Many individuals living with major depressive disorder (MDD) or treatment-resistant depression (TRD) find that traditional oral antidepressants offer limited relief, often due to low effectiveness or intolerable side effects. In response to this need, Spravato® (esketamine), a prescription nasal spray, has emerged as an innovative treatment option. FDA-approved in 2019, Spravato provides new hope for patients who have not responded to other medications. Backed by psychiatrists and supported by strong clinical evidence, it offers a safe, effective, and often insurance-covered alternative for those seeking meaningful and lasting relief from depression.
Unlike traditional medications, Spravato provides rapid relief of depressive symptoms, sometimes within hours of administration. It is also FDA-approved for individuals with MDD experiencing suicidal thoughts or behaviors, making it the only fast-acting antidepressant with this indication.
This article explores everything you need to know about Spravato, from how it works to what to expect during treatment.
What is Spravato?
Origin: Spravato is derived from ketamine, a well-established anesthetic first developed in the 1960s. Chemically, ketamine is made up of two mirror-image molecules, known as enantiomers: the R-enantiomer and the S-enantiomer. Spravato contains only the S-enantiomer (esketamine), which research has shown to have antidepressant effects.
FDA Approval: In 2019, the U.S. Food and Drug Administration (FDA) approved Spravato for treatment-resistant depression (TRD) when used in combination with an oral antidepressant, marking the first new mechanism for depression in decades. In 2020, its approval was expanded to include adults with major depressive disorder (MDD) who are experiencing acute suicidal ideation or behavior. Most recently, in January 2025, the FDA approved Spravato as the first and only monotherapy option for adults with TRD who have not responded adequately to at least two oral antidepressants. This significant update means that Spravato can now be prescribed on its own—without the need for concurrent oral antidepressants—for this patient population.
Formulation: Spravato is administered as a nasal spray under strict medical supervision in a certified healthcare setting, ensuring patient safety through required monitoring of blood pressure, oxygen saturation, sedation, and symptoms.
Regulation: Due to potential risks, Spravato is only available through a Risk Evaluation and Mitigation Strategy (REMS) program, meaning it must be given in a certified clinic with monitoring, which mandates that patients remain in the clinic for at least two hours after each dose before leaving with an escort.
This blog is proudly sponsored by Newy, the first physician-formulated mental health supplement created to boost neuroplasticity, support brain health, and complement ketamine therapy.
How Does Spravato Work?
Spravato works differently from traditional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), which primarily increase levels of serotonin and norepinephrine in the brain. Instead, Spravato targets the glutamate system, the brain’s most abundant neurotransmitter network, which plays a crucial role in regulating learning, memory, and mood. By modulating glutamatergic signaling, Spravato enhances synaptic plasticity and helps create new, adaptive neural circuits that counteract the rigid patterns often associated with depression. The specific mechanisms or actions of Spravato include:
NMDA Receptor Antagonism: Spravato works by blocking NMDA receptors, which helps calm their overactivity in the brain. This sets off a chain reaction—glutamate levels rise, AMPA receptors are activated, and the brain begins building new connections between nerve cells. These fresh connections strengthen communication in brain regions that regulate mood and emotions.
Enhanced Neuroplasticity: Spravato triggers a surge of glutamate, which promotes neuroplasticity—the brain’s capacity to adapt, reorganize, and create new pathways. This is especially important for patients with depression, as rigid and maladaptive brain circuits can perpetuate negative thought patterns and emotional states. By enhancing neuroplasticity, Spravato helps the brain “rewire” itself, contributing to long-lasting improvements in mood and resilience to stress.
BDNF Release: Increased glutamate activity raises levels of Brain-Derived Neurotrophic Factor (BDNF), which is a protein vital for the survival, growth, and repair of neurons. Higher levels of BDNF promote the regeneration of weakened neural circuits, enhance synaptic communication, and stabilize the structural changes necessary for maintaining remission from depression.
Rapid Onset of Relief: Unlike traditional antidepressants, which typically take 4 to 6 weeks to show effectiveness, Spravato can lead to noticeable improvements in mood and functioning within hours or days. This rapid response is especially important for individuals in acute distress or experiencing suicidal thoughts, as timely relief can be lifesaving.
Indications for Spravato Treatment
Spravato is currently FDA-approved for two primary depression-related indications:
1. Treatment-Resistant Depression (TRD):
This applies to adults who have not responded adequately to at least two different antidepressant medications taken at appropriate doses and durations during their current depressive episode. Treatment failure may involve either a lack of meaningful improvement in depressive symptoms or intolerable side effects that prevent continuation.
2. Major Depressive Disorder (MDD) with Suicidal Ideation or Behavior:
For adults experiencing acute suicidal thoughts or behaviors, Spravato may be considered as part of treatment. It must be prescribed in combination with an oral antidepressant and is administered under close medical supervision—often with the oversight of a psychiatrist—given the urgent and high-risk nature of the condition.
Although abundant and high-quality research has demonstrated the effectiveness of intravenous ketamine for conditions such as anxiety disorders, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and chronic pain, the official FDA approval for Spravato is currently limited to treatment-resistant depression and major depressive disorder with suicidal ideation or behavior.
The Spravato Treatment Experience
Spravato treatments follow a carefully structured and FDA-mandated process designed to ensure both safety and effectiveness:
1. Administration
Patients self-administer Spravato as a nasal spray while being directly supervised by a trained clinician. The medication is delivered into each nostril using a pre-measured device, with dosages of either 56 mg or 84 mg. Due to potential dissociative effects, patients are not allowed to drive home afterward and must arrange for transportation.
2. Observation and Monitoring
Following administration, patients are required to remain in the clinic for a minimum of two hours. During this time, clinicians monitor vital signs—particularly blood pressure, heart rate, and oxygen saturation—as well as mental status and any emerging side effects such as dizziness, sedation, nausea, or dissociation.
3. Treatment Frequency
Spravato treatment follows a structured schedule as outlined in the FDA prescribing information:
- Induction Phase (Weeks 1–4): Administered twice per week. This phase is intended to achieve rapid symptom relief and stabilization.
- Maintenance Phase (Week 5 and beyond): Administered once weekly during weeks 5–8, and then once every 1 to 2 weeks thereafter, depending on the patient’s clinical response and symptom stability.
4. Combination with Oral Antidepressants
Spravato was previously required to be prescribed alongside an oral antidepressant, such as an SSRI or SNRI, for treating adults with treatment-resistant depression. However, the FDA has now expanded its approval to allow Spravato to be used as a standalone treatment for adults with TRD who have not responded to at least two different oral antidepressants. While Spravato can still be used together with an oral antidepressant in certain cases, it is no longer mandatory for the TRD indication.
5. Ongoing Evaluation
Throughout treatment, patients meet regularly with their providers to assess mood, functionality, and side effects. Adjustments to dosing frequency, concurrent therapies, and overall treatment plans are made collaboratively to maximize effectiveness and ensure sustained recovery.
Effectiveness of Spravato
Clinical studies show that Spravato works quickly and can provide lasting benefits:
- Rapid Relief: Many patients notice improvement in mood within the first 24–48 hours of treatment (ASPIRE I & II trials, 2021).
- Response Rates: About 1 in 3 patients with treatment-resistant depression experience significant improvement after the first month of Spravato when added to an oral antidepressant (TRANSFORM-2 trial, 2019).
- Remission Rates: Roughly 1 in 4 patients achieve remission (minimal to no symptoms) within the first month (SUSTAIN-3 study, 2023).
- Lasting Benefits: For those who respond, continuing Spravato greatly lowers the chance of relapse—cutting the risk of depression returning by about half compared to stopping treatment (SUSTAIN-1 trial, 2019).
Side Effects and Safety Considerations
Side effects may include:
- Dizziness or lightheadedness
- Dissociation (feeling disconnected from reality)
- Nausea
- Elevated blood pressure
- Fatigue
While these effects may sound concerning, it’s important to emphasize that Spravato is remarkably safe when administered in a clinical setting. Side effects are typically mild, short-lived, and carefully monitored by trained staff. For example, nausea—though relatively uncommon—can be easily managed with medications like ondansetron (Zofran) if needed. Monitoring of blood pressure, heart rate, and oxygen levels during each treatment ensures that patients remain comfortable and safe throughout the process.
Spravato vs. IV Ketamine
Both IV ketamine and Spravato share the unique ability to deliver rapid relief from depressive symptoms. However, they differ in important ways—including their FDA approval status, methods of administration, insurance coverage, and clinical use guidelines. Understanding these distinctions can help patients and providers choose the treatment best suited to individual needs. For a more in-depth discussion comparing Spravato to ketamine, be sure to read: IV Ketamine vs. Nasal Spravato (Esketamine): In-Depth Comparison for Depression Treatment
| Feature | IV Ketamine Infusion | Nasal Spravato |
|---|---|---|
| Conditions Treated |
MDD, anxiety, PTSD, OCD chronic pain |
FDA approved for TRD & MDD with suicidality |
| Bioavailability | ~100% | ~40–50% |
| Administration | IV in clinic | Nasal spray in clinic |
| Onset of Relief | Hours | Hours |
| Efficacy | Higher (75–80%) | Moderate (~50%) |
| Cost & Insurance | Often self-pay | Frequently covered by insurance |
Table 1. Ketamine vs. Spravato (esketamine)
Who Should Avoid Spravato? (contraindications)
- Uncontrolled hypertension or heart disease
- History of aneurysm or hemorrhage
- Pregnancy or breastfeeding
- Current substance abuse
- Allergies to esketamine or formulation components
Innerbloom’s Approach to Spravato
At Innerbloom Ketamine Therapy in San Luis Obispo, we see Spravato not as a standalone cure, but as part of a comprehensive, holistic treatment plan. To enhance its effectiveness and ensure comfort, we emphasize the importance of both set and setting. Each treatment occurs in a private, comfortable room designed to promote safety and calmness. The environment is intentionally warm and inviting, featuring soft lighting, cozy blankets, eye shades, and noise-canceling headphones with curated playlists to encourage relaxation and introspection. Additionally, a therapy dog is on site to contribute to the nurturing atmosphere.
While Spravato can induce rapid change, combining it with psychotherapy may intensify and sustain those effects. Our ketamine-assisted certified therapist is available to guide patients through this process, and we collaborate with trusted community partners to support continued integration after sessions.
Final Thoughts and Next Steps
Spravato is a significant advancement in mental health treatment, providing a safe, accessible, and insurance-covered alternative to IV ketamine for those suffering from treatment-resistant depression. While not every patient qualifies or responds to it, many find considerable relief where other therapies have failed. For more information on how to take the next steps, please read: Getting Started with Spravato at Innerbloom Ketamine Therapy, or call us today to learn more.