CONCURRENT ORAL ANTIDEPRESSANT USE AND CLINICAL OUTCOMES FROM INTRAVENOUS KETAMINE OR INTRANASAL ESKETAMINE IN A REAL-WORLD SAMPLE

Background

Intravenous ketamine and intranasal esketamine produce rapid antidepressant effects in patients with treatment-resistant depression (TRD). In routine clinical practice, many patients continue oral antidepressants during ketamine/esketamine treatment; however, it remains unclear whether concurrent antidepressant use, as well as the specific class of antidepressant, influences clinical outcomes.

Objective

To examine the association between concurrent oral antidepressant class and clinical outcomes in a large real-world cohort of patients with TRD initiating treatment with intravenous (IV) ketamine or intranasal (IN) esketamine.

Methods

We conducted a retrospective observational study of patients treated with an acute course (6–8 sessions) of IV ketamine (0.5 mg/kg) or IN esketamine (56 or 84 mg) at the Yale Interventional Psychiatry Service between March 2015 and August 2023. The primary exposure was concurrent oral antidepressant use, divided by class—selective serotonin reuptake inhibitor (SSRI), serotonin–norepinephrine reuptake inhibitor (SNRI), other oral antidepressant, or no antidepressant. Outcomes included mean changes in Montgomery– Åsberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptomatology (QIDS) scores, as well as response (≥50% MADRS reduction) and remission (MADRS ≤10). Linear mixed-effects models assessed symptom change over time, and logistic regression models assessed odds of response or remission, adjusting for demographic and clinical covariates and treatment modality (IV ketamine vs. IN esketamine).

Results

The sample included 332 patients (149 IV ketamine; 183 IN esketamine). At treatment initiation, 84 patients were taking an SSRI, 98 an SNRI, 77 another oral antidepressant, and 73 no antidepressant. Depressive symptoms improved significantly over time across all groups (overall adjusted mean change in MADRS -11.7, 95% confidence interval -14.0 to -9.4, p < 0.01); however, adjusted changes in MADRS and QIDS scores did not differ significantly by antidepressant class relative to no antidepressant (p > 0.1 for all comparisons). Similarly, adjusted odds of response and remission were comparable across antidepressant classes (all p > 0.1).

Conclusions

In this real-world cohort, concurrent oral antidepressant use, including antidepressant class, was not associated with differential short-term clinical outcomes following IV ketamine or IN esketamine treatment. These findings suggest that oral antidepressant selection during ketamine/esketamine therapy may be guided by tolerability and prior treatment response rather than expectations of differential efficacy. Prospective, longer-term studies are needed to evaluate potential effects of concurrent antidepressant use on the durability of response to ketamine/esketamine.