Esketamine Nasal Spray for Depression: A Complete Clinical Guide to Spravato

Understanding Depression and Treatment-Resistant Depression

Depression is one of the most prevalent medical conditions in the world. According to the World Health Organization (WHO), approximately 280 million people globally live with depression — roughly 5% of the world's adult population — making it a leading cause of disability and accounting for 4.3% of the total global disease burden.

Despite the availability of treatments, a substantial subset of patients do not respond to standard antidepressants. Treatment-resistant depression (TRD) is clinically defined as an inadequate response to at least two different antidepressants at appropriate doses and durations within the same depressive episode. A peer-reviewed study in the Journal of Clinical Psychiatry estimated that among approximately 8.9 million US adults receiving medication for MDD, roughly 2.8 million (30.9%) meet TRD criteria. TRD accounts for 47.2% ($43.8 billion) of the estimated $92.7 billion total annual US cost of medication-treated MDD — a disproportionate share relative to the size of this patient group. Patients with TRD also face higher hospitalisation rates, greater functional impairment, and elevated suicide risk compared to those with non-resistant MDD.

What Is Esketamine?

Esketamine is a nasal spray antidepressant developed by Janssen Pharmaceuticals (Johnson & Johnson) and marketed under the brand name Spravato. Chemically, it is the S-enantiomer of ketamine — one of two mirror-image molecular forms of the anaesthetic compound in clinical use since the 1970s. The S-enantiomer was selected because it binds with greater affinity to NMDA receptors than racemic ketamine, enabling effective therapeutic dosing at lower concentrations.

Unlike IV ketamine — which remains off-label for psychiatric use — Spravato is an FDA-approved nasal spray delivered exclusively in certified clinical settings. It is classified as a Schedule III controlled substance, meaning it cannot be dispensed at a retail pharmacy or self-administered at home. As of January 2025, Spravato has regulatory approval in 77 countries and has been administered to more than 140,000 patients worldwide.

How Esketamine Works

Most conventional antidepressants — SSRIs and SNRIs — increase the availability of serotonin or norepinephrine and typically require four to eight weeks to produce clinically meaningful effects. Many patients with TRD cycle through several agents without finding one that works.

Esketamine operates through a fundamentally different pathway. It acts as a non-selective, non-competitive antagonist of NMDA (N-methyl-D-aspartate) receptors, which respond to glutamate — the brain's primary excitatory neurotransmitter. By modulating the glutamate system rather than monoamine pathways, esketamine exerts effects on neural circuits that can produce antidepressant responses within hours rather than weeks.

This mechanism is thought to promote synaptogenesis — the rapid formation of new synaptic connections — and to support neuroplasticity in regions implicated in depression, including the prefrontal cortex. It is important to note that the precise mechanism by which esketamine produces its antidepressant effect has not been definitively established, as stated explicitly in the FDA prescribing label. Research into the underlying neurobiology is ongoing.

FDA Approval History: Three Distinct Indications

Spravato has received three regulatory approvals in the United States:

March 2019 — TRD (with oral antidepressant). The FDA approved Spravato for adults with treatment-resistant depression, to be used alongside an oral antidepressant. It received Breakthrough Therapy Designation — reserved for drugs that demonstrate substantial improvement over available therapies for serious conditions — reflecting the clinical urgency of the unmet need.

August 2020 — MDD with Acute Suicidal Ideation or Behaviour (MDSI). Based on the Phase 3 ASPIRE I and ASPIRE II trials, Spravato was approved for depressive symptoms in adults with MDD and active suicidal ideation with intent. The ASPIRE trials demonstrated that esketamine reduced depressive symptoms as early as four hours after the first dose — clinically significant given that standard antidepressants require weeks to reach therapeutic effect.

January 21, 2025 — First-Ever Monotherapy for TRD. Following FDA Priority Review, Spravato became the first and only FDA-approved monotherapy for adults with TRD. It can now be prescribed as a standalone treatment without requiring concurrent use of a daily oral antidepressant — providing greater flexibility for patients with high pill burden, oral antidepressant intolerance, or polypharmacy concerns.

Clinical Trial Evidence

TRD4005 (Phase 4 — Monotherapy Approval): Study TRD4005 (NCT04599855) enrolled 477 adults with TRD in a randomised, double-blind, placebo-controlled trial. Both the 56 mg and 84 mg doses produced statistically significant MADRS improvements versus placebo (LS mean difference −5.1 and −6.8 respectively; both p < 0.001). Improvements were detectable as early as 24 hours. At Week 4, 22.5% of esketamine patients achieved remission (MADRS ≤ 12) versus 7.6% on placebo — nearly three times the remission rate.

TRANSFORM-2 (Phase 3 — 2019 Approval): Published in the American Journal of Psychiatry, TRANSFORM-2 demonstrated a statistically significant MADRS reduction for esketamine plus a new oral antidepressant versus placebo plus antidepressant at Day 28 (−4.0 point difference; 95% CI: −7.31 to −0.64).

SUSTAIN-1 — Relapse Prevention: Patients who achieved stable response during induction and continued maintenance therapy had a 51% lower risk of depressive relapse compared to those switched to placebo.

SUSTAIN-3 — Long-Term Safety: This trial followed 1,148 adults with TRD for up to 6.5 years (~3,777 cumulative patient-years). Final results confirmed no new long-term safety signals beyond those identified in short-term studies, supporting extended maintenance use.

ESCAPE-TRD — Head-to-Head: In a direct 32-week comparison with quetiapine extended-release, esketamine achieved significantly higher remission and response rates from Week 6 onward, with lower adverse-event-related discontinuation rates.

Administration: What Patients Can Expect

Spravato is only available through the SPRAVATO REMS (Risk Evaluation and Mitigation Strategy) program — a restricted FDA distribution system due to risks of sedation, dissociation, and misuse potential. Treatment cannot occur at home.

Each session involves the patient self-administering the nasal spray under direct clinical supervision, followed by a mandatory minimum two-hour on-site observation period for blood pressure monitoring and assessment of sedation and dissociation. Patients must arrange transportation; driving is prohibited on treatment days.

Side Effects and Safety

In the real-world ECHO study (570 patients, Europe and Israel), the most common treatment-emergent adverse events were dissociation (35.1%), dizziness (33.5%), and elevated blood pressure (21.4%) — somewhat higher than trial rates, reflecting a more complex patient population. Most adverse effects are transient, typically resolving within the two-hour post-dose window. SUSTAIN-3 data extending to 6.5 years confirmed no new long-term safety signals.

The FDA prescribing label carries Boxed Warnings — the agency's most serious category — covering risks of sedation and dissociation, potential for abuse and misuse, and the need to monitor for worsening depression or emergent suicidal ideation. Spravato is contraindicated in patients with hypersensitivity to esketamine or ketamine and requires careful evaluation in patients with uncontrolled cardiovascular conditions, history of psychosis, or active substance use disorders.

Cost and Insurance Coverage

Without insurance, Spravato sessions typically cost $590–$885 per session, meaning the eight-session induction phase can total $4,700–$7,000 or more before insurance coverage applies.

Coverage has expanded considerably since 2019:

• Medicare Part B covers Spravato as a physician-administered treatment, paying 80% after the annual deductible (~$257 in 2025); 20% patient responsibility remains unless covered by a supplemental plan
• Medicaid covers Spravato in many states; where covered, patient costs are often $0–$10 per session
• Major private insurers (Aetna, Cigna, Blue Cross Blue Shield, UnitedHealthcare) increasingly cover Spravato for qualifying TRD patients, requiring prior authorisation and documented treatment history
• After meeting their annual deductible, many insured patients pay $10–$50 per session in copays
• Janssen CarePath provides financial assistance for eligible uninsured or underinsured patients

Prior authorisation is nearly universal. Thorough documentation of prior antidepressant trials is the single most important factor in securing insurance approval.

Who May Qualify

Spravato is not a first-line treatment and requires a comprehensive psychiatric evaluation. For the TRD indication, candidacy generally requires a confirmed MDD diagnosis, documented inadequate response to at least two antidepressants at adequate doses and durations, ability to attend supervised in-clinic sessions, and no absolute contraindications. All eligibility decisions are made collaboratively between the patient and their treating psychiatrist.

Esketamine vs. Traditional Antidepressants

Frequently Asked Questions

1.Is Spravato the same as IV ketamine therapy?
No. Esketamine (Spravato) is the S-enantiomer of ketamine in nasal spray form with specific FDA approvals for TRD and MDSI. IV ketamine uses the racemic (combined) form, is administered intravenously, and remains off-label for psychiatric use. The two have different pharmacokinetic profiles and distinct regulatory statuses.

2.How long does treatment last?
The four-week induction phase is standard. Maintenance therapy is then individualised based on clinical response, typically moving to once every one to two weeks. SUSTAIN-3 supports safety and efficacy over up to 6.5 years for appropriate patients.

3.Does esketamine work for everyone with TRD?
Not universally. The TRD4005 trial found a 22.5% remission rate at Week 4 versus 7.6% on placebo — meaningful but indicating that a substantial proportion will not achieve remission during induction. Responses vary considerably between individuals.

4.Is Spravato covered by insurance?
Most major US insurers — including Medicare, Medicaid in many states, and large private carriers — cover Spravato for eligible TRD patients, typically with prior authorisation. After meeting the annual deductible, many insured patients pay $10–$50 per session. Patients without adequate coverage should ask their provider about the Janssen CarePath assistance program.

Conclusion

Esketamine nasal spray represents a clinically significant advance for the estimated 2.8 million US adults living with treatment-resistant depression. Its distinct glutamate-based mechanism, rapid onset, three FDA approvals — including the landmark 2025 monotherapy designation — and an evidence base spanning multiple controlled trials and real-world datasets make it one of the most thoroughly studied novel antidepressants in recent psychiatric history.

It is not a universal solution: a 22.5% remission rate at four weeks is meaningful but partial; treatment requires committed in-clinic attendance; and the FDA Boxed Warnings warrant careful clinical management. For patients who have exhausted conventional antidepressant options, esketamine offers a well-evidenced, regulatorily validated pathway that warrants a thorough discussion with a qualified psychiatrist.

About the Author
Written by Amy Della Rocca, MSN, MPH, PMHNP-BC — Clinical Director, Marpa Minds

Marpa Minds | Best Spravato® & Ketamine Therapy Clinic, White Plains, NY