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Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder
Abstract
Weight gain and increased production of leptin may be associated with immuno-modulation and insulin resistance in bipolar disorder. The links among inflammatory markers, leptin, and insulin of bipolar patients from acute mania to full remission remain unclear.
Thirty-three healthy, bipolar I patients under 45 years of age were enrolled. We measured the circulating levels of high-sensitivity C-reactive protein (hs-CRP), anti-inflammatory mediators (interleukin-1 receptor antagonist [IL-1Ra] and soluble tumor necrosis factor receptor 1 [sTNF-R1]), leptin, and insulin during acute mania and subsequent partial and full remission. The results were compared with 33 age- and gender-matched healthy subjects.
The levels of IL-1Ra and hs-CRP of bipolar patients in both acute mania and partial remission were significantly higher than their levels of control subjects. The hs-CRP level of bipolar patients was also elevated in full remission. The elevation of IL-1Ra and hs-CRP levels in acute mania was independent of each other. They were also independent of the body mass index (BMI) and levels of leptin and insulin measurements. The levels of leptin were all positively associated with insulin levels in the normal subjects and bipolar patients in three phases. However, a significant relationship between leptin and immunoparameter was only seen in full remission with sTNF-R1 (r=0.51). Furthermore, IL-1Ra was inversely correlated with sTNF-R1 (r=-0.37, p<0.05) during partly remission, and while levels of IL-1Ra tended to normalize when patients remitted, levels of hs-CRP and sTNF-R1 showed the opposite trend.
Activated inflammation was found in acute mania, as evidenced by high levels of IL-1Ra, hs-CRP, and sTNF-R1. The production of leptin may be more tightly linked to insulin than the immunomodulators. Chronic inflammation may exist in bipolar patients and is reflected by elevations of IL-1Ra and hs-CRP levels in acute mania and persistent higher hs-CRP in full remission.
... There were 1914 publication records initially identified through systematic searches (Fig. 1). Finally, 32 studies were included in systematic review and meta-analysis (Barbosa et al., 2012;Bond et al., 2017;Chang et al., 2021;Chen et al., 2021;Coello et al., 2019;Cordas et al., 2015;da Silva et al., 2017;Dolab et al., 2020;Dolapoglu et al., 2021;Elmslie et al., 2009;Fleet-Michaliszyn et al., 2008;Gergerlioglu et al., 2006;Guha et al., 2014;Huang et al., 2021;Hung et al., 2007;Juster et al., 2018;Mansur et al., 2020Mansur et al., , 2016Parlak et al., 2018;Platzer et al., 2020Platzer et al., , 2019Rasgon et al., 2010;Rosso et al., 2015;Soeiro-de-Souza et al., 2014;Su et al., 2011;Syk et al., 2019;Tsai et al., 2014Tsai et al., , 2012Tunçel et al., 2018;Vargas et al., 2014;Vianna-Sulzbach et al., 2015;Wei et al., 2020). Overview of included studies is shown in Table 1. ...
... The levels of leptin were determined by 16 studies (Barbosa et al., 2012;Chen et al., 2021;Cordas et al., 2015;Dolab et al., 2020;Gergerlioglu et al., 2006;Huang et al., 2021;Mansur et al., 2016;Parlak et al., 2018;Platzer et al., 2020;Rosso et al., 2015;Syk et al., 2019;Tsai et al., 2014Tsai et al., , 2012Tunçel et al., 2018;Vianna-Sulzbach et al., 2015;Wei et al., 2020). Forrest plot for the analysis of leptin levels is shown in Supplementary Fig. 1. ...
... The levels of insulin were measured by 17 studies (Chang et al., 2021;Chen et al., 2021;Coello et al., 2019;da Silva et al., 2017;Elmslie et al., 2009;Fleet-Michaliszyn et al., 2008;Guha et al., 2014;Huang et al., 2021;Hung et al., 2007;Juster et al., 2018;Mansur et al., 2016;Rasgon et al., 2010;Rosso et al., 2015;Tsai et al., 2014Tsai et al., , 2012Tunçel et al., 2018;Vargas et al., 2014). Forrest plot for the analysis of insulin levels is shown in Supplementary Figure 3. ...
Impaired hormonal regulation of appetite may contribute to higher cardiovascular risk in bipolar disorder (BD). We performed a systematic review and meta-analysis of studies investigating peripheral blood levels of appetite-regulating hormones in BD and controls. A total of 32 studies were included. Leptin and insulin levels were significantly elevated in patients with BD during euthymia, but not in other mood states. Greater differences in the number of male participants between patients with BD and healthy controls were associated with higher effect size estimates for the levels of insulin. There were significant positive correlations of effect size estimates for the levels of adiponectin with the percentage of individuals with type I BD and duration of BD. Our findings point to the mechanisms underlying high rates of cardiometabolic comorbidities in BD. Moreover, they suggest that investigating hormonal regulation of appetite might help to understand differences in the neurobiology of BD types.
... Quatro artigos incluíram pacientes nas diferentes fases do TB: mania, depressão e eutimia [17][18][19][20] , sendo que em um desses a fase de mania está retratada como "humor elevado" 19 e em outro, a fase de eutimia é citada como "remissão sustentada" 18 . Em nove trabalhos foram incluídos pacientes na fase de eutimia [21][22][23][24][25][26][27][28][29] , em oito havia pacientes na fase de mania [30][31][32][33][34][35][36][37] ; em um havia pacientes somente na fase de depressão 38 ; um estudo incluiupacientes tanto na fase de eutimia quanto na fase de mania 39 e dois trabalhos incluíram pacientes tanto na fase de mania quanto aqueles na fase de depressão 40,41 . ...
... Após 6 semanas de tratamento, houve diminuição dos níveis de IL-6 e permanência dos valores de TNF-α e IL-4. Os demais trabalhos incluíram pacientes que estavam em tratamento durante toda a realização do estudo e encontraram concentrações elevadas de IL-8 40 , TNF-α 40 , IL-6 17,40 , IL-2 17 , IL-4 17 , IL-10 18 , do receptor solúvel tipo 1 do Fator de Necrose Tumoral (sTNFR1) 19,34,39 e do antagonista do receptor de IL-1 (IL-1Ra) 34 no soro/plasma de pacientes em fase de mania. Além disso, quatro estudos avaliaram níveis de citocinas antes e após remissão dos sintomas. ...
... Após 6 semanas de tratamento, houve diminuição dos níveis de IL-6 e permanência dos valores de TNF-α e IL-4. Os demais trabalhos incluíram pacientes que estavam em tratamento durante toda a realização do estudo e encontraram concentrações elevadas de IL-8 40 , TNF-α 40 , IL-6 17,40 , IL-2 17 , IL-4 17 , IL-10 18 , do receptor solúvel tipo 1 do Fator de Necrose Tumoral (sTNFR1) 19,34,39 e do antagonista do receptor de IL-1 (IL-1Ra) 34 no soro/plasma de pacientes em fase de mania. Além disso, quatro estudos avaliaram níveis de citocinas antes e após remissão dos sintomas. ...
Introdução. O processo inflamatório leva à liberação de diversos mediadores lipídicos e proteicos dentre os quais estão as citocinas. Estudos recentes têm relacionado a ação das citocinas com a fisiopatologia do Transtorno Bipolar (TB). Objetivo. Revisar a literatura acerca de estudos que realizaram dosagens dos níveis sistêmicos (séricos ou plasmáticos) de citocinas no TB. Método. Foram pesquisados artigosde 01/1980 a01/2013,nos idiomas inglês e português, nas bases de dados MedLine e Scielo, com as palavras-chave Inflammation, Cytokinese Bipolar Disorder. Foram excluídos artigos que avaliaram produção in vitro de citocinas, que não estratificaram os pacientes de acordo com a fase do transtorno bipolar (mania, depressão ou eutimia). Resultados. Foram identificados 25trabalhos que avaliaram os níveis séricos ou plasmáticos de citocinas em pacientes com TB. As citocinas avaliadas foram: IL-8, INF-γ, IL-1β, TGF-β, IL-12, IL-6, IL-4, IL-10, IL-2, IL-17, IL-5, TNF-α e seus receptores solúveis sTNFR1 e sTNFR2, além de sIL-6R e IL-1Ra. Embora os estudos apresentem resultados conflitantes quanto aos níveis de citocinas pró e anti-inflamatóriasno soro ou plasma de pacientes com TB, existeuma tendência para um perfil pró-inflamatório nos pacientes em fase de depressão e mania. Conclusão. O presente estudo sugere queos parâmetros imunológicos, representados por alterações nos níveis plasmáticos e/ou séricos de citocinas podem estar relacionados com a fisiopatologia do TB.
... Five large studies have provided evidence that increased BMI is significantly associated with elevated CRP levels (Dieset et al., 2012;Dickerson et al., 2013;Bai et al., 2015; Benjamin I. Lee et al., 2013). However, one study only showed a trend association, nonetheless, with a similarly positive relationship (De Berardis et al., 2008) A C C E P T E D M A N U S C R I P T (Tsai et al., 2012(Tsai et al., , 2014. In a cohort of 361 BD and SCZ patients, Dieset et al. (2012) showed that hs-CRP levels were positively correlated with BMI (r = 0.27, p = 0.01) which was mediated by treatment with SGAs (β = 0.03, p = 0.012). ...
... Lee et al. (2013) in 117 patients showed that in drug-naïve BD euthymic (N=30) BD patients, a higher CRP levels associated with higher BMI but the difference did not reach statistical significance (De Berardis et al., 2008). Furthermore, in two studies of the same cohort, elevated hsCRP levels were independent of BMI across BD phases (acute mania, partial remission and full remission; Tsai et al., 2012Tsai et al., , 2014. A more recent study including 91 BD patients and 75 controls showed that plasma CRP levels were not significantly different between patients and controls (Chang et al., 2017). ...
... In the articles reviewed, there appears to be some evidence for the association of CRP with plasma glucose with one large study finding a positive association (Dieset et al., 2012) and three smaller (?) finding no association (Tsai et al., 2014(Tsai et al., , 2012; Vuksan-Cusa et al., 2013). In a cohort of 361 BD and SCZ patients, Dieset et al. (2012) showed a positive association between CRP and fasting glucose (r = 0.16, p < 0.001) which was further mediated by SGA treatment (β = 0.21, p = 0.003). ...
Objectives:
New research is revealing a strong association between inflammatory markers with bipolar disorder (BD), potentially due to the high prevalence of cardiovascular disease and cardiovascular risk factors in BD. We aimed to synthesize the literature examining the association between the clinically most relevant inflammatory marker, C-reactive protein (CRP) and cardiovascular disease and cardiovascular risk factors in patients with BD.
Methods:
MEDLINE, Embase and PsychInfo were systematically searched for all relevant English language articles published prior to April 2017. Articles were included if they examined the association between CRP and cardiovascular risk factors/disease in BD.
Results:
Fifteen relevant articles were retrieved. Studies were mostly cross-sectional and heterogeneous in the cardiovascular risk factors investigated. Overall, elevated CRP was associated with increased risk of metabolic syndrome, elevated body mass index, higher waist circumference, and obesity. CRP was inconsistently associated with elevated fasting glucose, insulin levels, serum triglycerides, total cholesterol levels, and low high density lipoprotein (HDL) levels. Atypical antipsychotic use may mediate some of these effects. No study examined CRP's association with actual cardiovascular disease (e.g. coronary artery disease) in BD.
Conclusions:
In BD, CRP is associated with increases in several cardiovascular risk factors, suggesting that systemic inflammation could be a shared driving force for both outcomes of BD and cardiovascular risk. Further longitudinal research is needed in this area to verify causality, including an examination of actual cardiovascular disease. Non-pharmacological and pharmacological treatments with anti-inflammatory effects should also be investigated, particularly in patients with increased CRP, for their potential to reduce cardiovascular risk in BD.
... Several clinical studies [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] have investigated the association between CRP concentration in the blood and diff erent mood states in bipolar disorder. Although most studies found an increase in CRP concentration during manic states, the data regarding depressive and euthymic states are less certain, with both positive and null fi ndings. ...
... 5 Regarding changes in CRP concentrations after amelioration of symptoms of index manic or depressive episodes, the data are varied, with studies showing increase, decrease, or no changes in CPR concentrations. 20,[32][33][34][37][38][39][40][41][42] A meta-analysis of 11 crosssectional studies of CRP concentrations in bipolar disorder 43 found that CRP concentrations increased in mania and euthymia but not in depression. However, owing to the small number of studies included, it did not analyse eff ects of any moderators such as severity of symptoms or the eff ects of treatment. ...
... 13,17,51 23 studies fulfi lled our inclusion criteria for the between-group meta-analyses, providing data on 83 669 participants, of whom 1737 were individuals with bipolar disorder and 81 932 were healthy controls. 13,17,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]51 Of those, 14 studies provided data for mania (500 subjects in mania and 1169 controls), [19][20][21][22][23][24][25][26][27]33,34,36,38,51 11 for depression (408 in depression and 955 controls), 19,21,22,24,26,28,30,32,37,38,51 and 17 for euthymia (829 in euthymia and 79 808 controls). 13,17,[19][20][21][22][23][24]26,29,[31][32][33][34][35]37,51 Ten studies were included in our within-group meta-analyses, 20,32-34,37-42 providing data on 424 subjects (141 for a manic index episode and 283 for an index depressive episode). ...
Background
Inflammatory processes and neural–immune interactions have been implicated in the pathogenesis of psychiatric conditions, but studies in bipolar disorder are inconclusive so far. We aimed to investigate whether peripheral concentrations of C-reactive protein (CRP), an acute-phase response protein of inflammatory activity, are increased in bipolar disorder across the mood spectrum.
Methods
In this systematic review and meta-analysis, we searched MEDLINE, the Cochrane Library, Scopus, and Web of Knowledge from database inception to Aug 14, 2016, for studies that measured serum and plasma CRP concentrations in adult patients with bipolar disorder (as defined by DSM-IV-TR) and healthy controls. We extracted data from published reports. We did three between-group meta-analyses comparing CRP concentrations in patients in mania, depression, or euthymia, with those in healthy controls (cross-sectional studies), and two within-group meta-analyses comparing changes in CRP concentrations before and after treatment of an index manic or depressive episode (longitudinal studies). We used Hedges' adjusted g to calculate effect sizes and pooled results using random-effect models. We also did meta-regression analyses by mood state to investigate possible moderators of CRP concentrations.
Findings
We identified 27 studies representing 2161 patients with bipolar disorder and 81 932 healthy controls. Compared with healthy individuals, CRP concentrations were moderately increased in people with bipolar disorder during depression (g 0·67, 95% CI 0·23 to 1·11; p=0·003) and euthymia (0·65, 0·40 to 0·90; p<0·0001) and more substantially increased during mania (0·87, 0·58 to 1·15; p<0·0001). The extent of the increases in CRP concentrations in mania and depression was not related to symptom severity (p=0·256 for mania and p=0·626 for depression). CRP concentrations were moderately decreased after resolution of an index manic episode (−0·36, −0·66 to −0·05; p=0·022) and slightly decreased after resolution of an index depressive episode (−0·18, −0·30 to −0·07; p=0·002).
Interpretation
CRP concentrations are increased in bipolar disorder regardless of mood state, but are higher during mania than in depression and euthymia, suggesting an increased inflammatory burden in mania.
... In mania and depression, some studies show that leptin levels are decreased, some are increased, and some show no difference when compared to healthy controls. In euthymia, the same pattern of equivocal findings is evident [11][12][13][14][15][16][17][18][19][20][21]. ...
... Of those, 27 were excluded on the basis of title and abstract, leaving 26 studies for further evaluation. Eleven studies fulfilled our inclusion criteria for the betweengroup meta-analyses, providing data on 1118 participants, of whom 525 were subjects with BD and 593 were healthy controls [11][12][13][14][15][16][17][18][19][20][21]. Of those, three studies provided data for mania (61 subjects in mania and 74 controls) [11,17,21], five for depression (166 in depression and 231 controls) [14,16,[18][19][20], and seven for euthymia (298 in euthymia and 288 controls) [11][12][13]15,16,20,21]. ...
... Eleven studies fulfilled our inclusion criteria for the betweengroup meta-analyses, providing data on 1118 participants, of whom 525 were subjects with BD and 593 were healthy controls [11][12][13][14][15][16][17][18][19][20][21]. Of those, three studies provided data for mania (61 subjects in mania and 74 controls) [11,17,21], five for depression (166 in depression and 231 controls) [14,16,[18][19][20], and seven for euthymia (298 in euthymia and 288 controls) [11][12][13]15,16,20,21]. Some studies provided more than one pairwise comparison (Fig. 1). ...
Background: Bipolar disorder (BD) is a psychiatric disorder associated with increased rates of obesity and inflammation. Leptin is an adipokine that is mainly produced by the white adipose tissue in response to insulin. It stimulates the immune system, increasing the production of pro-inflammatory cytokines. There is currently uncertainty regarding possible alterations in peripheral leptin levels across the mood states in BD.
Methods: This study comprises a between-group meta-analysis comparing serum and plasma leptin levels in persons with BD in mania, depression or euthymia and healthy controls. We conducted a systematic search for all possibly eligible-English and non-English peer-reviewed articles. We calculated the effect size (ES) utilizing Hedges's adjusted g using random effects.
Results: Eleven studies were included in the meta-analyses, providing data on 1118 participants. Serum and plasma leptin levels were not altered in subjects with BD when compared to healthy controls in mania (g = −0.99, 95% CI −2.43 to 0.43, p=0.171), in depression (g = 0.17, 95% CI −0.45 to 0.79, p=0.584), or in euthymia (g = 0.03, 95% CI −0.39 to 0.46, p=0.882). However, we did observe a stronger association between leptin levels and both age and BMI in patients with BD in euthymia compared to healthy controls, such that the greater the age of individuals, the greater the difference in leptin levels between BD and controls, and the higher the BMI, the greater the difference in leptin levels between BD and controls.
Conclusions: Our meta-analysis provides evidence that leptin levels are not altered in BD across the mood spectrum compared to healthy controls. The disproportionate increase of leptin levels with increase in BMI in BD speaks in favour of a potential inflammatory role of white adipose tissue in BD and a disproportionate increase of leptin levels with increase in age.
... These findings are similar to those reported in previous studies (11)(12)(13)(14). Indeed, Barbosa et al observed higher sTNF-R1 plasma levels in euthymic and manic BD patients than controls. ...
... But they did not investigate soluble TNF receptors and did not evaluate the euthymic phase (18). There are less study that reported similar levels of sTNF-R1 in depressed BD patients and healthy subjects (13). Sivek et al. compared sIL-1RA, sIL-2R, sIL-6R, sTNF-R1 and sTNF-R1 levels in bipolar disorder with healthy controls. ...
Introduction:
Current evidence suggests that pro-inflammatory cytokines, particularly tumor necrosis factor alpha (TNF-α) may play an important role in the pathophysiology of bipolar disorder (BD). Our study aims to compare BD patients and controls in terms of serum TNF-α, soluble tumor necrosis factor receptor 1 and soluble tumor necrosis factor receptor 2 (sTNF-R1, sTNF-R2) levels in different phases of BD.
Methods:
Eighty-three patients with BD type 1 (27 manic, 22 depressive and 34 euthymic) and twenty-nine healthy controls were included in the study. Serum levels of TNF-α, sTNF-R1, sTNF-R2 levels were evaluated with ELISA kit.
Results:
Levels of sTNF-R1 were showed a statistically significant difference between groups. Levels of sTNF-R1 were higher in depression or mania patients than euthymia patients and control subjects. A statistically significant difference in the serum level of sTNF-R1 between patients in acute episode (mania and depression) group and stabile (patients in euthymic episode and controls) group was found in logistic regression analysis. The probability of having acute episode increased threefold for each unit increase in serum level of sTNF-R1. There was no statistically significant difference between the mean serum values of TNF-α and sTNF-R2 between the groups.
Conclusions:
sTNF-R1 production was different between acute episode patients and controls or stable BD patients. The result of this study confirms that TNF-R1 may be a state marker representing disease activity for BD.
... In BD patients increased levels of pro-inflammatory cytokines, such as tumor necrosis factor (TNF), IL-1beta, IL-6 and IL-33 were observed [16][17][18][19] . Furthermore, BD patients have significantly elevated serum concentration of anti-inflammatory mediators, such as sTNFR1 18,20,21 , sIL-6R 21,22 , IL-1Ra 23,24 , and IL-10 16,25 as compared with healthy controls. Likewise, in bipolar disorder patients level of IL-4 (known as immunoregulatory cytokine) is raised 26 . ...
... In bipolar depressed and manic patients serum concentration of CRP is elevated. Also, Significantly higher serum levels of CRP in bipolar disorder in partial remission were noted 24,[27][28][29][30] . It should be emphasized that determination of immune and inflammatory parameters in mental disorder need to be considered in the context of metabolic parameters and body composition, since these parameters may significantly affect the immune system functions. ...
Background Antimicrobial peptides are components of the innate immune system. Cathelicidin LL-37 plays an important role in antimicrobial defense, exerts proinflammatory effect and strongly affects the immune system functioning. Our recent study revealed that serum concentration of LL-37 is increased in patients with bipolar disorder. Objectives The aim of this study is to re-evaluate serum LL-37 levels in patients with euthymic bipolar disorder and in healthy controls, matched for anthropometric and body composition parameters. Methods 36 adult patients with euthymic bipolar disorder and 68 non-depressed adults were included into the study. Concentration of LL-37 in serum was assessed using ELISA method. Detailed anthropometric measurements, body composition and biochemical analyses were performed. Results There was a statistically significant difference (p = 0.01) in serum LL-37 level between patients with bipolar disorder (4.97 ± 7.98 ng/mL) and control subjects (1.78 ± 2.69 ng/mL). Discussion Results of this study indicate that LL-37 serum level is increased in euthymic bipolar disorder patients. We found that this increase could not be attributed to analyzed anthropometric or body composition parameters.
... Of the case-control studies, 15 followed up participants before and after treatment. 30,46,52,[54][55][56]59,61,71,[74][75][76][77]79 For the purpose of the meta-analyses the values for biomarkers after treatment were only included where the study had explicitly stated participants were in remission following treatment and had defined the mood phase objectively, and these were analysed as separate case-control studies. 52,60,[75][76][77]79 ...
... 30,46,52,[54][55][56]59,61,71,[74][75][76][77]79 For the purpose of the meta-analyses the values for biomarkers after treatment were only included where the study had explicitly stated participants were in remission following treatment and had defined the mood phase objectively, and these were analysed as separate case-control studies. 52,60,[75][76][77]79 ...
Background
A reliable biomarker signature for bipolar disorder sensitive to illness phase would be of considerable clinical benefit. Among circulating blood-derived markers there has been a significant amount of research into inflammatory markers, neurotrophins and oxidative stress markers.
Aims
To synthesise and interpret existing evidence of inflammatory markers, neurotrophins and oxidative stress markers in bipolar disorder focusing on the mood phase of illness.
Method
Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a systematic review was conducted for studies investigating peripheral biomarkers in bipolar disorder compared with healthy controls. We searched Medline, Embase, PsycINFO, SciELO and Web of Science, and separated studies by bipolar mood phase (mania, depression and euthymia). Extracted data on each biomarker in separate mood phases were synthesised using random-effects model meta-analyses.
Results
In total, 53 studies were included, comprising 2467 cases and 2360 controls. Fourteen biomarkers were identified from meta-analyses of three or more studies. No biomarker differentiated mood phase in bipolar disorder individually. Biomarker meta-analyses suggest a combination of high-sensitivity C-reactive protein/interleukin-6, brain derived neurotrophic factor/tumour necrosis factor (TNF)-α and soluble TNF-α receptor 1 can differentiate specific mood phase in bipolar disorder. Several other biomarkers of interest were identified.
Conclusions
Combining biomarker results could differentiate individuals with bipolar disorder from healthy controls and indicate a specific mood-phase signature. Future research should seek to test these combinations of biomarkers in longitudinal studies.
Declaration of interest
None.
... (Jiang et al, 2014) This table was adapted from Iwata et al. (2013) and updated to include recent clinical findings. (Black and Miller, 2015;Fornaro et al, 2013;Hernandez et al, 2008;Huang and Lee, 2007;Leo et al, 2006;Liu et al, 2004;Maes et al, 1993;Owen et al, 2001;Simon et al, 2008) IL-1RA ↑ ↑ or ↓ (Liu et al, 2004;Maes et al, 1997;Tsai et al, 2012) IL-2 ↑ or -- (Fornaro et al, 2013;Hernandez et al, 2008;Liu et al, 2004;Sutcigil et al, 2007) IL-4 ↓ - (Liu et al, 2004;Sutcigil et al, 2007) IL-6 ↑ ↑ or ↓ (Basterzi et al, 2005;Berk et al, 1997;Hodes et al, 2014;Kapczinski et al, 2011;Maes et al, 1997;Maes et al, 1995;Munkholm et al, 2015;Sluzewska et al, 1996) IL-8 -n.d. (Mikova et al, 2001) IL-10 ↑ - (Fornaro et al, 2013;Hernandez et al, 2008;Huang et al, 2007;Kapczinski et al, 2011;Liu et al, 2004) IL-12 ↑ n.d. ...
... (Sutcigil et al, 2007) TNF-α ↑ ↑ or ↓ (Eller et al, 2008;Fornaro et al, 2013;Huang et al, 2007;Kapczinski et al, 2011;Su et al, 2011;Sutcigil et al, 2007) s-TNF-R1 n.d. ↑ (Tsai et al, 2012) IFN-γ ↑ ↓ (Fornaro et al, 2013;Hernandez et al, 2008;Liu et al, 2004) © 2016 Macmillan Publishers Limited. All rights reserved. ...
Diagnostic criteria for mood disorders including major depressive disorder (MDD) largely ignore biological factors in favor of behavioral symptoms. Compounding this paucity of psychiatric biomarkers is a need for therapeutics to adequately treat the 30–50% of MDD patients who are unresponsive to traditional antidepressant medications. Interestingly, MDD is highly prevalent in patients suffering from chronic inflammatory conditions, and MDD patients exhibit higher levels of circulating pro-inflammatory cytokines. Together, these clinical findings suggest a role for the immune system in vulnerability to stress-related psychiatric illness. A growing body of literature also implicates the immune system in stress resilience and coping. In this review, we discuss the mechanisms by which peripheral and central immune cells act on the brain to affect stress-related neurobiological and neuroendocrine responses. We specifically focus on the roles of pro-inflammatory cytokine signaling, peripheral monocyte infiltration, microglial activation and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in stress vulnerability. We also highlight recent evidence suggesting that adaptive immune responses and treatment with immune modulators (exogenous glucocorticoids, humanized antibodies against cytokines) may decrease depressive symptoms and thus represent an attractive alternative to current antidepressant treatments.
... Moreover, phasic differences in inflammatory markers may exist in bipolar disorder (Brown et al., 2014;Rowland et al., 2018). Research findings indicate that inflammatory parameters increase or decrease in bipolar mania, and changes in these parameters may be related to the severity of manic symptoms (de Sousa et al., 2014;Tsai and Huang, 2015;Tsai et al., 2012). Most studies on oxidative stress in acute mania are crosssectional, and researchers do not have sufficient information about the changes in oxidative stress markers at the beginning and end of the manic episode. ...
Objectives:
There is much recent evidence that inflammation contributes to the pathophysiology of acute mania in bipolar disorder (BD). However, no study was evaluated in which the change in thiol-disulphide homeostasis, ischemia-modified albumin (IMA), complete blood count-derived inflammatory markers (CBC-IMs) and C-reactive protein (CRP) levels in bipolar patients was followed-up from acute mania to early remission.
Methods:
Seventy-seven bipolar patients in acute mania and ninety-one HC were enrolled. We measured levels of thiol-disulphide parameters, IMA, and CBC-IMs such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), red-cell-distribution-width (RDW)-to-platelet ratio (RPR), systemic immune-inflammatory index (SII), and systemic inflammatory response index (SIRI), CRP and platelet-to-albumin ratio (PAR), after adjusting for age, gender, body-mass index (BMI) and smoking status, during acute mania to subsequent early remission. The results were compared with HC.
Results:
The levels or ratios of all thiol-disulphide parameters except for disulphide, IMA and CRP of bipolar patients in both acute mania and early remission were significantly different from HC, after adjusting for confounders. The NLR, SII, CRP and PAR values of bipolar patients were significantly higher in only acute mania compared to HC. Significant changes in thiol-disulphide parameters and IMA levels were not found in early remission after acute mania.
Limitations:
Short follow-up period and lack of drug-naive patients.
Conclusions:
Our results suggest that thiol-disulphide parameters, IMA level and SIRI value might be a trait biomarkers of inflammation in BD. In addition, NLR, SII and PAR values and CRP level might be a state biomarker of inflammation in bipolar patients in a manic phase.
... Differences in inflammatory cytokines across mood episodes have been observed [56][57][58]. In our study, we found that CRP were higher in manic phase than depressive phase. ...
Abstract Background Bipolar disorder (BD) is characterized by intensive mood fluctuations. While hormones imbalance plays important role in the mood swings, it is unknown whether peripheral hormones profiles could differentiate the manic and depressive mood episodes in BD. In this study, we investigated the changes of various hormones and inflammatory markers across distinct mood episodes of BD in a large clinical study to provide mood episode-specific peripheral biomarkers for BD. Methods A total of 8332 BD patients (n = 2679 depressive episode; n = 5653 manic episode) were included. All patients were in acute state of mood episodes and need hospitalization. A panel of blood tests were performed for levels of sex hormones (serum levels of testosterone, estradiol, and progesterone), stress hormones (adrenocorticotropic hormone and cortisol), and an inflammation marker (C-reactive protein, CRP). A receiver operating characteristic (ROC) curve was used to analyze the discriminatory potential of the biomarkers for mood episodes. Results In overall comparison between mood episodes, the BD patients expressed higher levels of testosterone, estradiol, progesterone, and CRP (P
... We reported baseline elevations of CRP in our TRBDD patients compared to Healthy Control (HC) subjects (Edberg et al., 2018), which were consistent with the literature (Dickerson et al., 2013;Tsai et al., 2012). Therefore, CRP may prove to be a useful biomarker for TRBDD, although possible confounding variables must be addressed, including BMI and other factors which are known to influence CRP. ...
Background:
Affective illness has been associated with a proinflammatory state, and it is generally accepted that the immune system plays a key role in the pathophysiology of mood disorders. Since inflammatory biomarkers are elevated in bipolar disorder, anti-inflammatory combination therapies may enhance response and reverse treatment resistance.
Purpose:
In the present study we investigated the possible impact of single nucleotide polymorphisms (SNPs) within the CRP gene on CRP blood levels, treatment response and level-of-stress perception in our cohort of treatment-resistant bipolar-depressed patients receiving escitalopram and celecoxib, or escitalopram and placebo, as previously reported (Halaris et al., 2020).
Methods:
Study design, clinical findings, and CRP blood levels have been reported previously (Halaris et al., 2020; Edberg et al., 2018). In this follow-up study we extracted DNA from blood cells collected at baseline. Genome-wide genotyping was performed for all subjects using the Infinium Multi-Ethnic Global-8 v1.0 Kit. Based on reports in the literature indicating possible associations with psychiatric conditions, ten previously reported CRP gene polymorphisms were evaluated in a preliminary analysis. We focused on rs3093059 and rs3093077 were in complete LD. Carriers were defined as those possessing at least one C allele for rs3093059, or at least one G allele for rs3093077. Additionally, we determined blood levels of the medications administered.
Results:
Non-carriers of rs3093059 and rs3093077 had significantly lower baseline CRP blood levels than carriers (p = 0.03). Increased rates of HAM-D17 response (p = 0.21) and remission (p = 0.13) and lower PSS-14 scores (p = 0.13) were observed in non-carriers among subjects receiving celecoxib but they did not reach statistical significance. When examining all subjects, nominally significant associations between carrier-status and remission (p = 0.04) and PSS-14 scores (p = 0.04) were observed after correcting for treatment arm. Non-carriers receiving celecoxib had the highest rates of response and remission, and the lowest stress scores.
Conclusions:
Carriers of the CRP SNPs may have higher baseline CRP levels, although non-carriers appear to benefit more from celecoxib co-therapy. Determination of the carrier status in conjunction with pretreatment blood CRP level measurement may contribute to personalized psychiatric practice, but replication of the present findings is needed.
... 30 Euthymia is generally associated with normal cytokine levels, except for sTNFR1, which remains elevated during partial or complete remission. 8,31,32 A systematic review of cytokine profiles in patients with bipolar disorder suggested that several cytokines (e.g., sIL-2R, IL-6) are "state-related" markers in medication-free bipolar disorder. 13 On this cytokine background, a pro-inflammatory response (marked by an increase of, for example, TNF-α and CRP levels) might distinguish, on serum, a manic episode from euthymia. ...
A growing number of studies support a bidirectional relationship between inflammation and bipolar disorders. Tumor Necrosis Factor-α (TNF-α) inhibitors have recently attracted interest as potential therapeutic compounds for treating depressive symptoms, but the risk for triggering mood switches in patients with or without bipolar disorders remains controversial. Thus, we conducted a systematic review to study the anti-TNF-α medication-induced manic or hypomanic episodes.
PubMed, Scopus, Medline, and Embase databases were screened for a comprehensive literature search from inception until November 2020, using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
Out of the initial 75 references, the screening resulted in the inclusion of 4 case reports (each describing one patient) and a cohort study (in which 40 patients out of 7600 – 0.53% – experienced elated mood episodes after infliximab administration). Of these 44 patients, 97.7% experienced a manic episode and 2.3% hypomania. 93.2% of patients had no history of psychiatric disorder or psychotropic treatment. Only 6.8% had a history of psychiatric disorders with the affective spectrum (4.6% dysthymia and 2.3% bipolar disorder). The time of onset of manic or hypomanic symptoms varied across TNF-α inhibitors with an early onset for Infliximab and a later onset for Adalimumab and Etanercept.
These findings suggest that medications targeting the TNF-α pathway may trigger a manic episode in patients with or without affective disorders. However, prospective studies are needed to evaluate the relative risk of such side effects and identify the population susceptible to secondary mania.
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... Another study manifested that in the acute phase of mania, we may face active inflammation and elevated levels of IL-1RA, sTNF-R1, and hs-CRP. Also, chronic inflammation could be seen in both the acute phase by the increased levels of hs-CRP and IL-1RA and the full remission period of mania by the sustained higher levels of hs-CRP (16). Furthermore, in the depressive episode of BP, persistent inflammation and increased levels of IL-1RA, hs-CRP, sIL-2R, and sTNF-R1 could be seen initiating in the acute phase and continuing to full remission (17). ...
Background: Bipolar I disorder (BP-I) is one of the significant disabling psychiatric disorders resulting in severe deficits in the social and personal function of suffering patients. Among its etiologies, immunologic and genetic disturbances are two important areas of interest. Objectives: This study aimed to assess the potential role of interleukin-1β (IL-1β)-511 polymorphism in BP-I pathogenesis based on a previous pilot study. Methods: After diagnostic interviews held by two psychiatrists using structured clinical interview for DSM disorder (SCID), 102 bipolar-diagnosed hospitalized patients in Ibn-e-Sina Hospital, Mashhad, Iran, were selected and compared with 102 healthy individuals of the control group. The DNA was extracted from the blood samples of each group. Genetic locus -511 of IL-1β was defined by its specific primers. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were also carried out. The two groups’ results were compared by SPSS-20 using the chi-square test. Results: There were no significant differences in the genotypic frequency of IL-1β locus -511 (P = 1) and C/T allelic frequency (P = 0.42) between bipolar and control groups. There was also no significant difference in the allelic frequency between psychotic and non-psychotic subgroups (P = 0.218) and suicidal and non-suicidal subgroups of bipolar patients (P = 0.829). The genotypic distribution of -511 IL-1β polymorphisms in the control group was in the Hardy-Weinberg equilibrium. Conclusions: In contrast with a previous pilot study, this study found no relationship between BP-I and genotypic and C/T allelic frequencies of -511 IL-1β polymorphism. There were also no associations between the allelic frequency and two subgroups of psychotic/non-psychotic and suicidal/non-suicidal of bipolar patients.
... Notably, peripheral IL-1β levels in bipolar patients correlate positively with both suicide risk and leptin (a marker of insulin resistance) [80,81]. This evidence strongly implicates the NLRP3 inflammasome as a nexus between oxidative damage, immune function, and cardiometabolic disease. ...
Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with a high individual and societal burden. While not all patients display overt markers of elevated inflammation, significant evidence suggests that aberrant immune signaling contributes to all stages of the disease, and likely explains the elevated rates of comorbid inflammatory illnesses seen in this population. While individual systems have been intensely studied and targeted, a relative paucity of attention has been given to the interconnecting role of inflammatory signals therein. This review presents an updated overview of some of the most prominent pathophysiologic mechanisms in bipolar disorder, from mitochondrial, endoplasmic reticular, and calcium homeostasis, to purinergic, kynurenic, and hormonal/neurotransmitter signaling, showing inflammation to act as a powerful nexus between these systems. Several areas with a high degree of mechanistic convergence within this paradigm are highlighted to present promising future targets for therapeutic development and screening.
... In general, inflammation is an important factor in affective pathogenesis [72][73][74][75][76] . Complementing clinical data, animal inflammation-related models of affective disorders are widely used to recapitulate affective pathogenesis 24 . ...
Stress-related neuropsychiatric disorders are widespread, debilitating and often treatment-resistant illnesses that represent an urgent unmet biomedical problem. Animal models of these disorders are widely used to study stress pathogenesis. A more recent and historically less utilized model organism, the zebrafish (Danio rerio), is a valuable tool in stress neuroscience research. Utilizing the 5-week chronic unpredictable stress (CUS) model, here we examined brain transcriptomic profiles and complex dynamic behavioral stress responses, as well as neurochemical alterations in adult zebrafish and their correction by chronic antidepressant, fluoxetine, treatment. Overall, CUS induced complex neurochemical and behavioral alterations in zebrafish, including stable anxiety-like behaviors and serotonin metabolism deficits. Chronic fluoxetine (0.1 mg/L for 11 days) rescued most of the observed behavioral and neurochemical responses. Finally, whole-genome brain transcriptomic analyses revealed altered expression of various CNS genes (partially rescued by chronic fluoxetine), including inflammation-, ubiquitin- and arrestin-related genes. Collectively, this supports zebrafish as a valuable translational tool to study stress-related pathogenesis, whose anxiety and serotonergic deficits parallel rodent and clinical studies, and genomic analyses implicate neuroinflammation, structural neuronal remodeling and arrestin/ubiquitin pathways in both stress pathogenesis and its potential therapy.
... This knowledge is mainly yielded from animal studies, epidemiological studies and other populations without a psychiatric comorbidity [23]. However, in a study from an acute psychiatric population elevation of inflammatory markers, independently of BMI, has been reported [24]. ...
Background:
Different psychiatric diagnostic groups have been reported to have cytokine levels deviating from healthy controls. In acute clinical settings however, the specific challenging symptoms and signs are more important than a diagnostic group. Thus, exploration of cytokines and immune activity and their role in specific symptoms is important. Reports in this field so far are sparse.
Objective:
In the present study, we aimed to examine the association between immune activity measured as levels of cytokines and agitation (independent of diagnostic group) in patients admitted to an acute psychiatric inpatient department.
Methods:
A total of 316 patients admitted to an acute psychiatric inpatient department were included. Thirty-nine patients with psychosis were subject to subgroup analyses. Agitation was assessed by the Positive and Negative Syndrome Scale, Excitement Component (PANSS-EC). Based on PANNS-EC patients were stratified into two groups: 67 agitated patients and 249 non-agitated patients. Serum concentrations of the following immune markers were measured: interleukin (IL) -1β, IL-4, IL-6, IL-10, tumor necrosis factor (TNF) -α, interferon (IFN) -γ and transforming growth factor (TGF) -β.
Results:
Serum levels of TNF-α were significantly higher in patients with agitation compared to those without, both when all patients were included in the analyses (p = 0.004) and in the psychosis group (p = 0.027). After correcting for multiple testing, only the findings in the total population remained significant.
Conclusions:
Our findings suggest an association between TNF-α and agitation in an acute psychiatric population. A similar trend was reproduced to the psychosis subgroup. This suggests that agitation might be an independent entity associated with cytokines across different diagnostic groups.
... Nutritional factors, as well as microbiome diversity affect the human body on gene expression and epigenetic levels (3). Taken together, multiple disease mechanisms like neurotransmitter imbalances, disturbed circadian rhythms, changes in neurodevelopment and neuroplasticity, endoplasmic reticulum (ER) stress and oxidative stress, chronic inflammation, and immunological reactions are propagating factors in BD (4)(5)(6)(7)(8)(9)(10)(11). Cellular stressors especially, which are commonly caused by obesity and chronic inflammation, have been in the spotlight of research for many years (12,13) (Figure 1). ...
Bipolar disorder (BPD) is a mood disorder, which is characterized by alternating affective states, namely (hypo)mania, depression, and euthymia. Evidence is growing that BPD has indeed a biologic substrate characterized by chronic inflammation, oxidative stress, and disturbed energy metabolism. Apart from this, there is obviously a hereditary component of this disease with multi-genetic factors. Most probably a susceptibility threshold favors the outbreak of clinical disease after a cascade of stress events that remain to be elucidated in more detail. Evidence is also growing that weak points in brain energy metabolism contribute to outbreak and severity of BPD. Conventional psychopharmacologic therapy must be reassessed under the aspects of weight cycling and development of central obesity as a deterioration factor for a worse clinical course leading to early cardiovascular events in BPD subgroups.
... The difference in IL-6 signalling was also reflected by the higher levels of circulating IL-6 observed in the Indian BD patients who were in residual phase or remission, in agreement with earlier reports (Hope et al., 2011;Kim et al., 2007;Tsai et al., 2012). However, we did not find any significant difference on comparing patients in acute phase with those in residual/remission phase or with controls. ...
Reports of association of genetic variants of IL6 and its receptor (IL6R) with psychiatric disorders are inconsistent, and there are few population-based studies thus far in bipolar disorder (BD). We genotyped the IL6 rs1800795 and IL6R rs2228145 polymorphisms in two independent sets of patients exposed to different environmental stimuli such as climatic conditions or specific infectious burden – a French sample and a south Indian Tamil sample of BD with quantitation of circulating plasma IL-6 levels in the latter sub-sample.
In both populations, allele and genotype frequencies did not differ significantly between cases and controls for either polymorphism. Upon stratifying based on age at onset, we found no associations with the IL6 rs1800795 variant. However, the IL6R rs2228145 C allele and CC genotype were associated with early onset of disease in the French sample when compared to late onset BD. A similar trend was observed in the Indian population where we also found that plasma IL-6 levels were significantly higher in BD and also in patients who were in residual phase or remission both as compared to controls.
Our findings are in favour of a possible trans-ethnic implication of the IL6R genetic diversity in BD and reinforce the notion that IL-6 is an important marker of the operating inflammatory processes in the disease.
... Even though many potential pathomechanisms of BD have been identified over the last decades, it is still largely unknown how these disease mechanisms interact with each other. Neurotransmitter dysbalances, neurotrophic factor imbalances, chronic inflammation, oxidative stress and disturbed circadian rhythms have been put forward as putative underlying mechanisms (Boland et al., 2012;Andreazza et al., 2008;Berk et al., 2011;Bengesser and Reininghaus, 2013;Tsai et al., 2012;Soczynska et al., 2011;Bengesser et al., 2016). Various genome wide association studies (GWAS), functional re-analyses of GWAS and hypothesis driven gene association studies have identified diverse susceptibility gene groups for BD like genes encoding for ion channel subunits and associated proteins (e.g. ...
Objectives The gut microbiome harbors substantially more genetic material than our body cells and has an impact on a huge variety of physiological mechanisms including the production of neurotransmitters and the interaction with brain functions through the gut-brain-axis. Products of microbiota can affect methylation according to preclinical studies. The current investigation aimed at analyzing the correlation between gut microbiome diversity and the methylation of the clock gene ARNTL in individuals with Bipolar Disorder (BD). Methods Genomic DNA was isolated from fasting blood of study participants with BD (n = 32). The methylation analysis of the ARNTL CG site cg05733463 was performed by bisulfite treatment of genomic DNA with the Epitect kit, PCR and pyrosequencing. Additionally, DNA was extracted from stool samples and subjected to 16S rRNA sequencing. QIIME was used to analyze microbiome data. Results Methylation status of the ARNTL CpG position cg05733463 correlated significantly with bacterial diversity (Simpson index: r= -0.389, p = 0.0238) and evenness (Simpson evenness index: r= -0.358, p = 0.044). Furthermore, bacterial diversity differed significantly between euthymia and depression (F(1,30) = 4.695, p = 0.039). Discussion The results of our pilot study show that bacterial diversity differs between euthymia and depression. Interestingly, gut microbiome diversity and evenness correlate negatively with methylation of ARNTL, which is known to regulate monoamine oxidase A transcription. We propose that alterations in overall diversity of the gut microbiome represent an internal environmental factor that has an epigenetic impact on the clock gene ARNTL which is thought to be involved in BD pathogenesis.
... Recent evidence indicates that immune system abnormalities in patients with BD are statedependent and are not a potential trait biomarker. Contrary to the above assumption, some studies did not find significant correlation between cytokine level and medication status [7,20,21]. It is assumed that anti-bipolar drugs, valproic acid and carbamazepine reduce the inflammation in BD, which partly explain their therapeutic effect. ...
Background: The role of inflammation has received
increasing attention as a potential pathophysiological mechanism
in bipolar disorder (BD).
Objective: To compare the level of soluble tumor necrosis
factor receptor 1 (sTNFR1) in euthymic state of BD to healthy
controls.
Method: Serum levels of sTNFR1 were measured with
enzyme linked immunosorbent assay techniques in 44 patients
with BD-I in full remission and 88 healthy controls recruited
from Kasr Al-Ainy Hospital, Cairo University. The severity
of the manic symptoms was assessed using Young Mania
Rating Scale (YMRS). Patients with BD-I in full remission
were subjected to Young Mania Rating Scale (YMRS) and
Hamilton Depression Rating Scale (HDRS).
Results: The level of sTNFR1 was higher in the healthy
control goup compared to patients with BD-I in full remission.
Conclusion: sTNFR1 can’t be considered as trait marker
in patients with BD-I during full remision.
Key Words: Bipolar disorder – Euthymic – Inflammation–
Tumor necrosis factor.
... Our results confirm those of Spencer et al. [22] who also found a positive correlation between BMI and neopterin in healthy subjects. Considering these results and taking into account other findings that point to an association between inflammation, psychiatric disorders, and obesity [55], one can suggest that BMI, immunity, and mental status interact. ...
Objective:
Cellular immune status in major depression (MD) patients differs from that in somatoform disorder (SFD) patients and healthy controls (HC). It is still questionable whether the patterns of immune parameters remain stable over time. Therefore, we studied lymphocyte and monocyte cell counts and neopterin levels in peripheral blood of MD and SFD patients and HC over 12 weeks and tested for correlations between biochemical and psychometric parameters.
Methods:
Thirty-nine patients with MD, 27 with SFD, and 51 HC were recruited. Peripheral blood was drawn at four visits, at 4-week intervals. We assessed the total cell count of B lymphocytes, natural killer (NK) cells, T lymphocyte subpopu-lations, and monocytes by flow cytometry, and neopterin serum levels by ELISA. Psychometric parameters were measured with questionnaires.
Results:
Counts of lymphocytes, monocytes, and neopterin were stable in the SFD and HC groups. In the MD group, total CD3+, CD3+CD8+, NK cells, and CD3+CD25+ T cells showed inhomogeneous variances in Friedman tests, particularly in females. Neopterin correlated with depressed mood in MD patients, and with body mass index in HC.
Conclusions:
Cellular immune parameters are stable in HC and SFD. Our results may indicate influences of MD and gender on some cellular immune parameters. This may need to be considered in future immunological studies.
... 35,36 The results suggest that there is a relationship between the IL-1Ra and sIL-2R and specific symptoms of the disease: the IL-1Ra with the severity of cognitive function and the number of episodes, and the sIL-2R with the length of illness. Studies have found elevated levels of IL-1Ra and sIL-2R in mania episodes, but not in states of euthymia, 22,37 which would indicate a relationship between the IL-1 and IL-2 system and the deterioration of specific symptoms, and express a state of chronic inflammation. Further cohort studies are required that analyze the levels of these markers in mania episodes and euthymia in early and late stages of the disease, so as to clarify whether or not they are related to the stage or to specific symptoms. ...
Background
Previous studies suggest that inflammatory molecules play an important role in the pathophysiology of Bipolar Disorder (BD). The evidence suggests that BD may present a progressive course. Therefore there are theories that postulate the relationship between progression and stages of the disease with distinct peripheral biomarkers.
Objective
The aim of this study was to carry out a systematic review of the literature of studies about the association between peripheral inflammatory markers and clinical variables related with staging in BD patients.
Methods
We conducted a systematic review using electronic databases: PubMed, SciELO, LiLACS and PsycINFO. Keywords were divided into inflammatory markers and, BD and staging. Studies involving euthymic BD patients, studies evaluating peripheral biomarkers and studies correlating these with clinical variables related to neuroprogression or stage of BD were included.
Results
We present and discuss the methods and findings of ten articles. The inflammatory markers were measured with different techniques and show some contradictories results. The TNF superfamily and inflammatory cytokines may have a relationship with the neuroprogression of the disease.
Conclusions
This study suggests that TNF and ILs could play a role in neuroprogression. However, longitudinal studies are needed to clarify the relationship between factors associated with neuroprogression.
... The statistically significantly greater decrease in HAMD-17 scores in the CBX group compared to the PBO group indicates that adjunctive SSRI treatment with CBX is more effective than SSRI alone at reducing depression and reversing treatment resistance in BD patients. Baseline elevations of CRP were noted in BDD patients compared to HC subjects, which was consistent with the literature (Dickerson et al., 2013;Tsai et al., 2012). Therefore, CRP may prove to be a useful biomarker for BDD, although possible confounding variables must be addressed, including BMI and other factors which are known to influence CRP. ...
Immune system activation and neuroinflammation appear to play a key role in the pathophysiology and treatment of bipolar depression (BDD). This study is the first to analyze blood levels of the pro-inflammatory biomarker C-reactive protein (CRP) in bipolar disorder patients treated with the cyclooxygenase-2 inhibitor, celecoxib (CBX). In this double-blind study, 47 consenting patients with BDD were randomized to receive either escitalopram (10 mg twice/day) + CBX (200 mg twice/day), or escitalopram (10 mg twice/day) + placebo (twice/day). Plasma CRP levels were measured in both patient groups at baseline, week 4, and week 8, and in a healthy control (HC) group of subjects (N = 35) once. Symptoms were rated using the 17-item Hamilton Depression Scale (HAMD-17). The CBX group had significantly lower HAMD-17 scores vs. placebo at week 4 (P = 0.026) and week 8 (P = 0.002). Therefore, SSRI + CBX is more effective than SSRI + placebo in reversing treatment resistance and augmenting antidepressant response in BDD. Baseline CRP levels were significantly increased amongst BDD patients versus HC subjects, indicating that CRP may be a useful biomarker for BDD (P = 0.044). No significant differences in CRP levels were measured between CBX and placebo groups at baseline (P = 0.156), but by week 8 CRP was significantly decreased in the CBX group vs. placebo (P = 0.003). This indicates reduced inflammation in CBX-treated patients, and that CRP may be a useful biomarker for monitoring treatment response in BDD patients during SSRI + CBX combination treatment. CRP and IL-6 levels were positively correlated in the CBX group, and CRP levels were positively correlated with BMI.
... Regarding blood levels, most studies report higher peripheral levels of IL-6, IL-6R, IL-2R, IL-1β and TNF-α during depressive and acute manic episodes compared with healthy controls [56][57][58][59][60][61][62][63][64][65]. Cross-sectional studies also observed increased CRP levels in BD patients during acute mania and/or a depressive phase compared with controls [64,[66][67][68][69]. Accordingly, cytokine levels may vary depending on mood state. ...
Introduction: Inflammation seems to play a role in the pathophysiology of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). In the last years several studies have shown increased levels of inflammatory and/or immune markers in patients with mood disorders. Accordingly, the immune system has become a target of interest for the development of biomarkers and therapeutics for mood disorders.
Areas covered: Here, we review the evidence showing low-grade inflammation in mood disorders and the studies evaluating immune-based strategies for the treatment of these conditions.
Expert commentary: Clinical trials with non-steroidal anti-inflammatory drugs, polyunsaturated acids, N-acetylcysteine, anti-cytokines, physical activity and probiotics have provided promising results in terms of antidepressant efficacy in patients with MDD and BD. Regarding stem cells, only studies with animal models have been performed so far with interesting pre-clinical results. Due to the preliminary nature of the results, most of the clinical studies need to be replicated and/or confirmed in larger clinical settings, embracing the highly heterogeneous pathophysiology of mood disorders.
... To the best of our knowledge a limited number of studies have investigated the relationship between bipolar disorder and adipocytokines. There are studies reporting that leptin levels decreased [26] or remained unchanged [27,28] in bipolar patients compared to healthy controls. The latest study on this subject was conducted by Barbosa et al. who found an increase in leptin levels in bipolar euthymic patients, which is similar to our findings [29]. ...
Purpose: Obesity and metabolic syndrome (MeS) are more frequently observed in bipolar patients than the general population. This may result from the differences of adipocytokines and ghrelin levels in bipolar disorder.
Material and methods: We evaluated the leptin, adiponectin, resistin and ghrelin levels in bipolar patients (n = 30) in manic episode and in a control group (n = 30). After treatment, the same patients were evaluated again during the euthymic episode. We also measured the insulin, glucose, insulin resistance (HOMA), trygliceride (TG), total cholesterol (TCHOL), high density lipoprotein cholesterol (HDL) and low density lipoprotein cholesterol (LDL) in relation to the (MeS).
Results: When controlling for age, BMI and glucose, leptin levels were higher in the bipolar disorder manic episode group (BD-ME) and bipolar euthymic episode group (BD-EE) than the control group; resistin levels were higher in the BD-ME compared to the control group and it had a positive correlation with Young Mania Rating Scale (YMRS). After treatment, ghrelin levels were higher in the BD-EE compared to the BD-ME group. There was no difference among the groups with respect to adiponectin.
Conclusions: The present results point that high leptin, resistin and ghrelin levels may be involved in the early pathophysiological process which can lead to later obesity and MeS in patients with bipolar disorder.
... Along with previous studies that found no correlation between medication use and cytokine levels (Barbosa et al. 2012(Barbosa et al. , 2011Tsai et al. 2012Tsai et al. , 2001, other research has demonstrated significant correlations between medication use and individual cytokine parameters (Guloksuz et al. 2010;Hope et al. 2011;Kim et al. 2004Kim et al. , 2002. Along these lines, a major limitation of our study was its inability to exclude potential inflammation-related effects of mood-stabilizing medication on TWEAK levels. ...
TNF-related weak inducer of apoptosis (TWEAK) and TNF-related apoptosis-inducing ligand (TRAIL) are members of TNF superfamily, which has various roles in immunologic and inflammatory reactions in the organism. Pathophysiology in bipolar disorder is still under investigation and altered serum levels of cytokines are often encountered. Aim of this study is to detect serum TWEAK and TRAIL levels of patients with bipolar disorder and healthy controls. For this purpose, 55 patients with bipolar disorder −27 manic episode (ME), 28 remission (RE) and 29 healthy controls (HC) were included. TWEAK levels of ME and RE groups were significantly lower than HC. TWEAK levels of bipolar patients (BP) were also lower than HC. TRAIL levels of ME, RE, HC groups and BP, HC groups were statistically similar. In our knowledge, this is the first study concerning about TWEAK and TRAIL levels in bipolar disorder and our results pointed that TWEAK-related immune response might be impaired in bipolar disorder, but our study fails to eradicate the confounders such as medication, smoking and body mass index. Studies having larger samples and limited confounders are needed to be able to evaluate these changes better and detect possible alterations about TRAIL and other TNF superfamily members.
... 11 Furthermore, chronic inflammation is observed in patients with bipolar depression or mania from the acute phase to full remission. 21,22 Therefore, our findings may provide additional evidence that systematic inflammation is a possible risk factor for early CVD mortality in patients with BD. Second, increased heart rate or systolic pressure on the first day of the index hospitalization may be another risk factor for early circulatory mortality in BD. ...
Aim:
We attempted to determine risk factors, particularly pathophysiological changes, for the early cardiovascular mortality in bipolar disorder.
Methods:
A total of 5416 in-patients with bipolar I disorder were retrospectively followed through record linkage for cause of death. A total of 35 patients dying from cardiovascular disease (CVD, ICD 9: 401-443) before the age of 65 years were identified. Two living bipolar patients and two mentally healthy adults were matched with each one deceased patient as control subjects according to age (±2 years), sex, and date (±3 years) of the final/index admission or the date of general health screening. Data were obtained through medical record reviews.
Results:
Eighty percent of CVD deaths occurred within 10 years following the index admission. Conditional logistic regression revealed that the variables most strongly associated with CVD mortality were the leukocyte count and heart rate on the first day of the index hospitalization, as the deceased bipolar patients were compared with the living bipolar controls. Systolic pressure on the first day of the index hospitalization can be substituted for the heart rate as another risk factor for CVD mortality.
Conclusion:
It is suggested that systemic inflammation and sympathetic overactivity during the acute phase of bipolar patients may be risk factors for the early CVD mortality.
... 35,36 The results suggest that there is a relationship between the IL-1Ra and sIL-2R and specific symptoms of the disease: the IL-1Ra with the severity of cognitive function and the number of episodes, and the sIL-2R with the length of illness. Studies have found elevated levels of IL-1Ra and sIL-2R in mania episodes, but not in states of euthymia, 22,37 which would indicate a relationship between the IL-1 and IL-2 system and the deterioration of specific symptoms, and express a state of chronic inflammation. Further cohort studies are required that analyze the levels of these markers in mania episodes and euthymia in early and late stages of the disease, so as to clarify whether or not they are related to the stage or to specific symptoms. ...
Background
Previous studies suggest that inflammatory molecules play an important role in the pathophysiology of Bipolar Disorder (BD). The evidence suggests that BD may present a progressive course. Therefore there are theories that postulate the relationship between progression and stages of the disease with distinct peripheral biomarkers.
Objective
The aim of this study was to carry out a systematic review of the literature of studies about the association between peripheral inflammatory markers and clinical variables related with staging in BD patients.
Methods
We conducted a systematic review using electronic databases: PubMed, SciELO, LiLACS and PsycINFO. Keywords were divided into inflammatory markers and, BD and staging. Studies involving euthymic BD patients, studies evaluating peripheral biomarkers and studies correlating these with clinical variables related to neuroprogression or stage of BD were included.
Results
We present and discuss the methods and findings of ten articles. The inflammatory markers were measured with different techniques and show some contradictories results. The TNF superfamily and inflammatory cytokines may have a relationship with the neuroprogression of the disease.
Conclusions
This study suggests that TNF and ILs could play a role in neuroprogression. However, longitudinal studies are needed to clarify the relationship between factors associated with neuroprogression.
... Bipolar disorder has a lifelong impact on patients' overall health status, quality of life, and functioning 3 . Although the etiology of bipolar disorder is not yet fully understood, it is thought that it is influenced by a combination of factors, including: genetics, biochemical, environmental, infections, immune system disturbances, and inflammatory processes [4][5][6][7][8][9] . ...
Background:
Recently, a growing number of publications have suggested that the immune-inflammatory system may be involved in the etiology of bipolar disorder (BD).
Objective:
The aim of this study was to investigate neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and red cell distribution width (RDW) in the three different phases of BD patients compared to each other and controls.
Methods:
One hundred eighty-seven bipolar patients (78 euthymic, 53 manic/hypomanic and 56 depressed), and 62 age and sex matched controls were enrolled. Sociodemographic variables and complete blood count parameters of the patients and the control group were recorded.
Results:
The groups did not differ from each other on the hematological parameters, except for NLR and RDW. Post-hoc analyses revealed that NLR values were significantly higher in the euthymic and manic/hypomanic bipolar groups compared to control group. In addition, post-hoc analyses revealed that RDW values were significantly higher in the manic/hypomanic bipolar group relative to the control group.
Discussion:
Longitudinal studies evaluating the levels of inflammatory markers in the early phases of the disorder, and their relationship with the development of different episodes and medical comorbidities may be useful to understand the role of inflammation in BD.
... Three other studies with a total of 248 patients, however, did not demonstrate significant differences in CRP across the mood states, which is corresponding to the current study results (Hornig et al. 1998;Hope et al. 2011;Tsai et al. 2012). ...
Background:
The association between inflammation and the course of mood disorders is receiving increased attention. This study aims to investigate whether a sub-group of patients with BD can be identified for which a higher CRP (C-reactive protein) level at baseline is associated with an unfavorable prognosis.
Methods:
This is a historic cohort study using CRP at baseline, with 15-month follow-up of mood status and medication. Cross-sectional analyses include boxplots, one-way ANOVA, receiver operating characteristics (ROC) curve and Chi square test, and the longitudinal analysis using multivariate Cox-regression.
Results:
Eighty-four bipolar disorder patients were included in the analyses. Cross-sectionally, no statistically significant difference was found in CRP distribution across mood states (p = 0.372) or rapid cycling state (p = 0.656). Also, no CRP cut-off level was distinguished between euthymic and non-euthymic patients according to the ROC curve (p = 0.449, AUC = 0.452, 95 % CI 0.327, 0.576), and a literature-derived cut-off value (3 mg/L) again demonstrated no difference (p = 0.530). Longitudinally, no association was found between CRP and prognosis of disease neither in euthymic [-2 log likelihood = 120.460; CRP: p = 0.866, B = -0.011, OR = 0.989 (95 % CI 0.874-1.120)] nor non-euthymic patients [(-2 log likelihood = 275.028; CRP: p = 0.802, B = 0.010, OR = 1.010 (95 % CI 0.937-1.088)]. Medication use did not affect these associations.
Conclusions:
We found no statistically significant association between CRP and a more unfavorable BD prognosis, suggesting that the application of CRP as a practical biomarker to predict outcome in a naturalistic outpatient care setting is not as straightforward as it may seem.
... Studies have reported a proinflammatory imbalance with higher levels of the inflammatory markers in levels of IL-6 42 , TNF-α , 42,55 and IL-1β 24 at late stages of BP. Although baseline IL-1β and IL-6 levels were significantly different between the SBP and BP-II groups, the changes in IL-1β and IL-6 levels during the 12 weeks of treatment were not significantly different after controlling for the effects of concomitant medications and group psychotherapy. ...
Patients with subthreshold hypomania (SBP; subthreshold bipolar disorder) were indistinguishable from those with bipolar disorder (BP)-II on clinical bipolar validators, but their analyses lacked biological and pharmacological treatment data. Because inflammation and neuroprogression underlies BP, we hypothesized that cytokines and brain-derived neurotrophic factor (BDNF) are biomarkers for BP. We enrolled 41 drug-naïve patients with SBP and 48 with BP-II undergoing 12 weeks of pharmacological treatment (valproic acid, fluoxetine, risperidone, lorazepam). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical responses at baseline and at weeks 0, 1, 2, 4, 8, and 12. Inflammatory cytokines (tumour necrosis factor [TNF]-α, transforming growth factor [TGF]-β1, interleukin [IL]-6, IL-8 and IL-1β) and BDNF levels were also measured. Mixed models repeated measurement was used to examine the therapeutic effect and changes in BDNF and cytokine levels between the groups. HDRS and YMRS scores significantly (P < 0.001) declined in both groups, the SBP group had significantly lower levels of BDNF (P = 0.005) and TGF-β1 (P = 0.02). Patients with SBP and BP-II respond similarly to treatment, but SBP patients may have different neuroinflammation marker expression.
... Bipolar Disorder (BD) is a devastating disease characterized by the recurrence of euthymic, manic and depressive episodes. The contemporary model of BD posits a multifactorial pathogenesis including genetic susceptibility, neurotransmitter imbalance, disturbed circadian rhythms, environmental and psychosocial factors, epigenetic changes, growth hormone alterations, Endoplasmic Reticulum (ER) stress, oxidative stress, chronic inflammation and immunological reactions [1][2][3][4][5][6]. Activated oxidative stress pathways *Address correspondence to this author at the Medical University of Graz, Department of Psychiatry, Auenbruggerplatz 31, A-8036 Graz, Austria; Tel: 0043/650/3164978; E-mail: Nina.Lackner@medunigraz.at show reciprocal associations with activated immune-inflammatory pathways which finally cause increased neurotoxicity, decreased neuroplasticity and neurogenesis [2,7,8]. ...
Background:
Hitherto literature indicates that mood stabilizers exert variable effects on oxidative and antioxidative systems, which are involved in the pathogenesis of Bipolar Disorder. Herein we primarily sought to characterize markers of peripheral oxidative stress during euthymia in adults with Bipolar Disorder under current intake of different mood stabilizers (lithium, anticonvulsants and atypical antipsychotics/ AAPs).
Methods:
Peripheral oxidative stress parameters (TBARS/ Thiobarbituric acid- reactive-substances, MDA/ malondialdehyde and carbonyl proteins) and antioxidative markers (SOD/ Cu/Zn superoxide dismutase, GST/ glutathione S-transferase and TAC/ total antioxidative capacity) were measured in serum of 115 euthymic bipolar individuals (50 females, 65 males; HAMD<11 and YMRS<8). Differences in (anti)oxidative markers between bipolar participants treated with different mood stabilizing medication were tested with MANCOVAS and ANCOVAS with SPSS.21.
Results:
Bipolar individuals taking lithium had significantly lower oxidative parameters than test persons without lithium (multivariate effect for MDA and TBARS: F(2/182)= 3.956, p= 0.021; univariate effect for MDA: F(2/182)= 7.880, p= 0.006, Partial η2= 0.041). Subjects with AAPs had significantly higher MDA and TBARS levels compared to participants without AAPs (multivariate effect F(2/182)= 3.122, p= 0.046, Partial η2= 0.033). Patients taking anticonvulsants had significantly lower GST levels than patients without antiepileptic medication (F(1/165)= 4.501, p= 0.035, Partial η2= 0.027).
Conclusion:
Lithium taking participants had the lowest MDA and TBARS levels, while AAP taking test persons had high oxidative stress markers. The observed effects on oxidative markers may provide a mechanistic basis for understanding lithium's neuroprotective effects.
Bipolar disorder (BD) and metabolic disturbance represent a chronic state of low-grade inflammation and corticostriatal circuitry alterations. Herein, we aimed to investigate whether plasma leptin, an adipokine that plays a key role in the interplay of metabolism and inflammation, is associated with corticostriatal connectivity in patients with BD. Twenty-eight BD I patients, 36 BD II patients and 66 healthy controls were enrolled and completed the Hamilton Depression Rating Scale, the Young Mania Rating Scale, and the Recent Life Change Questionnaire. Fasting plasma leptin and C-reactive protein (CRP) levels were measured, and corticostriatal connectivity was examined using functional magnetic resonance imaging (fMRI). The relationships between leptin, CRP and body mass index (BMI) identified in the controls and BD II patients were absent in the BD I patients. We did not find a significant group difference in the leptin level; nevertheless, the negative correlation between leptin level and corticostriatal connectivity (ventrolateral prefrontal cortex and inferior temporal gyrus) observed in the healthy controls was absent in the BD patients. The disproportionate increase in leptin level with increasing BMI in BD indicated a potential inflammatory role of white adipose tissue in BD. Furthermore, higher CRP levels in BD I patients might induce leptin resistance. Collectively, our results implied vulnerability to inflammatory and metabolic diseases in patients with BD, especially BD I.
Objective
This study aimed at exploring the changes of serum complement C1q levels in patients with Bipolar Disorder (BD) using a cross-sectional design, and the differences between Major Depressive Disorder (MDD) and BD. Moreover, the correlation between complement C1q and bech-rafaelsdn mania rating scales (BRMS) in patients with MDD and BD was assessed.
Methods
Serum complement C1q levels were measured by ADVIA 2400 biochemical analyser in 104 patients with MDD, 71 patients with BD type I and 42 patients with BD type II diagnosed by Diagnostic and Statistical of Mental Disorder 5 (DSM-5). Then simple and multivariate linear regression analysis was conducted between the level of serum C1q and BRMS among patients with BD.
Results
The serum complement C1q levels were higher in BD type I than BD type II (P < 0.001); Serum complement C1q levels were higher in MDD than BD type II (P < 0.001). We discovered that there was a positive correlation relationship between serum complement C1q levels and BRMS in BD type I (r = 0.756, P < 0.001).
Conclusion
We confirmed that serum complement C1q levels were higher in patients with BD type II than in MDD patients. These current results support the view that the complement C1q may play an important role in the pathophysiology of BD. Serum complement C1q was strongly associated with BD and is worth investigating in future studies.
Background
As non-specific markers of immune dysregulation, neutrophil–lymphocyte and platelet–lymphocyte ratios (NLR and PLR) have been consistently shown to be increased in major neuropsychiatric disorders. Although this increase seems to be trans-diagnostic, the extent to which its magnitude differs between disorders remains largely unclear.
Aim
The aim of this study was to directly compare the severity of inflammation (as reflected by NLR and PLR) between schizophrenia (Sch), bipolar mania (BD-M), bipolar depression (BD-D), major depressive disorder (MDD) and obsessive compulsive disorder (OCD).
Methods
NLR and PLR were obtained for a total of 417 subjects (91 Sch, 70 BD-D, 37 BD-M, 93 MDD, 37 OCD, and 95 controls) and analyzed for group differences.
Results
Sch, BD-M, BD-D and MDD presented with significantly higher NLR compared with both OCD and HC. NLR in BD-M was significantly higher than all the remaining groups, whereas Sch, BD-D and MDD presented with comparably elevated NLR. Moreover, BD-M, Sch and MDD had significantly higher PLR compared with HC.
Conclusion
These results suggest that the underlying inflammation may be most severe in BD-M, followed by Sch, BD-D and MDD. On the other hand, inflammation may be of negligible intensity in OCD, or at least undetectable by means of NLR or PLR.
Importance. It is unclear whether differences exist in the magnitude and variability of pro-inflammatory mediators in the different phases of bipolar disorder (BD) and among subjects with BD, as compared to healthy controls.
Objective
To run a comparative meta-analysis of C-Reactive Protein (CRP), IL-1, IL-6, TNF-α in BD vs healthy controls, measuring mean and variability effects on all subjects. Sensitivity analyses include disease activity.
Data Sources. Systematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020.
Study Selection. Case-control studies reporting inflammatory mediators' levels in BD and controls.
Data Extraction and Synthesis. Summary distribution measures of circulating CRP, IL-1β, IL-6, TNF-α in participants with BD and control groups were extracted. Random-effects multivariate meta-analyses were conducted based on individual study/mediator effect sizes (Hedge’s g).
Main Outcomes and Measures. Co-primary outcomes were inflammatory mediators' levels (Hedge’s g) and variability (coefficient of variance ratio (CVR)) differences between participants with BD across the mood spectrum and controls.
Results
Out of the initial 729 papers, 72 were assessed and then excluded after full-text review, and ultimately 53 studies were included in the systematic review, while 49 were included in the meta-analysis. The mean age was 36.96 (SD: 9.29) years, and the mean female percentage was 56.31 (SD: 16.61). CRP (g=0.70, 95% CI 0.31-1.09, k=37, BD=2,215 vs HC=3,750), IL-6 (g=0.81, 95% CI 0.46-1.16, k=45, BD=1,956 vs HC=4,106), TNF-α (g=0.49, 95% CI 0.19-0.78, k=49, BD=2,231 vs HC=3,017) were elevated in subjects with BD vs HC, but not IL-1β (g=-0.28, 95% CI -0.68-0.12, k=4, BD=87 vs HC=66). When considering euthymic, depressive, and manic episodes separately, CRP and TNF-α were elevated in both depressive and manic episodes, but not in euthymia, while IL-6 remained elevated regardless of the disease state. No difference in CVR emerged for CRP, IL-1β, and TNF-α, while a lower CVR was observed for IL-6. When considering disease phases, CVR was higher in BD than in HCs for CRP during depressive episodes, lower for IL-6 during euthymia, and higher during manic episodes for CRP, IL-6, and TNF-α. Sensitivity analyses after excluding outliers identified with funnel plot visual inspection, low-quality studies, and considering only studies matched per body mass index confirmed the main results. Meta-regression showed that age (IL-6, TNF-α), gender (CRP), duration of illness (CRP) moderated elevated individual inflammatory levels.
Conclusions and Relevance Peripheral pro-inflammatory marker elevations were confirmed in BD. CRP and TNF-α could represent state markers, as they were only elevated during mood episodes, while IL-6 appeared to be a trait marker for BD. Increased variability of specific inflammatory mediators in specific disease active states suggests that a subset of subjects with BD may exhibit elevated inflammation as part of a manic or depressive episode.
Advances in the understanding and management of bipolar disorder (BD) have been slow to emerge. Despite notable recent developments in neurosciences, our conceptualization of the nature of this mental disorder has not meaningfully progressed. One of the key reasons for this scenario is the continuing lack of a comprehensive disease model. Within the increasing complexity of modern research methods, there is a clear need for an overarching theoretical framework, in which findings are assimilated and predictions are generated. In this review and hypothesis article, we propose such a framework, one in which dysregulated energy expenditure is a primary, sufficient cause for BD. Our proposed model is centered on the disruption of the molecular and cellular network regulating energy production and expenditure, as well its potential secondary adaptations and compensatory mechanisms. We also focus on the putative longitudinal progression of this pathological process, considering its most likely periods for onset, such as critical periods that challenges energy homeostasis (e.g. neurodevelopment, social isolation), and the resulting short and long-term phenotypical manifestations.
Objectives:
Limited prospective data, mostly focused on bipolar I disorder, suggests that pro-inflammatory cytokines are elevated in abnormal mood states. We evaluated whether treatment normalizes peripheral markers of inflammation in bipolar II disorder.
Methods:
Using data from a randomized clinical trial of Interpersonal and Social Rhythm Therapy (IPSRT) + quetiapine vs. IPSRT + placebo for bipolar II depression, we examined whether these treatments for bipolar II depression impact inflammatory cytokines and whether observed changes in cytokines are associated with changes in depressive symptomatology as measured by the Hamilton Rating Scale for Depression (HRSD-17).
Results:
Cytokine values were available for 33 participants who completed baseline and 20-week followup visits. After excluding those with CRP values >=10 mg/L, there were 27 patients available for analysis (IPSRT+quetiapine N=10, IPSRT+placebo N=17). Baseline measure of inflammation did not appear to moderate treatment response, nor was change in HRSD-17 score correlated with changes in cytokines. Those who received IPSRT+quetiapine had significantly greater increases in IL-6 (p=0.02) and TNF-α (p=0.04), even after adjusting for changes in body mass index, than the IPSRT alone group. Descriptively, the quetiapine group showed increases in pro-inflammatory and decreases in anti-inflammatory cytokines and the psychotherapy group showed reduced pro-inflammatory cytokines.
Conclusions:
Despite both groups showing depression improvement, this small study suggests a more pro-inflammatory cytokine profile over time with quetiapine plus psychotherapy compared to psychotherapy alone. Elevated risk of cardiovascular morbidity and mortality among those with bipolar II disorder underscores the importance of delivering treatments that do not exacerbate these risk factors.
Introduction: Serious psychiatric illnesses like bipolar disorder lack specific biomarkers of diagnosis or prognosis. However, association between Bipolar Disorder (BD) and various inflammatory markers has been consistently demonstrated by earlier studies pointing to underlying inflammation/dysimmunity. Often implicated in particular is the acute phase C-Reactive Protein (CRP) of hepatic origin, a generic marker of inflammation which is robust and very easy to test even in field settings without the need for a laboratory. Aim: To study the status of CRP, a generic marker of inflammation, in a well-characterised south Indian Tamil BD cohort, and investigate whether it can be a specifier of disease state. Materials and Methods: CRP was qualitatively estimated by latex agglutination method in the serum of 145 BD patients and 151 healthy controls. Statistical analyses were performed to test the association of CRP with the disease state. Results: It was found that, after controlling for age, gender, BMI and smoking status, CRP positivity (>0.6 mg/dL) was: (i) significantly higher among BD patients compared to healthy controls; (ii) significantly higher among patients having an acute mood episode (both mania (n=85), and depression (n=9) combined) compared to patients with residual symptoms or in remission, as well as compared to healthy subjects; (iii) not significantly different between patients in acute mania versus acute depression, but significantly higher in both acute mania and in acute depression compared to patients with residual symptoms or in remission. Conclusion: CRP, a robust generic inflammatory marker is significantly higher among BD patients as compared to normal controls, pointing to underlying inflammation operating in the disease. Also, it can differentiate between patients in acute phase and those in remission or having residual symptoms. If validated in longitudinal follow-up studies, these results could be helpful in Point Of Care (POC), as well as field settings especially in low income countries to identify patients whose symptoms are progressing towards relapse, at low costs, and without the need for a sophisticated laboratory. © 2018, Journal of Clinical and Diagnostic Research. All rights reserved.
Background In the previous studies, the relevance of inflammatory processes to disorders of the brain and body may serve as an important touchstone for increasing integration of psychiatry and medicine. Until recently few studies have examined the potential role of inflammation in bipolar I disorder. We aimed to compare C-reactive protein (CRP) serum levels as a marker of systemic inflammation between bipolar disorder (BD) patients in different affective phases and matched healthy controls and to investigate the possible effects of CRP elevations on the cognitive function in BD remitted patients. Patients and methods A total of 42 patients with bipolar I disorder subdivided into manic, depressive, and full remitted groups were examined. We measured the circulating levels of high-sensitivity C-reactive protein (hsCRP); the results were compared with 42 age-matched and sexmatched healthy controls. Then the neuropsychological function for the full remitted group only was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status test and examine the correlation between the neuropsychological function and hsCRP levels in this group. Results It showed that the hsCRP levels were significantly higher in BD patients than in healthy controls. Also when comparing each group (manic, depressed, and remitted) separately with healthy controls, the difference was still statistically highly significant (Po0.001). There was statistically significant positive correlation between hsCRP levels and poor performance on the Repeatable Battery for the Assessment of Neuropsychological Status total and four of its five subscales (Po0.05) except for the visuospatial/constructional subtest (P >0.05). Conclusion Our finding adds to the growing evidence that inflammation has a role in the psychopathology of mood disorders.
The interplay between the immune system and behaviour is of increasing interest in psychiatry research. Specifically, accumulating data points to a link between inflammation and psychopathology, including affective symptomatology. We investigated the association between inflammation and affective polarity in psychiatric inpatients who were hospitalized due to an affective exacerbation. Data was collected retrospectively and comparisons were made between manic and depressed patients. C-reactive protein (CRP), a general laboratory marker of immune activation and inflammation, was used as a non-specific inflammatory biomarker. Age, smoking and body mass index were considered covariates. Manic polarity (n = 89) was associated with statistically significant elevated CRP levels compared to depressed polarity (n = 44, 56%; p = 0.036), after controlling for covariates. No differences were observed in CRP levels across Diagnostic and Statistical Manual of Mental Disorders-IV Edition-Text Revised psychiatric diagnoses. These findings suggest a transdiagnostic association between inflammation and manic polarity in affective inpatients.
Objective
Serum lipid levels may be associated with the affective severity of bipolar disorder, but data on lipid profiles in Asian patients with bipolar disorder and the lipid alterations in different states of opposite polarities are scant. We investigated the lipid profiles of patients in the acute affective, partial, and full remission state in bipolar mania and depression.
Methods
The physically healthy patients aged between 18 and 45 years with bipolar I disorder, as well as age-matched healthy normal controls were enrolled. We compared the fasting blood levels of glucose, cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein of manic or depressed patients in the acute phase and subsequent partial and full remission with those of their normal controls.
Results
A total of 32 bipolar manic patients (12 women and 20 men), 32 bipolar depressed participants (18 women and 14 men), and 64 healthy control participants took part in this study. The mean cholesterol level in acute mania was significantly lower than that in acute depression (p < 0.025). The lowest rate of dyslipidemia (hypertriglyceridemia or low high-density lipoprotein cholesterol) was observed in acute bipolar mania.
Conclusion
Circulating lipid profiles may be easily affected by affective states. The acute manic state may be accompanied by state-dependent lower cholesterol and triglyceride levels relative to that in other mood states.
Objectives:
The objectives of the study were to determine if adjunctive minocycline mitigates depressive symptom severity and improves cognitive function in individuals with bipolar I/II disorder (BD). The study also aimed to determine if changes in depressive and/or cognitive symptoms over the course of treatment were associated with changes in circulating inflammatory cytokine levels.
Methods:
A total of 29 (intention-to-treat: n=27) adults meeting DSM-IV-TR criteria for a major depressive episode as part of bipolar I or II disorder (i.e. Hamilton Depression Rating Scale 17-item [HAMD-17] ≥20) were enrolled in an 8-week, open-label study with adjunctive minocycline (100 mg bid). The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale (MADRS). The HAMD-17, Clinical Global Impression-Severity (CGI-S), cognitive test composite scores and plasma cytokines were secondary outcome measures. Plasma cytokines were measured with the 30 V-Plex Immunoassay from Meso Scale Discovery.
Results:
Adjunctive minocycline was associated with a reduction in depressive symptom severity from baseline to week 8 on the MADRS (P<.001, d=0.835), HAMD-17 (P<.001, d=0.949) and CGI-S (P<.001, d=1.09). Improvement in psychomotor speed, but not verbal memory or executive function, was observed only amongst individuals exhibiting a reduction in depression severity (P=.007, d=0.826). Levels of interleukin (IL)-12/23p40 (P=.002) were increased, while levels of IL-12p70 (P=.001) and C-C motif chemokine ligand 26 (CCL26) (P<.001) were reduced from baseline to week 8. A reduction in CCL26 levels was associated with a less favourable treatment response (P<.001).
Conclusions:
Results from the pilot study suggest that adjunctive minocycline may exert antidepressant effects in individuals with bipolar depression, possibly by targeting inflammatory cytokines.
Bipolar disorder (BD) is a neuropsychiatric disorder that is characterized by a phasic course of affective episodes interspersed with a euthymic state. Epidemiological, clinical, genetic, post-mortem and preclinical studies have shown that inflammatory reactions and immune modulation play a pivotal role in the pathophysiology of BD. It is conceptualized that biomarkers of inflammation and immune responses should be employed to monitor the disease process in bipolar patients. The objective of this systematic review is to analyse the inflammatory markers involved in human studies and to explore each individual marker for its potential clinical application and summarize evidence regarding their role in BD. A systematic review of human studies to measure inflammatory markers was conducted, and the studies were identified by searching PubMed/MEDLINE, PsycINFO, EMBASE, and Web of Science databases for peer-reviewed journals that were published until September 2015. In this review, we included peripheral markers, genetic, post-mortem and cell studies with inflammatory biomarker analysis in BD. One hundred and two (102) papers met the inclusion criteria. The pro-inflammatory cytokines were elevated and the anti-inflammatory cytokines were reduced in BD patients, particularly during manic and depressive phases when compared to the controls. These changes tend to disappear in euthymia, indicating that inflammation may be associated with acute phases of BD. Even though there are promising findings in this field, further clinical studies using more established detection techniques are needed to clearly show the benefit of using inflammatory markers in the diagnosis, follow-up and prognosis of patients with BD.
Background: Bipolar disorder (BD) is associated with increased levels of inflammatory cytokines, which may contribute to cognitive dysfunction. Anti-inflammatory intervention with minocycline is hypothesized to exert antidepressant and pro-cognitive effects in BD. The aims of the investigations were: 1) to identify inflammatory cytokine abnormalities in BD; 2) to identify inflammatory cytokines associated with cognitive dysfunction in BD; 3) to evaluate the efficacy of adjunctive minocycline for symptoms of bipolar depression and cognitive dysfunction.
Method: The first two study aims were evaluated with cross-sectional exploratory methods, comparing 29 depressed (HAMD-17 ≥ 20) and 46 euthymic (4 week verification) adults with DSM-IV-TR-defined BD as well as of 31 healthy controls (HCs). Plasma cytokine levels were measured with a 30 V-PLEX immunoassay. Evaluated cognitive domains were verbal memory, executive function and psychomotor speed. The efficacy of adjunctive minocycline (100 mg b.i.d.) was evaluated in an overlapping sample of depressed individuals (intent-to-treat: n=27) using an 8-week, open-label study. The primary efficacy measure was the MADRS, while, cognitive composites and plasma cytokines were secondary outcome measures.
Results: Results from multinomial logistic regression analyses indicate that IL-6 levels were increased in depressed and euthymic individuals with BD when compared to HCs, while, levels of CCL3, IL-15, and IL-17A were reduced below levels of HCs in euthymic individuals (Pseudo R2=.648, p<.001). Higher levels of CXCL8 were associated with worse verbal memory (R2=.343, p<.001) and psychomotor speed (R2=.431, p<.001), independent of illness activity. Adjunctive minocycline was associated with a reduction in depression severity on the MADRS (p<.001, d=.835), HAMD-17 (p<.001, d=.949) and CGI-S (p<.001, d=1.09). Minocycline did not exert pro-cognitive effects, independent of change in depressive symptom severity.
Conclusions: Increased levels of IL-6 and CXCL8 may be state-independent markers of BD and cognitive dysfunction, respectively. The interventional study provides ‘proof-of-concept’ evidence that reducing inflammation with minocycline mitigates symptoms of bipolar depression.
Previous studies suggest elevated inflammation in schizophrenia and bipolar disorder, with increased activity of the Interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF)-alpha, von Willebrand factor (vWf) and osteoprotegerin (OPG). It is unclear how immune activation is involved in the psychopathology. We investigated if elevated inflammation was associated with disease severity (trait) or current symptom level (state), comparing psychotic with general characteristics.
Plasma levels of sTNF receptor 1 (sTNF-R1), IL-1 receptor antagonist (IL-1Ra), IL-6, vWf and OPG were measured with ELISA techniques in 322 patients with schizophrenia spectrum and bipolar disorder. Current symptom level (state) was measured with Global Assessment of Functioning (GAF) and Positive and Negative Syndrome Scale (PANSS). Disease severity (trait) was measured with premorbid adjustment scale (PAS), age at onset, number of psychotic episodes and number and length of hospitalizations.
After controlling for confounders, IL-1Ra and TNF-R1 were independently associated with GAF, and significantly correlated with PANSS negative and positive, respectively. In addition, Il-1Ra was associated with PAS, and sTNF-R1 with number of hospitalizations and psychotic episodes. VWf was significantly correlated with psychotic episodes, OPG with hospitalizations and IL-6 with history of psychosis. Linear regression analysis showed that GAF remained associated with sTNF-R1 and IL-1Ra with PANSS, after controlling for the other clinical measures.
This supports that inflammatory markers, particularly IL-1Ra and sTNF-R1 are associated with both general disease severity and psychotic features. This supports a role of immune activation in the core pathological mechanisms of severe mental disorders.
The activation of inflammatory cascades has been consistently demonstrated in the pathophysiology of Alzheimer's disease (AD). Among several putative neuroinflammatory mechanisms, the tumor necrosis factor α (TNF-α) signaling system has a central role in this process. Recent evidence indicates that the abnormal production of inflammatory factors may accompany the progression from mild cognitive impairment (MCI) to dementia. We aimed to examine serum levels of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in patients with MCI and AD as compared to cognitively unimpaired elderly subjects. We further aimed to investigate whether abnormal levels of these cytokines predict the progression from MCI to AD upon follow-up. We utilized cross-sectional determination of serum levels of TNF-α, sTNFR1, and sTNFR2 (ELISA method) in a test group comprising 167 older adults (31 AD, 72 MCI, and 64 healthy controls), and longitudinal reassessment of clinical status after 18.9 ± 10.0 months. At baseline, there were no statistically significant differences in serum TNF-α, sTNFR1, and sTNFR2 between patients with MCI and AD as compared to controls. Nevertheless, patients with MCI who progressed to AD had significantly higher serum sTNFR1 levels as opposed to patients who retained the diagnosis of MCI upon follow-up (p = 0.03). Cox regression analysis showed that high serum sTNFR1 levels predicted the conversion from MCI to AD (p = 0.003), whereas no significant differences were found with respect to serum levels of TNF-α and sTNFR2. Abnormal activation of TNF-α signaling system, represented by increased expression of sTNFR1, is associated with a higher risk of progression from MCI to AD.
To review extant literature implicating inflammation in the pathophysiology of bipolar disorder. Furthermore, we review evidence regarding the anti-inflammatory actions of mood-stabilizing medication, the putative reciprocal association of inflammation with behavioral parameters and medical burden in bipolar disorder, and the potential role of anti-inflammatory agents in the treatment of bipolar disorder.
MEDLINE and PubMed searches were conducted of English-language articles published from 1950 to April 2008 using the search terms bipolar disorder, manic, or mania, cross-referenced with inflammation, inflammatory, interleukin, cytokine, C-reactive protein, or tumor necrosis factor. The search, which was conducted most recently on August 20, 2008, was supplemented by manually reviewing reference lists from the identified publications.
Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality.
Studies were reviewed for statistical comparisons of cytokines among persons with and without bipolar disorder, during symptomatic and non-symptomatic intervals and before and after pharmacologic treatment. Significant and nonsignificant findings were tabulated.
Available evidence indicates that bipolar disorder and inflammation are linked through shared genetic polymorphisms and gene expression as well as altered cytokine levels during symptomatic (i.e., mania and depression) and asymptomatic intervals. However, results are inconsistent. Several conventional mood stabilizers have anti-inflammatory properties. The cyclooxygenase-2-selective anti-inflammatory celecoxib may offer antidepressant effects. Inflammation is closely linked with behavioral parameters such as exercise, sleep, alcohol abuse, and smoking, as well as with medical comorbidities including coronary artery disease, obesity and insulin resistance, osteoporosis, and pain. Methodological limitations precluding definitive conclusions are heterogeneity in sample composition, cytokine assessment procedures, and treatment regimens. The inclusion of multiple ethnic groups introduces another source of variability but also increases the generalizability of study findings.
Inflammation appears relevant to bipolar disorder across several important domains. Further research is warranted to parse the reciprocal associations between inflammation and symptoms, comorbidities, and treatments in bipolar disorder. Studies of this topic among youth are needed and may best serve this purpose.
Reports of cognitive decline, symptom worsening and brain atrophy in bipolar disorder (BD) suggest that the disease progresses over time. The worsening neuropathology may involve excitotoxicity and neuroinflammation. We determined protein and mRNA levels of excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from 10 BD patients and 10 age-matched controls. The brain tissue was matched for age, postmortem interval and pH. The results indicated statistically significant lower protein and mRNA levels of the N-methyl-D-aspartate receptors, NR-1 and NR-3A, but significantly higher protein and mRNA levels of interleukin (IL)-1beta, the IL-1 receptor (IL-1R), myeloid differentiation factor 88, nuclear factor-kappa B subunits, and astroglial and microglial markers (glial fibrillary acidic protein, inducible nitric oxide synthase, c-fos and CD11b) in postmortem frontal cortex from BD compared with control subjects. There was no significant difference in mRNA levels of tumor necrosis factor alpha or neuronal nitric oxide synthase in the same region. These data show the presence of excitotoxicity and neuroinflammation in BD frontal cortex, with particular activation of the IL-R cascade. The changes may account for reported evidence of disease progression in BD and be a target for future therapy.
Circadian alterations of several immune functions in vivo are well established, and may have important physiological and clinical implications. In line with this, tumor necrosis factor (TNF)-alpha has been implicated in the circadian regulation of body temperature. As soluble TNF receptors (TNF-R) act as naturally occurring competitive inhibitors of this cytokine, we investigated plasma levels of the soluble sTNF-R55 and sTNF-R75 in comparison with plasma cortisol and body temperature in nine healthy male volunteers during a defined 16 h light/8 h dark cycle. It was found that sTNF-R75, but not sTNF-R55, exhibited a clear-cut circadian rhythm with a significant (P < 0.01) peak at 7:51 a.m. +/- 58 min. The phase of the sTNF-R75 rhythm preceded that of cortisol by approximately 1 h and inversely corresponded to the circadian rhythm of body temperature. Moreover, the individual amplitudes of sTNF-R75 and body temperature exhibited a significant (P < 0.01) positive correlation. These results suggest that (i) the two sTNF-R are regulated independently, (ii) the sTNF-R75 rhythm is not primarily due to the cortisol rhythm and (iii) the fluctuation of the sTNF-R may contribute to the regulation of body temperature by modulating the availability of free TNF.
Investigators first described the night-eating syndrome (NES), which consists of morning anorexia, evening hyperphagia, and insomnia, in 1955, but, to our knowledge, this syndrome has never been subjected to careful clinical study.
To characterize NES on the basis of behavioral characteristics and neuroendocrine data.
A behavioral observational study was conducted between January 1996 and June 1997 in a weight and eating disorders program at the University of Pennsylvania. A neuroendocrine study was conducted from May through August 1997 at the Clinical Research Center of the University Hospital, Tromso, Norway.
The behavioral study included 10 obese subjects who met criteria for NES and 10 matched control subjects. The neuroendocrine study included 12 night eaters and 21 control subjects. Behavioral study subjects were observed for 1 week on an outpatient basis, and neuroendocrine study subjects were observed during a 24-hour period in the hospital.
The behavioral study measured timing of energy intake, mood level, and sleep disturbances. The neuroendocrine study measured circadian levels of plasma melatonin, leptin, and cortisol.
In the behavioral study, compared with control subjects, night eaters had more eating episodes in the 24 hours (mean [SD], 9.3 [0.6] vs 4.2 [0.2]; P<.001) and consumed significantly more of their daily energy intake at night than did control subjects (56% vs 15%; P<.001). They averaged 3.6 (0.9) awakenings per night compared with 0.3 (0.3) by controls (P<.001). In night eaters, 52% of these awakenings were associated with food intake, with a mean intake per ingestion of 1134 (1197) kJ. None of the controls ate during their awakenings. In the neuroendocrine study, compared with control subjects, night eaters had attenuation of the nocturnal rise in plasma melatonin and leptin levels (P<.001 for both) and higher circadian levels of plasma cortisol (P = .001).
A coherent pattern of behavioral and neuroendocrine characteristics was found in subjects with NES.
To study the relation of fibrinogen and C-reactive protein (CRP) to various measures of body fat and body fat distribution and to investigate whether these relations were explained by differences in insulin sensitivity.
Cross-sectional analysis of the IRAS (Insulin Resistance Atherosclerosis Study), a large (n=1559) tri-ethnic population (non-Hispanic whites, African-Americans and Mexican-Americans) across different states of glucose tolerance.
Glucose tolerance (oral glucose tolerance test), insulin sensitivity (frequently sampled intravenous glucose tolerance test and minimal model analysis), assessment of body fat mass and distribution (weight, girths, bioelectrical impedance), subclinical atherosclerosis (B-mode ultrasonography of carotid artery intima-media thickness, IMT), CRP (highly sensitive immunoassay), fibrinogen (standard assay).
Both CRP and fibrinogen were related to all measures of body fat. Strong correlations (correlation coefficient r > or = 0.35) were found between CRP and body mass index (BMI), waist circumference and adipose body mass, respectively. The associations were consistent in non-diabetic and type-2 diabetic subjects, were generally stronger in women, and were only moderately attenuated by the prevailing insulin sensitivity (S(I)). In a multivariate linear regression model waist circumference explained 14.5% of the variability of circulating CRP levels (P=0.0001), BMI 0.4% (P=0.0067), and S(I) 1.7% (P=0.0001). Common carotid artery IMT was related to CRP and fibrinogen in men, but not in women, and was attenuated after adjusting for BMI or waist.
Our findings show that measures of body fat are strongly associated with circulating levels of CRP and fibrinogen. These associations were not explained by lower S(I) in obese subjects. Chronic, subclinical inflammation may be one pathophysiological mechanism explaining the increased risk of atherosclerotic disease associated with adiposity.
To explore the links between tumor necrosis factor alpha (TNFalpha) and leptin adipose tissue expression and low-grade systemic inflammation and to determine the relationship between inflammation and the degree of adiposity, the presence of type 2 diabetes, and other cardiovascular risk factors.
Ninety-one women (BMI 19 to 65 kg/m(2)) were divided into tertiles of CRP. Insulin resistance was calculated using the HOMA method. Albumin, fibrinogen, C-reactive protein (CRP), interleukin-6, sTNFR1, sTNFR2, and leptin levels were measured in serum and plasma samples. TNFalpha and leptin expression were measured by reverse transcription-polymerase chain reaction in abdominal subcutaneous adipose tissue samples.
CRP was positively related to BMI and upper distribution of adiposity. TNFalpha and leptin adipose tissue expression were higher in the upper tertile of CRP. Also, peripheral levels of both soluble TNFRs and leptin were higher in patients with the greatest inflammation degree. Diabetes, dislipidemia, and hypertension were most prevalent in patients in the upper CRP tertile. Inflammatory markers of diabetic women were significantly different from those of nondiabetic women, even after adjusting for differences in body fat. BMI, type 2 diabetes, and adipose TNFalpha mRNA levels were significant predictors of serum CRP levels (r(2) = 0.28, p < 0.001).
These results are in agreement with the hypothesis that the synthesis of adipose tissue TNFalpha and leptin could induce the production of interleukin-6, CRP, and other acute-phase reactants, thus contributing to the maintenance of chronic low-grade inflammation state involved in the progression of obesity and its associated comorbidities.
The secreted form of the interleukin-1 receptor antagonist (IL-1Ra) is an acute-phase protein intervening in the counterregulation of inflammatory processes. We previously showed that this cytokine antagonist is upregulated in the serum of obese patients, correlating with BMI and insulin resistance. In this study, we examined the expression pattern of IL-1Ra and showed that it is highly expressed not only in liver and spleen, but also in white adipose tissue (WAT), where it is upregulated in obesity. In WAT of obese humans, IL-1Ra was also markedly increased. Moreover, human WAT explants secreted IL-1Ra into the medium, a process that could be stimulated fivefold by interferon-beta. Finally, lipopolysaccharide administration induced a long-lasting expression of IL-1Ra in mouse WAT, suggesting that adipose tissue is an important source of IL-1Ra in both obesity and inflammation. In summary, we demonstrated that WAT is one of the most important sources of IL-1Ra quantitatively, suggesting that this tissue could represent a novel target for anti-inflammatory treatment. Moreover, it can be speculated that IL-1Ra, whose production is markedly increased in WAT in obese individuals, contributes further to weight gain because of its endocrine and paracrine effects on the hypothalamus and adipocytes, respectively.
Cross-sectional studies have associated obesity and other components of the so-called metabolic syndrome with low-grade inflammation. The temporal and causal relations of this association have not been fully explored. This study explored whether elevated levels of inflammation-sensitive plasma proteins (ISPs) (fibrinogen, orosomucoid, alpha1-antitrypsin, haptoglobin, and ceruloplasmin) are associated with future weight gain. Five ISPs were measured in 2,821 nondiabetic healthy men (38-50 years of age) who were reexamined after a mean follow-up of 6.1 years. Future weight gain was studied in relation to the number of elevated ISPs (i.e., in the top quartile). The proportion with a large weight gain (75th percentile >/= 3.8 kg) was 21.0, 25.9, 26.8, and 28.3%, respectively, among men with none, one, two, and three or more ISPs in the top quartile (P for trend 0.0005). This relation remained significant after adjustments for weight at baseline, follow-up time, height (at baseline and follow-up), physical inactivity (at baseline and follow-up), smoking (at baseline and follow-up), high alcohol consumption, and insulin resistance. The relations were largely similar for all individual ISPs. Elevated ISP levels predict a large weight gain in middle-aged men. This relation could contribute to the relation between inflammation, the metabolic syndrome, and cardiovascular disease.
Our knowledge concerning immune functioning in bipolar affective disorder (BAD) is limited, while lithium's immunomodulatory effects seem multiple and conflicting. Our aim was to evaluate cytokine production and lithium's effect on it in BAD patients, using ELISPOT technique as a sensitive tool.
Cytokine (IL-2, IL-6, IL-10 and IFN-gamma) production from isolated peripheral blood lymphocytes (PBLs) was evaluated (ELISPOT technique) in 40 euthymic BAD patients under chronic lithium treatment, in 20 healthy volunteers, and in 10 never medicated BAD patients before and after the introduction of lithium therapy. In all cases, cytokine plasma levels were also measured using ELISA.
BAD patients under chronic lithium treatment had significantly lower numbers of IL-2, IL-6, IL-10 and IFN-gamma secreting cells compared to healthy volunteers. The number of cytokine secreting cells decreased in never medicated patients after 3 months of lithium treatment. In vitro stimulation of PBLs with lithium did not affect the number of cytokine secreting cells either in the patients or in the healthy volunteers.
The significantly lower number of PBLs producing cytokines (IL-2, IL-6, IL-10 and IFN-gamma) in euthymic BAD patients under chronic lithium treatment result from the long-term (over 3 months) lithium administration. In vitro stimulation of PBLs with lithium did not change the number of cytokine producing cells. Our findings may be useful in elucidating possible downregulatory effects of lithium in humans.
Post-mortem studies conducted over the past 15 years suggest that apoptosis could play a role in the pathophysiology of bipolar disorder (BD) and, to a lesser degree, schizophrenia (SZ). To test this hypothesis, we have performed a post hoc analysis of an extant gene expression profiling database obtained from the hippocampus using a novel methodology with improved sensitivity. Consistent with the working hypothesis, BDs showed a marked upregulation of 19 out of 44 apoptosis genes; however, contrary to the hypothesis, the SZ group showed a downregulation of genes associated with apoptotic injury and death. These changes in the regulation of apoptosis genes were validated using quantitative RT-PCR. Additionally, antioxidant genes showed a marked downregulation in BDs, suggesting that accumulation of free radicals might occur in the setting of a previously reported decrease of the electron transport chain in this disorder. Overall, the changes seen in BDs and SZs do not appear to be related to exposure to either neuroleptics or mood stabilizers. We conclude that fundamental differences in the genetic regulation of apoptosis and antioxidant genes may help discriminate between the pathophysiology of BD and SZ and potentially point to new treatment strategies that are specific for each disorder.
Numerous studies have revealed an association between nutritional status, adiposity, and reproductive maturity. The role of
leptin, a hormone secreted from adipose tissue, in the onset of reproductive function was investigated. Normal prepubertal
female mice injected with leptin grew at a slower rate than controls as a result of the hormone's thinning effects, but they
reproduced up to 9 days earlier than controls and showed earlier maturation of the reproductive tract. These results suggest
that leptin acts as a signal triggering puberty, thus supporting the hypothesis that fat accumulation enhances maturation
of the reproductive tract.
After relative neglect in the age of melancholy during the 1970s and 1980s, there has been a renaissance of bipolar disorder during the last decade of the 20thcentury. The new bipolar era has also witnessed the development of innovative pharmacological and psychosocial interventions specifically geared for this disorder. The signs and symptoms of the classical cyclical illness are unmistakable. However, the illness may begin insidiously with manifestations of a subthreshold or disturbances of a temperamental nature buried in early childhood or adolescence. As the primary aim of this chapter is to review the current body of research evidence and clinical experience in the diagnosis and classification of bipolar disorder, there will be no attempt to exhaustively review comorbidity. The latter will be limited to the most disputed clinical boundaries of bipolar disorder.
The serum levels of soluble tumor necrosis factor receptor I (sTNF-RI) were measured in 74 noncachectic patients including
42 with gastric cancer and 32 with colorectal cancer, as well as in 39 patients with severe cachexia and 15 healthy volunteers.
The sTNF-RI levels increased with the advance of disease, being highest in the cachectic patients. The levels were inversely
correlated with the serum concentrations of nutritional parameters such as prealbumin, transferrin, retinol binding protein,
and the percentages of CD3(+) cells in the peripheral blood lymphocytes, and positively correlated with the serum concentration
of immunosuppressive acidic protein (IAP) and soluble interleukin-2 receptors. These findings suggest that sTNF-RI could be
an important prognostic factor to predict the advance of gastric and colorectal cancers and deterioration of the patient’s
nutritional and immune activity.
Key Wordstumor necrosis factor–gastric cancer–colorectal cancer–tumor immunology–macrophage
We investigated the association between serum levels of C-reactive protein (CRP), a marker of inflammation, and the severity of psychopathology in outpatients with bipolar disorder. We also compared the levels of CRP in the bipolar disorder individuals with those of a non-psychiatric control group.
We measured the level of CRP in N=122 outpatients with bipolar disorder and N=165 control individuals and evaluated the symptom severity of the bipolar disorder patients with the Young Mania Rating Scale (YMRS) and the Hamilton Depression Scale (Ham-D).
Within the bipolar disorder sample, CRP was significantly associated with the YMRS score (r=.306, p<.006), age of onset, gender, and race. CRP was not significantly associated with the Ham-D score or other clinical or demographic variables. In a multivariate analysis of covariance, CRP was the only independent predictor of YMRS score (F=11.7, p=.0009). The CRP levels of the n=41 individuals with YMRS >6 were significantly greater than the levels of the n=81 individuals with YMRS <or=6 (F=7.94, <.006). The CRP levels of the group with YMRS >6 were also significantly greater than the levels of the control group (p=.033) while the CRP levels of the group with YMRS <or=6 did not differ from that of controls (p>.05).
Our results suggest that outpatients with bipolar disorder with mania symptoms have increased levels of CRP as compared to those without mania symptoms and compared to individuals without psychiatric disorders. The long-term consequences of CRP in bipolar disorder should be the subject of future studies.
Insulin resistance, quantified by hyperinsulinemia, has been identified as a preclinical state for metabolic syndrome. Acute medicated bipolar patients are vulnerable to hyperinsulinemia in early remission. We examined the proportion of fasting serum insulin levels in remitted bipolar patients and considered what factors may contribute to hyperinsulinemia.
Measurements taken in this study included the fasting plasma levels of insulin, glucose, triglycerides, total cholesterol, high-density-lipoprotein-cholesterol, low-density-lipoprotein-cholesterol, and the body mass index (BMI) among 56 bipolar I manic patients in full remission. We examined serum insulin levels in order to explore the correlation between and within the hyperinsulinemia and non-hyperinsulinemia groups.
A total of 15 patients (26.8%) were identified as having hyperinsulinemia. Among all factors, only BMI was associated with higher serum insulin level (BMI ≥ 24: odds ratio of 8.57; P < 0.01; 95% confidence interval, 1.65-44.43).
Hyperinsulinemia was not more prevalent in medicated euthymic bipolar patients compared with the general population. However, increasing bodyweight may make these patients more vulnerable to hyperinsulinemia, irrespective of their mood stabilizers or antipsychotics. Weight management should not be ignored in euthymic bipolar patients to prevent the preclinical state for metabolic syndrome.
Some healthy older adults have difficulty regaining weight after acute weight loss, and the reason for this failure to regain weight is unknown. The objective of this study was to determine if elevated leptin or pro-inflammatory cytokine levels are associated with failure to regain weight over two years after an acute weight loss intervention.
Two year prospective study after an acute weight loss intervention.
University of Washington Medical Center from 2001-2006.
Nineteen older (≥ 70 years old) men and women.
Body weights, health status questionnaire, body composition data, serum leptin, glucose, insulin, C- reactive protein and pro-inflammatory cytokine levels were measured every six months for two years.
Five subjects out of 19 failed to regain weight after two years. The subjects who failed to regain weight after 2 years had higher circulating levels of tumor necrosis factor receptor particle 55 (TNFRp55) at baseline and at 6, 12, 18 and 24 months of follow up compared to subjects who regained weight after 2 years (P = 0.02 ).
Five out of 19 older subjects had difficulty regaining weight for up to 2 years following an acute weight loss intervention, and their TNFRp55 levels were persistently higher than in subjects who regained weight. Greater TNF α action, as reflected by higher circulating levels of TNFRp55, could be contributing towards inability of some older persons to regain weight after acute weight loss.
Bipolar disorder (BD) has been associated with a proinflammatory state in which TNF-α seems to play a relevant role. The aim of the present study was to evaluate the plasma levels of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in BD patients in mania and euthymia in comparison with control subjects. We evaluated 53 BD patients (34 in mania and 19 in euthymia) and 38 healthy subjects. All subjects were assessed by the Mini-International Neuropsychiatry Interview (MINI-Plus). Patients were also evaluated by the Young Mania Rating Scale (YMRS) and by Hamilton Depression Rating Scale (HDRS). Plasma TNF-α and its soluble receptors were measured by ELISA. The plasma TNF-α and sTNFR2 levels did not differ between groups, but higher sTNFR1 levels were found in BD patients. Of note, BD patients in mania had higher sTNFR1 levels than BD patients in euthymia and controls. The sTNFR1 and sTNFR2 levels correlated with BD duration, and sTNFR2 levels correlated with age of patients. Our data indicate a proinflammatory status in BD patients during mania and further suggest that inflammatory mechanisms may be involved with the physiopathology of BD.
The authors investigated the differences in cognitive function, medical burden, and sociodemographic characteristics between elderly community-dwelling bipolar patients and age-matched and education-matched normal individuals.
Case-control study.
Taipei Medical University Hospital, with 75 psychiatric beds, and Taipei City Psychiatric Center-a 612-bed psychiatric teaching hospital providing comprehensive psychiatric services.
Eighty-two euthymic outpatients with bipolar I disorder aged older than 60 years received assessment for research purpose, 59 of whom were matched with one normal control for age and years of education.
All subjects had measurements of cognitive function (Clock-drawing test and Mini-Mental State Examination [MMSE]). Medical morbidity and health condition were according to the medical records, results of free annual elderly health examination, and physical examination on research interviewing.
Elderly bipolar patients were found to be more likely than the comparison group to have diabetes mellitus (27.1%), atopic diseases (20.3%), abnormal education-adjusted MMSE scores (32.2%), smoking habit (23.7%), and unfavorable social functioning (22%). Despite having noticeably higher heart rates, the bipolar patients' mean systolic blood pressure and prevalence of hypertension (44.1%) were significantly lower than those of the comparison group.
Although community-dwelling elderly patients with bipolar disorder seem to be characterized by a greater likelihood of developing cognitive dysfunction and concurrent diabetes mellitus, there is no apparent increase in the morbidity of circulatory diseases, particularly less hypertension among those without previous dementia.
This review describes patients with schizophrenia and bipolar disorder. In such patients, a high inflammatory set point of circulating monocytes at the transcriptome level is observed, involving various inflammatory transcripts forming distinct fingerprints (the transcriptomic monocyte fingerprint in schizophrenia overlaps with that in bipolar disorder, but also differs with it at points). There are increased levels of compounds of the IL-1, IL-6 and TNF system in the serum (be it modest and inconsistent). There is also evidence that the IL-2 system is activated in patients with schizophrenia (and perhaps those with mania), although independently of the activation of the IL-1, IL-6 and TNF systems, suggesting separate inducing mechanisms for monocyte and T-cell activation. It is not yet known whether such T cell activation involves the Th1/Th2/Th17 or Treg systems.
Acute Myocardial Infarction (AMI) is one of the main causes of mortality and disability in Colombia. The factors associated to a new event in surviving subjects to a first AMI in our population have not yet been fully identified.
Two hundred and ninety five surviving subjects to a first AMI (58.8±12.6 years) were included in a prospective cohort study between 2000 and 2006. Lipid profile, glycemia and plasma insulin levels were measured. Deaths of cardiovascular origin, a new AMI, unstable angina, heart failure, stroke, new myocardial revascularization or angioplasty were considered new cardiovascular events.
The study included 61 (20.6%) women and 234 (79.4%) men. The mean follow up time was 50±30 months with a 38.9% incidence of new events. Fifty five patients (18.6%) were diabetic. Bi-varied analysis identified as risk factors for a new cardiovascular event the presence of: hypertension, anterior descending coronary artery stenosis, intrahospital cardiac failure, age over 55, low income, lack of education, Killip III-IV, heart rate over 76 bpm, pulse pressure over 80 mmHg, total cholesterol over 200 mg/dl and insulin over 10 IU/ml. After logistic regression analysis, the log values of insulin remained as the only significant predictor for new cardiovascular events.
Hyperinsulinism was the most important factor associated to the occurrence of new cardiovascular events in Colombian patients with AMI, which emphasizes the pivotal role of insulin resistance in the physiopathologic mechanisms of atherosclerosis, especially in undeveloped countries.
Alterations in the inflammatory system have been associated with schizophrenia and major depression, while bipolar disorder has been less studied. Most previous studies examined small samples, and the literature is inconsistent with regard to specific underlying immune mechanisms. In the present study, we examined markers representing different inflammatory pathways, and the aim was to investigate whether the levels of inflammatory parameters in a representative sample of bipolar disorder and schizophrenia are elevated compared to healthy controls, and to investigate whether the inflammatory profile is different between the groups.
Plasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), high-sensitivity CRP (hs-CRP), soluble CD40L ligand (sCD40L), and von Willebrand factor (vWf) were measured with ELISA techniques in a catchment area based sample of consecutively referred patients with severe mental disorders [N = 311, comprising bipolar disorder (n = 125) and schizophrenia (n = 186)] and in healthy volunteers (n = 244).
Plasma levels of sTNF-R1 and vWf were statistically significantly increased in both bipolar disorder and schizophrenia compared to controls (p < 0.00001), and were also increased in unmedicated patients, but there were no major differences between the two diagnostic groups. Controlling for age, gender, ethnicity, cardiovascular disorders, kidney and liver function, and other confounders did not affect the results. There were no differences in other inflammation factors between the groups.
The present results indicate specific alterations of endothelium-related inflammation processes in both bipolar disorder and schizophrenia.
Epidemiological studies suggest that elders with bipolar disorder (BD) may be at increased risk for dementia compared to the general population. We sought to investigate whether older adults with BD would present with more cognitive dysfunction than expected for their age and education, and whether they would experience a more rapid cognitive decline over three-year prospective follow-up.
Thirty-three subjects age > or = 50, mean (SD) age 69.7 (7.9) years, with BD I (n = 28) and II (n = 5) had neuropsychological examination at baseline and longitudinally over three years. All subjects were administered the Dementia Rating Scale (DRS) when euthymic. Thirty-six mentally healthy comparators ('controls'), equated on age and education, were selected from ongoing studies in our research center examining the longitudinal relationship between late-life mood disorders and cognitive function.
Compared to mentally healthy comparators, subjects with BD performed significantly worse on the DRS at baseline [mean (SD) 135.2 (4.7); n = 33 versus 139.5 (3.3); n = 36], and over follow-up [131.9 (7.7); n = 14 versus 139.1 (3.4); n = 22]. There was a group-by-time interaction between the subjects with BD and the controls [group x time: F(1,64) = 5.07, p = 0.028].
In our study, older adults with BD had more cognitive dysfunction and more rapid cognitive decline than expected given their age and education. Cognitive dysfunction and accelerated cognitive decline may lead to decreased independence, with increased reliance on family and community supports, and potential placement in assisted-living facilities.
An eleven item clinician-administered Mania Rating Scale (MRS) is introduced, and its reliability, validity and sensitivity are examined. There was a high correlation between the scores of two independent clinicians on both the total score (0.93) and the individual item scores (0.66 to 0.92). The MRS score correlated highly with an independent global rating, and with scores of two other mania rating scales administered concurrently. The score also correlated with the number of days of subsequent stay in hospital. It was able to differentiate statistically patients before and after two weeks of treatment and to distinguish levels of severity based on the global rating.
Synopsis
The problems which arise in the use of a psychiatric screening instrument in a language and culture other than that in which it was designed and developed are considered. An account is given of the development of a psychiatric screening questionnaire suitable for use in Chinese community samples. The questionnaire was derived from a Chinese translation of the General Health Questionnaire, with the addition of specially designed, culturally-relevant items. Discriminant function analysis was then used to select a subset of 12 items which discriminated well between ‘cases’ and ‘normals’ in the community.
The antipsychotic drug clozapine frequently induces fever during the first weeks of administration. In addition, it has been shown that clozapine increases plasma soluble interleukin-2 receptor (sIL-2r) levels as early as 1 week after treatment is started. These findings suggest that clozapine has immunomodulatory effects. To investigate this issue in more detail, we assessed the time course of rectal temperature, blood cell counts, and cytokine and soluble cytokine receptor plasma levels during 6 weeks of clozapine treatment in 27 schizophrenic patients. Clozapine increased the plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, and sIL-2r. These increases were independent of prior or concurrent medication and did also occur in patients who did not experience clozapine-induced fever. However, increases in TNF-alpha and sIL-2r levels were more pronounced in patients with clozapine-induced fever who showed in addition increased plasma IL-6 levels and granulocyte counts. Plasma IL-1 receptor antagonist levels and monocyte and lymphocyte counts were not affected by clozapine treatment. It is concluded that clozapine has consistent in vivo immunomodulatory effects. The results presented suggest that clozapine-induced fever is mediated by pyrogenic cytokines.
Numerous studies have revealed an association between nutritional status, adiposity, and reproductive maturity. The role of leptin, a hormone secreted from adipose tissue, in the onset of reproductive function was investigated. Normal prepubertal female mice injected with leptin grew at a slower rate than controls as a result of the hormone's thinning effects, but they reproduced up to 9 days earlier than controls and showed earlier maturation of the reproductive tract. These results suggest that leptin acts as a signal triggering puberty, thus supporting the hypothesis that fat accumulation enhances maturation of the reproductive tract.
Inflammation might promote the development of atherosclerosis, and high levels of C-reactive protein (CRP) and fibrinogen are associated with an increased risk of acute coronary events.
We assessed the levels of CRP and other risk factors in patients with angiographically documented coronary artery disease compared with healthy volunteers and patients undergoing coronary angiography who had normal coronary angiograms.
Ultrasensitive immunoassay was used to measure CRP levels in 142 patients with coronary disease (group 1), 37 patients with normal coronary angiograms (group 2), and 37 control healthy subjects (group 3).
CRP levels were higher in group 1 (7.1 +/- 11.2 mg/L) compared with group 2 (4.8 +/- 4.0 mg/L) and group 3 (2.3 +/- 3.6 mg/L). In group 1, CRP levels were higher for patients with previous myocardial infarction (8.7 +/- 9.2 mg/L) or unstable angina (11.6 +/- 18.8 mg/L). Though CRP levels in patients with coronary artery disease and stable symptoms were higher compared with healthy volunteers (5.15 +/- 7.2 mg/L vs 2.3 +/- 3.6 mg/L, P <.05), they were similar to those observed in the control population of patients with normal coronary angiograms (4.8 +/- 4.0 mg/L). Furthermore, CRP levels were positively correlated to plasma fibrinogen but not to Chlamydia pneumoniae or Helicobacter pylori serology.
These results suggest that CRP has a strong association with acute coronary events but do not support the hypothesis that CRP is a potent determinant of chronic stable coronary disease.
The purpose of this study was to examine the variability in cytokines and cytokine receptors in patients with heart failure in comparison with a group of healthy control subjects who were free of cardiovascular disease.
Despite increasing interest in cytokines as mediators of disease progression in heart failure and the recent interest in suppressing cytokines in clinical studies, the extent of variability in cytokines and cytokine receptors is largely unknown. This information is important for interpreting the results of studies in which changes in cytokine levels are measured in response to a specific form of therapy.
Circulating levels of tumor necrosis factor-alpha (TNF-alpha), and soluble TNF receptors (types 1 and 2), as well as interleukin (IL)-6 and IL-6 receptor were measured on a daily, weekly and monthly basis in heart failure patients (New York Heart Association class IIIa and IIIb; n = 10) and healthy volunteer subjects (n = 10). Measurements of cytokines and cytokine receptors were performed on plasma samples by enzyme-linked immunoassay. The daily, weekly and monthly degree of variability in cytokine and cytokine receptor levels was assessed by determining the coefficient of variation each point in time.
The coefficient of variation for TNF-alpha and IL-6 levels increased over time in patients with heart failure; moreover, the coefficient of variation in heart failure subjects was significantly greater for IL-6 than for TNF-alpha. The coefficient of variation in cytokine receptor levels was minimal, and did not differ significantly between heart failure and control subjects.
In patients with heart failure the degree of natural variability in circulating cytokine levels increases with time, and is greater for IL-6 than for TNF-alpha. Accordingly, the results of the present study suggest that the sample size needed to show a statistically significant change in the circulating level of a given cytokine will vary depending on the specific cytokine that is being measured, as well as the time period over which that cytokine is being assayed.
Evidence supports that macrophages as well as lymphocytes and their products may be involved in the pathophysiology of psychiatric disorders. Whether patients with bipolar disorder have activation or reduction of immunity during a manic episode remains unclear.
The purpose of this case-control study was to investigate the lymphocyte proliferation to phytohemagglutinin (PHA), concanavalin A, and pokeweed mitogen, and plasma levels of soluble interleukin-2 receptor (sIL-2R) and sIL-6R in patients with bipolar mania (DSM-III-R). The subjects were 23 physically healthy patients with Young Mania Rating Scale (YMRS) scores > or = 26 as well as aged < or = 45 years and 23 age- and gender-matched normal control subjects. The above immune variables were measured in acute mania and consequent remission (YMRS scores < or = 12) among bipolar patients.
The lymphocyte proliferation to PHA and the plasma sIL-2R levels, but not sIL-6R, of bipolar patients were significantly higher in acute mania than in consequent remission. These elevations were not due to differences in medication status. Only in acute mania were the plasma sIL-2R levels of patients significantly higher than control subjects. A positive correlation between the changes of manic severity and plasma sIL-2R levels was observed. Remitted bipolar patients and normal control subjects did not differ in any of these measures.
Cell-mediated immunity activation in bipolar mania was demonstrated and may be through a specifically state-dependent immune response.
This study investigates immune function in rapid cycling bipolar patients and normal volunteers before and after 30 days of lithium treatment. Previous small studies in symptomatic bipolar patients suggested that nonspecific immune activation might be present. While studies of the effects of lithium on immune function found that lithium increased serum SIL-2RS in normal volunteers and seemed to normalize immune function in bipolar patients. We hypothesized that the immune profile of rapid cycling bipolar patients would also manifest immune activation that lithium treatment might normalize. The more stable serum immune measures (SIL-2RS and SIL-6RS) were increased in symptomatic rapid cycling patients and did normalize with lithium treatment. Lithium treatment increased IL-2, SIL-2RS and SIL-6RS in normal volunteers. These data suggest that rapid cycling bipolar patients may have mild immune activation which seems to normalize with lithium treatment.
Severely obese (ob/ob) mice are deficient in the adipocyte-derived hormone leptin, which acts on the hypothalamus to control appetite and energy expenditure.1 The administration of leptin to these mice corrects their obesity by reducing their food intake and increasing their energy expenditure.2–4 These mice also have hyperinsulinemia, corticosterone excess, and infertility, which also are reversed by treatment with leptin.5 In humans, serum leptin concentrations, in general, correlate positively with indexes of obesity.6,7 We previously described two cousins with severe, early-onset obesity and undetectable serum leptin concentrations who were homozygous for a frame-shift mutation in the leptin . . .
Circulating soluble interleukin-2 receptors (sIL-2Rs) and soluble interleukin-6 receptors (sIL-6Rs) are stable immune measures. Elevated plasma sIL-2R levels are present in patients with schizophrenia, major depression, and bipolar mania, but not with minor psychiatric disorders. The increased plasma sIL-2R levels are state-dependent in bipolar mania. However, altered production of plasma sIL-6R and the effects of clinical characteristics on plasma sIL-6R and sIL-2R levels in bipolar disorder remains uncertain.
Plasma sIL-2R and sIL-6R levels were measured in 31 Taiwanese bipolar manic (DSM-IV) patients with Young Mania Rating Scale (YMRS) scores of > or =26 as well as during the subsequent remission (YMRS< or =12), and equal numbers of age- and gender-matched healthy controls. The relationships of clinical variables such as age, age of onset, smoking, medication status, coexisting psychotic features, number of prior episodes, duration of illness, presence of depression before or following the manic episode, and manic severity to plasma sIL-2R and sIL-6R levels in acute mania along with remission were examined.
Plasma sIL-2R but not sIL-6R levels were significantly higher in acute mania than in subsequent remission (P<0.05) and controls (P<0.0005). In acute mania, the plasma sIL-2R levels were significantly correlated to YMRS scores (r=0.34, P<0.05). The remaining clinical variables had no effect on plasma sIL-2R and sIL-6R levels in acute mania or remission. There was a significantly positive relationship between the reduction of plasma sIL-2R levels from the acute to follow-up measurements (DeltasIL-2R) and symptomatic improvement of acute mania (DeltaYMRS) (r=0.61, P<0.001). Limitations: Our sample included medicated and unmedicated patients in acute mania. The psychotropic medication may have divergent effects on the plasma sIL-2R levels in acute mania and subsequent remission.
Elevation of plasma sIL-2R but not sIL-6R levels in bipolar mania supports the idea that the immunomodulatory mechanism may vary in different psychotic disorders. In contrast to being a trait marker in schizophrenia and depressive disorder, plasma sIL-2R levels may be considered a biological indicator of manic severity in a group of bipolar affective patients.
Leptin is a 16 kDa protein mainly produced by adipose tissue in proportion to adipose tissue mass. Originally thought to be a satiety factor, leptin is a pleiotropic molecule. In addition to playing a role in energy regulation, leptin also regulates endocrine and immune functions. Both the structure of leptin and that of its receptor suggest that leptin might be classified as a cytokine. The secondary structure of leptin has similarities to the long-chain helical cytokines family, which includes interleukin 6 (IL-6), IL-11, CNTF, and LIF, and the leptin receptor is homologous to the gp-130 signal-transducing subunit of the IL-6-type cytokine receptors. Leptin plays a role in innate and acquired immunity. Leptin levels increase acutely during infection and inflammation, and may represent a protective component of the host response to inflammation. More important, leptin deficiency increases susceptibility to infectious and inflammatory stimuli and is associated with dysregulation of cytokine production. Leptin deficiency also causes a defect in hematopoiesis. Leptin regulates T cells responses, polarizing Th cells toward a Th1 phenotype. Low leptin levels occurring during starvation mediate the neuroendocrine and immune dysfunction of starvation.
Obesity may be a low-grade systemic inflammatory disease. Overweight and obese children and adults have elevated serum levels of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and leptin, which are known markers of inflammation and closely associated with cardiovascular risk factors and cardiovascular and non-cardiovascular causes of death. This may explain the increased risk of diabetes, heart disease, and many other chronic diseases in the obese. The complex interaction between several neurotransmitters such as dopamine, serotonin, neuropeptide Y, leptin, acetylcholine, melanin-concentrating hormone, ghrelin, nitric oxide, and cytokines and insulin and insulin receptors in the brain ultimately determines and regulates food intake. Breast-feeding of more than 12 mo is associated with decreased incidence of obesity. Breast milk is a rich source of long-chain polyunsaturated fatty acids (LCPUFAs) and brain is especially rich in these fatty acids. LCPUFAs inhibit the production of proinflammatory cytokines and enhance the number of insulin receptors in various tissues and the actions of insulin and several neurotransmitters. LCPUFAs may enhance the production of bone morphogenetic proteins, which participate in neurogenesis, so these fatty acids might play an important role in brain development and function. It is proposed that obesity is a result of inadequate breast feeding, which results in marginal deficiency of LCPUFAs during the critical stages of brain development. This results in an imbalance in the structure, function, and feedback loops among various neurotransmitters and their receptors, which ultimately leads to a decrease in the number of dopamine and insulin receptors in the brain. Hence, promoting prolonged breast feeding may decrease the prevalence of obesity. Exercise enhances parasympathetic tone, promotes antiinflammation, and augments brain acetylcholine and dopamine levels, events that suppress appetite. Acetylcholine and insulin inhibit the production of proinflammatory cytokines and provide a negative feedback loop for postprandial inhibition of food intake, in part, by regulating leptin action. Statins, peroxisome proliferator-activated receptor-gamma binding agents, non-steroidal antiinflammatory drugs, and infant formulas supplemented with LCPUFAs, and LCPUFAs themselves, which suppress inflammation, may be beneficial in obesity.
The inflammatory response is essential in the response to pathogens. TNF-alpha, IL-1 and IL-6 are key mediators of the response. They initiate metabolic changes to provide nutrients for the immune system, from host tissues. These changes include hyperlipidemia and increased gluconeogenesis. Insulin resistance and disordering of lipid metabolism occur in obesity, diabetes mellitus, atherosclerosis. This review examines recent research that links inflammation to insulin insensitivity.
Population studies show a strong association between indices of inflammation, and abnormal lipid and carbohydrate metabolism, obesity and atherosclerosis. TNF-alpha is produced, by cells of the immune system and by adipocytes. It may provide the link between inflammation and insulin sensitivity. TNF-alpha results in insulin insensitivity, indirectly by stimulating stress hormone production and directly by sustained induction of SOCS-3 which decreases insulin-induced insulin receptor substrate 1 (IRS1) tyrosine phosphorylation and its association with the p85, regulatory subunit of phosphatidylinositol-3 kinase; and by negative regulation of PPAR gamma. Adipose tissue produces both TNF-alpha and leptin. Production of the latter relates positively to adipose tissue mass and through its actions on immune function exerts a pro-inflammatory influence.
Recent studies on diseases which involve insulin insensitivity (e.g. obesity, type 2 diabetes and atherosclerosis) also show increased cytokine production and markers of inflammation. Evidence at present favours chronic inflammation as a trigger for chronic insulin insensitivity, rather than the reverse situation.
Animal studies provide consistent evidence for the pivotal role of inflammatory cytokines in inducing sickness behavior during systemic infection and inflammation. Because depression in humans shows a considerable symptomatic overlap with sickness behavior, it has been hypothesized that cytokines are also involved in affective disorders. This view is supported by studies showing that therapeutic administration of inflammatory cytokines can induce typical major depression and by evidence that stimulated cytokine-release during experimental endotoxemia provokes transient deterioration in mood and memory. However, in these conditions, similar to the animal models of acute infections, huge amounts of cytokines produced in the periphery act on the brain. In contrast, during most clinical conditions where depression might involve cytokine actions, such as chronic infection and inflammation, only low amounts of cytokines are circulating. The present paper addresses the question whether and how low amounts of circulating cytokines act on the human brain. Evidence is presented that very low amounts of circulating cytokines are likely to influence brain functions, even under baseline conditions. It is also likely that low levels of cytokines affect the same brain function as high levels do. However, it is uncertain whether these effects go in the same direction. NonREM sleep, for example, is promoted by a slight increase in cytokine levels, but suppressed by prominent increases. Because no comparable data are available for mood and other brain functions, the answer to the question whether and how low circulating amounts of cytokines affect mood depends on further experimental studies.
Kupka RW, Breunis MN, Knijff E, Ruwhof C, Nolen WA, Drexhage HA. Immune activation, steroid resistancy and bipolar disorder.
Bipolar Disord 2002: 4(Suppl. 1): 73–74. © Blackwell Munksgaard, 2002
Previously, we found an increased prevalence of thyroid autoantibodies in patients with bipolar disorder. In the present study, we investigated other signs of immune activation in bipolar patients, in particular an activation of the T cell system.
Fluorescence activated cell scanning (FACS) analysis was performed on lymphocytes of 64 outpatients with DSM-IV bipolar disorder using the T cell marker CD3 in combination with the activation markers MHC-class II, CD25, CD69 or CD71. In 34 patients, these assays were repeated after an interval of 2 years. In addition, T cell activation was determined by measuring serum soluble IL-2 receptor (sIL-2R) in 172 bipolar outpatients. Outcomes were compared with a healthy control group.
Significantly higher numbers of circulating activated T cells and raised sIL-2R levels were found in euthymic, manic, and depressed bipolar patients when compared with healthy controls. In general, these abnormalities were stable over time. Manic patients showed significantly higher levels of sIL-2R in comparison with depressed patients.
The T cell system was found to be activated in both symptomatic and euthymic patients with bipolar disorder. The pathophysiological significance of these findings remains to be explored.
Clara cell protein (CC16) and transferrin receptor (TfR) have been reported as possible biological markers for major depression and schizophrenia. However, the alternations of plasma TfR and CC16 levels and the influences of numerous clinical variables on them during bipolar mania are not sufficiently described. We investigated the immune function of 36 bipolar I, manic (DSM-IV) patients with Young Mania Rating Scale (YMRS) scores > or =26 as well as during the subsequent remission (YMRS < or =12) and age- and sex- matched healthy controls. The plasma TfR levels were increased during acute mania along with subsequent remission and were independent of medication status, individual variations, clinical and erythrocyte variables. Among inflammatory parameters and haematological variables, the plasma TfR levels merely had significant and negative relationship with the percentage of monocyte in circulating leukocyte counts despite of elevated plasma soluble interleukin-2 receptors levels during bipolar mania. The plasma levels of CC16 of bipolar patients did not significantly alter during acute mania, whereas smoking, body mass index, and co-existing psychotic features collectively contributed 42% of the plasma levels of CC16. We provide additional evidence to indicate the pathophysiological role of the immune systems in affective disorders. It is suggested that the elevation of plasma TfR levels might be a trait phenomenon in bipolar disorder.
White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name 'adipocytokines' or 'adipokines'. However, since most are neither 'cytokines' nor 'cytokine-like', it is recommended that the term 'adipokine' be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. The adipokinome (which together with lipid moieties released, such as fatty acids and prostaglandins, constitute the secretome of fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFalpha, IL-1beta, IL-6, IL-8, IL-10, transforming growth factor-beta, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1.
Several psychopharmacological agents induce weight gain. Recent studies have suggested that the tumor necrosis factor-alpha (TNF-alpha) cytokine system is pathophysiologically involved. To assess whether carbamazepine and lithium, which have been reported to lead to weight gain, have effects on the circulating levels of cytokines, we measured plasma levels of TNF-alpha, its soluble receptors sTNF-R p55 and p75, and leptin, as well as weight in 25 inpatients receiving lithium (n=10) or carbamazepine (n=15) weekly during the first 4 weeks of treatment. We found an increase in the body mass index and in TNF-alpha and its soluble receptor levels, but not in leptin levels over the 4 weeks of treatment. These changes did not differ between treatment groups. Changes of weight during the first week of treatment, but no other parameter, strongly predicted weight change until endpoint. We conclude that the mood stabilizers carbamazepine and lithium have similar effects on the TNF-alpha system and do not affect leptin levels.
Activation of the inflammatory response system has been reported in schizophrenia. Levels of serum IL-1 receptor antagonist (IL-1ra) and soluble IL-2 receptor (sIL-2R(alpha)) were studied in 32 schizophrenic and 22 age- and sex-matched healthy subjects before and after an 8-week treatment protocol. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). At weeks 0 and 8, sIL-2R(alpha) levels were significantly higher than in the schizophrenic patients, as well as in a neuroleptic-naive subgroup, than in controls. Patients' sIL-2R(alpha) levels did not vary significantly between weeks 0 and 8. IL-1ra levels in controls did not differ significantly from those in patients at week 0 but were significantly lower at week 8. The patients' serum IL-1ra levels varied significantly between weeks 0 and 8. IL-1ra levels were significantly higher in the subgroup of neuroleptic-naive patients at week 0 than in controls. Levels of sIL-2R(alpha) at week 0 were positively correlated with PANSS positive and negative symptom scores at week 8, and levels at week 8 were positively correlated with PANSS total, positive symptom, and negative symptom scores at week 8. IL-1ra levels at week 0 were positively correlated with PANSS scores at week 8. There were positive correlations between both delta (baseline values minus endline values) IL-1ra and delta sIL-2R(alpha) levels and delta PANSS negative symptoms. The results provide evidence for immune activation in some schizophrenic patients and suggest that medication differentially affects the production of sIL-2R(alpha) and IL-1ra.
Dendritic cells (DC) are key regulators of the immune system, which is compromised in patients with bipolar disorder. We sought to study monocyte-derived DC in bipolar disorder.
Monocytes purified from blood collected from DSM-IV bipolar disorder outpatients (n = 53, 12 without lithium treatment) and healthy individuals (n = 34) were differentiated into DC via standard granulocyte-macrophpage colony-stimulating factor/interleukin-4 culture (with/without 1, 5, and 10 mmol/L lithium chloride). The DC were analyzed for DC-specific and functional markers and for T-cell stimulatory potency.
Monocytes of bipolar patients showed a mild hampering in their differentiation into fully active DC, showing a weak residual expression of the monocyte marker CD14 and a relatively low potency to stimulate autologous T cells. Lithium treatment abolished this mild defect, and monocyte-derived DC of treated bipolar patients showed signs of activation (i.e., an up-regulated potency to stimulate autologous T cells and a higher expression of the DC-specific marker CD1a). This activated phenotype contrasted with the suppressed phenotype of monocyte-derived DC exposed to lithium in vitro (10 mmol/L) during culture.
Dendritic cells show mild aberrancies in bipolar disorder that are fully restored to even activation after in vivo lithium treatment.
Many of the prior mortality studies on bipolar disorder have emerged primarily from the larger health service groups, with a tendency to focus on suicide alone. This study examines personal and clinical characteristics of bipolar patients in Taiwan in order to identify the factors associated with early natural death.
Bipolar patients admitted to a psychiatric hospital in Taiwan between 1987 and 2002 were retrospectively followed through record linkage for cause of death. One living bipolar individual was matched to each deceased patient as a control subject for age, gender, and date of index admission. Clinical data and the results of laboratory examinations during the last period of hospitalization were obtained through a review of medical records.
In a total of 60 natural deaths, the principal cause was circulatory disease (33.3%). Conditional logistic regressions revealed that the variables most strongly associated with natural deaths were years of antipsychotic treatment prior to the last visit (95% CI for odds ratio [OR] = 0.77 to 0.98), serum alanine aminotransferase levels (95% CI for OR = 1.02 to 1.25), and leukocyte counts (95% CI for OR = 1.01 to 2.50). Years of lithium treatment (95% CI for OR = 0.74 to 0.97) may be substituted for antipsychotic treatment as a protective factor.
Systemic inflammation and nonhepatic tissue damage during the acute phase of bipolar disorder may be risk factors for early natural death. Psychiatric treatment, including medication with antipsychotics or lithium, could be a factor in protecting against early natural death.
The role of the immune system in mood disorders is predominately supported by studies in unipolar major depression. However activation of the immune system has also been demonstrated in bipolar mania. Our study examines pro-inflammatory and anti-inflammatory cytokines in both phases of bipolar affective disorder (BPAD).
Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in patients with BPAD who were depressed, or manic and in healthy controls.
Bipolar depression had significantly higher production of the pro-inflammatory cytokines, IL-8 (p < 0.001) and TNF-alpha (p < 0.05) compared to healthy subjects. The manic group also had increased production of IL-8 (p < 0.05) and TNF-alpha (p < 0.001) as compared to healthy subjects. Anti-inflammatory cytokine levels did not differ across the 3 groups.
A small sample size was studied. All patients remained on medication for this study.
BPAD is associated with increased production of pro-inflammatory cytokines both in the manic and in the depressed phase as compared to healthy subjects. This is the first study, which examined both mania and bipolar depression.
Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.