What the Research Says
A new analysis published in Psychiatric Times (April 2026) takes a close look at the side effect profiles and discontinuation rates associated with NMDA receptor antagonists — the drug class that includes both IV ketamine and intranasal esketamine (Spravato) — in patients with treatment-resistant depression (TRD). The piece synthesizes emerging clinical data and calls on prescribers to move faster and more systematically: optimize dosing sooner, pivot to alternative treatments when early signals are weak, and use structured outcome tracking tools like the PHQ-9 to guide decisions rather than relying on subjective impressions alone.
The core concern driving this guidance is that patients with TRD often spend too long on a treatment that isn't working — or that they're tolerating poorly — before a change is made. In a population that has already failed two or more antidepressant trials, time matters. Every extra week in a poorly tolerated or ineffective protocol is a week of continued suffering.
Understanding NMDA Antagonists and Their Side Effect Landscape
NMDA receptor antagonists work differently from conventional antidepressants. Rather than modulating serotonin or norepinephrine over weeks, these agents act on glutamate pathways and often produce rapid — sometimes within hours — improvements in depressive symptoms. But that mechanism also comes with a distinct and sometimes challenging side effect profile.
The most commonly reported effects during and shortly after ketamine or esketamine administration include dissociation (a feeling of detachment from one's body or surroundings), perceptual disturbances, nausea, dizziness, elevated blood pressure, and sedation. For most patients, these effects are transient — they peak during or just after infusion and resolve within one to two hours. But for a meaningful subset of patients, these experiences are distressing enough to prompt early discontinuation.
The Psychiatric Times analysis highlights that discontinuation rates across NMDA antagonist trials are not trivial. While exact figures vary by study design, patient population, and specific agent used, dropout due to adverse effects is a recognized challenge — and one that clinicians are being urged to address proactively rather than reactively. That means setting clear expectations before treatment begins, monitoring systematically at each session, and having a structured decision framework for when to adjust dose, switch agents, or stop treatment entirely.
Why This Matters Now
For patients and families navigating the landscape of ketamine-based therapies in 2026, this research is significant for a few reasons.
First, it confirms that the side effect conversation is not just a box-checking exercise — it's a clinical variable with real consequences for whether treatment succeeds or fails. A patient who feels blindsided by dissociative effects during their first infusion is far more likely to discontinue before reaching the number of sessions typically associated with sustained benefit. Informed patients, by contrast, tend to tolerate these effects better because they've been prepared for them.
Second, the push for structured outcome tracking — specifically the use of validated tools like the PHQ-9 at regular intervals — reflects a broader maturation in how ketamine therapy is being delivered. The early years of ketamine clinics were sometimes characterized by a lack of standardization: variable dosing protocols, inconsistent follow-up, and minimal documentation of outcomes. What this guidance calls for is a more rigorous, data-informed approach that mirrors how evidence-based medicine works in other specialties.
Third, the emphasis on switching sooner when early response is poor has direct implications for how patients should think about their treatment timeline. If you've completed three or four sessions and your depression scores haven't budged, that's clinically meaningful information. The guidance suggests that waiting passively for a response that isn't coming is not the right strategy — and that a good provider should be initiating that conversation with you, not waiting for you to raise it.
Practical Considerations for Patients Evaluating Ketamine Therapy
If you're currently exploring ketamine or esketamine as a treatment option, or if you're already in treatment, this research surfaces several questions worth bringing to your provider.
Ask about their monitoring protocol. Does your clinic track depression severity scores — using PHQ-9 or a similar validated scale — at each visit or at defined intervals? Or is outcome assessment informal and impressionistic? Clinics that measure systematically are better positioned to recognize early non-response and make evidence-based adjustments.
Ask how they handle side effects. What's their protocol if you experience significant dissociation or nausea? Is there a staff member present throughout your session? Do they adjust dosing based on tolerability, or is the protocol fixed? These questions help you assess whether the clinic has the infrastructure to individualize your care.
Ask about their decision criteria for continuing or stopping. A well-run program should be able to articulate — in plain language — what they're looking for across the first several sessions and at what point they'd recommend reconsidering the approach. Vague reassurances that "everyone is different" without any outcome benchmarks are a yellow flag.
Finally, if you're considering esketamine (Spravato) specifically, note that it is administered in a certified healthcare setting with mandatory monitoring under the REMS program — meaning the supervision infrastructure is built in by regulatory design. IV ketamine clinics operate without that formal oversight structure, which makes the quality of the individual clinic's protocols even more important to evaluate.
Key Takeaway for Patients
Side effects from ketamine-based therapies are common but usually short-lived — the more important question is whether your provider is tracking your response systematically and prepared to adjust course if treatment isn't working. Ask your clinic how they measure progress, what their discontinuation criteria are, and how they'll manage tolerability concerns before your first session, not after.
The Bottom Line
This Psychiatric Times analysis doesn't break new ground on ketamine's efficacy — that evidence base is well established for treatment-resistant depression. What it does is push the clinical conversation toward a higher standard of care delivery: faster pivots when treatment isn't working, more rigorous tracking of both response and tolerability, and a shared decision-making process that keeps patients genuinely informed.
For patients and families, the takeaway is practical: the quality of your ketamine experience — and your odds of reaching remission — has as much to do with how your provider structures and monitors your care as it does with the drug itself. Choosing a clinic that takes outcome measurement seriously, prepares you honestly for side effects, and knows when to change course isn't just a nice-to-have. According to the emerging clinical consensus, it's a core component of effective treatment.
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