“I'd like to increase your dose of Zoloft to 100 mg.”

“But why? I’ve been taking it for a month and I still feel terrible.”

“Because many of my patients do better on the higher dose.”

That clinical wisdom just took a hit...or did it?

A new study (Pérez et al., 2025, The Lancet Psychiatry) randomized 257 patients with SSRI-resistant depression into five groups. One of those groups received dose optimization—upping the SSRI to the max tolerable level.

It was the least effective strategy.

In fact, the authors didn’t hedge:

“Patients with MDD and insufficient response to SSRIs would benefit from any other second-line strategy aside from dose optimisation.”

But here’s the catch:

The study wasn’t blinded.

Patients knew if they were “just getting more of the same.”

Raj Mago, in his website Simple and Practical, put it plainly:

“I wonder how these patients must have felt when they found out they had been randomized to stay on the same antidepressant… If I put myself in their shoes, I don’t think this knowledge would make improvement in my depression more likely.”

It’s a reminder:

Study results aren’t gospel. Methodology matters.

And when a finding either threatens or confirms our biases, that’s when we need to read it most critically.

If this study's headlines tempted you to change your practice—pause and read the methods first.

Join the conversation on LinkedIn with Dr. Carlat