You started an antidepressant. You waited the six or eight weeks your provider mentioned. Nothing changed much. So you tried a second one. Still no real relief.
If that sounds familiar, you are not alone. And you are not out of options.
What Treatment-Resistant Depression Actually Means
What you are describing has a name. Providers call it treatment-resistant depression, or TRD. The name sounds discouraging, but it is not a dead end. It simply means the first medications tried were not the right fit for your brain chemistry, and a different approach is worth exploring.
Treatment-resistant depression is more common than most people think. Research suggests close to 30 percent of adults with major depressive disorder do not get enough relief from the first two antidepressants they try, even when those medications are given at a full dose for a full length of time. That is the working definition most providers use. Two honest attempts. Not enough improvement.
Why Some Depression Does Not Respond to the First Medication
Depression is not one condition with one cause. Brain chemistry differs from person to person. Genetics plays a role. So does the specific type of depression someone has. Two people with the same diagnosis can respond in completely different ways to the same drug.
Most standard antidepressants work by adjusting serotonin or norepinephrine levels in the brain. For a lot of people, that approach works well over time. For others, it barely moves the needle, no matter how many dose adjustments happen along the way.
This is where Spravato enters the picture.
What Is Spravato (Esketamine)?
Spravato is the brand name for esketamine, a prescription nasal spray approved by the FDA for adults with treatment-resistant depression. It works differently from standard antidepressants. Instead of targeting serotonin, it acts on a brain chemical called glutamate. That different mechanism is part of why it can help people who never responded to SSRIs or SNRIs.
Spravato was first approved in 2019 for use alongside an oral antidepressant. In January 2025, the FDA expanded that approval. Spravato can now be used on its own, as a standalone treatment, for adults who have not responded to at least two oral antidepressants. That gives providers more flexibility than before.
It is also approved for adults with major depressive disorder who are having suicidal thoughts, used together with an oral antidepressant in that specific situation.
How a Spravato Treatment Session Actually Works
A lot of patients picture something complicated when they hear about esketamine treatment. In practice, it follows a clear routine.
You self-administer the nasal spray at a certified clinic, under the direct supervision of your provider. You do not take it home. Every dose happens in person, in the office.
A typical visit includes:
- A check of your blood pressure and how you are feeling before you start
- Self-administering the nasal spray while your provider observes
- A required monitoring period of at least two hours afterward
- A final check to confirm you are stable before you leave
- A ride home, since driving yourself is not allowed that day
Treatment usually starts with two sessions a week for about four weeks. After that, most people move to once a week, then space out further to every other week or once a month, depending on how they respond. Your provider adjusts that schedule based on your progress, not a fixed calendar.
Why the Monitoring Requirement Exists
Some patients hear about the two-hour monitoring rule and assume something is wrong with the medication. That is not quite right.
Spravato carries a boxed warning, the strongest safety label the FDA uses, because of the risk of sedation and dissociation right after a dose. It is also a Schedule III controlled substance, which means it carries some potential for misuse.
Because of those risks, Spravato is only available through a restricted safety program called the Spravato REMS, short for Risk Evaluation and Mitigation Strategy. It requires every dose to be given in a certified setting, with trained staff watching closely for side effects in real time.
In plain terms, the monitoring is not red tape. It is the reason this medication can be offered safely outside a hospital at all.
What Side Effects Should You Expect?
Most side effects show up during the monitoring window and fade within a couple of hours. The most common ones include:
- A feeling of disconnection from your surroundings, sometimes described as floating or detached
- Drowsiness or feeling foggy
- Dizziness
- Nausea
- A short-term rise in blood pressure
Your care team checks your blood pressure throughout the session and watches for these effects directly. Most patients describe the dissociative feeling as strange rather than frightening, and it typically fades well before the two hours are up.
How Spravato Differs From Ketamine Clinics
You may have seen ads for ketamine clinics and wondered if it is the same thing. It is not, and the difference matters.
Ketamine itself is not FDA-approved for depression. Clinics that offer it are using it off-label, usually through an IV. There is no standard dosing schedule and no required monitoring program, since the FDA has not built specific safety requirements around that use.
Esketamine, the active ingredient in Spravato, is one-half of the ketamine molecule, isolated and reformulated as a nasal spray. It went through a full FDA review specifically for depression. That means clear dosing guidelines, a required safety program, and in many cases, insurance coverage that ketamine clinics rarely offer.
Both approaches can help some patients. Only one comes with FDA-backed evidence built specifically around treating depression.
Spravato Works Best as Part of a Bigger Plan
Medication alone rarely tells the whole story, and Spravato is no exception. Most people get the best results when it is paired with ongoing psychotherapy, not used in isolation.
Therapy helps with the patterns of thinking that medication cannot reach on its own. Sleep, exercise, and stress levels all play a role, too. Your provider should be tracking your mood and symptoms at every visit, not just running through the monitoring checklist and sending you home.
Is Spravato the Right Next Step for You?
Spravato is not a first option. It comes into the conversation after standard antidepressants have had a fair chance and have not worked well enough. If you are just starting medication for depression, a more typical first approach is usually the better place to begin.
But if you have already tried two or more antidepressants without enough relief, it may be time to ask about it. Your provider will also review your health history first, including blood pressure and any history of substance misuse, since both factors contribute to whether Spravato is appropriate for you. A proper psychiatric evaluation is the only way to know for sure whether you meet the criteria.
Frequently Asked Questions
What does treatment-resistant depression mean exactly?
It generally means you have tried two or more antidepressants, at a full dose for a full length of time, without enough improvement in your symptoms.
How fast does Spravato work?
Some people notice a difference within hours or days, which is much faster than typical antidepressants. Full benefit still builds over the first several weeks, and results vary from person to person.
Is Spravato the same as ketamine therapy?
No. Spravato contains esketamine, which went through full FDA approval specifically for depression. Ketamine clinics use a different, off-label form of the drug, usually given through an IV.
Will I be able to drive home after treatment?
No. You will need someone to drive you home after every session, since the medication can affect coordination and alertness for a few hours.
Does insurance cover Spravato?
Many insurance plans cover Spravato for patients who meet the treatment-resistant depression criteria. Coverage details vary by plan, so it is worth confirming with your insurer before starting.