Triple reuptake inhibitors as potential next-generation antidepressants: a new hope?

The current therapy for depression is less than ideal with remission rates of only 25-35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans.