Promotion of microglial M2-polarization by antidepressants

Macrophages and microglia are cells of the innate immune system. These phagocytic cells alter and adapt their phenotype depending on their prime activity, i.e. whether they participate in acute defence against pathogenic organisms (‘M1’-phenotype) or in clearing damaged tissues and performing repair activities (‘M2’-phenotype). Several risk factors for melancholic depression (agonists for Toll-like receptors, inflammatory cytokines, stress, alcohol abuse, obesity and neurological disorders) seem to promote M1-polarization. In the M1-polarized form, microglia and macrophages generate reactive oxygen- and nitrogen radicals to eradicate microbial pathogens. Inadvertently, also tetrahydrobiopterin (BH4) may become oxidized. This is an irreversible reaction that generates neopterin, a biomarker for depression. BH4 is a critical cofactor in the synthesis of dopamine, noradrenaline and serotonin and its loss could explain some of the symptoms of depression. Shifting the M1- to an M2- phenotype would limit the loss of BH4. In the current review we evaluate the evidence that antidepressant treatments (monoamine reuptake inhibitors, PDE4 inhibitors, lithium, valproate, agomelatine, tianeptine, electroconvulsive shock and vagus nerve stimulation) promote microglia/macrophage M2-polarization. We speculate that supplementation with BH4 might be an effective straightforward treatment for major depression