A Closer Look at Tolerability in Ketamine-Based Treatment
A new clinical review published in Psychiatric Times takes a structured look at how patients respond to — and sometimes stop — treatment with NMDA receptor antagonists, the drug class that includes both intravenous (IV) ketamine and intranasal esketamine (brand name Spravato). The piece comes from a clinical standpoint, urging prescribers to move faster and more systematically toward remission in treatment-resistant depression (TRD): optimizing doses earlier, switching agents sooner when a patient isn't responding, and tracking outcomes consistently using tools like the PHQ-9.
For patients and families already researching ketamine therapy, this kind of clinical perspective matters. It signals that even within the medical community, there's active conversation about how to manage these treatments more effectively — which directly affects the experience you or a loved one might have in a real clinic setting.
What the Evidence Actually Shows on Side Effects
NMDA receptor antagonists like ketamine and esketamine are meaningfully different from traditional antidepressants in how they work — and in how they feel. The review outlines the side effect landscape that clinicians are navigating in 2026:
- Dissociation: A temporary altered sense of reality or detachment is the most commonly cited acute side effect of both IV ketamine and esketamine. It typically peaks during or shortly after administration and resolves within hours. For most patients, it's manageable and expected; for some, it's disorienting enough to be a barrier to continued treatment.
- Cardiovascular effects: Transient increases in blood pressure and heart rate occur during infusions. This is why monitored administration settings are standard — and why patients with certain cardiovascular conditions require additional screening before starting.
- Nausea and dizziness: These are among the more common complaints, particularly with esketamine. Anti-nausea medications are often used prophylactically in well-run programs.
- Cognitive and perceptual effects: Some patients report short-term changes in concentration or perception. These typically resolve quickly after sessions end, though the review underscores the importance of tracking these systematically.
- Abuse potential and bladder concerns: The review acknowledges these as important longer-term considerations, especially with ketamine used outside of structured clinical protocols. Bladder issues (ketamine cystopathy) are well-documented in the context of heavy recreational use, and while they're rare in therapeutic settings, providers managing long-term maintenance treatment should monitor for urinary symptoms.
Discontinuation rates — how often patients stop treatment before completing a course — varied across studies and settings. The review highlights that discontinuation is often tied to tolerability, but also to perceived lack of early response. This is part of why the authors advocate for faster clinical decision-making: if a patient isn't improving and is experiencing burdensome side effects, waiting too long to adjust or switch the approach isn't serving them.
The Clinical Optimization Argument
The broader message from the Psychiatric Times piece isn't alarming — it's actually a call for more precision. The authors argue that the field has enough real-world data now to move away from a one-size-fits-all approach and toward individualized, data-tracked care. That means:
- Using validated depression scales (like the PHQ-9) at regular intervals, not just at intake
- Being willing to adjust dosing rather than defaulting to the same protocol for every patient
- Switching between agents (for example, from IV ketamine to esketamine or vice versa) if one isn't producing adequate response or is poorly tolerated
- Having honest, structured conversations with patients about what side effects to expect and how to report them
This is a meaningful shift in tone from earlier years of ketamine therapy, when the treatment was still novel and clinical protocols were less standardized. In 2026, the field is maturing — and that maturation benefits patients, because it means more experienced providers and better-defined expectations.
Key Takeaway for Patients
Side effects with ketamine and esketamine are real but generally short-lived and manageable in properly supervised settings. What this review reinforces is that the quality and attentiveness of your care team matters enormously. Clinics that track your symptoms over time, adjust protocols when needed, and communicate clearly about what you're experiencing tend to produce better outcomes — and better tolerability. Before starting treatment, ask prospective providers how they monitor progress, what they do when a patient isn't responding, and how they handle side effects. The answers will tell you a lot about the quality of care you'll receive.
What This Means If You're Evaluating Ketamine Therapy
If you or someone you care about is considering ketamine treatment for depression that hasn't responded to other therapies, the findings summarized in this review offer a few grounding points:
Side effects are expected and temporary for most patients. The dissociative experience that ketamine produces is not a sign something is going wrong — it's a known pharmacological effect. What separates a good treatment experience from a difficult one is often how well a provider prepares patients beforehand and monitors them during and after sessions.
Discontinuation happens — and that's useful information. Not everyone completes a full course of ketamine treatment, and that's not always a failure. Sometimes the treatment isn't a fit. The important thing is that your provider is paying attention, not simply assuming you'll push through. A clinic that tracks dropout rates and studies why patients stop is a clinic doing its job rigorously.
IV ketamine and esketamine have different profiles. Esketamine (Spravato) is FDA-approved for TRD and certain suicidal ideation presentations, administered in a certified healthcare setting. IV ketamine is used off-label for depression. Their side effect and discontinuation patterns differ somewhat, and the best choice for a given patient depends on clinical history, insurance coverage, provider experience, and individual response. Neither is universally superior.
Long-term use warrants ongoing monitoring. For patients who respond well to ketamine or esketamine and move into a maintenance phase, regular check-ins on urinary health, blood pressure, and mood tracking aren't optional extras — they're part of responsible care.
The full review is available at Psychiatric Times and is worth sharing with your treatment team if you want to have a more detailed clinical conversation about what to expect.
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