Immune changes and neurotransmitters: Possible interactions in depression?

A disturbed metabolism of catecholamines and other neurotransmitters appears to play a major role in the pathogenesis of neurospychiatric symptoms, such as changes in mood and depression. This symptomatology is common in patients with chronic inflammatory disorders such as infections, autoimmune diseases, or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic system but also with those of the adrenergic system. The pro-inflammatory cytokine interferon-γ stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is a co-factor for several aromatic amino acid mono-oxygenases and is rate-limiting for the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). Interferon-γ triggers the high output of reactive oxygen species in macrophages, which can destroy the oxidation-labile BH4. Recent data suggests that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients.

► Immune activation, the serotonin and the kynurenic acid pathway are linked via IDO. ► Breakdown of tryptophan by IDO seems insufficient to explain types of depression. ► Chronic immune activation correlates with moderately increased serum phenylalanine. ► Increased Phe/Tyr implies a reduced activity of phenylalanine hydroxylase (PAH). ► Immune biomarkers plus Phe/Tyr and Kyn/Trp as tools for personalized medicine.