Placebo effects are real, powerful, and deeply human, as I've discussed in my previous article. But a thorny question remains: How can we tell whether a depression treatment is producing genuine therapeutic change, or whether improvement comes entirely from belief?

To understand the challenge, imagine the following scenario.

Suppose I launch a new pharmaceutical company and announce a revolutionary antidepressant called "Placebin." It’s powerful, safe, and nearly free of side effects. To prove it, we will give Placebin to one million depressed Americans—free of charge.

Weeks later, 350,000 people report dramatic improvement from the amazing new drug. They flood the talk shows with testimonials. There are dramatic mood improvements and no side effects at all. Friends and family join the chorus. The headlines write themselves.

There’s just one catch: Placebin is a completely inert pill.

Was their “recovery” real? Yes, it was. But the highly touted “Placebin” had nothing to do with it. So how do we know whether any antidepressant—or supplement, or therapy—is doing something real?

For decades, researchers assumed the only way to study placebo effects was through randomized controlled trials, dividing patients into drug and placebo groups. While valuable, this approach has serious limitations:

Here’s an example. When our team sought to evaluate a digital mental health app, we were stunned to learn that a modest controlled outcome study comparing our app to any popular antidepressant could cost $30–100 million, or more. For a small startup, this was beyond impossible—so we took a different path.

Using real-world data from 290 beta testers for our........

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