Cytokines, brain-derived neurotrophic factor and C-reactive protein in bipolar I disorder - Results from a prospective study

Abstract

Background: Peripheral blood brain-derived neurotrophic factor (BDNF) and inflammatory markers may reflect key pathophysiological mechanisms in bipolar disorder in relation to disease activity and neuroprogression.

Aims: To investigate whether neutrophins and inflammatory marker vary with mood states and are increased in patients with bipolar disorder type I during euthymia as well as in all affective states as a group, compared to levels in healthy control subjects.

Methods: In a prospective 6-12 months follow-up study, we investigated state specific, intra-individual alterations in levels of BDNF, hsCRP, IL-1β, IL-6, IL-8, IL-18 and TNF-α in 60 patients with bipolar I disorder with an acute severe manic index episode and in subsequent euthymic and depressive and manic states and compared with repeated measurements in healthy control subjects. Data were analysed with linear mixed effects model and with adjustment for gender, age, BMI, alcohol intake and smoking.

Results: From inclusion to end of the 6-12 months follow-up, samples of blood were drawn from the 60 patients during a total of 180 affective states, comprising 57 manic, 11 mixed, 23 depressive and 89 states of euthymia. Further, 69 blood samples were drawn from 35 healthy control subjects with three months apart. In unadjusted mixed-model analysis, levels of IL-6 and IL-8 were increased 64% (b=1.64, 95% CI: 1.31-2.05, p=<0.0001) and 24% (b=1.24, 95% CI: 1.05-1.47, p=0.013), respectively in patients with bipolar disorder overall compared with healthy control subjects. However, in adjusted models, no statistically significant differences were found in any measure between patients and control individuals. Levels of hsCRP in depressive states were decreased with 40% (95% CI: 5-62%, p=0.029) compared with euthymia and with 48% (95% CI: 17-66%, p=0.006) when compared with hypomanic/manic states after adjustment. BDNF and the other inflammatory markers did not vary according to affective state in adjusted mixed models.

Limitations: Patients were all medicated, specifically with high doses of atypical antipsychotics during the manic index episodes.

Conclusions: In a sample recruited during hospitalization for acute mania, levels of hsCRP varied according to affective state with higher levels during manic states compared with depressive states.

Keywords: Bipolar disorder; Brain-derived neurotrophic factor; CRP; Cytokines; Mania.