The mission of the Interventional Psychiatry Network is to spread knowledge about emerging mental health treatments, and one of the most intriguing developments right now is in how we manage the calibration of esketamine dose for treatment-resistant depression (TRD). This article explains the recent findings from the TRANSFORM-2 study in simple language for clinicians, students, researchers, and patients.
Why dose matters in esketamine therapy
The nasal spray formulation of esketamine (brand name Spravato) was approved in 2019 for adults with TRD, in conjunction with an oral antidepressant, and more recently for monotherapy in some cases. The core question now is not simply whether it works, but how best to use it, including how to calibrate esketamine dose to achieve optimal symptom improvement with acceptable tolerability.
What the TRANSFORM-2 study showed
In the phase 3 TRANSFORM-2 trial, adults with major depressive disorder (MDD) who had failed at least two oral antidepressants in the current episode were randomized to receive either esketamine nasal spray plus a new oral antidepressant, or a new oral antidepressant plus placebo nasal spray.² The primary endpoint was the change from baseline to day 28 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.
The trial allowed flexible dosing of esketamine (56 mg starting dose with the option to up-titrate to 84 mg on days 4, 8, 11, or 15, twice weekly for 4 weeks).³ The results showed a statistically significant difference between the esketamine arm and control (least-squares mean difference around -4.0 in MADRS score at day 28) in favor of esketamine.
A key insight from this analysis was that participants whose dosing was titrated to 84 mg achieved numerically greater mean reductions in MADRS compared with those who remained at 56 mg. Although full split-dose data may not have been the main published endpoint, post-hoc analyses and dose-management data suggest benefit from early up-titration.
How this informs calibration of esketamine dose in practice
For clinicians and teams working in interventional psychiatry, here are practical takeaways on dose calibration:
- Begin with the approved starting dose (for example, 56 mg in the study) alongside a new oral antidepressant, then consider early up-titration to 84 mg if tolerated.
- Monitoring symptoms via MADRS (or equivalent clinical scale) offers a quantitative checkpoint. The study defined significant improvement as change in total score, and a clinically meaningful change has been argued in literature to be about 6 to 9 points on MADRS.
- Safety and tolerability remain central. In TRANSFORM-2 the safety profile between 56 mg and 84 mg was similar, with few discontinuations due to adverse events.³
- Dose calibration should be individualized, taking into account patient age, comorbidities, prior treatment history, and risk factors (such as dissociation, blood pressure increases, or sedation).
- Shared decision-making is key. Patients should be informed about possible benefits of higher dose versus potential side effects, and treatment teams should plan for monitoring and support during the dosing and induction period.
What this means for clinics, students, and patients
For clinicians, these findings reinforce that the right dose of esketamine is not static but may need early adjustment based on patient response and safety. For students and researchers, this trial illustrates how dose-titration strategies in neuromodulation or novel pharmacologic therapies can influence outcomes and how trial design impacts translation into practice. For patients, it means that if they are undergoing esketamine therapy for TRD, they should feel empowered to ask about dose strategy, monitoring plans, and what to expect in terms of timeline for improvement.
Looking ahead
While the calibration of esketamine dose is already showing promise, longer-term data are important. Maintenance strategies, real-world effectiveness, functional outcomes (not just symptom scores), and optimal integration with psychotherapy or other interventional modalities remain areas of active investigation. For example, recent real-world analyses show functional remission rates around 25.6 percent at six months for patients treated with esketamine nasal spray in addition to oral antidepressants.
In summary, the concept of calibration of esketamine dose invites a more dynamic, tailored approach to treatment-resistant depression, moving beyond approved starting dose to optimized therapeutic dose within an interventional psychiatry framework.
References
- Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438. (pubmed.ncbi.nlm.nih.gov)
- Clarification on 24-Hour Endpoint of SPRAVATO from TRANSFORM-2 Study. Janssen Medical Connect. (jnjmedicalconnect.com)