Targeting tryptophan hydroxylase 2 in affective disorder

Serotonin (5-HT) has been implicated in several psychiatric disorders including schizophrenia, depressive disorder and suicide. The key and rate limiting enzyme of 5-HT synthesis is tryptophan hydroxylase 2 (TPH2).The association between TPH2 and affective disorders as well as future vistas of its potential clinical targeting: i) TPH2 in the regulation of 5-HT-dependent behavior, ii) TPH2 gene polymorphism and human behavior, iii) TPH2 and sensitivity to antidepressants and iv) effect of dietary tryptophan manipulation on affective behavior are described.The main conclusions of the review are: i) there is an association between TPH2 and genetically defined behavioral variations, ii) the haplotypes, including some human TPH2 gene SNPs, can predict the risk of affective disorders and the sensitivity to antidepressant therapeutics, iii) mutations decreasing TPH2 activity produce negative effects on behavior and, possibly, on survival, iv) the effect of dietary tryptophan manipulations on human mood and behavior is modest compared with that of inhibitors of 5-HT transporter and monoamine oxidase.More comprehensive study of TPH2 genetics is needed to increase the clinical value of the enzyme as a predictor of affective disorder risk and efficacy of antidepressant drugs.