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Jeremy Howick Ph.D.

Depression

It's Time for Depression to Make Friends With the Placebo

Depression and the placebo effect both need to be taken seriously.

Elaine and Arthur Shapiro: Original work of the US Federal Government - public domain
Source: Elaine and Arthur Shapiro: Original work of the US Federal Government - public domain

I’ve created a kerfuffle on Facebook after discussing a new study about antidepressants :

Me: Antidepressants work (for mild to moderate depression) mostly through the placebo effect.

Friend: It can't be the placebo, because my depression is real, and the pills worked really well.

Me: The depression is real and so is the placebo effect (for depression).

Friend: But placebos are just sugar pills, and if sugar pills can cure my awful depression, you must be saying that my depression was nothing too.

Me: No!

This misunderstanding made me think that it’s time to help the poor placebo shed its negative connotation and to celebrate it as our friend.

Let me clarify two things before debunking some placebo myths. First, I’m not talking about severe depression. Placebos (or anything related to placebos) are completely inappropriate for people who are severely depressed or suicidal. If you or anyone you know is severely depressed, contact the relevant health care professionals in your country immediately. However, most depressed people (including my friend) are not severely depressed .

Even mild depression is awful. The fact that the evidence suggests that placebo effects can help does not mean that mild or moderate depression isn’t awful or unreal. It just means that placebo effects are real too.

Myth #1: Most antidepressant drugs are proven to be much better than placebo

Some researchers have questioned whether antidepressant drugs are relevantly better than placebos. In 2018, a paper was published in the prestigious journal The Lancet. Using the latest methods (a "network meta-analysis") they compared the effects of different antidepressant drugs with each other and with placebo . The conclusion stated: "all antidepressants … were more efficacious than placebo in adults with major depressive disorder." The paper has been widely reported in the news and tweeted by thousands, and is used to justify the widespread use of antidepressant drugs.

But a study published last week found some serious flaws with the Lancet study. The first main problem was publication bias. Many antidepressant trials—especially those that don’t have a positive effect—are not published. The Lancet study found that the benefit of antidepressants was smaller in the unpublished studies. However, their conclusion did not really reflect this limitation. Another main problem is that the study didn't consider the effect of "placebo run-in" periods. Before the actual clinical trial begins, many studies give all patients placebo pills for a few weeks. Then, they often exclude "placebo responders" who benefit from the placebo. But excluding placebo responders inflates the benefits of the drug compared with placebo. The combined effect of these and other biases suggests that the benefits of antidepressant drugs for mild to moderate depression (over and above the placebo effect) may not be clinically significant.

Myth #2: The placebo is "just a pill"

Many people associate placebos with sugar pills that don’t contain anything "real." But there's much more to the placebo effect than mere placebo pills. Placebos come in many forms, ranging from sugar pills and saltwater injections to neutral talking therapy and sham surgery. More importantly, placebos are not given in a vacuum—they are (usually) delivered by doctors. Studies show that doctors who offer empathic, positive care can benefit patients . The patient/doctor communication, as well as the meaning , context, and our beliefs surrounding the placebo pills also have effects.

Myth #3: The mind and body are separate

Beliefs are often considered to be fluffy, psychological things that are "just in the mind" and aren’t that "real." From this point of view, it sounds downright wacky to think that beliefs can affect our bodies and health in a meaningful way. This is related to the belief that humans are machines . This is partly true: Our bodies are (extremely complex) machines. But they are also more than machines, and our thoughts and beliefs are intertwined with our bodies. If thoughts and beliefs were not directly connected to physical bodies, then:

  • How could alcohol, which acts on your body, change your thoughts?
  • How could drugs—physical things—change your mood?
  • How come being in physical pain can make you depressed?​

There is nothing that is "just in the mind." What affects the mind affects the body and vice versa. Both are equally real.

Myth #4: It’s all about benefits

If antidepressant drugs work (mostly) because of placebo effects, should we start handing out placebo pills and telling patients they were real drugs? That would be unethical (although placebos can work even if patients know what they are ). So, why not continue doling out antidepressant drugs to those who are depressed, even if they are (mostly) placebos? If there were no harms or costs of the drugs, that might be a good idea. Harms of antidepressant drugs are rare, but they can be serious. They include sexual dysfunction and an increased risk of suicide . These risks need to be weighed alongside any benefits.

Myth #5: There's nothing else I can do

You don’t need a placebo pill to have a placebo effect. Besides empathic, positive care from doctors, there are things you can do. With the usual caveat that I’m not a medical doctor, so I can’t give medical advice, studies suggest that there are other great options for mild to moderate depression:

Take-home message

Depression is an awful disease that needs to be taken seriously by our family, friends, and the medical profession. By the same token, the placebo effect needs to be taken seriously as our helpful friend.

References

Cipriani, A., et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391, 1357-1366 (2018).

Howick, J., et al. Are treatments more effective than placebos? A systematic review and meta-analysis. PLoS One8, e62599 (2013).

Howick, J., et al. Effects of empathic and positive communication in healthcare consultations: a systematic review and meta-analysis. J R Soc Med, 141076818769477 (2018).

Munkholm, K., Paludan-Muller, A.S. & Boesen, K. Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis. BMJ Open, e024886 (2019).

Sharma, T., Guski, L.S., Freund, N. & Gotzsche, P.C. Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. BMJ352, i65 (2016).

Moerman, D.E. Meaning, medicine, and the "placebo effect" (Cambridge University Press, Cambridge, 2002).

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