Spravato vs. IV Ketamine: How the Two Ketamine Treatments Compare

# Spravato vs. IV Ketamine: How the Two Ketamine Treatments Compare

If you've been reading about ketamine for depression, you've probably noticed there are two very different versions being discussed — and the distinction matters more than most articles let on.

Two drugs, two regulatory paths

Spravato (esketamine) is an FDA-approved nasal spray manufactured by Janssen (Johnson & Johnson). It was approved in 2019 specifically for treatment-resistant depression and, later, for major depressive disorder with suicidal ideation. Because it's FDA-approved, it has a defined treatment protocol and is sometimes covered by insurance.

IV ketamine is the older generic anesthetic being used off-label for depression. It's been around since the 1960s. Clinics administer it intravenously, typically over 40 minutes. It is not FDA-approved for depression — but the evidence supporting it is substantial and growing.

The chemistry difference

Ketamine is a racemic mixture — it contains two mirror-image molecules called R-ketamine and S-ketamine. Spravato contains only the S-ketamine (esketamine) form. IV ketamine contains both.

This matters because emerging research suggests the R-ketamine component may contribute meaningfully to the antidepressant effect. Some researchers believe the racemic mixture (both forms together) may actually be more effective than esketamine alone — though this is still being studied.

How treatment looks in practice

Spravato is administered in a certified healthcare setting under a program called REMS. You spray the medication into your nose, then sit in the clinic for at least two hours of monitoring. Treatment typically starts at twice weekly for four weeks, then moves to weekly, then every other week.

IV ketamine is administered through an IV line over about 40 minutes in a clinic setting. Most protocols involve six infusions over two to three weeks for the initial series, then maintenance infusions as needed — often monthly.

Both require you to arrange transportation home. Neither should be taken casually.

What the research shows

The evidence base for IV ketamine in depression is now extensive — hundreds of studies over more than two decades showing rapid antidepressant effects, often within hours. Response rates in treatment-resistant depression range from 50-70% in most studies.

Spravato's FDA approval was based on clinical trials showing statistically significant improvement in depression scores when added to an oral antidepressant. The effect sizes have been more modest than what's seen in many IV ketamine studies, though direct head-to-head comparisons are limited.

A notable 2023 study published in the New England Journal of Medicine directly compared IV ketamine to Spravato and found IV ketamine was non-inferior — and by some measures, superior.

Cost and insurance

This is where things get complicated.

Spravato, despite being FDA-approved, often costs $600-900 per session before insurance. Many insurance plans do cover it, but prior authorization requirements are strict, and approval often requires documented failure of multiple antidepressants.

IV ketamine typically costs $400-800 per infusion and is almost never covered by insurance since it's off-label. Some clinics offer package pricing for the initial six-infusion series.

The total cost over time depends on how often you need maintenance treatments — which varies significantly between individuals.

The access question

Spravato is only available through certified treatment centers enrolled in the REMS program. IV ketamine clinics have proliferated rapidly, with varying levels of medical oversight and expertise.

Neither treatment is something you should pursue without careful evaluation by a physician who understands your full psychiatric and medical history.

Why this matters for the future

The ketamine conversation is part of a larger shift in how we think about treatment-resistant mental health conditions. The fact that a decades-old anesthetic can produce rapid antidepressant effects in people who haven't responded to anything else has fundamentally changed our understanding of depression neurobiology.

Whether Spravato or IV ketamine (or the next generation of glutamate-modulating drugs) ultimately becomes the standard of care, the underlying science is pointing toward mechanisms we didn't fully appreciate even ten years ago.

This is an area worth watching — and one where the research is moving faster than most people realize.

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This article is for educational purposes. Dr. Kim does not currently offer ketamine or Spravato treatment but follows this research closely as part of staying current in psychiatric medicine. If you're interested in treatment options for depression, [start a conversation with us](/intake/mental-health).