Ketamine, Esketamine, and the New Era of Treatment-Resistant Depression | Bharosa

She has tried six antidepressants over twelve years. Two SSRIs. Two SNRIs. A tricycle. An atypical. Each one helped a little, then stopped helping. Each one came with side effects she learned to tolerate. Each transition was its own quiet exhaustion. Today she is forty-one years old, still depressed, still showing up to work, still loving her family, and still living with the deep, grey weight that has been her constant companion since her late twenties. Her psychiatrist, sitting across from her last month, said the words she had been hearing for years. We are running out of standard options. And then said the words she had not heard before. Have you considered ketamine?

If you or someone you love has been through multiple antidepressants without lasting relief, this article is for you. The world of depression treatment has changed significantly over the last decade, and one of the most important changes has been the emergence of ketamine and its derivative esketamine as treatments for what psychiatrists call treatment-resistant depression. At Bharosa, we want to explain what these treatments are, what they do, who they help, and what they do not do — because the topic is surrounded by both excessive hype and excessive fear, and patients deserve a clear, honest clinical explanation.

What Treatment-Resistant Depression Actually Means

Treatment-resistant depression, or TRD, is a clinical term used when a patient has failed to respond adequately to at least two trials of standard antidepressant medications, given at appropriate doses for an appropriate duration. The American Psychiatric Association, the leading professional body of psychiatrists in the United States, recognises TRD as a distinct clinical category that requires specialised treatment approaches beyond first-line medication. Estimates from international studies suggest that roughly one-third of people with major depressive disorder will not respond fully to standard treatment, and this group has historically had very limited options.

What makes TRD particularly difficult is not just the persistence of symptoms but the accumulated weight of having tried, hoped, failed, and tried again multiple times. Patients with TRD often arrive at Bharosa exhausted not just by the depression but by the years of effort that did not work. They have been told to be patient, to give the next medication time, to try harder, to think positively. The treatments that help most TRD patients are not about willpower. They are about a different mechanism of action, and that is exactly what ketamine offers.

How Ketamine Works Differently From Standard Antidepressants

Standard antidepressants — including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants — work primarily by adjusting levels of serotonin and norepinephrine in the brain. They generally take four to eight weeks to produce a meaningful clinical effect, and for patients with TRD they often produce only partial relief. Ketamine works through an entirely different mechanism. It acts primarily on the N-methyl-D-aspartate (NMDA) receptor, part of the glutamate system, which is involved in the brain’s mechanisms for forming new neural connections.

The result, when ketamine is administered in carefully controlled clinical settings, is often a rapid antidepressant effect — sometimes within hours rather than weeks. The Lancet Psychiatry, one of the most respected peer-reviewed psychiatry journals in the world, has published extensive research on ketamine and esketamine for treatment-resistant depression, consistently showing meaningful clinical benefit in patients who had failed multiple previous treatments. This is important because for patients with TRD, the speed of response can be life-changing — particularly when suicidal thoughts are present and time matters.

The Difference Between Ketamine and Esketamine

Ketamine has been used as a medical anaesthetic for over fifty years and is on the World Health Organization’s list of essential medicines. It is generally given off-label for depression by intravenous infusion in carefully controlled settings. Esketamine is a derivative of ketamine that has been formally approved by the U.S. Food and Drug Administration, the federal agency responsible for medication safety and approvals in the United States, specifically for treatment-resistant depression. It is administered as a nasal spray under medical supervision and has rigorous safety protocols around its use, including required observation periods after each dose.

Both treatments have shown clinical benefit. Both require careful medical supervision. Neither is a casual outpatient prescription. Neither is suitable for self-administration. The integration of ketamine or esketamine into a depression treatment plan is a specialist decision made by a consultant psychiatrist after a thorough assessment of the patient’s history, prior treatments, medical conditions, and the specific risks and benefits in that individual case. Done well, this is one of the most important advances in depression treatment in a generation. Done badly, it carries risks that should not be minimised.

Who These Treatments Help and Who They Do Not

Ketamine and esketamine are not first-line treatments. They are reserved for patients who have failed multiple standard treatments or who have specific clinical features such as acute suicidal ideation that requires rapid intervention. They are not appropriate for patients with certain medical conditions, certain psychiatric histories, or certain substance use patterns. They are not a magic cure. They are not a replacement for psychotherapy, lifestyle change, or ongoing psychiatric care. They are a new tool in the depression treatment toolbox, and a powerful one when used in the right patient at the right time.

At Bharosa, our consultant MD Psychiatrists assess every patient with treatment-resistant depression carefully. We discuss the full range of evidence-based options — including newer treatments — and we are honest about what is currently available in India, what would require referral, what the risks are, and what the realistic expectations should be. Cognitive Behavioural Therapy (CBT) and other evidence-based psychotherapies remain core to treatment regardless of which medications are used. The goal is not just symptom relief. It is sustainable recovery.