Triple reuptake inhibitors: Next-generation antidepressants

A major advance in the pharmacotherapy of depression was the introduction of the selective serotonin reuptake inhibitors nearly 2 decades ago. These drugs succeed in treating depressed patients with few of the side effects common to tricyclic antidepressants, which they largely replaced. However, there are still unmet clinical needs with respect to efficacy, onset, and side-effect profile. The effects of the antidepressants occur almost immediately; however, a therapeutic lag is required to affect meaningful symptom improvement. Not all patients respond to antidepressants well, with some patients undergoing adverse events such as sexual dysfunction. Novel therapies or targets that may reduce side effects need to be addressed. Dopaminergic circuit dysfunction has been linked to depressive syndrome for many decades, and research on serotonin/norepinephrine-containing circuits has largely overshadowed its role in depression. It has been hypothesized that a broad-spectrum antidepressant will produce a more rapid onset and better efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine, in part due to the addition of the dopamine component. Triple reuptake inhibitors (serotonin, norepinephrine, and dopamine reuptake inhibitors) are being developed as a new class of antidepressant. This article presents the involvement of the dopaminergic neurotransmission underlying depressive symptoms, as well as preclinical and clinical trials of developing triple reuptake inhibitors.