The Placebo Effect: It Just Gets Better and Better

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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13 Responses to The Placebo Effect: It Just Gets Better and Better

  1. […] Steve Balt has a post on placebo. It’s worth reading. I’ve excerpted a small bit below. I have to preface it by saying that unfortunately Steve’s incredulousness about how placebo works “even” with “schizophrenics” further dehumanizes the population of folks labeled with schizophrenia. Why in the heck wouldn’t placebo work in  people with that label? I was bummed out when I saw him speak that way. […]

  2. stevebMD says:

    I, like you, am extremely fascinated by the placebo effect and similarly wish we could understand and/or apply it more extensively in psychiatric care.

    But please don’t misinterpret my comments as believing those labeled as schizophrenic are somehow less than human. All I mean to say is that schizophrenic patients often endorse and exhibit symptoms that are discrete, intrusive, and “foreign” (and patients with good insight will identify them as such), symptoms which cause great distress because they cause the patient to feel less like him- or herself (a phenomenon that loved ones will readily point out, too).

    If one sees his mood or behavior as the focus of treatment, and retains some sense of control over his moods or actions, it makes sense that a placebo effect might work, whether we call it “expectancy manipulation” or something else. But in severe cases of schizophrenia, there’s often a disconnect between one’s sense of self and the symptoms that bring him to clinical attention– a disconnect that can be profound and (at least to the medical eye) suggests some underlying pathophysiology. Antipsychotics often treat these symptoms quite effectively– perhaps by correcting the biochemical defect?– regardless of the patient’s level of insight.

    Finally, regarding the main thrust of the Kinon paper, it is unfortunate that pharmaceutical manufacturers, instead of trying to understand and harness the powerful placebo effect, are instead looking for ways to make it vanish.

    • giannakali says:

      thanks steve,
      I linked to your response on my blog so that you could have a voice. It struck me not having comments in this instance wasn’t so good. I appreciate your response.

      I can’t say I agree with you still. I worked exclusively with people who were labeled with schizophrenia for several years. I can’t say I ever saw a “disconnect” so profound that the self was completely obliterated. Perhaps the “medical” eye has been blinded a bit?

      I don’t believe antipsychotics correct anything ever. They do mute and soften things in the short run at least in some individuals.

      • Marian says:

        As someone labelled with “schizophrenia”, though lacking all “good (?) insight”, never drugged, working full-time, having a very satisfying social life, and being “symptom”free (oh yes, I do hear voices, but hearing voices isn’t a “symptom”, it’s being human) I believe the most profound “disconnect” to be that which interprets the voice of the self to be “symptoms” of a genetic, biological brain disease, and thus the self to be an “illness”. — So much, btw, for the slogan “You are not your illness”. Of course people are their illness when it is the self that is recognized as the alleged illness. And, no matter how politically incorrect, you’re right, Dr. Balt, to call people going through an intense personal crisis “schizophrenic” as, indeed, this is what they are. At least if we are to believe psychiatry’s concept of “mental illness”… — The true “disconnect” thus is biological psychiatry’s, disconnecting, alienating people from themselves, and turning them from being human beings into “schizophrenics”, and since “schizophrenia” is defined as an illness, i.e. something undesirable, “schizophrenics” are less than human.

        The question is whether it is ethically justifiable to label people “less than human” while no pathophysiology is identified that would support this view of these people, and while, in addition, helping approaches that do not view these people as brain-diseased, genetically defective lesser-than-humans, but rather as actually experiencing what it means to be a human being more directly and intensely than anybody else, produce far better outcomes than the usual “symptom management”. I don’t think it is.

  3. Matt says:

    I wonder how you steve define the effective treatment of the symptoms by the antipsychotics? By plunting the patient to be numb to everything? Because this is the very thing which happens with the antipsychotics and we have the patients to prove it for us.

    And how can we know that even the ones who are saying the drugs are making them better are not subject to placebo?

    It’s crazy how twisted the world of psychiatry really is.

    P.S. I liked the original post! Thanks!

  4. […] There’s an interesting placebo effect discussion going on in the blogosphere (beginning here and continuing here), and I’d like to pose my answer to a question that has come […]

  5. Thank you for starting this very important discussion about the placebo (self-healing) effect. Your post (and Gianna’s as well) inspired quite a bit of comment, so I wrote a post about it here. Great to hear your thoughts on the subject!

  6. Rossa Forbes says:

    As a layperson, I’m having trouble understanding the technicalities of the Schizophrenia Bulletin article. In this quote from your post, “reports that placebos are also show some improvement in schizophrenia” I assume you mean that people with schizophrenia show improvement when placed on placebos, in other words, it’s the people, not the pills, who are improving. I would also urge you to rethink how you view people with schizophrenia. They are not “schizophrenics,” as that implies something immutable and chronic, and less than human. People must think it’s okay to say “schizophrenics” because they’re just like diabetics, right? The idea that schizophrenia is just like diabetes was promoted by drug companies that wanted to push compliance with lifetime use of medication, just like if you have diabetes. The public has been fed a falsehood. Robert Whitaker exposed that lie by talking directly to a pharma rep. If you don’t agree that you have a negative impression of a person with schizophrenia (most psychiatrists do, so you’re not alone), notice that you refer to a “depressed person” in your article. Why not simply call them “depressives?” You also negate people with schizophrenia’s belief that there is greater chance for improvement for schizophrenia now than in the past ” (“although this is hard to believe for schizophrenia”). It is likely that I am not quite catching your intended meaning, but I urge you to look at the underlying tone of your writing. If there is any so-called illness where I would expect to see an unexpected response, it is with schizophrenia. The only response that I know that can be predicted is how well people with this unfortunate label respond to someone who takes an interest in them, learns to understand their story, and does not judge them or negate them. They get well and leave that label behind them.

  7. Kimbriel says:

    Psychiatrists need schizophrenics. The profession of psychiatry rises and falls with schizophrenia. And I would say the last person someone with schizophrenia needs is a psychiatrist.

  8. stevebMD says:

    Matt: “…By [b]lunting the patient to be numb to everything?”

    Absolutely not. This is my biggest complaint about the currently available antipsychotic agents, namely that most (but not all) seem to remedy psychotic symptoms by this very mechanism– or, at the very least, this is the subjective experience most patients report. I, for one, refuse to do this, unless it is to protect the safety of the patient or others, and even then I prefer to do so only temporarily.

    Rossa: “…In this quote from your post, ‘reports that placebos also show some improvement in schizophrenia’ I assume you mean that people with schizophrenia show improvement when placed on placebos, in other words, it’s the people, not the pills, who are improving….”

    Yes, thank you for that clarification. Medications affect neurochemistry, but “improvement” is subjective and experiential.

    Rossa: “…I would also urge you to rethink how you view people with schizophrenia. They are not “schizophrenics,” as that implies something immutable and chronic…”

    Believe it or not, I struggled with whether to use that word because I anticipated exactly this response. Patients are indeed people, not labels, and my use of a word like “schizophrenic” or “diabetic” or “hypertensive” is (at least for me) semantic shorthand, and in no way violates the human-ness of the patient who walks into my office. I understand, however, that many of my colleagues and plenty of lay people may think otherwise, so agree these terms should be used sparingly.

    • Rossa Forbes says:

      I understand what you mean about the semantic shorthand. Saying “person with a diagnosis of schizophrenia” is really a mouthful. I ask myself often if I come across as too politically correct by insisting on not calling someone “schizophhrenic.” But, it is important to be awkward sometimes in order to make people think about what’s behind the words. Thanks for your thoughts.

  9. […] Balt, S. (n.d.). The Placebo Effect: It Just Gets Better and Better | Thought Broadcast. Retrieved December 29, 2015, from https://thoughtbroadcast.com/2011/02/13/the-placebo-effect-it-just-gets-better-and-better/ […]

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