What Dropout Rates Reveal About NMDA Therapy Tolerability

The News: A Closer Look at Who Stops NMDA Treatment and Why

A new analysis published in Psychiatric Times in April 2026 is drawing attention to an underexamined dimension of NMDA receptor antagonist therapy for treatment-resistant depression (TRD): not just whether these medications work, but how well patients tolerate them over time — and what happens when they don't. The piece, written from a clinical vantage point, calls on psychiatrists to move faster and more deliberately: optimize doses sooner, switch agents when a patient isn't responding, and deploy structured tools like the PHQ-9 alongside side effect tracking to accelerate the path to remission.

NMDA receptor antagonists approved or used for TRD currently include IV racemic ketamine (administered off-label) and intranasal esketamine (Spravato, FDA-approved). Both work through the same basic mechanism — blocking NMDA glutamate receptors — but differ in bioavailability, administration route, dosing frequency, and side effect character. The Psychiatric Times piece draws on available trial data and real-world clinical experience to profile how these differences play out in tolerability and dropout.

Discontinuation rates in clinical trials for NMDA antagonists vary considerably depending on the agent and study design, but adverse effects consistently appear among the top reasons patients stop treatment. Dissociation, dizziness, nausea, elevated blood pressure, and perceptual disturbances are the most commonly reported side effects. For esketamine specifically, the FDA-mandated REMS program requires patients to be monitored in-clinic for at least two hours post-dose — a logistical burden that itself contributes to dropout independent of tolerability.

Reading Between the Lines: What Discontinuation Data Actually Tells Us

Dropout statistics in psychiatric drug trials are rarely straightforward. When a patient stops NMDA antagonist therapy, the reason matters enormously — and the categories don't always map cleanly onto what researchers measure. A patient who discontinues because symptoms fully remitted is categorically different from one who quits because of intolerable dissociation or a spike in blood pressure. Yet both count as discontinuations in aggregate analyses. The clinical community has been slow to parse this distinction rigorously, which is part of what makes this Psychiatric Times piece a useful corrective.

The analysis underscores something clinicians increasingly recognize: side effect burden is not static. For many patients, the acute dissociative and perceptual effects of ketamine diminish with repeated sessions. What feels destabilizing during session one may become manageable or even unremarkable by session four or five. This temporal arc is important context when interpreting early dropout data — some patients who stopped treatment might have adjusted well had the clinical team provided more anticipatory guidance or made proactive dosing modifications.

The article's emphasis on dose optimization is particularly relevant here. Unlike many antidepressants where the therapeutic dose is relatively fixed, NMDA antagonists allow for more granular adjustment. For IV ketamine, the standard 0.5 mg/kg infusion over 40 minutes is a starting convention, not a ceiling or a floor. Some patients do better at lower doses with longer infusion times; others may need upward titration. The key variable is finding the threshold where antidepressant effects are achieved without side effects that undermine adherence. The Psychiatric Times piece argues that clinicians are currently too slow to make these adjustments — and that the delay costs patients meaningful recovery time.

The recommendation to track PHQ-9 scores systematically alongside side effect documentation is straightforward in principle but inconsistently practiced. Standardized outcome tracking allows clinicians to distinguish true non-response from adequate-but-slow response, and to make switching decisions based on data rather than clinical gestalt. For patients navigating TRD, where the stakes of a prolonged ineffective treatment are high, this kind of structured monitoring can meaningfully compress the timeline to finding an effective regimen.

One area the article touches on carefully is the question of which patients are most likely to discontinue — and why this matters for initial treatment selection. Patients with histories of dissociative symptoms, high baseline anxiety, or significant cardiovascular concerns may be at elevated risk for side-effect-driven dropout and may benefit from modified protocols, more intensive pre-session preparation, or a preference for one NMDA agent over another. This is an area where clinical trial data is still catching up to practice, and where individualized assessment remains essential.

What This Means If You're Currently in — or Considering — Low-Dose Ketamine Treatment

For readers of this site, the practical implications of this analysis are real and specific. First, it reinforces the case for choosing a provider who monitors outcomes systematically, not just symptomatically. A clinic that tracks your PHQ-9 at each session, documents side effects with some structure, and is willing to adjust your dose or protocol based on what they observe is operating closer to the clinical standard being advocated here. That kind of responsive, data-informed care is meaningfully different from a one-size-fits-all approach.

Second, this analysis is a useful reminder that the side effect experience is not fixed at your first session. Many patients approach their initial infusion with a great deal of anxiety about dissociation or perceptual disturbances, and some do find those experiences difficult. But the available evidence — and the clinical experience reflected in this piece — suggests that tolerability tends to improve over the course of a treatment series for most patients. Setting realistic expectations before treatment begins can reduce the likelihood of abandoning a potentially effective therapy after one uncomfortable session.

Third, if you're approaching a decision about low-dose ketamine for treatment-resistant depression and have concerns about side effects, this is exactly the kind of nuanced conversation worth having with your prescriber before your first session. Questions worth asking: What is your protocol if I find the standard dose too intense? How do you adjust the infusion rate or dose based on my response? How will we know if it's working, and how long will we give it before reconsidering?

The broader message from this Psychiatric Times analysis is that NMDA antagonist therapy for TRD is still a field in active clinical refinement. The medications are not new, but the frameworks for optimizing their use — who gets what dose, how quickly clinicians intervene when something isn't working, how side effects are tracked and responded to — are becoming more sophisticated. That's good news for patients, particularly those who have tried multiple antidepressants without meaningful relief. The original article is available at Psychiatric Times.