REAL-WORLD EVIDENCE OF CLINICAL TREATMENT RESPONSE FOLLOWING INTRAVENOUS RACEMIC KETAMINE VERSUS INTRANASAL ESKETAMINE IN ADULTS WITH MAJOR DEPRESSIVE DISORDER

Background

Ketamine is a powerful and rapid-acting antidepressant, though intravenous (IV) racemic ketamine is not currently FDA-approved for any psychiatric condition. In contrast, the S-enantiomer of ketamine, esketamine, was approved by the FDA in 2019 as an adjunctive therapy for treatment-resistant depression. While pharmacologically related, it is not clear if there are significant clinical differences in treatment response or remission between IV ketamine and intranasal esketamine. Here we present real-world comparisons between these two treatment modalities.

Methods

We analyzed de-identified electronic health record data from a U.S. healthcare technology platform serving over 800 community psychiatric clinics to conduct a retrospective comparative effectiveness analysis of IV ketamine and intranasal esketamine. Patients with a clinical diagnosis of Major Depressive Disorder (MDD) who received IV racemic ketamine or intranasal esketamine were identified (those exposed to both were excluded). Cohorts were coarse-matched on age, gender, median income of the zip code of patient address, and baseline Patient Health Questionnaire-9 (PHQ-9) score.

Results

The PHQ-9 was used as a measure of depression severity. Logistic regression with robust standard errors estimated odds of remission (defined as PHQ-9 ≤ 4) and response (≥ 50% PHQ-9 reduction from baseline) within 90 days. Data were analyzed on a total matched sample of N=3,510 patients, with a mean age of 43.3 (SD=13.9). Most (61%) were women, and a majority of the sample identified as White (64%). The median household income (based on patient zip code) was $99,560. The mean baseline PHQ-9 was 17.9 (SD=5.2). Ketamine-treated patients achieved significantly higher remission rates than esketaminetreated patients (34.4% vs. 25.9%; odds ratio: 1.50, 95% CI: 1.30–1.73, p < 0.001; Number needed to treat = 12). Response rates also favored ketamine (63.1% vs. 58.3%; odds ratio: 1.22, 95% CI: 1.07–1.40, p = 0.004; Number needed to treat = 21).

Conclusions

In this large, longitudinal real-world cohort of adults with MDD, both treatments were associated with symptom improvement. However, IV racemic ketamine demonstrated higher remission and response rates compared with intranasal esketamine over 90 days, indicating that the route of administration and pharmacologic composition may meaningfully influence clinical outcomes. The main weakness of this analysis is that treatment assignments were not randomized, hence unmeasured confounding variables may contribute to differences in outcomes. These findings support further prospective investigation comparing the two treatment modalities.