What It Means When Antidepressants Don’t Work
Most first-line antidepressants — SSRIs and SNRIs — work by increasing the availability of serotonin or norepinephrine in the brain. These medications help a significant portion of people with major depressive disorder. But depression is not a single-pathway condition, and the serotonin system is not the only neurobiological pathway involved. For patients whose depression has not responded adequately to two or more antidepressant medications at appropriate doses and for sufficient duration, clinicians use the term treatment-resistant depression, or TRD (Mayo Clinic, 2023).
TRD is more common than many patients realize. Approximately one in three people with major depressive disorder will not achieve adequate relief from standard antidepressant treatment. This is not a character failing. It is not evidence that the depression is imaginary or that the person did not try hard enough. It is a clinical signal that the biology driving the depression may involve systems that standard medications do not directly address.
Understanding this distinction is important because it changes what comes next. The appropriate response to TRD is not simply trying another antidepressant from the same class. It is reassessing the mechanism and finding an approach that works differently.
Why SPRAVATO® Exists
SPRAVATO® (esketamine) was developed specifically for people in this situation. It is the first and only FDA-approved nasal spray for adults with treatment-resistant depression, and in January 2025, it received an expanded FDA approval as the first and only monotherapy for adults with major depressive disorder who have not responded to at least two oral antidepressants (Johnson & Johnson, 2025).
Unlike SSRIs and SNRIs, SPRAVATO® does not work on the serotonin system. It targets NMDA receptors in the glutamate system — the brain’s primary excitatory neurotransmitter network. This is a fundamentally different mechanism, which is precisely why it can produce results in patients for whom serotonin-targeted treatments have failed. The two approaches are not competing; they address different aspects of depression’s neurobiology. For patients whose depression is rooted in pathways that standard antidepressants do not reach, SPRAVATO® may offer a path forward that previous treatments simply could not (U.S. Food and Drug Administration, 2019).
One of the most significant aspects of SPRAVATO® is the speed at which it can act. Where most antidepressants require weeks to produce noticeable changes, SPRAVATO® has demonstrated antidepressant effects within twenty-four hours in clinical trials — a meaningful difference for patients who have spent years waiting for relief (Johnson & Johnson, 2025).
Who SPRAVATO® Is For
SPRAVATO® is specifically indicated for adults who meet the criteria for treatment-resistant depression — meaning inadequate response to at least two oral antidepressants at appropriate doses. It is administered in a certified clinical setting and is always paired with an oral antidepressant as part of a comprehensive treatment plan.
It is not a fit for every patient with depression, and not everyone who has struggled with antidepressants will qualify. Certain medical histories — including a history of aneurysms, uncontrolled high blood pressure, or hypersensitivity to esketamine — may make SPRAVATO® inappropriate. A thorough evaluation is always the starting point. At Vigeo Wellness, we approach that evaluation not as a gatekeeping exercise but as a genuine effort to understand your history and find the approach most likely to help you specifically.
Some patients arrive having already been told they have treatment-resistant depression. Others are not sure — they know antidepressants have not worked, but they have never heard the clinical term applied to their situation. Both are welcome starting points. What matters is the full picture: what you have tried, for how long, at what doses, and how your body and mood responded.
Addressing the “Why Bother” Question
We understand that patients who have been through multiple treatment failures can arrive skeptical. When you have been disappointed enough times, self-protection starts to look like realism. We do not try to talk people out of that feeling — we respect it. What we do offer is honesty: SPRAVATO® has a distinct mechanism from everything you have likely tried before. That distinction is clinically meaningful. Results still vary by individual, and we will not promise outcomes we cannot guarantee. What we can tell you is that having a long history of antidepressant failure does not predict how you will respond to a treatment that works differently.
The other question we hear often is about the experience itself — what a SPRAVATO® session actually involves. The process is structured and closely monitored. Each session takes place at our clinic, lasts approximately two and a half hours, and is supervised by our clinical staff throughout. The medication produces temporary effects that can feel unfamiliar, and we take time to prepare patients fully before their first session so that nothing comes as a surprise.
What Evaluation Looks Like at Vigeo Wellness
Before recommending SPRAVATO® or any other advanced treatment, our team conducts a thorough psychiatric and medical evaluation. We look at your full treatment history — not just what medications you have been on, but how long you took them, what doses you reached, and how you responded at each stage. We screen for conditions that can complicate depression treatment, including thyroid dysfunction and bipolar spectrum features, both of which can affect how depression presents and what treatment approach is most appropriate.
If SPRAVATO® is a clinical fit, we walk through exactly what the process looks like at our clinic, what to expect during sessions, and what the induction schedule involves. If it is not the right fit, we discuss what is. TMS therapy, ketamine therapy, and psychiatric medication management are all available at Vigeo Wellness, and our team does not have a preferred protocol — the recommendation comes from the evaluation, not the other way around.
Frequently Asked Questions
How do I know if I qualify for SPRAVATO®? The clinical threshold is inadequate response to at least two oral antidepressants at appropriate doses. If you are unsure whether your past medication trials meet that standard, our evaluation process will help clarify that. Some patients who have been told informally that they are treatment-resistant have never actually completed full therapeutic trials — and for others, the history makes the diagnosis straightforward.
Will I need to stop my current antidepressant to take SPRAVATO®? Not necessarily. SPRAVATO® is typically taken alongside an oral antidepressant as part of a combined treatment plan. Your provider will review your current medications and make a recommendation based on your specific history and clinical picture.
How quickly does SPRAVATO® work? Clinical trials have shown that SPRAVATO® can produce antidepressant effects within twenty-four hours for some patients. That said, the full benefit typically builds across the induction phase — two sessions per week for four weeks — rather than appearing all at once after a single session. Individual response varies.
Is SPRAVATO® covered by insurance? SPRAVATO® is an FDA-approved medication, and many major insurance plans cover it for patients who meet the criteria for treatment-resistant depression. Coverage varies by plan, and prior authorization is typically required. Our team handles that verification process before treatment begins and will walk you through the financial side of care before you commit to anything.
What if SPRAVATO® doesn’t work either? We discuss this honestly with every patient who asks. SPRAVATO® will not be effective for everyone, and we do not represent it otherwise. If SPRAVATO® is not producing adequate benefit, there are other paths worth exploring — you can read more about the benefits of SPRAVATO® for TRD and what comes next if it isn’t the right fit — and we will have that conversation with you directly. Our goal is to find something that works, not to cycle through options without a plan.
Key Takeaways
- Treatment-resistant depression is defined as inadequate response to at least two antidepressants at appropriate doses — it is a clinical designation that applies to roughly one in three people with major depressive disorder.
- SPRAVATO® works through the glutamate system rather than the serotonin pathways targeted by most antidepressants, which is why it may help patients for whom standard medications have not.
- SPRAVATO® is the first and only FDA-approved monotherapy for adults with treatment-resistant depression, with an expanded approval granted in January 2025.
- Clinical trials have demonstrated antidepressant effects within twenty-four hours for some patients — a significantly faster timeline than standard antidepressants.
- A thorough evaluation is the right starting point; not every patient will be a clinical fit, and we discuss all available options based on your individual history.
A long history of treatment attempts is not the same as running out of options. At Vigeo Wellness, we start every evaluation by taking that history seriously — because understanding what has not worked is the clearest guide to what might. Reach out to our Fort Worth office at 817-634-5521 or our Weatherford office at 817-672-9407, or contact us to schedule a consultation. You are heard. You matter.
References
Johnson & Johnson. (2025). SPRAVATO® (esketamine) approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression. https://www.jnj.com/…
Mayo Clinic. (2023). Depression (major depressive disorder) — symptoms and causes. https://www.mayoclinic.org/…
U.S. Food and Drug Administration. (2019). Drug approval package: Spravato (esketamine) NDA #211243. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211243Orig1s000TOC.cfm
Medical Disclaimer
The information in this blog is for educational purposes only and does not constitute medical advice. SPRAVATO® (esketamine) is a prescription medication approved for adults with treatment-resistant depression and should only be pursued under the supervision of a licensed provider 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.