Introduction: The dysfunctions of three very important monoamine neurotransmitters, serotonin (5-HT), norepinephrine (NE) and dopamine (DA), are associated with some of important CNS diseases such as depression; developing the triple reuptake inhibitors (TRIs) that can rebalance 5-HT, NE and DA through the inhibition of the monoamine reuptake transporters will lead to a more effective and safer antidepressant.
Areas covered: This article reviews past 7 years' advances in the development of TRIs; a patent review (2006 - 2012), covering the discovery of new chemical entities, and development status of leading TRI clinical candidates.
Expert opinion: The development of TRIs has several challenges, including discovering a "single" agent that has the activities against all three monoamine reuptake transporters SERT, NET and DAT. More important is that the agent must have a "right ratio" to be safer and better tolerated for the treatment of depression. The TRIs can potentially be used for the treatment of other CNS diseases, such as pain, Parkinson's and attention deficit hyperactivity disorder (ADHD), depending on ratios of SERT, NET and DAT.