Treatment-resistant depression affects millions of Americans, leaving patients and healthcare providers searching for effective solutions when traditional antidepressants fail. In March 2019, the FDA approved Spravato (esketamine nasal spray), marking a revolutionary advancement in depression treatment that offers hope for those who haven’t responded to conventional therapies.

What is Spravato (Esketamine)?

Spravato is a nasal spray containing esketamine, a derivative of the anesthetic ketamine that was originally approved by the FDA in 1970. Unlike traditional antidepressants that can take weeks or months to show effects, Spravato works within hours to days, providing rapid relief for patients with treatment-resistant depression.

The medication is actually related to PCP but represents a completely new approach to treating depression. It’s designed to be used in combination with a traditional oral antidepressant, not as a standalone treatment.

How Spravato Works

While the exact mechanism isn’t fully understood, Spravato appears to work differently than traditional antidepressants. Rather than focusing solely on serotonin and norepinephrine like SSRIs and SNRIs, esketamine seems to interact with the NMDA (N-methyl-D-aspartate) receptor system and may influence glutamine release in the brain.

Ketamine contains two chemical components called enantiomers – S-ketamine and R-ketamine. Research suggests that S-ketamine (the active ingredient in Spravato) is the more effective component for treating depression.

Treatment Protocol and Administration

Induction Phase (Weeks 1-4)

  • Frequency: Twice weekly treatments
  • Dosage: Starting at 56mg, with doses of either 56mg or 84mg
  • Duration: 4 weeks with evaluation at the end

Maintenance Phase (Weeks 5-8)

  • Frequency: Weekly treatments
  • Dosage: Continue at 56mg or 84mg
  • Long-term: After 8 weeks, treatments may be reduced to every other week

Administration Process

  1. Clear nasal passages by blowing nose
  2. Recline head backward at 45-degree angle
  3. Insert device ensuring medicine reaches deep into nasal cavity
  4. Close opposite nostril and breathe in while pressing plunger
  5. Repeat on other side after 5-minute rest
  6. Additional doses require another 5-minute wait

Each device contains 28mg and delivers only two sprays, so patients need 2-3 devices depending on their prescribed dose.

Important Safety Requirements

REMS Program

Spravato is available only through a Risk Evaluation and Mitigation Strategy (REMS) program, which means:

  • Treatment must occur in certified healthcare facilities
  • Patients must be enrolled in the program
  • Healthcare providers must be certified
  • Cannot be purchased at retail pharmacies
  • Cannot be used at home

Monitoring Requirements

  • Patients must remain in the clinic for at least 2 hours after treatment
  • Blood pressure monitoring at 40 minutes post-treatment
  • Cannot drive home – must have someone else drive
  • Should not drive until after a full night’s sleep

Who Should Not Use Spravato

Contraindications

  • Aneurysms of any type (thoracic, abdominal, intracranial, peripheral)
  • History of intracerebral hemorrhage
  • Arteriovenous malformations
  • Uncontrolled hypertension (>140/90 mmHg)

Use with Caution

  • Cardiovascular or cerebrovascular disease
  • Patients taking MAO inhibitors or psychostimulants
  • Pregnancy and breastfeeding
  • Liver impairment
  • History of substance abuse

Common Side Effects

Most Frequent (>10-20% of patients)

  • Dissociation reactions (feeling spacey, floating sensations, time/space distortion)
  • Sedation (affects 50-60% of patients)
  • Dizziness and vertigo
  • Nausea
  • Headaches
  • Abnormal taste sensations
  • Anxiety

Serious Concerns

  • Blood pressure increases: 1 in 6 patients may experience systolic increases >40 points
  • Cognitive impairment: Decreased attention, judgment, and reaction time
  • Potential for abuse: Classified as a Schedule III controlled substance
  • Suicidal thoughts: May increase for up to 4 hours post-treatment

Clinical Effectiveness

Spravato has been shown to be 70–80% effective in treating depression, especially in patients who haven’t responded to traditional antidepressants.

Study Results

Clinical trials involving approximately 1,700 patients showed:

  • Montgomery-Åsberg Depression Rating Scale (MADRS) improvements of about 21 points versus 17 points for placebo
  • Most significant effects occur within the first 24 hours
  • Two-thirds of patients received the 84mg dose twice weekly
  • About half of patients showed meaningful response to treatment

Treatment-Resistant Depression Criteria

To qualify for Spravato treatment, patients must have:

  • Major depressive disorder
  • Failed to respond to at least two adequate antidepressant trials
  • Current depressive episode requiring treatment

Cost Considerations

Spravato represents a significant financial investment, with first-month costs averaging around $12,000 prior to insurance coverage. This is considerably higher than the cost of traditional antidepressants, which are typically much more affordable. However, Spravato for Depression is covered by most major insurance plans including Medicare and Medicaid, so patients typically rely on their insurance to offset the majority of expenses—making prior authorization and insurance approval critical steps in the treatment process.

The Future of Depression Treatment

Spravato’s approval represents a paradigm shift in understanding depression treatment. By demonstrating that rapid antidepressant effects are possible through different neurochemical pathways, it opens new avenues for research and development.

The FDA is currently evaluating Spravato for additional indications, including treatment of suicidal ideation, which could expand its therapeutic applications significantly.

While Spravato isn’t appropriate for everyone with depression, it offers genuine hope for patients with treatment-resistant depression who have exhausted other options. The rapid onset of action and novel mechanism of action make it a valuable addition to the psychiatric treatment arsenal.

However, the strict administration requirements, potential side effects, and high cost mean that careful patient selection and thorough medical evaluation are essential. Patients considering Spravato should work closely with qualified healthcare providers to determine if this innovative treatment is right for their specific situation.

For those struggling with treatment-resistant depression, Spravato represents a breakthrough that could significantly improve quality of life and potentially save lives when other treatments have failed.