Et tu, Seroquel?

What could be worse than Bristol-Myers Squibb marketing its powerful and risky antipsychotic Abilify for simple depression, when there are so many effective and safer alternatives? How about AstraZeneca marketing its equally powerful and risky antipsychotic Seroquel for depression and generalized anxiety? A few days ago the FDA heard arguments from the company to do just that; lengthy background material as well as evaluations by FDA staffers are available here.

The issue is the same whether the drug is Abilify, Seroquel, or any of the other newer, patent-protected antipsychotics that are sure to follow in their footsteps. Even if Seroquel treats depression or anxiety better than placebo:

(1) there are already a great many approved medications for these indications,

(2) the existing alternatives are generally safer and much less expensive, and yet

(3) intense marketing directed to professionals and consumers will lead to widespread, unwarranted prescribing of the product.

Here are the words of one FDA scientist reviewing AstraZeneca's claims that Seroquel is safe and effective for major depressive disorder (MDD):

[T]he safety profile we are seeing in the MDD population is not different from the profile we have already observed in other populations. However, it is of some concern that approving these claims will likely greatly expand the use of this product. Thus, we need to think carefully about the risks and benefits of such expanded use, particularly with regard to longer-term risks which are not yet fully established.

Unfortunately, the comments of other FDA reviewers did not express this concern.

FDA approval of antipsychotics for non-psychotic conditions is hardly a new practice. The typical antipsychotic Stelazine (trifluoperazine) was FDA approved for non-psychotic anxiety decades ago. This 1973 journal ad shows, in addition to the awkward sexism of the era, the same lopsided presentation we see now: modest benefits overshadowing serious risks. Of course, trifluoperazine has been available generically and inexpensively for years; there is no economic incentive to promote this particular agent anymore. In contrast, there is great economic incentive for the makers of Abilify, Seroquel, and similar products to tap expanded markets.

One argument offered in favor of approving atypical antipsychotics for depression goes like this: Even with 25 approved medications already out there (accurate figure), it's a net benefit to have a 26th that might help the occasional patient. Why not leave the weighing of risks and benefits in the hands of the doctor, as long as the drug does what it claims?

This highlights a central question: What does FDA approval mean? Physicians are already free to prescribe "off-label," and to weigh risks and benefits on a case by case basis. For example, the FDA has not approved the use of atypical antipsychotics as sleeping aids, yet according to some reports, over half of all Seroquel is prescribed for sleep and other non-approved uses. FDA approval must mean more than "doctors have the right to prescribe it," since we already do. The public reasonably assumes that FDA approval adds an endorsement, something like "it's usually a good idea for doctors to prescribe it for this particular indication." The latter is a complex judgment that weighs risks as well as benefits, and that takes existing alternatives into account. In my view it is hard to justify stamping such an imprimatur on the use of powerful antipsychotics for common, relatively minor problems that already have good treatments. FDA approval gives a drug maker permission to market its product for the approved use. Antipsychotics are already being (mis)used in various ways even without such marketing. The wheels of commerce hardly need to be greased by a federal agency charged with public safety.

I haven't said much about the generalized anxiety indication, but this could be a huge public health misstep if approved. In the 1960s the tranquilizer Valium was the most prescribed drug in the US. It was generally effective and well tolerated. Its major drawback was addiction and withdrawal effects, shortcomings shared by its contemporary successors such as Ativan, Xanax, and Klonopin. If the FDA approves Seroquel for anxiety, the aggressive marketing campaign for Seroquel will strongly emphasize its lack of addiction or withdrawal effects, issues that many physicians are wary of, and somewhat sensitive about. In an effort to sidestep the real (but manageable) problem of addiction, patients will receive Seroquel instead, even though it carries far more serious medical risks and is hugely more expensive (especially the time-release version AstraZeneca is promoting, the rationale for which is dubious at best). Seroquel could become the new "Mother's Little Helper" — resulting in a bumper crop of obese, diabetic mothers (and fathers).

Interesting additional discussion on Seroquel and its new proposed indications can be found here.

NY Times roundup

Here are three recent New York Times articles that caught my eye. On March 13th, Tara Parker-Pope's health blog "Well" reprinted "The 12 Most Annoying Habits of Therapists." Actually, the list comes from PsychCentral, a blog written by psychologist John M. Grohol, and in my opinion reads better there. I won't list all 12 habits — you can look for yourself — but they include starting sessions late, eating in session, falling asleep, and so forth. The voluminous comments on both blogs relate the sad state of so much therapy out there, including professional lapses far worse than the listed 12. I plan to use the blog post itself, and some of the commentary, as a teaching handout when I lead a psychotherapy seminar later this year. Even beginning therapists should not make these mistakes. Speaking of psychiatry training, on March 16th, psychiatrist Richard A. Friedman M.D. wrote about a growing lack of confidence in psychiatry residents, citing their inability to make clinical decisions in routine cases, e.g., when to hospitalize or medicate patients. He blames faculty over-concern:

The fault, I believe, lies with medical educators like me. In the pursuit of patient safety, we have deliberately prevented residents from acting independently on their own judgment in situations where a patient poses a theoretical risk.

I share his concern to this point. I encounter resident insecurity much more often than overconfidence. I also agree that one reason for this may be a medical culture that increasingly recognizes a single right (or safe) way to proceed; independent judgment is discouraged.

But Friedman then goes on to blame "a series of reforms that began in the 1980s with limits on residents’ work hours." The current limits set by ACGME include an 80-hour workweek with a maximum shift of 30 hours. Friedman apparently feels such a schedule lacks "ample opportunity to stand on your own — and risk making a mistake."

I beg to differ. Sleep deprivation is not a teaching tool. There is no evidence it trains anyone to make decisions with more accuracy or confidence, although it is often justified this way post-hoc. Conflating confidence-building with hazing oversimplifies a complex issue. We don't need to toughen up residents, we need to help them make confident decisions. Two different things.

Besides, psychiatry residents generally worked fewer hours than residents of other specialties even before the ACGME limits. In other words, the recent limits have had less effect in psychiatry than in specialties such as surgery or ob-gyn. Could it be that psychiatry pays a bit more attention to how people think, feel, and learn, and therefore we were ahead of the curve?

And speaking of being ahead of the curve, today the Times reported that the American Psychiatric Association is ending industry-financed medical seminars at its annual meeting. President Nada L. Stotland, M.D. said the APA was not aware of any other organization that had made a similar decision on seminar sponsorship. Perhaps we psychiatrists will start a trend in medicine. (Neither the article nor the APA website says whether this change will occur in time for the annual meeting held here in San Francisco this May. I imagine not.)

I confess that I attended one of these seminars when the huge APA meeting was in San Francisco some years ago. Normally I avoid all industry largesse, but I was curious and justified it as research. Ironically, although it was lavishly catered and slickly presented, it was perhaps the least biased industry-sponsored talk I've ever heard. The smaller local ones are much worse in my experience, presumably because the level of scrutiny is so much higher at the annual meeting. There is press coverage, for example.

In any event, this is the right direction for psychiatry and medicine in general. But speaking of press coverage, I am curious about one detail. The Times, as well as Reuters, reported the APA policy change today, yet blogger Daniel Carlat M.D. scooped them by almost a week. Do official news agencies wait for press releases, while bloggers do the real investigative reporting?

Abilify for depression?

clench

I've written about this before — the expanded use of antipsychotic medication for indications other than psychosis. These run the gamut from acute mania, where a solid rationale exists, all the way to simple insomnia, for which there is no good rationale. Somewhere in between, but closer to the insomnia end of the scale, is the FDA-approved use of Abilify for unipolar depression. When I first heard the atypical antipsychotic Abilify (aripiprazole) was being marketed by Bristol-Myers Squibb and Otsuka for depression, I shook my head in disbelief. (You can watch the tv ad on the official Abilify site here.) To its credit, the commercial recites the major, sometimes disabling or even lethal, side-effects, including neuroleptic malignant syndrome, irreversible tardive dyskinesia, dangerously high blood sugar, akathisia, etc, in a nice slow cadence rather than an auctioneer's rapid-fire staccato. But nowhere is it mentioned that Abilify is an antipsychotic. Nor that antipsychotics are traditionally prescribed by specialists (psychiatrists), not primary-care providers, due to the unique and considerable risks of this class of drugs. The manufacturers paint a picture that looks like this: A depressed-but-functioning patient seeks help from a primary-care doctor, who prescribes an SSRI antidepressant like Prozac or Zoloft. It doesn't help enough, so the MD adds Abilify and voila, success!

This is a dangerous scenario on several counts. First, in my opinion, primary-care doctors should not prescribe antipsychotics for psychiatric disorders, period. This is not to disparage the skills of internists and family practitioners who see common psychiatric presentations such as depression and anxiety on a regular basis, and know how to treat them. In fact, most antidepressants in the US are prescribed by primary-care MDs, not psychiatrists. But it is one thing to diagnose depression and prescribe a relatively safe antidepressant, and quite another to handle treatment-resistant cases, to distinguish among bipolar disorder, schizophrenia, organic psychotic states, severe personality disorders, etc, or to know the complex risks and benefits of various mood stabilizers and antipsychotics. These are jobs for a specialist. Can a primary-care doctor treat depression with an SSRI antidepressant, and maybe try a second one if the first doesn't work? Sure. After that, I'd suggest referral to a psychiatrist.

The next danger in the advertised scenario: Even in a psychiatrist's hands, there are several safer and smarter alternatives than adding Abilify to an unsuccessful antidepressant. Increase the antidepressant dose. Switch to a different antidepressant. Augment the antidepressant with thyroid supplementation, lithium, buspirone, or another antidepressant. (All of these are more or less controversial, and I tend to avoid them, but all are safer than Abilify. See this article on augmentation.) And perhaps the best and safest option, add psychotherapy. While medications help many depressed people, in my experience they most commonly don't work when the patient's problem is of a sort better addressed by psychotherapy than chemical intervention. Of course, you'll never hear about that in a drug ad.

Most concerning are the questions that have been raised about the scientific evidence for using Abilify for depression. This is a very expensive medication with potentially grave side-effects being promoted as treatment for a very common problem. When a patient suffers severe symptoms such as psychosis or acute mania, the benefits of treatment outweigh even considerable risk and expense. But non-psychotic depression? Abilify would have to do a fantastic job to justify the drawbacks. Apparently it doesn't. These blogs critique the thin, and perhaps biased, evidence base for using Abilify for depression. An 11% improvement on average hardly seems worth it — unless you're a pharmaceutical company aiming to capture part of a vast market.

Prescribing by habit and evidence

A recent Rolling Stone article on the over-prescribing of Eli Lilly's anti-psychotic Zyprexa (olanzapine) started me thinking in a general way about the psychology of choosing what to prescribe.  I've written before about the effects of pharmaceutical marketing, how billions are spent to influence doctors' prescribing habits at both rational and non-rational levels.  The Zyprexa article offers more on this topic.  But it also widened the issue for me as I reflected on my own prescribing.  For today I'll let Big Pharma off the hook and look at other influences that affect prescribing.

Most doctors have "favorite" medications within a particular class that we prefer to prescribe.  Besides marketing influences, this can result from anecdotal experience:  If my last patient had a wonderful result on this drug, maybe my next will too.  Conversely, if my last patient had a terrible reaction, how can I risk giving the same drug to my next patient?  Such reasoning is unscientific yet very compelling.  First-hand outcomes are psychologically hard to discount, even when careful studies of large numbers of subjects provide far better evidence for the risks and benefits of a given treatment than anyone's limited personal experience.  Likewise, the opinion of a trusted colleague (or attending physician, if one is a trainee) tends to make an impact regardless of the popularity of, or evidence base for, that opinion.

These are the sorts of biases that the evidence-based medicine (EBM) movement tries to stamp out.  According to EBM, we should base clinical decisions on the best available evidence, ideally large randomized controlled trials.  On the one hand, the need for Western medicine to declare itself "evidence-based" is almost an embarrassment; it should go without saying.  The scientific method is the bedrock of allopathic Western medicine.  It separates physicians from faith healers and snake-oil salesmen.

On the other hand, many areas of medicine lack the EBM gold-standard of randomized controlled trials (or the trials are inconclusive, conflict with each other, etc).  Studies of certain treatments, like dynamic psychotherapy, present severe methodological challenges. Randomized studies of invasive surgical procedures can be unethical.  Some studies are funded and others are not, for reasons having nothing to do with science.  Moreover, the results of randomized controlled trials are population averages, and individual patients do not always react the way the "average" patient does.  Fully evidence-based practice is an ideal, not possible in real life.

More important, both the prescribing physician and the patient are people, and we humans have feelings and preferences that affect our choices.  Doctors often prescribe particular drugs within a class purely out of habit.  The familiarity is comforting; dosing is easier, potential side-effects and interactions with other drugs are no surprise and are handled in stride. Experience prescribing one drug increases at the expense of familiarity with equally good alternatives.  Conversely, some physicians are "early adopters" who like to prescribe the newest product out.  While this is not my style, I assume the motivation is to be on the cutting-edge of the field.  The effect of the prescriber's personality on treatment decisions sounds like a ripe area for research.  A brief PubMed search reveals a few interesting abstracts: 1, 2, 3, 4.

Patients, too, have preferences, not only for heavily advertised products, but also for medications taken by relatives and friends.  And doctors, knowing that a patient's belief in a treatment can aid its success, are inclined to prescribe what the patient asks for — if it is in the right ballpark.  Patients also weigh risks and benefits in personal ways.  One patient may disregard potential weight gain as a trivial concern, while another flatly refuses any treatment that can add pounds.  EBM can never account for such personal preferences.  (Some PubMed abstracts on patient attitudes and preferences: 1, 2, 3, 4.)

The prescribing of psychiatric medications is a combination of evidence-based medicine and the art of medicine.  The latter includes unfortunate biases — at times leading to overprescribing of medications such as Zyprexa — as well as essential sensitivity to psychological issues and patient preferences.  Until doctors are replaced by computers, and patients accept treatment without regard to individual preference, medicine will always reflect this combination.

No free lunch

philosopher

The following is my article originally published in Ethical Times (No. 16, Fall 2008), the bulletin of the Program in Medicine and Human Values at California Pacific Medical Center. Since this piece appeared, PhRMA has voluntarily suspended the distribution of branded items and certain food gifts to doctors (see my post).  The ethical argument still holds and is, I believe, still widely overlooked.  Reprinted by permission. Pharmaceutical promotion is big business. In the US alone, the industry spends billions each year (about $16 billion in 2000) to market its products. Most of this budget pays for extensive, multifaceted marketing to doctors, much of it delivered in person by salespeople called "pharmaceutical representatives." A smaller but still sizable portion of funds produce direct-to-consumer "ask your doctor" ads on television and elsewhere. Pundits debate whether such lavish promotion drives up the cost of health care or helps to contain it, whether it enhances or detracts from patient care. Most of this focus has been on the industry side of the equation. Yet medical ethics demands that we physicians assess the other side of the equation: our own participation in these promotional efforts.

Advertising and product promotion are everywhere in our society, exerting their influence in largely non-rational ways. We imagine that we rationally weigh the features and benefits of competing products and make logical choices. Yet advertisers "sell the sizzle, not the steak." Catchy jingles, the look of a product and its packaging, celebrity endorsements, associations with attractive people or lifestyles — these appeal to our emotions, often bypassing intellect and logic.  In everyday life we sense no ethical impropriety in allowing ourselves to be influenced this way. Who knows, or cares, why we prefer one brand of soap over another? If we choose a household product for its captivating name or fancy packaging we may be misguided or superficial, but we are certainly not evil. We face no ethical dilemma in accepting a free food sample at the supermarket, even if it evokes pleasant associations in us about being fed or induces a subtle wish to reciprocate the generosity. Marketing works at both surface and subterranean levels. As a society we accept that.

Likewise, it is not ethically problematic for patients to respond to television ads by "asking their doctors" about prescription medicines, even though these ads employ the same non-rational enticements used by other industries, such as memorable product names, evocative catch phrases, and scenes of active, happy people. (Some argue it is unethical for the companies to advertise this way, but that is not our focus.) A patient may inquire about a particular medicine for countless reasons, ranging from careful research, e.g., on the Internet, to an offhand comment by a friend. There is no requirement or expectation that a patient's interest be rationally based. From the patient's perspective, there is nothing wrong in hearing about a medicine, even from an ad, and asking one's doctor about it.

The physician, however, is in a very different position. There is an expectation that a doctor's interest in a particular treatment be rationally based. Moreover, medical ethics requires it.

The doctor-patient relationship is fiduciary. It is founded on the patient's trust that the doctor always practices medicine in the patient's best interest. Like other fiduciary relationships (e.g., bank-customer, corporation-shareholder, and attorneys and accountants with their clients), the doctor-patient relationship is vulnerable to conflicts of interest that can undermine trust. In all of these fields, professional ethics dictate that the trustee take reasonable steps to avoid conflicts of interest and divided loyalties.

Physicians in particular must strive to practice medicine in an unbiased, scientific fashion. This is more difficult than it sounds, since influences that are widely accepted and considered benign in everyday life can represent trust-threatening conflicts of interest here. The non-rational influences of product promotion — the gratifying visits by friendly, attractive salespeople bearing personal gifts and free food — directly threaten the fiduciary doctor-patient relationship. By participating in these encounters, physicians actively invite non-rational bias into treatment decisions, in direct violation of the trust patients place in us. It follows that medical ethics should condemn active involvement in this process by physicians, and that reasonable steps should be taken by ethical physicians to avoid participation in promotional activities.

Many physicians defend current practice by claiming that they are immune to non-rational promotional efforts. The pharmaceutical industry does its best, they say, but smart doctors see through the attempted influence and "ignore" it. This rebuttal is not new.

A historical review (1) in a recent issue of JAMA quotes the same view from apologists 50 years ago. However, then as now, there is no evidence that doctors enjoy any special resistance to non-rational product promotion. On the contrary, several empirical studies document the effectiveness of such promotion in swaying the prescribing patterns of doctors. It is tortured logic to assume that a sophisticated industry wastes billions every year on harmlessly ineffective promotional efforts — especially when the very same strategies work well in other industries. Wishful thinking and hubris alone cannot stand up to this evidence.

Increased public scrutiny has prompted modest reforms over the past few years. A growing number of medical centers and teaching institutions now restrict promotional activities on campus. The pharmaceutical industry itself has voluntarily dropped or limited some types of product promotion. Congress is working on legislation requiring public reporting of industry largesse to doctors. These actions recognize the seriousness of the problem. But, beyond all efforts to prevent undue compensation or to make it transparent, the ethics of the physician are the strongest bulwark against improper influence on prescribing practices. Unfortunately, at this time only a small percentage of individual doctors decline sales calls and similar contact with industry. Surveys show that patients express more concern than physicians over this issue.

Being a physician bestows many rewards and gratifications. These are balanced by the restrictions on our actions that are part of ethical practice. We must act professionally and always in our patients' best interest. We must be competent and skillful, stay current in our field, and use evidence-based approaches when possible. And we must strive to avoid making clinical decisions based on non-rational factors. While this ethical restriction may deprive us of branded coffee mugs and pens, free lunches, and opulent sponsored "educational" dinners, it is a small price to pay for earning our patients' trust.

—

(1) Podolsky SH, Greene JA, "A Historical Perspective of Pharmaceutical Promotion and Physician Education,"

Journal of the American Medical Association

300(7), 20 August 2008, p 831-833.