Spravato (Esketamine): The FDA-Approved Ketamine Nasal Spray

Spravato made history in March 2019 when the FDA approved it as the first ketamine-derived medication for treatment-resistant depression -- and the first truly novel antidepressant mechanism approved in over 30 years. Developed by Janssen Pharmaceuticals (a Johnson & Johnson company), Spravato uses esketamine, the S-enantiomer of ketamine, delivered as a nasal spray under medical supervision.

For patients with treatment-resistant depression, Spravato offers a critically important advantage: insurance coverage. While off-label IV ketamine typically costs $400-$800 per session out of pocket, Spravato is covered by many commercial insurance plans and Medicare, potentially reducing patient costs to a manageable copay.

This guide covers how Spravato works, who qualifies, what the REMS program entails, what the research shows, and how it compares to other forms of ketamine therapy.

What Is Spravato?

Spravato is the brand name for esketamine nasal spray, manufactured by Janssen Pharmaceuticals. It differs from generic ketamine in several important ways:

Esketamine vs. Racemic Ketamine

Ketamine is a chiral molecule, meaning it exists in two mirror-image forms called enantiomers:

• S-ketamine (esketamine): The "left-handed" enantiomer -- this is what Spravato contains. It has approximately 3-4 times greater affinity for NMDA receptors than the R-enantiomer
• R-ketamine (arketamine): The "right-handed" enantiomer -- currently in research as a potential antidepressant with different properties
• Racemic ketamine: A 50/50 mixture of both enantiomers -- this is what is used in standard IV and IM ketamine treatments

The clinical significance of using esketamine versus racemic ketamine continues to be debated. Some researchers argue that the R-enantiomer may contribute to antidepressant effects through different mechanisms, while others contend that esketamine's higher NMDA potency makes it a more targeted treatment.

FDA-Approved Indications

Spravato is currently approved for two specific indications:

1. Treatment-Resistant Depression (TRD): Major depressive disorder that has not adequately responded to at least two different antidepressant medications taken at adequate doses for adequate durations
2. Major Depressive Disorder with Suicidal Ideation or Behavior (MDSI): Added in August 2020, this indication allows Spravato to be used as a rapid-acting treatment for patients actively experiencing suicidal thoughts

Importantly, Spravato is approved in conjunction with an oral antidepressant -- it is not approved as monotherapy.

How Spravato Is Administered

The REMS Program

Spravato is distributed exclusively through the REMS (Risk Evaluation and Mitigation Strategy) program, an FDA-mandated safety framework. The REMS program requires:

• Certified facilities only: Spravato can only be administered at healthcare settings enrolled in the REMS program
• Supervised administration: A healthcare provider must observe the patient self-administer the spray
• Mandatory monitoring: Patients must be monitored for at least 2 hours after each dose
• No take-home doses: Patients cannot take Spravato home; every dose is administered at the facility
• Patient enrollment: Patients must sign a Patient Enrollment Form acknowledging the risks
• Registry tracking: All administration is tracked in a national registry

Step-by-Step Administration

1. Arrival and check-in: Vital signs recorded; confirm no contraindications (e.g., uncontrolled hypertension)
2. Blood pressure check: Blood pressure must be below 140/90 mmHg before administration (elevated BP is a contraindication for that session)
3. Self-administration: The patient sprays the esketamine device into each nostril while seated under observation
4. Dosing: Two or three spray devices used per session (28 mg, 56 mg, or 84 mg total dose)
5. Rest and monitoring: The patient reclines in a monitored area for at least 2 hours
6. Vital sign checks: Blood pressure monitored at 40 minutes, 1 hour, and 2 hours post-dose
7. Dissociation assessment: Clinical staff assess for resolution of dissociative symptoms
8. Discharge: Patient is released to a designated driver once stable

What to Avoid on Treatment Days

• Do not eat for at least 2 hours before treatment (reduces nausea)
• Do not drink liquids for 30 minutes before treatment
• If using nasal corticosteroids or decongestants, use them at least 1 hour before Spravato
• Do not drive or operate heavy machinery until the next day after a restful sleep

Dosing and Protocols

FDA-Approved Dosing Schedule

Induction Phase (Weeks 1-4):

• Dose: 56 mg or 84 mg
• Frequency: Twice weekly
• Minimum sessions: 8 (over 4 weeks)

Optimization Phase (Weeks 5-8):

• Dose: 56 mg or 84 mg (adjusted based on response and tolerability)
• Frequency: Once weekly

Maintenance Phase (Week 9+):

• Dose: 56 mg or 84 mg
• Frequency: Once weekly or once every 2 weeks
• Duration: Continued as long as clinically indicated

Available Doses

| Dose | Devices | Sprays | |------|---------|--------| | 28 mg | 1 device | 1 spray per nostril | | 56 mg | 2 devices | 1 spray per nostril per device | | 84 mg | 3 devices | 1 spray per nostril per device |

The starting dose for most patients is 56 mg. Patients aged 65+ start at 28 mg, potentially increasing to 56 mg or 84 mg.

Conditions Treated

Primary Indications

• Treatment-Resistant Depression: Patients who have failed at least 2 adequate antidepressant trials
• Major Depression with Suicidal Ideation: Rapid-acting relief from active suicidal thoughts

Off-Label Uses (Limited)

Some providers prescribe Spravato for conditions beyond its FDA-approved indications:

• Anxiety Disorders: When co-occurring with treatment-resistant depression
• PTSD: Limited use for trauma-related depression

Unlike generic ketamine, Spravato's use is more tightly regulated, and off-label prescribing is less common due to REMS requirements and the documentation needed for insurance coverage.

Research Evidence

Pivotal Clinical Trials

TRANSFORM-1 (2019): A Phase III trial that randomized patients with treatment-resistant depression to esketamine nasal spray (56 mg or 84 mg) plus a newly initiated oral antidepressant versus placebo nasal spray plus a newly initiated oral antidepressant. While the primary endpoint narrowly missed statistical significance, clinically meaningful improvement was observed in the esketamine groups.

TRANSFORM-2 (2019): This Phase III trial used flexible dosing (56 mg or 84 mg) and demonstrated a statistically significant improvement in depression scores compared to placebo at Day 28. This was the pivotal study supporting FDA approval. The esketamine group showed a 4.0-point greater reduction in MADRS score compared to placebo.

SUSTAIN-1 (2019): This relapse prevention study found that patients who continued Spravato maintenance had significantly lower relapse rates than those switched to placebo (26.7% vs. 45.3% for stable responders). This demonstrated the importance of continued Spravato treatment for maintaining antidepressant effects.

Suicidal Ideation Studies

ASPIRE I and II (2021): Two identical Phase III trials studied esketamine nasal spray (84 mg) for patients with major depressive disorder and active suicidal ideation. Both studies demonstrated rapid improvement in depressive symptoms within 24 hours of the first dose. These results led to the expanded FDA approval for this indication.

Long-Term Safety

Wajs et al. (2020): An open-label, long-term safety study following patients for up to 1 year found that esketamine nasal spray was generally well tolerated with a safety profile consistent with the Phase III trials. Treatment-emergent adverse events were typically mild to moderate and occurred primarily on treatment days.

Real-World Evidence

Post-marketing studies (2023): Real-world data from clinical practice settings have generally confirmed the efficacy and safety observed in clinical trials, with some studies reporting even higher response rates in real-world settings, possibly because clinicians can optimize treatment duration and frequency.

What to Expect During a Session

The Spravato Experience

A typical Spravato session involves:

• Duration at facility: 2.5-3 hours (15 min admin + 2 hours monitoring + discharge)
• Nasal spray administration: Self-administered under observation, 2-3 devices over ~15 minutes
• Onset: Effects typically begin within 15-20 minutes
• Peak: 30-60 minutes after administration
• Common sensations: Mild dissociation, dizziness, altered perception, a "head in the clouds" feeling
• Intensity: Generally milder dissociation than IV ketamine due to lower peak concentration
• Resolution: Most acute effects resolve within 90 minutes

Side Effects Profile

Side effects observed in clinical trials (occurring in more than 5% of patients):

• Dissociation: 61-75% (typically mild)
• Dizziness: 45-58%
• Nausea: 25-37%
• Sedation: 23-35%
• Vertigo: 20-29%
• Hypoesthesia (decreased sensation): 16-22%
• Increased blood pressure: 8-17%
• Anxiety: 9-14%
• Vomiting: 5-11%

These side effects generally peak within 40 minutes and resolve within 2 hours, which is why the REMS monitoring period is set at a minimum of 2 hours.

Pros and Cons of Spravato

Advantages

• FDA-approved: Regulatory validation of safety and efficacy
• Insurance coverage: Covered by most major commercial plans and Medicare
• Lower patient cost: With insurance, copays are typically $50-$200 vs. $400-$800 out-of-pocket for IV
• Non-invasive: Nasal spray rather than IV needle or injection
• Standardized protocol: FDA-approved dosing eliminates guesswork
• REMS safety: Mandated monitoring ensures supervised administration
• Janssen savings program: Additional cost assistance for eligible patients
• Approved for suicidal ideation: Unique indication for rapid treatment of active suicidality

Limitations

• REMS restrictions: Must visit a certified facility every time; no take-home option
• Long monitoring period: 2+ hours at the facility per session
• Lower bioavailability (~48%): Less reaches the bloodstream compared to IV (100%)
• Less dosing flexibility: Only 28, 56, or 84 mg options (vs. continuous IV adjustment)
• Must take with oral antidepressant: Not approved as monotherapy
• Prior authorization: Insurance approval can be a multi-week process
• Facility access: Not all areas have certified REMS providers nearby
• Nasal congestion: Allergies or colds can reduce absorption
• Higher facility cost: The monitoring requirement adds overhead that some smaller clinics cannot accommodate

Cost and Insurance

Sticker Price vs. Patient Cost

| Component | Without Insurance | With Insurance | |-----------|------------------|----------------| | Spravato (56 mg) per dose | $590-$890 | Varies by plan | | Spravato (84 mg) per dose | $590-$890 | Varies by plan | | Facility/monitoring fee | $150-$300 | Usually covered | | Total per session | $740-$1,190 | $50-$200 copay | | Induction month (8 sessions) | $5,920-$9,520 | $400-$1,600 copay | | Annual maintenance | $9,620-$23,140 | $1,300-$5,200 copay |

Getting Insurance Approval

1. Documentation: Your psychiatrist documents your history of treatment-resistant depression
2. Prior authorization: Submit evidence of at least 2 failed antidepressant trials
3. Approval timeline: Typically 1-3 weeks for initial authorization
4. Step therapy: Some plans may require additional documentation or a trial of another treatment first
5. Appeals: If initially denied, your provider can submit an appeal with supporting clinical evidence

Cost Assistance Programs

• Janssen Savings Program: Eligible patients may pay as little as $10 per session
• Patient assistance programs: For uninsured or underinsured patients
• HSA/FSA: Spravato qualifies for health savings account reimbursement
• Insurance coverage guide: Detailed walkthrough of maximizing coverage

Finding a Spravato Provider

REMS-Certified Facilities

To receive Spravato, you must visit a REMS-certified healthcare facility. These include:

• Psychiatry practices enrolled in the REMS program
• Hospital outpatient clinics with Spravato certification
• Ketamine clinics that have added REMS certification
• Academic medical centers with specialized treatment-resistant depression programs

How to Find a Certified Facility

1. Spravato.com: Janssen's website has a provider finder tool
2. Your insurance company: Request a list of in-network Spravato providers
3. Our clinic directory: Search for clinics offering Spravato in your area
4. Your psychiatrist: They may be certified or can refer you to a certified facility

What to Ask the Facility

• Are you currently accepting new Spravato patients?
• Which insurance plans do you accept?
• What is the typical copay for Spravato sessions?
• Do you help with prior authorization paperwork?
• What is the monitoring environment like? (Private room vs. shared space)
• Can sessions be scheduled around my work hours?

Spravato vs. IV Ketamine: Which Is Right for You?

The choice between Spravato and IV ketamine often comes down to practical considerations:

Choose Spravato if:

• Your insurance covers it (this alone can save thousands annually)
• You meet the criteria for treatment-resistant depression
• You prefer a non-invasive nasal spray over IV access
• You want the assurance of an FDA-approved treatment
• A REMS-certified facility is accessible to you

Choose IV ketamine if:

• You do not have insurance coverage for Spravato
• You want the maximum bioavailability (100% vs. 48%)
• You need treatment for conditions beyond TRD (chronic pain, PTSD, anxiety)
• You prefer the precise dose control that IV provides
• You want to avoid the longer monitoring periods required by REMS
• No REMS-certified facilities are nearby

Many patients try one approach and switch to the other based on their experience. Some even alternate between the two. The most important step is starting the conversation with a qualified provider. Find a ketamine clinic near you to explore your options.