The Placebo Effect: It Just Gets Better and Better

The following was originally posted to Thought Broadcast.

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 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.