IV Ketamine and Spravato for Treatment-Resistant Depression: What the Research Shows

By Steven Mee, MD · November 11, 2026

For many people, depression improves with the first or second medication they try. For others, it does not. If you have tried several antidepressants without enough relief, newer options such as ketamine and esketamine (Spravato) may be worth discussing with a psychiatrist. This article explains what they are, what the research shows, how they differ, and what treatment looks like at our Los Alamitos office.

What "treatment-resistant depression" means

Treatment-resistant depression (TRD) usually describes major depression that has not responded to at least two antidepressants, each taken at an adequate dose for an adequate time during the current episode. That is the definition used in the large trial that led to Spravato's approval (Popova et al., 2019).

TRD is common and is not a personal failing. It means the treatments tried so far were not the right fit, and that a different approach may help.

How ketamine differs from standard antidepressants

Most antidepressants act on serotonin, norepinephrine or dopamine and often take several weeks to work. Ketamine acts on a different system: it blocks the NMDA receptor, part of the brain's glutamate signaling.

That difference showed up early in research. In a 2006 placebo-controlled study at the National Institute of Mental Health, a single IV dose of ketamine improved depression scores in people with TRD within about two hours compared with placebo, and the difference lasted through the following week (Zarate et al., 2006). The study was small (18 participants), and the effect of one dose faded for most people. Later research has focused on repeated treatments within a structured plan.

Spravato (esketamine): FDA-approved, with built-in safeguards

Spravato is a nasal spray made from esketamine, one form of the ketamine molecule. According to its current FDA label (revised March 2026), it is approved for adults with:

• treatment-resistant depression, either on its own or with an oral antidepressant; and
• depressive symptoms in major depressive disorder with acute suicidal thoughts or behavior, together with an oral antidepressant.

The label also states that Spravato has not been shown to prevent suicide or reduce suicidal thoughts or behavior, and that it does not replace hospitalization when that is needed (FDA label).

In a phase 3 trial of 227 adults with TRD, people who started Spravato plus a new oral antidepressant had greater improvement in depression scores at four weeks than people who started a new antidepressant plus a placebo spray (Popova et al., 2019). The most common side effects were dissociation (feeling detached or unreal), nausea, vertigo, an altered sense of taste and dizziness. They generally began soon after a dose and resolved within about 1.5 hours.

Because of these effects, Spravato is available only through an FDA safety program called a REMS. It can be given only in a certified healthcare setting, where a clinician monitors you for at least two hours after each dose. You cannot drive until the next day, after a restful sleep, so you need a ride home (FDA label).

IV ketamine: off-label, with a growing evidence base

Ketamine was first brought into medical use as an anesthetic, and it is still very commonly used in anesthesia today. Using IV ketamine to treat depression is off-label, meaning the FDA has not approved it for that purpose. It is, however, informed by a large body of research. Physicians may prescribe medications off-label when published evidence and clinical judgment support it, and you should know when that is the case.

The evidence has grown. In a 2023 randomized trial published in the New England Journal of Medicine, 403 adults with TRD who had been referred for electroconvulsive therapy (ECT) were assigned to either ECT or IV ketamine twice weekly for three weeks. About 55% of the ketamine group and 41% of the ECT group responded, and ketamine was found to be noninferior to ECT (Anand et al., 2023). ECT was linked to a temporary drop in memory recall, while ketamine was linked to dissociation. The trial was open-label and limited to people without psychosis, so its results do not apply to everyone.

Expert groups advise that IV ketamine for mood disorders should follow careful screening, a clear treatment plan and monitoring during and after each infusion (Sanacora et al., 2017).

Who may not be a good fit

Ketamine-based treatment is not right for everyone. Spravato's label lists conditions in which it should not be used, including certain blood-vessel conditions such as aneurysms and a history of bleeding in the brain. A careful evaluation also looks at blood pressure, heart health, pregnancy, past psychosis and substance-use history. In some situations the safest choice is a different treatment.

What treatment looks like at our Los Alamitos office

Our Ketamine Augmented Treatment Program is designed to add to your existing care, not replace it. IV ketamine is our primary treatment, and we offer two types of program:

• Standard course for treatment-resistant depression. For adults who have only partly responded to oral medications or could not tolerate them: six sessions over two to three weeks, with one or two appointments with Dr. Mee to assess your response.
• Personalized programs. For other needs, depending on what brings you to us, such as augmenting psychotherapy, or as part of care for treatment-resistant OCD, trauma or PTSD. These plans are built individually, often with fewer sessions alongside ongoing therapy. These uses are off-label and the research is still developing, so we discuss the evidence, risks and alternatives with you openly.

Whichever program fits, the steps are similar:

1. Evaluation. Every patient starts with an evaluation. A virtual evaluation is available to adults anywhere in California. We review your history, current treatment and safety factors to see whether ketamine-based treatment is appropriate. As part of our signature approach, we may also assess psychological pain before treatment begins.
2. IV ketamine first. For most patients we recommend IV ketamine, given in a monitored clinical setting. As a certified Spravato treatment site, we also offer Spravato for patients who cannot receive or tolerate IV treatment.
3. A clear plan. Your course, whether the standard six sessions or a personalized program, is agreed in advance, with check-ins with Dr. Mee along the way.
4. Monitoring. A physician is on the premises and a registered nurse attends each session, with heart and vital-sign monitoring. You will need someone to drive you home.

We coordinate with your therapist, psychiatrist or primary care clinician. Individual results vary, and ketamine-based treatment works best as one part of a broader plan. For more on how we think about psychological pain and outcomes, see Measuring Psychological Pain to Direct Care Where It Is Needed.

Questions to ask any ketamine provider

• Which treatment is FDA-approved for my condition, and which would be off-label?
• Who screens me, and who is on site during treatment?
• How will you monitor me during and after each session?
• How many sessions do you plan, and how will we decide whether it is working?
• How will this fit with my current medications and therapy?

Talk with us

If you or someone you care for is living with depression that has not improved with standard treatment, contact us or email smee@asperahealth.com to ask about an evaluation. Clinicians can find referral information on our website.

If you are in crisis or thinking about suicide, call or text 988, or call 911.

This article is for general education and is not medical advice. Talk with a qualified clinician about your own situation.