What the Research Says
A new clinical analysis published in Psychiatric Times in April 2026 is drawing attention to the side effect profiles and discontinuation rates of NMDA receptor antagonists — the drug class that includes ketamine and esketamine — in patients with treatment-resistant depression (TRD). The core message from clinicians: the field needs to move faster, lean harder on outcome data like PHQ-9 scores, optimize dosing more aggressively, and be willing to switch agents sooner when a patient isn't responding or tolerating treatment well.
The review underscores a tension that patients and prescribers alike will recognize: NMDA antagonists work remarkably well for many people with TRD, but they come with a side effect burden that can — and does — cause people to stop treatment before reaching remission. Understanding that burden by route of administration, and by individual patient factors, is increasingly seen as central to improving real-world outcomes.
Side Effects Across the NMDA Antagonist Landscape
The NMDA antagonist class in clinical use spans several formats: intravenous (IV) racemic ketamine infusions, intranasal esketamine (Spravato), and oral ketamine in tablet or troche form. Each carries a recognizable cluster of potential side effects — dissociation, perceptual disturbances, elevated blood pressure, nausea, and dizziness are the most commonly reported — but the intensity, timing, and clinical manageability of these effects differ meaningfully based on how the drug enters the body.
IV ketamine delivers the highest and most rapid peak plasma concentrations, which correlates with the most pronounced dissociative experiences and the most robust blood pressure elevations. These effects are time-limited to the infusion window, but they require clinical monitoring infrastructure and can be distressing enough to prompt patients to discontinue the series entirely. Intranasal esketamine blunts the peak somewhat, but still requires in-office monitoring for at least two hours post-dose due to dissociation and sedation risk.
Oral ketamine tablets occupy a distinct pharmacokinetic space. Because ketamine is subject to significant first-pass metabolism when swallowed, oral bioavailability is lower — typically estimated in the 16–29% range — and peak plasma concentrations are both lower and delayed compared to IV or intranasal routes. This flatter absorption curve translates, in practice, to a generally milder and more gradual onset of dissociative and cardiovascular effects. For many patients, this is a feature rather than a limitation: the psychoactive experience is more manageable, daily or near-daily dosing is feasible at home, and the side effect burden is easier to live alongside a normal schedule.
Key Takeaway for Tablet Patients
If you're using oral ketamine tablets and experiencing side effects significant enough to make you consider stopping, talk to your prescriber before discontinuing. The clinical literature increasingly supports dose adjustment and regimen optimization as a first step — not a switch to a different modality or an end to treatment. Tracking your own PHQ-9 scores and logging side effects at each dose gives your provider the data they need to act quickly.
Discontinuation: A Bigger Problem Than Often Acknowledged
The Psychiatric Times review shines a light on discontinuation rates — a metric that often gets overshadowed by efficacy data in clinical discussions. Dropout from NMDA antagonist treatment due to side effects is a genuine problem across all delivery routes, and it represents a particularly painful outcome in TRD, where patients have typically already failed multiple antidepressants and may feel they are running out of options.
For oral ketamine users specifically, the discontinuation picture is nuanced. The milder side effect profile lowers one common barrier to staying on treatment. But oral ketamine is also commonly used in a home-dosing model with less frequent clinical check-ins, which means side effects can go unreported and unaddressed for longer. Nausea, which is a frequent complaint at higher oral doses, is manageable with antiemetics and timing adjustments — but only if a patient and provider are in close enough communication to catch it early.
The clinical guidance embedded in this research is relevant here: prescribers are being encouraged to use structured outcome tracking tools like the PHQ-9, to be proactive about dose optimization rather than waiting for a patient to report feeling worse, and to consider switching formulations or agents if a patient isn't tolerating or responding within a reasonable window. For oral ketamine patients, this means the conversation at each follow-up appointment should include both symptom tracking and an honest accounting of side effects — not just a general check-in.
How Oral Tablets Compare on Tolerability
For patients weighing treatment options, or considering whether to continue with oral tablets versus exploring IV infusions or nasal esketamine, the tolerability data is worth understanding in context. Oral tablets are not the most potent delivery method, and for some patients in acute crisis, the delayed and attenuated effect may not be sufficient. But for maintenance treatment, step-down protocols after an initial infusion series, or for patients who cannot access or afford in-clinic treatment, the tolerability advantages of oral tablets are clinically meaningful.
Troches (sublingual/buccal lozenges) sit somewhere between oral tablets and IV on the absorption curve — mucosally absorbed ketamine bypasses first-pass metabolism more effectively, producing higher bioavailability and faster onset than a swallowed tablet, but still without the sharp peak of an infusion. Patients who find oral tablets insufficiently effective but who struggle with the intensity of IV ketamine sometimes find troches a useful middle ground. The side effect profiles differ accordingly.
What the broader clinical literature — including this new review — continues to confirm is that there is no universally optimal route. The right choice depends on acuity, access, individual pharmacokinetics, lifestyle, and side effect tolerance. What's changing is the expectation that clinicians will treat this as a dynamic, data-driven decision rather than a one-time assignment.
What This Means for Your Treatment
If you are currently using oral ketamine tablets for treatment-resistant depression, here are the practical implications of this emerging clinical guidance:
- Track your outcomes formally. PHQ-9 scores, logged consistently, give your provider the signal they need to optimize your dose or adjust your regimen. Don't rely on subjective check-ins alone.
- Report side effects specifically. Nausea, dizziness, blood pressure changes, cognitive fog — these are all adjustable with dose timing, antiemetic support, or formulation changes. Staying silent about them until they become intolerable is the path most likely to end in unnecessary discontinuation.
- Ask about dose optimization proactively. The clinical consensus is moving toward faster adjustments based on data, not a wait-and-see approach. If you're three or four weeks in without meaningful symptom movement, that's a conversation worth initiating.
- Understand the route tradeoffs. If oral tablets aren't providing sufficient relief, that doesn't mean ketamine isn't right for you — it may mean a different formulation or delivery route deserves consideration. Your prescriber should be able to walk you through that comparison.
The full analysis is available via Psychiatric Times.
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