Clinicians Are Pushing for Smarter, Faster Depression Treatment
A new clinical analysis published in Psychiatric Times is making the case that treating treatment-resistant depression (TRD) with NMDA receptor antagonists — a class that includes both IV ketamine and intranasal esketamine (Spravato) — requires more rigorous, data-driven decision-making from providers. The core argument: clinicians should be optimizing doses sooner, switching treatments when the current one isn't working, and consistently tracking standardized outcomes like the PHQ-9 depression scale to get patients to remission faster.
For the estimated 30% of depression patients who don't respond to standard antidepressants, these recommendations matter a great deal. NMDA antagonists have become a frontline option in TRD precisely because they work through a different mechanism than SSRIs and SNRIs — and they often work faster. But with multiple options now available and varying side effect profiles between them, the question of which treatment to use, at what dose, and for how long has become more complicated. This analysis takes a step toward answering that.
How the Side Effect Profiles Actually Compare
Not all NMDA antagonists are the same. While ketamine (administered intravenously or intramuscularly in clinic settings) and esketamine nasal spray share a mechanism, their side effect profiles and discontinuation rates differ in clinically meaningful ways.
IV ketamine is known for producing dissociative effects during infusion — alterations in perception, a dreamlike state, and occasional feelings of derealization. For many patients these effects are transient and resolve within an hour of treatment ending. Nausea and elevated blood pressure during infusion are also common and are typically managed with pre-treatment medications. Because IV ketamine is administered in a monitored clinical setting, acute side effects are generally well-managed.
Intranasal esketamine (Spravato) carries a similar dissociative profile but is delivered differently. Patients self-administer the nasal spray under supervision in a certified healthcare setting, then observe a mandatory two-hour monitoring period. Nasal discomfort, dizziness, and nausea are the most frequently reported side effects. Because esketamine has FDA approval specifically for TRD and major depressive disorder with acute suicidal ideation, its safety data pool is now significantly larger than for off-label IV ketamine.
The Psychiatric Times analysis specifically highlights discontinuation rates as a meaningful data point that often gets overlooked in clinical conversations. A patient who stops treatment early — whether because of side effects, lack of response, cost, or logistical barriers — hasn't reached remission. Understanding which patients are most likely to discontinue, and why, allows providers to intervene earlier, adjust protocols, or consider switching to an alternative formulation.
Emerging oral and sublingual ketamine formulations also enter this picture. While bioavailability is lower and efficacy data is still developing compared to IV or intranasal routes, these options carry their own side effect considerations — particularly around GI tolerance and the challenge of consistent dosing without clinical oversight.
Key Takeaway for Patients
If you are in a ketamine or esketamine treatment program and not seeing meaningful improvement after several sessions, ask your provider about your PHQ-9 trajectory and whether a dose adjustment or route change is warranted. Research increasingly supports acting on that data sooner rather than waiting through a full course of a treatment that isn't working for you.
Why Tracking PHQ-9 Scores Is More Than Paperwork
The PHQ-9 is a nine-question standardized depression screening tool that produces a numerical score. In routine clinical care it is sometimes treated as an intake formality, but the guidance highlighted in this analysis urges providers to use it as a dynamic tracking tool throughout treatment — not just at the start and end of a course.
For ketamine patients, this matters because the drug's antidepressant effects can appear rapidly, sometimes within hours of the first infusion, and can also taper off between sessions. Tracking PHQ-9 scores at regular intervals gives both patient and provider objective data on response durability, the timing of symptom return, and whether the current dosing frequency is sufficient. A patient whose scores drop significantly after session one but return to baseline before session four is telling the clinician something important about their dosing interval needs.
This kind of precision tracking is also what allows providers to make defensible decisions about when to switch treatments. Anecdotal impressions of improvement — or of tolerability — aren't enough to guide complex TRD care. Standardized measurement creates a paper trail that supports better clinical decisions and, increasingly, insurance justifications for continued treatment.
What This Means If You're Comparing Treatment Options
For patients currently evaluating ketamine treatment, this analysis reinforces a few practical realities worth keeping in mind as you compare providers and modalities.
Ask how your provider tracks response. A clinic that uses structured outcome measures — not just a check-in conversation — is operating closer to the standard of care this research advocates for. Some ketamine clinics have incorporated digital symptom tracking between sessions; others rely primarily on clinical judgment. Knowing which approach your provider uses helps you understand how treatment decisions will be made.
Side effects are manageable but should be discussed upfront. Dissociation, nausea, and elevated blood pressure during treatment are common across NMDA antagonists. None of these should be a surprise, and a good provider will walk you through what to expect before your first session, how they manage these effects in-clinic, and what the plan is if side effects are significant.
Route of administration affects both side effects and oversight. IV ketamine delivers the drug directly into the bloodstream with fast onset and precise dosing control, but requires a clinic visit. Esketamine nasal spray is FDA-approved and covered by some insurance plans, with a mandatory monitoring period built in. Oral or sublingual ketamine is more accessible in some telehealth models but involves less direct oversight. There is no universally best option — the right route depends on your history, provider relationship, cost constraints, and how you tolerate the experience.
Don't stay on a treatment that isn't working. Perhaps the most actionable message in this research is the simplest: if NMDA antagonist therapy isn't moving your depression scores in the right direction within a reasonable timeframe, that's clinical information. Advocate for a dose change, a schedule adjustment, or a switch to a different modality. Waiting passively through a full treatment course that isn't working costs time, money, and wellbeing.
Read the full analysis at Psychiatric Times.
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