The Lancet recently published a new paper reporting on a large-meta-analysis of studies on antidepressants done by Cipriani et al., “Comparative efficacy and acceptability of 21 antidepressant drugs.” All 21 antidepressants reviewed in the study were found to be more effective than placebo. Various news agencies, referred to it as “a groundbreaking study;” or as confirming “that antidepressants are effective for major depressive disorder (MDD);” and, “New study: It’s not quackery—antidepressants work. Period.” But the excitement and conclusions noted here seem to have been overdone and a bit premature.

Let’s start with the articles quoted in the first paragraph. The author of an article for The Guardian thought the “groundbreaking” Lancet study showed antidepressants were effective; and “we should get on with taking and prescribing them.” The upshot for him was that the millions of people taking antidepressants (including him) “can continue to do so without feeling guilt, shame or doubt about the course of treatment.” Doctors should feel no compunction about prescribing these drugs. “It’s official: antidepressants work.”

An article for bigthink, “New study: It’s not quackery—antidepressants work. Period,” also thought the Cipriani et al. study was helping to put some of the debate about the effectiveness of antidepressants to bed. Again the reported result was that all antidepressants performed better than placebos. The bigthink author related that in order for a drug to be considered “effective, it had to reduce depression symptoms by at least 50 percent,” which would be an astounding discovery for even one antidepressant, let alone all 21. But that was no quite how the Cipriani et al. study authors defined drug efficacy for their study. The authors said efficacy was the “response rate measured by the total number of patients who had a reduction of ≥50% of the total score on a standardised observer-rating scale for depression,” not a 50% or greater reduction in depressive symptoms. Cipriani was then quoted as saying: “We were open to any result. This is why we can say this is the final answer to the controversy.”

The opening sentence of an article on the Medscape website, “Confirmed: Antidepressants Work for Major Depression,” said: “A large meta-analysis confirms that antidepressants are effective for major depressive disorder (MDD).” Here we find the correct description of efficacy in the study: “Results showed that each studied antidepressant was significantly more efficacious, defined as yielding a reduction of at least 50% in the total score of a standardized scale for depression, than placebo after 8 weeks.” Two additional quotations of Cipriani from a press release about the study are given, suggesting while antidepressants can be an effective tool, they shouldn’t necessarily be the first line of treatment. “Medications should always be considered alongside other options, such as psychological therapies, where these are available.”

Reflecting on these three articles, I thought the Guardian and bigthink articles weren’t as careful as they could have been in their rhetoric about the results of the Cipriani et al. study. Although the Medscape article was more nuanced, it also seemed to lead to the same conclusions as the Guardian article, namely: “The demonstration of the extent of antidepressant superiority over placebo reassures patients and health-care professionals of the efficacy of [this] treatment despite high placebo response rates.” But is this conclusion by the Medscape article accurate? In the discussion section of the Cipriani et al. study, the authors said: “We found that all antidepressants included in the meta-analysis were more efficacious than placebo in adults with major depressive disorder and the summary effect sizes were mostly modest.”  Further on was the following:

It should also be noted that some of the adverse effects of antidepressants occur over a prolonged period, meaning that positive results need to be taken with great caution, because the trials in this network meta-analysis were of short duration. The current report summarises evidence of differences between antidepressants when prescribed as an initial treatment. Given the modest effect sizes, non-response to antidepressants will occur. 

It does not seem the study conclusively found that antidepressants work for major depression. The authors even said in some individuals antidepressants won’t be effective. Now look at the following two assessments of the Cipriani et al. study from an individual (Neuroskeptic) and an organization (The Mental Elf) that I have found to be fair, nuanced and helpful in their assessments of research into psychiatric and medication-related issues.

The Mental Elf article does have a positive title: “Antidepressants can help adults with major depression” and an overall positive assessment, but there were some clear limitations noted as well. First, gleaning results from the study, it reported the most effective antidepressants studied were: agomelatine (Valdoxan, Melitor, Thymanax), amitriptyline (Elavil), escitalopram (Lexapro), mirtazapine (Remeron), paroxetine (Paxil), venlafaxine (Effexor) and vortioxetine (Brintellix). And it noted the least effective ones studied were: fluoxetine (Prozac), fluvoxamine (Luvox), reboxetine (Edronax) and trazodone (many different brand names). The most tolerable antidepressants were: agomelatine, citalopram (Celexa), escitalopram, fluoxetine, sertraline (Zoloft) and vortioxetine. And the least tolerable were: amitriptyline, clomipramine (Anafranil), duloxetine (Cymbalta), fluvoxamine (Luvox  or Faverin), reboxetine (Edronax and others), trazodone and venlafaxine.

The included data only covered a short time period—8-weeks of treatment. So the results may not apply to longer-term antidepressant use. “And some antidepressant side effects occur over a prolonged period, so positive results should be interpreted with caution.” Another concern the author noted was that seventy-eight percent of the trials included in the study were funded by pharmaceutical companies. While industry funding was not associated with substantial differences in response or dropout rates, non-industry funded trials were limited and many trials did not report or disclose their funding.

Another 73% of the included trials were rated as having a moderate risk of bias, with 9% rated as a high risk of bias and only 18% as having a low risk of bias. Significantly, the review pointed out the study did not address specific adverse events, withdrawal symptoms, or when antidepressants were used in combination with other non-drug treatments—information most patients would have found useful. Nevertheless, the Mental Elf reviewer thought the study struck a nice balance between “strong evidence that antidepressants work for adult depression” while “accepting the limitations and potential biases” in the study.

Neuroskeptic who wrote “About that New Antidepressant Study,” thought that while it was a nice piece of work, it told very little new information and had a number of limitations. He thought the media reaction to the paper was “frankly bananas.” He put the effectiveness ratings into perspective by pointing out the “mostly moderate” effect size was .30 on the Standardized Mean Difference (SMD) measure, where .2 was ‘small’ and .5 was ‘medium.’ “The thing is, ‘effective but only modestly’ has been the established view on antidepressants for at least 10 years.” He then cited a previous meta-analysis that found the overall effect size to be almost identical—.31! He then turned to the findings of Irving Kirsch’s research with antidepressants, saying:

Cipriani et al.’s estimate of the benefit of antidepressants is also very similar to the estimate found in the notorious Kirsch et al. (2008) “antidepressants don’t work” paper! Almost exactly a decade ago, Irving Kirsch et al. found the effect of antidepressants over placebo to be SMD=0.32, a finding which was, inaccurately, greeted by headlines such as “Anti-depressants ‘no better than dummy pills.”The very same newspapers are now heralding Cipriani et al. as the savior of antidepressants for finding a smaller effect…

The media hype has been “frankly bananas” about the Cipriani et al. study. More balanced reviews by Neuroskeptic and The Mental Elf thought it was “a nice piece of work” and “a nice balance” between the evidence that antidepressants work for adults with depression while accepting “the limitations and potential biases” in the data. The hype is claiming clear effectiveness for a measure that only shows modest effectiveness over the short-term of 8 weeks. Ironically, the trumpeted findings of Cipriani et al are actually lower than those of Irving Kisrch (.32), who pointed out that the SMD criterion suggested by NICE (National Institute for Health and Care Excellence) was .50. Kirsch et al. said: Thus, the mean change exhibited in trials provides a poor description of results.”

Be sure to read Part 2 of “The Lancet Story on Antidepressants” to see what anti-antidepressant voices have to say about the Cipriani et al. study. For more information on the antidepressant research by Irving Kirsch, see: “Dirty Little Secret” and “Do No Harm with Antidepressants.”