Fig. 3.

The partial schematic diagram elucidated the most studied hypothesis linked to the pathophysiology of depression/MDD. The numerous pathways are involved in MDD, but only a few of them are represented in the figure. (a) Monoaminergic theory where deficiency of monoamines in the CNS implicates MDD. In particular, increased concentration of monoamine oxidase (MAO) enzymes and pro-inflammatory cytokines (IL-6, CRP, TNF-α) shifted the tryptophan (Trp) route from serotonin synthesis to neurotoxic quinolinic acid. Additionally, dopamine is synthesized from tyrosine (Try) released in the synaptic cleft, where instead of binding to the dopamine receptor on the post-synaptic terminal, it binds to the reuptake channels and is oxidized by the MAO enzyme. Hence, upregulation of MAO enzymes has been implicated in MDD by making monoamines neurotransmitter unavailable in different brain regions. (b) Representing an alteration in the GR-mediated negative feedback system on the HPA axis causes hyperactivity of the HPA system, thus increasing the cortisol concentration in various tissues. (c)Depict that dysregulation of glutamate/GABAergic neurotransmission has been involved in MDD, where upregulation of NMDA receptor on GABAergic interneurons interferes with the glutamate release and decreases the glutamate level in the synaptic cleft. Thereby resulting in downregulation of glutamate neurotransmission and reduces the number of synapses and functions.