The Rest of the Story

We usually keep some carrots around, in case someone wants a quick low-fat snack.  This evening, I found out that my wife has eaten all the carrots.  Thus, with my foraging instinct activated but unfulfilled, I searched the web frantically, looking for information about new psychotropic drugs that might be available in the next few years.  Not as good as a carrot, but no calories, either.

The first one I'll mention is desvenlaxafine.  As the name suggests, the drug is good old venlafaxine (Effexor) with a methyl group removed.  This is the structure:


This is in phase III trials, which is the last phase before it can be approved.  FDA approval is never guaranteed, but this one probably will make it to the market.  Like venlafaxine, it inhibits reuptake of serontonin and norepinephrine.   At first glance, it seems like another "me-too" drug.  However, it probably will have some real clinical utility. 

The oldest antidepressant on the market, imipramine, also inhibits reuptake of serotonin and norepinephrine.  It does a lot of other things, too, which accounts for the greater adverse effect burden.  Desipramine is the same molecule as imipramine, but with a methyl group removed.  Relative to imipramine, desipramine has a weaker effect on serotonin, and a stronger effect on norepinephrine.  It is well established that some patients respond to one and not the other, and some tolerate one and not the other.  Therefore, it is reasonable to expect that desvenlafaxine will help some people who either do not respond to, or do not tolerate, existing antidepressants.  Not too exciting, but worth mentioning.

Another phase III drug is agomelatine (Valdoxan).  Unlike desvenlafaxine, agomelatine has a novel mechanism of action: it is a melatoninergic agonist and a 5-HT2c antagonist.  The action on melatonin receptors may be responsible for an unusual property of agomelatine.  That is, it improves sleep continuity without causing any daytime somnolence. 

This study indicates that it has efficacy comparable to paroxetine.  This study indicates that it could be effective for hospitalized depressed patients.  The mechanism of action suggests that it will not cause sexual dysfunction.  If that turns out to be the case, it would be a significant advantage.

It has been about ten years since we have gotten an antidepressant with a truly novel mechanism of action.  The most recent one, mirtazapine, works well but tends to increase appetite and cause weight gain.  Agomelatine probably will not affect weight, although that was not mentioned specifically in any of the studies I could find.  The fact that another novel agent is so close to approval should be encouraging to that 5-10% of depressed patients who are refractory to treatment with existing drugs.