The harmful misconception that antidepressants are ‘no better than placebo’ is a popular one, making the rounds year after year.  Equivocations like this are not only false but a gross misrepresentation of the evidence.  A new meta-analysis published in the Lancet will hopefully take this falsehood behind the barn and put it down for good. Antidepressants are incontrovertibly effective when prescribed appropriately to patients suffering from moderate to severe major depressive disorder.  This is not always the case however, and herein lies the problem. Patients who are mildly depressed or simply unhappy are inappropriately prescribed, yet these conditions do not meet the prescribing criteria and have no strong evidence of effectivity.  Modern antidepressants are not designed for this use: they are not ‘happy pills’.

This notion of ‘no better than placebo’ likely came about from a widely critiqued meta-analysis published in 1998 that claimed 75% of antidepressants’ effects were due to placebo and suggested the remaining 25% were likely placebo as well.  Further, in 2008 a New England Journal of Medicine review found a strong publication bias in the reporting of antidepressant effects.  The published studies showed a rate of positive results of 94%, but this figure fell to 51% after including the unpublished trials as well.

They stated: “Selective reporting deprives researchers of the accurate data they need to estimate effect size realistically. Inflated effect sizes lead to underestimates of the sample size required to achieve statistical significance. Underpowered studies — and selectively reported studies in general — waste resources and the contributions of investigators and study participants, and they hinder the advancement of medical knowledge. By altering the apparent risk–benefit ratio of drugs, selective publication can lead doctors to make inappropriate prescribing decisions that may not be in the best interest of their patients and, thus, the public health.”

A later analysis of this study showed that the results were misunderstood or misrepresented.  Every single drug analyzed was in fact better than placebo, but not to the degree that published literature would suggest.  So even though the effect size may be up for debate, drug efficacy is not.

A new 2018 study reviewed data from 522 randomized double-blind controlled experiments which tested 21 antidepressant drugs.  They attempted to include as much unpublished data as possible.  This dataset consisted of more that 115,000 patients who were properly diagnosed with major depression and treated with antidepressants for at least 8 weeks.  The criteria that this study established for effectivity of the drug was a 50% or greater reduction of symptoms based on physician evaluations, which are far more accurate than self-report information.  These modern techniques found that every one of the 21 antidepressants tested was significantly more effective than placebo.

The diagram on the left shows the results from this study.  Each of the blue boxes indicate the odds ratio, showing how much more effective the drug was than the placebo. Amitriptyline performed the best, being rated as 2.13 times more likely to reduce symptoms than the placebo.  The black lines indicate confidence bars, meaning that the study showed 95% certainty that the results lie within the range of the black line.  Importantly, none of the confidence lines cross the ‘1’ mark.  This means that even if the estimate is somewhat inaccurate, the drug is still more effective than placebo.

Though every drug analyzed worked above placebo, it is also important to note the wide disparity between various drugs.  For example, Fluoxetine (Prozac), was among the least effective, even though it is still widely prescribed.  Another interesting aspect of the study is the patient dropout rate.  The rate of patients who do not complete a study is a good indication of a drug’s side effects.  Clomipramine had the highest rate of patient dropout.  This information is all publicly available and will help physicians make the best decisions in the future.

This new study is very comprehensive, rigorous, and impressive.  The evidentiary support for the efficaciousness of modern antidepressant medication is simply overwhelming.  Going forward, this study should arm responsible healthcare providers against denialists’ attacks on science.  As a scientific discipline, there is ongoing room to improve our knowledge about dosing, effect size, and other prescription guidelines, but the data is conclusive that all these drugs do work significantly better than placebo.  Depression is a serious illness that takes the lives of thousands.  Antidepressants save lives, relieve suffering, and provide critical quality of care for an embattled patient population.  It is vital to defend their efficacy and use when the science so clearly backs them up.




“Antidepressants and the Placebo Effect.” Zeitschrift Für Psychologie,

Turner, Erick H., and Annette M. Matthews. “Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy.” New England Journal of Medicine, vol. 358, no. 3, 2008, pp. 252–260., doi:10.1056/nejmsa065779.

Cipriani, Andrea, and Toshi A Furukawa. “Comparative Efficacy and Acceptability of 21 Antidepressant Drugs for the Acute Treatment of Adults with Major Depressive Disorder: a Systematic Review and Network Meta-Analysis.” The Lancet, 2018, doi:10.1016/s0140-6736(17)32802-7.

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