How Doctors Choose TRD Treatments in 2026

The Growing Menu of TRD Options — And How Clinicians Navigate It

For the roughly one-third of people with major depressive disorder who don't respond to standard antidepressants, treatment-resistant depression (TRD) is not just a diagnosis — it's a daily reality. As of 2026, clinicians have more tools than ever to address TRD, but more options also means more complexity in choosing the right one. A new analysis published in Psychiatric Times outlines the key factors guiding treatment selection, with particular attention to fast-acting glutamate-based therapies, esketamine nasal spray, and brain stimulation approaches like TMS and ECT.

The report highlights that clinical decision-making in TRD is no longer purely algorithm-driven. Patient preference, prior treatment history, speed-of-response needs, and access logistics all play meaningful roles in what a prescribing clinician recommends — and what a patient is likely to actually stick with.

Where Oral Ketamine Tablets Fit Into the Clinical Picture

The Psychiatric Times analysis centers much of its discussion on esketamine (Spravato), the FDA-approved intranasal formulation, and compares it against neuromodulation approaches. But the broader conversation about glutamatergic, fast-acting treatments directly applies to oral ketamine — including tablet and troche formulations — which are widely used in off-label clinical contexts across the United States.

Here's how oral tablets stack up against the options discussed in the analysis:

• Speed of action: Ketamine, across all delivery routes, is noted for its rapid antidepressant effects — often within hours to days rather than the weeks required by SSRIs or SNRIs. Oral tablets, while slower to peak plasma concentration than IV infusions or nasal spray, still offer meaningfully faster onset than traditional antidepressants. For patients in acute distress who need relief without clinical infusion access, this remains a significant advantage.
• Bioavailability and dosing: One trade-off with oral ketamine tablets is lower and more variable bioavailability compared to IV (roughly 20–30% for oral versus near 100% for IV). Clinicians prescribing tablets must account for first-pass metabolism, which reduces the amount of active drug reaching systemic circulation. This is why oral doses are typically higher in milligram terms than IV doses, and why consistent timing relative to food intake matters for patients managing their own schedules at home.
• Patient preference and access: The analysis specifically calls out patient preference as a guiding factor — and this is where oral tablets have a structural advantage. Home-based dosing removes the logistical burden of repeated clinic visits required for esketamine or IV infusion protocols. For patients with demanding work schedules, caregiving responsibilities, or limited transportation, a prescribed tablet regimen can mean the difference between starting treatment and not starting it at all.
• Safety monitoring: Esketamine requires in-office administration with a mandatory two-hour post-dose observation window due to dissociation and sedation risks. Oral ketamine prescribed for home use places more responsibility on patients and requires robust informed consent, safety planning, and ideally a support person during dosing sessions. This isn't a reason to avoid oral tablets, but it is a reason to take the safety protocol seriously — and to work only with prescribers who provide thorough guidance.

What This Means If You're Navigating TRD Treatment Decisions

The clinical framework described in the Psychiatric Times piece is useful for patients, not just providers. Understanding that your clinician is weighing factors like functional improvement (not just symptom scores), speed of response, and your own logistical realities can help you have a more productive conversation about your options.

If you've already tried multiple antidepressants without adequate relief, here are practical questions worth raising with your provider:

• Am I a candidate for a fast-acting glutamate-based treatment? If yes, what delivery format makes sense given my schedule, access, and support system?
• How will we measure functional improvement — not just mood scores? The analysis emphasizes that functional outcomes (work, relationships, daily activities) are increasingly central to how TRD treatment success is defined.
• If oral ketamine tablets are prescribed, what's the safety protocol? A responsible prescriber should cover dissociation risk, contraindications (including personal or family history of psychosis), and what to do if a dose feels overwhelming.
• How does oral dosing fit into my broader treatment plan? Ketamine — in any form — works best as part of a comprehensive approach that may include therapy, lifestyle support, and ongoing psychiatric care. It's a tool, not a standalone cure.

The expansion of clinical thinking around TRD is genuinely good news for patients who have struggled to find relief. Oral ketamine tablets represent one accessible, flexible entry point into fast-acting treatment — but like all ketamine modalities, their effectiveness depends heavily on appropriate patient selection, prescriber expertise, and adherence to safety best practices.

Source: Psychiatric Times — Factors Guiding Treatment Selection in Treatment Resistant Depression