Treatment-Resistant Depression: Why Antidepressants Fail

What Counts as Treatment-Resistant Depression

Treatment-resistant depression, or TRD, describes major depressive disorder that does not improve after a person has tried at least two different antidepressant medications at adequate doses for an adequate length of time. A report published by The Hindu on October 10, 2026, examines this exact question: what happens when standard antidepressants do not work. The piece lays out the basic clinical picture that doctors and patients already know well, that roughly one in three people with depression do not respond fully to the first few medications they try, and that the search for a working treatment can stretch across years.

The Hindu's report is a general explainer rather than a study announcement or a policy change, and it does not name a specific drug trial, regulatory action, or new guideline. Its value for readers is in framing a question that directly affects anyone who has cycled through SSRIs, SNRIs, or other first-line antidepressants without relief: what are the next steps once standard options have been exhausted.

Where Ketamine and Esketamine Fit in the TRD Pathway

Esketamine, sold under the brand name Spravato, is a nasal spray form of ketamine that the U.S. Food and Drug Administration approved specifically for treatment-resistant depression in 2019, administered under medical supervision in a certified clinic. Generic racemic ketamine, given off-label as an IV infusion, intramuscular injection, or compounded lozenge, is the other major route patients encounter, and it is not FDA-approved for depression but is prescribed off-label by many psychiatrists and ketamine clinics. Both work through a different mechanism than SSRIs: rather than slowly adjusting serotonin levels over weeks, ketamine acts on the brain's glutamate system and can produce a rapid, though often temporary, reduction in depressive symptoms within hours to days.

That speed is the main reason ketamine and esketamine get raised in conversations like the one The Hindu's report describes. For someone who has spent a year or more failing one antidepressant after another, a treatment that can show effect within a single week is a meaningfully different proposition than waiting another six to eight weeks to see if the next pill works. The tradeoff is that ketamine's antidepressant effect is not permanent on its own. Most protocols involve an induction series of multiple sessions over two to four weeks, followed by maintenance sessions spaced weeks or months apart, and symptoms can return if treatment stops.

What This Means for Readers Weighing Options

The Hindu's report does not make specific claims about ketamine's effectiveness, cost, or availability, so readers should not assume it is endorsing any one treatment path. What it does usefully reinforce is the two-trial threshold: if you have genuinely completed two full, adequately dosed courses of different antidepressants without sufficient improvement, you meet the clinical definition that most ketamine and esketamine clinics use for eligibility, and that is the point at which a conversation about alternative treatments becomes clinically appropriate rather than premature.

Before pursuing ketamine or esketamine, it helps to have documentation of which medications you tried, at what doses, and for how long, since clinics will generally ask for this history to confirm TRD status and because insurers that cover esketamine typically require it. Cost and access remain the practical hurdles. Esketamine administered in a certified clinic may be covered in part by insurance depending on plan and country, while off-label IV ketamine is frequently self-pay and can run from several hundred to over a thousand dollars per session depending on the clinic and region.

Practical Steps Before Your Next Appointment

If antidepressants have not worked for you, three things are worth doing before your next psychiatry visit. First, write a timeline of every medication, dose, and duration you have tried, since this is the evidence a provider needs to confirm treatment resistance. Second, ask your prescriber directly whether you meet criteria for treatment-resistant depression and what options they consider appropriate, including esketamine, off-label ketamine, transcranial magnetic stimulation, or augmentation strategies that add a second medication rather than switching entirely. Third, if ketamine or esketamine comes up, ask any clinic you consider about their monitoring protocol during dosing, how they handle maintenance scheduling, and what their plan is if symptoms return between sessions, since the quality of follow-up care varies widely between providers.

This article is Ketamine Resource's analysis of a general-interest explainer from The Hindu, published October 10, 2026. Read the original report for its full framing of the treatment-resistant depression landscape: The Hindu's report on treatment-resistant depression.