Traditional and novel possible targets for antidepressant drugs

Abstract

Antidepressant drugs have been available since the late 1950s. A large number of such drugs have been developed over the years. Unraveling their mechanism of action paved the way to the development of the earlier hypotheses of depression such as the monoamine theory and beta-receptor downregulation hypothesis. This led to yet more antidepressant drugs being produced, all of which worked via the noradrenergic and serotonergic systems. They increased monoamine neurotransmitter system activity usually by blocking the presynaptic reuptake mechanism, binding the monoamine oxidase intraneuronally or targeting specific receptors on the postsynaptic membrane. Although generally effective, current antidepressants are successful in less than two thirds of depressed patients. More recent developments in the understanding of the pathophysiology of depression have stimulated a rethinking in the approach to drug development. Novel drugs need to take into account the current knowledge on brain dysfunction in relation to depression and target available and future biomarkers of this condition. Various avenues are being explored in keeping with the new approach of "precision medicine" with the view to develop drugs based on "molecular diagnoses." Depression is a multifactorial condition and not all abnormalities and biomarkers apply to all patients. The skill of future approaches to treatment would be to identify the specific abnormalities relevant to the individual patient and target these biomarkers with specific drugs.