What is the most effective route of administration for ketamine in treating depression?

From the Guidelines

For depression, intravenous (IV) ketamine is generally considered the most effective route of administration. The standard protocol involves 0.5 mg/kg administered over 40 minutes, typically given 2-3 times per week for 2-3 weeks, followed by maintenance treatments as needed 1.

Key Points to Consider

• Intranasal esketamine (Spravato) is FDA-approved and more accessible but may be slightly less effective than IV ketamine 1.
• It's administered at 56-84 mg twice weekly for 4 weeks, then weekly for 4 weeks, and then weekly or biweekly for maintenance.
• Oral and sublingual ketamine are more convenient but have lower bioavailability (around 20-30%) and may require higher doses (0.5-1.0 mg/kg) 1.
• Intramuscular ketamine offers good bioavailability but has a more rapid onset and shorter duration than IV.
• The best route depends on individual factors including treatment access, cost considerations, and patient preference.
• IV ketamine works most effectively because it provides 100% bioavailability and allows precise control of blood levels, which is important for targeting NMDA receptors and triggering neuroplasticity mechanisms that help alleviate depression symptoms 1.

Important Considerations

• Ketamine lacks long-term efficacy and safety trials in MDD, and the bulk of the evidence on short-term (7-day) efficacy is from studies in patients who have previously not responded to adequate trials of antidepressants 1.
• Although there is evidence to support longer-term maintenance use of esketamine, it too has been primarily studied in patients who have previously not responded to trials of antidepressants 1.

From the Research

Ketamine Routes for Depression

• The most commonly employed route of administration for ketamine is intravenous 2, but other routes such as oral, sublingual, transmucosal, intranasal, intramuscular, and subcutaneous have also been described as safe and effective 2.
• Intranasal esketamine has shown a comparable antidepressant effect to intravenous ketamine and has been granted a "breakthrough therapy" designation by the US FDA 3.
• A study found that a single rapid 1-minute injection of ketamine 0.5 mg/kg via the intravenous route can be well tolerated and is efficacious in rapidly reducing depression symptoms and suicidal thoughts in outpatients with treatment-resistant depression 4.
• Subcutaneous, intranasal, and oral ketamine may warrant further study due to their potential for clinical practicability 2.
• The choice of route may depend on individual patient needs and the clinical setting, with intravenous ketamine often used in controlled medical settings and intranasal esketamine potentially offering an improved tolerability profile 3, 5.

Comparison of Routes

• A narrative review of ketamine for depression found that the effect of ketamine lasts for 1-2 weeks after infusion, but a longer-term effect is little reported 5.
• A study of ketamine/esketamine in bipolar depression found that intravenous ketamine and intranasal esketamine were effective in reducing depression severity, with 39% of patients achieving clinical response and 13.2% achieving remission 6.
• The safety and efficacy of different routes of administration, including intranasal esketamine, are being further studied, with ongoing research aiming to explore efficacy and safety issues of ketamine in depression 3, 5, 6.