To assess the safety, tolerability, and efficacy of oral ketamine compared to intranasal esketamine and placebo in treatment-resistant depression (TRD).
Approach:
Study Design: Two studies were conducted: a phase 1 trial comparing oral ketamine to intranasal esketamine in healthy volunteers and a phase 2 RCT assessing oral ketamine in adults with TRD.
Key Findings:
The phase 2 trial indicated early significant reduction in depressive symptoms at days 4 and 7, but did not meet the primary efficacy endpoint at day 21.
Interpretation:
The inconclusive findings may relate to pharmacokinetics, including extensive first-pass metabolism and potentially low oral doses that may not achieve necessary plasma levels for therapeutic effects.
Limitations:
The mean improvement in MADRS scores may have masked true efficacy.
Conclusion:
Current clinical trial results have been disappointing, and the evidence from controlled trials is insufficient to support the efficacy of oral ketamine for TRD.
