People's expectations about how effective their antidepressant medication is going to be almost entirely predicts their response to it, such that giving patients a placebo pill as active therapy during an 8-week period results in very similar reductions in symptoms, new research shows.
Investigators at the David Geffen School of Medicine at the University of California, Los Angeles, found that patients assigned to either active antidepressant therapy or placebo pills had better clinical outcomes than supportive care alone and that there was little difference between outcomes for the medication and placebo groups.
"There are several factors that contribute to patients with depression getting better," lead investigator Andrew Leuchter, MD, told Medscape Medical News.
"Supportive interaction with the subject helped them get better, and antidepressant therapy helped them get better, but I think our key finding was that patients' belief in the effectiveness of medication was a unique factor that contributed to them getting well. So belief in the power or effectiveness of the medication may be a contributor to placebo responses in the treatment of depression."
The study was published online September 11 in the British Journal of Psychiatry.
Double-Blind Study
In the double-blind study, 88 individuals between 18 years and 65 years of age who had a diagnosis of depression were all assigned to supportive care. Twenty patients received supportive care alone, 29 patients were assigned to placebo, and 39 patients were assigned to receive antidepressant medication.
"Patients knew if they took a pill, there was an equal likelihood that it would be medication or placebo, so they were in a position of doubt as to what they were getting," Dr. Leuchter noted. "And we found that patients were actually pretty inaccurate at [guessing] what they were getting."
Supportive care consisted of a 30-minute session of interpersonal clinical interaction that was repeated 2, 4, and 8 weeks after the initial visit. During these visits, treatment providers assessed risk, side effects, and symptoms and provided support and encouragement but refrained from engaging in problem solving that might result in therapeutic effects.
Researchers also measured patients' expectations as to how effective they thought medication and general treatment would be as well as their impressions of the strength of their relationship with the supportive care provider.
At study outset, patients completed the Hamilton Rating Scale for Depression. After 8 weeks of treatment, patients who received active antidepressant medication improved an average of 46%.
In comparison, the placebo group improved an average of 36%, and those who received supportive care alone improved an average of just 5%.
Researchers also found that people who received supportive care alone were more likely to discontinue treatment early than those who received pills.
Table. Treatment Outcome in the ITT Sample
| Placebo | Medication | Supportive Care Alone | |
| Mean time in study | 8.3 weeks | 7.6 weeks | 5.7 weeks |
| % change in Hamilton scores from baseline to week 8 | -.36 | -.46 | -.05 |
| Proportion | 11/29 | 17/39 | 1/20 |
Great Expectations
Treatment expectations, averaged across 3 time points, did not differ between those assigned to antidepressant medication and those assigned to placebo.
In contrast, those later randomly assigned to receive supportive care had lower expectations of treatment at baseline. This may reflect a certain bias in this particular group of individuals who were coming to a university research setting and who may have hoped they were going to receive pills, said Dr. Leuchter.
"When they didn't get pills, they may have been disappointed," he said, "so we need a bit of caution when interpreting these results."
Very importantly as well, researchers observed that the strength of the therapeutic alliance with research personnel was significantly associated with clinical outcomes whether patients were on medication or placebo.
"Good, compassionate care, connecting with your patients, letting them know that you want them to do well, that you are strongly bonded with them, that is all part of the art of medicine," Dr. Leuchter told Medscape Medical News.
"And I hope that this message is going to a major take-home from this study ― that patients get well in good measure because they connect with those who are providing care for them."
Dr. Leuchter also noted that although antidepressant medication only had a modest advantage over placebo across this 8-week study, "if you take a longer view, the effectiveness of medication becomes much more important," he said.
For example, if clinicians look beyond symptom improvement toward an arguably more meaningful improvement in function — being able to go back to work, to take care of their families, to engage in life — "you find that medication does a much better job of getting people completely well and keeping them well," he said.
"I think what we add with this study is that patients' belief in the effectiveness of treatment has a lot to do with the fact that placebo response rates are going up overall," said Dr. Leuchter.
"As we speculate in the article, it may not be a coincidence that placebo response rates have been going up at the same time the pharmaceutical industry is investing billions of dollars in direct-to-consumer advertising. So peoples' expectations may be going up for societal reasons, because in fact we found that patients came into the trial with high expectations that seemed to be shaped by forces beyond the trial," he added.
Only for Extreme Depression?
Commenting on the study for Medscape Medical News, Irving Kirsch, PhD, director of the Program in Placebo Studies, Harvard Medical School, Boston, Massachusetts, said he agrees with Dr. Leuchter and colleagues that patients' expectations of antidepressants largely dictates response.
"People do feel better taking the drug, but they also feel better taking a placebo, and the difference between the 2 is very small and for most people, probably not of clinical importance," Dr. Kirsch said.
Other studies suggest antidepressants may have a greater effect in very severe depression, which accounts for about 10% of all depressed patients.
That said, "it's not that severely depressed patients get any better response to the antidepressant, it's just that they don't get as much response to placebo," said Dr. Kirsch.
Dr. Kirsch largely disagreed with Dr. Leuchter and colleagues about the more meaningful long-term effects of antidepressants.
"Compared to other treatments, including psychotherapy, long-term effects for antidepressants seem to be worse, because relapse rates seem to be worse on antidepressants," he said.
For example, studies have shown that if one group of depressed patients is given antidepressants and another receives organized physical activity, "you get a much higher relapse rate in the group given antidepressants at 1 year than in the exercise group," Dr. Kirsch said.
Moreover, if antidepressants are added to the exercise group, "antidepressants seem to produce a greater risk of relapse," he noted. "So over the long term, antidepressants seem to induce a vulnerability for recurrent episodes more than other treatments."
Dr. Kirsch feels that if antidepressants are to be used at all, they should only be used in extremely severe depression and only after other treatments have been tried and found not to work.
If after an interval of 6 to 8 weeks, antidepressants themselves do not seem to be working, "they should be discontinued," said Dr. Kirsch.
"We know that antidepressants can cause some harm, and if you are not getting any benefit, there is no reason to continue them, especially given that there is this possibility for enhancing vulnerability to relapse."
Research support for this study was received from the National Center for Complementary and Alternative Medicine of the National Institutes of Health; Eli Lilly and Company, and Wyeth Pharmaceuticals (now owned by Pfizer). Dr. Leuchter discloses that within the past 5 years, he has received research support from the National Institutes of Health, Wyeth Pharmaceuticals, and Eli Lily, among other pharmaceutical companies. He is CEO of Brain Biomarker Analytics and owns stock options in NeoSync Inc. Dr. Kirsch reports no relevant financial relationships.
Br J Psychiatry. Published online September 11, 2014. Abstract