Abstract
Inflammation and psychological stress are risk factors for major depression and suicide. Both increase central glutamate levels and activate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Both factors also affect the function of the chloride transporters, Na-K-Cl-cotransporter-1 (NKCC1) and K-Cl-cotransporter-2 (KCC2), and provoke interleukin-6 (IL-6) trans-signaling. This leads to measurable increases in circulating corticosteroids, catecholamines, anxiety, somatic and psychological symptoms, and a decline in cognitive functions. Recognition of the sequence of pathological events allows the prediction of novel targets for therapeutic intervention. Amongst others, these include blockade of the big-K potassium channel, blockade of the P2X4 channel, TYK2-kinase inhibition, noradrenaline α2B-receptor antagonism, nicotinic α7-receptor stimulation, and the Sgp130Fc antibody. A better understanding of downstream processes evoked by inflammation and stress also allows suggestions for tentatively better biomarkers (e.g., SERPINA3N, MARCKS, or 13C-tryptophan metabolism).
Highlights
Major depressive disorder (MDD) is worldwide a leading cause of years lived with disability [1,2]
The direction of anion-flux through the gamma-aminobutyric acid-A (GABAA) channel depends on the electrochemical gradient for the chloride ion and is determined by the expression and activity of two trans-membrane chloride-transporters, K-Cl-cotransporter-2 (KCC2) and Na-K-Cl-cotransporter-1 (NKCC1)
The authors confirmed that acute restraint stress decreased KCC2 levels in the paraventricular nucleus (PVN); this effect was short-lasting and returned to baseline within 5 days post stress. These data indicate that acute stress impairs GABA control over Corticotrophin-releasing factor (CRF) neurons via a decrease in KCC2 function, whereas chronic stress-induced impairment is mediated via an increase in NKCC1 expression
Summary
Major depressive disorder (MDD) is worldwide a leading cause of years lived with disability [1,2]. Based on insights provided by ongoing academic research efforts, it is possible to reinterpret the wealth of information on the pathophysiological processes in major depressive disorder. This better understanding enables proposals for novel pharmacological treatment targets. The current review starts off with a reinterpretation of existing disease knowledge. This is subsequently used to list hitherto underexplored pharmacological treatment options. It provides proposals for novel biomarkers for endophenotypic depression symptoms, as well as suicide risk
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