What the Psychiatric Times Report Found
A new clinical review published in Psychiatric Times (April 2026) takes a close look at the side effect profiles and discontinuation rates of NMDA receptor antagonists — the drug class that includes both IV/IM ketamine and the FDA-approved esketamine nasal spray (Spravato) — in patients with treatment-resistant depression (TRD). The review's central argument is that clinicians are moving too slowly: they're tolerating inadequate responses, under-documenting side effects, and not making dose or agent switches quickly enough. The authors advocate for a more structured, data-driven approach — anchored by routine PHQ-9 tracking, systematic side effect logging, and willingness to adjust protocols sooner rather than later.
While the piece covers the full NMDA antagonist landscape, it has direct relevance for anyone receiving or considering low-dose ketamine therapy. Understanding why patients discontinue — and what side effects actually drive those decisions — can meaningfully shape expectations and inform conversations with prescribers.
The Side Effect Landscape: What We Know
NMDA antagonists produce a recognizable cluster of acute side effects that distinguish them from conventional antidepressants. The most frequently reported include dissociative symptoms (a feeling of detachment from body or surroundings), perceptual distortions, transient increases in blood pressure and heart rate, nausea, dizziness, and sedation. These effects are typically dose-dependent and time-limited — peaking during or shortly after administration and resolving within one to two hours for most patients.
Importantly, the review distinguishes between side effects that lead patients to discontinue treatment and those that are unpleasant but tolerable when properly managed. Dissociation, often framed in public discussions as alarming, is frequently rated as mild-to-moderate by patients receiving lower doses and may even be perceived neutrally or positively by some. Nausea and blood pressure elevation, by contrast, are more consistently cited as drivers of early dropout — particularly when clinics fail to use prophylactic antiemetics or cardiovascular monitoring protocols.
Cognitive side effects, including short-term memory blunting and difficulty concentrating in the hours following a session, are also documented but appear less persistent than those seen with electroconvulsive therapy (ECT), another common TRD intervention. Longer-term cognitive concerns — which have been raised in the context of recreational ketamine use at much higher doses — are not well-established at the therapeutic doses used in clinical settings, though the review appropriately flags this as an area requiring more longitudinal data.
Discontinuation Rates: The Numbers Matter
The review's analysis of discontinuation rates across published trials and real-world cohorts reveals a meaningful gap between esketamine and IV/IM ketamine. Esketamine (Spravato) trials reported discontinuation rates ranging from roughly 15–25% due to adverse events or insufficient response in acute-phase treatment. IV ketamine real-world data is more variable, but dropout due to side effects alone tends to be lower — partly because IV administration allows for more precise dose titration, and partly because the clinical setting typically involves closer monitoring.
What the review underscores is that many discontinuations are potentially preventable. Patients who stopped treatment due to side effects frequently did so in the first two to four sessions — a window where dose adjustments and supportive care interventions (antiemetics, blood pressure management, environmental modifications like dimmed lighting and reduced stimulation) could have altered the outcome. The authors argue that this represents a system-level failure: not enough clinics are building structured side effect assessments into their intake and post-session workflows, which means problems go unaddressed until the patient simply stops showing up.
This finding matters especially for low-dose protocols, where the therapeutic rationale depends on sustained, repeated administration over weeks or months. A patient who drops out after session two due to unmanaged nausea has lost the opportunity to experience whether the treatment would have worked at all.
The Push for Faster, Data-Driven Optimization
The piece's policy-level argument — that clinicians should optimize doses and switch agents sooner — has practical implications for how ketamine programs are structured. The authors specifically cite PHQ-9 monitoring as underutilized: many clinics administer it at intake but not systematically between sessions, making it difficult to identify partial responders who might benefit from dose adjustment versus non-responders who should be transitioned to a different approach.
For low-dose ketamine specifically, this raises the question of what constitutes an adequate trial before concluding the treatment isn't working. The review doesn't offer a universal answer, but the emerging clinical consensus leans toward reassessing response after four to six sessions, with PHQ-9 scores and side effect burden both factored into that decision. Waiting longer without structured re-evaluation risks prolonging a non-response or allowing manageable side effects to quietly compound into a reason to quit.
Key Takeaway
Most discontinuations from NMDA antagonist therapy happen early — often within the first two to four sessions — and are frequently driven by manageable side effects like nausea and blood pressure changes rather than fundamental treatment intolerance. If you're experiencing side effects in your low-dose ketamine protocol, flag them explicitly with your provider before stopping. Dose adjustments, antiemetic support, and session environment changes can significantly alter the experience. Stopping early means losing the chance to find out whether the treatment would have worked.
What This Means for Low-Dose Ketamine Patients
Several practical points emerge from this review for anyone currently in or evaluating a low-dose ketamine program:
Side effects should be reported systematically, not just mentioned in passing. If your clinic isn't giving you a structured way to report what you experience between sessions — even a simple numeric scale for nausea, dissociation, and next-day cognitive fog — ask for one. The review's finding that many dropouts are preventable hinges on clinics having this data early enough to act on it.
Your PHQ-9 score between sessions is informative. Completing a PHQ-9 (or equivalent validated scale) before each session gives your provider a trajectory, not just a snapshot. A score that's moving in the right direction — even modestly — after two or three sessions is a different clinical picture than one that's flat or worsening. Know your numbers.
Dose optimization is a legitimate clinical tool, not a sign of failure. The review explicitly pushes back against the tendency to keep patients on a fixed dose that isn't working. If your response is partial or side effects are burdensome, a dose adjustment is a standard clinical move — not a last resort. Low-dose protocols have more titration room than many patients realize.
The evidence base is still maturing. The review is a useful synthesis of what's currently known, but it also makes clear that long-term data — particularly on sustained remission rates, cognitive effects beyond one year, and optimal maintenance dosing intervals — remains limited. This doesn't mean low-dose ketamine isn't worth pursuing for appropriate candidates, but it does mean that anyone presenting it as a fully characterized, risk-free treatment is overstating the current evidence. Honest uncertainty is part of the picture.
The full review is available at Psychiatric Times.
Share