Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature

PLoS Medicine is an open-source, peer-reviewed journal that recently published an interesting article about the publication of advertising directed toward consumers to encourage them to “talk to their doctor” about a specific medication. In this case, the focus is on SSRI antidepressants.

While the article is a little dense to wade through, the relevant bits can be found in the article’s conclusion near the end. I found this interesting bit that I wanted to bring to your attention about the scientific backing for SSRI antidepressants. While many professionals are aware of the weak results for SSRIs (especially as compared to virtually every other antidepressant), many consumers aren’t. Nor are many aware that in some research, placebos (sugar pills) do nearly equally as well as SSRIs.

Reasoning backwards, from SSRI efficacy to presumed serotonin deficiency, is thus highly contested. The validity of this reasoning becomes even more unlikely when one considers recent studies that even call into question the very efficacy of the SSRIs. Irving Kirsch and colleagues, using the Freedom of Information Act, gained access to all clinical trials of antidepressants submitted to the Food and Drug Administration (FDA) by the pharmaceutical companies for medication approval. When the published and unpublished trials were pooled, the placebo duplicated about 80% of the antidepressant response [13]; 57% of these pharmaceutical company–funded trials failed to show a statistically significant difference between antidepressant and inert placebo [14]. A recent Cochrane review suggests that these results are inflated as compared to trials that use an active placebo [15]. This modest efficacy and extremely high rate of placebo response are not seen in the treatment of well-studied imbalances such as insulin deficiency, and casts doubt on the serotonin hypothesis.

Also problematic for the serotonin hypothesis is the growing body of research comparing SSRIs to interventions that do not target serotonin specifically. For instance, a Cochrane systematic review found no major difference in efficacy between SSRIs and tricyclic antidepressants [16]. In addition, in randomized controlled trials, buproprion [17] and reboxetine [18] were just as effective as the SSRIs in the treatment of depression, yet neither affects serotonin to any significant degree. St. John’s Wort [19] and placebo [20] have outperformed SSRIs in recent randomized controlled trials. Exercise was found to be as effective as the SSRI sertraline in a randomized controlled trial [21]. The research and development activities of pharmaceutical companies also illustrate a diminishing role for serotonergic intervention—Eli Lilly, the company that produced fluoxetine (Prozac), recently released duloxetine, an antidepressant designed to impact norepinephrine as well as serotonin. The evidence presented above thus seems incompatible with a specific serotonergic lesion in depression.

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    Last reviewed: By John M. Grohol, Psy.D. on 9 Nov 2005