Interleukin-1β is associated with depressive episode in major depression but not in bipolar disorder

Journal of Psychiatric Research 47 (2013) 2011e2014

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Interleukin-1b is associated with depressive episode in major depression but not in bipolar disorder Rosana Mota a, 1, Marta Gazal a, 1, Bruna A. Acosta a, Pâmela B. de Leon a, Karen Jansen a, Ricardo T. Pinheiro a, Luciano D. Souza a, Ricardo A. Silva a, Jean P. Oses a, Luciana Quevedo a, Diogo R. Lara b, Gabriele Ghisleni a, Manuella P. Kaster a, * a b

Programa de Pós-Graduação em Saúde e Comportamento, Universidade Católica de Pelotas, Brazil Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Brazil

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 July 2013 Received in revised form 5 August 2013 Accepted 26 August 2013

Our work was sought to investigate possible changes in peripheral levels of interleukin-1b (IL-1b) according to the diagnosis of major depression (MD) and bipolar disorder (BD) and in different mood episodes. This is a cross-sectional nested in a population-based study comparing 240 young adults (80 controls, 80 MD and 80 BD), balanced for age and gender. Serum levels of IL-1b were significantly higher in MD when compared to control or BD subjects. In addition, when divided by current mood episode, MD subjects in current depression presented higher IL-1b levels than controls. No differences in IL-1b levels were found between different episodes of BD (euthymic, depressed, mania or mixed). Moreover, the use of psychiatric medication was very low in our sample and not associated with changes in IL-1b levels. In conclusion, increased peripheral IL-1b might be a useful marker associated with a depressive episode in the context of MD. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: IL-1b Major depression Bipolar disorder Current episode

1. Introduction Mood disorders, such as major depression (MD) and bipolar disorder (BD), are associated with substantial social and occupational impairments, high medical costs and are set to become the major socio-economic healthcare burden over the coming decades (Andlin-Sobocki et al., 2005; Collins et al., 2011). The recognition that inflammation is involved in the pathophysiologic mechanism of chronic illness, including psychiatric disorders, was one of the major scientific advances of the last decades. Although not entirely consistent, peripherally derived immune cells and inflammatory molecules are implicated in a variety of behavioral, neuroendrocrine and neurochemical alterations that accompany psychiatric disorders (Marques et al., 2007; Felger and Lotrich, 2013). The origin of the elevated cytokines in mood disorders is still a matter of debate, but several studies have shown increased

* Corresponding author. Programa de Pós-Graduação em Saúde e Comportamento, Centro de Ciências da Vida e da Saúde, Universidade Católica de Pelotas, Rua Gonçalves Chaves 373, 96015560 Pelotas, Rio Grande do Sul, Brazil. Tel.: þ55 53 2128 8031; fax: þ55 53 2128 8229. E-mail addresses: [email protected], [email protected] (M.P. Kaster). 1 Both authors equally contributed to the manuscript. 0022-3956/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpsychires.2013.08.020

inflammatory cytokines in patients with MD and BD (Schiepers et al, 2005; Goldstein et al., 2009; Kunz et al., 2011; Lotrich, 2012; Munkholm et al., 2013). In addition, cytokine therapy can lead to depressive symptoms, mania/hypomania episodes and mixed states (Constant et al., 2005; Marques et al., 2007; Myint et al., 2009). However, other studies have failed to find an association between inflammatory markers and psychiatric disorders (Haack, 1999; Rothermundt et al., 2001; Steptoe, 2003; Schiepers et al, 2005; Marques-Deak et al., 2005). These findings suggest that inflammation might be a state-dependent phenomenon, modified by the symptom severity (Goldstein et al., 2009; Tsai et al., 2012), stage (Kapczinski et al., 2009; Berk et al., 2011), and specially by mood episodes (Ortiz-Dominguez et al., 2007; Brietzke et al., 2009). Interleukin-1b (IL-1b) is a potent pro-inflammatory cytokine that act as a key driver of both peripheral and central immune responses (van de Veerdonk and Netea, 2013). This cytokine is produced by a variety of cell types including immune cells in the periphery as well as glial cells and neurons (Dinarello, 1996). The involvement of IL-1b in mood disorders stems from three lines of evidence: first, epidemiological data showing increased levels of IL1b in peripheral circulation and cerebrospinal fluid (CSF) from MD and BD patients (Anisman et al., 1999; Owen et al., 2001; Kaestner et al., 2005; Söderlund et al., 2011); secondly, different therapeutic strategies used to control mood disorders cause effects on IL-1b

2012

R. Mota et al. / Journal of Psychiatric Research 47 (2013) 2011e2014

levels (Hannestad et al., 2011; Maes et al., 2012); thirdly, preclinical studies show that IL-1b administration modifies behavioral and neurochemical responses considered relevant for mood function in humans (Anisman et al., 2008; Koo and Duman, 2009). Despite the growing amount of evidence showing cytokine abnormality in mood disorders, a recent meta-analysis evidenced that only a limited number of studies explored the role of IL-1b, specially in different mood episodes (Modabbernia et al., 2013). The aim of this study was to investigate whether the characteristic profile of peripheral IL-1b might be associated with diagnosis and with the current mood episode in patients with MD or BD. 2. Methods This is a cross-sectional nested in a population-based study of people aged 18 to 35. The sample consisted of 1380 participants living in urban Pelotas, (Brazil). Sample selection was performed by clusters (June 2011 to October 2012), considering a population of 97,000 people in that age range in the current census of 448 sectors in the city. In order to ensure the necessary sample inclusion, 86 census-based sectors were systematically drawn. After identification, the subjects signed the informed consent and answered to a socio-demographic questionnaire. In order to ascertain current and lifetime psychiatric disorders, trained psychologists used the Mini International Neuropsychiatric Interview 5.0 (MINI), according to DSM-IV criteria (Sheehan et al., 1998). After the diagnosis, we recruited the participants with past or current history of mania/hypomania from the 1380 individuals interviewed (BD group). According to Jansen et al. (2011) the prevalence of hypomania/mania is around 5.3e7.5% in our population and we obtained 80 subjects in BD group. The other two groups were randomly selected and balanced by gender and age. People without history of mood disorders (control sample) and people with current depression but no past history of mania/hypomania (unipolar MD group). Thus, our final sample consisted in 240 subjects (80 controls, 80 MD and 80 BD). Exclusion criteria included infectious diseases or medical illness that required treatment with immunosuppressors. Importantly, we did not exclude people on account of any other mental disorder. The study was approved by the Ethics Committee of our University (2010/15). 2.1. Determination of serum IL-1b levels Ten milliliters of blood were withdrawn (8:00e11:00 a.m.) by venipuncture into a free-anticoagulant vacuum tube after the interview. The blood was immediately centrifuged at 4000  g for 15 min, and serum was kept frozen at 80  C until analysis. Serum levels of IL-1b were measured using an IL-1b immunoassay kit (DuoSet ELISA Development, R&D Systems, Inc., USA). The intraassay coefficient of variation (C.V.) was less than 5% and the interassay C.V. was less than 10%. In addition, the assay sensitivity was 1 pg/mL and the detection limit 3.9 pg/mL. Levels of IL-1b bellow the detection limit were considered to be 0. Values were expressed in pg/mL. 2.2. Statistical analyses Statistical analyzes were performed by GraphPad Prism 5.0 and Statistical Program for Social Sciences (SPSS) 13.0. IL-1b levels had a non-Gaussian distribution and were logarithmically transformed. The Chi-Square and Analysis of Variance (ANOVA) test were used to in order to analyze sample characteristics. Comparisons between IL-1b levels in MD, BD and control group, or between mood episodes were made by ANOVA, followed by Duncan post hoc test. IL-

1b levels were presented as mean and standard deviation (S.D.). p < 0.05 was considered statistically significant. 3. Results Our final sample consists in 240 subjects, 80 MD, 80 BD and 80 controls with no history of mood disorders. The socio-demographic information according to diagnosis is summarized in Table 1. The sample was balanced by gender (55 women and 25 men in each group, p ¼ 1.0), age (p ¼ 0.846), ethnicity (p ¼ 0.136) and socioeconomic status (p ¼ 0.669). In addition, we found no differences in body mass index (BMI, p ¼ 0.861) and regular physical activity (p ¼ 0.136) between groups. The use of psychiatric medications was absent in the control and very low in the other groups. We found 26 subjects (10.4%) using antidepressants, antipsychotics and/or anxiolytics (18 in the BD group and 7 in the MD group). The results analyzed by two-way ANOVA showed no interaction between medication use and diagnosis on IL-1b levels [F(1,234) ¼ 0.083 p ¼ 0.773]. In addition, no significant effects were found for the interaction between diagnosis and tobacco use on IL-1b levels [F(1,234) ¼ 1.52 p ¼ 0.218]. The other physical and sociodemographic parameters evaluated were also not associated to changes in IL-1b levels (data not shown). The results presented in Table 1 also show that IL-1b levels were significantly higher in subjects diagnosed with MD (12.58  20.69 pg/mL) when compared to control (4.46  6.22 pg/mL) or BD (6.54  7.59 pg/ mL) (F (2,237) ¼ 11.22, p ¼ 0.001). As presented in Fig. 1, by dividing subjects according to the current mood episode, we found increased levels of IL-1b in unipolar MD (12.58  20.69 pg/mL) when compared to control (4.46  6.22 pg/mL) and euthymic BD subjects (3.54  3.91 pg/mL). No differences in IL-1b levels were found in BD individuals in current depression, mania/hypomania or mixed episodes when compared to control subjects (F (5,234) ¼ 5.996, p ¼ 0.001). Of note, the statistical analysis was performed in log-transformed values but Fig. 1 presents the original data.

Table 1 Distribution of socio-demographic and clinical information of the sample according to diagnosis. Clinical Diagnostic Variables

Control

BD

MD

p

Age (years) Ethnicity Caucasian Non-Caucasian Years of education Socioeconomic class High Intermediate Low Psychiatric medication Yes No Regular physical activity Yes No Tobacco use Yes No BMI IL-1b (pg/mL) Total

26.19  4.67

26.48  5.26

26.63  4.59

0.846 0.136

69 (86.2%) 11(13.8%) 11.64  3.40

59 (73.8%) 21 (26.2%) 10.21  3.76

64 (80.0%) 16 (20.0%) 10.53  3.65

27 (33.8%) 25 (31.2%) 28 (35.0%)

21 (26.2%) 23 (28.8%) 36 (45.0%)

22 (31.4%) 22(31.4%) 36 (36.0%)

0 (0%) 80 (100%)

18 (22.5%) 62 (77.5%)

4 (5.0%) 76 (95.0%)

26 (32.5%) 54 (67.5%)

22 (27.5%) 58 (72.5%)

16 (20%) 64 (80%)

16 (20%) 64 (80%) 26.65  5.71 4.46  6.22 80

40 (50%) 40 (50%) 26.86  6.67 6.54  7.59 80

28 (35%) 52 (65%) 27.19  6.36 12.58  20.69 80

0.066 0.669

0.001

0.136

0.001

0.861 0.001

Results are displayed as number and % and analyzed by Pearson c2 or by mean  standard deviation (S.D.) and analyzed by one-way ANOVA. Abbreviations: BMI, body mass index, BD, bipolar disorder, MD, unipolar major depression.

R. Mota et al. / Journal of Psychiatric Research 47 (2013) 2011e2014

Fig. 1. Serum interleukin-1b (IL-1b) levels (pg/mL) in control subjects (n ¼ 80), unipolar major depressive subjects in current depression (UDep, n ¼ 80) and bipolar disorder (BD) subjects in euthymic (18), depressive (BDep, n ¼ 34), mania/hypomania (n ¼ 17) or mixed episode (n ¼ 11). Values are expressed as mean  S.E.M. Comparative analyses were carried out using ANOVA followed by Duncan test. **p < 0.001 vs control and euthymic BD group.

4. Discussion The present study showed that peripheral levels of IL1b are increased in subjects diagnosed with MD but not BD. However, the main finding of our work was that increased levels of IL-1b were specific for the depressive state in the context of unipolar MD but not BD, suggesting differences in the biochemical features in the depressive episode according to the diagnostic. It is important to highlight that our sample consisted in young subjects and with a very low use of psychiatric medications. The advantage of selecting a population-based sample of young subjects lies on the possibility of having subjects unaware of their condition and relatively free of psychiatric intervention. In addition, most BD individuals have their first episode in the period between late adolescence and early adulthood (Lewinsohn et al., 2003). The hypothesis that mood disorders are associated with immune activation is not new, and despite the growing amount of evidence, the clinical relevance of these findings is still limited. Most of the studies investigating peripheral levels of IL-1b have reported elevated concentrations of IL-1b in patients with MD (Owen et al., 2001; Piletz et al., 2009) or dysthymia (Anisman et al., 1999; Brambilla et al., 2004) and a positive correlation with symptom severity (Anisman et al., 1999). In BD patients, data is less clear and increased IL-1b levels were found during the depressive phase in the serum (Remlinger-Molenda et al., 2012), or during the euthymic phase in the CSF (Söderlund et al., 2011). As discussed by the authors, the influence of the large variety of drugs prescribed to BD patients on cytokine levels cannot be ruled out (Söderlund et al., 2011). However, Ortiz-Dominguez et at (2007) found decreased IL1b levels during mania, in subjects free of psychopharmacological treatment for at least three weeks. This is the first report showing that differences in IL-1b concentration might be specific for the depressive state in unipolar MD but not in the depression associated with BD. Indeed, establishing whether a depressive episode is part of MD or BD is essential for diagnosis and treatment planning. Although major depressive episodes are characteristic of MD, they also occur in BD patients. In BD, the depressive episode is more easily recognized and generally more distressing to the patients, leading to the misdiagnosed as

2013

unipolar MD (Angst, 2006). Indeed, studies have indicated that BD features can be detected, in approximately one-quarter of patients diagnosed with MD (Benazzi, 1997). Over recent years, studies have discussed the psychopathological characteristics in each type of depressive episode (Motovsky and Pecenak, 2012). Indeed, neuroimaging studies comparing the depressive episode in the context of MD and BD suggest different pathophysiologic processes, especially in neural circuitry regulating emotion, reward and attention (Cardoso de Almeida and Phillips, 2013). However, no peripheral biomarkers are available so far to identify these episodes. Pro-inflammatory cytokines, in addition to their classical role in immune responses, are involved in the tonic control of numerous brain processes affecting behavior (Marques et al., 2007; McCusker and Kelley, 2013). The actions of IL-1b on neuronal circuits are complex and diverse, including direct and indirect effects on neurotransmission (Dinarello, 1996; van de Veerdonk and Netea, 2013). It has been demonstrated that peripheral cytokines, including IL-1b may cross the bloodebrain barrier, increasing serotonin turnover and inducing the hyperactivity of the hypothalamicepituitaryeadrenal axis (HPA), mechanisms resembling those found in depressed patients (Leonard, 2000; Schiepers et al, 2005; Pariante and Miller, 2001). Our findings should be considered in light of some limiting factors: first, only IL-1b was evaluated and given the multifaceted aspect of the immune response, multiple cytokine testing would help to better clarify the relationship between peripheral inflammation and mood disorders. In addition, information on fasting/ post-prandial state and data on illness duration, number of episodes and symptom severity would help to better clarify the involvement of IL-1b in mood disorders. However, our study has the methodological strength of using a well-balanced populationbased sample of young subjects with a very low use of psychiatric medications, limiting possible confounders. Taken together, the results presented in this study suggested that IL-1b might be a useful marker to identify the nature of a depressive episode in the context of MD or BD, avoiding inappropriate treatment and relapse.

Contributors Authors Kaster MP, Lara DR, Ghisleni G, Silva RA, Pinheiro RT, Souza LD, Jansen K designed the study and wrote the protocol. Authors Mota R, Gazal M, Acosta BA, de Leon PB performed the biochemical analyses. Authors Kaster MP, Gazal M and Mota R managed the literature searches and analyses. Authors Jansen K, Souza LD, Quevedo L, Oses JP and Ghisleni G undertook the statistical analysis, and authors Kaster MP, Gazal M and Mota R draft of the manuscript. All authors contributed to and have approved the final manuscript.

Role of the funding source CNPq, FAPERGS, CAPES-Brazil.

Conflict of interest None.

Acknowledgments This study was supported by CNPq, FAPERGS and CAPES Brazil.

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