LAUSR

In 1952, Life magazine, a widely-read general interest U.S. weekly periodical, published dazzling photos of patients institutionalized for tuberculosis literally dancing and singing in the halls during a clinical trial of a new drug, iproniazid. What proved startling was not, as first seemed obvious, that people were happy at finally finding relief from a then incurable, contagious disease, but that the apparent euphoria—or mania—extended to individuals whose lung condition was not responding to the new intervention. In these patients the medication was not affecting pulmonary function, but brain function, through what was later determined to be inhibition of monoamine oxidase (MAO). By the end of the decade, MAO inhibitors, joined by the seemingly less toxic tricyclic antidepressants (TCAs), had become the mainstay of pharmacotherapy of depression. In the subsequent half-century, other classes of drugs, including antibiotics and cancer chemotherapy, have advanced through multiple generations, each accompanied by drugs which were generally stronger and safer, and offered more options for personalizing treatment for the individual. After some fits and starts, antidepressants too moved on to a second generation, largely represented by the selective serotonin reuptake inhibitors (SSRIs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs). But the numbered generations stopped at two, as the marketplace filled with “me-too” (and active metabolite) variations on the theme, and basic questions about antidepressant effectiveness were raised as the literature began to reflect disappointing remission rates and rising placebo response rates in clinical trials. So it is that we have now arrived at a point where the conclusion of a recent Lancet network meta-analysis—involving hundreds of controlled clinical trials with over 100,000 subjects—that “All antidepressants were more efficacious than placebo in adults with major depressive disorder” is not only not startling, but is newsworthy [1]. The international authors of that report, led by Cipriani and colleagues in the UK, have in fact done a masterful job of analyzing and synthesizing tens of thousands of data sets, published and nonpublic, industry-sponsored and independent, to further our understanding of the relative roles of 21 antidepressants and placebo in the acute treatment of their primary indication, in their words “the most comprehensive analysis of the evidence base ever undertaken.” [2].