SPRAVATO® (esketamine) became the first FDA-approved nasal spray specifically indicated for treatment-resistant depression — a designation that took decades of antidepressant research and a fundamentally different mechanism of action to achieve. Unlike every oral antidepressant approved before it, SPRAVATO® does not work through the serotonin or norepinephrine systems that have defined depression pharmacology since the 1980s. At the Houston Center for Advanced Psychiatric Treatment, we are a certified SPRAVATO® treatment center, and understanding how this medication works — and why that mechanism matters for patients who have not responded to standard treatments — is something we walk through with every patient we evaluate.
What Makes SPRAVATO® Mechanistically Different
Standard antidepressants — SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors) — work by increasing the availability of monoamine neurotransmitters, primarily serotonin and norepinephrine, at synaptic junctions. This approach is effective for many people with depression. But for patients with treatment-resistant depression (TRD) — clinically defined as inadequate response to at least two antidepressants at therapeutic doses — it often means the neurobiology of their depression extends beyond the pathways those medications address.
SPRAVATO® works through the glutamate system. It targets NMDA receptors — N-methyl-D-aspartate receptors, which are a subtype of glutamate receptor central to synaptic plasticity and mood regulation — producing rapid and significant changes in depressive symptoms through a pathway that SSRIs and SNRIs do not engage (PMC: NMDA Receptors). This is not a refinement of existing antidepressant chemistry. It is a different mechanism entirely, which is why the FDA granted it a separate approval category and why it can produce responses in patients for whom years of monoamine-targeted treatment have not been sufficient (FDA: SPRAVATO® Approval for TRD).
In 2024, SPRAVATO® also received FDA approval as the first and only monotherapy — meaning it can be used as a standalone treatment, not only as an add-on — for adults with treatment-resistant depression (Johnson & Johnson). That designation reflects the strength and consistency of the clinical evidence supporting it.
What the Clinical Evidence Shows
Clinical trials support SPRAVATO®’s effectiveness across several meaningful outcome measures. Traditional antidepressants typically show response rates of 40 to 60 percent in standard depression populations; SPRAVATO® has demonstrated response rates of up to 70 percent in clinical trials for treatment-resistant depression. The time-to-effect difference is equally significant: conventional antidepressants often require four to six weeks before noticeable improvement, whereas patients using SPRAVATO® may experience relief within 24 hours. For patients who have already spent months or years waiting for medication trials to work, that speed is not a minor feature — it is clinically meaningful.
On sustained remission, data suggests that SPRAVATO® used alongside an oral antidepressant may lead to remission rates averaging between 35 and 50 percent — compared to the 15 to 30 percent typically seen with conventional antidepressants alone. Results vary by individual, and not every patient will reach remission on any treatment. What the data reflects is a consistent, reproducible advantage for a population that has historically had limited options. Our post on 4 Things We Now Know About Treatment-Resistant Depression explores why this population is so difficult to treat with standard approaches.
How SPRAVATO® Is Administered at Our Practice
SPRAVATO® is a nasal spray, but it is not a medication patients take at home. It is administered exclusively in a certified healthcare setting under medical supervision — a requirement built into its FDA approval and Risk Evaluation and Mitigation Strategy (REMS) program. Our practice is a certified SPRAVATO® treatment center in Houston, TX, and the administration process follows a structured protocol.
Patients self-administer the nasal spray in our clinic in a calm, controlled environment. Following administration, patients are monitored for at least two hours to ensure safety and to address any side effects such as dizziness, dissociation, or transient increases in blood pressure. Patients should not drive on the day of treatment, eat for two hours before, or drink liquids in the 30 minutes prior to their session. A trusted driver or transportation arrangement is required.
The treatment schedule follows a defined arc. The induction phase, which runs through weeks one to four, involves two sessions per week. The maintenance phase, weeks five through eight, reduces to one session per week. Ongoing care from week nine forward involves one treatment every one to two weeks, customized to each patient’s response and stability over time. This is not a fixed endpoint — SPRAVATO® treatment is an ongoing clinical relationship, and our team remains engaged throughout, coordinating with any referring or existing mental health providers to ensure continuity.
Before the first session begins, we conduct a comprehensive evaluation covering medical and psychiatric history, current medications, and any contraindications. Patients should inform our team about any history of high blood pressure, vascular conditions, aneurysms, or certain psychiatric disorders, as these may affect candidacy. Drug interactions — particularly with antidepressants, sedatives, or other central nervous system medications — are reviewed during the evaluation.
Who SPRAVATO® Is Approved For
SPRAVATO® carries two distinct FDA-approved indications, and we treat both at our practice. The first is treatment-resistant depression in adults — defined as depression that has not responded adequately to at least two antidepressant treatments. The second is major depressive disorder (MDD) with acute suicidal ideation or behavior, where SPRAVATO® serves as a fast-acting option for patients experiencing severe, acute depressive symptoms. These are the only two indications for which SPRAVATO® is FDA-approved, and we do not use it outside these parameters.
Insurance Coverage and What to Expect on Cost
One of the most meaningful practical facts about SPRAVATO® is that it is covered by most major insurance plans — a significant distinction from IV ketamine treatment in Houston, which is not covered by insurance. At our practice, we work with Aetna, BlueCross BlueShield, Cigna, and United Healthcare, and we handle insurance verification and prior authorization on behalf of our patients before treatment begins. We do not ask patients to manage that process independently.
For patients with coverage questions or gaps, we discuss those directly before any treatment commitment is made. Our philosophy is that insurance paperwork should not be a barrier to a treatment that is specifically designed for patients who have already struggled through an extended treatment history. We take care of the administrative side because we know the clinical side is already demanding enough.
Addressing Two Common Hesitations
“I already tried ketamine and it didn’t work — is SPRAVATO® just the same thing?” This is a reasonable question, and the honest answer is: related, but not identical. SPRAVATO® is esketamine — the S-enantiomer (a specific molecular orientation) of ketamine — while IV ketamine uses racemic ketamine, a combination of both molecular orientations. The delivery method, dosing structure, pharmacokinetics, and clinical supervision protocol differ between the two. Some patients who have had limited response to IV ketamine respond well to SPRAVATO®, and vice versa. They are not interchangeable, and a conversation about your specific history will help clarify which is more appropriate or whether a combination approach may be worth considering.
“I’m concerned about experiencing dissociation during treatment.” Dissociation — a sense of detachment from one’s surroundings or a dreamlike quality of perception — is a known transient effect of SPRAVATO® that occurs in some patients during the monitoring window after administration. It is temporary and resolves before patients leave the clinic. Our team is present throughout the monitoring period specifically to support patients through any side effects. Many patients find the experience mild; some find it unusual but tolerable; and for a small number it is a reason to discuss whether SPRAVATO® remains the right fit. We have that conversation openly, and we do not minimize either the effect or the clinical benefit that most patients experience alongside it. Results vary by individual, and your experience will be assessed and discussed with you throughout treatment.
Frequently Asked Questions
How is SPRAVATO® different from regular antidepressants I’ve already tried? SPRAVATO® works through the glutamate system by targeting NMDA receptors — a mechanism that standard SSRIs and SNRIs do not engage. It is specifically approved for patients whose depression has not responded to at least two prior antidepressants, which means it is designed for exactly the population for which conventional medications have fallen short. It also acts much faster than oral antidepressants, with some patients noticing improvement within 24 hours.
Is SPRAVATO® covered by insurance? Yes, SPRAVATO® is covered by most major insurance plans. We work with Aetna, BlueCross BlueShield, Cigna, and United Healthcare and handle verification and prior authorization before your first session. We discuss any coverage questions or gaps directly during consultation so there are no surprises.
Can I take SPRAVATO® if I’m already on an antidepressant? SPRAVATO® is typically used alongside an oral antidepressant rather than as a replacement — though it has also received FDA approval as a monotherapy for TRD. Whether you continue, adjust, or change existing medications is something our team evaluates based on your specific history and current regimen. We review all medications during the initial evaluation, including any potential interactions.
What happens after the induction phase? After the four-week induction phase of twice-weekly sessions, treatment moves to a maintenance phase — once weekly for weeks five through eight, then once every one to two weeks from week nine onward. The maintenance schedule is adjusted based on your response and stability. Our team provides ongoing support and regular follow-ups throughout, and we coordinate with any existing mental health providers as needed.
What if SPRAVATO® doesn’t produce adequate relief for me? If SPRAVATO® does not produce sufficient improvement, we discuss the full range of other interventional options available at our practice — including IV Ketamine, Deep TMS, and the ONE-D TMS: IV Ketamine + Deep TMS combination protocol. A lack of response to one treatment does not close the door on others, and we approach each patient’s care as an ongoing clinical conversation rather than a single decision point.
Key Takeaways
- SPRAVATO® is an FDA-approved nasal spray for treatment-resistant depression and for major depressive disorder with acute suicidal ideation or behavior — the only two indications for which it is approved.
- It works through the glutamate system by targeting NMDA receptors, a mechanism entirely distinct from SSRIs and SNRIs, which is why it can produce responses in patients for whom monoamine-targeted treatments have not worked.
- Clinical trials show response rates of up to 70% for TRD and the potential for symptom relief within 24 hours — a meaningful advantage over standard antidepressants that require weeks to assess.
- SPRAVATO® is covered by most major insurers; our team handles verification and prior authorization before treatment begins and coordinates with Aetna, BlueCross BlueShield, Cigna, and United Healthcare.
- Administration requires a certified treatment setting with at least two hours of post-dose monitoring — patients cannot take SPRAVATO® at home, and our practice is a certified center where the full protocol is conducted under medical supervision.
SPRAVATO® represents a genuine advance for patients with treatment-resistant depression — not because it is newer, but because it works through a different pathway than anything that came before it. If you have tried multiple antidepressants without adequate relief and want to understand whether SPRAVATO® is an appropriate next step for your specific history, schedule a consultation with our team to get started. Call us at 832-436-4055 or request a consultation online at sprashadmd.com. We will review your history, verify your coverage, and give you a direct answer.
References
SPRAVATO® FDA Approval — Treatment-Resistant Depression. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified
SPRAVATO® — Monotherapy Approval. Johnson & Johnson. https://www.jnj.com/media-center/press-releases/spravato-esketamine-approved-in-the-u-s-as-the-first-and-only-monotherapy-for-adults-with-treatment-resistant-depression
NMDA Receptors. PMC. https://pmc.ncbi.nlm.nih.gov/articles/PMC9965111/
Medical Disclaimer
The information in this blog is for educational purposes only and does not constitute medical advice. SPRAVATO® and other interventional treatments for depression should only be pursued under the supervision of a licensed psychiatric provider who is familiar with your full medical and psychiatric history. Individual results vary. If you are experiencing a mental health crisis or thoughts of self-harm, please call or text 988 to reach the Suicide and Crisis Lifeline or go to your nearest emergency room.