How Doctors Choose Ketamine vs. Other TRD Treatments

A New Look at How Psychiatrists Navigate Treatment-Resistant Depression

For patients who have tried multiple antidepressants without relief, the landscape of available treatments has expanded significantly in recent years — but more options also means more complexity. A clinical overview published in Psychiatric Times in April 2026 sheds light on how psychiatrists are currently thinking through treatment selection for treatment-resistant depression (TRD), with a particular focus on fast-acting glutamate-based therapies like esketamine (Spravato) and IV ketamine alongside brain stimulation approaches like transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT).

The piece reflects a growing recognition in psychiatry that TRD is not a single, uniform condition — and that matching a patient to the right intervention requires weighing a range of clinical, practical, and personal factors. For patients and families currently navigating this process, understanding what goes into that decision can make consultations more productive and help set realistic expectations.

What Clinicians Are Actually Weighing

According to the Psychiatric Times analysis, several core factors shape how psychiatrists approach TRD treatment selection in 2026:

• Speed of response: Ketamine and esketamine are notable for producing antidepressant effects within hours to days — a meaningful advantage for patients with acute suicidal ideation or severe functional impairment. Brain stimulation options like TMS typically require weeks of daily sessions before benefits emerge, though ECT can act more rapidly.
• Patient preference and lifestyle: Esketamine (administered intranasally in certified clinical settings) and IV ketamine require in-office monitoring, but their session frequency decreases over time. TMS involves daily clinic visits for four to six weeks. Patient tolerance for each model varies significantly, and clinicians are increasingly factoring this into recommendations.
• Functional outcomes, not just symptom scores: The article highlights a shift toward evaluating how treatments affect a patient's ability to work, maintain relationships, and engage in daily life — not just whether depressive symptoms decrease on a rating scale. Glutamate-targeting therapies have shown particular promise in restoring functional capacity relatively quickly.
• Prior treatment history: How many antidepressants a patient has tried, whether augmentation strategies were attempted, and whether there is a history of bipolar features or psychosis all influence which pathway is considered safest and most appropriate.
• Access and insurance coverage: Esketamine (Spravato) holds FDA approval for TRD and major depressive disorder with acute suicidal ideation, making it more likely to receive insurance coverage than IV ketamine, which remains off-label for depression. This practical distinction continues to drive treatment decisions for many patients regardless of clinical preference.

The overview also notes that brain stimulation and ketamine-based treatments are not necessarily competing options — some patients cycle through multiple modalities over time, or use them in combination with ongoing medication management.

The Esketamine vs. IV Ketamine Distinction

One area the clinical guidance touches on — and one that frequently confuses patients — is the difference between FDA-approved esketamine (Spravato) and IV ketamine infusions. Both work on the glutamate system and share a pharmacological relationship, but they are administered differently, studied in different clinical trial populations, and covered differently by insurance.

Esketamine is the S-enantiomer of ketamine and is delivered as a nasal spray under direct clinical supervision. It has the backing of large randomized controlled trials and regulatory approval, which strengthens the evidence base and opens insurance pathways. IV ketamine, by contrast, has a longer clinical history of use and a substantial body of research, but lacks FDA approval specifically for depression — meaning it is prescribed off-label, often paid for out-of-pocket, and less uniformly standardized across providers.

Neither is universally superior. Some patients respond better to one than the other, and factors like cost, proximity to certified Spravato providers, and individual clinical history all legitimately influence which path a patient and their psychiatrist pursue. What the Psychiatric Times piece reinforces is that this decision should be made collaboratively, with a clinician who understands both options in depth.

What This Means If You're Evaluating Ketamine Therapy

For patients specifically considering ketamine or esketamine, the clinical framework described in this overview is a useful lens. It suggests that a well-qualified provider should be asking about your treatment history, the urgency of your symptoms, your functional goals, and your practical constraints — not simply offering a one-size-fits-all protocol.

Red flags worth noting: providers who don't conduct a thorough intake evaluation, who don't discuss how ketamine fits alongside your existing psychiatric care, or who can't clearly explain the difference between IV ketamine and esketamine and why they're recommending one over the other. The expansion of TRD treatment options is genuinely good news for patients, but it also means that provider quality and clinical judgment matter more than ever.

You can read the original clinical overview at Psychiatric Times.