Psychopharm R&D Cutbacks II: A Response to Stahl

August 28, 2011

A lively discussion has emerged on the NEI Global blog and on Daniel Carlat’s psychiatry blog about a recent post by Stephen Stahl, NEI chairman, pop(ular) psychiatrist, and promoter of psychopharmaceuticals.  The post pertains to the exodus of pharmaceutical companies from neuroscience research (something I’ve blogged about too), and the changing face of psychiatry in the process.

Dr Stahl’s post is subtitled “Be Careful What You Ask For… You Just Might Get It” and, as one might imagine, it reads as a scathing (some might say “ranting”) reaction against several of psychiatry’s detractors: the “anti-psychiatry” crowd, the recent rules restricting pharmaceutical marketing to doctors, and those who complain about Big Pharma funding medical education.  He singles out Dr Carlat, in particular, as an antipsychiatrist, implying that Carlat believes mental illnesses are inventions of the drug industry, medications are “diabolical,” and drugs exist solely to enrich pharmaceutical companies.  [Not quite Carlat’s point of view, as  a careful reading of his book, his psychopharmacology newsletter, and, yes, his blog, would prove.]

While I do not profess to have the credentials of Stahl or Carlat, I have expressed my own opinions on this matter in my blog, and wanted to enter my opinion on the NEI post.

With respect to Dr Stahl (and I do respect him immensely), I think he must re-evaluate his influence on our profession.  It is huge, and not always in a productive way.  Case in point: for the last two months I have worked in a teaching hospital, and I can say that Stahl is seen as something of a psychiatry “god.”  He has an enormous wealth of knowledge, his writing is clear and persuasive, and the materials produced by NEI present difficult concepts in a clear way.  Stahl’s books are directly quoted—unflinchingly—by students, residents, and faculty.

But there’s the rub.  Stahl has done such a good job of presenting his (i.e., the psychopharmacology industry’s) view of things that it is rarely challenged or questioned.  The “pathways” he suggests for depression, anxiety, psychosis, cognition, insomnia, obsessions, drug addiction, medication side effects—basically everything we treat in psychiatry—are accompanied by theoretical models for how some new pharmacological agent might (or will) affect these pathways, when in fact the underlying premises or the proposed drug mechanisms—or both—may be entirely wrong.  (BTW, this is not a criticism of Stahl, this is simply a statement of fact; psychiatry as a neuroscience is decidedly still in its infancy.)

When you combine Stahl’s talent with his extensive relationships with drug companies, it makes for a potentially dangerous combination.  To cite just two examples, Stahl has written articles (in widely distributed “throwaway” journals) making compelling arguments for the use of low-dose doxepin (Silenor) and L-methylfolate (Deplin) in insomnia and depression, respectively, when the actual data suggest that their generic (or OTC) equivalents are just as effective.  Many similar Stahl productions are included as references or handouts in drug companies’ promotional materials or websites.

How can this be “dangerous”?  Isn’t Stahl just making hypotheses and letting doctors decide what to do with them?  Well, not really.  In my experience, if Stahl says something, it’s no longer a hypothesis, it becomes the truth.

I can’t tell you how many times a student (or even a professor of mine) has explained to me “Well, Stahl says drug A works this way, so it will probably work for symptom B in patient C.”  Unfortunately, we don’t have the follow-up discussion when drug A doesn’t treat symptom B; or patient C experiences some unexpected side effect (which was not predicted by Stahl’s model); or the patient improves in some way potentially unrelated to the medication.  And when we don’t get the outcome we want, we invoke yet another Stahl pathway to explain it, or to justify the addition of another agent.  And so on and so on, until something “works.”  Hey, a broken clock is still correct twice a day.

I don’t begrudge Stahl for writing his articles and books; they’re very well written, and the colorful pictures are fun to look at– it makes psychiatry almost as easy as painting by numbers.  I also (unlike Carlat) don’t get annoyed when doctors do speaking gigs to promote new drugs.  (When these paid speakers are also responsible for teaching students in an academic setting, however, that’s another issue.)  Furthermore, I accept the fact that drug companies will try to increase their profits by expanding market share and promoting their drugs aggressively to me (after all, they’re companies—what do we expect them to do??), or by showing “good will” by underwriting CME, as long as it’s independently confirmed to be without bias.

The problem, however, is that doctors often don’t ask for the data.  We don’t  ask whether Steve Stahl’s models might be wrong (or biased).  We don’t look closely at what we’re presented (either in a CME lesson or by a drug rep) to see whether it’s free from commercial influence.  And, perhaps most distressingly, we don’t listen enough to our patients to determine whether our medications actually do what Stahl tells us they’ll do.

Furthermore, our ignorance is reinforced by a diagnostic tool (the DSM) which requires us to pigeonhole patients into a small number of diagnoses that may have no biological validity; a reimbursement system that encourages a knee-jerk treatment (usually a drug) for each such diagnosis; an FDA approval process that gives the illusion that diagnoses are homogeneous and that all patients will respond the same way; and only the most basic understanding of what causes mental illness.  It creates the perfect opportunity for an authority like Stahl to come in and tell us what we need to know.  (No wonder he’s a consultant for so many pharmaceutical companies.)

As Stahl writes, the departure of Big Pharma from neuroscience research is unfortunate, as our existing medications are FAR from perfect (despite Stahl’s texts making them sound pretty darn effective).  However, this “breather” might allow us to pay more attention to our patients and think about what else—besides drugs—we can use to nurse them back to health.  Moreover, refocusing our research efforts on the underlying psychology and biology of mental illness (i.e., research untainted by the need to show a clinical drug response or to get FDA approval) might open new avenues for future drug development.

Stahl might be right that the anti-pharma pendulum has swung too far, but that doesn’t mean we can’t use this opportunity to make great strides forward in patient care.  The paychecks of some docs might suffer.  Hopefully our patients won’t.

Silenor II: The Human Laboratory

April 10, 2011

After my recent post on Silenor, the new sleeping drug, I received many nice—and not-so-nice—comments and emails from people who challenged my conclusions.  The “not-so-nice” responses–which I did not publish–were, for the most part, from readers who were clearly invested in Somaxon Pharmaceuticals and must have feared that my comments would further weaken the value of their stock (as if my input was that powerful – lol).  [BTW I have no financial interest, long or short, in Somaxon.]

But others were professional and well-reasoned, and emphasized the true need for a medication like Silenor: an effective sleeping medication with little daytime “hangover” effect and few other adverse effects.  Some comments (which you can read on my page) were from users who seem to have had good experiences with Silenor.

Assuming these comments are truly from satisfied users of Silenor (a big assumption, as this is still the internet!!), I started to think about something that every psychopharmacologist (including myself) struggles with on a regular basis:  namely, the fact that some people respond exactly the way we expect them to respond, based on our biochemical hypotheses, whereas others have completely different responses.  Or to put it another way, our models—and the research that is done to support those models—often have very little predictive value when you translate this information to the real world.  And nowhere is this more apparent than in psychiatry.

In medical school and residency, I was a bit of a pharmacology nut.  (I’d use the word “wonk,” but I always thought that word was reserved for “insiders,” of which I am decidedly not one.)  Pharmacology, indeed, is a fascinating subject.  Bioavailability, pharmacokinetics, receptor-binding affinities, metabolism, drug-drug interactions—each of these is a discipline unto itself, with its own language, experimental methods, and predictive power.

In psychiatry, the intricacies of pharmacology become even more elaborate.  There’s a lot of research (not to mention pages and pages of textbook chapters and lots of drug company promotional materials) describing the details drug dosing regimens, drug-drug interactions, receptor-binding affinities and their putative relationships with symptom profiles, etc.  Just to pick out some familiar examples, the dosing strategies for Seroquel XR and Abilify seem quite detailed indeed:  the predicted effects of very low doses are thought to be different from “mid-range” doses, which are different still from higher doses.  And so on.

The truth of the matter is, these subtleties often make very little difference in the real world.  That’s not to say that the theories of action are wrong. (Maybe Seroquel XR really is an effective norepinephrine reuptake inhibitor at moderate concentrations.)  Instead, it speaks to the enormous variability among human beings, and the fact that our real-world patients sometimes don’t fit the models we construct for them.

Back to Silenor.  I received a detailed email from Martin Scharf, a professor of psychiatry at Wright State University who has spent decades researching sleep medications.  In fact, he was involved in several of the studies on low-dose doxepin which set the stage for Silenor.  (See some of his work here and here.)  In his email he claimed that I “misse[d] the point of the uniqueness of the dosage selection” for Silenor, citing how the low dose (i.e., <10 mg/d) makes the drug more specific for the histamine receptor and avoids side effects that can be attributed to its interaction with other receptor subtypes.  Thus Silenor causes “virtually no next day effects,” whereas “at the 10 mg dose there is little doubt as to next day effects.”  [Indeed, I should point out here that the same arguments were made, in great detail, in the Stephen Stahl article that I cited in my post.]

My response to Dr Scharf is:  OK.  But what do patients actually experience?  In fact, I would take issue with the comment that “there is little doubt as to next day effects” because I have patients taking 25 or 50 mg doxepin who do not report next day effects (and some MDs who responded to my first post said the same thing).  Or if they do experience next-day effects, perhaps they’re not bothersome and they’re only apparent upon questioning.  In other words, the numbers predict one thing, but what do patients report?

The human body is a laboratory, and each drug we prescribe is an “experiment” in that laboratory.  For many people, however, the laboratory doesn’t resemble the pristine one in the clinical trials.  People take extra doses of drugs, or skip doses altogether.  They’ll take drugs at different times than prescribed.  Once inside the body (and even this process is highly variable), the drugs are metabolized differently, or they’ll react with existing chemicals (foods, other drugs, neurotransmitter receptors, different polymorphisms of receptors, etc) in ways that we can only begin to understand, due to this substantial combinatorial complexity.

Unfortunately (or fortunately, depending on how you look at it), bringing a drug like Silenor to market requires that the molecule be tested in very rigorous (and therefore “pristine”) conditions in both animals and humans.  Dr Scharf and his colleagues have done painstaking work in showing precisely how drugs like Silenor work—ideally.  But in the real world, “all bets are off,” as they say.   Patients taking 25 or 50 mg doxepin often feel “just fine” and have no QT prolongation or weight gain, regardless of what the clinical trials would predict.  Similarly, patients taking 6 mg might report absolutely no benefit at all.

I should emphasize, I do NOT advocate reckless prescribing—e.g., giving “PRN” prescriptions to everyone and ask them to adjust the dose according to what makes them feel better, or prescribing without consideration of all of the potential biological effects of our drugs.  We clinicians do have a responsibility to look out for drug-drug interactions (which can be lethal at times), to check drug levels (for certain medications, even regardless of clinical response) and to prescribe potentially abusable medications cautiously.  Knowledge of all of the principles of pharmacology is necessary to ensure the safe use of medications, and taking advantage of this knowledge can improve patient outcomes.

But in the real world it is all about the patient, and if they “do well” on doses of medications that seem to make no sense at all (and all safety measures are in place), isn’t that what counts most?  And, moreover, shouldn’t that lead us to question the hypotheses that led us to those doses in the first place?

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…)

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