Ketamine and Spravato both work on the glutamate system, the brain's most abundant excitatory neurotransmitter, rather than the serotonin or norepinephrine pathways standard antidepressants target. That shared mechanism is why both can help patients who haven't responded to SSRIs or SNRIs. But they're not interchangeable, and the differences matter for which one your insurance covers and what your treatment day actually looks like.
What Spravato Is
Spravato® (esketamine) is the first and only FDA-approved nasal spray specifically for adults with treatment-resistant depression, approved since 2019 for patients who've tried 2 or more oral antidepressants without success. It's delivered as a self-administered nasal spray under direct clinical supervision at a REMS-certified site like Health 210 Psychiatry. Because it's FDA-approved for this specific indication, it has defined insurance coverage criteria, including Medicare Part D coverage when criteria are met.
What IV Ketamine Is
IV and IM ketamine use racemic ketamine, an FDA-approved anesthetic, administered intravenously or intramuscularly at a sub-anesthetic dose. Because ketamine's use for depression is off-label rather than a dedicated FDA-approved indication, it's often not covered by insurance for psychiatric use, and treatment is typically self-pay. What you gain in exchange is more flexibility in dosing and route (IV, IM, or oral), and research shows it's effective for approximately 70% of patients with treatment-resistant depression.
The Insurance Difference Is the Real Difference
Clinically, both treatments produce rapid antidepressant effects and both require a 2-hour post-dose observation period since you can't drive yourself home afterward. The practical difference most patients actually weigh is coverage: Spravato's FDA approval for this specific use gives it defined coverage criteria across commercial insurance and Medicare Part D, while ketamine for depression is more often an out-of-pocket decision. If cost is the deciding factor, that's usually the first thing to check with your insurer, not the clinical evidence.
Which One Is Right for You?
If insurance coverage is a priority and you meet the 2-or-more-failed-antidepressants criteria, Spravato is often the more accessible starting point. If you want more flexibility in dosing or route, or you're comfortable with a self-pay plan, IV ketamine may be worth discussing, particularly for the most severe or urgent cases. Neither is a first-line treatment; both are considered after standard antidepressants and therapy haven't provided enough relief. Your psychiatrist can walk through your specific treatment history and insurance situation to help you decide.
Learn more about our Spravato program or our ketamine therapy program, or reach out and we'll help you determine which fits your situation.
