Tryptophan hydroxylase 2 and tryptophan mediate depression by regulating serotonin levels

Depression is a neurological disorder that can affect any individual and manifests symptoms like prolonged periods of low moods and loss of appetite. The high incidence and suicide rates of depression pose a threat to daily life and social development. Researchers have identified the defective synthesis of serotonin (5-HT) as a critical risk factor for depression. Extant literature revealed several mechanisms affecting 5-HT levels, of which the tryptophan hydroxylase 2 (TPH2) isozyme and tryptophan pathways are closely linked to depressive-like behaviors. in previous studies, patients taking the current antidepressants that target the serotonergic system experience many side effects and have high relapse rates after medicine withdrawal, suggesting that the current knowledge of the serotonergic system is insufficient. Mutations on the gene encoding the TPH2 enzyme, the first and rate-limiting factor on endogenous 5-HT synthesis, can lead to abnormal levels of synthesized 5-HT. TPH2 enzymatic activity depends on tryptophan, which also participates in the kynurenine pathway to form various neuroactive metabolites that can decrease 5-HT levels by drawing away tryptophan concentrations for 5-HT synthesis and destroying 5-HT both indirectly and directly. Potential treatments targeting these two mechanisms may increase 5-HT levels in patients with depression. However, current data is inadequate to confirm the feasibility of TPH2- and tryptophan pathway-based treatments, so more experiments are desired. Further investigation on TPH2 and tryptophan pathways in relation to depression may lead to a breakthrough in treatment development for depression by augmenting current medications.