Hope S, Dieset I, Agartz I, et al. Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia

Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway.
Journal of Psychiatric Research (Impact Factor: 3.96). 08/2011; 45(12):1608-16. DOI: 10.1016/j.jpsychires.2011.08.003
Source: PubMed


Elevated levels of inflammation are reported in bipolar disorders (BP), but how this relates to affective symptoms is unclear. We aimed to determine if immune markers that consistently have been reported elevated in BP were associated with depressive and manic symptoms, and if this was specific for BP.
From a catchment area, 112 BP patients were included together with 153 schizophrenia (SCZ) patients and 239 healthy controls. Depression and mania were assessed and the patients were grouped into depressed, neutral, and elevated mood. We measured the immune markers tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), interleukin 6 (IL-6), high sensitive C-reactive protein (hsCRP), osteoprotegerin (OPG) and von Willebrand factor (vWf) which have been found increased in severe mental disorders.
In BP all inflammatory markers were lowest in depressed state, with significant group differences after control for confounders with respect to TNF-R1 (p = 0.04), IL-1Ra (p = 0.02), OPG (p = 0.004) and IL-6 (p = 0.005). STNF-R1 was positively correlated with the item elevated mood (p = 0.02) whereas sad mood was negatively correlated with OPG (p = 0.0003), IL-1Ra (p = 0.001) and IL-6 (p = 0.006). Compared to controls the neutral mood group had significantly higher levels of OPG (p = 0.0003) and IL-6 (p = 0.005), and the elevated mood group had higher levels of TNF-R1 (p = 0.000005) and vWf (p = 0.002). There were no significant associations between affective states orsymptoms in SCZ.
The current associations between inflammatory markers and affective symptomatology in BP and not SCZ suggest that immune related mechanisms are associated with core psychopathology of BP.

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    • "These two results are consistent with some novel views about the physiology of BD that is likely to be considered as a multisystemic disorders (Leboyer et al., 2012) with major immune-inflammatory deregulations (Hamdani et al., 2013; Munkholm et al., 2013). Indeed , the immune system may interact with brain systems (such as the monoaminergic system) to modulate affect intensity, as reported by Hope et al. (Hope et al., 2011), who showed a correlation between levels of these inflammatory markers and all affective states in bipolar disorder. The two other SNPs suggestive for association are located on regions 11p15.1 and 11q14.1 but are not located in known genes. "
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    ABSTRACT: Background: Emotional reactivity has been proposed as a relevant intermediate phenotype of bipolar disorder (BD). Our goal was to identify genetic factors underlying emotional reactivity in a sample of bipolar patients. Methods: Affect intensity (a proxy measure of emotional reactivity) was measured in a sample of 281 euthymic patients meeting DSM-IV criteria for BD. We use a validated dimensional tool, the 40-item self-report Affect Intensity Measure scale developed by Larsen and Diener. Patients with BD were genotyped for 475. 740 SNPs (using Illumina HumanHap550 Beadchips or HumanHap610 Quad chip). Association was investigated with a general mixed regression model of the continuous trait against genotypes, including gender as covariate. Results: Four regions (1p31.3, 3q13.11, 11p15.1 and 11q14.4) with a p-value lower or equal to 5×10(-6) were identified. In these regions, the joint effect of the four variants accounted for 24.5% of the variance of AIM score. Epistasis analysis did not detect interaction between these variants. In the 11p15.1 region, the rs10766743 located in the intron of the NELL1 gene remained significant after correction for multiple testing (p=2×10(-7)). Conclusions: These findings illustrate that focusing on quantitative intermediate phenotypes can facilitate the identification of genetic susceptibility variants in BD.
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    • "1.68 0.000 0.87 0.021 0.87 0.000 0.40 0.259 0.53 0.133 0.91 0.010 0.51 0.000 0.08 0.451 1.12 0.000 2.06 0.000 0.55 0.205 0.31 0.404 0.24 0.545 0.38 0.007 0.32 0.082 0.63 0.004 0.35 0.021 1.12 0.000 0.12 0.607 Akanji et al., 2009 Carrizo et al., 2008a Carrizo et al., 2008b Carrizo et al., 2008c Dickerson et al., 2013 Hope et al., 2011 Kliushnik et al., 2008 Kuo et al., 2013 Lin et al., 2013a Lin et al., 2013b Lin et al., 2013c Suvisaari et al, 2011 "
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    ABSTRACT: The inflammatory hypothesis of schizophrenia (SZ) posits that inflammatory processes and neural–immune interactions are involved in its pathogenesis, and may underpin some of its neurobiological correlates. SZ is the psychiatric disorder causing the most severe burden of illness, not just owing to its psychiatric impairment, but also owing to its significant medical comorbidity. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation worldwide. There are some conflicting results regarding the behaviour of CRP in SZ. The aims of this study were to verify whether peripheral CRP levels are indeed increased in SZ, whether different classes of antipsychotics divergently modulate CRP levels and whether its levels are correlated with positive and negative symptomatology. With that in mind, we performed a meta-analysis of all cross-sectional studies of serum and plasma CRP levels in SZ compared to healthy subjects. In addition, we evaluated longitudinal studies on CRP levels before and after antipsychotic use. Our meta-analyses of CRP in SZ included a total of 26 cross-sectional or longitudinal studies comprising 85 000 participants. CRP levels were moderately increased in persons with SZ regardless of the use of antipsychotics and did not change between the first episode of psychosis and with progression of SZ (g = 0.66, 95% confidence interval (95% CI) 0.43 to 0.88, P o 0.001, 24 between-group comparisons, n = 82 962). The extent of the increase in peripheral CRP levels paralleled the increase in severity of positive symptoms, but was unrelated to the severity of negative symptoms. CRP levels were also aligned with an increased body mass index. Conversely, higher age correlated with a smaller difference in CRP levels between persons with SZ and controls. Furthermore, CRP levels did not increase after initiation of antipsychotic medication notwithstanding whether these were typical or atypical antipsychotics (g = 0.01, 95% CI − 0.20 to 0.22, P = 0.803, 8 within-group comparisons, n = 713). In summary, our study provides further evidence of the inflammatory hypothesis of SZ. Whether there is a causal relationship between higher CRP levels and the development of SZ and aggravation of psychotic symptoms, or whether they are solely a marker of systemic low-grade inflammation in SZ, remains to be clarified.
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    • "Furthermore, tumor necrosis factor alpha (TNF-alpha) and interleukin (IL) 6 show a significant increase during the late stages of BD, but IL-10 does not. In synthesis, pro-inflammatory cytokines, such as IL-6, IL-8, C-reactive protein (CRP) and TNF-alpha, seem to be elevated during depressive episodes [118] [119] [120]; IL-2, soluble interleukin-2 receptor (sIL-2R), IL-4, IL-6, IL-8, TNF-alpha, and soluble TNF receptor 1 (sTNFR1) seem to be elevated during manic episodes [118] [119] [120] [121] [122] [123]; and high-sensitivity Creactive protein (hs-CRP), IL-6 and sTNFR1 [122] [124] seem to be elevated during euthymia in BD patients compared to healthy controls. Taken together, these findings indicate that BD patients are likely to be in a pro-inflammatory state [120] [125], which worsens in later stages, and inflammatory cytokines may have the potential to serve as markers of illness progression in BD. "
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