Thought Broadcast

Well, what do you know… I turn my back for one second and now the FDA has gone ahead and approved another antidepressant.

This new one is vilazodone, made by Massachusetts-based company Clinical Data, Inc., and will be sold under the name Viibryd (which I have absolutely no idea how to pronounce, but I’m sure someone will tell me soon).

At first glance, vilazodone seems promising. It’s not exactly a “me-too” drug, a molecule similar in structure and function to something that already exists. Instead, it’s a “dual-action” antidepressant, a selective serotonin reuptake inhibitor and partial agonist at serotonin 1A receptors. In other words, it does two things: it blocks the reuptake of serotonin into neurons (much like the existing SSRIs like Prozac, Zoloft, and Lexapro) and it acts as a partial agonist at a particular type of serotonin receptor called “1A.” A partial agonist is a molecule that binds to a receptor on a target cell and does not activate that cell fully but doesn’t entirely prevent its response, either.

(Note: don’t let the name fool you. “Dual-action” agents are not “twice as effective” as other agents, and sometimes work just the same.)

If you buy the serotonin hypothesis of depression (closely derived from the “monoamine hypothesis“), then depression is caused by a deficiency in serotonin. SSRIs cause an increase in serotonin between two cells. However, the higher levels of serotonin serve as “negative feedback” to the first-order cell in order to keep the system in balance. (Our bodies do this all the time. If I keep yelling at you for no clear reason, you’ll rapidly “downregulate” your attention so that you don’t listen to me anymore. Neurons work this way, too.) The idea behind a partial agonist is that it will only do “part” of the work that serotonin will do (actually, it will effectively block the negative feedback of serotonin) to increase serotonin release even more.

Remember– that’s only if you agree that low serotonin is responsible for depression. And there are plenty of respectable people who just don’t buy this. After all, no one has convincingly shown a serotonin deficit in depression, and when SSRIs do work (which they do, remarkably well sometimes), they may be acting by a totally different mechanism we just don’t understand yet. Nevertheless, vilazodone did show a significant effect as early as the first week, an effect that lasted for eight weeks.

Specifically, a phase III trial of 410 adults with depression showed decreases in MADRS and HAM-D scales relative to placebo, as well as on the CGI-I, CGI-S, and HAM-A scales, with a decrease in MADRS score from a mean of 30.8 at baseline to about 18 at the 8-week timepoint (the placebo group showed a decrease of about 10 points). A similar decrease was seen in the HAM-D. As is typical with these studies, the phase III trial did not compare vilazodone to an existing drug. However, unpublished phase II trials did compare it to fluoxetine (Prozac) and citalopram (Celexa), and to placebo, and results show that the drugs were comparable (and placebo response rates were high, as high as 40% in some trials). Incidentally, 9.3% of patients in the phase III trial dropped out due to adverse effects, mainly diarrhea.

So is a blockbuster in the works? Well, it’s not quite as “new” as one would think. SSRIs have been in widespread use for years, and there’s already a serotonin 1A partial agonist available called BuSpar (generic = buspirone) which is sort of a “ho-hum” drug– effective for some, but nothing to get too excited about. It seems that one could make “homemade” vilazodone by combining buspirone with an SSRI. (Kids, don’t try this at home. Please consult an expert.) This is a fairly common combination, although most psychiatrists have been underwhelmed by buspirone’s efficacy (one of my teachers called it “holy water”). Maybe vilazodone will convince me otherwise.

To go back to my original question, do we really need this? My gut reaction is no, as it seems too similar to what we already have available. There may be a small group of treatment-resistant depressed patients for whom vilazodone will be a wonder drug, a true lifesaver. In an attempt to discover this small group, the manufacturer is simultaneously studying “biomarkers that may predict treatment response.” In other words, they’re looking for genetic “fingerprints” that might predict patients who will respond to their drug (or who will get side effects). They have no “hits” yet (one of the markers they studied in phase III proved to have no predictive value in a follow-up trial), but it’s appealing to think that we might get more data on how to use– or avoid– this new drug more wisely.

While it’s good to have more tools in our toolkit, I sincerely hope this doesn’t turn into yet another in a long line of medications that we give to depressed patients in the trial-and-error process that unfortunately characterizes a lot of depression management. What’s truly needed is not just another serotonin agent, but a guideline (like a genetic test) to predict who’s likely to respond, or, better yet, a more sophisticated understanding of what’s happening in the minds of “depressed” patients. (And the differences among depressed patients far outweigh their similarities.) Until then, we’ll just be making incremental progress toward an elusive goal.