When depression has not improved after several treatment attempts, another medication recommendation can bring mixed feelings. You may want something different. You may also want a clear explanation of why it is different, beyond the phrase “a new option.”
At Eudaimonia Psychiatric Mental Health Clinic, we offer SPRAVATO® for treatment-resistant depression. We believe that conversation should begin with understandable information. What does this medication do? How strong is the evidence? And why does a nasal spray require a clinic visit?
If you are exploring care for depression, we want you to understand both the possibilities and the limits before making a treatment decision.
What makes depression treatment-resistant?
Treatment-resistant depression generally means major depression that has not improved enough after at least two antidepressant treatments. Those treatments need to have been taken at appropriate doses for enough time. The term does not mean that you have failed treatment or that improvement is impossible.
The details matter. We need to understand which medications you tried, how long you took them, and whether side effects limited treatment. We also want to know what actually changed. “It did not work” might mean no improvement, partial relief, or improvement that did not last.
We review your symptoms and health history rather than treating the label as the whole story. That careful attention reflects our approach to care: understanding your experience before deciding what comes next.
How SPRAVATO® is thought to work
SPRAVATO® contains esketamine, a molecule closely related to ketamine. Many familiar antidepressants act primarily through serotonin, norepinephrine, or both. Esketamine acts differently. It blocks a receptor called the NMDA receptor, part of the brain’s glutamate signaling system.
Glutamate helps nerve cells communicate. Researchers are studying how blocking NMDA receptors may affect other signals, including those involving AMPA receptors. These changes may influence how connections between nerve cells strengthen and adapt. A review of glutamatergic treatments explains these proposed mechanisms and their role in treatment research (McIntyre et al., 2024).
That is the plain-language idea: the medication may help change how certain brain circuits communicate and adapt. But the exact mechanism responsible for its antidepressant effects is not fully understood. We would not describe it as a proven “brain reset” or a repair of damaged brain tissue.
A different mechanism gives us a different treatment option. It does not tell us in advance whether that option will help you.
Esketamine, ketamine, and FDA approval are not interchangeable
SPRAVATO® is an FDA-approved prescription esketamine nasal spray. For adults with treatment-resistant depression, its current labeling permits use alone or with an oral antidepressant. Whether to continue another medication is an individual prescribing decision, not something to change on your own.
That approval applies to a specific product and its labeled uses. It does not extend to ketamine in general. Ketamine’s psychiatric uses are off-label. Findings about intravenous ketamine, compounded nasal products, or other forms should not automatically be treated as findings about SPRAVATO®.
The product, dose, delivery method, patient group, and supervision all matter. When you compare treatment descriptions, ask which medication and which type of evidence the description actually concerns.
What research can tell us, and what it cannot
Research can help answer several different questions. Does treatment reduce symptoms on average? Which symptoms change? How do people experience the treatment process? Can we identify who is more likely to benefit? Those questions require different study designs.
A symptom score is useful, but it is not your whole life
Clinical studies often use structured depression rating scales. An analysis of depression symptoms examined how symptoms grouped together and changed during esketamine treatment (Borentain et al., 2022). This kind of work helps researchers look beyond a single total score.
In our conversations, we also want concrete examples. Are you getting out of bed more consistently? Can you follow a conversation? Has the effort required for ordinary tasks changed? A score can help track progress, but it cannot replace those details.
Patient experience adds another perspective
A study of patient experience explored intranasal esketamine treatment in everyday clinical settings (Di Nicola et al., 2025). This research can illuminate parts of care that symptom scales do not fully capture.
Still, reported experiences are not a promise about yours. Observational studies do not control every difference between patients. People who participate may not represent everyone considering treatment.
Predicting an individual response remains difficult
A prospective study of response predictors examined mentalization and emotional-cognitive rigidity in relation to esketamine’s effects (Olivola et al., 2026). In plain language, these concepts concern how people understand mental states and how flexibly they think and respond emotionally.
Related research on personalizing treatment also examines psychological pain and suicidality alongside these factors (Olivola et al., 2025). This work explores whether individual differences might help guide future care.
These findings are not a simple screening test that can tell you whether treatment will work. We use research to inform a discussion, not to turn an emerging association into certainty about one person.
Why this nasal spray is not an at-home medication
SPRAVATO® is administered in person in a certified healthcare setting under its required safety program. You use the nasal spray under supervision. The clinical team then monitors you for at least two hours. It is not prescribed for unsupervised home use or administered through a video appointment.
Monitoring matters because treatment can cause sedation, dissociation, increased blood pressure, and breathing problems. Dissociation can feel like being detached from yourself or your surroundings. Your readiness to leave is assessed after monitoring. Some visits may take longer than two hours.
Plan transportation home. You should not drive or operate machinery until the next day after a restful sleep. Before treatment, we review your health history, medications, substance use, and practical concerns. If you have questions about scheduling or transportation, contact our team before your visit.
You can explore our available services, but choosing among them begins with an assessment rather than a product preference.
Bring your treatment history and your questions
A useful first discussion does not require you to know the neuroscience. Bring a medication list, any treatment records you have, and examples of what depression is preventing you from doing. Ask what would count as meaningful improvement, how side effects would be handled, and when we would reassess the plan.
You can request an appointment with us to discuss whether an evaluation for SPRAVATO® makes sense. We can work through the unanswered questions together, without asking you to decide before you understand the commitment.
If you are in emotional crisis or having suicidal thoughts, call or text 988 for the suicide and crisis lifeline (988 Suicide and Crisis Lifeline, n.d.). If there is immediate danger or a medical emergency, call 911. Do not wait for a scheduled treatment discussion to seek urgent help.
Works Cited
1. McIntyre RS, et al. Glutamatergic Modulators for Major Depression from Theory to Clinical Use. CNS Drugs. 2024. https://pubmed.ncbi.nlm.nih.gov/39150594/
2. Borentain S, et al. Montgomery-Åsberg Depression Rating Scale factors in treatment-resistant depression at onset of treatment: Derivation, replication, and change over time during treatment with esketamine. Int J Methods Psychiatr Res. 2022. https://pubmed.ncbi.nlm.nih.gov/35749277/
3. Di Nicola M, et al. Patient Experience with Intranasal Esketamine in Treatment-Resistant Depression: Insights from a Multicentric Italian Study (REAL-ESKperience). J Pers Med. 2025. https://pubmed.ncbi.nlm.nih.gov/40278340/
4. Olivola M, et al. Mentalization and Emotional-Cognitive Rigidity as predictors of esketamine’s effects on Treatment-Resistant Depression: Findings from a prospective observational study. J Affect Disord. 2026. https://pubmed.ncbi.nlm.nih.gov/40907711/
5. Olivola M, et al. Personalizing esketamine treatment in TRD and TRBD: the role of mentalization, cognitive rigidity, psychache, and suicidality. Front Psychiatry. 2025. https://pubmed.ncbi.nlm.nih.gov/41659188/
6. 988 Suicide and Crisis Lifeline. https://988lifeline.org/
Disclaimer
This article is for educational purposes only and is not a substitute for individualized evaluation, diagnosis, or treatment from a qualified healthcare professional.