May 15, 2012

One of the highlights of the American Psychiatric Association (APA) Annual Meeting is the Exhibit Hall.  Here, under bright lights and fancy multimedia displays, sponsors get to show off their new wares.  If anyone wonders whether modern psychiatry isn’t all about psychopharmacology, one visit to the APA Exhibit Hall would set them straight.  Far and away, the biggest and glitziest displays are those of Big Pharma, promising satisfaction and success—and legions of grateful patients—for prescribing their products.

At the 2012 Annual Meeting last week, I checked out most of the Pharma exhibits, mainly just to see what was in the pipeline.  (Not much, it turns out.)  I didn’t partake in any of the refreshments—lest I be reported to the Feds as the recipient of a $2 cappuccino or a $4 smoothie—but still felt somewhat like an awestruck Charlie Bucket in Willie Wonka’s miraculous Chocolate Factory.

One memorable exchange was at the Nuedexta booth.  Nuedexta, as readers of this blog may recall from a 2011 post, is a combination of dextromethorphan and quinidine, sold by Avanir Pharmaceuticals and approved for the treatment of “pseudobulbar affect,” or PBA.  PBA is a neurological condition, found in patients with multiple sclerosis or stroke, and characterized by uncontrollable laughing and crying.  While PBA can be a devastating condition, treatment options do exist.  In my blog post I wrote that “a number of medications, including SSRIs like citalopram, and tricyclic antidepressants (TCAs), are effective in managing the symptoms of PBA.”  One year later, Nuedexta still has not been approved by the FDA for any other indication than PBA.

In my discussion with the Avanir salesman, I asked the same question I posed to the Avanir rep one year ago:  “If I had a patient in whom I suspected PBA, I’d probably refer him to his neurologist for management of that condition—so why, as a psychiatrist, would I use this medication?”  The rep’s answer, delivered in that cool, convincing way that can only emerge from the salesman’s anima, was a disturbing insight into the practice of psychiatry in the 21st century:

“Well, you probably have some patients who are real trainwrecks, with ten things going on.  Chances are, there might be some PBA in there, so why not try some Nuedexta and see if it makes a difference?”

I nodded, thanked him, and politely excused myself.  (I also promptly tweeted about the exchange.)  I don’t know if his words comprised an official Nuedexta sales pitch, but the ease with which he shared it (no wink-wink, nudge-nudge here) suggested that it has proven successful in the past.  Quite frankly, it’s also somewhat ugly.

First of all, I refuse to refer to any of my patients as “trainwrecks.”  Doctors and medical students sometimes use this term to refer to patients with multiple problems and who, as a result, are difficult to care for.  We’ve all used it, myself included.  But the more I empathize with my patients and try to understand their unique needs and wishes, the more I realize how condescending it is.  (Some might refer to me as a “trainwreck,” too, given certain aspects of my past.)  Furthermore, many of the patients with this label have probably—and unfortunately—earned it as a direct result of psychiatric “treatment.”

Secondly, as any good scientist will tell you, the way to figure out the inner workings of a complicated system is to take it apart and analyze its core features.  If a person presents an unclear diagnostic picture, clouded by a half-dozen medications and no clear treatment goals, the best approach is to take things away and see what remains, not to add something else to the mix and “see if it makes a difference.”

Third, the words of the Avanir rep demonstrate precisely what is wrong with our modern era of biological psychopharmacology.  Because the syndromes and “disorders” we treat are so vague, and because many symptoms can be found in multiple conditions—not to mention everyday life—virtually anything a patient reports could be construed as an indication for a drug, with a neurobiological mechanism to “explain” it.  This is, of course, exactly what I predicted for Nuedexta when I referred to it as a “pipeline in a pill” (a phrase that originally came from Avanir’s CEO).  But the same could be said for just about any drug a psychiatrist prescribes for an “emotional” or “behavioral” problem.  When ordinary complaints can be explained by tenuous biological pathways, it becomes far easier to rationalize the use of a drug, regardless of whether data exist to support it.

Finally, the strategy of “throw a medication into the mix and see if it works” is far too commonplace in psychiatry.  It is completely mindless and ignores any understanding of the underlying biology (if there is such a thing) of the illnesses we treat.  And yet it has become an accepted treatment paradigm.  Consider, for instance, the use of atypical antipsychotics in the treatment of depression.  Not only have the manufacturers of Abilify and Seroquel XR never explained how a dopamine partial agonist or antagonist (respectively) might help treat depression, but look at the way they use the results of STAR*D to help promote their products.  STAR*D, as you might recall, was a large-scale, multi-step study comparing multiple antidepressants which found that no single antidepressant was any better than any other.  (All were pretty poor, actually.)  The antipsychotic manufacturers want us to use their products not because they performed well in STAR*D (they weren’t even in STAR*D!!!) but because nothing else seemed to work very well.

If the most convincing argument we can make for a drug therapy is “well, nothing else has worked, so let’s try it,” this doesn’t bode well for the future of our field.  This strategy is mindless and sloppy, not to mention potentially dangerous.  It opens the floodgates for expensive and relatively unproven treatments which, in all fairness, may work in some patients, but add to the iatrogenic burden—and diagnostic confusion—of others.  It also permits Pharma (and the APA’s key opinion leaders) to maintain the false promise of a neurochemical solution for the human, personal suffering of those who seek our help.

This, in my opinion, is the real “trainwreck” that awaits modern psychiatry.  And only psychiatrists can keep us on the tracks.


The Balance of Information

May 19, 2011

How do doctors learn about the drugs they prescribe?  It’s an important question, but one without a straightforward answer.  For doctors like me—who have been in practice for more than a few years—the information we learned in medical school may have already been replaced by something new.  We find ourselves prescribing drugs we’ve never heard of before.  How do we know whether they work?  And whom do we trust to give us this information?

I started to think about this question as I wrote my recent post on Nuedexta, a new drug for the treatment of pseudobulbar affect.  I knew nothing about the drug, so I had to do some research.  One of my internet searches led me to an active discussion on a site called (SDN).  SDN is a website for medical students, residents, and other medical professionals, and it features objective discussions of interesting cases, new medications, and career issues.  There, I found a thread devoted to Nuedexta; this thread contained several posts by someone calling himself “Doogie Howser”—and he seemed to have a lot of detailed information about this brand-new drug.

Further internet sleuthing led me to a message board on Yahoo Finance for Avanir Pharmaceuticals, the company which makes Nuedexta.  In one of the threads on this board, it was suggested that the “Doogie Howser” posts were actually written by someone I’ll call “TS.”  Judging by the other posts by this person, “TS” clearly owns stock in Avanir.  While “TS” never admitted to writing the SDN posts, there was much gloating that someone had been able to post pro-Nuedexta information on a healthcare website in a manner that sounded authoritative.

Within 24 hours of posting my article, someone posted a link to my article on the same Yahoo Finance website. I received several hundred “hits” directly from that link.  Simultaneously (and ever since), I’ve received numerous comments on that article, some of which include detailed information about Nuedexta, reminiscent of the posts written by “Doogie Howser.” Others appear to be written by “satisfied patients” taking this drug.  But I’m skeptical. I don’t know whether these were actual patients or Avanir investors (or employees); the IP address of one of the pro-Nuedexta commenters was registered to a public-relations firm in Arizona. Nevertheless, I have kept the majority of the posts on the blog, except those that contained personal attacks (and yes, I received those, too).

The interesting thing is, nothing “TS”/”Doogie Howser” said about Nuedexta was factually incorrect.  And most of the posts I received were not “wrong” either (although they have been opinionated and one-sided).  But that’s precisely what concerns me. The information was convincing, even though—if my hunch is correct—the comments were written for the sake of establishing market share, not for the sake of improving patient care.

The more worrisome issue is this: access to information seems to be lopsided.  Industry analysts (and even everyday investors) can have an extremely sophisticated understanding of new drugs on the market, more sophisticated, at times, than many physicians.  And they can use this sophistication to their advantage. Some financial websites and investor publications can read like medical journals.  Apparently, money is a good motivator to obtain such information and use it convincingly.  Quality patient outcomes? Not so much.

So what about the doctor who doesn’t have this information but must decide whether to prescribe a new medication?  Well, there are a few objective, unbiased sources of information about new drugs (The Medical Letter and The Carlat Report among them).  Doctors can also ask manufacturers for the Prescribing Information (“PI”) or do their own due diligence to learn about new treatments.  But they often don’t have the time to do this, and other resources (like the internet) are far more accessible.

However, they’re more accessible for everyone.  When the balance of information about new treatments is tipped in favor of drug manufacturers, salespeople, and investors—all of whom have financial gain as their top priority—and not in favor of doctors and patients (whose lives may be at stake), an interesting “battle of wits” is bound to ensue.  When people talk a good game, and sound very much like they know what they’re talking about, their motives must always be questioned.  Unfortunately—and especially under the anonymity of the internet—those motives can sometimes be hard to determine.  In response, we clinicians must be even more critical and objective, and not necessarily believe everything we hear.

Nuedexta: “Pipeline in a Pill” or Pipe Dream?

April 18, 2011

If you’re like me, you’ve probably seen numerous Internet ads for a new medication called Nuedexta from Avanir Pharmaceuticals.  Nuedexta was approved in October 2010 for the treatment of “pseudobulbar affect,” or PBA.  My first reaction was one of surprise, as PBA is relatively uncommon, or so I was taught: why would a drug company be aggressively advertising a drug with such a niche market?  However, as I thought about the symptoms that define PBA—and then, last week, I received a Nuedexta promotional packet in the mail—I figured I should take a look “under the hood.”

First of all, I reviewed the presentation and biology of PBA.  I remember being taught in residency that it is a fairly uncommon manifestation of neurological illness, although it has a very distinctive presentation, namely, emotional expressions that are disconnected from any subjective emotional changes.  Indeed, an alternate name for it is “pathological laughing and crying.”  Certainly, the discrepancy between a patient’s emotional display—which may be extreme, and cause great distress to caregivers—and the lack of any subjective change in mood, is highly suggestive of a focal brain abnormality.

PBA is typically caused by a specific brain lesion between the cortex (the source of voluntary thought/action) and the brainstem (the source of involuntary emotional expression like laughing and crying).  Normally, we’re stimulated to laugh or cry by something funny or sad; these emotions are first processed in the cortex, which then sends a message to the brainstem to express that emotion.  If you have a lesion between your cortex and brainstem (e.g., from a stroke, multiple sclerosis, or a degenerative process) then the emotional expression can be entirely separated from the conscious awareness of it.

Over the last decade some research groups have begun to look at dextromethorphan as a potential treatment for PBA.  Dextromethorphan, also known as DXM, is a cough suppressant, the active ingredient in Robitussin, not to mention a drug often used recreationally for its dissociative and hallucinogenic properties.  Dextromethorphan is an NMDA antagonist (i.e., it prevents glutamate from activating target cells via NMDA receptors) as well as an agonist of a type of receptor called “sigma-1,” whose role is much less understood.

When dextromethorphan is combined with quinidine, another widely available drug (used to treat heart arrhythmias), the quinidine inhibits dextromethorphan’s metabolism, allowing it to penetrate the brain at doses low enough to avoid any peripheral toxicity.  Once inside the brain, it “may act on regions implicated in emotional expression” (by an unknown mechanism) and, indeed, it improves PBA symptoms with the only significant side effects being dizziness and diarrhea.  The new drug Nuedexta is a combination of 20 mg dextromethorphan and 10 mg quinidine, and the estimated cost will be from $3000-$5000 per year.

(BTW, note the theme here, which is similar to what I wrote about with Contrave:  Nuedexta is actually a combination of two existing, generic—i.e., cheap—drugs, with a significant markup, to cover the costs of clinical testing, marketing, and, of course, shareholder profits.)

Physicians—and patients—may wonder why we need a new drug to treat PBA.  Certainly, this is a good question (although I think PBA is simply Avanir’s “foot in the door,” as I’ll discuss below).  A 2007 review in the Annals of Neurology shows that a number of medications, including SSRIs like citalopram, and tricyclic antidepressants (TCAs), are effective in managing the symptoms of PBA (see also here).  And, as I mentioned earlier, the proper diagnosis of PBA requires the presence of an underlying neurological disorder, and treatment of the disorder, too, may ameliorate the PBA symptoms.

Interestingly, while I searched for literature references discussing PBA, I found that most—if not all—of the literature from the last 5-6 years has been funded or underwritten by Avanir Pharmaceuticals—and all of which discussed the benefits of dextromethorphan/quinidine.  This included an “educational review” published by the National Stroke Association in 2005.  In fact, the editors of the Annals of Neurology issue I cited above tried to get someone to write a review on PBA but couldn’t find any authors “untouched by Avanir.”  It certainly seems that Avanir’s PR effort has paid off.

The coup de grâce, in my opinion, is an “expert review” on PBA published in the journal CNS Spectrums in October 2005.  It’s a roundtable discussion on how to distinguish PBA from other psychiatric and neurologic disorders—and, of course, the benefits of dextromethorphan/quinidine.  It seems like a fair review, although the authors make comments that broaden the definition of PBA to include other disturbances of affect, which are extremely common among psychiatric patients. “It may be useful to regard affective lability,” they write, “as a disorder of affect that exists at a point on a continuum between normal affective variability and the more severe end of the continuum characterized by [PBA].”  Furthermore, they encourage clinicians to “include a specific assessment for PBA” in all patients with any neurological condition, to prevent their being “misdiagnosed” with a psychiatric disorder—the implication being that what we might call “poststroke depression” might actually be PBA.  And they even open the door to the possibility that “PBA-like” symptoms might not have a recognizable neurological basis:  “In some cases PBA may be the only clinically identifiable manifestation of the neurological condition.  In light of the overlap between the neurology of affect regulation and the neurology of psychiatric conditions, … PBA may sometimes occur in the latter context as well.” [Emphasis mine.]

You can see where this is all headed—and probably why I received a promotional packet for Nuedexta, even though I’m not a neurologist.  Here we have a new medication, which has been approved for a neurological syndrome whose major manifestation is “affective instability.”  Even though the proper diagnosis of PBA requires far more than that, clinicians will undoubtedly use it off-label for the affective lability seen in many other conditions (such as bipolar disorder, schizophrenia, autism, dementia, maybe even childhood irritability, etc).  And my bet is that Avanir will try to get Nuedexta approved for all of these conditions.

(BTW, Nuedexta has never been compared head-to-head with SSRIs or TCAs, and the trials which led to Nuedexta’s approval showed only slight improvement vs. placebo in patients with PBA due to multiple sclerosis and ALS.)

Indeed, Avanir’s investor materials (see pdf here) already state that the company will seek approval for multiple sclerosis-related pain, and for behavioral symptoms in dementia.  And when one considers how atypical antipsychotics have been affected by “indication creep,” it is probably only a matter of time before Nuedexta will be tested for other disorders characterized by affective changes, including the big kahunas: depression and bipolar disorder.  To that end, during a November 2009 conference call to shareholders, Keith Katkin, Avanir’s CEO, described Nuedexta as a “pipeline in a pill.”

I should note here that I have not tried Nuedexta so I can’t say whether it is effective.  I also have no financial interest in Avanir Pharmaceuticals.  I don’t see how Nuedexta’s pharmacological properties might control affective outbursts (but then again, I can’t explain precisely how SSRIs treat depression, either).  Certainly I’ve read of isolated cases in which Nuedexta has led to “dramatic improvement,” but those cases are from spokespeople with “skin in the game,” so to speak.  Nuedexta might be a blockbuster drug in neurology and psychiatry alike, and I’m willing to give it that chance.  However, at this stage the marketing speaks far louder than the data, and the seeds are already being sown for the more widespread use of this relatively unproven agent.  We need to be cautious not to be swayed by the influence of those who want to make a few bucks (or a few billion) off our ignorance.

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