Toxicity and neuroprotection in bipolar disorder - The acute mood episode and beyond
13 mei 2019
PZ Duffel, zaal De Tichelrij - Stationsstraat 22c - 2570 Duffel
Seline Van den Ameele
Prof B. Sabbe, Prof M. Morrens
PhD defence Seline Van den Ameele - Faculty of Medicine and Health Sciences(Presentation in Dutch)
Pathophysiological mechanisms underlying bipolar disorder (BD) are still largely unknown. Although the finding of an increased pro-inflammatory state in patients with BD is rather robust, cautious interpretation of results remains warranted because of many confounding factors. In our systematic literature review, we assessed cytokine levels in medication-free patients with BD and the effect of single mood-stabilizing drugs on these levels. We found evidence for a mood state-related increase in pro-inflammatory cytokines (TNF-α and IL-6) with normalization during euthymia in medication-free patients. Euthymic lithium users had cytokine levels similar to healthy controls.
Cytokines are able to contribute to the development of psychiatric symptoms by stimulating key enzymes in both kynurenine metabolism and BH4 dependent monoamine synthesis. Kynurenine metabolism gives rise to several neuroactive metabolites, some with neurotoxic and others with rather neuroprotective properties. Objectivation of this interaction in clinical populations is limited.
In our study, we aimed for a longitudinal evaluation of mood, as well as inflammation, kynurenine metabolism and BH4 dependent monoamine synthesis in patients with BD versus healthy controls. We included patient with BD during an acute mood episode (depression or (hypo)mania) and had 6 test moments over 8 months follow-up. No differences in inflammatory markers (CRP, IFN-y, TNF-α and IL-6) were found between patients in different mood states and controls. Similar to a pro-inflammatory status accompanying healthy aging, we saw increasing pro-inflammatory markers with age, but with a premature onset in patients. Independent of mood state, patients had low KYNA levels, a putative neuroprotective kynurenine metabolite. In patients with chronic subsyndromal depressive symptoms, we found a decreased neuroprotective ratio KYNA/3-HK during the whole follow-up. In presence of mood symptoms, i.e. acute manic as well as chronic subsyndromal depressive symptoms, we saw a strong association between inflammation and a neurotoxic shift in kynurenine metabolism. During mania, TNF-α was strongly correlated to neurotoxic kynurenine metabolites (3-HK and QA), while during chronic depressive symptoms, IFN-y was related to increased neurotoxic QA and activation of IDO-1, the key enzyme in activation of kynurenine metabolism in response to pro-inflammatory cytokines.
Regarding BH4 dependent monoamine synthesis, monoamines levels (TYR, TRP and PHE), were lower in patients and this most pronounced during depression. Furthermore, we saw an increased correlation between neopterin and PHE/TYR in patients overall, typical for situations of chronic inflammation and suggesting increased neopterin formation at the expense of BH4 synthesis and compromised monoamine synthesis.
In normal situations, pro-inflammatory and neurotoxic processes balance with neurotrophic processes. We assessed trophic markers BDNF, VEGF and soluble VEGF receptor at baseline and 2 months follow-up. Despite rigorous methodology, we could not identify differences in levels of these markers between patients and controls. Better understanding of methodological issues are needed to guide future research.
To conclude, our research shows evidence for increased neurotoxicity along the illness trajectory of BD with more pronounced toxicity when mood symptoms were present. Our data should be interpreted with caution and need replication.