Racemic Ketamine Matches Esketamine in Depressive Symptom Reduction for TRD
Key Clinical Summary:
- Racemic ketamine was noninferior to intranasal esketamine for reducing depressive symptoms in adults with treatment-resistant depression (TRD) over 4 weeks.
- Remission rates favored esketamine, with 38.7% achieving remission compared with 15.6% with racemic ketamine.
- Safety profiles were similar, although racemic ketamine was associated with slightly more transient blood pressure elevations.
According to a retrospective observational study published in the Journal of Affective Disorders, racemic ketamine was noninferior to esketamine for reducing depressive symptoms in adult patients with treatment-resistant depression (TRD) over a 4-week induction period.
Study Design and Findings
Conducted at the Centre for Affective Disorders, University Psychiatric Clinics (UPK) Basel in Switzerland, the researchers used the target trial framework to emulate a pragmatic non-inferiority randomized control trial comparing intranasal racemic ketamine and intranasal esketamine for TRD. Participants were outpatients aged 18 years or older with TRD and received either off-label racemic ketamine (n=45) or esketamine (n=31) in 8 sessions over a 4-week induction phase.
The researchers evaluated change in Montgomery–Åsberg Depression Rating Scale (MADRS) scores as the primary outcome. Remission (MADRS ≤12) was also assessed as a secondary outcome.
Participants in both groups saw significant improvement in depressive symptoms, with a mean MADRS reduction of −9.3 in the esketamine group and −10.0 in the racemic ketamine group (p = 0.41). However, remission rates were significantly higher in the esketamine group (38.7%) than in the racemic ketamine group (15.6%, OR 0.29, 95% CI 0.10–0.86), failing the noninferiority criterion. Bayesian analysis further indicated a 98.6% posterior probability of esketamine’s superiority.
Safety profiles were similar across both treatments, although slightly more transient blood pressure elevations were observed in the ketamine group.
Clinical Implications
For clinicians working with patients with TRD, these findings suggest that ketamine may provide comparable short-term symptom relief to esketamine during induction treatment. In settings where cost, insurance coverage, or infrastructure requirements may limit access to esketamine, a potential cost-effective alternative could significantly expand access to rapid-acting antidepressant therapy.
However, the cause of the observed discrepancy in remission rates between the 2 agents remains unclear and requires further investigation. Additional comparison beyond the induction phase of treatment is also needed.
Expert Commentary
“Given its substantially lower cost and greater accessibility, racemic ketamine may represent a valuable treatment option for a broader population of individuals with TRD, particularly in resource-limited settings,” wrote Jan Sarlon, MD, University Psychiatric Clinics Basel, and study coauthors.
The researchers also acknowledged several limitations of the study, including its observational, non-randomized nature, variability in participant concomitant psychotropic medication use, and the potential impact of expectation effects in an open-label setting.
“Taken together, these factors render the current analysis interim; ongoing data collection will enable a more robust evaluation, and replication in independent, diverse samples is needed to establish generalizability and validity,” they concluded.