Do Antidepressants Work?

The CBS newsmagazine 60 Minutes offered a provocative segment featuring a Harvard scientist (Dr. Irving Kirsch) making the claim that medications commonly used to treat depression are effective, but for many, it’s not the active ingredient that’s making people feel better, but a placebo effect. Here’s a link to the 60 Minutes segment along with a link to the transcript of the segment…unfortunately, I couldn’t figure out a way to embed the CBS media player on WordPress:

The controversy as to whether antidepressants are effective has been simmering for many years in the psychiatric community, especially when it comes to using medication to treat depression in kids.

The vast majority of clinical trials of antidepressant medication for the treatment of depression in children and teens have failed to demonstrate a statistically significant difference between the response to medication vs. placebo pills. We used to think that kids responded differently to antidepressants than adults because of developmental differences in the activity of neurotransmitters, such as serotonin. It turns out there’s little difference between the response of these medications in adults to what we see in kids and teens. To explore this further, allow me to introduce you to the concept of effect size.

When a pharmaceutical company submits a drug to the FDA for marketing approval, they’re required to demonstrate in two separate clinical trials that the drug is better than nothing (placebo). As a clinician, I want to know how much better than nothing the drug is for the condition I’m seeking to treat. That’s where effect size comes in.

Zoloft_bottlesEffect size is a measure of the magnitude of the difference between the change from baseline seen with an active treatment compared to the change from baseline seen with placebo. Without going into the formula for calculating effect size (beyond the scope of this post), we usually end up with a ratio ranging from zero to one. When an effect size is below 0.20, the benefit of the treatment to an outside observer would be essentially imperceptible. An effect size of 0.50 suggests a moderate effect. Effect sizes of 0.80 and above suggest a robust effect. For the sake of comparison, here are some examples of effect sizes of treatments for ADHD:

Diets restricting artificial dyes and preservatives: 0.19

Omega-3 fatty acid supplementation: 0.36

Atomoxetine (Strattera): 0.60

Methylphenidate-based stimulants (Concerta, Focalin): 0.80

Amphetamine-based stimulants (Adderall, Adderall XR, Vyvanse): 0.93

Check out the illustration below…This data is taken from an independent review commissioned by the FDA of all the placebo-controlled trials of serotonin reuptake inhibitors (SSRIs) and other second-generation antidepressants in children and teens. SSRIs are the most commonly used antidepressants…Prozac, Zoloft, Celexa, Lexapro, Paxil and Luvox are SSRIs:

It turns out that the antidepressants are reasonably effective anti-anxiety treatments in children and teens. SSRIs are moderately effective for Obsessive-Compulsive Disorder. The effect size of SSRIs for treating depression is relatively small.

Another way of looking at this issue is by considering another statistical concept, the number needed to treat (NNT). The NNT represents the average number of patients one would need to treat to be assured a positive response was due to the effect of medication as opposed to placebo. The NNT for antidepressants in kids when used to treat depression is 10. For OCD, the NNT is 6. For other anxiety disorders, the NNT is 3.

Here’s the meta-analysis of the research literature on antidepressants in adults that Dr. Kirsch made reference to in the 60 Minutes segment, authored by Dr. John Ioannidis. Quoting from the paper:

The meta-analysts found 74 eligible FDA-registered trials with 12,564 patients. Among them, a third (n = 26 trials [31%] with 3449 patients) had remained unpublished. The FDA had determined that half of the registered trials (38/74) had found statistically significant benefits for the antidepressant (“positive” trials). All but one of these trials had been published in journals. Conversely, of the other half trials (36/74) that were deemed to be “negative” by the FDA, one in three were published as “negative” results; another 11 trials were published, but the results were presented in such a way so as to seem “positive” and 22 “negative” trials were silenced and never appeared in the literature.

The meta-analysts studied the estimated effectiveness of these drugs when data were combined from the FDA records and when data were combined from the published literature. For all drugs, the published literature inflated the effect sizes. The inflation varied from 11% to 69% and it was 32% on average. The FDA data would suggest that these agents had small, modest benefits (standardized effect size [ES] = 0.31 on average). Conversely, for 4 of the 12 agents, if one were to perform unawares only a meta-analysis of the published data, the summary result would suggest clinically important effectiveness (ES>0.5). This was not true for any agent based on more complete FDA data.

Here are a couple of thoughts to consider…

The professional community, parents and families hold assumptions about the effectiveness of psychotropic medication, especially medication for depression, that are unrealistic based upon our understanding of the research literature.

It’s very possible (I’d argue it’s very likely) that adults and children who respond positively to antidepressants do so not because they’re experiencing a placebo response, but because we’re treating anxiety symptoms that frequently predispose, precipitate and perpetuate feelings of depression.

Updated June 7, 2016



About Dr. G

This entry was posted in Controversies, Depression, Mental Health and tagged , , , , , , , , , , , . Bookmark the permalink.

3 Responses to Do Antidepressants Work?


    Steve, thank you SO MUCH for clarifying this in a way that they layman can understand!


  2. Mark says:

    Interesting. I am on 75mg of effexor, I believe a min dose. All I can say is that it is powerful stuff. Miss a day and boy the Virtigo.


  3. The medications I take to help with my depression are not a cure all but they help me get to a point where I want to do the other things that I know will also help me as I live my life with the depsression.


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