Thought Broadcast

The world may need to wait a little while longer for the next generation of antidepressants.  Last week, AstraZeneca and Targacept, working together on a new drug called TC-5214, released the first data from a phase III trial.  TC-5214 failed as an add-on antidepressant in a trial of 295 European patients with treatment-refractory depression.

This news is clearly a disappointment to those of us waiting for some fresh alternatives to our existing armamentarium.  But it’s also a heavy blow to Targacept, a company whose sole focus is the development of “neural nicotinic receptor [NNR] modulators” for several different diseases.  NNRs are receptors for a neurotransmitter called acetylcholine.  While (unlike serotonin or norepinephrine) acetylcholine is not one of the chemicals commonly associated with depression, a growing body of evidence over the last several years—as well as reports dating back to the 1970s—suggests that acetylcholine/adrenergic imbalances might underlie depressive symptoms.

TC-5214 is also known as mecamylamine (actually, the S-enantiomer of this compound, for those of you keeping score at home).  Mecamylamine is an NNR antagonist.  It was used in the 1950s as a blood pressure drug, due to its ability to block sympathetic outflow (technically, it’s considered a “ganglionic blocker”).  Scientists started investigating mecamylamine as an antidepressant when they observed that many existing antidepressants actually block NNRs at therapeutic doses, and also that it was effective in several animal models of depression.

Early human studies were very promising.  In 2009, phase-II trial data of 265 patients showed an average 6-point improvement in HAM-D scores when taking mecamylamine, as well as improvements on several other secondary measures.  But the phase III study failed to replicate this finding.  In fact, the failure was so colossal (and so unexpected) that Targacept lost 60% of its market value in one day (and AstraZeneca slid 3.2%, too).

These reports prompted me to look more closely at why an NNR antagonist might work as an antidepressant.  Unfortunately, the whole NNR story is rather confusing.  For starters, consider the first “N” in NNR:  it stands for nicotine, which binds to the NNR, and (as any smoker will tell you) nicotine is a mood-enhancing chemical.  Granted, the mood-enhancing effect of nicotine might not be due solely to its action at the NNR.  However, animal studies show that other NNR agonists and partial agonists do have antidepressant effects.

Two of these NNR partial agonists with antidepressant properties are cytisine and varenicline.  Varenicline, of course, is also known as Chantix, the popular smoking-cessation drug.  Indeed, several groups have found varenicline to have a “robust and sustained” antidepressant effect when added to antidepressants alone.   At the same time, however, varenicline has received notoriety for its apparent tendency to cause suicidal thoughts in some patients.  (To be sure, all antidepressants include a “black box warning” about the potential for increased suicidal thoughts, but the effects of Chantix appear to be of a different, and more severe, character.)  How to explain this paradox is unclear.

But let’s get back to mecamylamine.  It’s an NNR antagonist.  So why would both an NNR antagonist and an NNR agonist work as antidepressants?  Actually, psychopharmacologists love these kinds of questions because it gives them a chance to hypothesize a mechanism (everything in psychiatry has a “hypothetical mechanism,” you know).  Here goes:

Exposure to a low concentration of agonist [like nicotine] initially activates the nAChR, but this is then followed by a rapid desensitization.  Nicotine’s predominant effect on many nAChR subtypes over time is that of an antagonist.  However, some nAChR subtypes are more resistant to desensitization than others, and there is some evidence that certain receptor subtypes become more sensitive to repeated agonist exposure. [PDF from 2002 here]

Huh???  I’m sure I lost the non-psychiatrists (and probably most of the psychiatrists) with that passage.  The bottom line is, we really don’t know what’s happening at the nAChR/NNR, but doggone it, let’s test a bunch of “NNR modulators” and find one that works.

Targacept, the company developing and testing TC-5214, has devoted its entire research and development enterprise to NNR modulators.  The Targacept website boasts a “robust product pipeline” including candidates for “MDD [presumably, TC-5214], ADHD, Alzheimer’s disease, and cognitive dysfunction in schizophrenia.”  All of these are areas in desperate need of better therapeutics, and the relatively unexplored NNR might yield novel treatments that are particularly efficacious.  The wide range of potential compounds (and target disorders) discussed on Targacept’s website, however, make the search look more like a fishing expedition than rational drug design.  Of course, even if ONE drug turns out to be significantly more effective than anything else available, patients (and Targacept shareholders) will benefit.  But the inevitable failures (like that of TC-5214) along the way should give us pause, and lead us to rethink the “Grand Neurotransmitter Narrative” with which we delude ourselves on a regular basis.  In other words, we may learn more about psychiatry from our failures than from our successes—even if it sets us back a few notches in the clinical arena.

Which brings me to my final comments about how we learn about drug trials.  As I’ve written before, clinical trial results (successes and failures) are transmitted far more readily via the financial press than by the medical literature.  In fact, the only reason I even know about TC-5214’s poor phase III trial was because I saw the jaw-dropping 10+ point fall in TRGT (Targacept) in pre-market trading on the CNBC stock ticker last Tuesday morning.  Searching for more info online, I found some incredibly detailed and thoughtful articles on financial websites like Seeking Alpha and TheStreet.com.

On the other hand, it may be months (or, perhaps, never) before I see the TC-5214 results published in a psychiatric journal.  And even then, I’d have to hope that my employer provides access to the journal, otherwise I’d have to shell out $35 or more for a copy of the article.

In an era when it’s easy to criticize drug companies and Wall Street for their corruption of psychiatry, we also have to remember that it’s those same companies and investors who publicize this information most efficiently—because there’s money on the line.  Nonetheless, it is a curious phenomenon when speculators and day traders know more about new medications, novel drug mechanisms, and R&D pipelines, than the doctors who will use these drugs, or the patients who ultimately stand to gain (or lose) the most.

ADDENDUM:   While writing this post, I also came across this post by Neuroskeptic, about another failed antidepressant trial.  A depressing week for antidepressants, I guess.

ADDENDUM 2:  Special thanks to reader L. Lundt, who points out that Targacept was spun off from R.J. Reynolds Tobacco Co. in 2000.  As of Targecept’s IPO in 2006, RJR owned 5.8% of the company.

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