What the Research Says
A new clinical review published in Psychiatric Times takes a hard look at the side effect profiles and discontinuation rates of NMDA receptor antagonists — the drug class that includes both IV ketamine and intranasal esketamine (Spravato) — in patients with treatment-resistant depression (TRD). The authors argue that clinicians need to move faster and more decisively: optimize doses earlier, switch formulations sooner when a patient isn't responding, and use structured tools like the PHQ-9 to track outcomes rather than relying on subjective impression.
The piece reflects a broader frustration in the field. Many patients cycle through months of inadequate treatment before a provider adjusts the approach — costing time, money, and in some cases, worsening their condition. The review pushes back on that inertia with a data-driven framework for when to stay the course and when to change course.
The Side Effect Landscape Across Routes
Both IV ketamine and intranasal esketamine share a common pharmacological target, but their side effect profiles differ in meaningful ways — largely because of how each drug is delivered, how long it stays active, and the clinical setting required.
IV ketamine tends to produce more pronounced dissociative effects during infusion — perceptual distortions, a sense of detachment, and in some cases, intense psychedelic-adjacent experiences. These effects resolve quickly after the infusion ends, typically within an hour. Blood pressure elevation is common and is monitored during treatment. Nausea occurs in a subset of patients but is usually manageable with pre-medication. Because IV ketamine is administered in a controlled clinic setting with direct observation, acute side effects can be addressed in real time.
Intranasal esketamine (Spravato) requires patients to self-administer under supervision in a certified healthcare setting and then remain monitored for two hours post-dose. Dissociation, dizziness, and nausea are the most commonly reported effects. The nasal route means slower, more variable absorption compared to IV, which can affect both the therapeutic experience and side effect intensity. Some patients tolerate this better; others find the monitoring burden and lingering effects harder to manage week after week.
Discontinuation — meaning patients stopping treatment before completing a recommended course — is a real concern for both options. The review highlights that side effects are a primary driver, but so are logistical barriers like time commitment, cost, and lack of perceived benefit. When patients don't see improvement within a reasonable window and providers aren't adjusting the protocol, dropout becomes more likely.
Key Takeaway for Patients
If you're several sessions into ketamine or esketamine treatment and aren't noticing improvement, don't assume the therapy has failed — ask your provider whether your dose, frequency, or formulation has been formally evaluated. The clinical guidance published in 2026 specifically calls out under-optimization as a preventable reason patients discontinue too early.
Why This Matters for Patients Comparing Options
For someone researching ketamine treatment for the first time, this review is a useful reality check in both directions. On one hand, side effects are real — dissociation, blood pressure changes, and nausea aren't rare, and it's worth going in with clear expectations rather than being caught off guard. On the other hand, the data suggest that most patients who experience side effects don't find them intolerable, and structured clinical management can reduce dropout substantially.
The emphasis on PHQ-9 tracking is worth noting for patients as well as providers. The PHQ-9 is a nine-question depression screening tool that takes minutes to complete and produces a numeric score. If your clinic isn't using some form of standardized outcome measurement between sessions, you're navigating treatment largely on feel — which makes it harder to distinguish real improvement from a placebo response or short-term mood fluctuation. Asking your provider how they measure your progress is a reasonable and informed question.
The push for faster dose optimization is also relevant to the cost conversation. Ketamine treatment is expensive, and most insurance coverage remains limited. If a protocol isn't working at its starting parameters, extending it at the same ineffective dose wastes both time and money. Clinicians who follow the kind of adaptive framework this review advocates are more likely to either get you to remission efficiently or tell you clearly when ketamine isn't the right fit — both of which serve patients better than prolonged, unmodified treatment.
The Bigger Picture
This research sits within a maturing conversation about how to professionalize ketamine care. The early years of the ketamine clinic boom were characterized by inconsistent protocols, variable patient selection, and limited follow-up. What papers like this one represent is the field pushing toward standardization — not to restrict access, but to improve outcomes and give patients and providers a shared language for evaluating whether treatment is working.
For anyone weighing IV ketamine against esketamine, or trying to decide whether to continue or discontinue a course of treatment, the message is practical: side effects are manageable with the right clinical support, dropout is often premature, and structured measurement matters. The source article is available via Psychiatric Times for readers who want the full clinical detail.
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