Depression affects millions of people around the world. For many, traditional antidepressants help restore balance and mood. But for others, these medications provide little or no relief, even after trying several types or doses.
This often results in a diagnosis of treatment-resistant depression (TRD,) with roughly a third of adults with depression falling into this category. For these individuals, newer options like ketamine and Spravato® (esketamine) have become powerful alternatives that can work quickly, sometimes within hours instead of weeks.
Understanding the differences between ketamine vs Spravato can help patients and their providers decide which option might be the best fit for their needs.
Ketamine vs Spravato: Understanding the differences
Ketamine was first developed in the 1960s as a surgical anesthetic. Over time, researchers discovered that small doses of ketamine could dramatically reduce depression symptoms, even in patients who had not responded to traditional medications.
Spravato, on the other hand, is a nasal spray form of esketamine, which is a more refined version of ketamine. Unlike ketamine infusions, Spravato has been approved by the US Food and Drug Administration (FDA) to treat TRD as a standalone treatment and major depressive disorder (MDD) with suicidal thoughts along with an antidepressant.
Both ketamine and Spravato work by targeting the brain’s N-methyl-D-aspartate (NMDA) receptors within the glutamate system. This process helps restore and strengthen neural connections in areas of the brain responsible for mood regulation, memory, and emotional processing.
In short: both ketamine and Spravato work on the same brain system. What’s different is how they’re given, regulated, and covered by insurance.
Ketamine administration
Ketamine therapy is most commonly delivered through an IV infusion in a medical office. Each infusion lasts about 40 to 60 minutes, during which the medication is slowly delivered through a vein. Patients are monitored closely for blood pressure, heart rate, and oxygen levels, as ketamine can cause short-term increases in blood pressure and feelings of dissociation (such as a dreamlike or detached state).
While IV infusion is the most common method for treating depression, ketamine can also be delivered in other ways:
- IV infusion: the most widely used method for psychiatric treatment, given in a clinical setting with close monitoring.
- Intramuscular (IM) injection: injected into a muscle, often used when IV access is difficult or unavailable.
- Sublingual/oral tablets or lozenges: placed under the tongue or swallowed. Often used in maintenance therapy or off-label protocols
- Intranasal spray: a compounded form, not to be confused with Spravato®, which is FDA-approved esketamine
- Subcutaneous injection: less common, injected under the skin, sometimes used in pain management
Most people undergo a series of six to eight infusions over the course of two to four weeks, followed by occasional maintenance sessions depending on their response.
It’s important to note that ketamine infusions for depression are considered off-label, meaning they are not FDA-approved for this specific use. As a result, insurance may not cover the cost. Many patients still pursue this option due to its accessibility through private offices and reported effectiveness in relieving symptoms when other treatments haven’t worked.
Spravato treatment
Spravato (esketamine) is a prescription nasal spray administered in certified treatment centers under medical supervision.
During each session:
- Patients self-administer the spray under the guidance of a healthcare professional.
- Each treatment involves several sprays spaced a few minutes apart.
- Patients then rest comfortably for about two hours while the clinical staff monitors for side effects like dizziness, sedation, or increased blood pressure.
The treatment schedule typically involves two sessions per week for the first four weeks, then gradually decreases to weekly or every-other-week maintenance sessions.
Spravato is often used alongside an oral antidepressant and must be given under supervision. Patients cannot take it home.
Because of this approval, Spravato is often covered by insurance, including Medicare, making it more accessible for many patients.
Side effects and safety
Both ketamine and Spravato can cause side effects, most of which are short-lived and occur during or shortly after treatment.
Common side effects include:
- Dizziness or lightheadedness
- Nausea or vomiting
- Feeling detached or “floaty” (dissociation)
- Increased blood pressure or heart rate
- Sleepiness or fatigue
Because both treatments affect perception and blood pressure, patients must arrange for transportation after sessions and should avoid driving until the next day.
In rare cases, more serious effects, such as extreme sedation, confusion, or elevated blood pressure, can occur. Clinics are equipped to monitor and manage these reactions safely.
Risk of misuse:
Both medications are classified as Schedule III controlled substances due to their potential for abuse. However, Spravato’s controlled clinical setting greatly reduces that risk.
FDA approval and insurance coverage
This is one of the most significant differences between ketamine vs Spravato.
- Spravato underwent full FDA clinical testing for depression and has specific safety guidelines, known as the Risk Evaluation and Mitigation Strategy program (REMS.)
- Ketamine, while effective, has not been formally approved by the FDA for depression. It’s considered off-label use.
Because of this distinction:
- Spravato is much more likely to be covered by insurance.
- Ketamine infusions often require out-of-pocket payment.
Patients should always verify insurance coverage and discuss financial options with their provider before beginning treatment.
Key differences: ketamine vs Spravato
While ketamine and Spravato share similarities in how they work, here’s a breakdown of how they are different.
| Feature | Ketamine | Spravato (Esketamine) |
| Form | IV infusion, injections, nasal spray, tablets, lozenges | Nasal spray |
| Setting | Private clinics, often outpatient | Certified treatment centers only |
| FDA Approval | Off-label for depression | Approved for TRD and MDD with suicidal thoughts |
| Insurance Coverage | Rarely covered | Often covered, including Medicare |
| Monitoring Time | ~1 hour | ~2 hours post-treatment |
| Frequency | Usually 6–8 initial sessions | Twice weekly for 4 weeks, then tapering |
| Abuse Potential | Higher risk if misused | Controlled and monitored by healthcare providers |
In short:
- Ketamine offers flexibility and accessibility but is off-label and often not covered by insurance.
- Spravato provides an FDA-approved, monitored option that’s covered more often but must be administered in a certified facility.
Ketamine vs Spravato: Making the choice
Deciding between ketamine vs Spravato depends on several factors, including your medical history, treatment goals, insurance coverage, and personal preference.
You might consider Spravato if you:
- Prefer a nasal spray over IV infusions
- Want a treatment that’s FDA-approved and usually covered by insurance
- Are comfortable with regular clinic visits and observation periods
You might consider ketamine infusions if you:
- Want to start treatment more quickly or through a private clinic
- Don’t mind paying out-of-pocket for off-label care
- Have responded well to ketamine in the past
In both cases, treatment should be overseen by a qualified mental health provider who can monitor safety, manage side effects, and coordinate ongoing care.
Summary
When comparing ketamine vs Spravato, both treatments offer new hope for people with depression who haven’t responded to traditional antidepressants.
The best treatment depends on your unique needs, health status, and preferences. Talk with your psychiatrist or mental health provider to determine which option may help you find lasting relief.
Frequently asked questions
Is Spravato the same as ketamine?
Not exactly. Spravato contains esketamine, a form of ketamine that is more potent and designed for nasal delivery. Both work on the same brain system but differ in formulation and regulation.
How quickly do ketamine and Spravato work?
Both can reduce depression symptoms within hours or days, compared to the weeks traditional antidepressants take.
Which lasts longer, ketamine or Spravato?
Both require maintenance treatments to sustain results. The frequency depends on your response and your provider’s plan.
Is one safer than the other?
Both are safe when administered by trained professionals. Spravato’s FDA approval means it follows strict safety guidelines, while ketamine requires careful oversight in private clinics.
Ketamine vs Spravato: Key takeaways
- Ketamine and Spravato® (esketamine) are fast-acting treatments that can relieve symptoms of treatment-resistant depression (TRD)—often within hours or days.
- Ketamine has been used for decades as an anesthetic and is now used off-label for depression in infusion form.
- Spravato, a nasal spray version of esketamine (a form of ketamine), is FDA-approved for TRD and for major depressive disorder (MDD) with suicidal thoughts.
- Both target the glutamate system in the brain, which helps restore healthy communication between brain cells and improves mood.
- The main differences between the two include method of administration, FDA approval, and insurance coverage.
Looking for Spravato or ketamine treatment near you?
Pacific Mind Health offers Spravato (esketamine) and ketamine therapy for treatment-resistant depression, major depressive disorder, and more. Our experienced clinicians provide compassionate, evidence-based care to help you feel better.
Ready to take the next step? Schedule a free consultation today to see if Spravato or ketamine is right for you.
