Trazodone Outperforms SSRIs? Depends Who’s Watching.

Trazodone was launched in 1981 with an ominous campaign

In trying to demonstrate trazodone’s superiority, this trial reveals something else

STUDY: Dudek D et al, Front. Pharmacol. 2026;17:1739359

STUDY TYPE: Non-randomized, open-label naturalistic study

FUNDING: Angelini Pharma Polska (Trazodone ER manufacturer)

Background

Serotonin reuptake inhibitors (SSRIs) are often credited with heralding the new antidepressant era in 1988, but trazodone got their first in 1981.

Trazodone has a few advantages over SSRIs:

• A better balance of positive-to-negative studies, including trials in hospitalized or severe depression
• Less apathy and sexual side effects
• Improves (rather than worsens) sleep quality

This industry-funded trial compares them. But before we get to the results, let’s look at their earlier match-ups in randomized trials of depression:

• 1988: Trazodone = fluoxetine (n=43), with better sleep outcomes
• 1989: Trazodone = fluoxetine (n=27) in geriatric depression
• 1990: Trazodone = fluoxetine on cognitive outcomes in depression
• 2005: Trazodone ER = paroxetine (n=108), with better sleep outcomes
• 2006: Trazodone ER = sertraline (n=122), with similar side effect rate

So far, looks like an even match. But this trial used a new technique that might favor trazodone: Industry-sponsored, unblinded raters. It also wasn’t randomized, allowing those investigators to select who took each med (though, in fairness, they gave trazodone to the more chronically ill patients).

The original trial was published in 2023, and the new paper is a re-analysis.

The Original Trial

The trial compared the two meds over 12 weeks in Poland in 160 adults with major depression. Non-randomized, open-label.

Approximately half were given trazodone ER (150–300 mg/day) and half an SSRI (sertraline, escitalopram, citalopram, or paroxetine, but not fluoxetine). The groups were similar but the trazodone group had a longer prior treatment history. .

By week 12, remission rates were substantially higher with trazodone ER across all three depression scales: 78% versus 48% on MADRS, 79% versus 52% on clinician-rated QIDS for depression, and 66% versus 43% on self-rated QIDS.

Trazodone also outperformed SSRIs on anxiety and insomnia, with the sleep advantage apparent as early as week 4. On anhedonia, trazodone trended positive but lost significance after adjusting for prior treatment history.

Dropout rates were identical at 16% in both groups.

The Re-Analysis

The re-analysis looked at before-and-after effect sizes for the various measures (Cohen’s d).

• Week 2: No difference
• Week 4: Trazodone surpassed SSRIs (effect size 2.13-2.16 on self- and clinician-rated scales, vs 1.30-1.39 for SSRIs)
• Week 12: Trazodone surpassed SSRIs (effect size 2.54 vs 1.81 on clinician-rated scale)

The pattern repeated across every secondary domain: Anhedonia, anxiety, and insomnia. SSRIs essentially stopped improving after week 4 on anxiety and week 8 on depression; trazodone XR kept going.

Limitations: Single-center, non-randomized, open-label study funded by the maker of trazodone ER (which can bias rating scales and patient selection). The trazodone group had more smokers and a longer psychiatric history at baseline (though this would actually predict poorer response).

What about the ER?

This trial used trazodone ER, a branded version that fell off the US market due to underuse in 2015 (as Oleptro). But I doubt that explains trazodone’s superiority here, as even the prolonged-released version equaled SSRIs in the 2005 and 2006 trials above.

Practice Implications

1. When the blind is lifted, the funding-bias reveals itself.
2. If trazodone was truly superior, we would have seen that in the randomized, blinded trials.
3. Still, the oft-repeated saying “Trazodone is a great sleep med, but a lousy antidepressant” is equally unfair.
4. Trazodone is underutilized for depression, and takes some skill to dose. Raising it slowly improves mood outcomes (minimizing peaks in its metabolite, mCPP). Giving it all at night reduces fatigue (and was done successfully in trials with instant release, but caution: orthostasis). Learn how to use it in our Carlat Psychiatry Report review.

— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report

What’s Your Take? Share in Comments

1. Have you used trazodone for depression? What have you seen?