If you or someone you love is considering Spravato (esketamine) for treatment-resistant depression, the question of developing a tolerance to Spravato has probably crossed your mind. It is a fair one, and it deserves a straight answer.
The short answer: Tolerance to Spravato is possible with prolonged or frequent use, but it is much less of a concern with Spravato than with many other medications. The structured, supervised dosing schedule is specifically designed to minimize this risk. Most patients go through treatment without experiencing a significant loss of effectiveness over time.
Here is what you actually need to know when weighing the risks and benefits of Spravato.
What Does “Tolerance” Even Mean?
Tolerance happens when your body adapts to a medication over time. Essentially, the same dose produces a weaker response than it did before. With some drugs, this can become a serious problem because doses need to keep climbing to get the same effect.
With Spravato, clinicians take this seriously. The FDA prescribing information notes that tolerance has been reported with prolonged ketamine use. Because Spravato is the S-enantiomer of ketamine, similar tolerance would be expected with prolonged esketamine use. That is why the dosing structure matters so much.
Why Spravato Is Designed Differently
Spravato is not taken every day at home like a traditional antidepressant. It follows a very specific schedule that actually works in your favor when it comes to tolerance.
Here is how the schedule works:
- Induction phase (weeks 1 to 4): Treatments twice per week
- Maintenance phase (months 2 to 3): Treatments once per week
- Long-term maintenance: Treatments once every one to two weeks
That built-in spacing is intentional. It gives your brain time to respond and reset between sessions. This is very different from the kind of daily, frequent use that tends to produce tolerance in other medications.
How Spravato Works in the Brain
Understanding the mechanism helps put the question of tolerance in perspective.
Spravato works by targeting NMDA receptors, which are glutamate receptors in the brain. This is a completely different pathway from traditional antidepressants like SSRIs or SNRIs, which work on serotonin and norepinephrine.
In depression, the brain shows structural and functional changes at synapses. Spravato appears to help restore that synaptic connectivity by acting on glutamate signaling. The result is that changes can happen faster, often within hours to days rather than weeks. You can read more about that in our post on how effective Spravato is for depression.
Because the mechanism is so different from traditional antidepressants, the tolerance picture also looks different. The concern is real but manageable, especially within the supervised framework that Spravato requires.
What the Real-World Evidence Shows
A major study called the Esketamine CoHOrt (ECHO) study followed 570 real-world patients with treatment-resistant depression across Europe and Israel. Patients received treatment for an average of about 9 months. The results supported durable effectiveness without needing continuous dose escalation to maintain results.
That is meaningful. It suggests that when Spravato is used as directed, many patients can maintain their response over time.
That said, everyone’s brain is different. Some patients may notice changes in how they respond over time. That is exactly why every Spravato session at our practice happens in-office with clinical oversight. We are watching, we are tracking your response, and we will adjust the plan if needed.
How We Monitor and Manage This for You
Every Spravato session at Autumn Leaves Psychiatry is administered in our certified clinical setting here in Idaho Falls, with patients coming from Ammon, Pocatello, Blackfoot, and surrounding communities in eastern Idaho. You are never on your own with this treatment.
During each session, our team monitors how you are doing. After the induction phase, we evaluate whether the treatment is working and whether continuing makes sense. If your response changes, we will talk about it together and figure out the next step.
The goal is always to use the lowest effective dose and the right frequency. More is not always better, and we take that seriously.
A Note on Dependence vs. Tolerance
These two concepts often get lumped together, but they are different.
Tolerance means you need more of a drug to get the same effect.
Dependence means your body relies on the drug and may react if you stop suddenly.
Spravato carries some risk of both with prolonged use, which is another reason it is a controlled substance (Schedule III) and only available in certified healthcare settings. It is not a medication you pick up at a pharmacy and take on your own. That controlled environment is a feature, not a limitation. It exists to protect you.
Is Spravato Right for You?
If you have tried multiple antidepressants without success, or if you are dealing with severe depressive symptoms that have not responded to standard treatment, Spravato may be worth a serious conversation. The tolerance question is real, but it is also manageable within the right clinical framework.
Our team serves patients throughout the greater Idaho Falls area, including Rexburg, Pocatello, Blackfoot, and Ammon. We offer personalized evaluations to help you understand whether Spravato fits your situation. No pressure, no generic answers. Just an honest conversation about your options.
Ready to Learn More?
If you are curious about Spravato and want to talk through whether it makes sense for you, reach out to our team. We are here to answer your questions clearly and help you take the next step with confidence.
Frequently Asked Questions About Tolerance to Spravato
Can Spravato stop working over time?
It is possible for some patients to notice a reduced response with prolonged use, since the FDA notes that tolerance has been reported with extended ketamine use and similar effects could apply to esketamine. However, the structured dosing schedule, which spaces sessions out more and more over time, is specifically designed to reduce this risk. Many patients maintain their response through long-term maintenance dosing. If your response does change, your provider can evaluate the treatment plan and adjust accordingly.
What happens if Spravato becomes less effective for me?
If you and your provider notice that Spravato is becoming less effective, the next step is a thorough clinical review. Options may include adjusting your dosing frequency, reassessing your oral antidepressant regimen, or exploring other treatment approaches. You are not left without options. That is exactly why every Spravato session happens in a supervised clinical setting rather than at home.
Is tolerance to Spravato the same as addiction?
No, these are different things. Tolerance means your body adapts so that the same dose produces a weaker effect over time. Addiction involves compulsive drug-seeking behavior despite harm. Spravato does carry some potential for physical dependence with prolonged use, which is why it is a controlled substance administered only in certified healthcare settings. The supervised structure significantly reduces misuse risk compared to medications taken independently at home.
How long can you stay on Spravato?
There is no universal cutoff. The FDA-approved protocol includes an induction phase of twice-weekly treatments for 4 weeks, followed by weekly and then biweekly maintenance doses. Some patients benefit from longer-term maintenance treatment. Your provider evaluates your response after the induction phase and continues to reassess over time. The goal is always to use the least frequent dosing that keeps your depression controlled.
Does everyone experience tolerance to Spravato?
No. Many patients complete induction and move into long-term maintenance dosing without significant loss of effectiveness. Real-world data from the ECHO study, which followed patients for an average of about 9 months, supported durable outcomes without dose escalation in a large portion of participants. Individual responses vary, which is why ongoing monitoring matters throughout treatment.
Can I take a break from Spravato and restart it later?
This is a question worth discussing directly with your provider, as it depends on your specific history and how your depression has responded. Some patients do take breaks and later resume treatment. Stopping too abruptly after prolonged use can carry some risk, so any changes to your Spravato schedule should always happen in coordination with your clinical team, not independently.