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Abilify for Bipolar Maintenance: More Hard Questions

May 31, 2011

Much attention has been drawn to a recent PLoS Medicine article criticizing the evidence base for the use of Abilify as maintenance treatment for bipolar disorder.  The major points emphasized by most critics are, first, that the FDA approved Abilify for this purpose in 2005 on the basis of flawed and scanty evidence and, secondly, that the literature since that time has failed to point out the deficiencies in the original study.

While the above may be true, I believe these criticisms miss a more important point.  Instead of lambasting the FDA or lamenting the poor quality of clinical research, we psychiatrists need to use this as an opportunity to take a closer look at what we treat, why we treat, and how we treat.

Before elaborating, let me summarize the main points of the PLoS article.  The authors point out that FDA approval of Abilify was based on only one “maintenance” trial by Keck et al published in 2007.  The trial included only 161 patients (only 7 of whom, or 1.3% of the total 567 who started the study, were followed throughout 26 weeks of stabilization and 74 follow-up weeks of maintenance).  It also consisted of patients who had already been stabilized on Abilify; thus, it was “enriched” for patients who had already shown a good response to this drug.  Furthermore, the “placebo failures” consisted of patients who were abruptly withdrawn from Abilify and placed on placebo; their relapses might thus be attributed to the researchers’ “randomized discontinuation” design rather than the failure of placebo.  (For more commentary, including follow-up from Bristol-Myers Squibb, Abilify’s manufacturer, please see this excellent post on Pharmalot.)

These are all valid arguments.  But as I read the PLoS paper and the ongoing discussion ever since, I can’t help but think, so what??  First of all, most psychiatrists probably don’t know about the PLoS paper.  And even if they did, the major questions for me would be:  would the criticism of the Keck et al. study change the way psychiatrists practice?  Should it?

Let’s think about psychiatric illness for a moment.  Most disorders are characterized by an initial, abrupt onset or “episode.”  These acute episodes are usually treated with medications (plus or minus psychotherapy or other psychosocial interventions), often resulting in rapid symptomatic improvement—or, at the very least, stabilization of those symptoms.

One big, unanswered (and, unfortunately, under-asked) question in psychiatry is, then what?  Once a person is stabilized (which in some cases means nothing more than “he’s no longer a danger to himself or others”), what do we do?  We don’t know how long to treat patients, and there are no guidelines for when to discontinue medications.  Instead we hear the common refrain:  depression, schizophrenia, and bipolar disorder, are lifelong illnesses—”just like hypertension or diabetes”—and should be treated as such.

But is that true?  At the risk of sounding like a heretic (and, indeed, I’d be laughed out of residency if I had ever asked this question), are there some cases of bipolar disorder—or schizophrenia, or depression, for that matter—which only require brief periods of psychopharmacological treatment, or none at all?

The conventional wisdom is that, once a person is stabilized, we should just continue treatment.  And why not?  What doctor is going to take his patient off Abilify—or any other mood stabilizer or antipsychotic which has been effective in the acute phase—and risk a repeat mood episode?  None.  And if he does, would he attribute the relapse to the disease, or to withdrawal of the drug?  Probably to the disease.

For another example of what I’m talking about, consider Depakote.  Depakote has been used for decades and is regarded as a “prototypical” mood stabilizer.  Indeed, some of my patients have taken Depakote for years and have remained stable, highly functional, and without evidence of mood episodes.  But Depakote was never approved for the maintenance treatment of bipolar disorder (for a brilliant review of this, which raises some of the same issues as the current Abilify brouhaha, read this article by The Last Psychiatrist).  In fact, the one placebo-controlled study of Depakote for maintenance treatment of bipolar disorder showed that it’s no better than placebo.  So why do doctors use it? Because it works (in the acute phase.)  Why do patients take it?  Again, because it works—oh, and their doctors tell them to continue taking it.  As the old saying goes, “if it ain’t broke, don’t fix it.”

However, what if it is broke[n]?  Some patients indeed fail Depakote monotherapy and require additional “adjunctive” medication (which, BTW, has provided another lucrative market for the atypical antipsychotics).  In such cases, most psychiatrists conclude that the patient’s disease is worsening and they add the second agent.  Might it be, however, that after the patient’s initial “response” to Depakote, the medication wasn’t doing anything at all?

To be sure, the Abilify study may have been more convincing if it was larger, followed patients for a longer time, and had a dedicated placebo arm consisting of patients who had not been on Abilify in the initial stage.  But I maintain that, regardless of the outcome of such an “improved” trial, most doctors would still use Abilify for maintenance treatment anyway, and convince themselves that it works—even if the medication is doing absolutely nothing to the underlying biology of the disease.

The bottom line is that it’s easy to criticize the FDA for approving a drug on the basis of a single, flawed study.  It’s also easy to criticize a pharmaceutical company for cutting corners and providing “flawed” data for FDA review.  But when it comes down to it, the real criticism should be directed at a field of medicine which endorses the “biological” treatment of a disorder (or group of disorders) whose biochemical basis and natural history are not fully understood, which creates post hoc explanations of its successes and failures based on that lack of understanding, and which is unwilling to look itself in the mirror and ask if it can do better.

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The FDA Should Really Look Into This Drug

April 1, 2011

The Food and Drug Administration (FDA) regulates and approves medications for use in humans.  Their approval process is rigorous, and they do extensive monitoring of drugs they’ve already approved (“postmarketing surveillance”) to ensure their continued safety and efficacy.

As a psychiatrist, I see one particular drug used very frequently by my patients, usually prescribed by another physician for management of a physical or mental disorder.  In certain cases, however, I wonder whether it might actually worsen the symptoms I’m treating.  Furthermore, I’ve seen several recent references in the medical literature describing how this particular drug can increase the risk of psychotic symptoms and might even cause schizophrenia, a lifelong condition with high morbidity and mortality.

This month’s British Medical Journal, for instance, contains an article showing that users of this drug are more than twice as likely to have psychotic symptoms than nonusers; it “significantly increased the risk of psychotic experiences” over a 10-year period, and “adjustment for other psychiatric diagnoses did not change the results.”  Similarly, a meta-analysis published last month in the Archives of General Psychiatry showed that “the age at onset of psychosis for users [of this drug] was 2.70 years younger than for nonusers,” and that exposure to this drug “is associated with a decline in cognitive performance in young people.”  Finally, an article in the August 2010 American Journal of Psychiatry reported that use of this drug “is associated with an adverse course of psychotic symptoms, even after taking into account other clinical, substance use, and demographic variables.”

Given all this bad news, it’s surprising that this drug is still on the market—particularly in light of the FDA’s recent decisions to pull the plug on other medications with potentially dangerous side effects:  heart rhythm abnormalities (in the case of Darvon), coronary heart disease (Vioxx), increased risk of myocardial infarction (Avandia), fainting and non-cancerous ovarian cysts (Zelnorm), and so on.  So what gives?

And what is this horrible drug anyway?

It’s medical marijuana.

To be fair, asking why the FDA hasn’t withdrawn medical marijuana from the market is not exactly a reasonable question because, technically, it has never been on the market.  The DEA labels it a schedule I drug, which means, according to their definition, that it has a high potential for abuse, no recognized medical use, and no “accepted safety profile.”  However, several states (sixteen at last count, including my home state of California) have approved its use, and annual sales are around $1.7 billion, rivaling the annual sales of Viagra.

Let me point out that I have no official position on medical cannabis.  (See my previous post on the subject.)  I do not prescribe it, but that’s a professional decision, not a personal or moral one.  As noted above, I’ve seen some of my patients benefit from it, and others harmed by it.

Many other substances that are readily available to my patients—whether legal or not—have the potential for both benefit and harm.  People “self-medicate” in all kinds of ways, and we physicians have a responsibility to ensure that they’re doing so in a way that doesn’t cause long-term damage.  We encourage people to stop smoking cigarettes, for instance, and make sure that patients use alcohol in moderation.  (Alcohol and nicotine, of course, are legal but not “prescribed” as medications.)

But once we (i.e., the medical profession and the government) designate a drug as a “medication,” this should imply a whole new level of scientific rigor and safety.  This designation communicates to patients that the substance will provide some sort of measurable benefit and the relative lack of adverse effects when used as prescribed.  I’m not sure medical marijuana passes this test.  Not only have its benefits not been rigorously proven (a fact that is probably due to the reluctance of the NIH to fund such research), but, as demonstrated in the research above, it’s not really “safe” enough to meet criteria for an FDA-approved medication.

As a result, we have a situation where the “medical” label is being used to describe a product that is used for “medicinal” use (although, in my experience, patients often use it for recreational purposes only), but which also has the potential to exacerbate existing conditions or cause new ones.  Medications shouldn’t do this.  Medical cannabis, if subjected to the FDA approval process in its current form, would go nowhere.

Don’t get me wrong:  I understand the potential benefit of cannabis and the compounds in the natural marijuana product, and I support any measure to bring more effective treatments to our patients.  But the current awkward “medicalization” of marijuana imposes too much cognitive dissonance on prescribers and users.  We believe intuitively that it may “help” but also know its potential risks, and that’s hard for any honest physician to endorse.

I see two solutions to this dilemma:  Perform the rigorous, controlled studies to prove its efficacy and safety; or just do away with the whole “medical” façade and legalize it already.


Thank You, Somaxon Pharmaceuticals!

March 18, 2011

One year ago today, the pharmaceutical company Somaxon introduced Silenor, a new medication for the treatment of insomnia, and today I wish to say “thanks.”  Not because I think Silenor represented a bold new entry into the insomnia marketplace, but because Somaxon’s R&D and marketing departments have successfully re-introduced doctors to a cheap, old medication for a very common clinical complaint.

You see, Silenor is a branded version of a generic drug, doxepin, which has been around since the 1970s.  Doxepin is classified as a tricyclic antidepressant, even though it’s not used much for depression anymore because of its side effects, mainly sedation.  Of course, in psychiatry we sometimes exploit the side effects of certain drugs to treat entirely different conditions, so it’s not surprising that doxepin—which has been generic (i.e., cheap) for the last few decades—has been used occasionally for the treatment of insomnia.  However, this is an “off-label” use, and while that doesn’t prevent doctors from prescribing it, it may make us less likely to consider its use.

Somaxon spent several years, and millions of dollars, developing Silenor, a low-dose formulation of doxepin.  Stephen Stahl (paid by Somaxon) even publicized low-dose doxepin in his CNS Spectrums column.  Generic doxepin is currently available in comparatively high doses (10, 25, 50, 75, 100, and 150 mg), but Somaxon found that lower doses (6 and 3 mg, even 1 mg) can be used to treat insomnia.  Silenor is sold at 3 and 6 mg per tablet.

The obvious question here (to both expert and layman alike) is, what’s so special about the 3 or 6 mg dose?  Why can’t I just take a generic 10 mg pill and cut it in half (or thereabouts), for a homemade 5-mg dose?  Well, for one thing, the 10 mg dose is a capsule, so it can’t be split.  (There is a generic 10 mg/ml doxepin solution available, which would allow for very accurate dosing, but I’ll ignore that for now.)

Okay, so there’s the practical issue: pill vs. capsule.  But is 6 mg any better than 10 mg?  For any drug, there’s always variability in how people will respond.  The relative difference between 6 and 10 is large, but when you consider that people have been taking doses of up to 300 mg/day (the maximum approved dose for depression) for decades, it becomes relatively meaningless.  So what gives?

It’s natural to ask these questions.  Maybe Somaxon was hoping that doctors and patients simply assume that they’ve done all the necessary studies to prove that, no, doxepin is an entirely different drug at lower doses, and far more effective for sleep at 3 or 6 mg than at any other dose, even 10 mg.  Indeed, a few papers have been published (by authors affiliated with Somaxon) showing that 3 and 6 mg are both effective doses.  But they still don’t answer:  how are those different from higher doses?

I contacted the Medical Affairs department at Somaxon and asked this very question.  How is 3 or 6 mg different from 10 mg or higher?  The woman on the other end of the line, who (one would think) must have heard this question before, politely responded, “Doxepin’s not approved for insomnia at doses of 10 mg or higher, and the 3 and 6 mg doses are available in tablet form, not capsule.”

I knew that already; it’s on their web site.  I would like to think that no psychiatrist asking my question would settle for this answer.  So I asked if she had some additional information.  She sent me a six-page document entitled “Is the 10 mg Doxepin Capsule a Suitable Substitute for the Silenor® 6 mg tablet?”  (If you’re interested in reading it, please email me.)

After reading the document, my response to this question is, “well, yes, it probably is.”  The document explains that doxepin hasn’t been studied as an insomnia agent at higher doses (in other words, nobody has tried to get FDA approval for doxepin in insomnia), and the contents of the tablet are absorbed at a different rate than the capsule.

But what really caught my eye was the following figure, which traces plasma concentration of doxepin over a 12-hour period.  The lower curve is for 6 mg of Silenor.  The higher curve is for “estimated” 10 mg doxepin.

Huh?  “Estimated”?  Yes, that’s right, the upper curve was actually obtained by giving people 50 mg doxepin capsules and then “estimating” the plasma concentrations that would result if the person had actually been given 10 mg capsules.  (I know, I had to read it twice myself.)  I don’t know how they did the estimation.  Did they divide the plasma concentration by 5?  Use some other equation involving fancy things like logarithms or integrals?  I don’t know, and they don’t say.  Which only begs the question: why didn’t they just use 10 mg capsules for this study???

That seems a little fishy.  At any rate, their take-home message is the fact that with the lower dose, there’s less doxepin left over in the bloodstream after 8 hours, so there’s less of a “hangover” effect the next morning.  But this just raises even more questions for me.  If this is the case, then what about all those people who took 75-150 mg each day for depression?  Wouldn’t that result in a constant “hangover” effect?  I didn’t practice in the 1970s and 1980s, but I’m guessing that depressed people on doxepin weren’t in bed 24 hours a day, 7 days a week.  (I know, the serotonergic and noradrenergic effects “kick in” at higher doses, but the histamine and alpha-1 adrenergic receptors are already saturated.)  A related question is, what plasma concentration of doxepin is required to induce sleep anyway?  What plasma concentration accounts for a “hangover” effect?  0.5?  1.0?  2.0?  Does anyone know?

The Somaxon document states that “clinical trials demonstrated only a modest increase in mean sleep maintenance efficacy when the dose is increased from 3 mg to 6 mg.”  But according to the graph above, the 3 mg curve would be expected to look quite different, as it’s a 50% reduction in dose.  (And I can’t even begin to think what the 1 mg curve would look like, but that apparently works, too.)

We all know (or should know) that tables, charts, and graphs can be used to convey just about any message.  It’s important to look at which data are presented, but also which data are not presented, in order to draw any conclusions.  We must also ask what the data actually mean (i.e., the importance of a plasma concentration—what does it actually mean for a clinical effect?).  In the end, Somaxon’s “explanation” seems like a pretty flimsy explanation for using a very expensive name-brand drug.

That said, I do have to say “thank you” to Somaxon for reminding me of yet another medication that I can use to help treat insomnia.  Not Silenor, but low-dose generic doxepin (10 mg).  It’s a shame they had to spend the millions of dollars on R&D, clinical trials, and marketing, to convince me to prescribe the generic version of their drug, which costs only pennies a pill, but then again, you pays your money, you takes your chances.

(Postscript:  Speaking of money, Somaxon stock closed at $2.70/share today, down from a high of $10.01 on the day Silenor was approved, a loss of $258 million of market capitalization.  Imagine all the soft pillows, soothing music CDs, and OTC sleep aids that money could have bought…)


Off-Label Meds: Caveat Prescriptor

March 13, 2011

In medicine we say that a drug is “indicated” for a given disorder when it has gone through rigorous testing for that condition. Typically, a drug company will perform clinical trials in which they select patients with the condition, give them the new drug, and compare them with similar patients who are given a placebo (or an established drug which is already used to treat the disease). In the US, when the FDA approves a drug, the drug company is then permitted to advertise it in magazines, journals, TV, the internet, and directly to doctors, but they must specify its “approved” use.

In the past few years, several drug companies have found themselves in trouble after accusations of marketing their drugs for off-label indications. Total fines have reached into the billions, and many companies have vowed to change their marketing practices in response.

It should be emphasized, however, that doctors use drugs off-label very frequently. This is particularly true in psychiatry, where an estimated 31% of all prescriptions are off-label. Some familiar examples include trazodone (an antidepressant) for insomnia or beta blockers (originally approved for hypertension and heart failure) for anxiety. Furthermore, some very common symptoms and conditions, such as personality disorders, impulsivity, nightmares, eating disorders, and PTSD, have no (or few) “indicated” medications, and yet we often treat them with medications, sometimes with great success. And since the FDA restricts its approvals to medications and devices, even psychotherapy—something we routinely recommend and “prescribe” to patients—is, technically, off-label.

One colleague took this one step further and explained that virtually any psychiatric drug which has been prescribed for more than 8 or 12 weeks is being used “off-label” since the studies to obtain FDA approval are generally no longer than that. Admittedly, that’s nitpicking, but it does demonstrate how the FDA approval process works with a very limited amount of clinical data.

Drug companies that deliberately market their drugs for off-label indications are indeed guilty of misrepresenting their products and deceiving doctors and consumers. But to blame them for bad patient outcomes conveniently ignores the one missing link in the process: the doctor who decided to prescribe the drug in the first place. Whether we like it or not, drug companies are businesses, they sell products, and as with everything else in our consumerist society, the buyer (in this case the doctor) must beware.

Here’s an example. A new drug came to market in February called Latuda, which has been FDA approved for the treatment of schizophrenia. Before a few months ago, most community psychiatrists (like me) knew absolutely nothing about this drug.

If a sales rep visits my office tomorrow and tells me that it’s approved for schizophrenia and for bipolar disorder, she is obviously giving me false information. This is not good. But how I choose to use the drug is up to me. It’s my responsibility—and my duty, frankly—to look at the data for schizophrenia (which exists, and which is available on the Latuda web site and in a few articles in the literature). If I look for data on bipolar disorder, I’ll find that it doesn’t exist.

That’s just due diligence. After reviewing the data, I may conclude that Latuda looks like a lousy drug for schizophrenia (I’ll save those comments for later). However, I might find that it may have some benefit in bipolar disorder, maybe on particular symptoms or in a certain subgroup of patients. Or, I might find some completely unrelated condition in which it might be effective. If so, I should be able to go ahead and use it—assuming I’ve exhausted the established, accepted, and less costly treatments already. Convincing my patient’s insurance company to pay for it would be another story… but I digress.

I don’t mean to imply that marketing has no place in medicine and that all decisions should be made by the physician with the “purity” of data alone. In fact, for a new drug like Latuda, sales reps and advertising materials are effective vehicles for disseminating information to physicians, and most of the time it is done responsibly. I just think doctors need to evaluate the messages more critically (isn’t that something we all learned to do in med school?). Fortunately, most sales reps are willing to engage doctors in that dialogue and help us to obtain hard data if we request it.

The bottom line is this: psychiatric disorders are complicated entities, and medications may have potential far beyond their “approved” indications. While I agree that pharmaceutical marketing should stick to proven data and not anecdotal evidence or hearsay, doctors should be permitted to use drugs in the ways they see fit, regardless of marketing. But—and this is critical—doctors have a responsibility to evaluate the data for both unapproved and approved indications, and should be able to defend their treatment decisions. Pleading ignorance, or crying “the rep told me so,” is just thoughtless medicine.


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