Medically reviewed by Dr. Lisa Parker, DNP, APRN, NP — Owner & Clinical Director, Parker Neuroscience, Omaha, Nebraska
Millions of people fill a prescription, take it exactly as directed, and keep waiting to feel like themselves again. For a large share of them, that feeling doesn’t come, or it arrives as a kind of numbness rather than relief. If that’s the reality right now, the first thing worth hearing clearly is this: that isn’t a personal failure. It’s an extremely common outcome, and it has a name and a real explanation behind it.
You Didn’t Fail Treatment
There’s a phrase in psychiatry, treatment-resistant depression, that tends to land hard. It sounds like a permanent verdict. Clinically, it simply means depression that hasn’t adequately improved after trying at least two different antidepressants, each at a sufficient dose for an adequate length of time, usually somewhere around six to eight weeks per medication.
That definition is a categorization tool, not a character assessment. What it actually reflects is that the first-line treatments tried so far didn’t fit this particular person’s biology, not that the person did something wrong or is somehow untreatable.
The Numbers Are Bigger Than Most People Assume
There’s a common assumption that if a standard antidepressant doesn’t work, that’s a rare, almost unlucky outcome. The data doesn’t support that. According to NIMH’s own summary of the STAR*D trial, the largest real-world antidepressant study ever conducted, only about a third of participants reached full remission on their first medication trial. Needing a second, third, or further attempt isn’t rare. It’s closer to the norm than the exception, and every additional medication trial in the same class tends to carry somewhat lower odds of success than the one before it.
Response Is Not the Same as Remission
This distinction matters more than it might seem. In clinical terms, a response means symptoms have improved by roughly half. Remission means the symptoms are essentially gone. A lot of people settle for the first one and call it good enough, especially after having lived somewhere much harder. Getting asked how they’re doing, and answering “better” because they’re no longer at their lowest point, even while still operating at a fraction of their actual capacity.
That’s worth naming directly: if a current treatment has taken someone from barely functioning to, say, getting through the day but still feeling flat, foggy, or exhausted, that’s a response, not necessarily a finish line. Real relief looks like getting actual energy and capacity back, not just a less severe version of the same struggle. That’s a reasonable thing to want, and a reasonable thing to say plainly to a clinician rather than minimizing.
Why the First Medications Sometimes Miss
Most standard antidepressants, SSRIs and SNRIs, work by increasing the amount of serotonin available between neurons, operating on the assumption that a serotonin shortage is the core problem. For a meaningful number of people, though, the biology driving their depression isn’t primarily a serotonin issue, so adding more of it doesn’t resolve the underlying picture.
There are also clinical explanations that get missed more often than people realize. Sometimes what looks like treatment-resistant depression is actually an undiagnosed sleep disorder, a thyroid condition, or subtle bipolar spectrum features that don’t look like the dramatic version most people picture, sometimes it’s closer to agitated depression: sadness combined with racing thoughts, irritability, and restlessness. Prescribing a standard antidepressant on top of an unrecognized bipolar pattern can make things worse rather than better. There’s also the reality of side effects: fatigue, brain fog, weight changes, and emotional flatness lead many people to stop treatment, not because the depression lifted, but because the treatment itself became difficult to tolerate.
A Different Target: The Glutamate System
Over the past decade, a meaningful amount of clinical attention has shifted toward a different neurotransmitter system entirely. Where serotonin gradually adjusts mood over time, glutamate, the brain’s most abundant excitatory neurotransmitter, is directly involved in the structural growth and communication between neurons. In a prolonged depressive episode, the physical branches of neurons, called dendrites, can actually shrink back, weakening those connections.
IV ketamine targets the glutamate system directly, which is part of why some patients notice meaningful change within hours or days rather than the six or more weeks standard medications typically require. It creates a temporary window of increased neuroplasticity, the brain’s capacity to form new connections, which is a significant part of why it’s frequently paired with therapy. Standard talk therapy can be difficult to fully engage with while someone is in the depth of a severe depressive episode, and that window of increased flexibility is often when therapeutic work becomes more possible, not despite the treatment, but because of it.
Spravato (esketamine) works through a related mechanism and carries FDA approval specifically for treatment-resistant depression and depression with acute suicidal ideation. It’s administered as a nasal spray, self-administered under direct clinical observation, with monitoring for roughly two hours afterward as part of its required safety protocol. Because it holds that FDA approval, it also has a real insurance pathway that off-label IV ketamine doesn’t share in the same way, though coverage still depends on the specific plan. Current details on what’s accepted are on our insurance and payment page.
It’s Additive, Not a Replacement
A common fear is that asking about a treatment like this means giving up on current medication or therapy entirely. That’s not how it typically works. These options are usually added alongside existing care rather than replacing it, building an additional layer of support onto a foundation that’s currently struggling to hold the weight on its own, not tossing that foundation out.
One of the most overlooked first steps, before any advanced treatment is even on the table, is simply revisiting the original diagnosis with a clinician who has the time to look closely, screening for the sleep, thyroid, or mood-spectrum factors mentioned above. A full evaluation covering medication history and diagnostic clarity is part of what mental health medication support at Parker Neuroscience is built around, and it’s also exactly what determines whether an evaluation for treatment-resistant depression care makes sense next.
What to Actually Say at Your Next Appointment
If any of this sounds familiar, it’s worth bringing up directly rather than describing symptoms in general terms. Be specific about what’s been tried, at what doses, for how long, and what daily life actually looks like right now, not the polished version. Then ask plainly: does this meet the clinical definition of treatment-resistant depression, and what are the options beyond another standard medication trial? It’s entirely reasonable to name treatments directly, asking whether ketamine or Spravato could be appropriate based on that history is a legitimate, informed question, not an overreach.
Questions related to this one
What’s the difference between response and remission in depression treatment? A response means symptoms have improved by roughly half. Remission means symptoms are essentially gone. Many people settle for a response and assume that’s the best available outcome, when it may just mean the current treatment hasn’t gone far enough yet.
Why don’t SSRIs work for everyone? SSRIs work by increasing available serotonin, based on the idea that a serotonin shortage is the core issue. For a meaningful share of people, the biology driving their depression isn’t primarily serotonin-based, so the medication doesn’t resolve the underlying problem even when taken correctly.
Could something else be causing my depression symptoms to not improve? Sometimes. Undiagnosed sleep disorders, thyroid conditions, and subtle bipolar spectrum features can all look like standard depression that simply isn’t responding to treatment. A full diagnostic reevaluation is often the most overlooked and most useful first step.
Do I need to stop my current antidepressant to try IV ketamine or Spravato? No. These treatments are typically added alongside existing medication or therapy rather than replacing it. The goal is building additional support, not discarding progress already made.