Short-term ketamine interventions for depressive disorders: practical best-practice recommendations for psychiatrists using oral, subcutaneous, and nasal formulations

Objectives: Ketamine and esketamine are increasingly used for treatment-resistant depressive disorders, particularly when rapid symptom reduction is clinically desirable. Intranasal esketamine has a product-specific regulatory framework in several jurisdictions, whereas most racemic ketamine formulations remain off-label for psychiatric indications. This narrative review provides practical recommendations for psychiatrists considering short-term ketamine interventions in depressive disorders, with emphasis on oral solution, oral tablets, subcutaneous injection, and nasal spray formulations.

Methods: We conducted a narrative review and clinical-practice synthesis of PubMed/MEDLINE-indexed literature, open bibliographic sources, and regulatory documents, searched through 20 July 2026. Search concepts covered ketamine and esketamine, treatment-resistant major depressive disorder, intravenous, oral, subcutaneous, and intranasal administration, dosing, monitoring, treatment setting, substance-use risk, misuse/diversion, and short-term intervention. Evidence was prioritized by study design and regulatory status; practical recommendations were categorized according to whether they were label-supported, directly evidence-supported, or based mainly on expert-practice synthesis.

Results: Evidence is strongest for labeled intranasal esketamine and intravenous racemic ketamine. Among the non-IV approaches reviewed here, subcutaneous racemic ketamine has coherent randomized evidence for flexible-dose short-term treatment; oral ketamine has limited but supportive small-trial and systematic-review evidence, with newer prolonged-release tablets remaining formulation-specific and investigational; and compounded racemic intranasal ketamine has weaker, more heterogeneous evidence. For all off-label racemic formulations, optimal dosing, frequency, durability, long-term safety, misuse risk, and maintenance strategy remain incompletely established.

Conclusions: Short-term ketamine treatment should be protocolized, measurement-based, supervised, time-limited, and embedded in a broader treatment plan for depressive disorders. For off-label racemic ketamine, the best-supported non-IV short-term regimen is supervised subcutaneous dosing with response-guided titration. Oral ketamine may be considered when parenteral or regulated nasal options are inaccessible, but it requires cautious patient selection, controlled dispensing, and objective monitoring. Esketamine nasal spray should follow the approved product label where available, whereas compounded racemic nasal ketamine should be reserved for exceptional circumstances.