Fig. 1
From: A unified model of the biology of peripartum depression
1. Tryptophan is mainly synthesized into serotonin (<5%) or kynurenine and its breakdown products (>95%), culminating in the generation of nicotinamide adenine dinucleotide (NAD+), an important cellular energy source. The kynurenine pathway has two branches – one that leads to quinolinic acid and NAD+, which comprises several neurotoxins, and one that leads to kynurenic acid, which is neuroprotective. 2. Immune cells, in different phases of pregnancy, intensify kynurenine production at the expense of serotonin, mainly via the indoleamine 2,3-dioxygenase (IDO) enzyme. 3. Stress further intensifies this process, chiefly via the effect of the glucocorticoid receptor on the tryptophan dioxygenase (TDO) enzyme. 4. Reproductive hormones, especially estradiol, intensify the production of quinolinic acid and NAD+ at the expense of kynurenic acid via the inhibition of kynurenine aminotransferase (KAT). Progesterone is a protective hormone, but the body may develop progesterone resistance because of the immune system response. Quinolinic acid (QUIN), which is excessively metabolized under these conditions, is a potent agonist of glutamate’s N-methyl-D-aspartate receptor (NMDAR), which exerts neurotoxic effects via at least nine different mechanisms and brings about the main symptoms of depression. QUIN also inhibits glutamate uptake into astrocytes, inducing cessation of responding and anhedonia. Serotonin and melatonin are depleted, affecting appetite, learning, memory, and sleep. It also hinders one of the main pathways of pain reduction – that of serotonin – that could promote mental pain and suicide ideation 5. CD38 generates cADPR out of NAD + that further activates the immune response and secretion of oxytocin (OT). OT can then inhibit the immune and stress responses, indirectly reducing overall symptoms. Lack of physical touch, breastfeeding, and support reduce OT levels, and prolonged inflammation may hinder the secretion of OT via CD38-cADPR. Chronic stress may also downregulate the expression of potassium-chloride cotransporter-2 (KCC2), causing OT to exacerbate the stress response rather than inhibit it because of the dysregulation of gamma-aminobutyric acid receptors (GABAA). The figure was created with BioRender.com.
