Key takeaways
- The longest available data on Spravato® (esketamine) covers up to 6.5 years of treatment, and researchers have not identified new safety concerns beyond what’s seen in shorter studies.
- The most common side effects — headache, dizziness, nausea, and dissociation — tend to occur on dosing days and resolve within hours, even with years of continued use.
- Long-term studies have found no evidence of cognitive decline, bladder or urinary tract damage, or increased risk of misuse with Spravato as prescribed.
- Most people who stay on Spravato discontinue treatment for reasons other than side effects, most commonly because symptoms have improved enough that ongoing dosing is no longer needed.
Spravato’s longest available data, covering patients treated for up to 6.5 years, has not identified new long-term safety concerns beyond what’s seen in shorter studies. The most common side effects — headache, dizziness, nausea, and dissociation — are temporary and typically resolve the same day. Long-term studies show no evidence of cognitive decline or bladder damage from prescribed use.
If you’re considering Spravato (esketamine) for treatment-resistant depression (TRD), you may be wondering not just whether it works, but what happens to your body and brain after months or years of treatment. It’s a fair question, as Spravato isn’t a short course of medication. Many patients stay on a maintenance schedule for an extended period to keep symptoms from returning, so understanding what long-term use looks like matters.
The good news is that Spravato now has some of the longest continuous safety data of any treatment developed specifically for TRD, including a study that followed patients for up to 6.5 years.
What is Spravato and how does it work?
Spravato is a prescription nasal spray approved by the FDA for treatment-resistant depression and for depressive symptoms in adults with major depressive disorder who have suicidal thoughts or actions. It’s a form of ketamine, a medicine originally developed as an anesthetic.
Rather than targeting serotonin like most antidepressants, Spravato targets glutamate, a different chemical messenger involved in how brain cells communicate. According to US Food and Drug Administration prescribing information, esketamine is a non-competitive antagonist of the NMDA receptor. Although the exact mechanism behind its antidepressant effect isn’t fully understood, this glutamate-related pathway is believed to support the brain’s ability to form new connections.
Spravato is typically used alongside an oral antidepressant. In a randomized clinical trial, patients in stable remission who continued Spravato had a 51% lower risk of relapse compared to those switched to a placebo nasal spray.
What does long-term safety data show?
The most detailed picture of Spravato’s long-term effects comes from SUSTAIN-3, an open-label study that followed 1,148 adults with TRD for a mean of about 3.5 years, with some patients treated for up to 6.5 years. Researchers found that the overall safety profile held steady over time, with no new safety signals compared to shorter studies.
A few specific findings from this long-term data stand out:
- Cognitive function remained stable. Performance on tests of memory, learning, and executive function did not decline over years of treatment, in both younger and older adult patients.
- No cases of treatment-related bladder or urinary tract damage were reported. This matters because long-term, off-label misuse of ketamine has been linked to bladder problems in some people. That pattern was not observed in this monitored, prescribed use.
- Blood pressure increases didn’t worsen with continued use. Spravato can raise blood pressure shortly after dosing, but this effect didn’t become more frequent or severe over years of treatment.
- There was no evidence of increasing misuse or abuse. Esketamine is a controlled substance because of its abuse potential, but researchers found no signal of growing misuse within the structure of supervised, in-clinic dosing.
- Most people who stopped treatment did so for reasons other than side effects. Across the study, only about 6% of participants discontinued Spravato specifically because of an adverse event.
“What’s reassuring about this data is that it’s not just safety holding steady. Symptom improvement held steady too,” said Joshua Flatow, MD, medical director and chief psychiatrist at Pacific Mind Health. “Patients aren’t just tolerating years of treatment. Many are staying well because of it.”
What are the most common side effects over time?
Even with years of treatment, the most frequently reported side effects in long-term studies are the same ones patients typically notice early on: headache, dizziness, nausea, dissociation, fatigue, and a temporary rise in blood pressure. These effects are almost always tied to the day of dosing rather than building up between sessions, and the large majority resolve the same day they occur.
Dissociation, a temporary sense of detachment from your body, thoughts, or surroundings, remains the most recognizable effect of Spravato, even after extended use. It typically begins within minutes of treatment and resolves within a couple of hours. This is one reason every Spravato session includes direct clinical supervision and at least two hours of monitoring, regardless of how long someone has been in treatment.
Are there any risks unique to long-term use?
Long-term Spravato studies specifically monitor for issues that wouldn’t show up in shorter trials, including effects on the liver, kidneys, and bladder, along with ongoing cognitive testing. So far, this monitoring hasn’t turned up new safety concerns tied specifically to extended use.
That said, “long-term” in Spravato research still means a defined, monitored period of years, not an indefinite, open-ended timeline. Researchers continue to study Spravato as more patients reach longer treatment durations, and your clinician will reassess your treatment plan on an ongoing basis rather than assuming long-term use is automatically appropriate for everyone.
How does maintenance treatment work?
Most Spravato treatment plans follow a similar pattern, though your clinician will adjust based on your response:
- Induction phase: Two sessions a week for about four weeks.
- Optimization phase: Treatment frequency reduces to once a week for several weeks.
- Maintenance phase: Sessions typically taper further, often to once every one to two weeks, depending on how you’re doing.
- Booster sessions: These can be scheduled if symptoms return or during particularly stressful periods.
Your care team will check in regularly, monitor for side effects, and adjust your schedule as needed. Staying in communication with your provider, especially about how you’re feeling between sessions, is one of the most useful things you can do to support both safety and long-term symptom relief.
If you or someone you know is in crisis, call or text 988 to reach the Suicide and Crisis Lifeline.
Looking for Spravato or ketamine treatment near you?
Pacific Mind Health offers Spravato (esketamine) and ketamine therapy for treatment-resistant depression, major depressive disorder, and more.
Located in Southern California and serving patients across the state, Pacific Mind Health was founded by Joshua Flatow, MD, a board-certified psychiatrist and published peer-reviewed research author.
Ready to take the next step? Schedule a free consultation today to see if Spravato or ketamine is right for you.
Frequently asked questions
What are the most common long-term side effects of Spravato?
The most common side effects in long-term studies are the same ones seen early in treatment: headache, dizziness, nausea, dissociation, and fatigue. These are typically tied to the day of dosing and resolve within hours, even after years of treatment.
Does Spravato cause cognitive decline over time?
Long-term studies, including data covering up to 6.5 years of treatment, have found that cognitive function remains stable over time, with no evidence of meaningful decline in memory, learning, or executive function.
Can Spravato cause bladder problems with long-term use?
Long-term, off-label misuse of ketamine has been linked to bladder issues in some people, but no cases of treatment-related bladder or urinary tract damage have been reported in long-term Spravato studies of prescribed, supervised use.
Is Spravato safe to use indefinitely?
“Long-term” in current research refers to a monitored period of several years, not an open-ended timeline. Your clinician will regularly reassess whether continued treatment, dose adjustments, or a different approach makes sense for you.
Why do people stop taking Spravato?
In long-term studies, most people who discontinued Spravato did so for reasons other than side effects — most often because their symptoms had improved enough that ongoing treatment was no longer needed. Only a small percentage stopped specifically due to an adverse event.
