Triple reuptake inhibitors as potential next-generation antidepressants: a new hope?
A review article on a new class of antidepressant molecules. Future Med. Chem. (2015) 7(17), 2384–2405
Major depressive disorder (MDD) is a severe form of depression characterized by symptoms like anhedonia, depressed mood leading to suicidal thoughts and impaired cognitive functions. Selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors are the current first line treatment options for major depressive disorder Although a plethora of antidepressants are in market, it is believed that approximately 30–40% of patients do not respond to the therapy, thus reflecting an unmet need to develop novel therapeutics to combat MDD. Triple reuptake inhibitors (TRIs) have emerged as a promising class that target SERT, NET and DAT at the same time. This review summarizes this new class of antidepressant drugs TRIs as the next-generation antidepressants. The concept of triple uptake inhibition has gained credence based on the evidence that dopamine plays an important role in the pathophysiology and treatment of depression. Several TRIs have been investigated in preclinical stage. Few candidates including DOV 216,303, DOV 21,947, BMS 820836, GSK 1360707, GSK 372,475 and SEP 225289 have gone through clinical trials. Our laboratory has developed D-473 as a novel TRI with potent in vivo efficacy which is currently under development. Proposed occupancy required for a TRI for producing superior antidepressant effect is 70–80% for SERT, 50–70% for NET and 30–40% for DAT. Although the optimal potency ratio for all three transporters is yet to be established, it has become apparent that optimal in vivo occupancy of transporters has a greater significance to produce efficacy in the clinic. Future clinical studies will reveal whether the TRIs have any broader advantages over the SSRIs or SNRIs in terms of efficacy, early onset and side effects. We hope that this review will stimulate further interest in the development of TRIs.