What the New Guidance Says
A April 2026 review published in Psychiatric Times takes a hard look at the side effect profiles and discontinuation rates associated with NMDA receptor antagonists — the class of drugs that includes both IV ketamine and intranasal esketamine (Spravato) — in patients with treatment-resistant depression (TRD). The core message from clinicians: the field has been moving too slowly, too cautiously, and without enough data discipline. The authors push for a more structured, faster-paced approach: optimize doses earlier, switch treatments sooner when response is inadequate, and use validated tracking tools like the PHQ-9 consistently across visits to make decisions grounded in evidence rather than intuition.
This isn't a dramatic new discovery — it's a call to tighten clinical practice around tools and drugs already in use. But for patients currently in low-dose ketamine protocols, or those considering starting, the implications are worth unpacking carefully.
Understanding the Side Effect Landscape
NMDA receptor antagonists work by blocking glutamate receptors in the brain, producing rapid antidepressant effects that set them apart from traditional SSRIs and SNRIs. But that same mechanism of action also produces a distinctive side effect profile that patients and clinicians need to understand going in.
The most commonly reported acute side effects include dissociation (a sense of detachment from one's body or surroundings), dizziness, nausea, elevated blood pressure, and perceptual disturbances. These effects are typically dose-dependent and transient — they peak during or shortly after administration and resolve within hours. At low doses, many patients experience only mild versions of these effects, or none at all, which is part of the appeal of sub-anesthetic ketamine protocols.
However, the Psychiatric Times review highlights that side effect burden is one of the leading drivers of treatment discontinuation — and that discontinuation often happens before patients have had enough exposure to the drug to determine whether it works for them. This is a meaningful clinical problem. If a patient stops after two or three sessions because of manageable nausea or transient dissociation, they may be walking away from a treatment that could have helped them significantly with better preparation and support.
The review also distinguishes between acute side effects (which are well-characterized and time-limited) and longer-term tolerability concerns, including potential impacts on cognition, bladder health with chronic high-dose use, and psychological dependence risk. These longer-term signals are relevant primarily in the context of high-frequency or high-dose protocols, but they underscore why the authors advocate for systematic monitoring rather than anecdotal check-ins.
Discontinuation Rates: What the Data Shows
Discontinuation rates across NMDA antagonist studies are heterogeneous — they vary depending on the dose, the delivery route (IV, intranasal, oral), the setting, and the patient population. Esketamine (Spravato) trials have reported discontinuation rates in the range of 10–25% across longer-term studies, with side effects and lack of efficacy cited as the two primary reasons. IV ketamine data shows similar patterns, though the outpatient nature of many low-dose ketamine programs means real-world discontinuation may look different from controlled trial data.
What the Psychiatric Times piece argues is that these rates could be reduced — and outcomes improved — through two levers: better dose optimization and faster decision-making. Rather than running a patient through a fixed course of six infusions at a standard dose and then evaluating, clinicians are encouraged to track response more granularly, adjust dosing within protocols when early response signals are absent, and be willing to pivot to a different approach (a different NMDA agent, a different delivery route, or a combination strategy) without waiting for a full course to conclude when evidence of non-response is clear.
The PHQ-9 as a Clinical Compass
The emphasis on PHQ-9 tracking deserves specific attention. The PHQ-9 is a nine-question validated depression screening tool that produces a numerical score from 0 to 27. It's simple, quick, and widely used — but its use in ketamine and esketamine clinics has been inconsistent. Some practices administer it at every visit; others rely on clinical impression alone.
The authors argue that consistent PHQ-9 tracking at each session creates an objective trail that can inform dose decisions, flag early non-response, and document trajectory over time. For patients in low-dose ketamine protocols, this matters practically: if your score isn't moving meaningfully after the initial induction phase, that's data — and that data should prompt a clinical conversation, not continued passive administration of the same protocol.
It's worth noting what PHQ-9 scores can and can't tell you. They measure self-reported symptom frequency over the prior two weeks, which means they lag slightly behind acute effects. Ketamine's rapid-acting nature can produce shifts that outpace the PHQ-9's two-week window in the short term. But across a treatment course, consistent tracking provides a signal that anecdotal reporting often misses.
Key Takeaway for Patients
Side effects like dissociation, nausea, and dizziness are real but typically transient at low doses — and they shouldn't be a reason to stop treatment prematurely without first discussing management strategies with your provider. Equally important: if you're not seeing measurable improvement in your PHQ-9 scores after a full induction course, that's a signal worth raising. The new clinical guidance says to optimize sooner, switch sooner, and use data — not just intuition — to guide decisions. Patients who track their own symptoms between sessions and come prepared with that information are better positioned to participate in those conversations.
What This Means for Low-Dose Ketamine Protocols Specifically
The Psychiatric Times review focuses on the broader NMDA antagonist class, but its practical implications land most directly on the outpatient low-dose ketamine space, where protocol variation is wide and monitoring rigor is uneven across providers.
A few things to watch for if you're currently in a low-dose ketamine program or evaluating one:
- Ask about their tracking methodology. Does your provider administer the PHQ-9 or a similar validated tool at every session, or are they relying on subjective impression? Structured measurement is increasingly considered standard of care.
- Understand the dose adjustment policy. Good protocols aren't rigid. If you're not responding, or if side effects are significant, there should be a clear framework for adjusting — not just waiting it out.
- Side effect preparation reduces discontinuation. Knowing in advance that transient dissociation or mild depersonalization is a normal, temporary effect of the drug — not a sign something is wrong — meaningfully reduces the panic response that can lead to premature stopping.
- The goal is remission, not management. The authors are explicit: the aim of treatment optimization is reaching remission faster, not just tolerating a chronic maintenance protocol indefinitely. That framing matters for how patients should think about their own trajectory.
The evidence base for ketamine in treatment-resistant depression continues to strengthen, and clinical practice is slowly catching up. This review represents the field's push to close that gap — not by changing the drugs, but by being more disciplined about how they're used. For patients navigating this space, that's broadly good news, provided it translates into better clinical practice on the ground.
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