Why Patients Quit NMDA Therapy—And What Providers Should Do

A Clinical Conversation Patients Deserve to Hear

A new review published in Psychiatric Times is drawing attention to a problem that sits quietly at the center of treatment-resistant depression (TRD) care: many patients stop NMDA receptor antagonist therapy—ketamine, esketamine (Spravato), or dextromethorphan-bupropion (Auvelity)—before they have a real chance to reach remission. The authors argue that this isn't inevitable. In many cases, it reflects a gap in how clinicians monitor, adjust, and respond to side effects and early treatment signals.

For patients and families who are weighing these treatments—or who are already in them—this review offers something valuable: a clearer picture of what tolerability actually looks like across the NMDA class, and a vocabulary for the conversations you should be having with your provider.

What the Review Found

NMDA receptor antagonists work by blocking a specific glutamate receptor in the brain, producing rapid antidepressant effects that traditional antidepressants cannot match. But this mechanism also produces side effects that are unlike anything most patients have encountered in psychiatric care. Dissociation, dizziness, nausea, elevated blood pressure, and perceptual disturbances are common—particularly in the first few sessions. For some patients, these effects are manageable or even unremarkable. For others, they are enough to trigger early dropout.

The review draws distinctions between the three main approved or commonly used NMDA agents. IV racemic ketamine, administered in infusion clinics, tends to produce more pronounced dissociative effects but is also more titrateable—meaning clinicians can more precisely adjust the dose in real time. Intranasal esketamine (Spravato), the FDA-approved formulation for TRD, has a fixed-dose protocol that offers less flexibility but a more standardized safety monitoring framework. Auvelity, the oral dextromethorphan-bupropion combination, has a milder side effect profile but also a slower onset and different efficacy ceiling.

Discontinuation rates across these agents vary, but the review emphasizes a consistent finding: patients who drop out early—within the first two to four sessions—disproportionately do so because of side effects that were either not adequately anticipated, not well managed, or not met with a prompt clinical response. The conclusion from the clinicians cited: too many providers are adopting a passive wait-and-see stance when the evidence supports faster, more deliberate intervention.

The Case for Faster, More Active Management

The review's most actionable argument is directed at prescribers, but its implications flow directly to patients. The authors urge clinicians to treat validated outcome tracking—tools like the PHQ-9 depression scale—as a live dashboard, not a formality. If a patient completes three or four sessions without meaningful symptom movement, that's a signal to act: adjust the dose, reassess the frequency of sessions, or consider switching to a different agent in the class.

This represents a meaningful shift from how NMDA therapy has sometimes been practiced, particularly in the earlier years of ketamine clinic proliferation. In some settings, patients received a standard six-infusion induction series and were sent on their way with limited follow-up or measurement. The review is part of a broader clinical push to bring more rigor to these decisions—treating TRD with the same iterative optimization that oncologists apply to chemotherapy regimens or endocrinologists apply to insulin dosing.

For patients, this matters in a practical and sometimes urgent way. Treatment-resistant depression by definition has already failed multiple prior therapies. Time is not a neutral variable. The longer a patient remains symptomatic, the greater the risk of functional decline, hospitalization, or crisis. If a provider can catch a non-response or tolerability issue at session three rather than session twelve, the difference in outcomes—and in cost, burden, and suffering—can be substantial.

The review also surfaces an important nuance around the dissociative side effects that many patients find alarming. While dissociation is often framed as a drawback, some research has suggested it may actually correlate with antidepressant response for certain patients. This doesn't mean dissociation is desirable or should be maximized—but it does mean the clinical picture is more complex than a simple side-effect-to-avoid framing. Patients who experience dissociation and immediately want to discontinue may benefit from a conversation with their provider about whether that experience is a signal worth tolerating through, at least temporarily.

What This Means If You're a Patient or Caregiver

If you're currently in a ketamine or esketamine treatment program, or considering starting one, this review reinforces several principles worth holding onto.

First, side effects in the first one to two sessions are not a reliable indicator of long-term tolerability. Many patients find that dissociation, nausea, and dizziness diminish significantly after the first few treatments as their bodies acclimate to the medication. Dropping out after a difficult first session—without discussing the experience with your provider—may mean abandoning a treatment that would have become manageable.

Second, if you are tolerating the treatment but not improving after several sessions, the right response is not simply to continue without adjustment. You should be having an active conversation with your provider about whether your dose, frequency, or even the specific agent you're using needs to change. A provider who is not measuring your depression symptoms systematically—with a validated scale, not just a general check-in—may not have the data to make those decisions well.

Third, the differences between IV ketamine, intranasal esketamine, and Auvelity are real and clinically meaningful. If you have tried one and found it intolerable or ineffective, that is not necessarily a verdict on the entire class. The right provider will help you understand whether a different agent or delivery route might offer a better profile for your specific situation.

Finally, access and cost remain real barriers that this review does not resolve. IV ketamine is largely out-of-pocket in the United States, with infusion series ranging from $2,000 to $6,000 or more. Spravato has broader insurance coverage for qualifying TRD patients but carries its own logistical burden—it must be administered in a certified healthcare setting with post-dose monitoring. Auvelity is oral and easier to take, but may not be covered and carries its own prior authorization hurdles. None of these practical realities disappear because the clinical guidance is getting sharper—but understanding the landscape helps you advocate for yourself more effectively. Read the full review in Psychiatric Times.