Ketamine vs. Esketamine: Depression Treatment in Germany

Introduction to Ketamine and Esketamine for Depression

Since 2021, esketamine nasal spray (EN) has been approved in Germany for treating treatment-resistant depression (TRD). This approval followed positive results from clinical trials on subnarcotic ketamine infusions (SKI), which had been used off-label for TRD. Despite their common use, direct comparative studies between SKI and EN are lacking, although evidence suggests they are equivalent in effectiveness, safety, and tolerability.

Mechanism and Context of Treatment Modalities

Both SKI and EN target the NMDA receptor, a novel mechanism compared to traditional antidepressants. SKI is administered intravenously, typically at a dose of 0.5 mg/kg over 40-45 minutes, while EN is given as a nasal spray, with doses ranging from 56 to 84 mg. The narrative review analyzed data from nine meta-analyses and seven real-world studies, finding circumstantial evidence for their equivalence in acute treatment efficacy.

Policy and Research Implications

In Germany, the cost of inpatient treatment with SKI is significantly lower, being 2.3 to 3.8 times cheaper than EN. The review suggests that German healthcare guidelines should consider including SKI as an alternative to EN, as is already the case in the USA and Canada. This could lead to significant cost savings and broader accessibility for patients. The review also calls for health insurance companies to cover SKI costs and for the Joint Federal Committee (GB-A) to evaluate its off-label use.

Risks and Unknowns

While the review presents a compelling case for SKI, it acknowledges the lack of long-term safety data for serial SKI treatments. In contrast, EN has been used safely in serial treatments for over five years. The confidence in the equivalence of SKI and EN is currently rated as low to moderate, according to the GRADE system. A direct comparative clinical study, expected to conclude by 2030, may provide more definitive answers.

Future Directions

The narrative review emphasizes the need for updated clinical guidelines that reflect the cost-effectiveness of SKI. It also highlights the importance of ongoing research to establish the long-term safety and efficacy of SKI. As the field evolves, stakeholders in Germany and beyond will need to balance economic considerations with patient safety and treatment efficacy.