What Happens If Spravato Stops Working?

If you’re considering or currently undergoing treatment with Spravato (esketamine), one of the most important questions you may have is:

“What happens if I get better… and then my symptoms come back?”

It’s a thoughtful and important question—and one that both research and real-world clinical experience can help answer.

In this post, we’ll walk through what the science shows, what we see in practice, and how we approach this situation at Innerbloom.

First: Does Spravato Actually Last?

Spravato is unique compared to traditional antidepressants. Instead of working primarily through serotonin, it targets the glutamate system and promotes neuroplasticity—essentially helping the brain form new, healthier connections.

Because of this, many patients experience rapid improvement, often within weeks rather than months.

But depression—especially treatment-resistant depression (TRD)—is typically a chronic condition. So the real question becomes:

Can Spravato help you stay well over time?

What the research shows

One of the most important studies on this topic is the SUSTAIN-1 trial, published in JAMA Psychiatry.

In this study:

• Patients with TRD were treated with Spravato + an oral antidepressant for about 16 weeks
• Only those who improved significantly (response or remission) continued into the next phase
• Then, they were split into two groups:
  • Continue Spravato
  • Stop Spravato (placebo nasal spray) but continue the antidepressant

The results were clear:

• Among patients who continued Spravato, about 26% relapsed
• Among those who stopped Spravato, about 45–58% relapsed

In other words, continuing Spravato reduced relapse risk by roughly half.

So… Why Do Some Patients Still Relapse?

Even with continued treatment, about 1 in 4 patients experienced a return of symptoms.

This is not a failure of the treatment—it reflects the complexity of depression.

There are several reasons why this can happen:

• Biological variability: Not all brains respond the same way over time
• Dosing frequency: Some patients need more frequent treatment than others
• Life stressors: Work, relationships, health issues, and major life changes matter
• Comorbid conditions: Anxiety, trauma, sleep issues, or medical conditions can drive symptoms
• Integration and support: Therapy and behavioral changes are critical to sustaining gains

Depression is not just a chemical imbalance—it’s a systems-level condition involving brain biology, psychology, and environment.

If You Relapse, Does That Mean Spravato Stopped Working?

Not necessarily.

This is one of the most important (and reassuring) points:

Many patients who relapse can regain benefit with continued or adjusted treatment.

What the research and clinical experience show

While the SUSTAIN-1 trial focused on relapse prevention, follow-up and extension studies (like SUSTAIN-3) and real-world experience show that:

• Some patients improve → worsen → improve again
• Patients who relapse after stopping Spravato can often respond again when treatment is restarted
• Even during ongoing treatment, increasing frequency can help recapture response

In clinical practice, this pattern is not uncommon:
Initial response → partial relapse → adjustment → improvement again

What Do We Do If Symptoms Start Coming Back?

This is where personalized care becomes essential.

At Innerbloom, we don’t view relapse as the end of treatment—we view it as a signal to adjust the plan.

A common and effective approach:

• Increase treatment frequency (e.g., from every 2 weeks → weekly)
• Reassess contributing factors:
  • Sleep quality
  • Anxiety levels
  • Therapy engagement
  • Life stressors
• Continue for ~4–6 weeks to evaluate response

This is similar to a “booster phase” rather than starting from scratch.

Why this works

In the SUSTAIN-1 study, patients who required more frequent dosing (weekly) were more likely to relapse if treatment was stopped—suggesting that some individuals simply need more consistent support.

So when symptoms return, increasing frequency often helps stabilize and restore progress.

How Long Should You Continue If You’re Not Improving Again?

If a patient has relapsed and we’ve increased treatment frequency:

• We typically allow 4–6 weeks to assess whether the benefit returns
• If there is partial improvement, we may continue and build on that
• If there is no meaningful improvement, we reassess the overall treatment strategy

This might include:

• Adjusting medications
• Enhancing psychotherapy
• Addressing medical or lifestyle factors
• Considering alternative treatments (e.g., IV ketamine or TMS)

Is Spravato Meant to Be Long-Term?

For many patients, yes.

This is one of the biggest mindset shifts.

Just like:

• Blood pressure medications
• Diabetes treatments
• Thyroid replacement

Spravato is often part of a long-term management plan, not a one-time intervention.

That said, not everyone needs the same duration or frequency. Some patients:

• Space out to every 2 weeks
• Eventually stop and remain stable
• Need ongoing weekly or intermittent maintenance

There is no one-size-fits-all approach.

What About Twice-Weekly Treatment Long-Term?

This is a common question.

In clinical trials, including SUSTAIN-1:

• Twice-weekly dosing is used during the initial induction phase (first 4 weeks)
• Long-term maintenance is typically weekly or every 2 weeks

There is no strong research data on long-term twice-weekly maintenance, but in select cases, clinicians may temporarily increase frequency to regain stability.

The Bigger Picture: What Actually Sustains Improvement?

Spravato is powerful—but it works best as part of a broader system.

The patients who tend to do best long-term are those who combine treatment with:

• Psychotherapy (especially with someone who understands ketamine/esketamine work)
• Lifestyle changes (sleep, exercise, nutrition)
• Stress management
• Intentional integration of insights and behavioral changes

This is where the concept of neuroplasticity becomes important.

Spravato opens a window for change—but what you do during and after that window determines how lasting those changes are.

Our Perspective at Innerbloom

We think about treatment in three phases:

1. Getting you better (acute response)
2. Keeping you better (maintenance and relapse prevention)
3. Helping you build long-term resilience

Spravato can be an incredibly effective tool—but it’s not a “set it and forget it” solution.

It requires:

• Ongoing evaluation
• Personalization
• And a whole-person approach

Final Thoughts

If you’re worried about relapse, you’re asking the right question.

The research is reassuring:

• Continuing Spravato significantly reduces relapse risk
• Some patients still relapse—but many can improve again with adjustments
• Treatment is dynamic, not static

Most importantly:

Relapse is not failure—it’s feedback.

And with the right approach, it can be a turning point toward more durable, long-term improvement.

About the Author

Dr. Rivas is a ketamine specialist and board-certified acute care and trauma surgeon with over 12 years of experience in ketamine administration. Before founding Innerbloom Ketamine Therapy in 2022, Dr. Rivas served on the frontlines of emergency and trauma medicine in Santa Maria, CA, and Austin, TX. Dr. Rivas applies his extensive medical expertise to provide safe, evidence-based ketamine treatments for mood disorders, including depression, anxiety, PTSD, and chronic pain. His passion lies in helping patients find relief and rediscover hope through personalized, compassionate care.

Newy: Bridging the Gap Between Ketamine Treatment and Everyday Wellness

A supplement formulated by Dr. Rivas for enhanced brain and mood support. The formula pairs especially well with ketamine therapy by helping extend and enhance the neuroplasticity effects. That said, the ingredients are equally effective on their own, so it’s a supportive option whether or not someone is undergoing ketamine treatment. Learn more about how Newy supports cognitive function detoxification and cellular repair.

References

Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2019;76(9):893–903. doi:10.1001/jamapsychiatry.2019.1189

Zaki, Naim et al. “Long-term safety and maintenance of response with esketamine nasal spray in participants with treatment-resistant depression: interim results of the SUSTAIN-3 study.” Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology vol. 48,8 (2023): 1225-1233. doi:10.1038/s41386-023-01577-5

Medical Disclaimer

All content on this website, including but not limited to this article, blog posts, testimonials, and FAQs, is not medical advice and should not be considered as such. This website cannot diagnose or treat any medical condition. Only a licensed medical professional who is familiar with you and your medical history can provide medical advice, diagnosis, or treatment.

The information provided here is for educational and informational purposes only. It is not intended to replace a consultation with a qualified healthcare provider. If you are experiencing symptoms of depression or any mental health condition, please consult with a licensed mental health professional or your primary care physician.

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Ready to explore whether ketamine therapy is right for you? Contact Innerbloom Ketamine Therapy at (805) 592-5085 or visit us at 100 Casa Street, Suite D3, San Luis Obispo, CA 93405.