If you've been researching treatment options for depression that hasn't responded to traditional medication, you've probably come across two names: ketamine and Spravato. They sound like they should be the same thing, and in a sense, they're related. Both are based on the same molecule. Both target the brain's glutamate system rather than the serotonin pathways that most antidepressants work on. And both have generated significant attention for their potential to help people who haven't found relief elsewhere.
But they're not interchangeable. They differ in how they're administered, how they're regulated, what they cost, and who they're designed for. Understanding those differences is important, especially if you're weighing your options and trying to figure out which one might be worth discussing with your provider.
What Is Ketamine Therapy?
Ketamine is a medication that has been used in medicine since the 1960s, primarily as an anesthetic. It remains one of the most widely used anesthetics in emergency medicine and surgery worldwide. Over the past two decades, researchers have studied ketamine at much lower, sub-anesthetic doses for its potential effects on mood disorders, particularly depression.
When used for depression, ketamine is considered an off-label treatment. That means the FDA has approved ketamine as an anesthetic, but its use for depression is based on clinical research and provider judgment rather than a specific FDA indication for that purpose. Off-label prescribing is legal and common across medicine, but it's an important distinction to understand.
Ketamine therapy for depression is typically administered in one of two ways:
- Intravenous (IV) infusion: Ketamine is delivered directly into the bloodstream through an IV line over approximately 40 minutes. This is the most widely studied method for depression.
- Intramuscular (IM) injection: Ketamine is injected into a muscle, typically the upper arm or thigh. Onset is slightly slower than IV but still relatively rapid.
In both cases, treatment is provided in a clinical setting under direct medical supervision. Patients are monitored throughout the session and for a period afterward before being cleared to leave. You cannot drive yourself home after a ketamine session.
The mechanism of action is different from traditional antidepressants. Rather than targeting serotonin, norepinephrine, or dopamine, ketamine acts on the glutamate system and appears to promote the growth of new synaptic connections in brain regions associated with mood regulation. Some patients report noticing changes in mood within hours to days, rather than the weeks typically required for conventional antidepressants to take effect. However, individual responses vary, and not all patients experience this rapid response.
What Is Spravato (Esketamine)?
Spravato is the brand name for esketamine, a nasal spray manufactured by Janssen Pharmaceuticals. Esketamine is the S-enantiomer of ketamine, meaning it's one of the two mirror-image molecules that make up the ketamine compound.
In 2019, the FDA approved Spravato specifically for treatment-resistant depression (TRD) in adults, defined as depression that has not responded adequately to at least two different antidepressant medications. In 2020, the indication was expanded to include adults with major depressive disorder who have current suicidal ideation or behavior.
Because of its potential for misuse and the side effects associated with treatment, Spravato is available only through a restricted distribution system called the REMS (Risk Evaluation and Mitigation Strategy) program. This means:
- It can only be administered in a certified healthcare facility
- Patients must be observed for at least two hours after each dose
- Patients cannot take the medication home
- The prescribing provider and the pharmacy must be enrolled in the REMS program
Spravato is used alongside an oral antidepressant, not as a standalone treatment. The nasal spray is self-administered by the patient under the supervision of a healthcare provider in the office.
Key Differences at a Glance
| Ketamine (IV/IM) | Spravato (Esketamine Nasal Spray) | |
|---|---|---|
| Administration | Intravenous infusion or intramuscular injection | Self-administered nasal spray (under clinical supervision) |
| FDA Status | Off-label use for depression (FDA-approved as anesthetic only) | FDA-approved for treatment-resistant depression and MDD with suicidal ideation |
| Insurance Coverage | Typically not covered by insurance | May be covered by insurance; prior authorization usually required |
| Approximate Cost | Varies by provider and region; often paid out of pocket | Copay and deductible dependent when covered by insurance; manufacturer assistance programs available |
| Monitoring | In-office medical supervision during and after treatment | Minimum 2-hour in-office observation required by REMS program |
| Typical Course | Often 6 initial sessions over 2-3 weeks, then maintenance as needed | Twice weekly for weeks 1-4, then weekly for weeks 5-8, then weekly or every 2 weeks |
| Used Alongside Other Medication | May be used with or without other antidepressants (provider discretion) | Must be used with an oral antidepressant (per FDA label) |
| Evidence Base | Extensive research literature; multiple meta-analyses and RCTs | Phase III clinical trials leading to FDA approval; ongoing post-market studies |
Who May Be a Good Candidate?
Both ketamine and Spravato are generally considered for individuals who meet specific clinical criteria. These are not first-line treatments. They're typically explored after other options have been tried.
A provider may consider ketamine-based treatment if you:
- Have been diagnosed with major depressive disorder or treatment-resistant depression
- Have tried at least two different antidepressant medications at adequate doses and durations without sufficient improvement
- Are experiencing significant functional impairment from your depression
- Do not have certain contraindications, such as uncontrolled hypertension, a history of psychosis, or active substance use disorder (evaluated on a case-by-case basis)
For Spravato specifically, the FDA indication requires a diagnosis of treatment-resistant depression (failure of at least two adequate antidepressant trials) or major depressive disorder with current suicidal ideation or behavior.
The decision about which treatment to pursue is made collaboratively between you and your provider, taking into account your diagnosis, treatment history, insurance coverage, medical history, and personal preferences. There is no one-size-fits-all answer.
What to Expect During Treatment at Ascend
At Ascend Mind and Body, ketamine therapy is provided at our Wesley Chapel location under the supervision of our psychiatric team. Here's what the process looks like:
Step 1: Comprehensive evaluation. Before any treatment begins, you'll have a thorough psychiatric evaluation with Anna Stouffer, PMHNP. This includes a review of your diagnosis, treatment history, current medications, medical history, and goals. Not everyone is a candidate, and a responsible provider will tell you that directly.
Step 2: Treatment planning. If you and your provider determine that ketamine-based treatment is appropriate, you'll discuss the specific approach, number of sessions, what to expect during and after treatment, and how to coordinate with any other providers involved in your care.
Step 3: Treatment sessions. Each session takes place in a comfortable, supervised clinical environment. Your vital signs are monitored throughout. You may experience temporary dissociative effects, changes in perception, dizziness, or nausea during treatment. These effects typically resolve within one to two hours. You will need someone to drive you home after each session.
Step 4: Follow-up and maintenance. After the initial series, your provider will evaluate your response and discuss next steps. Some patients benefit from periodic maintenance sessions. Others may transition to ongoing psychiatric care and therapy.
It's important to set realistic expectations. Ketamine-based treatments have shown promise for many patients with treatment-resistant depression, but they are not effective for everyone. Response rates vary, and some patients may not experience meaningful improvement. Your provider will monitor your progress closely and adjust the treatment plan as needed.
Frequently Asked Questions
Is ketamine therapy safe?
Ketamine has been used safely in medical settings for over 60 years. When administered at sub-anesthetic doses in a clinical setting with proper monitoring, it has a well-established safety profile. Side effects during treatment may include dissociation, dizziness, nausea, increased blood pressure, and altered perception. These effects are temporary and typically resolve within a few hours. Your provider will review your medical history to determine whether you're a safe candidate.
How quickly can ketamine or Spravato work?
Some patients report changes in mood within hours to days of their first treatment. This is notably faster than traditional antidepressants, which may take four to six weeks to reach full effect. However, not everyone experiences rapid improvement, and some patients require several sessions before noticing a change. Speed of response varies significantly from person to person.
Can I do ketamine therapy if I'm already on antidepressants?
In many cases, yes. Ketamine therapy is often provided alongside existing medications. Spravato is specifically designed to be used in combination with an oral antidepressant. Your provider will review your full medication list and make recommendations about any adjustments. Never stop or change your current medications without consulting your prescriber.
Does insurance cover ketamine therapy?
Traditional IV or IM ketamine therapy is generally not covered by insurance, as it is an off-label use. Spravato, because of its FDA approval, may be covered by some insurance plans, though prior authorization is typically required and coverage varies. We recommend contacting your insurance provider directly or speaking with our team about your specific situation. Visit our insurance and fees page for more information.
What's the difference between ketamine and Spravato at a molecular level?
Ketamine is a racemic mixture, meaning it contains two mirror-image molecules: S-ketamine and R-ketamine. Spravato (esketamine) contains only the S-enantiomer. Some researchers believe the two enantiomers may have different effects on the brain, and ongoing studies are exploring whether R-ketamine may also have therapeutic potential. From a practical standpoint, the most relevant differences for patients are the administration method, FDA status, and insurance coverage rather than the molecular distinction.
For more detail on how these treatments compare for specific conditions, see our guide on Spravato vs. ketamine and our page on ketamine for PTSD.
Deciding What's Right for You
If you've been living with depression that hasn't responded to traditional medication, you don't have to accept that this is as good as it gets. Ketamine-based treatments represent a different approach, one that works through a different mechanism in the brain and may offer relief where other treatments have not.
But the decision isn't one to make from a Google search alone. It requires a thorough evaluation, an honest conversation with a qualified provider, and realistic expectations about what treatment can and cannot do.
Schedule an evaluation with our psychiatric team, or call (813) 670-3005 to discuss whether ketamine-based treatment might be appropriate for you.
This article was written by the clinical team at Ascend Mind and Body and reviewed by Anna Stouffer, PMHNP. It is for informational purposes only and does not constitute medical advice. Ketamine therapy is an off-label treatment that has not been FDA-approved for the treatment of depression. Spravato (esketamine) is FDA-approved for treatment-resistant depression and major depressive disorder with suicidal ideation. Individual results vary. No treatment is guaranteed to be effective for every patient. If you are experiencing a mental health crisis or thoughts of self-harm, call or text 988 for the Suicide and Crisis Lifeline, or call 911. For personalized guidance, consult a qualified healthcare provider.