2015), http://dx.doi.org/ 10.1016/j.schres.2015.05.005
2
Letter to the Editor
Contributors Koola wrote the first draft of the manuscript with significant intellectual contributions from Duncan. We thank Drs. Robert Buchanan and Robert McMahon for editing the manuscript. Conflict of interest Dr. Duncan is a full time attending psychiatrist in the Mental Health Service Line of the Atlanta Veterans Affairs Medical Center, Decatur, Georgia, and receives grant support from Posit Science Corporation and Auspex Pharmaceuticals, Inc. Dr. Koola has no conflict of interest. Acknowledgments N/A.
References Balistreri, C.R., Caruso, C., Candore, G., 2010. The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediat. Inflamm. 802078. Barak, V., Barak, Y., Levine, J., Nisman, B., Roisman, I., 1995. Changes in interleukin-1 beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic patients. J. Basic Clin. Physiol. Pharmacol. 6 (1), 61–69. Fernandez-Egea, E., Bernardo, M., Donner, T., Conget, I., Parellada, E., Justicia, A., Esmatjes, E., Garcia-Rizo, C., Kirkpatrick, B., 2009. Metabolic profile of antipsychotic-naive individuals with non-affective psychosis. Br. J. Psychiatry 194 (5), 434–438. Gonçalves, R.B., Coletta, R.D., Silvério, K.G., Benevides, L., Casati, M.Z., da Silva, J.S., Nociti Jr., F.H., 2011. Impact of smoking on inflammation: overview of molecular mechanisms. Inflamm. Res. 60 (5), 409–424. Haack, M., Hinze-Selch, D., Fenzel, T., Kraus, T., Kühn, M., Schuld, A., Pollmächer, T., 1999. Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J. Psychiatr. Res. 33 (5), 407–418. Katila, H., Hurme, M., Wahlbeck, K., Appelberg, B., Rimón, R., 1994. Plasma and cerebrospinal fluid interleukin-1 beta and interleukin-6 in hospitalized schizophrenic patients. Neuropsychobiology 30 (1), 20–23.
McAllister, C.G., van Kammen, D.P., Rehn, T.J., Miller, A.L., Gurklis, J., Kelley, M.E., Yao, J., Peters, J.L., 1995. Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am. J. Psychiatry 152 (9), 1291–1297. Miller, B.J., Buckley, P., Seabolt, W., Mellor, A., Kirkpatrick, B., 2011. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol. Psychiatry 70 (7), 663–671. Müller, N., Empl, M., Riedel, M., Schwarz, M., Ackenheil, M., 1997. Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 247 (6), 308–313. Potvin, S., Stip, E., Sepehry, A.A., Gendron, A., Bah, R., Kouassi, E., 2008. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol. Psychiatry 63 (8), 801–808.
Maju Mathew Koola Sheppard Pratt Health System, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA Corresponding author at: Clinical Research Program, Sheppard Pratt Health System, 6501 N Charles St, Baltimore, MD 21204, USA. Tel.: +1 410 938 5429; fax: +1 410 938 3111. E-mail address: [email protected]. Erica J. Duncan Mental Health Service, Atlanta Veterans Affairs Medical Center, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA 28 April 2015 Available online xxxx
Please cite this article as: Koola, M.M., Duncan, E.J., Cytokines in schizophrenia: Methodological Issues, Schizophr. Res. (2015), http://dx.doi.org/ 10.1016/j.schres.2015.05.005
