What the New Guidance Says
A clinical review published in Psychiatric Times in April 2026 outlines the factors psychiatrists are weighing when selecting treatments for treatment-resistant depression (TRD) — broadly defined as depression that has failed to respond to at least two adequate antidepressant trials. The piece maps out a landscape that now includes esketamine (Spravato), repetitive transcranial magnetic stimulation (rTMS), electroconvulsive therapy (ECT), and — implicitly — compounded racemic ketamine infusions as fast-acting glutamatergic options.
Key factors driving treatment selection include speed of symptom relief, patient preference, functional restoration (not just mood scores), tolerability, access, and insurance coverage. Notably, the review gives explicit weight to glutamate-pathway interventions as a distinct category from monoaminergic antidepressants, reflecting a maturing consensus that treatment-resistant cases often require a different mechanism entirely.
The Esketamine vs. Racemic Ketamine Question
The review does not resolve — and arguably cannot yet resolve — the longstanding clinical debate between FDA-approved intranasal esketamine and IV or oral compounded racemic ketamine. What it does do is legitimize the broader glutamatergic category as a first-line consideration in TRD, rather than a last resort after exhausting brain stimulation options.
For patients and clinicians weighing esketamine against low-dose ketamine protocols, several practical distinctions remain relevant. Esketamine requires in-office administration with a two-hour post-dose monitoring window and carries REMS program restrictions. Compounded racemic ketamine — whether delivered intravenously, intramuscularly, or via sublingual or oral troches — offers more flexibility in setting and dosing schedule, though it lacks the same regulatory approval pathway and insurance reimbursement structure.
The clinical review's emphasis on patient preference as a legitimate selection criterion is meaningful here. It signals that the field is moving away from a rigid hierarchy of interventions toward a more individualized, shared decision-making model — which aligns well with how many low-dose ketamine providers already operate.
Functional Outcomes, Not Just Symptom Scores
One of the more significant framings in the review is the shift toward measuring functional restoration as a treatment goal, not just reductions on depression rating scales like the MADRS or PHQ-9. This matters for ketamine patients specifically because one of the consistent findings across ketamine trials is that improvements in anhedonia, motivation, and daily functioning can emerge quickly — sometimes before subjective mood fully lifts.
If your clinician is using functional benchmarks (return to work, social engagement, self-care capacity) alongside symptom scores, that is increasingly aligned with best practice. Conversely, if a treatment course produces score improvements on paper but leaves daily function unchanged, the review's framing suggests that should prompt a reassessment of dose, frequency, or modality.
This also has implications for maintenance scheduling. The question of when to taper, extend, or consolidate a ketamine series is partly a symptom question but increasingly a function question: Is the patient doing more? Engaging more? Sustaining gains between sessions? These are the markers that matter for long-term decision-making.
Key Takeaway
The evolving clinical framework for TRD places low-dose ketamine squarely within a recognized, guideline-adjacent category of fast-acting glutamatergic treatments. Patient preference, speed of response, and functional outcomes — not just symptom checklists — are now explicitly named as selection criteria. If you are navigating a TRD diagnosis, this framing supports a more direct conversation with your provider about ketamine's role in your treatment plan, including how maintenance decisions should be tied to functional recovery, not symptom scores alone. The evidence base here is still developing, and individual responses vary considerably; this guidance reflects expert opinion more than large randomized trial data.
What This Means for Patients Researching Low-Dose Ketamine
If you have been told your depression is treatment-resistant, this clinical review reinforces several things worth knowing. First, the standard of care is genuinely evolving — glutamatergic options are no longer considered experimental fringe treatments in serious psychiatric circles. Second, the decision between esketamine and compounded ketamine is legitimately complex, and a clinician who presents it as simple in either direction warrants some skepticism. Third, treatment selection in TRD is increasingly individualized, which means your history, preferences, access constraints, and functional goals should all be part of the conversation.
For those already in a low-dose ketamine protocol, the review's emphasis on functional outcomes is a useful reframe for evaluating your own progress. Tracking not just mood but also energy, motivation, social engagement, and daily capacity gives you and your provider a richer picture of whether the current approach is working — and whether the dosing schedule, frequency, or adjunct therapy support needs adjustment.
The original review is available at Psychiatric Times.
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