Can Esketamine Work Alone Without Other Antidepressants for Treatment-Resistant Depression?
Yes. Esketamine nasal spray works effectively as monotherapy for treatment-resistant depression, with significant improvements observed within 24 hours of the first dose and sustained through 28 days of treatment. A randomized clinical trial published in JAMA Psychiatry shows both 56mg and 84mg doses administered twice weekly provide rapid and clinically meaningful improvement compared to placebo, offering a standalone treatment option for patients who cannot tolerate or have not responded to oral antidepressants.
What the data show:
- Rapid onset: Significant improvements observed within 24 hours of first dose, dramatically faster than conventional antidepressants
- Sustained efficacy: Benefits maintained throughout 28 days of twice-weekly treatment
- Dose response: Both 56mg and 84mg doses showed statistically significant and clinically meaningful improvement versus placebo
- Treatment-resistant population: Study included 378 adults who had failed multiple antidepressant trials
- Monotherapy efficacy: Effective as standalone treatment without requiring concurrent oral antidepressants
- Response rates: Significantly higher response and remission rates compared to placebo
- Mechanism: Esketamine works by rapidly blocking NMDA receptors, leading to increased glutamate release, enhanced synaptic plasticity, and rapid restoration of neural connections in brain regions involved in mood regulation - this mechanism explains the rapid onset of antidepressant effects within hours rather than weeks
Dr. Kumar’s Take
This is a game-changer for treatment-resistant depression. Until now, esketamine was only approved as an add-on to oral antidepressants, but this study proves it can work as monotherapy. The fact that patients saw improvement within 24 hours - compared to weeks with traditional antidepressants - is remarkable. This opens up esketamine treatment for patients who can’t tolerate oral antidepressants or have failed multiple medications. It’s particularly valuable for patients experiencing treatment-limiting side effects from conventional antidepressants.
Study Snapshot
This double-blind, multicenter, randomized clinical trial enrolled 378 adults with treatment-resistant depression across multiple sites. Participants were randomized to receive esketamine nasal spray at 56mg, 84mg, or placebo, administered twice weekly for 28 days. The study used the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary efficacy endpoint, with assessments conducted at multiple timepoints including 24 hours post-first dose.
Results in Real Numbers
Both esketamine doses demonstrated statistically significant and clinically meaningful improvements compared to placebo. The 56mg and 84mg doses showed rapid onset of antidepressant effects, with significant improvements observed as early as 24 hours after the first dose. These improvements were sustained throughout the 28-day double-blind treatment phase.
The efficacy analysis dataset included patients who had failed to respond to adequate trials of multiple antidepressants, representing a truly treatment-resistant population. Response rates and remission rates were significantly higher in both esketamine groups compared to placebo, with dose-dependent effects observed between the two active treatment groups.
Safety and tolerability profiles were consistent with previous esketamine studies, with dissociative symptoms being the most common side effects, typically resolving within hours of administration.
Who Benefits Most
Patients with treatment-resistant depression who have failed multiple oral antidepressant trials may benefit most from esketamine monotherapy. The study findings particularly support this approach for patients experiencing treatment-limiting tolerability concerns with oral antidepressants or those showing nonresponse to conventional treatments.
Individuals who require rapid symptom relief may be ideal candidates, given the 24-hour onset of effects compared to the weeks typically required for oral antidepressants. Patients who have discontinued oral antidepressants due to side effects now have a monotherapy option that doesn’t require concurrent oral medication.
Safety, Limits, and Caveats
Esketamine requires administration in certified healthcare facilities with monitoring for dissociative effects and blood pressure changes. The study was conducted over 28 days, so longer-term monotherapy outcomes require further investigation. Individual responses vary, and not all patients with treatment-resistant depression will respond to esketamine monotherapy.
The treatment requires twice-weekly clinic visits initially, which may be challenging for some patients. Insurance coverage for monotherapy use may differ from the previously approved combination therapy indication.
Practical Takeaways
- Discuss esketamine monotherapy with specialized providers if you have treatment-resistant depression and have struggled with oral antidepressant tolerability
- Understand that esketamine can now be considered as a standalone treatment rather than only as an add-on to other antidepressants
- Prepare for twice-weekly clinic visits initially and plan for monitoring requirements during and after each treatment session
- Recognize that rapid improvement (within 24 hours) is possible, which differs dramatically from conventional antidepressant timelines
- Consider this option if you’ve discontinued oral antidepressants due to side effects but still need depression treatment
What This Means for Depression Treatment
This trial establishes esketamine as a viable monotherapy option for treatment-resistant depression, expanding treatment possibilities for patients who cannot tolerate or have not responded to oral antidepressants. The rapid onset of action provides hope for patients needing urgent symptom relief.
The findings also support a paradigm shift toward considering esketamine as a primary treatment rather than just an adjunctive option for appropriate patients with treatment-resistant depression.
Related Studies and Research
- Ketamine vs Esketamine: Systematic Review Comparison
- STAR*D Treatment Steps and Declining Success Rates
- 21 Antidepressants Compared: Network Meta-Analysis
- Major Depressive Disorder: Comprehensive Overview
FAQs
How quickly does esketamine monotherapy work?
The study showed significant improvements within 24 hours of the first dose, which is dramatically faster than conventional antidepressants that typically take weeks to show effects.
Is esketamine monotherapy as effective as combination therapy?
This study demonstrates efficacy as monotherapy, but direct comparisons to combination therapy would require head-to-head trials. The choice depends on individual patient factors and tolerability.
Who is a good candidate for esketamine monotherapy?
Patients with treatment-resistant depression who have failed multiple oral antidepressants, especially those with tolerability issues or nonresponse to conventional treatments.
Bottom Line
Esketamine nasal spray monotherapy provides rapid and sustained improvement in treatment-resistant depression within 24 hours, offering a new standalone treatment option for patients who cannot tolerate or have not responded to oral antidepressants. This expands treatment possibilities for one of the most challenging patient populations in psychiatry.
