Inflammatory matters:Exploring the underlying pathophysiology of unipolar and bipolar disorder

Stemmingsstoornissen, zoals een depressieve stoornis (MDD) of een bipolaire stoornis (BD), zijn veel voorkomende ziektebeelden die een grote impact hebben op de levenskwaliteit. Bij BD duurt het vaak jaren voordat de juiste diagnose gesteld wordt en dit heeft belangrijke klinische consequenties. Als we meer begrip hebben van de onderliggende ziektemechanismen van deze stoornissen, dan zou dit ons kunnen helpen om ze van elkaar te onderscheiden. In de loop van de jaren zijn twee theorieën over de ontwikkeling van stemmingsstoornissen onder de aandacht gekomen. De eerste beschouwt een ontregeld immuunsysteem als oorzaak voor stemmingsstoornissen, terwijl de andere een ontregeld stress systeem als de drijvende kracht achter stemmingsstoornissen ziet. Echter, kunnen het immuun- en stress systeem elkaar op meerdere niveaus beïnvloeden. Daarom heeft dit proefschrift verschillende aspecten van het immuun- en stresssysteem van BD en MDD patiënten onderzocht. In alle onderzochte delen van het immuunsysteem werden verschillen gevonden tussen de patiënten: in cytokines, T-helper cel differentiatie en in de aangeboren immuunrespons. Deze bevindingen wijzen op structurele biologische verschillen tussen BD en MDD. Bovendien werd in het stresssysteem wederom significante verschillen tussen beide patiëntengroepen gevonden. Ten slotte hebben we de onderlinge samenhang van beide systemen onderzocht, waarbij we vonden dat de specifieke combinatie van verhoogde immunologische activiteit en ontregeling van het stress systeem het risico op een bipolaire depressie verhoogde. Dit benadrukt het belang om deze systemen samen te onderzoeken. Met deze thesis hopen we enkele missende puzzelstukken toe te hebben kunnen voegen, waardoor er meer inzicht ontstaat in het onderliggende ziektemechanisme van stemmingsstoornissen

Disturbances in Hypothalamic-Pituitary-Adrenal Axis and Immunological Activity Differentiating between Unipolar and Bipolar Depressive Episodes

Differentiating bipolar depression (BD) from unipolar depression (UD) is difficult in clinical practice and, consequently, accurate recognition of BD can take as long as nine years. Research has therefore focused on the discriminatory capacities of biomarkers, such as markers of the hypothalamic-pituitary-adrenal (HPA) axis or immunological activity. However, no previous study included assessments of both systems, which is problematic as they may influence each other. Therefore, this study aimed to explore whether cortisol indicators and inflammatory markers were a) independently associated with and/or b) showed effect modification in relation to a lifetime (hypo)manic episode in a large sample of depressed patients.Data were derived from the Netherlands Study of Depression and Anxiety and comprised 764 patients with a DSM-IV depressive disorder at baseline, of which 124 (16.2%) had a lifetime (hypo)manic episode at the 2-year assessment, or a more recent episode at the 4-year or 6-year assessment. Baseline cortisol awakening response, evening cortisol and diurnal cortisol slope were considered as cortisol indicators, while baseline C-reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α) were included as inflammatory markers.In depressed men and women, none of the cortisol indicators and inflammatory markers were (independently) associated with a (hypo)manic episode. However, effect modification was found of diurnal cortisol slope and CRP in relation to a (hypo)manic episode. Further analyses showed that depressed men with high levels of diurnal cortisol slope and CRP had an increased odds (OR=10.99, p=.001) of having a (hypo)manic episode. No significant differences were found in women.Our findings suggest that the combination of high diurnal cortisol slope and high CRP may differentiate between UD and BD. This stresses the importance of considering HPA-axis and immunological activity simultaneously, but more research is needed to unravel their interrelatedness

Inflammatie als marker voor de aanwezigheid en het ontstaan van manische symptomen in patiënten met een unipolaire depressie

Introduction: The underlying pathophysiology of unipolar and bipolar depression is receiving growing interest from researchers. One of the most prominent venues is the cytokine hypothesis. Because unipolar and bipolar depression are hard to differentiate from one other (especially in an early stage), there is a need for understanding the underlying etiology and pathophysiology. The present study aimed to define the difference between current depressive patients with and without manic symptoms at baseline and follow-up and healthy controls by measuring inflammatory markers. Methods: Baseline measurement of C-reactive protein (CRP), Interleukin-6 (IL-6) and Tumor Necrosis Factor alpha (TNF-α) were performed in a large group of currently depressed patients (N=957) assesd by Composite Interview Diagnostic Instrument CIDI and healthy controls (N=430). Then the presence of manic symptoms was assessed using Mood Disorder Questionnaire (MDQ) on baseline and 2 year follow-up. Based on the MDQ groups were formed and the mean inflammatory marker values were compared with eachother, before and after adjustment for possible confounding factors (sociodemographics, lifestyle and disease-related factors). Results: After adjustment for possible confounders, no significant difference was found between depressed patients with and without manic symptoms and controls in the cross-sectional analyses. However, the prospective analyses showed that high CRP levels in currently depressed men predict the development of manic symptoms in follow up (p<0.001). Conclusion: These findings show that high levels of CRP in currently depressed men may predict the onset of manic symptoms at follow-up.

The circulating levels of CD4+t helper cells are higher in bipolar disorder as compared to major depressive disorder

Introduction: Clinical differentiation between bipolar disorder (BD) and major depressive disorder (MDD) is difficult. Research has therefore focused on discriminatory biological markers. Previous studies in MDD reported T cell deficits, while the limited studies in BD reported T cell activation. Studies directly comparing circulating numbers of T cells and T cell subsets between BD and MDD are lacking. The studies in the MOODINFLAME consortium make such a comparison possible. Methods: The number of circulating leukocyte populations (lymphocytes, monocytes, NK cells, B cells, T cells, CD3+CD8+ T cytotoxic cells, CD3+CD4+ T helper cells, Th1, Th2, Th17 and T regulatory cells) was determined using FACS technology in a cohort of 83 euthymic BD patients, 8 BD patients with a current mood episode and 165 healthy controls (HC). Data were compared to those of 34 moderately and 56 severely depressed MDD patients. Results: Compared to MDD patients, BD patients showed significantly increased levels of Th17, Th2, Th1 and T regulatory cells (all p <.02). In BD patients, levels of Th17 and T regulatory cells were increased compared to HC (p = .03, p = .02, respectively), while MDD patients showed decreased levels of Th17 and Th2 compared to HC (p = .03, p = .01, respectively). Of the various medications only SSRI/SNRI usage could explain part of the Th2 decrease in MDD. Conclusion: This study shows CD4+ T helper cell deficits in MDD patients, while normal or even raised levels of these cells were found in BD patients. The differences in CD4+ T helper cell differentiation was most outspoken for Th17 cells

Significance of interactions between cortisol indicators and inflammatory markers in relation to a lifetime (hypo)manic episode^a.

<p>Abbreviations: AUCg, area under the curve with respect to the ground; AUCi area under the curve with respect to increase; CRP, C-reactive Protein; IL-6, Interleukin-6; TNF-α, Tumor Necrosis Factor Alpha.</p><p>^a Based on multivariable logistic regression analyses comparing depressed patients with a lifetime (hypo)manic episode to depressed patients without a lifetime (hypo)manic episode (reference), adjusted for basic covariates (sociodemographics, sampling factors).</p><p>Significance of interactions between cortisol indicators and inflammatory markers in relation to a lifetime (hypo)manic episode<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133898#t004fn002" target="_blank">^a</a>.</p

Associations of cortisol indicators and inflammatory markers with a lifetime (hypo)manic episode.

<p>Abbreviations: OR, odds ratio; CI, confidence interval, AUCg, area under the curve with respect to the ground; AUCi area under the curve with respect to increase; CRP, C-reactive Protein; IL-6, Interleukin-6; TNF-α, Tumor Necrosis Factor Alpha.</p><p>^a Based on multivariable logistic regression analyses comparing depressed patients with a lifetime (hypo)manic episode to depressed patients without a lifetime (hypo)manic episode (reference), adjusted for basic covariates (sociodemographics, sampling factors).</p><p>Associations of cortisol indicators and inflammatory markers with a lifetime (hypo)manic episode.</p

Sample characteristics.

<p>Abbreviations: sd, standard deviation; AUCg, area under the curve with respect to the ground; AUCi area under the curve with respect to increase; CRP, C-reactive Protein; IL-6, Interleukin-6; TNF-α, Tumor Necrosis Factor Alpha.</p><p>^a Based on T-tests for continous variables and χ²-test for dichotomous and categorical variables.</p><p>^b To normalize parameters, evening cortisol, CRP, IL-6 and TNF-α were ln-transformed, for interpretation means and standard deviations were back transformed.</p><p>Sample characteristics.</p

Pearson’s correlations between cortisol indicators and inflammatory markers.

<p>Abbreviations: even., evening cortisol; diurn., diurnal cortisol slope; AUCg, area under the curve with respect to the ground; AUCi area under the curve with respect to increase; CRP, C-reactive Protein; IL-6, Interleukin-6; TNF-α, Tumor Necrosis Factor Alpha.</p><p>* = p <.05.</p><p>Pearson’s correlations between cortisol indicators and inflammatory markers.</p

Associations of combined cortisol and inflammatory groups with a lifetime (hypo)manic episode.

<p>Abbreviations: OR, odds ratio; CI, confidence interval, AUCg, area under the curve with respect to the ground; AUCi area under the curve with respect to increase; CRP, C-reactive Protein; IL-6, Interleukin-6; TNF-α, Tumor Necrosis Factor Alpha.</p><p>^a Based on multivariable logistic regression analyses comparing depressed patients with a lifetime (hypo)manic episode to depressed patients without a lifetime (hypo)manic episode (reference), adjusted for basic covariates (sociodemographics, sampling factors).</p><p>^b Based on multivariable logistic regression analyses comparing depressed patients with a lifetime (hypo)manic episode to depressed patients without a lifetime (hypo)manic episode (reference), additionally adjusted for health factors.</p><p>Associations of combined cortisol and inflammatory groups with a lifetime (hypo)manic episode.</p