Did The APA Miss A Defining Moment?

April 1, 2012

Sometimes an organization or individual facing a potential public-relations disaster can use the incident as a way to send a powerful message, as well as change the way that organization or individual is perceived.   I wonder whether the American Psychiatric Association (APA) may have missed its opportunity to do exactly that.

Several weeks ago, the CBS news program 60 Minutes ran a story with the provocative argument that antidepressants are no better than placebo.  Reporter Lesley Stahl highlighted the work of Irving Kirsch, a psychologist who has studied the placebo effect for decades.  He has concluded that most, and maybe all, of the benefit of antidepressants can be attributed to placebo.  Simply put, they work because patients (and their doctors) expect them to work.

Since then, the psychiatric establishment has offered several counterarguments.  All have placed psychiatry squarely on the defensive.  One psychiatrist (Michael Thase), interviewed on the CBS program, defended antidepressants, arguing that Kirsch “is confusing the results of studies with what goes on in practice.”  Alan Schatzberg, past APA president and former Stanford chairman, said at a conference last weekend (where he spoke about “new antidepressants”) that the APA executive committee was “outraged” at the story, glibly remarking, “In this nation, if you can attack a psychiatrist, you win a medal.”  The leadership of the APA has mounted an aggressive defense, too.  Incoming APA president and Columbia chairman Jeffrey Lieberman called Kirsch “mistaken and confused, … ideologically based, [and] … just plain wrong.”  Similarly, current APA president John Oldham called the story “irresponsible and dangerous [and] … at odds with common clinical experience.”

These are indeed strong words.  But it raises one very important question:  who or what exactly are these spokesmen defending?  Patients?  Psychiatrists?  Drugs?  It would seem to me that the leadership of a professional medical organization should be defending good patient care, or at the very least, greater opportunities for its members to provide good patient care.  The arguments put forth by APA leadership, however, seem to be defending none of the above.  Instead, they seem to be defending antidepressants.

For the purposes of this post, I won’t weigh in on the question of whether antidepressants work or not.  It’s a complicated issue with no easy answer (we’ll offer some insight in the May issue of the Carlat Psychiatry Report).  However, let’s just assume that the general public now has good reason to believe that current antidepressants are essentially worthless, thanks to the 60 Minutes story (not to mention—just a few weeks earlier—a report on NPR’s “Morning Edition,” as well as a two-part series by Marcia Angell in the New York Review of Books last summer).  Justifiably or not, our patients will be skeptical of psychopharmacology going forward.  If we psychiatrists are hell-bent on defending antidepressants, we’d better have even stronger reasons for doing so than simply “we know they work.”

But why are psychiatrists defending antidepressants in the first place?  If anyone should be defending antidepressants, it should be the drug companies, not psychiatrists.  Why didn’t 60 Minutes interview a Lilly medical expert to explain how they did the initial studies of Prozac, or a Pfizer scientist to explain why patients should be put on Pristiq?  (Now that would have been fun!!)  I would have loved to hear Michael Thase—or anyone from the psychiatric establishment—say to Lesley Stahl:

“You know, Dr. Kirsch might just be onto something.  His research is telling us that maybe antidepressants really don’t work as well as we once thought.  As a result, we psychiatrists want drug companies to do better studies on their drugs before approval, and stop marketing their drugs so aggressively to us—and to our patients—until they can show us better data.  In the meantime we want to get paid to provide therapy along with—or instead of—medications, and we hope that the APA puts more of an emphasis on non-biological treatments for depression in the future.”

Wouldn’t that have been great?  For those of us (like me) who think the essence of depression is far more than faulty biology to be corrected with a pill, it would have been very refreshing to hear.  Moreover, it would help our field to reclaim some of the “territory” we’ve been abdicating to others (therapists, psychologists, social workers)—territory that may ultimately be shown to be more relevant for most patients than drugs.  (By the way, I don’t mean to drive a wedge between psychiatry and these other specialties, as I truly believe we can coexist and complement each other.  But as I wrote in my last post, psychiatry really needs to stand up for something, and this would have been a perfect opportunity to do exactly that.)

To his credit, Dr. Oldham wrote an editorial two weeks ago in Psychiatric News (the APA’s weekly newsletter) explaining that he was asked to contribute to the 60 Minutes piece, but CBS canceled his interview at the last minute.  He wrote a response but CBS refused to post it on its website (the official APA response can be found here).  Interestingly, he went on to acknowledge that “good care” (i.e., whatever works) is what our patients need, and also conceded that, at least for “milder forms of depression,” the “nonspecific [placebo] effect dwarfs the specific [drug] effect.”

I think the APA would have a pretty powerful argument if it emphasized this message (i.e., that the placebo effect might be much greater than we believe, and that we should study this more closely—maybe even harness it for the sake of our patients) over what sounds like a knee-jerk defense of drugs.  It’s a message that would demand better science, prioritize our patients’ well-being, and, perhaps even reduce treatment costs in the long run.  If, instead, we call “foul” on anyone who criticizes medications, not only do we send the message that we put our faith in only one form of therapy (out of many), but we also become de facto spokespersons for the pharmaceutical industry.  If the APA wants to change that perception among the general public, this would be a great place to start.

To Treat Depression, Just Give ‘Em What They Want

February 23, 2011

A doctor’s chief task is to determine the cause of a patient’s suffering and to develop a course of treatment.  In psychiatry, the task is no different: examine the patient, determine a diagnosis, and initiate treatment.  However, “treatment” comes in many forms, and what works for one patient may not work for another.  A good psychiatrist tries to figure out which approach is ideal for the patient in his office, rather than reflexively reaching for the prescription pad and the latest drug option.

How to determine what’s the best course of action for a patient?  Recent research suggests one potentially foolproof way:  Ask him.

A paper in this month’s Psychotherapy and Psychosomatics by Mergl and colleagues shows that patient preference (that is, whether the patient prefers medications or psychotherapy) predicts how effective a treatment will be.  In their study, patients who expressed a preference for medications at the beginning of treatment had a better response to Zoloft than to group therapy, while patients who preferred therapy showed the exact opposite response.

In an even larger study published in 2009 by James Kocsis and colleagues at Weill-Cornell in New York (comparing nefazodone, an antidepressant, with a cognitive therapy approach called CBASP), a similar result was obtained:  patients with chronic major depression who entered the study expressing a preference for drug treatment had higher remission rates when receiving medication than when receiving psychotherapy, and vice versa.

The numbers were quite shocking:

Patients who preferred medication:

Treatment received Remission rate Avg. depression score (HAM-D) at end of study (high score = more depressed)
Meds 45.5% 11.6
Therapy 22.2% 21.0

Patients who preferred therapy:

Treatment received Remission rate Avg. depression score (HAM-D) at end of study
Meds 7.7% 18.3
Therapy 50.0% 12.1

(original HAM-D scores were approximately 26-27 for all patients, constituting major depression, and patients in this study had been depressed for over two years)

Thus, if a depressed patient wanted therapy but got medications instead, their chances of “remitting” (ie, having a fully therapeutic response to nefazodone) were less than 1 in 12.  But if they did get therapy, those chances improved to 1 in 2.  Interestingly, patients who preferred therapy and got combination treatment (meds and therapy) actually did worse than with therapy alone (remission rate was only 38.9%), leading the authors to conclude that “few patients who stated a preference for psychotherapy benefited much from the addition of medication.”

It’s not surprising, at first glance, that people who “get what they want” do better.  After all, a depressed patient who insists on taking meds probably won’t get much better if he’s dragged into psychotherapy against his will, and the patient who believes that a weekly session with a therapist is exactly what she needs, will probably have some resistance to just getting a pill.

But then again, isn’t depression supposed to be a hard-wired biological illness?  Shouldn’t a medication have a more profound effect, regardless of whether the patient “wants” it or not?

Apparently not.  The fact that people responded to the treatment they preferred means one of two things.  There may be two different types of depression, one that’s biological and one that’s more behavioral or “exogenous,” and people just happen to choose the appropriate treatment for their type due to some predisposition or innate tendency (self-knowledge?).  Alternatively, the “biological” basis of depression is not all it’s cracked up to be.

One question raised by these results is, why don’t we listen more to our patients and give them what they say they want?  If half the people who want therapy actually get better with therapy, doesn’t that make it hard to justify meds for this population?  Conversely, when we talk about “treatment-resistant depression,” or “depression that doesn’t respond to antidepressants alone,” could it be that the people who don’t respond to pills are simply those who would rather engage in psychotherapy instead?

I believe the implications of these findings may be significant.  For one thing, insurers are becoming less likely to pay for therapy, while they spend more and more money on antidepressant medications.  These studies say that this is exactly what we don’t want to do for a large number of patients (and these patients are easy to identify—they’re the ones who tell us they don’t want meds!).  Furthermore, trials of new antidepressant treatments should separate out the self-described “medication responders” and “therapy responders” and determine how each group responds.  [Note:  in the large STAR*D trial, which evaluated “switching” strategies, patients were given the opportunity to switch from meds to therapy or from one med to a different one of their choosing, but there was no group of patients who didn’t have the option to switch.]  If the “therapy responders” routinely fail to respond to drugs, we need to seriously revamp our biological theories of depression.  Its chemical basis may be something entirely different from how our current drugs are thought to work, or maybe depression isn’t “biological” at all in some people.  This will also keep us from wasting money and resources on treatments that are less likely to work.

While it’s often risky to ask a patient what he or she wants (and to give it to them), depression may be just the opportunity to engage the patient in a way that respects their desires.  These data show that the patient may know more than the doctor what “works” and what doesn’t, and maybe it’s time we pay closer attention.

The Placebo Effect: It Just Gets Better and Better

February 13, 2011

The placebo response is the bane of clinical research.  Placebos, by definition, are inert, inactive compounds that should have absolutely no effect on a patient’s symptoms, although they very frequently do.  Researchers compare new drugs to placebos so that any difference in outcome between drug and placebo can be attributed to the drug rather than to any unrelated factor.

In psychiatry, placebo effects are usually quite robust.  Trials of antidepressants, antianxiety medications, mood stabilizers, and other drugs typically show large placebo response rates.  A new paper by Bruce Kinon and his colleagues in this month’s Current Opinion in Psychiatry, however, reports that placebos are also show some improvement in schizophrenia.  Moreover, placebos seem to have become more effective over the last 20 years!

Now, if there’s any mental illness in which you would not expect to see a placebo response, its schizophrenia.  Other psychiatric disorders, one might argue, involve cognitions, beliefs, expectations, feelings, etc.—all of which could conceivably improve when a patient believes an intervention (yes, even a placebo pill) might make him feel better.  But schizophrenia, by definition, is characterized by a distorted sense of reality, impaired thought processes, an inability to grasp the differences between the external world and the contents of one’s mind, and, frequently, the presence of bizarre sensory phenomena that can only come from the aberrant firing of the schizophrenic’s neurons.  How could these symptoms, which almost surely arise from neurochemistry gone awry, respond to a sugar pill?

Yet respond they do.  And not only do subjects in clinical trials get better with placebo, but the placebo response has been steadily improving over the last 20 years!  Kinon and his colleagues summarized placebo response rates from various antipsychotic trials since 1993 and found a very clear and gradual improvement in scores over the last 15-20 years.

Very mysterious stuff.  Why would patients respond better to placebo today than in years past?  Well, as it turns out (and is explored in more detail in this article), the answer may lie not in the fact that schizophrenics are being magically cured by a placebo, but rather that they have greater expectations for improvement now than in the past (although this is hard to believe for schizophrenia), or that clinical researchers have greater incentives for including patients in trials and therefore inadequately screen their subjects.

In support of the latter argument, Kinon and his colleagues showed that in a recent antidepressant trial (in which some arbitrary minimum depression score was required for subjects to be included), researchers routinely rated their subjects as more depressed than the subjects rated themselves at the beginning of the trial—the “screening phase.”  Naturally, then, subjects showed greater improvement at the end of the trial, regardless of whether they received an antidepressant or placebo.

A more cynical argument for why antipsychotic drugs don’t “separate from placebo” is because they really aren’t that much better than placebo (for an excellent series of posts deconstructing the trials that led to FDA approval of Seroquel, and showing how results may have been “spun” in Seroquel’s favor, check out 1BoringOldMan).

This is an important topic that deserves much more attention.  Obviously, researchers and pharmaceutical companies want their drugs to look as good as possible, and want placebo responses to be nil (or worse than nil).  In fact, Kinon and his colleagues are all employees of Eli Lilly, manufacturer of Zyprexa and other drugs they’d like to bring to market, so they have a clear interest in this phenomenon.

Maybe researchers do “pad” their studies to include as many patients as they can, including some whose symptoms are not severe.  Maybe new antipsychotics aren’t as effective as we’d like to believe them to be.  Or maybe schizophrenics really do respond to a “placebo effect” the same way a depressed person might feel better simply by thinking they’re taking a drug that will help.  Each of these is a plausible explanation.

For me, however, a much bigger question arises: what exactly are we doing when we evaluate a schizophrenic patient and prescribe an antipsychotic?  When I see a patient whom I think may be psychotic, do I (unconsciously) ask questions that lead me to that diagnosis?  Do I look for symptoms that may not exist?  Does it make sense for me to prescribe an antipsychotic when a placebo might do just as well?  (See my previous post on the “conscious” placebo effect.)  If a patient “responds” to a drug, why am I (and the patient) so quick to attribute it to the effect of the medication?

I’m glad that pharmaceutical companies are paying attention to this issue and developing ways to tackle these questions.  Unfortunately, because their underlying goal is to make a drug that looks as different from placebo as possible (to satisfy the shareholders, you know) I question whether their solutions will be ideal.  As with everything in medicine, though, it’s the clinician’s responsibility to evaluate the studies critically—and to evaluate their own patients’ responses to treatment in an unbiased fashion—and not to give credit where credit isn’t due.

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