If depression has continued despite therapy, medication, or both, you may be researching faster-acting treatments such as ketamine, esketamine (Spravato), or transcranial magnetic stimulation (TMS).
These treatments are related, but they are not interchangeable. They differ in chemistry, administration, FDA approval, monitoring, cost, and the amount of long-term evidence available.
At Light-tunnel Behavioral Health Services Inc. in New Haven, psychiatric providers (including Dr. Omolola Aragbada, PMHNP) can help you compare options within a personalized treatment plan.
Ketamine and Esketamine: Similar Biology, Different Medicines
Ketamine is a medication that blocks N-methyl-D-aspartate (NMDA) receptors, which are part of the brain’s glutamate system. This may influence downstream AMPA signaling and synaptic plasticity — the brain’s ability to strengthen or reorganize connections between nerve cells.
A useful metaphor is to imagine depression as a communication network with certain routes congested or underused. Ketamine-type treatments may temporarily help open alternate routes, making it easier for emotional regulation, behavioral change, and therapy to gain traction.
Racemic ketamine
Most IV ketamine treatments use racemic ketamine, which contains two mirror-image molecules:
- R-ketamine
- S-ketamine
Racemic ketamine is commonly administered by intravenous infusion and, in some settings, by intramuscular injection. Its use for depression is generally off-label.
Esketamine (Spravato)
Esketamine is the S-enantiomer, or one molecular form, of ketamine. Spravato is a prescription intranasal esketamine spray administered in a supervised healthcare setting.
Although the medications are chemically related, you should not assume that an IV ketamine dose and a Spravato dose are equivalent. They have different formulations, routes, dosing protocols, blood-level patterns, and regulatory requirements.
Ketamine vs. Spravato: Side-by-Side Comparison
| Feature | IV/IM racemic ketamine | Esketamine (Spravato) |
|---|---|---|
| Chemical composition | R- and S-ketamine mixture | S-ketamine only |
| Common route | IV infusion; sometimes IM | Intranasal spray |
| FDA approval for depression | No; FDA-approved as an anesthetic | Yes, for specific adult depressive indications |
| Depression use | Off-label | On-label when prescribing criteria are met |
| Setting | Clinic protocols vary | Certified healthcare setting under REMS requirements |
| Observation | Determined by the treating clinic | At least two hours after each dose |
| Insurance | Often self-pay for depression treatment | Often covered by commercial insurance or Medicare, subject to eligibility and prior authorization |
| Long-term evidence | Growing, but protocols vary | Structured maintenance and relapse-prevention evidence |
FDA Approval: What Each Treatment Can and Cannot Legally Claim
The FDA approved ketamine as an anesthetic, not as a depression medication. A licensed clinician may legally prescribe an FDA-approved medication for an off-label purpose when medically appropriate. However, IV ketamine should not be represented as FDA-approved to treat depression.
Spravato has a specific FDA-approved role. The current prescribing information includes:
- Treatment-resistant depression in adults, including use as monotherapy or with an oral antidepressant according to the current label
- Depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior, used with an oral antidepressant
Importantly, Spravato is not a stand-alone suicide-prevention treatment. A person with imminent risk may require emergency evaluation, hospitalization, or another level of care.
The 2025 randomized clinical trial by Janik and colleagues found that esketamine monotherapy improved depressive symptoms more than placebo over four weeks in adults with treatment-resistant depression. The findings are important because earlier pivotal trials primarily studied esketamine alongside a newly initiated oral antidepressant. However, the trial was short-term, so it does not answer every question about long-term monotherapy or relapse prevention. (Janik et al., 2025)
Monitoring: Why Spravato Requires REMS
Spravato is subject to the FDA’s Risk Evaluation and Mitigation Strategy (REMS) because of risks that include:
- Dissociation
- Sedation
- Increased blood pressure
- Respiratory depression
- Abuse and misuse
You self-administer the nasal spray, but only under direct observation. You do not take Spravato home for unsupervised use.
Before treatment, the clinical team generally reviews your blood pressure, medications, medical history, and current mental state. After dosing, you remain in the clinic for at least two hours while staff monitor respiratory status, oxygen saturation, blood pressure, alertness, dissociation, and other symptoms.
You also need transportation home and should not drive, operate machinery, or make important decisions until the next day after restful sleep, according to your provider’s instructions and the prescribing information.
With IV ketamine, monitoring practices are determined by the individual clinic. A responsible program should still assess cardiovascular risk, sedation, breathing, dissociation, and recovery after the infusion. However, there is no depression-specific REMS program that standardizes every infusion clinic in the same way.
How Quickly Do They Work, and How Long Do Effects Last?
Both ketamine and esketamine may act more quickly than many traditional antidepressants. Some people notice changes in mood, motivation, or suicidal thinking within hours or days. Others do not respond, or need repeated treatments before the clinical picture becomes clear.
You should be cautious with advertisements promising an immediate or permanent cure. Rapid improvement is possible, but treatment response varies substantially.
Evidence for Spravato
The evidence for esketamine includes several randomized controlled trials:
- In TRANSFORM-1, Fedgchin and colleagues studied fixed-dose esketamine plus a newly initiated oral antidepressant. The primary comparison for the 84-mg group did not reach statistical significance, illustrating why individual trials must be interpreted carefully. (Fedgchin et al., 2019)
- In TRANSFORM-2, flexible-dose esketamine plus an oral antidepressant produced a significantly greater improvement in depressive symptoms than placebo nasal spray plus an oral antidepressant after four weeks. (Popova et al., 2019)
- In SUSTAIN-1, continuing esketamine after a patient had responded or remitted reduced the risk of relapse compared with stopping esketamine. (Daly et al., 2019)
- In ESCAPE-TRD, esketamine plus an oral antidepressant outperformed quetiapine extended release plus an oral antidepressant on important response and remission outcomes in adults with treatment-resistant depression. (Reif et al., 2023)
These studies support a cautious conclusion: Spravato can produce rapid improvement for some adults and may help maintain gains when continued. They do not guarantee that you will respond or establish that Spravato is superior to every form of ketamine treatment.
Evidence for IV ketamine
Randomized trials and meta-analyses support rapid antidepressant effects from IV racemic ketamine in some people with treatment-resistant depression. However, infusion studies often differ in dose, frequency, setting, maintenance plan, and patient selection.
There are also no large, definitive randomized head-to-head trials proving that IV racemic ketamine is universally better than Spravato. Indirect comparisons can be informative, but they may be affected by differences between study populations and treatment protocols.
Side Effects and Misuse Potential
Both treatments can cause:
- Dissociation or feeling detached from your body or surroundings
- Sleepiness or sedation
- Dizziness or vertigo
- Nausea
- Temporary increases in blood pressure
- Anxiety or unusual perceptual experiences
- Impaired attention and coordination
IV ketamine may feel more intense for some patients because infusion dosing can produce higher or more sustained medication exposure. Spravato’s standardized dosing and observation period may feel more predictable, although it can still be powerful and unfamiliar.
Both medications are Schedule III controlled substances and require careful screening when there is a history of substance use disorder, medication misuse, uncontrolled hypertension, or certain cardiovascular conditions.
Cost, Insurance, and Self-Pay Options
Cost is often one of the most practical differences.
Because Spravato is FDA-approved for specific indications, commercial insurance and Medicare may cover it when medical criteria, documentation, and prior authorization requirements are met. Coverage varies by plan, and you should verify benefits before beginning treatment.
IV ketamine for depression is usually self-pay because its antidepressant use is off-label. The total cost may include the medication, infusion service, clinical monitoring, and follow-up appointments.
At Light-tunnel Behavioral Health Services Inc., self-pay clients can discuss psychiatric evaluations, medication management, therapy, TMS, and esketamine/Spravato treatment when clinically appropriate. The practice also accepts a wide range of major insurance plans. Ask about current availability, fees, authorization requirements, and whether a payment plan or alternative treatment pathway may be appropriate.
Where Does TMS Fit?
TMS is different from both ketamine treatments because it uses magnetic stimulation rather than medication.
TMS may be appealing if you prefer a non-drug treatment or want to avoid dissociation and sedation. Treatment usually involves repeated sessions over several weeks, and improvement may build gradually. TMS does not require the same two-hour post-dose observation used for Spravato.
BrainsWay Deep TMS is one of the most researched TMS systems and may be discussed as part of a treatment-resistant depression plan when clinically appropriate. The best choice depends on your symptoms, previous treatment response, medical history, schedule, insurance, and preferences, not on a single “strongest” treatment for everyone.
What to Do Before Choosing a Treatment
Do
- Ask whether your diagnosis, medication history, and medical conditions support the treatment.
- Request a clear explanation of dosing, monitoring, transportation, and follow-up.
- Review your blood pressure, cardiovascular history, pregnancy status, and substance-use history.
- Ask what happens if you do not respond after the initial treatment phase.
- Compare expected costs, insurance coverage, and self-pay responsibilities.
- Combine interventional treatment with therapy, medication management, sleep support, and safety planning when appropriate.
Avoid
- Do not purchase or use ketamine outside medical supervision.
- Do not assume IV ketamine and Spravato are interchangeable.
- Do not drive after Spravato or ketamine treatment until cleared by your provider.
- Do not combine treatment with alcohol, opioids, sedatives, or recreational drugs without medical guidance.
- Do not stop antidepressants or other psychiatric medications abruptly.
- Do not delay emergency care because you are waiting for a treatment appointment.
A psychiatric provider can help you decide whether Spravato, IV ketamine, TMS, medication changes, therapy, or another level of care fits your needs. At Light-tunnel Behavioral Health Services Inc. in New Haven, Dr. Omolola Aragbada, PMHNP, and the broader care team focus on collaborative, individualized treatment planning.
Medical Safety Disclaimer and Crisis Resources
This article is for education only and does not replace an evaluation by a qualified healthcare professional. Ketamine and Spravato have important contraindications, interactions, monitoring requirements, and misuse risks. Only a licensed clinician can determine whether either treatment is appropriate for you.
If you may hurt yourself, have a suicide plan, cannot stay safe, or are experiencing an immediate medical or psychiatric emergency:
- Call or text 988 for the Suicide & Crisis Lifeline.
- Call 911 or go to the nearest emergency department.
- Contact a trusted person and avoid remaining alone.
References
- Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: TRANSFORM-1. International Journal of Neuropsychopharmacology. 2019. doi:10.1093/ijnp/pyz039
- Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression. American Journal of Psychiatry. 2019;176(6):428–438. PubMed
- Daly EJ, Trivedi MH, Janik A, et al. Esketamine nasal spray plus oral antidepressant treatment for relapse prevention in treatment-resistant depression: SUSTAIN-1. JAMA Psychiatry. 2019;76(9):893–903. PubMed
- Reif A, Bitter I, Buyze J, Cebulla K, Frey R, Fu DJ, Ito T, Kambarov Y, Llorca PM, Oliveira-Maia AJ, Messer T, Mulhern-Haughey S, Rive B, von Holt C, Young AH, Godinov Y; ESCAPE-TRD Investigators. Esketamine nasal spray versus quetiapine for treatment-resistant depression. New England Journal of Medicine. 2023;389(14):1299–1309. doi:10.1056/NEJMoa2304145
- Janik A, et al. Esketamine monotherapy in adults with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2025. PubMed
- U.S. Food and Drug Administration. SPRAVATO (esketamine) nasal spray prescribing information.
Next in the Series
What to Expect During Spravato Treatment: A Step-by-Step Guide to Esketamine Therapy in New Haven