Chemical Imbalances and Mental Illness? Go for the Placebo with Side Effects

Marcia Angell has a wonderful review, The Epidemic of Mental Illness: Why?, up at the New York Review of Books. I want to highlight two things: (1) the fall of the “chemical imbalances” theory of the brain, cloaked in the language of neurotransmitters and synapses; and (2) that healing matters, in particular signs people can interpret that drugs they are getting must be making a difference.

Chemical imbalances is our most recent folk theory of mental illness in the Western world. A focus on doctors and therapists doing, rather than on how healing happens, is the corollary – the imbalance, whether chemical or psychoanalytic, needs to be corrected. Both of these are rich arenas for medical anthropology, and I particularly hope people will dig into work on how healing and placebos work.

But for those also interested in the brain, Angell’s piece gives some great overview of how our understanding of brain function and treatment is progressing. Here she is on the chemical imbalance approach:

Because certain antidepressants increase levels of the neurotransmitter serotonin in the brain, it was postulated that depression is caused by too little serotonin. (These antidepressants, like Prozac or Celexa, are called selective serotonin reuptake inhibitors (SSRIs) because they prevent the reabsorption of serotonin by the neurons that release it, so that more remains in the synapses to activate other neurons.) Thus, instead of developing a drug to treat an abnormality, an abnormality was postulated to fit a drug.

That was a great leap in logic, as all three authors point out. It was entirely possible that drugs that affected neurotransmitter levels could relieve symptoms even if neurotransmitters had nothing to do with the illness in the first place (and even possible that they relieved symptoms through some other mode of action entirely). As Carlat puts it, “By this same logic one could argue that the cause of all pain conditions is a deficiency of opiates, since narcotic pain medications activate opiate receptors in the brain.” Or similarly, one could argue that fevers are caused by too little aspirin.

But the main problem with the theory is that after decades of trying to prove it, researchers have still come up empty-handed. All three authors document the failure of scientists to find good evidence in its favor. Neurotransmitter function seems to be normal in people with mental illness before treatment. In Whitaker’s words:

Prior to treatment, patients diagnosed with schizophrenia, depression, and other psychiatric disorders do not suffer from any known “chemical imbalance.” However, once a person is put on a psychiatric medication, which, in one manner or another, throws a wrench into the usual mechanics of a neuronal pathway, his or her brain begins to function…abnormally.

Carlat refers to the chemical imbalance theory as a “myth” (which he calls “convenient” because it destigmatizes mental illness), and Kirsch, whose book focuses on depression, sums up this way: “It now seems beyond question that the traditional account of depression as a chemical imbalance in the brain is simply wrong.”

And here is the relevant piece on anti-depressants, placebos, and really getting at the science of what is going on.

Kirsch was also struck by another unexpected finding. In his earlier study and in work by others, he observed that even treatments that were not considered to be antidepressants—such as synthetic thyroid hormone, opiates, sedatives, stimulants, and some herbal remedies—were as effective as antidepressants in alleviating the symptoms of depression. Kirsch writes, “When administered as antidepressants, drugs that increase, decrease or have no effect on serotonin all relieve depression to about the same degree.” What all these “effective” drugs had in common was that they produced side effects, which participating patients had been told they might experience.

It is important that clinical trials, particularly those dealing with subjective conditions like depression, remain double-blind, with neither patients nor doctors knowing whether or not they are getting a placebo. That prevents both patients and doctors from imagining improvements that are not there, something that is more likely if they believe the agent being administered is an active drug instead of a placebo. Faced with his findings that nearly any pill with side effects was slightly more effective in treating depression than an inert placebo, Kirsch speculated that the presence of side effects in individuals receiving drugs enabled them to guess correctly that they were getting active treatment—and this was borne out by interviews with patients and doctors—which made them more likely to report improvement. He suggests that the reason antidepressants appear to work better in relieving severe depression than in less severe cases is that patients with severe symptoms are likely to be on higher doses and therefore experience more side effects.

To further investigate whether side effects bias responses, Kirsch looked at some trials that employed “active” placebos instead of inert ones. An active placebo is one that itself produces side effects, such as atropine—a drug that selectively blocks the action of certain types of nerve fibers. Although not an antidepressant, atropine causes, among other things, a noticeably dry mouth. In trials using atropine as the placebo, there was no difference between the antidepressant and the active placebo. Everyone had side effects of one type or another, and everyone reported the same level of improvement.

Link to Marcia Angell’s The Epidemic of Mental Illness: Why?

The photo was taken by Chris Szbala; the original can be found here. Big hat-tip to Medical Skeptic for pointing it out as “The science of depression: chemical imbalance- the quick and easy version.”

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14 Responses to Chemical Imbalances and Mental Illness? Go for the Placebo with Side Effects

  1. Jennifer Jo Thompson says:

    Great piece on an important topic! A few quick points: in light of the high placebo response rates for antidepressant trials, pharmaceutical companies are getting increasingly sophisticated in the design of clinical trials. As Lakoff points out in his 2002 article in Molecular Interventions, being able to identify and eliminate placebo responders upfront (i.e., in a ‘double-blind placebo run-in’, for example) is the key to producing data that indicates drug efficacy. The question remains, whose interest does this serve?

    What this really indicates, however, is that it is time to unpack the black box of placebo, to look at expectation, hope, conditioning, symbolic significance, emotion, ritual performativity, and the therapeutic relationship for what they are: are genuine, embodied, components of the healing process—not some kind of sham or deception or even simulated therapy, but a key part of the **real thing.**

    Researchers are increasingly acknowledging the importance of disentangling these ‘non-specific’ effects of treatment. At the same time, researchers are recognizing the importance of translating this emerging understanding into a clinical context, to ‘harness’ the placebo effect and create what Jonas has called an ‘optimal healing environment’. I point readers to the 2011 special volume on placebo in Philosophical Transactions of the Royal Society.

  2. daniel.lende says:

    A reader sent me this interesting and relevant paper, Allan Horowitz (2011), Creating an Age of Depression: The Social Construction and Consequences of the Major Depression Diagnosis (pdf).

    Intraprofessional dynamics rather than external pressures generated perhaps the major transformation resulting from the Diagnostic and Statistical Manual of Mental Disorders, third edition, diagnostic revolution in 1980—the rise of Major Depressive Disorder as the central diagnosis of the psychiatric profession. Other interests, including the drug industry and advocacy groups, capitalized on the features of this diagnosis only after its promulgation. The social construction of depression illustrates how social and cultural processes can have fundamental influences over diagnostic processes even in the absence of struggles among forces external to the mental health professions. It also indicates how diagnoses themselves can have major professional, economic, political, and social consequences.

  3. Aron says:

    It makes sense that chemicals would impact how people think and feel. We’ve known that for a long time. They’re called drugs.

    The problem isn’t that there is no chemistry involved(our thoughts have to have some material basis) the problem is that psychiatry has become lazy and in it just for the money. If a study can be used to suggest something they run with it without considering alternative explanations for the results.

    Another problem is that we assume if it’s chemical the person’s thoughts have nothing to do with it in spite of the fact that studies already show chemical changes in the brain even from just thinking different kinds of thoughts. So it is not unreasonable that talk therapy would have chemical effects on a person that could even be better than using drugs.

  4. Michael Toyama says:

    Great post Dr. Lende. Have you read Anatomy of an Epidemic by Robert Whitaker? He runs through the history of these drugs and a bit of the research done to prove or disprove the neurotransmitter hypothesis.

    • daniel.lende says:

      I haven’t read it yet, but that is one of the books reviewed by Angell – looks like a powerful piece, full of both research and polemics.

      • Michael Toyama says:

        Heh. That’ll teach me to not follow links in posts to check out the originals.

  5. Janis says:

    I don’t doubt that chemical processes in the brain can go wrong — the brain is a physical device, and physical devices malfunction. But … the first thing that came to MY mind at that sign in the picture was not that depression was a flaw in chemistry, but that sometimes depression is a quite reasonable sign that your life SUCKS AND NEEDS TO CHANGE.

    I can’t tell you how many blogs written by people with clinical depression talk about unbelievably unhappy childhoods and abusive spouses and whatnot. Jesus. Who wouldn’t feel lousy living with a drunk who beat you up, or having grown up in a family that didn’t defend you when you were repeatedly molested? Or having had too many kids too early, or not being able to have kids when you want them? Being poor and without insurance, and having physical problems? Sometimes I want to tell these people that the fact that they are depressed, with their lives in the state they are in, is a sign that their brains are working correctly. Yet, this is the elephant in the living room — no one wants to name it out loud.

    Again, sometimes the brain can work incorrectly, like any organ can. But sometimes, it’s these people’s LIVES that truly do stink, not their brain chemistries. But saying something like:

    “You had too many kids too early and now you just have to deal because they’re here and they need to be taken care of.”

    “Your elder relative molested you as a kid, and your family stood by because they are fucked up.”

    “No, your husband doesn’t love you or mean well. People who love you don’t hit you.”

    “It sucks that you had to drop out of college and shelve your dreams because you’re poor, and most of society doesn’t care.”

    — is a lot more frightening, and a much bigger problem with no real solution, than, “You have an imbalance, here’s a pill.”

    • Aron says:

      But what if those experiences lead to the imbalance because of how the brain was wired to react to things in the environment?

      If an individual is depressed because of lifestyle changes they are failing to make then it makes no sense to prescribe a pill. But if there’s nothing they can really do about it, then it’s better for the person to live happily.

      The fact that they would naturally be sad doesn’t mean that the moral thing to do is for them to stay sad when we have technology.

  6. Dirk Hanson says:

    Folks are still getting tripped up over the difference between everyday melancholia and chronic unipolar depression. If you look at the pool of patients who have been truly, diagnostically, clinically depressed their whole lives, and who have responded dramatically and positively to SSRI antidepressants over the years, the picture looks more like normal pharmacological treatment for a host of other diseases. No need for Big Pharma to “invent” unipolar depression–it already existed.

  7. James Noble says:

    I’m sorry, I may have missed this in above comments, but I would really like to read that active placebo study if you could provide a link or citation. Also, do you know how relatively common/rare active placebo trials are?

  8. Pingback: Interactions Make the Difference: On Placebos, Healing Environments and Integrative Medicine | Neuroanthropology