Esketamine Combo Bests SSRIs for TRD in Head-to-Head Trial

Esketamine combined with a serotonin-norepinephrine reuptake inhibitor (SNRI) for treatment-resistant depression (TRD) was linked to significantly lower rates of several adverse outcomes than esketamine plus a selective serotonin reuptake inhibitor (SSRI), new research showed.

Prior research has suggested that esketamine combined with either antidepressant is effective for TRD. But whether an add-on SNRI would yield better results than an add-on SSRI was unclear due to a lack of head-to-head comparisons. 

The retrospective cohort study of more than 55,000 participants with TRD showed that adding an SNRI to esketamine nasal spray was associated with significantly lower rates of all-cause mortality, hospitalization, and depression relapse than add-on SSRI. 

However, esketamine plus an SSRI was linked to a lower incidence of suicide attempts. 

While both treatment combinations were linked with reduced outcomes, “notable differences exist between them,” study investigator Antonio Del Casale, MD, PhD, Sapienza University of Rome, Rome, Italy, and colleagues wrote. 

“These findings emphasize the critical role of selecting the appropriate antidepressant partner for esketamine and tailoring treatment to an individual patient profile,” they added.

The results were published online on April 2 in JAMA Psychiatry. 

Lower Relapse Rate

For the study, researchers assessed data collected in electronic medical records across 20 countries. They included 55,480 participants with TRD, half of whom were treated with esketamine plus an SNRI (58.6% women; mean age, 45.9 years) and the half treated with esketamine plus an SSRI (57.7% women; mean age, 46 years).

SNRIs used were desvenlafaxine, duloxetine, levomilnacipran, milnacipran, or venlafaxine. SSRIs used were citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone. 

Results showed that in the overall study population, relapse rates for depression (17.8%), all-cause mortality (7.2%), hospitalization (0.1%), and suicide attempts (0.4%) were low throughout the 5-year observation period.

However, the group receiving esketamine plus an SNRI vs add-on SSRI had a significantly lower relapse rate (14.8% vs 21.2%; risk ratio [RR], 1.43) and lower rates of all-cause mortality (5.3% vs 9.1%; RR, 1.72) and hospitalization (0.1% vs 0.2%; RR, 3.01; all P < .001)

Although low in both groups, incidence of nonfatal suicide attempts was slightly but significantly lower in the group receiving esketamine plus an SSRI (0.3% vs 0.5%, P = .04).

Further survival analysis showed a 91.4% 5-year survival probability for the esketamine plus SNRI group vs 86.9% for the esketamine plus SSRI group (P < .001).

“Across the study sample, esketamine combined with either an SSRI or an SNRI demonstrated consistently low risks across all outcomes,” the researchers wrote.

Still, there were differences, and the study showed that “choice of antidepressant combined with esketamine can significantly impact clinical outcomes in TRD,” they added.

The investigators reported no relevant financial relationships.