Cytokines and C-reactive protein alterations with respect to cognitive impairment in schizophrenia and bipolar disorder: A systematic review

Schizophrenia Research 192 (2018) 16–29

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Cytokines and C-reactive protein alterations with respect to cognitive impairment in schizophrenia and bipolar disorder: A systematic review Błażej Misiak a,⁎, Bartłomiej Stańczykiewicz b, Kamila Kotowicz b, Janusz K. Rybakowski c, Jerzy Samochowiec d, Dorota Frydecka b a

Department of Genetics, Wroclaw Medical University, 1 Marcinkowski Street, 50-368 Wroclaw, Poland Department of Psychiatry, Wroclaw Medical University, 10 Pasteur Street, 50-367 Wroclaw, Poland Department of Adult Psychiatry, Poznan University of Medical Sciences, 27/33 Szpitalna Street, 60-572 Poznan, Poland d Department of Psychiatry, Pomeranian Medical University, 26 Broniewski Street, 71-460 Szczecin, Poland b c

a r t i c l e

i n f o

Article history: Received 26 September 2016 Received in revised form 4 April 2017 Accepted 7 April 2017 Available online 14 April 2017 Keywords: Inflammation Cognitive performance Cytokines Interleukins Schizophrenia Bipolar disorder

a b s t r a c t Background: The aim of this article was to perform a systematic review of studies investigating the association between peripheral levels of cytokines and C-reactive protein (CRP), cytokine gene polymorphisms and cognition in patients with schizophrenia and bipolar disorder (BD). Methods: The following databases: PubMed, CINAHL Complete, Academic Search Complete, ERIC and Health Source: Nursing/Academic Edition databases were searched according to the PRISMA guidelines. We included studies that investigated the association between peripheral levels of CRP and cytokines, cytokine gene polymorphisms and cognitive performance in schizophrenia and/or BD patients. Subsequently, quality assessment of eligible publications was performed. Results were synthesized by discussing main findings around correlations between inflammatory markers and cognition. Results: Most consistent results indicate worse cognitive performance in schizophrenia patients with higher CRP levels. Less consistent evidence suggests better cognitive functioning of schizophrenia patients with higher levels of tumour necrosis factor-α (TNF-α). Evidence for the involvement of other cytokines in cognitive impairment in patients with schizophrenia is less convincing due to discordant results or scarcity of studies. Due to low number of studies, it is difficult to draw conclusions on the involvement of CRP and cytokine alterations in the development of cognitive deficits in BD. Single studies suggest the role of CRP, interleukin(IL)-1 receptor antagonist, IL-6 and TNF-α with its receptors in the development of cognitive impairment in BD. Conclusions: Peripheral inflammation might be related to cognitive deficits in schizophrenia and BD. Unequivocal conclusions cannot be made due to methodological heterogeneity and low number of studies investigating particular cytokines. © 2017 Elsevier B.V. All rights reserved.

1. Introduction Schizophrenia and bipolar disorder (BD) represent complex psychiatric disorders with overlapping clinical and biological characteristics (Moller, 2003). Both disorders are characterized by robust cognitive impairments in intellectual ability, speed of information processing, encoding and retrieval, rule discovery as well as response generation and response inhibition that represent quantitative rather qualitative differences (Bortolato et al., 2015b; Moustafa et al., 2016; Stefanopoulou et al., 2009). In addition, it has been demonstrated that some cognitive impairments are strongly dependent on a history of psychosis rather than a categorical and diagnostic distinction (Frydecka et ⁎ Corresponding author at: Department of Psychiatry, Wroclaw Medical University, 10 Pasteur Street, 51-367 Wroclaw, Poland. E-mail address: [email protected] (B. Misiak).

http://dx.doi.org/10.1016/j.schres.2017.04.015 0920-9964/© 2017 Elsevier B.V. All rights reserved.

al., 2014). Importantly, cognitive deficits are clearly apparent in the early course of BD and schizophrenia (Bora and Pantelis, 2015). It has been reported that some cognitive impairments appear to be specific for distinct phases of the illness and tend to improve with symptomatic recovery. In turn, other cognitive dysfunctions persist even during phases of symptomatic stability (Kurtz and Gerraty, 2009; Shmukler et al., 2015). To date, various biological mechanisms have been associated with distinct mood states in BD and phases of acute relapse or symptomatic stability in schizophrenia. Indeed, accumulating evidence indicates that immune-inflammatory processes might be involved in the pathophysiology of both disorders and mediate illness relapse (Miller et al., 2011). Initially, the involvement of these processes has been proposed on the basis of epidemiological studies showing that schizophrenia patients tend to develop autoimmune disorders (Muller et al., 2015). It has been also demonstrated that prenatal exposure to viral infections

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increase the likelihood of schizophrenia (Kinney et al., 2009). Emerging evidence also indicates that this observation holds true for BD (Marangoni et al., 2016). Finally, a number of immune-inflammatory alterations have been reported in patients with schizophrenia and BD, including changes in proportions of immune system cellular component (Karpinski et al., 2016; Miller et al., 2013), elevated levels of specific and non-specific autoantibodies (Ezeoke et al., 2013; Pearlman and Najjar, 2014), central indices of microglial activation (Laskaris et al., 2016), elevated C-reactive protein (CRP) levels (Fernandes et al., 2016), and cytokine alterations (Miller et al., 2011; Potvin et al., 2008). Cytokines represent pleiotropic molecules and include chemokines, interleukins, interferons, lymphokines and tumour necrosis factors that are produced by various immune and non-immune cells. Importantly, cytokines have been found to regulate dopaminergic and serotoninergic neurotransmission (Baganz and Blakely, 2013; Felger and Miller, 2012). A recent meta-analysis (Miller et al., 2011) revealed that distinct cytokine alterations including elevated peripheral levels of interleukin(IL)-1β, IL-6 and transforming growth factor-β (TGF-β) might be state markers of schizophrenia as they were increased in acutely relapsed and first-episode psychosis (FEP) patients and normalized following antipsychotic treatment. In turn, IL-12, interferon-γ (IFNγ), tumour necrosis factor-α (TNF-α) and soluble IL-2 receptor (sIL-2R) were found to serve as trait markers since levels of these cytokines remained elevated in acute relapse and after antipsychotic treatment. In agreement with these results, it has been proposed that antipsychotics may exert anti-inflammatory effects (Tourjman et al., 2013). A recent meta-analysis of cytokine alterations in BD demonstrated increased levels of sIL-2R, TNF-α, soluble tumour necrosis factor receptor-1 (sTNFR1), sIL-6R and IL-4 (Munkholm et al., 2013). Finally, a cross-diagnostic meta-analysis revealed increased levels of IL-6, TNFα, sIL-2R, IL-1RA in acutely relapsed schizophrenia patients, bipolar mania and major depressive disorder (MDD) compared to controls (Goldsmith et al., 2016). After treatment of the acute phase, IL-6 levels significantly decreased in schizophrenia and MDD patients while sIL2R levels increased in schizophrenia and IL-1RA levels in bipolar mania decreased. In chronic patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic BD and MDD compared with controls. Peripheral levels of IL-1β and sIL-2R were significantly increased in both chronic schizophrenia and euthymic BD patients. Finally, some studies have demonstrated that polymorphisms in cytokine genes might affect susceptibility to schizophrenia and BD (Clerici et al., 2009; Hudson and Miller, 2016). Recent meta-analyses revealed elevated CRP levels in patients with schizophrenia and BD (Dargel et al., 2015; Fernandes et al., 2016). A recent birth cohort study also demonstrated that elevated CRP at the age of 15–16 years might predict subsequent development of schizophrenia-spectrum disorders (Metcalf et al., 2017). In addition, it has been found that elevated CRP levels in schizophrenia occur regardless of antipsychotic treatment (Fernandes et al., 2016). CRP, most commonly measured in its high-sensitivity form (hs-CRP), is a reliable marker of subclinical and systemic inflammatory state (Windgassen et al., 2011). It has been also linked to metabolic dysregulation that is widely observed in patients with schizophrenia and BD (Vuksan-Cusa et al., 2010; Vuksan-Cusa et al., 2013). There are also studies showing that cytokine alterations might be associated with structural neuroimaging findings that are widely observed in patients with schizophrenia and BD (Benedetti et al., 2016; Najjar and Pearlman, 2015). Furthermore, it has been demonstrated that cytokine alterations might impact cognitive performance in both disorders. Although three systematic reviews of studies examining the association between cytokines levels and cognition in schizophrenia and BD have been published so far, a number of studies in this field appeared afterwards (Bauer et al., 2014; Ribeiro-Santos et al., 2014; Rosenblat et al., 2015). In addition, these systematic reviews have not included and analysed studies from both diagnostic categories

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simultaneously. Therefore, the aim of this article was to provide an updated systematic review of studies examining the association between cytokine levels, CRP and cognitive performance in schizophrenia and BD.

2. Method 2.1. Search strategy Two people (B.S. and K.K.) were involved in independent online search for relevant publications in PubMed, CINAHL Complete, Academic Search Complete, ERIC and Health Source: Nursing/Academic Edition databases, using the following combination of keywords: 1) ‘schizophrenia’ or ‘psychosis’ or ‘bipolar disorder’, 2) ‘cytokine(s)’ or ‘interleukin(s)’ or ‘chemokine(s)’ or ‘interferon(s)’ or ‘tumour necrosis factor(s)’ or C-reactive protein or CRP and 3) cognition or cognitive. Discrepancies were resolved in discussion with the third author (B.M.). Online search was performed in accordance with the PRISMA guidelines (Moher et al., 2009) and captured publication records from database inception to Aug. 30, 2016. We included cross-sectional studies that measured serum or plasma cytokine levels or determined cytokine gene polymorphisms and assessed cognitive performance in patients with BD and/or schizophrenia. The following papers were excluded: 1) reviews and metaanalyses; 2) hypotheses; 3) animal model studies; 4) post-mortem studies; 5) clinical trials; 6) study protocols; 7) case reports and 8) studies on other diseases. We extracted the following data from eligible publications: 1) the number of participants; 2) clinical characteristics of patients; 3) cytokine or CRP levels (expressed as mean ± SD) with corresponding p-values for comparisons between patients and controls; 4) type of biological material used for assessment of cytokine or CRP levels (serum/plasma); 5) information about tools used for assessment of cognitive performance and 6) correlation coefficients with corresponding p-values for associations between CRP or cytokine levels and cognitive performance.

2.2. Quality assessment It should be noted that there is a lack of validated tools for quality assessment of studies investigating the role of subclinical inflammation in psychiatry (Bauer et al., 2014). Therefore, we used quality assessment instruments proposed in the previous systematic review synthesizing studies investigating the role of inflammatory mediators of cognitive impairment in patients with BD (Bauer et al., 2014). Quality assessment was performed using the Centre for Reviews and Dissemination (CRD) hierarchy of evidence (Cochrane, 2003) and a revised version of quality evaluation scale implemented in previous studies (Bauer et al., 2014; Ibrahim et al., 2013). The CRD Hierarchy of evidence recognizes five ranks of study designs: 1. Experimental studies; 2. Quasi experimental studies; 3. Controlled observational studies, 3a. Cohort studies, 3b. Case control studies, 4. Observational studies without control groups, 5. Expert opinion based on theory, laboratory research or consensus. The quality evaluation scale included the following items: 1. Representativeness of a clinical sample (eligible cases recruited over a defined period of time in a defined catchment area, in case of hospital populations – consecutive psychiatric admissions with a diagnosis of interest), 2. Appropriate matching of controls (patients and controls matched for at least two confounding variables: age and/or sex and/or education level and/or BMI), 3. Sample size calculations and/or power analysis were performed by authors, 4. Valid methodology of measurement of CRP and/or cytokine levels and/or genotyping of polymorphisms in cytokine genes was described, 5. Well-established measures of cognitive performance were used, 6. Effect sizes and/or confidence intervals of main findings were reported by authors. One point per item was scored if the criterion was satisfied.

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3. Results Out of 393 records identified, 29 articles (20 studies performed on patients with schizophrenia or FEP, 6 studies performed on patients with BD and 3 studies performed on both groups of patients) were finally included in systematic review. The PRISMA flow diagram was presented in Fig. 1 (Moher et al., 2009). Final search results were clustered into five distinct groups: 1) studies testing the association between CRP levels and cognition; 2) studies testing the association between IL-2 and cognition; 3) studies testing the association between IL-6 and cognition; 4) studies testing the association between IL-8 and cognition; 5) studies testing the association between TNF-α together with its receptors and cognition; 6) studies testing the association between other cytokines and cognition (in case of single studies measuring particular cytokines or their polymorphisms). Summary of reviewed studies was presented in Table 1. Insignificant correlations in healthy controls were not commented. 3.1. CRP vs. cognition The association between CRP levels and cognitive performance was tested in seven studies on schizophrenia patients (Bulzacka et al., 2016; Dickerson et al., 2014; Dickerson et al., 2007b; Dickerson et al., 2012; Frydecka et al., 2015a; Joseph et al., 2015; Micoulaud-Franchi et al., 2015), two studies on patients with BD (Chung et al., 2013; Dickerson et al., 2013) and two studies from both groups of patients

(Hope et al., 2015; Johnsen et al., 2016). In all studies with healthy controls, CRP levels were significantly higher in the patients' group. However, it should be noted that three studies addressing various hypotheses regarding the effects of CRP on cognition in schizophrenia patients were performed in overlapping samples of schizophrenia patients (Dickerson et al., 2014; Dickerson et al., 2007b; Dickerson et al., 2012). Abnormal CRP levels were associated with worse cognitive performance on general intellectual ability, abstract reasoning, memory, working memory, semantic memory, learning abilities, attention, mental flexibility and processing speed (Bulzacka et al., 2016) as well as global cognition (Dickerson et al., 2007b) in patients with schizophrenia. In the study by Frydecka et al. (2015a), there was a negative correlation between CRP levels and cognitive performance on verbal learning and memory. Interestingly, in this study higher CRP levels were associated with chronic schizophrenia course with deterioration. In one study, herpes simplex virus type 1 seropositivity and elevated CRP levels were independent and additive predictors of lower global cognitive performance (Dickerson et al., 2012). In the study by Micoulaud-Franchi et al. (2015), elevated CRP levels were associated with worse cognitive performance on Stroop task measuring executive function. In acutely relapsed patients with psychosis, CRP levels negatively correlated with scores of attention, delayed memory and global cognitive performance on admission but not after 4 weeks of treatment (Johnsen et al., 2016). However, CRP levels have not been found to predict longitudinal changes in cognitive performance (Dickerson et al., 2014). In one study, no significant correlations between CRP levels and cognitive

Fig. 1. PRISMA flow diagram of studies selected for systematic review (Moher et al., 2009).

Table 1 Studies examining the association between cytokines, CRP levels and cognition in schizophrenia and BD patients. Sample

Immune-inflammatory markers

Measures of cognitive performance

Main findings

Bulzacka et al. (2016)

369 SCZ patients

Plasma levels of CRP

The National Adult Reading Test, WAIS-III, Seven subtest short form, TMT-A and TMT-B, California Verbal Learning Test, Doors Test, the Continuous Performance Test

Hori et al. (2016)

146 chronic SCZ patients Plasma levels of IL-6, 51 HCs TNF-α Serum levels of CRP 124 patients with acute relapse of psychosis (schizophrenia, schizoaffective disorder, acute and transient psychotic disorder, delusional disorder, drug-induced psychosis, BD except manic psychosis, MDD with psychotic features)

BACS-J

Zhang et al. (2016)

92 chronic SCZ patients and 60 HCs

Serum levels of TNF-α, IL-2, IL-6 and IL-8

PANSS cognitive factor score

Wu et al. (2016)

70 chronic SCZ patients 75 HCs

Serum levels of IL-18

RBANS

Xiu et al. (2016)

270 drug-naïve FES patients 540 HCs

Serum levels of IL-10 and its −592A/C polymorphism

RBANS

Abnormal CRP levels (N3 mg/l) were associated with worse cognitive performance on general intellectual ability and abstract reasoning (OR = 0.56, 95%CI 0.35–0.90, p = 0.14) after adjustment for age, sex, education level, psychotic symptoms, treatments and addiction comorbidities. Abnormal CRP levels were also associated with worse performance on all components of working memory (ES estimates between 0.25 and 0.38, p-value between 0.004 and 0.04), memory (ES = 0.26, p = 0.026), semantic memory (ES = 0.26, p = 0.026), learning abilities (ES = 0.28, p = 0.035), visual attention (ES = 0.23, p = 0.004), mental flexibility (ES = 0.26, p = 0.044) and processing speed (ES = 0.23, p = 0.043). There were no significant correlations between cognitive performance, TNF-α and IL-6 levels. There was a negative correlation between CRP levels and attention (B = −0.404, β = −0.239, p = 0.012), delayed memory (B = −0.484, β = −0.213, p = 0.020) and global cognitive (B = −0.290, β = −0.198, p = 0.031) performance on admission after controlling for years of education, antipsychotic drug status, cigarette smoking status, drug abuse and CVD risk score in linear regression analysis. There were no significant correlations between CRP and cognitive performance after 4 weeks of treatment. There were significantly lower BDNF (6.9 ± 2.4 vs. 9.7 ± 4.5 ng/ml, p b 0.001) and TNF-α (10.0 ± 2.0 vs. 37.2 ± 5.1 ng/ml, p b 0.001) levels together with higher IL-2 (7.0 ± 2.9 vs. 4.2 ± 2.6 ng/ml, p b 0.001), IL-6 (0.35 ± 0.11 vs. 0.29 ± 0.19 ng/ml, p = 0.008) and IL-8 (0.97 ± 0.30 vs. 0.88 ± 0.57 ng/ml, p = 0.014) levels in SCZ patients compared to HCs. There was a significant negative effect of the interaction between BDNF and TNF-α levels on the PANSS cognitive factor score (β = −0.29, t = −0.210, p b 0.05) after controlling for age, sex, education and BMI in binary logistic regression. There were significantly higher levels of IL-18 in patients with SCZ compared to HCs (240.6 ± 63.4 vs. 191.0 ± 41.7, p b 0.001). Patients with SCZ scored significantly lower on domains of immediate and delayed memory. There was a significant positive correlation between IL-18 levels and RBANS total score (r = 0.292, p = 0.014) as well as scores of immediate (r = 0.268, p = 0.025) and delayed memory (r = 0.277, p = 0.020) in patients with SCZ. The A allele was significantly more frequent in FES patients than in HCs (70.1 vs. 63.7%, p = 0.03). This variant was associated with reduced IL-10 levels and worse attentional performance in FES patients (1-way ANOVA: F = 3.81, df = 2, 239, p = 0.02) but not in HCs (1-way ANOVA: F = 0.40, df = 2, 288, p =

Johnsen et al. (2016)

RBANS

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Study

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Table 1 (continued) Study

Sample

Immune-inflammatory markers

43 patients with SCZ and schizoaffective disorder 43 HCs

Peripheral mRNA levels of cytokines (IL-1β, IL-2, IL-6, IL-8, IL-18)

Hamdani et al. (2015)

42 euthymic patients with BD 36 HCs

Peripheral IL-6 mRNA levels and antibodies to Toxoplasma gondii

Hope et al. (2015)

121 patients with SCZ spectrum disorders 111 patients with BD spectrum 241 HCs

Serum levels of sTNFR1, IL-1Ra, sCD40 ligand, OPG, vWF, IL-6 and CRP

Joseph et al. (2015)

88 patients with SCZ and schizoaffective disorder 71 HCs

Plasma CRP levels

Lv et al. (2015)

89 chronic SCZ patients 43 HCs

Serum levels of TNF-α

Micoulaud-Franchi et al. (2015)

55 SCZ patients

Serum levels of CRP

Main findings

0.67). Lower serum levels of IL-10 were associated with worse global cognitive performance (r = 0.217, p = 0.012) and attention (r = 0.267, p = 0.002) in FES patients, especially in those with A allele. There was a significant 28.4% increase in IL-1β WTAR, expression among patients with SCZ compared to COWAT FAS Letter Fluency test, HCs [t(82) = 2.64, p b 0.01]. Patients scored From WMS-III: Logical Memory I and II significantly lower on all cognitive measures From WAIS-III: Letter Number-Sequencing subtest, Picture compared to HCs. Elevated IL-1β mRNA levels Completion, Digit-Symbol Coding, Similarities and predicted lower COWAT verbal fluency score (β = Arithmetic Subtest −0.38, p b 0.0001) with WTAR test score used as a covariate. In the group of patients, those with elevated cytokine levels (determined in cluster analysis) had poorer performance on COWAT letter fluency [F(1,40) = 15.7, p b 0.001]. CVLT, Vocabulary Subtest of WAIS-III, cognitive deterioration There were significantly higher IL-6 expression levels (6.42 ± 6.52 vs.3.38 ± 3.64, p = 0.015) and T. gondii index that was calculated from domains less sensitive to seropositivity rates (88.1 vs. 52.7%, p = 0.005) in BD deterioration (vocabulary and information) and more patients compared to HCs. The cognitive sensitive to deterioration (digit symbol coding), based on deterioration index was significantly higher in BD WAIS-III (Bilder et al., 1992) patients and significantly correlated with IL-6 mRNA levels only in those infected by T. gondii (rho = 0.43, p = 0.01). Expression levels of IL-6 mRNA were twice greater in deteriorated BD patients. WASI – four tests including two subtests for verbal cognition There were significantly higher levels of sTNFR1 and (Similarities and Vocabulary) and two tests for performance vWF in SCZ (0.95 ± 0.25 ng/ml and 87 ± 49%) and BD patients (1.06 ± 0.31 ng/ml and 106 ± 50%) than in HCs abilities (Block design and Matrix reasoning) were used to (1.04 ng/ml and 103 ± 56). OPG levels were assess general cognitive abilities significantly higher in BD patients (2.6 ± 1.38 ng/ml) compared to SCZ patients (2.5 ± 0.93 ng/ml) and HCs (2.9 ng/ml). General cognitive abilities were significantly associated with IL-1RA (B = −0.11, t = −2.1, p = 0.04) and sTNFR1 (B = −0.12, t = 2.5, p = 0.01) levels in patients with SCZ, with CD40L (B = −0.10, t = −2.2, p = 0.03) and IL-1RA (B = −0.1, t = −2.1, p = 0.03) levels in BD patients and with sTNFR1 (B = −0.44, t = −3.3, p = 0.001) levels in HCs using linear regression analysis (covariates: age, sex, BMI, education, smoking, alcohol intake, cholesterol, ALT, glucose, time of blood sampling, depressive symptoms, antipsychotic medication, mood stabilizers). CRP was significantly higher in patients compared to Subtests from the Delis-Kaplan Executive Function System: controls (4.3 ± 5.4 vs. 2.3 ± 3.8 mg/l, p = 0.001). Trail Making, Color Word Inhibition and the Letter Fluency There were no significant correlations between Task cognitive performance and CRP levels in the group of patients. There was a significant negative correlation between CRP level and executive functioning composite score in HCs (r = −0.246, p = 0.039). PANSS cognitive factor score There were significantly lower levels of TNF-α in SCZ patients compared to HCs (10.1 ± 2.0 vs. 37.8 ± 3.4 pg/ml, p b 0.001). There was a significant negative correlation between TNF-α levels and PANSS cognitive factor score (r = −0.22, p b 0.05). TMT-A, TMT-B, Stroop interference test, category fluency Patients with higher levels of CRP (N5 mg/l) had and digit symbol coding worse performance on Stroop interference test (37.31 ± 10.72 vs. 28.21 ± 14.93, p = 0.026).

B. Misiak et al. / Schizophrenia Research 192 (2018) 16–29

Fillman et al. (2016)

Measures of cognitive performance

160 chronic and treatment-resistant SCZ patients 60 HCs

Serum levels of IL-2

PANSS cognitive factor score

Asevedo et al. (2014)

29 SCZ patients 26 HCs

Serum levels of IL-2

Dickerson et al. (2014)

132 SCZ patients (longitudinal study)

Frydecka et al. (2015a)

151 SCZ patients 194 HCs

Serum levels of CRP and antibodies to HSV-1 Serum levels of IL-6 and its −174G/C polymorphism, CRP

The Hopkins Verbal Learning Test, phonemic and semantic verbal fluency test, VWMT, Keep Track Test, Letter Memory Task, Forward Digit Span Test (WAIS), Plus-minus task, Number-Letter Task, Tower of London, shortened version of the Wisconsin Sorting Card Test, Computerized Stroop Task, Semantic Generation Task, the Non-Verbal Intelligence Task RBANS

Lotrich et al. (2014)

21 euthymic BD patients 26 HCs

Serum levels of IL-1Ra and IL-6

Xiu et al. (2014)

128 drug-naïve first-episode psychosis patients 62 HCs

Serum levels of IL-10

Asevedo et al. (2013)

30 SCZ patients 27 HCs

Serum levels of chemokines (IP-10, IL-8, CCL-11, eotaxin 2, MCP-1, MIP-1)

There were significantly higher levels of IL-2 levels in SCZ patients compared to HCs (6.7 ± 2.2 vs. 4.2 ± 1.6 pg/ml, p b 0.001). There was a significant positive correlation between IL-2 levels and PANSS cognitive factor score (r = 0.40, p b 0.001). Patients with SCZ had lower serum levels of IL-2 than HCs [0.699 (SE: 0.105) vs. 1.146 (SE: 0.120), p b 0.001]. Serum levels of IL-2 were positively correlated with scores of the Digit Span Test (rho = 0.416, p = 0.025) and non-verbal intelligence (rho = 0.464, p = 0.011).

CRP levels did not predict changes in cognitive performance. RAVLT, TMT, Verbal Fluency Tests, Stroop and subscales from Serum levels of IL-6 (1.4 ± 2.23 vs. 1.07 ± 0.77 pg/ml, p = 0.049) and CRP (3.3 ± 3.7 vs. 2.3 ± 1.6 WAIS-R-Pl (Similarities, Digit Symbol Coding, Digit Span mg/l, p b 0.001) were significantly higher in SCZ Forward and Backward) performed only in SCZ patients. patients than in HCs. After Bonferroni correction, higher IL-6 levels were associated with worse performance on TMT-A (r = 0.38, p = 0.001), TMT-B (r = 0.48, p = 0.001), RAVLT (3rd immediate recall: r = −0.40, p = 0.001, 4th immediate recall: −0.39, p = 0.001, 5th immediate recall: r = −0.37, p = 0.001) and digit symbol coding (r = −0.45, p b 0.001), while higher CRP levels were related to worse performance on RAVLT (1st immediate recall: r = −0.38, p b 0.001, 2nd immediate recall: r = −0.33, p b 0.001). There were significantly higher IL-1Ra levels in BD 21 tests measuring multiple cognitive domains. Based on patients compared to HCs (439 ± 326 vs. 269 ± 109 factor analysis 4 z-scores were determined: language, delayed memory, visuomotor ability, information processing pg/ml, p = 0.004). Both groups had similar levels of IL-6 (1.5 ± 1.3 vs. 2.19 ± 1.7 pg/ml, p = 0.15). Serum speed/executive function. levels of IL-1Ra were negatively correlated with z-scores of global cognition (rho = −0.372, p = 0.01), visual cognition (rho = −0.313, p = 0.03), memory cognition (rho = −0.345, p = 0.02), speed/executive cognition (rho = −0.404, p = 0.005). PANSS cognitive factor score Patients had significantly lower levels of IL-10 compared to controls (39.2 ± 25.4 vs. 51.2 ± 36.6 pg/ml, p = 0.01). There was a significant negative correlation between IL-10 levels and the PANSS cognitive factor score (r = −0.201, p = 0.025). This association was insignificant in multiple regression analysis taking into account the effects of age, sex, duration of illness, age of onset and smoking. IP-10 levels were significantly lower in SCZ patients VWMT, Keep Track Task, Letter Memory Task, Plus-Minus Task, Number-Letter Task, Stroop test, Semantic Generation compared to HCs [median (p25-p75): 1.61 Task, Tower of London, WCST, Hopkins Verbal Learning Test (1.20–4.82) vs. 8.53 (0.77–67.76) pg/ml, p = 0.036], while CCL-11 levels were significantly higher in SCZ and FAS verbal fluency task. patients than in HCs [median (p25-p75): 295.12 (216.39–621.25) vs. 212.90 (148.45–362.55) pg/ml, p = 0.016] There were significant correlations in the group of patients with SCZ but not in HCs. CCL-11 was negatively correlated with performance on VWMT (rho = −0.40, p = 0.034) and positively correlated with performance on Plus-Minus task (rho = 0.51, p = 0.007). IL-8 was positively correlated with verbal fluency (rho = 0.38, p = 0.048). Eotaxin-2 was positively correlated with semantic generation ability

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Tan et al. (2015)

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Table 1 (continued) Study

Sample

Immune-inflammatory markers

Chung et al. (2013)

17 euthymic type I BD patients

Serum levels of CRP

Dickerson et al. (2013)

107 BD patients (85 inpatients and 22 outpatients)

Serum levels of CRP

Serum levels of TNF-α, sTNFR1 and sTNFR2

Frydecka et al. (2015b)

151 SCZ patients 279 HCs

Serum levels of TGF-β and its gene polymorphisms (+869T/C and +915G/C)

Zhang et al. (2013)

77 drug-naïve FES patients 75 HCs

Serum levels of IL-18

Main findings

(rho = 0.42, p = 0.024) and letter memory task (rho = 0.38, p = 0.049). WCST Elevated CRP levels were associated with reduced volume of orbitofrontal cortex (left: r = −0.62, p b 0.01, right: r = −0.67, p b 0.005). The association between CRP levels and WCST scores was not tested. RBANS, TMT-A, WAIS Information and Letter Sequencing Total score of RBANS was significantly lower in patients with CRP levels higher than the 90th percentile and the 75th percentile of the control group. Linear regression analysis revealed negative correlations between CRP levels and total RBANS score (t = −2.48, p = 0.015), RBANS immediate memory score (t = −2.16, p = 0.033), RBANS attention score (t = −2.18, p = 0.032), RBANS language score (t = −2.13, p = 0.036) and TMT-A score (t = −2.39, p = 0.019). WCST, RAVLT Patients with BD has significantly higher levels of sTNFR1 (1.35 ± 0.88 vs. 0.86 ± 0.59 ng/ml, p = 0.029) and sTNFR2 (9.17 ± 4.53 vs. 6.40 ± 3.32 ng/ml, p = 0.014) compared to HCs. Both groups had similar levels of TNF-α. Patients with BD scored significantly worse on WCST (number of perseverative responses and number of category achieved) and RAVLT (maximum learning score and learning error score). There was a significant negative correlation between TNF-α levels and the delayed recall in RAVLT (r = −0.275, p = 0.044). Serum TGF-β levels were significantly higher in SCZ RAVLT, Trail Making Test, Verbal Fluency Tests, Stroop and subscales from WAIS-R-Pl (Similarities, Digit Symbol Coding, patients than in HCs (median ± interquartile range: 43.56 ± 13.36 vs. 35.15 ± 11.83 ng/ml, p b 0.0001). Digit Span Forward and Backward) performed only in SCZ Both polymorphisms did not impact TGF-β levels. patients. Patients with the +869T allele performed significantly worse in comparison with +869CC homozygotes on Stroop task (congruent: 45.39 ± 19.56 vs. 37.47 ± 11.13, p = 0.02), Verbal Fluency task (F words: 8.47 ± 3.24 vs. 6.49 3.76, p = 0.03) and Digit Symbol Coding task (trend-level significance: 42.18 ± 13.11 vs. 35.05 ± 14.00, p = 0.06). There was a significant difference in cognitive performance on Digit Symbol Coding task with respect to the TGFB1 +869T/C polymorphism among female schizophrenia patients (β = −0.57, t = −2.78, p = 0.02) after controlling for possible confounders (age, education, illness duration, total PANSS score, BMI, smoking, chlorpromazine equivalent and TGF-β level). RBANS There were no significant differences in IL-18 levels between FES patients and HCs (206.0 ± 92.9 vs. 193.2 ± 41.8, p = 0.28). The group of FES patients scored significantly worse on almost all domains of cognitive performance except for visuospatial/constructional index. There was a significant positive correlation between IL-18 levels and cognitive deficits in the

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Doganavsargil-Baysal et al. 54 type I euthymic BD patients (2013) 18 HCs

Measures of cognitive performance

Barbosa et al. (2012)

35 euthymic type I BD patients 25 HCs

Frontal Assessment Battery, MMSE

Martinez-Cengotitabengoa 28 FEP patients and 28 HCs et al. (2012)

Plasma levels of MCP-1

Dickerson et al. (2012)

588 SCZ patients

Serum levels of CRP and HSV-1 antibodies

WAIS III digits forward Time to complete TMT-A Number of correct items Stroop words Number of correct items Stroop colors WAIS III key number WAIS III digits backward WAIS III number–letter sequencing WMS III logical memory I, II WMS III verbal paired associates I, II Number of words on the VFT Stroop interference WCST number of perseverative errors WCST number of errors WCST conceptual level responses RBANS

Dickerson et al. (2007a)

351 SCZ patients 122 BD patients 160 HCs

The LTA gene polymorphisms (rs2857713 and rs1800683) and the TNF-α gene polymorphism (rs1800629)

RBANS

Dickerson et al. (2007b)

413 SCZ patients

Serum levels of CRP

RBANS

There were independent and additive effects of HSV-1 seropositivity and elevated CRP levels on RBANSS cognitive scores. The LTA Cys/Cys homozygotes (rs2857713) had significantly higher RBANS total scores and attention scores compared to other genotypes (Cys/Arg, Arg/Arg) in the group of SCZ patients (F = 4.86, p = 0.008), but not in BD patients (F = 0.49, p = 0.6) and HCs (F = 0.12, p = 0.88). A similar association was found for attention in the group of SCZ patients (F = 5.28, p b 0.006), but not in BD and HCs, after adjustment for age, sex, race, education and HSV-1 seropositivity. There were no significant effects of other polymorphisms on cognition. There were significantly lower RBANS total scores in patients with CRP levels N 5 mg/μl compared to those with lower CRP levels (64.1 13.7 vs. 68.3 13.9, F = 8.07, p = 0.047).

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Plasma levels of TNF-α, sTNFR1 and sTNFR2

visuospatial/constructional domain (r = 0.25, p = 0.03). Multiple regression, controlling for education and PANSS positive symptoms score, confirmed this association (β = 0.22, t = 2.12, p = 0.038). There were no significant differences in plasma levels of TNF-α, sTNFR1 and sTNFR2. Patients with BD scored significantly worse on measures of executive functioning, particularly sensitivity interference and inhibitory control than HCs. Plasma levels of TNF-α were positively correlated with inhibitory control (rho = 0.50, p = 0.02) in BD patients while motor programming was negatively correlated with sTNFR2 (rho = −0.47, p = 0.02) plasma levels in HCs. There were no significant differences in levels of MCP-1 between FEP patients and HCs (7644.70 ± 7458.26 vs. 6419.33 ± 4948.56 ng/ml, p = 0.822). MCP-1 levels were negatively correlated with measures of learning and memory (verbal and working) in FEP patients (B = −0.382, p = 0.009) after adjustment for atypical antipsychotics' use at admission and at the time of cognitive assessment.

Data expressed as mean ± SD unless otherwise indicated. Abbreviations: BACS-J – Brief Assessment of Cognition (Japanese version), BD – bipolar disorder, COWAT – Controlled Oral Word Association Test, CRP – C-reactive protein, CVD – cardiovascular disease, ES – effect size, FEP – first-episode psychosis, FES – first-episode schizophrenia, HCs – healthy controls, HSV-1 – Herpes Simplex Virus type 1, IL – interleukin, IP-10 - interferon-γ-induced protein 10, LTA – lymphotoxin, MCP-1 – monocyte chemoattractant protein-1, MDD – major depressive disorder, MMSE – Mini-Mental State Examination, PANSS – the Positive and Negative Syndrome Scale, RAVLT – Rey Auditory Verbal Learning Test, RBANS – Repeatable Battery for Assessment of the Neuropsychological Status, SCZ – schizophrenia, sTNFR1 – soluble P55 TNF receptor, sTNFR2 – soluble P75 TNF receptor, TGF-β – transforming growth factor-β, TMT – Trail Making Test, TNF-α – tumour necrosis factor-α, vWF – von Willebrand Factor, VWMT – Visual Working Memory Task (Salthouse et al., 1991), WASI – Wechsler Abbreviated Scale of Intelligence, WCST – Wisconsin Card Sorting Test, WMS – Wechsler Memory Scale, WTAR – Wechsler Test of Adult Reading.

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performance in tasks measuring verbal cognition and performance abilities in patients with BD and schizophrenia as well as healthy controls were found (Hope et al., 2015). Another study revealed no significant correlations between CRP levels and cognitive performance in patients with schizophrenia or schizoaffective disorder (executive functioning); however, in healthy controls CRP levels negatively correlated with performance of executive functioning (Joseph et al., 2015). Finally, in the study by Dickerson et al. (2013) on patients with BD, global cognitive performance was significantly lower in patients with CRP levels higher than the 90th percentile and the 75th percentile of the control group. There were negative correlations between CRP levels and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score, RBANS immediate memory score, RBANS attention score, RBANS learning score and Trail Making Test, part A (TMT-A) score. In one study on patients with BD, CRP were negatively correlated with orbitofrontal cortex volumes (Chung et al., 2013). 3.2. IL-2 vs. cognition The association between IL-2 levels and cognitive performance was examined in four studies from schizophrenia patients. In two studies (Tan et al., 2015; Zhang et al., 2016), IL-2 levels were significantly higher, while in one study (Asevedo et al., 2014) IL-2 levels were significantly lower in patients with schizophrenia compared to healthy controls. In one study (Fillman et al., 2016), no significant differences in IL-2 levels were found between schizophrenia patients and healthy controls. In another study (Tan et al., 2015), IL-2 were positively correlated with the Positive and Negative Syndrome Scale (PANSS) cognitive factor score and the severity of positive symptoms, while in the study by Asevedo et al. (2014) serum levels of IL-2 were positively correlated with the Digit Span Test score and non-verbal intelligence. In other studies, no significant correlations between IL-2 levels and cognitive performance were reported (Fillman et al., 2016; Zhang et al., 2016). 3.3. IL-6 vs. cognition Effects of IL-6 on cognition were tested in five studies from schizophrenia patients (Fillman et al., 2016; Frydecka et al., 2015a; Hope et al., 2015; Hori et al., 2016; Zhang et al., 2016) and two studies from BD patients (Hamdani et al., 2015; Lotrich et al., 2014). In three studies (Frydecka et al., 2015a; Hamdani et al., 2015; Zhang et al., 2016), increased levels of IL-6 in patients with schizophrenia or BD were reported. In the study by Hamdani et al. (2015), IL-6 levels were positively correlated with cognitive deterioration index, which was calculated from domains less sensitive to deterioration (vocabulary and information) and more sensitive to deterioration (digit symbol coding) (Bilder et al., 1992), in patients with BD. Higher IL-6 levels were associated with worse cognitive performance on visual attention, visuomotor processing speed, semantic and working memory, task-switching ability and executive control function in the study by Frydecka et al. (2015a). No significant correlations between IL-6 levels and cognitive performance were reported in other studies. However, Fillman et al. (2016) revealed that IL-6 levels contributed to the effects of all measured cytokines on cognitive performance in patients with schizophrenia (see below). 3.4. IL-8 vs. cognition Patients with schizophrenia had elevated IL-8 levels only in the study by Zhang et al. (2016). In one study, IL-8 levels were positively correlated with verbal fluency (Asevedo et al., 2013). No significant correlations between IL-8 levels and cognitive performance were reported in other studies from schizophrenia patients (Fillman et al., 2016; Zhang et al., 2016). There were no studies addressing the association between IL-8 levels and cognitive functioning in patients with BD.

3.5. TNF-α and its receptors vs. cognition The association between TNF-α and/or its receptors levels and cognition was assessed in three studies on schizophrenia patients (Hori et al., 2016; Lv et al., 2015; Zhang et al., 2016), two studies from patients with BD (Barbosa et al., 2012; Doganavsargil-Baysal et al., 2013) and one study from both groups (Hope et al., 2015). In one study (Dickerson et al., 2007a), the association between the TNF-α rs1800629 polymorphism and cognitive performance (assessed by means of RBANS) in patients with schizophrenia, BD and HCs was examined; however, no significant effects of this polymorphism on cognition were found. In two studies, TNF-α levels were significantly lower in patients with schizophrenia compared to HCs (Lv et al., 2015; Zhang et al., 2016). In one study, sTNFR1 were significantly higher in patients with schizophrenia and BD compared to healthy controls (Hope et al., 2015). Similarly, type I BD patients had significantly higher sTNFR1 and sTNFR2 levels than healthy controls (Doganavsargil-Baysal et al., 2013). In one study (Zhang et al., 2016), there was a significant negative effect of the interaction between levels of brain-derived neurotrophic factor (BDNF) and TNF-α on the PANSS cognitive factor score. Similarly, there was a significant negative correlation between TNF-α levels and the PANSS cognitive factor score in the study by Lv et al. (2015). General cognitive abilities were significantly associated with sTNFR1 levels in patients with schizophrenia and BD (Hope et al., 2015). In the study by Barbosa et al. (2012), plasma levels of TNF-α were positively correlated with inhibitory control in BD patients while motor programming was negatively correlated with sTNFR2 plasma levels in healthy controls. Finally, in one study patients with BD scored significantly worse on the Wisconsin Card Sorting Test (WCST) in terms of the number of perseverative responses and the number of category achieved and the Rey's Auditory Verbal Learning Test (RAVLT) with respect to the maximum learning score and the learning error score (DoganavsargilBaysal et al., 2013). There was also a significant negative correlation between TNF-α levels and the delayed recall in RAVLT. No significant correlations between TNF-α and cognitive performance were found in other studies. 3.6. Other cytokines vs. cognition One study revealed significantly higher levels of IL-18 in chronic schizophrenia patients compared to healthy controls (Wu et al., 2016). In this study, there was a significant positive correlation between IL18 levels and RBANS total score as well as scores of immediate and delayed memory in patients with schizophrenia. Another study (Xiu et al., 2016) tested the effects of serum IL-10 levels and its −592A/C polymorphism in drug-naïve first-episode schizophrenia (FES) patients. The A allele was significantly more frequent in FES patients than in HCs. This variant was associated with reduced IL-10 levels and worse attentional performance in FES patients but not in HCs. Lower serum levels of IL-10 were associated with worse cognitive performance especially in the attentional domain in FES patients with A allele. The same group revealed a negative correlation between IL-10 levels and the PANSS negative factor score in drug-naïve patients with FEP (Xiu et al., 2014). A broad panel of cytokine expression levels (IL-1β, IL-2, IL-6, IL-8, IL-18) was measured in patients with schizophrenia in the above mentioned study by Fillman et al. (2016). Expression levels of IL-1β were significantly higher in the group of schizophrenia patients and negatively predicted verbal fluency scores. Patients with elevated cytokine levels (determined in cluster analysis) had poorer performance on COWAT letter fluency. Interestingly, this study also revealed reduced volumes of the left pars opercularis (Broca's area) in patients with elevated cytokine levels compared to patients with normal cytokine levels. Elevated levels of IL-1β were the only cytokine contributor of volume reductions. Two studies determined IL-1RA levels (Hope et al., 2015; Lotrich et al., 2014). However, only in the study by Lotrich et al. (2014), IL-1RA were significantly higher in patients with BD compared to healthy

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controls. In this study, serum levels of IL-1RA were negatively correlated with z-scores of global cognition, visual cognition, memory cognition and speed/executive cognition. In one study, polymorphisms in the lymphotoxin (LTA) gene were assessed with respect to cognition in patients with schizophrenia, BD and healthy controls. The LTA Cys/Cys homozygotes (rs2857713) had significantly higher RBANS total scores and attention scores compared to other genotypes (Cys/Arg, Arg/Arg) in the group of SCZ patients, but not in BD patients and HCs (Dickerson et al., 2007a). In one study TGF-β levels together with its gene polymorphisms +869T/C and +915G/C were assessed with respect to cognitive functioning in schizophrenia patients and healthy controls (Frydecka et al., 2015b). Serum TGF-β levels were significantly higher in SCZ patients than in HCs. Both polymorphisms did not impact TGF-β levels. Patients with the + 869T allele performed significantly worse in comparison with + 869CC homozygotes on Stroop task, Verbal Fluency task and Digit Symbol Coding task. There was a significant difference in cognitive performance on Digit Symbol Coding task with respect to the TGFB1 + 869T/C polymorphism among female schizophrenia patients after controlling for possible confounders. Finally, Martinez-Cengotitabengoa et al. (2012) provided evidence for the involvement of chemokines in the development of cognitive impairment. Authors found no significant differences in the levels of MCP-1 between FEP patients and HCs. However, MCP-1 levels were negatively correlated with measures of learning and memory (verbal and working) in FEP patients. Another study (Asevedo et al., 2013) also tested the association between chemokine levels and cognitive performance in patients with schizophrenia. Authors found significantly lower levels of interferon-γ-inducible protein-10 and significantly higher levels of CCL-11 in patients with schizophrenia compared to controls. There were significant correlations in the group of patients with SCZ but not in healthy controls. CCL-11 was negatively correlated with performance on verbal working memory and positively correlated with performance of set-shifting. 3.7. Tools for assessment of cognitive performance A summary of tests measuring distinct cognitive abilities was presented in Table 2. Tools selected in studies reviewed in this article included measures of attention, executive function, inhibition, intelligence, learning, mathematical problem solving, mental control, memory, orientation, processing speed and set shifting as well as verbal fluency. Although there was a high variability in the use of certain tests, there was a trend toward the use of selected subtests from the Wechsler Adult Intelligence Scale 3rd Edition (WAIS-III) (Wechsler, 1997b) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (Randolph et al., 1998). In some studies, the score of cognitive factor from PANSS (Kay et al., 1987), which is a proxy measure of cognitive performance, was used. The following symptoms were included to calculate the PANSS cognitive factor in studies reviewed in this article: conceptual disorganization (P2), difficulty in abstract thinking (N5) and poor attention (G11). 3.8. Quality assessment Results of quality assessment were presented in Supplementary Table 1. The majority of studies adopted a case control design, while eight studies were classified as observational and did not include a group of healthy controls (Bulzacka et al., 2016; Chung et al., 2013; Dickerson et al., 2007a; Dickerson et al., 2014; Dickerson et al., 2012, 2013; Johnsen et al., 2016; Micoulaud-Franchi et al., 2015). Studies were scored between 1 and 4 points in the quality assessment instrument. It should be noted that a majority of studies did not include a representative sample of patients with schizophrenia or BD. In three studies, patients and controls were not sufficiently matched for potential confounding factors (Dickerson et al., 2007a; Hamdani et al., 2015; Hope et al., 2015). Sample size calculations or power analysis were performed only in three studies (Dickerson et al., 2007b;

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Doganavsargil-Baysal et al., 2013; Lotrich et al., 2014). In two studies (Dickerson et al., 2014; Micoulaud-Franchi et al., 2015), methodology of measurement of cytokine or CRP levels was not described. Some studies used only the PANSS cognitive factor score as a proxy measure of cognitive performance (Lv et al., 2015; Tan et al., 2015; Xiu et al., 2014; Zhang et al., 2016). Effect size estimates and confidence intervals for major findings were not calculated in the majority of studies. 4. Discussion This systematic review implies that subthreshold inflammatory state measured by peripheral blood levels of CRP and cytokines might be an important contributor of cognitive impairment observed in patients with schizophrenia and BD. In case of schizophrenia patients, this statement holds true especially for the levels of CRP and TNF-α or its receptors, where the majority of studies have reported positive findings. Evidence for the involvement of IL-2 and IL-6 in cognitive impairment in patients with schizophrenia is less convincing due to discordant results across various studies. There is no evidence for the role of IL-8 in the development of cognitive deficits in patients with schizophrenia. There are only single studies suggesting that alterations in the levels of IL-1β, IL-10, IL-18, TGF-β and polymorphism of the LTA gene might impact cognitive functioning in patients with schizophrenia. It should be noted that less attention has been paid to the association between CRP and cytokine levels in patients with BD. Preliminary evidence suggests the involvement of CRP, IL-1RA, IL-6 and TNF-α with its receptors in the development of cognitive impairment in patients with BD. In the vast majority of studies, correlations reported in the patients' group were insignificant in controls. However, it should be noted that a number of limitations and methodological differences may underlie discordant results across studies reviewed in this article. Firstly, these studies were performed on patients in various age groups and phases of the illness, including FEP patients, acutely relapsed multi-episode patients, clinically stable patients and chronic patients, who may present a differential extent of cognitive impairment and immune system dysregulation. These studies have also used various types of biological material for the measurement of cytokine alterations including serum, plasma and mRNA levels. Another point is that some studies did not include a group of healthy controls and thus disease-specific contribution of peripheral immune-inflammatory markers cannot be established. Furthermore, there was a considerable heterogeneity in the selection of tools for assessment of cognitive performance, although some trends toward the use of WAIS-III subscales and RBANS can be observed. At this point, it should be noted that some studies used the PANSS cognitive factor score, which is only a proxy measure of cognitive performance based on symptomatic manifestation. Finally, some studies have not controlled for potential confounding factors including i.e. body-mass index, cigarette smoking, illness duration, a number of symptomatic exacerbations as well as type and duration of treatment. Indeed, treatment effects have been regularly shown to significantly impact both the immune system and cognitive functioning (Miller et al., 2011; Miller et al., 2013). Moreover, there are few studies with relatively small sample seize that may not allow to reach sufficient power to detect differences at the significance level, taking into account the effect sizes reported in meta-analytic studies on cytokine alterations in psychotic disorders. Accumulating evidence indicates that cytokines may play an important role in shaping individual cognitive abilities via various mechanisms. Indeed, cytokines have been found to impact neurogenesis (Borsini et al., 2015), hippocampal-dependent synaptic plasticity (McAfoose and Baune, 2009), memory consolidation (Alboni et al., 2014), central neurotransmission systems (Zalcman et al., 1994) and hypothalamic-pituitary-adrenal axis response (Wang and Dunn, 1998). Regarding IL-1β, it has been reported that this cytokine can modulate neurotransmission in the hippocampus and promotes long-term potentiation. In physiological conditions and normal concentrations

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Table 2 Summary of tests measuring cognitive performance. Test/task

Cognitive domain

Arithmetic subtest from WAIS-III BACS-J (Kaneda et al., 2007)

Mathematical problem solving Verbal memory, working memory, motor speed, verbal fluency, attention, processing speed and executive function Performance abilities Executive function Verbal learning and memory Verbal fluency Attention Executive function

Block design from WASI (Hays et al., 2002) Category fluency (Shao et al., 2014) California Verbal Learning Test (Elwood, 1995) COWAT F-A-S letter (Malek-Ahmadi et al., 2011) D2 attention task (Bates and Lemay, 2004) Delis-Kaplan Executive Function System: Trail Making, Color Word Inhibition, Letter Fluency Task (Homack et al., 2005) Digit Span from WAIS-III Digit Symbol Coding from WAIS-III Doors test (Davis et al., 1999) Frontal Assessment Battery (Dubois et al., 2000) Forward Digit Span from WAIS-III Backward Digit Span from WAIS-III Information from WAIS-III The Hopkins Verbal Learning Test (Rasmusson et al., 1995) Keep Track test (Yntema, 1963) Letter Memory Task (Greub and Suhr, 2006) Letter Number Sequencing from WAIS-III Logical Memory I and II from WMS-III Matrix Reasoning from WAIS-III or WASI (Hays et al., 2002) MMSE (Folstein et al., 1975) Number-letter task (Rogers and Monsell, 1995) Number-letter sequencing from WAIS-III PANSS - cognitive factor (Kay et al., 1987; Wallwork et al., 2012) Phonemic and semantic verbal fluency (Asevedo et al., 2014) Picture completion from WAIS-III Plus-minus task (Jersild, 1927) Rey's Auditory Verbal Learning Test (Rey, 1964) RBANS (Randolph et al., 1998) Semantic generation task (Seabra et al., 2009; Thompson-Schill et al., 1997) Seven subtest short form based on WAIS-III Shortened version of WCST, full version of WCST (Liu et al., 2011) Similarities from WAIS-III or WASI (Hays et al., 2002) Stroop task – computerized (Penner et al., 2012) Supermarket test (Kessler et al., 1988) The Continuous Performance Test – Identical Pairs (Nuechterlein et al., 2008) The National Adult Reading Test (Nelson and O'Connell, 1978) The non-verbal intelligence task (Asevedo et al., 2014) Trail Making Test (Reitan, 1955) Tower of London (Krikorian et al., 1994) Verbal Paired Associates I and II from WMS-III Visual Working Memory (Salthouse et al., 1991) Vocabulary from WAIS-III or WASI (Hays et al., 2002) Wechsler Test for Adult Reading (Whitney et al., 2010)

Attention, working memory and mental control Visual-motor coordination, motor and mental speed Visual recognition memory Executive function Attention and processing speed Working memory General information acquired from culture, semantic memory Verbal learning Working Memory Working Memory Working Memory Immediate and delayed declarative memory Non-verbal abstract problem solving, inductive spatial reasoning Orientation, attention, memory and language Set shifting Working memory P2 – conceptual disorganization, N5 – difficulty in abstract thinking, G11 – poor attention Verbal fluency Visual exploration and detail perception Set shifting Verbal learning and memory Immediate memory, visuospatial/constructional abilities, language, attention, delayed memory and global cognition Inhibition Full Scale IQ, Verbal IQ and Performance IQ Executive function Abstract verbal reasoning Inhibition, executive functions Verbal fluency Sustained, focused attention and vigilance Premorbid intelligence Intelligence Control of attention, visual exploration, speed and mental flexibility Executive function Learning and memory Working Memory Working memory and verbal ability Premorbid Intelligence

BACS-J – Brief Assessment of Cognition (Japanese version), IQ – Intelligence Quotient, RBANS – Repeatable Battery for Assessment of the Neuropsychological Status, WAIS-III – Wechsler Adult Intelligence Scale (Wechsler, 1997b), WMS-III – Wechsler Memory Scale (Wechsler, 1997a), WASI – Wechsler Abbreviated Scale for Intelligence, WCST – the Wisconsin Card Sorting Test.

IL-1β exerts beneficial effects on hippocampal-dependent memory processing, whereas in excessive concentrations as well as during stress or aging IL-1β may impair memory processes (Goshen et al., 2008; Goshen et al., 2007; Li et al., 2008). In turn, IL-6 plays an important role in neurogenesis and blocks long-term potentiation (McAfoose and Baune, 2009). Finally, TNF-α may impact cognitive performance via the effects on glutamatergic neurotransmission, long-term depression and long-term potentiation as well as synaptic scaling (Bortolato et al., 2015a; McAfoose and Baune, 2009). Although this systematic review was focused on studies examining the relationship between peripheral blood cytokines levels and cognitive performance, a number of studies have revealed indices of central inflammatory processes in patients with schizophrenia and BD. However, due to a scarcity of studies, it remains unknown whether there is a correlation between peripheral and central cytokines levels. Indeed, we found no studies examining the association between cerebrospinal fluid (CSF) levels of cytokines and cognitive performance in both groups of patients. Additionally, in one study performed on

serum and CSF, only CSF levels of IL-6 were significantly higher in patients with schizophrenia compared to healthy controls and no significant correlation between CSF and serum levels of IL-6 was found (Sasayama et al., 2013). Another study revealed decreased serum and CSF levels of IL-1β as well as decreased levels of sIL-2R in CSF but increased sIL-2R levels in serum from schizophrenia patients compared to healthy controls (Barak et al., 1995). Therefore, investigating concordance patterns in cytokine alterations in patients with schizophrenia and BD seems to be an important future direction. Nevertheless, a recent systematic review of post mortem studies from schizophrenia patients demonstrated almost consistent increase in the expression of SERPINA3, which acts as a protease inhibitor involved in inflammatory processes and connective tissue turnover, and interferon-induced transmembrane proteins in various cortical brain regions, especially within the prefrontal cortex (Trepanier et al., 2016). Furthermore, cytokine alterations have been reported in post mortem studies of schizophrenia and BD patients. For instance, higher protein and mRNA levels of IL-1β and IL-1 and decreased mRNA levels of TGF-β have been found in frontal

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cortex of BD patients (Bezchlibnyk et al., 2001; Rao et al., 2010). Similarly, increased mRNA levels of IL-1β and TNF-α have been reported in frontal cortex from patients with schizophrenia (Rao et al., 2013). However, effects of peripheral cytokine levels on brain structure in studies reviewed in this article have been addressed only in two studies. Fillman et al. (2016) demonstrated reduced volumes of the left pars opercularis (Broca's area) in patients with elevated cytokine levels compared to patients with normal cytokine levels. Main effects of IL-1β on volume reductions were also significant. In turn, Chung et al. (2013) found a negative correlation between CRP and orbitofrontal cortex volume in euthymic BD patients. Importantly, cytokine alterations might also explain the effects of childhood traumatic events on cognitive performance in patients with schizophrenia-spectrum disorders and BD. Indeed, a history of childhood trauma in psychosis is highly prevalent and has been associated with worse performance of general cognitive abilities, memory and executive functions (Aas et al., 2014; Misiak et al., 2017). A recent metaanalysis revealed that a history of childhood trauma might be associated with subclinical inflammation in terms of elevated CRP, IL-6 and TNF-α levels (Baumeister et al., 2016). In addition, various types of childhood adversities might have differential effects on inflammatory markers. Indeed, physical and sexual abuse has been associated with increased levels of IL-6 and TNF-α, while parental absence during early development has been shown to exert effects on CRP levels (Baumeister et al., 2016). Finally, it should be noted that indicating cytokine alterations in patients with schizophrenia and BD might hold a great promise for the development of novel anti-inflammatory treatment strategies. Indeed, there are studies showing that augmentation of antipsychotic treatment with certain anti-inflammatory drugs including erythropoietin, minocycline, N-acetylcysteine or non-steroid anti-inflammatory drugs might be beneficial in terms of improving cognitive deficits in patients with schizophrenia and BD (for review see (Andrade, 2016; Kroken et al., 2014; Rosenblat et al., 2015)). Interestingly, genetic variation in the IL-1α gene has been also found to predict neurocognitive outcomes in patients with schizophrenia (McClay et al., 2011). Emerging evidence indicates that a low-grade systemic inflammatory state might play an important role in the development of cognitive impairment in patients with schizophrenia and BD. Addressing this issue in future studies seems to be important for the development of novel targets for specific anti-inflammatory therapeutic interventions. However, central immune-inflammatory markers, neuro-structural and neuro-functional parameters should be included to provide further support for this link. Moreover, a direction of causality should be more precisely addressed by testing reciprocal interrelationships between medication effects, improvement in psychopathological symptoms and cognitive performance. Therefore, future studies should further explore the association between cytokine alterations and cognitive performance by implementing comprehensive tools for the measurement of various cytokines and assessment of cognition, taking into account a number of potential confounding factors. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.schres.2017.04.015.

Contributors Writing and editing the manuscript – B.M., D.F., J.R., J.S. Online search and quality assessment – B.S., K.K., B.M.

Role of the funding source This study was performed in frame of statutory activities of Wroclaw Medical University (task ST-971).

Conflict of interest None to declare.

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Acknowledgement None.

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