Rationale for the development of noradrenaline reuptake inhibitors

Elucidation of the mechanism of action of antidepressants led to the hypothesis that depression is caused by dysfunction in either the noradrenergic or serotonergic neurotransmitter systems. As inconsistencies in studies designed to confirm this hypothesis arose, the consensus on the biological basis of depression is being refined. The need for better tolerated and effective antidepressants has resulted in the development of agents with more specific receptor binding profiles than the tricyclic antidepressants. These newer antidepressants selectively inhibit the reuptake of noradrenaline (selective NARIs), serotonin (SSRIs) or both (SNRIs). They are useful tools for describing changes in neuroreceptors and intracellular events that occur during antidepressant pharmacotherapy. Reboxetine, a selective NARI, down-regulates beta-adrenergic receptors and desensitises noradrenaline-coupled adenylate cyclase. It also affects cAMP- and Ca2+/calmodulin-dependent phosphorylation systems in a different manner to tricyclic antidepressants and SSRIs. This implies that although different classes of antidepressants may affect common central pathways, the ways in which they do this are distinctive. In conclusion, reboxetine, a selective NARI which is well tolerated and effective in the treatment of depression, has provided us with a new insight into the action of antidepressants and thus will help us to refine our theory of the biological basis of depression.

Elucidation of the mechanism of action of antidepressants led to the hypothesis that depression is caused by dysfunction in either the noradrenergic or serotonergic neurotransmitter systems. As inconsistencies in studies designed to confirm this hypothesis arose, the consensus on the biological basis of depression is being refined. The need for better tolerated and effective antidepressants has resulted in the development of agents with more specific receptor binding profiles than the tricyclic antidepressants. These newer antidepressants selectively inhibit the reuptake of noradrenaline (selective NARIs), serotonin (SSRIs) or both (SNRIs). They are useful tools for describing changes in neuroreceptors and intracellular events that occur during antidepressant pharmacotherapy. Reboxetine, a selective NARI, down-regulates β-adrenergic receptors and desensitises noradrenaline-coupled adenylate cyclase. It also affects cAMP- and Ca2+/calmodulin-dependent phosphorylation systems in a different manner to tricyclic antidepressants and SSRIs. This implies that although different classes of antidepressants may affect common central pathways, the ways in which they do this are distinctive. In conclusion, reboxetine, a selective NARI which is well tolerated and effective in the treatment of depression, has provided us with a new insight into the action of antidepressants and thus will help us to refine our theory of the biological basis of depression.