F Hieronymus, A Lisinski, S Nilsson and E Eriksson. Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. Molecular Psychiatry. In press.
It has been suggested that the superiority of antidepressants over placebo in controlled trials is merely a consequence of side effects enhancing the expectation of improvement by making the patient realize that he/she is not on placebo. We explored this hypothesis in a patient-level post hoc-analysis including all industry-sponsored, Food and Drug Administration-registered placebo-controlled trials of citalopram or paroxetine in adult major depression that used the Hamilton Depression Rating Scale (HDRS) and included a week 6 symptom assessment (n=15). The primary analyses, which compared completers on active treatment without early adverse events to completers on placebo (with or without adverse events) with respect to reduction in the HDRS depressed mood item showed larger symptom reduction in patients given active treatment, the effect sizes being 0.48 for citalopram and 0.33 for paroxetine. In actively treated subjects reporting early adverse events, who also outperformed those given placebo, the severity of the adverse events did not predict response. Several sensitivity analyses, for example, including (i) those using change of the sum of all HDRS-17 items as effect parameter, (ii) those excluding all subjects with adverse events (that is, also those on placebo) and (iii) those based on the intention-to-treat population, were all in line with the primary analyses. The finding that both paroxetine and citalopram are clearly superior to placebo also when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects.
Investigators are hoping a new "mega-analysis" puts a final cap on the ongoing controversy over whether antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are effective for depression.
The review of 15 studies, with more than 3300 patients, showed that compared with those who received placebo, participants without early adverse events (AEs) who received either of the SSRIs citalopram (multiple brands) or paroxetine (multiple brands) had significantly greater reductions in symptoms, as assessed with the Hamilton Depression Rating Scale (HDRS) depressed mood item.
Previous research suggests antidepressants' superiority is "merely a psychological consequence of the side effects of the drugs enhancing the expectation of improvement," the investigators write.
However, the new analysis showed that patients who had early AEs and who were receiving one of the active drugs also had significantly greater reductions in symptoms vs their counterparts who were taking placebo. This suggests that "the severity of the adverse events did not predict response," the investigators write.
"I think, once and for all, we've answered the SSRI question. And we have effectively rebutted the side-effects theory," principal investigator Elias Eriksson, PhD, professor of pharmacology at the University of Gothenburg, Sweden, told Medscape Medical News.
In 2010, a study by University of Pennsylvania investigators that was published in JAMA suggested that although patients with severe depression may significantly benefit from antidepressant treatment, there would be little to no benefit for those with mild to moderate depression compared with receiving placebo.
The arguments boiled over in 2012 when the news program 60 Minutes broadcast an episode with psychologist Irving Kirsch, PhD, associate director of the Program in Placebo Studies at Harvard Medical School, Boston, Massachusetts.
The episode featured Dr Kirsch and his book The Emperor's New Drugs, which claims there are no clinical differences in the effectiveness of antidepressants vs placebo in depression. This was followed by a terse statement from the American Psychiatric Association (APA) countering the claims.
Then incoming President-elect of the APA Jeffrey Lieberman, MD, Columbia University, New York City, told Medscape Medical News at the time that that information was "misleading to people and potentially harmful to those who really suffer from depression."
"There has been considerable [news] in and out of the United States suggesting that SSRs are not effective. On the one hand, patients get these drugs from doctors, but on the other hand, they're reading the newspapers," said Dr Eriksson. "So we wanted to clarify these matters."…
The analysis included 2759 participants who completed trials in which paroxetine was compared with placebo. Of these, 938 patients received placebo; 421 received paroxetine and had no "early" AEs, defined as AEs that occur within the first 2 weeks of treatment; and 1399 received paroxetine and did have early AEs.
There were also 585 patients who completed trials comparing citalopram with placebo. Of these, 132 patients received placebo, 93 received citalopram and had no early AEs, and 360 received citalopram and did have early AEs.
Results showed that in the active-treatment groups, with and without AEs, there were significantly greater reductions in scores on the HDRS depressed mood measure at 6 weeks compared with the placebo groups.
"The finding that both paroxetine and citalopram are clearly superior to placebo...when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects," write the investigators.
In addition, "our results indirectly support the notion that the two drugs under study do display genuine antidepressant effects caused by their pharmacodynamics properties."
The paroxetine-treated patients with early AEs did have a small yet significantly greater reduction in symptoms than those receiving the drug who did not have early AEs (effect size, 0.15; P = .008). There were no significant differences between the citalopram-treated patients with or without early AEs.
Commenting on the findings for Medscape Medical News, Dr Kirsch said that even if there is an effect from antidepressants, that effect is so small as to be clinically insignificant.
Dr Eriksson countered that perhaps Dr Kirsch investigated doses that are too low to be effective. He also noted that using the HDRS-17-sum "has been severely criticized. That measure has been shown to not be reliable," which is why they chose to focus just on the scale's depressed mood item. "And we did have an impressive, robust difference between active drug and placebo," he added.
Dr Kirsch went on to note that the new analysis "was interesting" but questioned the investigators' not using the full HDRS scale.
"To use just one item is unusual," he said. But more important was that the difference "of about half a point between placebo and the active drugs is so tiny as to have no clinical meaning. Doctors evaluating a patient would see no real change at all."
The question comes down to this: At what extent is a clinically meaningful difference "really due to the drug or to patients realizing they're receiving the active drug rather than the placebo, hence the placebo effect?" said Dr Kirsch. "They found evidence that that may be partially the case with one of the two drugs assessed," he added.
"However, from their findings, at least part of this tiny difference between drug and placebo may actually be due to something not related to side effects. And that may very well be, but we don't have enough data right now to really know for sure," Dr Kirsch said.
"The bottom line is, what is the cause of this miniscule, clinically meaningless difference? What one ought to do is look at side-effect profile and health risks and then use the safest of the alternative treatments available. And that's certainly not an SSRI."