Depression is a global challenge, affecting millions and often proving difficult to treat effectively. While traditional treatments provide relief for some, many are left searching for better options. Enter esketamine and IV ketamine – two innovative treatments offering rapid antidepressant effects. But which one is more effective in the real world?

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The results, presented at the recent ASCP annual meeting alongside luminaries like Gerard Sanacora, M.D., Ph.D., Balwinder Singh, M.D., Roger McIntyre, M.D., FRCPC, and Samuel Wilkinson, M.D., shed new light on this important question.

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The key finding? Response to IV ketamine is at least twice as fast as that of esketamine and of a slightly larger amplitude even when controlling for covariates. Of note, the median dose of IV ketamine at the end of 6 treatments was 0.85 mg/kg while patients received a maximum of 84 mg of esketamine per treatment, translating to only 25-42 mg given its bioavailability of 30-50% via intranasal administration. It is not clear if differences in dosing could explain the differences in effectiveness between treatments.

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Methods

To ensure robust conclusions, the study carefully selected patients who had received either IV ketamine or esketamine based on criteria including age, diagnosis, and availability of depressive symptom scores before and after treatment. This process yielded 7,003 IV ketamine and 541 esketamine patients.

Comparing the two treatments was challenging due to variations in patient responses over time and the influence of external factors in real-world settings. To address this, advanced statistical modeling techniques were used to estimate average and individual treatment response trajectories.

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Results

We estimated the amplitude, asymptote (plateau), shift (time until the response kicks in) and slope (speed at which the response develops once it is initiated).

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Quantitative comparison showed that the response to IV ketamine is at least twice as fast as to esketamine with a slightly greater magnitude of response and lower asymptote. These differences persisted even after controlling for differences in patient characteristics. Esketamine patients tended to have slightly higher baseline depressive symptoms, were more likely to have medicaid, and also tended to have more prior medication trials.

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Conclusion and Implications

In one of the largest real-world studies comparing these two breakthrough treatments, response to IV ketamine was at least twice as fast as that for esketamine. It is possible that dose plays a role in this finding. We look forward to the the head to head, multi-site randomized control trial of esketamine versus IV ketamine that is being launched by Dr Sam Wilkinson of Yale university with PCORI funding.

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