Dov’s Triple Reuptake Inhibitor Enters Phase II Major Depression Trial

Implications: Triple-reuptake inhibitors (TRIs) represent an emerging class of antidepressant drugs in development with potential application for other disorders including ADHD and obesity.   By potentiating all three of the main monoamine neurotransmitters implicated in depression  - serotonin, norepinephrine, and dopamine – they potentially offer a degree of efficacy that will separate them from existing antidepressant treatments and may carry an improved side effect profile (ie, less weight gain, enhanced profile on energy/motivation in the short and long term).   It’s too early to say much about DOV Pharmaceutical’s DOV 21,947, which hopes to have this Phase II depression data within a year, but TRI’s should have a significant place in the depression market in a few years. 

Analysis: Looking at Triple Reuptake Inhibitors in general, we don’t see anything profoundly groundbreaking or novel – we’re still in the monoamine system, perhaps providing neurotransmitter effects not unlike that of the rarely used class of Monoamine Oxidase Inhbitors (MAOIs) but with a potentially better side effect and food-drug interaction profile.   But longer term use of SSRIs may lead to downregulation of the dopamine system, contributing to fatigue, apathy and weight gain in some patients.   TRIs may provide a built in counterbalance with their dopamine properties and, at least in theory, may be especially helpful for what is called ‘atypical depression,’ characterized by increased sleep, appetite, and fatigue.   Also, emerging new drugs for depression treatment seem to have a litmus test of whether they cause sexual side effects or weight gain and it would appear TRIs may look good here and there is data showing weight loss with DOV 21,947.
 
There is no hard data to show that there is enhanced efficacy but the mechanism of action suggests the possibility; major depression still carries a full remission rate of less than 50% in most antidepressant studies, with partial responders and non-responders unfortunately all too common.  How these drugs will work on anxiety symptoms, often comorbid with major depression, is not clear either and may have signficant clinical impacts - we know that SSRIs are generally favorable in this regard.    A number of TRIs are in development by other companies, including a GlaxoSmithKline’s 272, 475, in-licensed from Neurosearch, and Sepracor’s SEP-225289, both in Phase II trials for depression.