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Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia
Psychiatry Research 149 (2007) 267 – 271 www.elsevier.com/locate/psychres
Brief report
Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia Xiaoduo Fan a,b,⁎, Cynthia Pristach c,d , Emily Y. Liu d,e , Oliver Freudenreich a,b , David C. Henderson a,b , Donald C. Goff a,b a
d
Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA b Harvard Medical School, Boston, MA, USA c Department of Psychiatry, Erie County Medical Center, Buffalo, NY, USA School of Medicine and Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA e Women and Children's Hospital of Buffalo, Buffalo, NY, USA Received 14 March 2006; received in revised form 29 June 2006; accepted 27 July 2006
Abstract The present study examined the hypothesis that elevated serum levels of C-reactive protein (CRP) would be associated with more severe clinical symptoms in patients with schizophrenia. Twenty-six inpatients with schizophrenia or schizoaffective disorder were enrolled. Serum levels of CRP were measured, and each patient was assessed with the Positive and Negative Syndrome Scale (PANSS). Subjects with CRP levels above the normal range (CRP > 0.50 mg/dl, elevated CRP group, N = 5) scored significantly higher than those with CRP levels in the normal range (CRP ≤ 0.50 mg/dl, normal CRP group, N = 21) on the PANSS total score, negative symptom subscale score and general psychopathology subscale score. There was no significant difference between the two groups on the PANSS positive symptom subscale score. An inflammatory process, as reflected by elevated serum levels of CRP, might be associated with more severe psychopathology in a subgroup of patients with schizophrenia. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: C-reactive protein; Inflammation; Schizophrenia
1. Introduction The roles of immune dysfunction and inflammation have been described in patients with schizophrenia (Rapaport and Lohr, 1994; Müller et al., 2000; Maes et al., 2002; Sirota et al., 2005). Previous research has tried to identify specific inflammatory markers in relation to ⁎ Corresponding author. Freedom Trail Clinic, 25 Staniford Street, Boston, MA 02114, USA. Tel.: +1 617 912 7800; fax: +1 617 912 7820. E-mail address: [email protected] (X. Fan).
schizophrenia but with conflicting findings. For example, both Naudin et al. (1997) and Lin et al. (1998) found that patients with chronic schizophrenia, compared with normal controls, had significantly higher serum levels of tumor necrosis factor α (TNFα) and interleukin 6 (IL-6). In a separate study by Schattner et al. (1996), no difference of TNFα levels was found between schizophrenia patients and normal controls. In a study with 10 neuroleptic-free schizophrenia patients and 10 healthy subjects matched for sex and age, levels of cerebrospinal fluid (CSF) interleukin 2 were found to be higher in the patient group (Licinio et al., 1993). But two other
0165-1781/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2006.07.011
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X. Fan et al. / Psychiatry Research 149 (2007) 267–271
research groups were unable to replicate this finding (elMallakh et al., 1993; Rapaport et al., 1997). The inconsistent results in the literature might be explained by the heterogeneity of schizophrenia, difference in illness state (acute versus chronic) and effects of antipsychotic medication (Schattner et al., 1996). Several studies have suggested that the regulation of inflammatory and immunological processes is likely related to the manifestation of symptoms and treatment response of schizophrenia. For example, in 79 patients with schizophrenia who withdrew from haloperidol treatment for up to 6 weeks, higher baseline levels of cerebrospinal fluid pro-inflammatory cytokine interleukin-2 (IL-2) were associated with worsening psychotic symptoms during the haloperidol withdrawal period (McAllister et al., 1995). In a more recent 12week study with 78 schizophrenia patients who were treated with either risperidone or haloperidol, patients with lower baseline serum levels of IL-2 had greater improvement in clinical symptoms (Zhang et al., 2004). Researchers also tried to examine the potential benefit of anti-inflammatory agents in treating schizophrenia. Celecoxib is a selective cyclooxygenase-2 (COX-2) anti-inflammatory agent. Müller et al. (2002) reported that celecoxib, when added to risperidone in patients with an acute exacerbation of schizophrenia, significantly reduced psychopathology as measured by the total score on the Positive and Negative Syndrome Scale. However, in a different sample of symptomatic outpatients with schizophrenia, celecoxib did not improve clinical symptoms or measures of disability (Rapaport et al., 2005). Among many inflammatory markers, there is particular interest in C-reactive protein (CRP). CRP is an acute-phase reactant that originates in the liver and has many pathophysiological roles in the inflammatory process (Roberts et al., 2000). CRP consistently has been associated with an increased risk of cardiovascular diseases, diabetes and other metabolic dysfunction (Bassuk et al., 2004; Pfutzner and Forst, 2006). In addition, elevated levels of CRP have been associated with depression (Ford and Erlinger, 2004; Lesperance et al., 2004) and cognitive impairment (Yaffe et al., 2003; Weuve et al., 2006). However, the role of CRP in relation to the psychopathology of schizophrenia remains unknown. The present study was intended to directly examine the relationship between CRP and the clinical manifestations of schizophrenia. It was hypothesized that elevated serum levels of CRP would be associated with more severe psychopathology in patients with schizophrenia.
2. Materials and methods 2.1. Sample Psychiatric inpatients, who met the DSM-IV criteria for schizophrenia or schizoaffective disorder and who were relatively stable on antipsychotic medications, were recruited from a county general hospital. All subjects were in the age range of 18–65 years old. Patients were excluded if they had any of the following conditions: (1) substance use during the past year; (2) treatment with anti-inflammatory or immunosuppressive medication; (3) overt infectious disease or auto-immune disease; and (4) inability to provide informed consent. The study protocol was approved by the institutional review board of the State University of New York at Buffalo. Written informed consent was obtained from each subject after a complete description of the study. 2.2. Procedure Blood samples for complete blood cell count (CBC) and CRP measurement were drawn in the morning after an overnight fast. Blood samples for CBC were assayed on the same day of study; blood samples for CRP measurement were processed, and the specimens were aliquoted and frozen at − 70 °C. CRP was assayed in batches of approximately every 10 subjects. The CRP assay was performed by means of particle enhanced immunonephelometry using BN System (Dade Behring, Deerfield, IL) with a lowest detectable limit of 0.35 mg/ dl, a suggested upper normal limit of 0.5 mg/dl and an intraassay coefficient of variation of 2.3%. Subjects were therefore categorized into the normal/elevated CRP groups using 0.50 mg/dl as the cutoff value. Assays were performed blind to the subject's identity. Each subject was assessed with the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) on the same day when the blood sample was obtained. The PANSS was analyzed blind to the blood assay results. 2.3. Statistical analyses Statistical analyses were performed using SPSS (version 13.0, Chicago, IL). Descriptive statistics were used to describe demographic and clinical measures. Group comparisons between the normal and elevated CRP groups were performed by nonparametric Mann– Whitney U-test for continuous variables and Fisher's exact test for categorical variables. All statistical tests were interpreted at the 5% significance level (two-tailed).
X. Fan et al. / Psychiatry Research 149 (2007) 267–271
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(PANSS total and subscale scores) were compared between patients on olanzapine and those on risperidone, which accounted for most of the study subjects. No differences were found between the olanzapine group and the risperidone group on PANSS total or any subscale scores (P's > 0.60). As shown in Table 1, there were no significant differences between the normal/elevated CRP groups regarding demographic and general clinical characteristics, such as age, gender, race, education level, age of illness onset, history of substance use, smoking status, WBC and current antipsychotic medication used (P's > 0.05). However, the elevated CRP group had significantly higher PANSS total score, negative symptom subscale score and general psychopathology subscale score compared with the normal CRP group (P's < 0.05). The two groups did not differ on the PANSS positive symptom subscale score (P > 0.05).
3. Results Twenty-six subjects were enrolled in the study. With a serum level of 0.50 mg/dl as the cutoff value, 21 subjects were in the normal CRP group (CRP ≤ 0.50 mg/ dl) and five subjects were in the elevated CRP group (CRP > 0.5 mg/dl). Within the elevated CRP group, two subjects had a serum CRP value of 0.6 mg/dl, one subject 1.1 mg/dl, one subject 2.0 mg/dl and one subject 3.0 mg/dl. Among 26 subjects who participated in the study, nine were on olanzapine (dose range 5–25 mg/day), eight on risperidone (dose range 2–6 mg/day), two on quetiapine (dose range 300–400 mg/day), three on ziprasidone (dose range 160–240 mg/day) and one on aripiprazole (15 mg/day). The remaining three subjects were on typical antipsychotic agents (two on haloperidol with the dose range 5–15 mg/day, one on fluphenazine 15 mg/day). Psychopathology measures
Table 1 Comparison of demographic and clinical characteristics between the normal/elevated CRP groups Characteristics
Age (years) Age of onset (years) Disease duration (years) Education (years) WBC (103/μl)
Gender Female Male Race White Non-white History of substance use Yes No Current antipsychotic Atypical Typical Smoking status Yes No
PANSS—total PANSS—positive PANSS—negative PANSS—general
Normal CRP group (N = 21)
Elevated CRP group (N = 5)
Analysis
Median
Range
Median
Range
Z
P
31 26 8 14 9.0
20–64 12–63 1–29 6–19 4.6–12.3
45 21 14 13 9.6
25–53 15–29 2–32 8–19 4.2–15.9
− 0.85 − 0.59 − 1.53 − 0.29 − 0.42
0.397 0.561 0.125 0.768 0.705
X2
df
P
60 40
3.44
1
0.101
3 2
60 40
0.08
1
1.000
24 76
3 2
60 40
2.48
1
0.281
18 3
86 14
5 0
100 0
0.81
1
0.369
15 6
71 29
2 3
40 60
1.76
1
0.297
N
%
N
4 17
19 81
3 2
14 7
67 33
5 16
%
Median
Range
Median
Range
Z
P
59 14 12 32
38–90 9–25 7–25 22–47
76 16 23 38
70–77 15–19 16–23 34–40
− 2.38 − 1.05 − 2.42 − 2.45
0.017 0.296 0.016 0.014
WBC: white blood cell count. PANSS: Positive and Negative Syndrome Scale, including positive symptom, negative symptom and general psychopathology subscales.
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4. Discussion To our knowledge, this is the first study directly examining the relationship between serum level of CRP and the psychopathology profile of schizophrenia. The present study found that elevated serum levels of CRP were associated with more severe clinical symptoms of schizophrenia as reflected by the PANSS total score, negative symptom subscale score and general psychopathology subscale score. Our results are consistent with previous findings linking schizophrenia to activation of the inflammatory response system (Rapaport and Lohr, 1994; Lin et al., 1998; Maes et al., 2000; Müller et al., 2000; Sirota et al., 2005). The underlying mechanisms relating inflammation to schizophrenia are still speculative. Studies have found that patients with schizophrenia show deficient regional blood flow in different brain areas, especially the frontal and temporal lobes (Bachneff, 1996; Shinba et al., 2004). Decreased frontal blood flow is associated with negative symptoms (Lahti et al., 2001; Vaiva et al., 2002). Hanson and Gottesman (2005) proposed that chronic inflammation might damage the micro-vascular system in the brain and disrupt the regulation of blood-brain barrier and cerebral blood flow. These alterations in homeostatic mechanisms of the brain might lead to the development of psychotic symptoms. Besides the small sample size, there are several other important methodological limitations in this study. First, participants in this study were a group of stabilized inpatients with schizophrenia. Patients were either continued or restarted with a previously used antipsychotic medication, or switched around different medications during their hospital stay. Therefore, the duration and influence of a specific antipsychotic medication could not be estimated for all patients. Yet, different antipsychotic medications may have differential effects on the inflammatory process and immune function (Maes et al., 1995; Akiyama, 1999; Pollmächer et al., 2000; Sirota et al., 2005). Second, because of the cross-sectional design and small sample size in this study, a causal relationship between serum CRP levels and severity of psychopathology remains uncertain. It is unclear whether inflammation is a byproduct of the pathophysiology of schizophrenia or directly contributes to the clinical manifestations of schizophrenia. Prospective studies are needed to examine the relationship between inflammation, as reflected by elevated serum levels of CRP, and treatment response, as well as the moderating role of specific antipsychotic medications, in patients with schizophrenia. It is still too
early to predict whether inflammation might represent a useful target for new interventional strategies. References Akiyama, K., 1999. Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration. Schizophrenia Research 37, 97–106. Bachneff, S.A., 1996. Regional cerebral blood flow in schizophrenia and the local circuit neurons hypothesis. Schizophrenia Bulletin 22, 163–182. Bassuk, S.S., Rifai, N., Ridker, P.M., 2004. High-sensitivity C-reactive protein: clinical importance. Current Problems in Cardiology 29, 439–493. el-Mallakh, R.S., Suddath, R.L., Wyatt, R.J., 1993. Interleukin-1 alpha and interleukin-2 in cerebrospinal fluid of schizophrenic subjects. Progress in Neuro-psychopharmacology & Biological Psychiatry 17, 383–391. Ford, D.E., Erlinger, T.P., 2004. Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey. Archives of Internal Medicine 164, 1010–1014. Hanson, D.R., Gottesman, I.I., 2005. Theories of schizophrenia: a genetic-inflammatory vascular synthesis. BMC Medical Genetics 6, 7. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261–276. Lahti, A.C., Holcomb, H.H., Medoff, D.R., Weiler, M.A., Tamminga, C.A., Carpenter Jr., W.T., 2001. Abnormal patterns of regional cerebral blood flow in schizophrenia with primary negative symptoms during an effortful auditory recognition task. American Journal of Psychiatry 158, 1797–1808. Lesperance, F., Frasure-Smith, N., Theroux, P., Irwin, M., 2004. The association between major depression and levels of soluble intercellular adhesion molecule 1, interleukin-6, and C-reactive protein in patients with recent acute coronary syndromes. American Journal of Psychiatry 161, 271–277. Licinio, J., Seibyl, J.P., Altemus, M., Charney, D.S., Krystal, J.H., 1993. Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients. American Journal of Psychiatry 150, 1408–1410. Lin, A., Kenis, G., Bignotti, S., Tura, G.J., De Jong, R., Bosmans, E., Pioli, R., Altamura, C., Scharpé, S., Maes, M., 1998. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophrenia Research 32, 9–15. Maes, M., Bosmans, E., Calabrese, J., Smith, R., Meltzer, H.Y., 1995. Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. Journal of Psychiatric Research 29, 141–152. Maes, M., Bocchio Chiavetto, L., Bignotti, S., Battisa Tura, G., Pioli, R., Boin, F., Kenis, G., Bosmans, E., de Jongh, R., Lin, A., Racagni, G., Altamura, C.A., 2000. Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics. European Neuropsychopharmacology 10, 119–124. Maes, M., Bocchio Chiavetto, L., Bignotti, S., Battisa Tura, G.J., Pioli, R., Boin, F., Kenis, G., Bosmans, E., de Jongh, R., Altamura, C.A., 2002. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the
X. Fan et al. / Psychiatry Research 149 (2007) 267–271 stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophrenia Research 54, 281–291. 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. American Journal of Psychiatry 152, 1291–1297. Müller, N., Riedel, M., Gruber, R., Ackenheil, M., Schwarz, M.J., 2000. The immune system and schizophrenia: an integrative view. Annals of the New York Academy of Sciences 917, 456–467. Müller, N., Riedel, M., Scheppach, C., Brandstätter, B., Sokullu, S., Krampe, K., Ulmschneider, M., Engel, R.R., Möller, H.J., Schwarz, M.J., 2002. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. American Journal of Psychiatry 159, 1029–1034. Naudin, J., Capo, C., Giusano, B., Mege, J.L., Azorin, J.M., 1997. A differential role for interleukin-6 and tumor necrosis factor-alpha in schizophrenia? Schizophrenia Research 26, 227–233. Pfutzner, A., Forst, T., 2006. High-sensitivity C-reactive protein as cardiovascular risk marker in patients with diabetes mellitus. Diabetes Technology and Therapeutics 8, 28–36. Pollmächer, T., Haack, M., Schuld, A., Kraus, T., Hinze-Selch, D., 2000. Effects of antipsychotic drugs on cytokine networks. Journal of Psychiatric Research 34, 369–382. Rapaport, M.H., Lohr, J.B., 1994. Serum-soluble interleukin-2 receptors in neuroleptic-naive schizophrenic subjects and in medicated schizophrenic subjects with and without tardive dyskinesia. Acta Psychiatrica Scandinavica 90, 311–315. Rapaport, M.H., McAllister, C.G., Pickar, D., Tamarkin, L., Kirch, D.G., Paul, S.M., 1997. CSF IL-1 and IL-2 in medicated schizophrenic patients and normal volunteers. Schizophrenia Research 25, 123–129. Rapaport, M.H., Delrahim, K.K., Bresee, C.J., Maddux, R.E., Ahmadpour, O., Dolnak, D., 2005. Celecoxib augmentation of
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continuously ill patients with schizophrenia. Biological Psychiatry 57, 1594–1596. Roberts, W.L., Sedrick, R., Moulton, L., Spencer, A., Rifai, N., 2000. Evaluation of four automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications. Clinical Chemistry 46, 461–468. Schattner, A., Cori, Y., Hahn, T., Sirota, P., 1996. No evidence for autoimmunity in schizophrenia. Journal of Autoimmunity 9, 661–666. Shinba, T., Nagano, M., Kariya, N., Ogawa, K., Shinozaki, T., Shimosato, S., Hoshi, Y., 2004. Near-infrared spectroscopy analysis of frontal lobe dysfunction in schizophrenia. Biological Psychiatry 55, 154–164. Sirota, P., Meiman, M., Herschko, R., Bessler, H., 2005. Effect of neuroleptic administration on serum levels of soluble IL-2 receptor-alpha and IL-1 receptor antagonist in schizophrenic patients. Psychiatry Research 134, 151–159. Vaiva, G., Cottencin, O., Llorca, P.M., Devos, P., Dupont, S., Mazas, O., Rascle, C., Thomas, P., Steinling, M., Goudemand, M., 2002. Regional cerebral blood flow in deficit/nondeficit types of schizophrenia according to SDS criteria. Progress in Neuropsychopharmacology & Biological Psychiatry 26, 481–485. Weuve, J., Ridker, P.M., Cook, N.R., Buring, J.E., Grodstein, F., 2006. High-sensitivity C-reactive protein and cognitive function in older women. Epidemiology 17, 183–189. Yaffe, K., Lindquist, K., Penninx, B.W., Simonsick, E.M., Pahor, M., Kritchevsky, S., Launer, L., Kuller, L., Rubin, S., Harris, T., 2003. Inflammatory markers and cognition in well-functioning African– American and white elders. Neurology 61, 76–80. Zhang, X.Y., Zhou, D.F., Cao, L.Y., Zhang, P.Y., Wu, G.Y., Shen, Y.C., 2004. Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. Journal of Clinical Psychiatry 65, 940–947.
Brief report
Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia Xiaoduo Fan a,b,⁎, Cynthia Pristach c,d , Emily Y. Liu d,e , Oliver Freudenreich a,b , David C. Henderson a,b , Donald C. Goff a,b a
d
Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA b Harvard Medical School, Boston, MA, USA c Department of Psychiatry, Erie County Medical Center, Buffalo, NY, USA School of Medicine and Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA e Women and Children's Hospital of Buffalo, Buffalo, NY, USA Received 14 March 2006; received in revised form 29 June 2006; accepted 27 July 2006
Abstract The present study examined the hypothesis that elevated serum levels of C-reactive protein (CRP) would be associated with more severe clinical symptoms in patients with schizophrenia. Twenty-six inpatients with schizophrenia or schizoaffective disorder were enrolled. Serum levels of CRP were measured, and each patient was assessed with the Positive and Negative Syndrome Scale (PANSS). Subjects with CRP levels above the normal range (CRP > 0.50 mg/dl, elevated CRP group, N = 5) scored significantly higher than those with CRP levels in the normal range (CRP ≤ 0.50 mg/dl, normal CRP group, N = 21) on the PANSS total score, negative symptom subscale score and general psychopathology subscale score. There was no significant difference between the two groups on the PANSS positive symptom subscale score. An inflammatory process, as reflected by elevated serum levels of CRP, might be associated with more severe psychopathology in a subgroup of patients with schizophrenia. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: C-reactive protein; Inflammation; Schizophrenia
1. Introduction The roles of immune dysfunction and inflammation have been described in patients with schizophrenia (Rapaport and Lohr, 1994; Müller et al., 2000; Maes et al., 2002; Sirota et al., 2005). Previous research has tried to identify specific inflammatory markers in relation to ⁎ Corresponding author. Freedom Trail Clinic, 25 Staniford Street, Boston, MA 02114, USA. Tel.: +1 617 912 7800; fax: +1 617 912 7820. E-mail address: [email protected] (X. Fan).
schizophrenia but with conflicting findings. For example, both Naudin et al. (1997) and Lin et al. (1998) found that patients with chronic schizophrenia, compared with normal controls, had significantly higher serum levels of tumor necrosis factor α (TNFα) and interleukin 6 (IL-6). In a separate study by Schattner et al. (1996), no difference of TNFα levels was found between schizophrenia patients and normal controls. In a study with 10 neuroleptic-free schizophrenia patients and 10 healthy subjects matched for sex and age, levels of cerebrospinal fluid (CSF) interleukin 2 were found to be higher in the patient group (Licinio et al., 1993). But two other
0165-1781/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2006.07.011
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research groups were unable to replicate this finding (elMallakh et al., 1993; Rapaport et al., 1997). The inconsistent results in the literature might be explained by the heterogeneity of schizophrenia, difference in illness state (acute versus chronic) and effects of antipsychotic medication (Schattner et al., 1996). Several studies have suggested that the regulation of inflammatory and immunological processes is likely related to the manifestation of symptoms and treatment response of schizophrenia. For example, in 79 patients with schizophrenia who withdrew from haloperidol treatment for up to 6 weeks, higher baseline levels of cerebrospinal fluid pro-inflammatory cytokine interleukin-2 (IL-2) were associated with worsening psychotic symptoms during the haloperidol withdrawal period (McAllister et al., 1995). In a more recent 12week study with 78 schizophrenia patients who were treated with either risperidone or haloperidol, patients with lower baseline serum levels of IL-2 had greater improvement in clinical symptoms (Zhang et al., 2004). Researchers also tried to examine the potential benefit of anti-inflammatory agents in treating schizophrenia. Celecoxib is a selective cyclooxygenase-2 (COX-2) anti-inflammatory agent. Müller et al. (2002) reported that celecoxib, when added to risperidone in patients with an acute exacerbation of schizophrenia, significantly reduced psychopathology as measured by the total score on the Positive and Negative Syndrome Scale. However, in a different sample of symptomatic outpatients with schizophrenia, celecoxib did not improve clinical symptoms or measures of disability (Rapaport et al., 2005). Among many inflammatory markers, there is particular interest in C-reactive protein (CRP). CRP is an acute-phase reactant that originates in the liver and has many pathophysiological roles in the inflammatory process (Roberts et al., 2000). CRP consistently has been associated with an increased risk of cardiovascular diseases, diabetes and other metabolic dysfunction (Bassuk et al., 2004; Pfutzner and Forst, 2006). In addition, elevated levels of CRP have been associated with depression (Ford and Erlinger, 2004; Lesperance et al., 2004) and cognitive impairment (Yaffe et al., 2003; Weuve et al., 2006). However, the role of CRP in relation to the psychopathology of schizophrenia remains unknown. The present study was intended to directly examine the relationship between CRP and the clinical manifestations of schizophrenia. It was hypothesized that elevated serum levels of CRP would be associated with more severe psychopathology in patients with schizophrenia.
2. Materials and methods 2.1. Sample Psychiatric inpatients, who met the DSM-IV criteria for schizophrenia or schizoaffective disorder and who were relatively stable on antipsychotic medications, were recruited from a county general hospital. All subjects were in the age range of 18–65 years old. Patients were excluded if they had any of the following conditions: (1) substance use during the past year; (2) treatment with anti-inflammatory or immunosuppressive medication; (3) overt infectious disease or auto-immune disease; and (4) inability to provide informed consent. The study protocol was approved by the institutional review board of the State University of New York at Buffalo. Written informed consent was obtained from each subject after a complete description of the study. 2.2. Procedure Blood samples for complete blood cell count (CBC) and CRP measurement were drawn in the morning after an overnight fast. Blood samples for CBC were assayed on the same day of study; blood samples for CRP measurement were processed, and the specimens were aliquoted and frozen at − 70 °C. CRP was assayed in batches of approximately every 10 subjects. The CRP assay was performed by means of particle enhanced immunonephelometry using BN System (Dade Behring, Deerfield, IL) with a lowest detectable limit of 0.35 mg/ dl, a suggested upper normal limit of 0.5 mg/dl and an intraassay coefficient of variation of 2.3%. Subjects were therefore categorized into the normal/elevated CRP groups using 0.50 mg/dl as the cutoff value. Assays were performed blind to the subject's identity. Each subject was assessed with the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) on the same day when the blood sample was obtained. The PANSS was analyzed blind to the blood assay results. 2.3. Statistical analyses Statistical analyses were performed using SPSS (version 13.0, Chicago, IL). Descriptive statistics were used to describe demographic and clinical measures. Group comparisons between the normal and elevated CRP groups were performed by nonparametric Mann– Whitney U-test for continuous variables and Fisher's exact test for categorical variables. All statistical tests were interpreted at the 5% significance level (two-tailed).
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269
(PANSS total and subscale scores) were compared between patients on olanzapine and those on risperidone, which accounted for most of the study subjects. No differences were found between the olanzapine group and the risperidone group on PANSS total or any subscale scores (P's > 0.60). As shown in Table 1, there were no significant differences between the normal/elevated CRP groups regarding demographic and general clinical characteristics, such as age, gender, race, education level, age of illness onset, history of substance use, smoking status, WBC and current antipsychotic medication used (P's > 0.05). However, the elevated CRP group had significantly higher PANSS total score, negative symptom subscale score and general psychopathology subscale score compared with the normal CRP group (P's < 0.05). The two groups did not differ on the PANSS positive symptom subscale score (P > 0.05).
3. Results Twenty-six subjects were enrolled in the study. With a serum level of 0.50 mg/dl as the cutoff value, 21 subjects were in the normal CRP group (CRP ≤ 0.50 mg/ dl) and five subjects were in the elevated CRP group (CRP > 0.5 mg/dl). Within the elevated CRP group, two subjects had a serum CRP value of 0.6 mg/dl, one subject 1.1 mg/dl, one subject 2.0 mg/dl and one subject 3.0 mg/dl. Among 26 subjects who participated in the study, nine were on olanzapine (dose range 5–25 mg/day), eight on risperidone (dose range 2–6 mg/day), two on quetiapine (dose range 300–400 mg/day), three on ziprasidone (dose range 160–240 mg/day) and one on aripiprazole (15 mg/day). The remaining three subjects were on typical antipsychotic agents (two on haloperidol with the dose range 5–15 mg/day, one on fluphenazine 15 mg/day). Psychopathology measures
Table 1 Comparison of demographic and clinical characteristics between the normal/elevated CRP groups Characteristics
Age (years) Age of onset (years) Disease duration (years) Education (years) WBC (103/μl)
Gender Female Male Race White Non-white History of substance use Yes No Current antipsychotic Atypical Typical Smoking status Yes No
PANSS—total PANSS—positive PANSS—negative PANSS—general
Normal CRP group (N = 21)
Elevated CRP group (N = 5)
Analysis
Median
Range
Median
Range
Z
P
31 26 8 14 9.0
20–64 12–63 1–29 6–19 4.6–12.3
45 21 14 13 9.6
25–53 15–29 2–32 8–19 4.2–15.9
− 0.85 − 0.59 − 1.53 − 0.29 − 0.42
0.397 0.561 0.125 0.768 0.705
X2
df
P
60 40
3.44
1
0.101
3 2
60 40
0.08
1
1.000
24 76
3 2
60 40
2.48
1
0.281
18 3
86 14
5 0
100 0
0.81
1
0.369
15 6
71 29
2 3
40 60
1.76
1
0.297
N
%
N
4 17
19 81
3 2
14 7
67 33
5 16
%
Median
Range
Median
Range
Z
P
59 14 12 32
38–90 9–25 7–25 22–47
76 16 23 38
70–77 15–19 16–23 34–40
− 2.38 − 1.05 − 2.42 − 2.45
0.017 0.296 0.016 0.014
WBC: white blood cell count. PANSS: Positive and Negative Syndrome Scale, including positive symptom, negative symptom and general psychopathology subscales.
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4. Discussion To our knowledge, this is the first study directly examining the relationship between serum level of CRP and the psychopathology profile of schizophrenia. The present study found that elevated serum levels of CRP were associated with more severe clinical symptoms of schizophrenia as reflected by the PANSS total score, negative symptom subscale score and general psychopathology subscale score. Our results are consistent with previous findings linking schizophrenia to activation of the inflammatory response system (Rapaport and Lohr, 1994; Lin et al., 1998; Maes et al., 2000; Müller et al., 2000; Sirota et al., 2005). The underlying mechanisms relating inflammation to schizophrenia are still speculative. Studies have found that patients with schizophrenia show deficient regional blood flow in different brain areas, especially the frontal and temporal lobes (Bachneff, 1996; Shinba et al., 2004). Decreased frontal blood flow is associated with negative symptoms (Lahti et al., 2001; Vaiva et al., 2002). Hanson and Gottesman (2005) proposed that chronic inflammation might damage the micro-vascular system in the brain and disrupt the regulation of blood-brain barrier and cerebral blood flow. These alterations in homeostatic mechanisms of the brain might lead to the development of psychotic symptoms. Besides the small sample size, there are several other important methodological limitations in this study. First, participants in this study were a group of stabilized inpatients with schizophrenia. Patients were either continued or restarted with a previously used antipsychotic medication, or switched around different medications during their hospital stay. Therefore, the duration and influence of a specific antipsychotic medication could not be estimated for all patients. Yet, different antipsychotic medications may have differential effects on the inflammatory process and immune function (Maes et al., 1995; Akiyama, 1999; Pollmächer et al., 2000; Sirota et al., 2005). Second, because of the cross-sectional design and small sample size in this study, a causal relationship between serum CRP levels and severity of psychopathology remains uncertain. It is unclear whether inflammation is a byproduct of the pathophysiology of schizophrenia or directly contributes to the clinical manifestations of schizophrenia. Prospective studies are needed to examine the relationship between inflammation, as reflected by elevated serum levels of CRP, and treatment response, as well as the moderating role of specific antipsychotic medications, in patients with schizophrenia. It is still too
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