Toward a better understanding of depression and anxiety: The involvement of stress and tryptophan hydroxylase activation

Tryptophan hydroxylase (TPH) has been implicated as the key enzyme involved in the etiology of the affective disorders, anxiety and depression. In addition to its activation by stress, TPH is also activated by the amino-acid decarboxylase inhibitor, NSD 1015, which is widely used for the determination of serotonin turnover. The blockade of this activation by the established antidepressants provides a new, distinct concept to account for the beneficial activity of these compounds. The blockade of the stress-induced activation of TPH by the benzodiazepine, diazepam, is consistent with its anxiolytic activity involving TPH activation inhibition. In support of the concept, a selective TPH activation inhibitor, AGN 2979, has been reported to exert both powerful antidepressant and anxiolytic effects in the clinic, with a notable lack of the side effects associated with transmitter reuptake inhibition and benzodiazepine receptor interactions.