What Clinicians Are Saying About Tolerability
A new clinical review published in Psychiatric Times examines how well patients with treatment-resistant depression (TRD) tolerate NMDA receptor antagonists — the drug class that includes both IV ketamine and intranasal esketamine (Spravato) — and how often they stop treatment before completing a full course.
The review's central argument is that clinicians should move faster and more deliberately: track standardized outcome measures like the PHQ-9, optimize dosing based on individual response, and transition patients to an alternative agent sooner when a current treatment isn't working or tolerated. The goal is shorter time to remission through active, data-driven management rather than a passive wait-and-see approach.
For anyone weighing a ketamine-based treatment option — or trying to understand what a course of treatment actually involves — this review offers a grounded look at real-world tolerability across the two main options currently available.
The Side Effects That Come Up Most
NMDA receptor antagonists work through a fundamentally different mechanism than traditional antidepressants, and their side effect profiles reflect that. Rather than gradual, cumulative effects built up over weeks of daily dosing, ketamine-class medications produce acute, transient experiences during and shortly after each session — most of which resolve within hours.
The most commonly reported side effects across both IV ketamine and esketamine include:
- Dissociation: A temporary sense of unreality, detachment from surroundings, or mild perceptual distortion. This is the most discussed side effect and is dose-dependent — it can range from subtle and tolerable to genuinely disorienting, and is generally more pronounced with IV ketamine than with intranasal esketamine.
- Nausea and dizziness: Common during the treatment window; typically manageable with anti-nausea medication and positioning.
- Blood pressure elevation: Both agents raise blood pressure transiently. This is why pre-treatment cardiovascular screening matters, and why patients with uncontrolled hypertension require careful evaluation before starting.
- Headache: Reported somewhat more frequently with esketamine in some data sets.
- Sedation: Both routes of administration require a monitored observation period and prohibit driving for the remainder of the day.
An important pattern noted in the review: side effect burden tends to be highest in the first few sessions and often diminishes as patients become accustomed to the experience. This has direct implications for dropout — patients who stop early may be discontinuing before they have had a chance to adapt, and before antidepressant effects have had time to accumulate.
Why Patients Stop — and What That Actually Reflects
Discontinuation in any ongoing treatment is worth examining carefully, because the reasons vary significantly. The review identifies several distinct drivers: side effect intolerance, inadequate antidepressant response, and logistical or financial barriers — often in combination.
Esketamine (Spravato), as an FDA-approved treatment with a mandatory in-office REMS protocol, faces a particular adherence challenge. The twice-weekly induction schedule is demanding, and for patients managing work, family, or transportation constraints, sustaining that schedule can become unsustainable regardless of how well they're tolerating the treatment itself. IV ketamine, administered across roughly six sessions over two to three weeks, front-loads the commitment — which some patients find more manageable once it's done, while others find the initial intensity a barrier to starting.
The clinical review recommends that providers not passively wait out an inadequate response. Proactive dosing adjustments, or an earlier switch to the alternative agent, may prevent unnecessary dropout and move patients toward remission more efficiently. This is a meaningful shift in clinical posture — away from administering a fixed protocol and toward iterative, responsive management.
Key Takeaway
Most side effects from ketamine and esketamine are short-lived and often improve after the first few sessions. The greater risk may be stopping too early — before antidepressant effects have had time to build — due to initial discomfort that frequently diminishes with subsequent treatments. If early sessions feel difficult, tell your provider before discontinuing. Dose adjustments or a switch to the alternative agent may be options.
What This Means If You Are Evaluating Treatment Options
This clinical guidance maps directly onto practical questions patients face when comparing ketamine-based treatments. A few things worth knowing:
Outcome tracking should be standard, not optional. The PHQ-9 is a validated depression scale that should be measured at baseline and throughout treatment. If your provider isn't systematically tracking your scores, neither of you has a reliable way to know whether the treatment is actually working — or when it's time to adjust course.
The side effect window is predictable and short. Both IV ketamine and intranasal esketamine produce their primary side effects during the session itself, generally resolving within two to four hours. These are not lingering week-long effects. Understanding this ahead of time can meaningfully reduce anticipatory anxiety and help patients contextualize what they feel during early sessions.
Route of administration shapes the experience. IV ketamine, administered over roughly 40 minutes, tends to produce a more pronounced dissociative experience than intranasal esketamine. Esketamine is self-administered under clinical supervision and generally produces milder perceptual effects. Neither route is universally preferable — the right choice depends on your medical history, what's available locally, and your insurance situation.
Cost and access drive dropout more than many studies acknowledge. Esketamine is FDA-approved and increasingly covered by insurance, though prior authorization requirements remain a real friction point. IV ketamine is almost always out-of-pocket, with per-session costs ranging from several hundred to over a thousand dollars. Discontinuation data should be read with this in mind: some patients stop not because of side effects or lack of response, but because the financial or scheduling burden becomes untenable.
Provider engagement matters as much as the drug itself. The core clinical message in this review is that active management — adjusting doses, switching agents, tracking outcomes systematically — produces better results than administering a fixed protocol and waiting. When you're evaluating providers, it's worth asking how they track response, how they decide when to adjust dosing, and at what point they would recommend a different approach. That level of clinical attentiveness is as important to your outcome as which medication or route of administration you ultimately use.
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