Are Antidepressants Mostly Placebos? Should We Care?

“Where there is a love of humanity, there is a love for the art of medicine” –Hippocrates, the father of western medicine

When I was in middle school, I went to Lake Tahoe with my best friend on a ski trip. I had only been skiing a few times before, and even though my friend was only twelve, she was already a talented and experienced skier.

She was patient with me, but I became increasingly frustrated as I had trouble going down even the most basic runs without falling. At one point, after falling several times in a row, I gave up, and plopped down onto the snow, completely discouraged.

My friend maneuvered over to me and sat down. She explained that she knew a technique that would help my skis work better. She reassured me that once she fixed my skis, I wouldn’t have any more problems.

Then, she took a handful of snow and carefully rubbed it on the bottom of my skis.  “This will help you get better traction,” she explained. She worked meticulously, as if she were engaged in a very important task. As I sat there, I began to feel relieved. She finished, and I got up, encouraged. We both made our way down the mountain, with minimal falling on my part.

The powerful placebo effect

Of course, it makes absolutely no sense that rubbing snow on the bottom of skis would help them work better (I must have been kind of slow in my middle school days), but what matters is that I believed it would. What matters is that I trusted my friend and felt reassured by her attention. What matters is that her actions helped transform my discouragement into motivation to get down the mountain.

Antidepressants and the placebo effect

For years, psychiatrists prescribed antidepressants only for the most severely depressed patients, as the early antidepressants (such as tricyclic antidepressants, or TCAs, and monoamine oxidase inhibitors, or MAOIs) had many side effects. Then Prozac, the first selective seratonin reuptake inhibitor (SSRI), came out in the late 1980s, and was much safer and better tolerated than the older-generation antidepressants. Prescriptions for antidepressant medications skyrocketed.

For a while, the efficacy of antidepressants was not questioned. Doctors would see their patients get better, with few side effects, and keep writing scripts. But over time, as more studies were done, it became evident that antidepressants were not much more effective than the sugar pills they were compared with in clinical trials.

In 2009, the psychologist and researcher Irving Kirsch published a book titled The Emperor’s New Drugs: Exploding the Antidepressant Myth. He cited clinical evidence suggesting that the most widely-prescribed drugs in psychiatry were not as effective as previously believed. In January 2010, the cover of Newsweek read, “Do Antidepressants Work?” The feature article had the sensationalist title, “The Depressing News About Antidepressants: Studies Suggest That the Popular Drugs Are No More Effective Than a Placebo. In Fact, They May Be Worse.”

Summaries of the evidence demonstrate that antidepressants are effective for depression about 31-70% of the time, while placebos are effective 12-50% of the time, for an average antidepressant-placebo difference of 20%. So, while antidepressants appear more effective than placebo, only a fraction of the benefit we see in patients is likely from a direct neurobiological impact of the medication itself.

One meta-analysis (a statistical summary of the evidence) argues that 25% of the benefit we see from antidepressants is due to a direct impact of the medication, while 25% is due to spontaneous remission (people who would have gotten better anyway), and 50% is due to the “expectation of benefit,”—also known as the placebo effect.

Interestingly, the antidepressant-placebo difference seems to be decreasing over time—not because antidepressants are becoming less effective, but because placebos are becoming more effective, at a rate of 7% a decade. How on earth could placebos be becoming more effective, when, by definition, they do not have any therapeutic value?

Researchers have suggested many possible explanations for this phenomenon, including that more people with mild-to-moderate depression are being including in clinical trials than in the past. The evidence suggests that antidepressants are quite effective for people with severe depression, but less effective, or not effective at all (when compared with placebo), for people with mild-to-moderate depression.

Why is ‘placebo’ a dirty word?

Okay, so the evidence shows that antidepressants are not as effective as we’d like to think. As psychiatrists, we need to be honest that more of what we do is “the placebo effect” than we’d like to believe.

But—dare I say it—so what?

I prescribe antidepressants because I see people get better with them. Yes—researchers need to pay attention to the placebo effect in randomized controlled trials, but do clinicians? Who cares what is making patients feel better if they’re feeling better? Who cares what is alleviating their suffering, if they are getting relief? Why is placebo such a dirty word?

Did you know that some soldiers in World War II who were given saline injections instead of morphine (because of depleted morphine stocks) experienced relief from their pain? Did you know that a placebo can lead to airway dilation in asthma, when the person is told they received a bronchodilator, like albuterol? Did you know that in one study, 50% of people with osteoarthritis reported decreased knee pain with a high-tech surgery, while 50% experienced relief with… sham surgery?

Did you know that there are case reports of women given ipecac, known to induce vomiting, who reported a relief in their nausea when they were told the ipecac was an anti-nausea medication? Did you know that physical symptoms of hypoglycemia (sweating, increased heart rate, tremor) have been induced by placebo when a patient is told they are getting insulin? Did you know a flavored drink can suppress a person’s immune system (as measured by biochemical tests), when in the past that flavored drink was paired with the immunosuppressive drug cyclosporine?

Oh, and here’s my favorite: Did you know that despite the evidence that acupuncture is no more effective than sham acupuncture, in China—where people believe strongly in the power of acupuncture—it has been used in lieu of traditional anesthesia during open-heart surgery? I didn’t believe it until I read the study myself.

In psychiatry, we know that placebos not only work clinically, but lead to similar functional brain changes as antidepressants.

We also know that the placebo effect has an equal opposite: the nocebo effect. Just as the suggestion of positive benefit can help, the suggestion of negative outcome can harm. In antidepressant clinical trials, for example, about 25% of people report side effects from the placebo—side effects that match the ones they were told could happen with the active medication during the informed consent process.

How to harness the placebo effect

Yes, there are ethical considerations when it comes to placebos. Clinicians are obligated to give informed consent, and can not ethically lie to patients about treatments they are getting. No, we should not offer treatments that have no scientific benefit when they might cause harm. I’m not saying we should go around giving people ipecac for nausea or performing fake surgery for knee pain.

Clearly, though, the placebo effect is much more than “in our heads.” Hope and expectation can cause biological and functional changes in our brains and bodies. Shouldn’t physicians be interested in this phenomenon? Shouldn’t we pay attention to it? If it has the potential to heal, shouldn’t we harness it?

And more importantly, why do we argue ad nauseam about evidence-based medicine (should I give my patient an SSRI or an SNRI? Cognitive behavioral therapy or psychodynamic psychotherapy?) when the evidence suggests that the specific intervention we choose is a fraction as important as the way we deliver it?

What is lumped together as “the placebo effect” is probably a collection of multiple factors. It is the therapeutic alliance a person has with their healthcare provider, it is their belief in the power of the treatment, it is our society’s cultural expectations about sickness and health. It is the personality and style of the physician and their ability to demonstrate compassion and instill confidence. It is reassurance, it is ritual between doctor and patient, it is ceremony.

The evidence about placebos tells us that we clinicians need to do a lot more than just write scripts to serve our patients and our communities. We need to:

• Respect individual beliefs and treatment preferences.
• Study the placebo effect with the same scientific rigor with which we study the medications we use.
• Listen empathetically and communicate compassionately.
• Share our hope and positive expectations with patients.
• Not attribute all of a patient’s improvement to medication, and instead reinforce the patient’s self-healing mechanisms.
• Be honest about the possible side effects of medications, but emphasize the potential benefits.
• Consider carefully the cultural message that pharmaceutical companies are spreading in their pervasive consumer advertising (“Take our brand-name medication and you’ll be running through a field of daisies in no time!”).
• Consider that unreputable sources on internet, unfortunately, might be creating a nocebo effect.
• Strive to be encouraging and supportive of our patients. We clinicians should be placebos for our patients, not nocebos.

Yes, I use drugs, but this is only one tool in my arsenal. I use words, I use hope, and I use heart. I care about science, but I also care about our humanity. Isn’t that what medicine is all about, anyway? When my patients tell me that antidepressants help, who am I to tell them they’re wrong?

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Photo by Sam Catch