A New Oral Option: Esketamine Shows Promise for Tough-to-Treat Depression

Posted: June 4, 2025

The Challenge of Treatment-Resistant Depression

Major depressive disorder (MDD) is a common and debilitating mental health condition that affects millions worldwide. While many individuals find relief with standard antidepressant medications and psychotherapy, a significant portion, estimated to be up to one-third of patients, do not respond adequately to multiple treatment attempts. This is known as treatment-resistant depression (TRD), a condition that poses a profound challenge for both patients and clinicians. Individuals with TRD often endure prolonged periods of suffering, impaired functioning, and a significantly reduced quality of life. The search for effective and accessible treatments for this population is therefore a critical area of psychiatric research. In recent years, ketamine, an anesthetic medication, has emerged as a rapid-acting antidepressant, particularly for TRD. Its S-enantiomer, esketamine, has been approved in an intranasal formulation for TRD in conjunction with an oral antidepressant. While intravenous (IV) and intranasal esketamine have shown efficacy, they often require administration in a clinical setting, which can present logistical and accessibility challenges. This has spurred interest in oral formulations of esketamine, which could offer advantages in terms of convenience and patient-friendliness. This article will explore the findings of a recent study by Veraart et al. (2025), published in the Journal of Psychopharmacology, which investigated the effectiveness, safety, and tolerability of oral esketamine in a real-world setting for patients with severe TRD. Our goal is to present this information in a professional yet approachable way for those seeking to understand new options in psychedelic psychotherapy, particularly for difficult-to-treat depression.

Understanding Esketamine and Its Role in Depression

Ketamine, and by extension its component esketamine, works differently from traditional antidepressants like SSRIs (Selective Serotonin Reuptake Inhibitors) or SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors). While traditional antidepressants primarily target monoamine neurotransmitter systems (serotonin, norepinephrine, dopamine), a process that can take weeks to yield effects, esketamine is thought to exert its antidepressant effects primarily through the glutamatergic system, specifically by modulating NMDA (N-methyl-D-aspartate) receptors. This different mechanism of action is believed to contribute to its rapid antidepressant effects, often seen within hours or days rather than weeks. The development of esketamine, particularly in its intranasal form (Spravato®), marked a significant advancement in TRD treatment. However, the administration protocol for intranasal esketamine typically involves self-administration under the supervision of a healthcare professional in a certified clinic, followed by an observation period. This is due to potential side effects such as dissociation, sedation, and transient increases in blood pressure. An effective and well-tolerated oral formulation could potentially simplify treatment delivery, reduce the burden on healthcare facilities, and improve accessibility for patients, provided safety can be maintained.

Investigating Oral Esketamine in a Real-World Setting

The study by Veraart and colleagues aimed to address the gap in knowledge regarding oral esketamine for TRD by evaluating its use in a naturalistic, or "real-world," setting. This is important because clinical trials often have strict inclusion and exclusion criteria, and their results may not always translate directly to the broader, more diverse patient populations seen in everyday clinical practice. Study Design and Participants: The researchers conducted a six-week open-label treatment program involving 185 adults diagnosed with severe TRD. The term "open-label" means that both the researchers and the participants knew what treatment was being administered (there was no placebo group in this specific part of the evaluation, though the authors note the outcomes were in the range of studies investigating other routes which often do have placebo arms). The participants in this study were highly treatment-resistant; on average, they had previously tried 8.1 different antidepressant treatments without success, and 63% had even undergone electroconvulsive therapy (ECT) without beneficial outcomes. This patient population represents some of the most challenging cases of depression. Participants received oral esketamine twice weekly for six weeks. The doses were individually titrated, meaning they were adjusted based on each patient's response and tolerability, ranging from 0.5 to 3 milligrams per kilogram of body weight (mg/kg).Outcome Measures: To assess the effectiveness of the treatment, the researchers used several measures:

Hamilton Depression Rating Scale (HDRS17): This is a clinician-administered scale widely used to measure the severity of depressive symptoms. The primary outcome was the change in HDRS17 scores from baseline (before treatment) to the end of the six-week period.
Minimal Clinically Important Difference (MCID): This refers to the smallest change in a treatment outcome that a patient would identify as important or beneficial. Achieving MCID suggests the treatment has made a noticeable positive difference.
Response Rate: Typically defined as a 50% or greater reduction in HDRS17 scores from baseline.
Remission Rate: Typically defined as an HDRS17 score below a certain threshold (e.g., ≤7), indicating that the patient is largely free of depressive symptoms.
Self-Reported Symptom Improvement and Functioning: Patients also reported on their own perceived improvement and ability to function in daily life.
Side Effects and Tolerability: The researchers carefully monitored and recorded any side effects experienced by the participants.

Key Findings: Effectiveness of Oral Esketamine

The results of the Veraart et al. (2025) study were encouraging, particularly given the high level of treatment resistance in the study population:

Significant Reduction in Depressive Symptoms: Oral esketamine treatment led to a statistically significant improvement in depressive symptom severity. The average HDRS17 score decreased from 21.2 (indicating moderate to severe depression) at baseline to 15.8 at the end of six weeks.
Clinically Meaningful Improvement: Nearly half of the participants (47.1%) achieved the Minimal Clinically Important Difference (MCID), suggesting that the improvement was not just statistically significant but also subjectively meaningful to the patients.
Response and Remission Rates: The response rate (≥50% reduction in HDRS17) was 26.8%, and the remission rate (symptoms largely absent) was 15.6%. While these numbers might seem modest compared to treatments for less severe depression, they are quite significant in the context of such a highly treatment-resistant group. For individuals who have not benefited from numerous prior treatments, achieving response or remission is a major step forward.
Sustained Benefit and Continued Treatment: Importantly, in 45.9% of participants, the treatment was continued beyond the initial six weeks to maintain the positive effects they had experienced. This suggests that for a substantial subgroup, oral esketamine offered a viable longer-term treatment strategy.

Safety and Tolerability: A Patient-Friendly Option?

A crucial aspect of any new treatment is its safety and how well patients tolerate it. The study by Veraart et al. (2025) found that:

Side Effects Were Common but Tolerable: Side effects were reported frequently, which is common with (es)ketamine treatments. These can include dissociation (feeling detached from oneself or reality), dizziness, nausea, and temporary increases in blood pressure. However, the study reported that these side effects were, overall, well tolerated by the participants.
Low Drop-Out Rate: The drop-out rate due to side effects or lack of efficacy was relatively low at 7.6%. This low rate further supports the notion that the treatment was generally manageable for most patients in the study.
No Significant Urinary Tract or Cognitive Issues: Concerns have been raised in the past about potential long-term effects of ketamine use, particularly regarding urinary tract problems (seen more with chronic, high-dose illicit use) and cognitive impairment. Encouragingly, this six-week study found no significant adverse effects associated with the urinary tract or cognition in the participants receiving oral esketamine.

What This Means for People Uncertain About Psychedelic Psychotherapy

For individuals who are uncertain about psychedelic psychotherapy, particularly when facing severe and persistent depression, these findings offer several points of consideration:

A New Avenue of Hope: For those who feel they have exhausted all other options, the emergence of treatments like oral esketamine provides a new avenue of hope. The fact that it showed effectiveness in a population that had not responded to an average of eight prior treatments, including ECT for many, is significant.
Different from Classic Psychedelics: It's important to understand that esketamine, while it can have dissociative and psychoactive effects, is often considered differently from classic psychedelics like psilocybin or LSD in terms of its subjective experience and therapeutic model. While all fall under the broad umbrella of

psychedelic or psychedelic-like therapies, the approach with esketamine is often more focused on its direct antidepressant effects, though psychological support is still a crucial component.

Oral Formulation Offers Convenience: The potential for an oral formulation that is safe and effective could make treatment more accessible and less burdensome than IV infusions or clinic-based intranasal administration. This could be particularly beneficial for individuals who have difficulty accessing specialized clinics or prefer a less invasive treatment route.
Tolerability and Safety Profile: While side effects are possible, the study suggests that oral esketamine was generally well-tolerated, even in a severely ill population. The absence of significant urinary or cognitive issues in this short-term study is also reassuring, though longer-term monitoring is always important.
Discussion with a Healthcare Professional is Key: As with any treatment for depression, especially TRD, it is crucial for individuals to have a thorough discussion with their psychiatrist or mental health professional. They can help determine if a treatment like oral esketamine is appropriate, considering the individual’s specific history, symptoms, and overall health.

Conclusions: A Promising Development for TRD

The study by Veraart et al. (2025) provides valuable real-world evidence that repeated treatment with oral esketamine can be effective in improving depressive symptom severity in patients with highly treatment-resistant depression. The findings suggest that it is a safe, well-tolerated, and patient-friendly option, with outcomes comparable to other routes of (es)ketamine administration, even in this very challenging patient group. While this research is a promising step forward, more studies, including larger, randomized controlled trials with longer follow-up periods, will be needed to further establish the efficacy, optimal dosing strategies, and long-term safety of oral esketamine for TRD. However, for individuals and clinicians grappling with the often-discouraging reality of treatment-resistant depression, these findings offer a welcome indication that new, more accessible, and effective treatments are on the horizon. The development of an oral option like this could significantly enhance the therapeutic armamentarium for one of the most difficult-to-treat forms of depression.

Disclaimer: Psychedelic Assisted Psychotherapy has not been approved by any regulatory agencies in the United States, and the safety and efficacy are still not formally established at the time of this writing.

Reference

Veraart, J. K., Smith-Apeldoorn, S. Y., van der Meij, A., Spijker, J., Schoevers, R. A., & Kamphuis, J. (2025). Oral esketamine for patients with severe treatment-resistant depression: Effectiveness, safety, and tolerability of a six-week open-label treatment program. Journal of Psychopharmacology, Online ahead of print. https://doi.org/10.1177/02698811251332831 (Abstract retrieved from https://pubmed.ncbi.nlm.nih.gov/40285334/ )