[Intravenous Subnarcotic Ketamine Infusions for Treatment-Resistant Depression: Historical Development, Comparison with Esketamine Nasalspray, and Prospects].

Introduction: Esketamine nasal spray (EN) has been approved in Germany since 2021 for the treatment of treatment-resistant depression (TRD). Historically, the development of EN resulted from the positive results of randomized clinical trials on the off-label use of subnarcotic ketamine infusions (SKI) for TRD. How effective, tolerable, and safe is off-label SKI compared to EN?

Methods: Narrativ review. Selective literature search in PubMed for clinical studies comparing SKI and EN for TRD. International guidelines for depression and the cost-effectiveness of SKI and EN in inpatient treatment were also considered.

Results: Randomized direct comparative studies between EN and SKI are currently lacking. There is solid circumstantial evidence for the equivalence of acute treatment of TRD with SKI (usually 0.5 mg/kg body weight intravenously over 40-45 minutes) or EN (usually 56 or 84 mg per dose) in terms of effectiveness, safety, and tolerability: 9 meta-analyses (2 network meta-analyses) and 7 real-world studies (1 prospective, 6 retrospective comparative studies). SKI and subanesthetic esketamine infusions were also equivalent. A similar picture is emerging for serial treatment. Favorable tolerability and safety data have been available for EN for over 5 years (for serial SKI no such long-term observations). The USA and Canada have included off-label SKI as an alternative to approved EN in their guidelines for add-on treatment of TRD. For the German healthcare system, inpatient add-on treatment with SKI is about 2.3 to 3.8 times cheaper than with EN. Discussion and

Conclusion: Based on the above evidence, we estimate that there is currently low to moderate confidence according to GRADE for assuming the equivalence in effectiveness, tolerability, and safety of add-on treatment of TRD with SKI or EN. A more accurate assessment will be possible in 2030 at the earliest, when the results of an ongoing direct comparative clinical study are available. When updating the guidelines, we recommend checking whether the off-label add-on SKI can be provisionally placed at the same level as the add-on EN in the TRD treatment algorithm, as is the case in the USA and Canada. We hereby also encourage (i) health insurance companies to cover the costs of add-on SKI and (ii) the German authorities to review the off-label prescribability of SKI for TRD by the Joint Federal Committee (GB-A).