High C-reactive protein levels are associated with ...

Journal of Affective Disorders 225 (2018) 671–675

Contents lists available at ScienceDirect

Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

High C-reactive protein levels are associated with depressive symptoms in schizophrenia

MARK

⁎

M. Faugerea,b, , J.-A. Micoulaud-Franchic,d, C. Faget-Agiusa,b, C. Lançona,b, M. Cermolaccee, R. Richieria,b a

Department of Psychiatry, La Conception University Hospital, 13005 Marseille, France EA 3279 – Self perceived Health Assessment Research Unit, Aix-Marseille University, 13005, Marseille, France c Department of Clinical Neurophysiology, Sleep Clinique, Pellegrin University Hospital, 33076 Bordeaux, France d Bordeaux University, USR CNRS 3413 SANPSY, Research Unit, 33000 Bordeaux, France e SHU Adult Psychiatry, Sainte Marguerite Hospital, 13274 Marseille Cedex 9, France b

A R T I C L E I N F O

A B S T R A C T

Keywords: C-reactive protein Schizophrenia Depression Antidepressant Metabolic syndrome

Background: Depressive symptoms are frequently associated with schizophrenia symptoms. C - Reactive protein (CRP), a marker of chronic inflammation, had been found elevated in patients with schizophrenia and in patients with depressive symptoms. However, the association between CRP level and depressive symptoms has been poorly investigated in patients with schizophrenia. The only study conducted found an association between high CRP levels and antidepressant consumption, but not with depressive symptoms investigated with the Calgary Depression Rating Scale for Schizophrenia (CDSS). Objectives: The aim of this study was to evaluate CRP levels and depressive symptoms in patients with schizophrenia, and to determine whether high CRP levels are associated with depressive symptoms and/or antidepressant consumption, independently of potential confounding factors, especially tobacco-smoking and metabolic syndrome. Methods: Three hundred and seven patients with schizophrenia were enrolled in this study (mean age = 35.74 years, 69.1% male gender). Depressive symptoms was investigated with the CDSS. Patients were classified in two groups: normal CRP level (≤ 3.0 mg/L) and high CRP level (> 3.0 mg/L). Current medication was recorded. Results: 124 subjects (40.4%) were classified in the high CRP level group. After adjusting for confounding factors, these patients were found to have higher CDSS scores than those with normal CRP levels in multivariate analyses (p = 0.035, OR = 1.067, 95% CI = 1.004–1.132). No significant association between CRP levels and antidepressants consumption was found. Limitations: The size sample is relatively small. The cut-off point for high cardiovascular risk was used to define the two groups. CRP was the sole marker of inflammation in this study and was collected at only one time point. The design of this study is cross-sectional and there are no conclusions about the directionality of the association between depression and inflammation in schizophrenia. Conclusion: This study found an association between high rates of CRP levels and depressive symptoms in patients with schizophrenia, but no association with antidepressant consumption. Further studies are needed to investigate the impact of inflammation in schizophrenia.

1. Introduction

Prevalence rates of major depressive disorder (MDD) in schizophrenia range from 30% to 70% (Majadas et al., 2012; Peitl et al., 2016). Presence of depressive symptoms in patients with schizophrenia has been associated with overall worse outcomes, greater comorbidity, poorer quality of life (Andrianarisoa et al., 2017), work impairment, deterioration of psychosocial functioning, greater risk of relapse and increased risk of suicide (Tandon et al., 2009). Better understanding of the pathophysiology of depressive symptoms in schizophrenia is thus

Schizophrenia occurs in around approximately 1% of the population worldwide and around 0.6–0.8% in France (McGrath et al., 2008). It is a chronic disease characterized by psychotic symptoms, cognitive impairment and functional decline (Dickinson et al., 2004; Bruijnzeel and Tandon, 2011). Depressive symptoms are also frequently associated in schizophrenia (Tandon et al., 2009; Andrianarisoa et al., 2017). ⁎

Correspondence to: Pôle Psychiatrie Centre, CHU La Conception, 147 bd Baille, 13005 Marseille, France. E-mail address: [email protected] (M. Faugere).

http://dx.doi.org/10.1016/j.jad.2017.09.004 Received 7 July 2017; Received in revised form 11 August 2017; Accepted 6 September 2017 Available online 08 September 2017 0165-0327/ © 2017 Elsevier B.V. All rights reserved.


M. Faugere et al.

2.2. Data collection

necessary. The contribution of chronic inflammation to major mental disorders has received increased attention in the last decade (Fond et al., 2014). Among other inflammatory factors, C-reactive protein (CRP) is a nonspecific marker that has the following two advantages: i) it is easily measured in blood samples, and ii) it provides a reliable marker of chronic inflammation. CRP was first extensively studied as a predictor of cardiovascular disease (Emerging Risk Factors Collaboration et al., 2010), which is one of the leading causes of early mortality in patients with schizophrenia (Mitchell et al., 2013). Moreover, CRP levels were found elevated in patients with schizophrenia (Miller et al., 2014) and in patients with MDD (Howren et al., 2009; Strawbridge et al., 2015; Valkanova et al., 2013). In schizophrenia patients, high CRP levels have been associated not only with cardiovascular risk but also with more psychotic symptoms (Fan et al., 2007), with greater cognitive impairment (Dickerson et al., 2007, 2012; Bulzacka et al., 2016), and with greater sensory processing impairment (Micoulaud-Franchi et al., 2015) than in patients with low CRP levels. In patients with MDD, high CRP levels are considered to be a useful biomarker for predicting the risk of major depressive episode (Duivis et al., 2013; Wium-Andersen et al., 2014), and have been associated with the persistence of depressive symptoms under treatment (Zalli et al., 2016) and with differential response rates to antidepressants (Uher et al., 2014). However, whereas CRP levels are known to be associated with MDD, their association with depressive symptoms in schizophrenia has received little attention. Fond et al. (2016) found an association between high CRP levels in schizophrenia and antidepressant consumption, but not with depressive symptoms investigated with the Calgary Depression Rating Scale for Schizophrenia (CDSS). This study sought to evaluate CRP levels and the level of depressive symptoms investigated with the CDSS but also to determine the prevalence of high CRP levels, MDD and antidepressant consumption rates in a sample of patients with stable schizophrenia. We sought to determine whether high CRP levels are associated with depressive symptoms and/or antidepressant consumption in patients with schizophrenia, independently of potential confounding factors, especially tobacco-smoking and metabolic syndrome.

1. Socio-demographic information: gender, age, educational level 2. Clinical characteristics: duration of illness and age at illness onset, body mass index (BMI), tobacco, cannabis and alcohol consumption, psychotic symptoms based on the Positive and Negative Syndrome Scale (PANSS), with five factors (negative, positive, excited, depressive, cognitive) (Kay et al., 1986; Lançon et al., 2000), current depressive symptoms based on the Calgary Depression Rating Scale for Schizophrenia (CDSS) (Addington et al., 1993). The CDSS was specifically designed to identify specific depressive symptomatology that cannot be related to negative symptoms of schizophrenia. Depression is defined as scores above 6 (current “major depressive disorder” (MDD)), with a sensitivity of 88.9% and a specificity of 75% (Reine et al., 2000; Lançon et al., 1999). 3. Drug information: antipsychotic medication and chlorpromazine equivalent dose (in milligrams per day), use of antidepressants and mood stabilizing agents, used antipsychotic types and antidepressant classes. 4. Chronic inflammation marker: serum CRP levels were determined using sensitive regular immunoassays (ELISA). The results were expressed as milligrams per liter. The detection limit was 0.08 µg/ ml. Patients were classified in two groups: normal CRP level (≤ 3.0 mg/L) and high CRP level (> 3.0 mg/L) (Wysokiński et al., 2014; Emerging Risk Factors Collaboration et al., 2010). 5. Metabolic Syndrome: diagnosis of metabolic syndrome was made according to the National Cholesterol Education Program ATP-III criteria (Grundy, 2005), including three or more of the following criteria: waist circumference > 88 cm in women and > 102 cm in men; fasting serum triglycerides ≥ 1.69 mmol/L; serum HDL < 1.3 mmol/L in women and < 1.0 mmol/L in men; blood pressure ≥ 190/85 mmHg; and fasting blood glucose levels ≥ 5.6 mmol/L. Waist circumference was measured at the midpoint between the lower rib margins and the iliac crest. Arterial blood pressure was recorded using a standard mercury sphygmomanometer. Glucose and lipoprotein concentrations were analyzed in fasting venous blood samples using standard enzymatic techniques. 6. Abdominal obesity was defined by the presence of both hypertriglyceridemia (≥ 1.7 mmol/L) and high waist circumference (> 94 cm for men and > 80 cm for women) (Després and Lemieux, 2006).

2. Methods 2.1. Study participants

2.3. Statistical analysis The study evaluated all prospective patients attending daytime hospital hours in our university and psychiatric hospital over a period of 5 years from June 2010 to June 2015. The inclusion criteria were as follows: (1) age 18–85 years old, (2) diagnosis of schizophrenia according to the DSM-IV-TR criteria, (3) antipsychotic and possibly antidepressant or mood stabilizing agent medication stable for a minimum of 3 months, and (4) French as native language. The exclusion criteria were as follows: (1) diagnoses other than schizophrenia or MDD on axis 1 of the DSM-IV-TR, except for nicotine dependence, (2) major nonpsychiatric disease, (3) mental retardation and (4) any identifiable acute, intermittent or chronic infection or being on routine anti-inflammatory or immunosuppressive therapy. Acute and intermittent inflammations and infections have been excluded by a complete medical examination realized by a medical professional who investigate the body of the patient for symptoms and signs for disease, and in particular inflammation and infection diseases. Moreover, serologies were conducted for the following chronic infections: Human Immunodeficiency Virus, Hepatitis B Virus and Hepatitis C Virus. The data collection was approved by the Commission Nationale de l’Informatique et des Libertés (CNIL number 1223715). The study was designed in accordance with the Declaration of Helsinki and French good clinical practice. All of the patients were informed of the study and gave written informed consent.

Socio-demographics, clinical characteristics and comorbidities were presented using measures of means and dispersion (standard deviation) for continuous data and frequency distribution for categorical variables. Univariate associations between demographic and clinical characteristics of patients with high CRP levels were performed using the chisquare test for categorical variables and the Student t-test for continuous variables. To explore the relationship between CRP level and depressive symptoms (CDSS score) in schizophrenia, we used a multivariate logistic regression model adjusting for potential confounders: age, gender, current tobacco consumption, use of antidepressants, presence of metabolic syndrome, and psychotic symptomatology (PANSS total score). All the tests were two-sided. Statistical significance was defined as p < 0.05. Statistical analysis was performed using the SPSS version 18.0 software package (SPSS Inc., Chicago, IL, USA). 3. Results 3.1. Patient characteristics Three hundred and seven patients with schizophrenia participated 672


M. Faugere et al.

Table 1 Socio-demographic, clinical and biological characteristics of study sample (n = 307). Whole sample Mean (%) Number of patients (n) Socio-demographic characteristics Gender Women Men Age (years) Education level (> 12 years) Illness characteristics Duration of illness (years) Age at illness onset (years) PANSSb total score PANSS Negative score PANSS Positive score PANSS Excited score PANSS Depressive score PANSS Cognitive score Current MDDc CDSSd score Comorbidities Current daily tobacco-smoking Cannabis consumption (yes) Alcohol consumption (yes) Metabolic variables BMIe mean High fasting glucose Hypertriglyceridemia High waist circumference Metabolic Syndrome Abdominal Obesity Treatment First generation antipsychotic treatment Second generation antipsychotic treatment Chlorpromazine equivalent doses Antidepressant treatment SSRIf SNRIg Tricyclics Others antidepressants MAOIh Mood-stabilizing agent

CRP ≥ 3.0 mg/L

CRP < 3.0 mg/L SD

Mean (%)

SD

Mean (%)

307 (100%)

183 (59.3%)

124 (40.4%)

95 (30.9%) 212 (69.1%) 35.74 166 (54.1%)

51 (27.9%) 132 (72.1%) 34.60 106 (57.9%)

44 (35.5%) 80 (64.5%) 37.43 60 (48.4%)

13.07 22.67 73.79 28.41 17.67 8.99 11.28 7.42 65 (21.2%) 4.21

11.61

9.67 7.56 20.93 9.63 7.17 3.92 4.37 2.97

12.36 22.24 71.57 28.07 16.73 8.76 10.76 7.28 32 (17.5%) 3.58

4.62

174 (56.7%) 52 (16.9%) 52 (16.9%) 26.70 40 (13.0%) 85 (27.7%) 142 (46.3%) 54 (17.6%) 71 (23.1%) 59 (19.2%) 287 (93.5%) 894.88 90 (29.3%) 56 (18.2%) 24 (7.8%) 2 (0.7%) 8 (2.6%) 0 (0.0%) 21 (6.8%)

11.46

9.82 7.20 21.25 10.30 6.84 4.06 4.05 3.04 4.02

100 (54.6%) 33 (18.0%) 31 (16.9%) 5.40

25.11 20 (10.9%) 40 (21.9%) 61 (33.3%) 21 (11.5%) 33 (18.0%) 34 (18.6%) 172 (94.0%) 874.11 48 (26.2%) 29 (15.8%) 11 (6.0%) 1 (0.5%) 7 (3.8%) 0 (0.0%) 16 (8.7%)

768.55

14.12 23.31 77.15 28.93 19.08 9.34 12.08 7.63 33 (26.6%) 5.14

(p) SD

11.67

9.37 8.06 20.05 8.54 7.46 3.67 4.71 2.84 5.28

868.83

29.07 20 (16.1%) 45 (36.3%) 81 (65.3%) 33 (26.6%) 38 (30.6%) 25 (20.2%) 115 (92.7%) 925.80 42 (33.9%) 27 (21.8%) 13 (10.5%) 1 (0.8%) 1 (0.8%) 0 (0.0%) 5 (4.0%)

0.118 0.222 0.024 0.429 0.005 0.208 0.010 0.321 0.035a 0.008 0.201a 0.334a 0.547a

74 (59.7%) 19 (15.3%) 21 (16.9%) 4.84

0.099a 0.036 0.059a

5.33

590.73

< 0.001 0.119a 0.004a < 0.001a 0.001a 0.008a 0.406a 0.521a 0.565 0.095a 0.122a 0.113a 0.645a 0.099a – 0.082a

×2 test for qualitative variables. Positive And Negative Syndrome Scale. c Major Depressive Disorder. d Calgary Depression rating Scale for Schizophrenia. e Body Mass Index. f Selective Serotonin Reuptake Inhibitors. g Serotonin-Norepinephrine Reuptake Inhibitor. h Monoamine Oxydase Inhibitors.

a

b

the CDSS score which specifically explores depression independently of negative symptoms of schizophrenia (p = 0.035 and OR = 0.573). They also had significantly different metabolic characteristics with higher BMI values (p < 0.001 and OR = 1.162), higher rate of hypertension (p = 0.005), higher rate of hypertriglyceridemia (p = 0.004 and OR = 4.169), higher rate of high waist circumference (p < 0.001 and OR = 3.854), higher rate of metabolic syndrome (p = 0.001 and OR = 2.797) and higher rate of abdominal obesity (p = 0.008 and OR = 2.008).

in the study (Table 1). The mean age of the patients was 35.74 years ( ± 11.61), and 69.1% were male. They had moderately severe symptoms with a mean PANSS total score of 73.79 ( ± 20.93), and a mean 5factor scores of 28.41 ( ± 9.63), 17.67 ( ± 7.17), 8.99 ( ± 3.92), 11.28 ( ± 4.37) and 7.42 ( ± 2.97) for negative, positive, excited, depressive and cognitive factors. Of the total number of patients, 29.3% were treated by antidepressants and 6.8% were treated by mood stabilizing agent. All patients were treated by antipsychotics.

3.2. Comparison of patients with normal CRP level and high level of CRP 3.3. Factors associated with high level of CRP Among the 307 patients with schizophrenia, 124 (40.4%) had a high CRP level defined by hs-CRP > 3 mg/L. Compared to patients with normal CRP levels, those with high levels were significantly older (p = 0.036 and OR = 1.021), had significantly higher PANSS scores for total score (p = 0.024 and OR = 1.013), positive score (p = 0.005 and OR = 1.047) and depressive score (p = 0.010 and OR = 1.073). They had a higher rate of current major depressive disorder (MDD) according to

In order to explore the association between high CRP levels and depressive symptoms (CDSS scores), we performed multivariate logistic regression analyses (Table 2). The relationship between CDSS score and CRP levels remained significant (p = 0.035 and OR = 1.067) after adjusting for socio-demographic, clinical, metabolic and pharmacological characteristics. The adjustment was conducted with the PANSS 673


M. Faugere et al.

schizophrenia or not. This is a transnosographical point of view consistent with other studies (Zalli et al., 2016; Valkanova et al., 2013) that consider inflammation as being functionally involved in the development of depressive symptoms through direct effects on the central nervous system, in line with the sickness behavior hypothesis (Dantzer et al., 2008). Despite significant correlation in univariate analyses between PANSS scores and CRP level, our study did not find significant relationship after adjusting for potential confounding factors, especially tobacco-smoking and metabolic syndrome. The differences with the previous results of Fan et al. (2007) could be due to different CRP thresholds between the studies (5.0 mg/L Vs 3.0 mg/L in our present study) but also to difference in the definition of the factors scores of the PANSS (3 factors Vs 5 factors in our study) (Fan et al., 2007). Concerning the absence of significant relationship between the depressive factor of the PANSS and CRP level, this result confirmed the necessity to use dedicated scale, as the CDSS, to investigate depressive symptoms in schizophrenia. Lastly, our study find an association between high CRP levels and metabolic syndrome, which is completely consistent with previous findings and has ever been largely demonstrated (Fawzi et al., 2011; Fond et al., 2016; Vuksan-Cusa et al., 2013).

Table 2 Factors associated with high CRP: multivariate analysis. Factors

Adjusted odds ratio

95%CIa

p-value

Antidepressant (yes) Age Sex Current tobacco-smoking Metabolic syndrome PANSS score Calgary score

1.072 1.020 1.299 1.257 2.933 1.003 1.067

0.616–1.867 0.998–1.044 0.745–2.265 0.748–2.111 1.527–5.635 0.989–1.016 1.004–1.132

0.805 0.076 0.357 0.388 0.001 0.690 0.035

a

Confidence Interval.

total score. However, the results remains significant when we replaced PANSS total score by PANSS positive score in the multivariate model. Current daily tobacco-smoking has been added in the adjusted parameters because of the well-established association between tobacco and CRP (Fond et al., 2017). A higher rate of metabolic syndrome remained significantly associated with high CRP levels in multivariate analysis (p = 0.001 and OR = 2.933). Despite significant correlations in univariate analyses between PANSS total, positive and depressive scores, and CRP level, there was an absence of significant relationship with the multivariate analysis.

5. Limitations and perspectives 4. Discussion Several limitations should be considered in this study. First, the size of the sample is relatively small, and further researches should replicate the findings in larger studies. Second, there is the problem of the definition of the groups (normal and high CRP level according to a 3.0 mg/L threshold). While there are no generally accepted criteria for the threshold, we chose the most consensual threshold in the recent scientific literature, which is recognized as the cut-off point for high cardiovascular risk (Wysokiński et al., 2014). Third, CRP was the sole marker of inflammation. Although CRP is strongly associated with IL-6 activity, we did not directly assess any of the cytokines. Future studies with extensive assessment of inflammatory markers may be required. Fourth, we measured CRP levels at only one time point, yet repeated testing has been recommended to confirm elevated plasma levels because concentrations can be affected by acute inflammation or infection. However, patients with acute infections were excluded in our study. Nevertheless, further research are needed with repeated measures in order to better investigated the role of chronic inflammation in the development of psychiatric symptoms (Kivimäki et al., 2014). Fifth, in this study, MDD diagnosis was determined by the CDSS score, and not according to a structured clinical assessment (SCID or MINI). However, the sensibility and the specificity of the CDSS to diagnose MDD in patients with schizophrenia is considered as satisfactory (Reine et al., 2000; Lançon et al., 1999). Six, the sample was predominantly male and this could have affected the results. Indeed, females exhibit lower CRP levels than males (Vetter et al., 2013; Tayefi et al., 2017), so the proportion of patients with high CRP levels in our sample could be overvalued. The present results should be replicated in a sample with higher proportion of females. Seven, the cross-sectional design of the study precludes any conclusions about the directionality of the association between depression and inflammation in schizophrenia. Thus, the present result has to be confirmed with longitudinal studies. Despite these limitations, the present result suggests that high rates of high CRP levels and depression in schizophrenia are related, and shows that further studies are needed to investigate the impact of inflammation in schizophrenia.

This study investigated the prevalence of high CRP levels, MDD and antidepressant consumption and the relationship between depressive symptoms and high CRP levels in patients with schizophrenia. Our findings provide evidence for a high prevalence of high CRP levels in our sample of patients with schizophrenia. The prevalence of high CRP levels (40.4%) is comparable with the global prevalence of abnormal CRP levels found in our previous study (Faugere et al., 2015) and in other studies (Wysokiński et al., 2014). The prevalence of MDD in schizophrenia is estimated to be around 25% (Siris, 2000; Fond et al., 2016), which is close to our finding of 26.6%. Lastly, the prevalence of antidepressant consumption (33.9%) is close to the 25% reported by Dickerson et al. (2013) and high CRP levels were also associated with age and BMI, which is also consistent with the literature (de Heredia et al., 2012). The significant result in this study is that high CRP levels were associated with depressive symptoms in schizophrenia, but not with antidepressant consumption, independently of other confounding variables including metabolic syndrome. To our knowledge, only one study has previously investigated the relationship between CRP levels and depressive symptoms in schizophrenia (Fond et al., 2016). Our finding is in disagreement with that study, which found that high CRP levels were associated with antidepressant consumption in schizophrenia but not with depressive symptoms (Fond et al., 2016). The discrepancies between Fond et al. results and our results could be due to uncontrolled confounding factors in the two studies. In particular, factors that may be associated with both depressive symptoms and chronic inflammation, as sleep disorders or chronic infections (as Human Endogenous Retroviruses, toxoplasma status, Herpes Simplex Virus…) have not been investigated in these two studies. Further researches are thus needed to investigate the impact of such confounding factors on the relationship between high CRP levels and depressive symptoms and/or antidepressant consumption in patients with schizophrenia. From a theoretical point of view, Fond et al. suggested that high CRP levels may be associated with an increased risk of depressive symptoms that lead to antidepressant consumption or that the consumption of antidepressants may increase peripheral inflammation in schizophrenia. Moreover, they suggested that the depressive mechanisms in schizophrenia could be different from those in patients with MDD without schizophrenia. Our results suggest rather that the same pathophysiological mechanism of depression occurs in patients with

Funding This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. 674


M. Faugere et al.

doi.org/10.1017/S0029665112000092. Howren, M. Bryant, Lamkin, Donald M., Suls, Jerry, 2009. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom. Med. 71 (2), 171–186. http://dx.doi.org/10.1097/PSY.0b013e3181907c1b. Kay, S.R., Opler, L.A., Fiszbein, A., 1986. Significance of positive and negative syndromes in chronic schizophrenia. Br. J. Psychiatry: J. Ment. Sci. 149 (October), 439–448. Kivimäki, M., Shipley, M.J., Batty, G.D., Hamer, M., Akbaraly, T.N., Kumari, M., Jokela, M., et al., 2014. Long-Term inflammation increases risk of common mental disorder: a cohort study. Mol. Psychiatry 19 (2), 149–150. http://dx.doi.org/10.1038/mp. 2013.35. Lançon, C., Auquier, P., Nayt, G., Reine, G., 2000. Stability of the five-factor structure of the Positive and Negative Syndrome Scale (PANSS). Schizophr. Res. 42 (3), 231–239. Lançon, C., Auquier, P., Reine, G., Toumi, M., Addington, D., 1999. Evaluation of depression in schizophrenia: psychometric properties of a French version of the Calgary Depression Scale. Psychiatry Res. 89 (2), 123–132. Majadas, Susana, Olivares, Jose, Galan, Jaime, Diez, Teresa, 2012. Prevalence of depression and its relationship with other clinical characteristics in a sample of patients with stable schizophrenia. Compr. Psychiatry 53 (2), 145–151. http://dx.doi.org/10. 1016/j.comppsych.2011.03.009. McGrath, John, Saha, Sukanta, Chant, David, Welham, Joy, 2008. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol. Rev. 30, 67–76. http://dx.doi.org/10.1093/epirev/mxn001. Micoulaud-Franchi, Jean-Arthur, Faugere, Mélanie, Boyer, Laurent, Fond, Guillaume, Richieri, Raphaëlle, Faget, Catherine, Cermolacce, Michel, Philip, Pierre, Vion-Dury, Jean, Lancon, Christophe, 2015. Elevated C-reactive protein is associated with sensory gating deficit in schizophrenia. Schizophr. Res. http://dx.doi.org/10.1016/j. schres.2015.03.018. Miller, Brian J., Culpepper, Nick, Rapaport, Mark H., 2014. C-reactive protein levels in schizophrenia: a review and meta-analysis. Clin. Schizophr. Relat. Psychoses 7 (4), 223–230. http://dx.doi.org/10.3371/CSRP.MICU.020813. Mitchell, Alex J., Vancampfort, Davy, Sweers, Kim, van Winkel, Ruud, Yu, Weiping, De Hert, Marc, 2013. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders–a systematic review and meta-analysis. Schizophr. Bull. 39 (2), 306–318. http://dx.doi.org/10.1093/schbul/sbr148. Peitl, Vjekoslav, Vidrih, Branka, Karlović, Zoran, Getaldić, Biserka, Peitl, Milena, Karlović, Dalibor, 2016. Platelet serotonin concentration and depressive symptoms in patients with schizophrenia. Psychiatry Res. 239, 105–110. http://dx.doi.org/10. 1016/j.psychres.2016.03.006. Reine, G., Bernard, D., Auquier, P., Le Fur, B., Lançon, C., 2000. Psychometric properties of French version of the Calgary depression scale for schizophrenics (CDSS). L’Encéphale 26 (1), 52–61. Siris, S.G., 2000. Depression in schizophrenia: perspective in the era of ‘atypical’ antipsychotic agents. Am. J. Psychiatry 157 (9), 1379–1389. http://dx.doi.org/10.1176/ appi.ajp.157.9.1379. Strawbridge, R., Arnone, D., Danese, A., Papadopoulos, A., Herane Vives, A., Cleare, A.J., 2015. Inflammation and clinical response to treatment in depression: a meta-analysis. Eur. Neuropsychopharmacol.: J. Eur. Coll. Neuropsychopharmacol. 25 (10), 1532–1543. http://dx.doi.org/10.1016/j.euroneuro.2015.06.007. Tandon, Rajiv, Nasrallah, Henry A., Keshavan, Matcheri S., 2009. Schizophrenia, ‘just the facts' 4. Clinical features and conceptualization. Schizophr. Res. 110 (1–3), 1–23. http://dx.doi.org/10.1016/j.schres.2009.03.005. Tayefi, Maryam, Shafiee, Mojtaba, Kazemi-Bajestani, Seyyed Mohammad Reza, Esmaeili, Habibolah, Darroudi, Susan, Khakpouri, Samaneh, Mohammadi, Maryam, et al., 2017. Depression and anxiety both associate with serum level of Hs-CRP: a genderstratified analysis in a population-based study. Psychoneuroendocrinology 81 (July), 63–69. http://dx.doi.org/10.1016/j.psyneuen.2017.02.035. Uher, Rudolf, Tansey, Katherine E., Dew, Tracy, Maier, Wolfgang, Mors, Ole, Hauser, Joanna, Dernovsek, Mojca Zvezdana, et al., 2014. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am. J. Psychiatry 171 (12), 1278–1286. http://dx.doi.org/10.1176/ appi.ajp.2014.14010094. Valkanova, Vyara, Ebmeier, Klaus P., Allan, Charlotte L., 2013. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J. Affect. Disord. 150 (3), 736–744. http://dx.doi.org/10.1016/j.jad.2013.06.004. Vetter, M.L., Wadden, T.A., Vinnard, C., Moore, R.H., Khan, Z., Volger, S., Sarwer, D.B., Faulconbridge, L.F., POWER-UP Research Group, 2013. Gender differences in the relationship between symptoms of depression and high-sensitivity CRP. Int. J. Obes. 37 (Suppl 1), S38–S43. http://dx.doi.org/10.1038/ijo.2013.95. Vuksan-Cusa, Bjanka, Sagud, Marina, Jakovljevic, Miro, Peles, Alma Mihaljevic, Jaksic, Nenad, Mihaljevic, Sanea, Zivkovic, Maja, Mikulic, Suzan Kudlek, Jevtovic, Sasa, 2013. Association between C-reactive protein and homocysteine with the subcomponents of metabolic syndrome in stable patients with bipolar disorder and schizophrenia. Nord. J. Psychiatry 67 (5), 320–325. http://dx.doi.org/10.3109/ 08039488.2012.745601. Wium-Andersen, M.K., Orsted, D.D., Nordestgaard, B.G., 2014. Elevated C-reactive protein associated with late- and very-late-onset schizophrenia in the general population: a prospective study. Schizophr. Bull. 40 (5), 1117–1127. http://dx.doi.org/10.1093/ schbul/sbt120. Wysokiński, Adam, Margulska, Aleksandra, Strzelecki, Dominik, Kłoszewska, Iwona, 2014. Levels of C-reactive protein (CRP) in patients with schizophrenia, unipolar depression and bipolar disorder. Nord. J. Psychiatry 1–8. http://dx.doi.org/10.3109/ 08039488.2014.984755. Zalli, A., Jovanova, O., Hoogendijk, W.J.G., Tiemeier, H., Carvalho, L.A., 2016. Lowgrade inflammation predicts persistence of depressive symptoms. Psychopharmacology 233 (9), 1669–1678. http://dx.doi.org/10.1007/s00213-0153919-9.

Acknowledgements Our thanks to all the patients and staff who helped with the study. References Addington, D., Addington, J., Maticka-Tyndale, E., 1993. Assessing depression in schizophrenia: the Calgary Depression Scale. Br. J. Psychiatry 22 (December), 39–44. Andrianarisoa, M., Boyer, L., Godin, O., Brunel, L., Bulzacka, E., Aouizerate, B., Berna, F., et al., 2017. Childhood trauma, depression and negative symptoms are independently associated with impaired quality of life in schizophrenia. Results from the National FACE-SZ Cohort. Schizophr. Res., Jan. http://dx.doi.org/10.1016/j.schres.2016.12. 021. Bruijnzeel, Dawn, Tandon, Rajiv, 2011. The concept of schizophrenia: from the 1850s to the DSM-5. Psychiatr. Ann. 41 (5), 289–295. http://dx.doi.org/10.3928/0048571320110425-08. Bulzacka, Ewa, Boyer, Laurent, Schürhoff, Franck, Godin, Ophélia, Berna, Fabrice, Brunel, Lore, Andrianarisoa, M.éja, et al., 2016. Chronic peripheral inflammation is associated with cognitive impairment in schizophrenia: results from the multicentric FACE-SZ dataset. Schizophr. Bull. 42 (5), 1290–1302. http://dx.doi.org/10.1093/ schbul/sbw029. Dantzer, Robert, O’Connor, Jason C., Freund, Gregory G., Johnson, Rodney W., Kelley, Keith W., 2008. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9 (1), 46–56. http://dx.doi.org/10. 1038/nrn2297. Després, Jean-Pierre, Lemieux, Isabelle, 2006. Abdominal obesity and metabolic syndrome. Nature 444 (7121), 881–887. http://dx.doi.org/10.1038/nature05488. Dickerson, Faith, Stallings, Cassie, Origoni, Andrea, Boronow, John, Yolken, Robert, 2007. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr. Res. 93 (1–3), 261–265. http://dx.doi.org/10.1016/j.schres.2007.03.022. Dickerson, Faith, Stallings, Cassie, Origoni, Andrea, Vaughan, Crystal, Khushalani, Sunil, Yolken, Robert, 2012. Additive effects of elevated C-reactive protein and exposure to Herpes Simplex Virus Type 1 on cognitive impairment in individuals with schizophrenia. Schizophr. Res. 134 (1), 83–88. http://dx.doi.org/10.1016/j.schres.2011. 10.003. Dickerson, Faith, Stallings, Cassie, Origoni, Andrea, Vaughan, Crystal, Khushalani, Sunil, Yang, Shuojia, Yolken, Robert, 2013. C-reactive protein is elevated in schizophrenia. Schizophr. Res. 143 (1), 198–202. http://dx.doi.org/10.1016/j.schres.2012.10.041. Dickinson, Dwight, Iannone, Virginia N., Wilk, Christopher M., Gold, James M., 2004. General and specific cognitive deficits in schizophrenia. Biol. Psychiatry 55 (8), 826–833. http://dx.doi.org/10.1016/j.biopsych.2003.12.010. Duivis, Hester E., Vogelzangs, Nicole, Kupper, Nina, de Jonge, Peter, Penninx, Brenda W.J.H., 2013. Differential association of somatic and cognitive symptoms of depression and anxiety with inflammation: findings from the Netherlands Study of Depression and Anxiety (NESDA). Psychoneuroendocrinology 38 (9), 1573–1585. http://dx.doi.org/10.1016/j.psyneuen.2013.01.002. Emerging Risk Factors Collaboration, Sarwar, N., Gao, P., Kondapally Seshasai, S.R., Gobin, R., Kaptoge, S., et al., Di Angelantonio, E., 2010. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet (London, England) 375 (9733), 2215–2222. http://dx.doi.org/10.1016/S0140-6736(10)60484-9. Fan, Xiaoduo, Pristach, Cynthia, Liu, Emily Y., Freudenreich, Oliver, Henderson, David C., Goff, Donald C., 2007. Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia. Psychiatry Res. 149 (1–3), 267–271. http://dx.doi.org/10.1016/j.psychres.2006.07. 011. Faugere, Melanie, Micoulaud-Fanchi, Jean-Arthur, Alessandrini, Marine, Richieri, Raphaëlle, Faget-Agius, Catherine, Auquier, Pascal, Lançon, Christophe, Boyer, Laurent, 2015. Quality of life is associated with chronic inflammation in schizophrenia: a cross-sectional study. Sci. Rep. 5 (June), 10793. http://dx.doi.org/10. 1038/srep10793. Fawzi, Mounir H., Fawzi, Mohab M., Fawzi, Maggie M., Said, Nagwa S., 2011. C-reactive protein serum level in drug-free male egyptian patients with schizophrenia. Psychiatry Res. 190 (1), 91–97. http://dx.doi.org/10.1016/j.psychres.2011.05.010. Fond, G., Berna, F., Andrianarisoa, M., Godin, O., Leboyer, M., Brunel, L., Aouizerate, B., et al., 2017. Chronic low-grade peripheral inflammation is associated with severe nicotine dependence in schizophrenia: results from the National Multicentric FACESZ Cohort. Eur. Arch. Psychiatry Clin. Neurosci. 267 (5), 465–472. http://dx.doi.org/ 10.1007/s00406-017-0771-4. Fond, G., Godin, O., Brunel, L., Aouizerate, B., Berna, F., Bulzacka, E., Capdevielle, D., et al., 2016. Peripheral sub-inflammation is associated with antidepressant consumption in schizophrenia. Results from the multi-center FACE-SZ data set. J. Affect. Disord. 191 (February), 209–215. http://dx.doi.org/10.1016/j.jad.2015.11.017. Fond, G., Hamdani, N., Kapczinski, F., Boukouaci, W., Drancourt, N., Dargel, A., Oliveira, J., et al., 2014. Effectiveness and tolerance of anti-inflammatory drugs' add-on therapy in major mental disorders: a systematic qualitative review. Acta Psychiatr. Scand. 129 (3), 163–179. http://dx.doi.org/10.1111/acps.12211. Grundy, S.M., 2005. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112 (17), 2735–2752. http://dx.doi.org/10.1161/CIRCULATIONAHA. 105.169404. de Heredia, Fátima Pérez, Gómez-Martínez, Sonia, Marcos, Ascensión, 2012. Obesity, inflammation and the immune system. Proc. Nutr. Soc. 71 (2), 332–338. http://dx.

675