What technically counts as treatment-resistant depression?

The most widely used definition is failure to achieve adequate response after at least two antidepressant trials of adequate dose and duration during the current depressive episode. Some definitions require the trials to come from different drug classes. Adequate dose and duration generally means a therapeutic dose taken consistently for six to eight weeks. About one-third of people with major depressive disorder meet this threshold, which is why TRD is a clinical reality, not an edge case.

Is ketamine a last resort for depression?

We do not think of it that way, and the evidence does not require you to. Ketamine is best understood as a next reasonable step once two adequate antidepressant trials have not delivered the response you need. Waiting until every option has been exhausted is not the only path. The faster onset of ketamine, often within 24 to 72 hours, can be especially relevant when symptoms are severe or stalled. Talk with your prescribing provider about timing.

How is IV ketamine different from Spravato?

Spravato is esketamine, the S-enantiomer of ketamine, delivered as a nasal spray and FDA-approved for treatment-resistant depression. IV ketamine uses the racemic molecule, both enantiomers together, and is administered intravenously off-label for depression. The route, the molecule, and the regulatory status all differ. We compare the two head-to-head in our IV-versus-Spravato article. Both target the NMDA-glutamate system; the right choice depends on insurance, response history, and clinical fit.

How long do the effects of ketamine last for depression?

Honest answer: it varies. After a single infusion, response often lasts about one to two weeks. The aan het Rot 2010 study in Biological Psychiatry found that after six infusions over 12 days, most responders relapsed roughly 19 days after the final session. Most clinics, including ours, use an induction series followed by individualized maintenance to extend benefit. Durability depends on the person, the protocol, and what other supports are in place.

What if ketamine does not work for me?

Roughly 30 to 50 percent of TRD patients in the published literature do not achieve a meaningful response. We screen for likely response during the consultation and define what success would look like before booking a full series. If the first one or two sessions show no signal, we pause and rethink rather than push more sessions. We will also discuss alternatives like Spravato, ECT, or TMS, which sometimes succeed where IV ketamine does not.

Ketamine for Treatment-Resistant Depression: An Evidence Update

What treatment-resistant depression actually means

Treatment-resistant depression, or TRD, is not a fuzzy clinical mood. It is a defined threshold. The most widely used definition is failure to achieve adequate response after at least two antidepressant trials of adequate dose and duration during the current depressive episode. Some research definitions tighten this further by requiring that the trials come from different drug classes, for example one SSRI and one SNRI.

Roughly one in three people with major depressive disorder will meet this threshold at some point. That is a large group of patients living through long, frustrating loops of medication adjustment, side effects, and waiting weeks to find out if a new prescription will help. By the time someone arrives at our clinic asking about ketamine, they have usually been through several of those loops. The question they are bringing is not abstract. It is whether something genuinely different is on the table.

It is worth saying clearly: ketamine is FDA-approved as an anesthetic, and its use for depression is off-label. Esketamine, the S-enantiomer marketed as Spravato, is FDA-approved for treatment-resistant depression. Racemic IV ketamine, which is what most clinics including ours actually deliver, sits in the off-label space supported by two decades of peer-reviewed research.

How ketamine differs from traditional antidepressants

Standard antidepressants act on monoamine systems: serotonin, norepinephrine, dopamine. SSRIs raise synaptic serotonin. SNRIs do the same plus norepinephrine. These drugs were built around a chemical-imbalance model that has dominated psychiatry for forty years, and they help many people. They also leave a substantial group behind, and they typically take four to eight weeks to produce a meaningful clinical effect.

Ketamine works in a fundamentally different place. It is an N-methyl-D-aspartate (NMDA) receptor antagonist. By blocking NMDA receptors on inhibitory interneurons, ketamine triggers a brief surge of glutamate, the brain’s main excitatory neurotransmitter. That surge activates AMPA receptors, increases brain-derived neurotrophic factor, and drives a window of synaptic plasticity, the formation of new connections in mood-relevant brain circuits.

A 2019 review of the mechanism literature, summarized by Krystal and colleagues across Neuron and related journals, argued that ketamine’s rapid antidepressant effect is driven by glutamate and AMPA-mediated synaptic plasticity rather than by anything in the monoamine system. That is not just a different drug. That is a different theory of what depression is. Our mechanism explainer goes deeper, and our brain-research roundup tracks newer imaging and biomarker work.

The evidence: Krystal, aan het Rot, Murrough, and beyond

The clinical story of ketamine for depression is older than most people realize. The first randomized, placebo-controlled trial of IV ketamine in depression was published by Berman and colleagues in Biological Psychiatry in 2000, with seven patients. Small, but striking. John Krystal’s lab at Yale built on that signal through the early 2000s.

The aan het Rot 2010 study published in Biological Psychiatry moved the field forward by asking what happens with repeated dosing. The investigators gave ten TRD patients six open-label IV ketamine infusions over 12 days. Mean MADRS depression scores dropped about 85% from baseline, and most responders relapsed roughly 19 days after the sixth infusion. That second number is just as important as the first. It told the field that ketamine is not a one-and-done; durability hinges on what happens after the initial series.

The Murrough 2013 two-site RCT, also published in American Journal of Psychiatry, is the study most often cited as the proof point. Seventy-three TRD patients were randomized to a single dose of IV ketamine or to midazolam, an active control chosen specifically to mimic ketamine’s sedating side effects so patients and raters could not easily tell which they had received. At 24 hours, the response rate was 64% in the ketamine arm versus 28% in the midazolam arm. That difference held through statistical analysis and made the active-control concern hard to dismiss.

From 2013 forward the literature broadened. Systematic reviews and meta-analyses through the 2010s and into the 2020s consistently reported response rates in the 50 to 70% range across TRD populations, with rapid onset within 24 to 72 hours. The American Psychiatric Association issued a consensus statement in 2017 acknowledging the evidence and laying out safety guardrails for clinical use. The trajectory culminated, on the regulatory side, in the FDA’s March 2019 approval of esketamine nasal spray for treatment-resistant depression in adults, the first novel-mechanism antidepressant approval in a generation.

Spravato vs. IV ketamine: on-label vs. off-label

Spravato is esketamine, the S-enantiomer of the ketamine molecule, delivered as a nasal spray under a Risk Evaluation and Mitigation Strategy (REMS) program. Patients self-administer the spray in a certified clinic and stay for two hours of monitoring. It is FDA-approved for TRD when used alongside an oral antidepressant.

IV ketamine, the racemic form, is the molecule used in nearly all of the foundational research, including aan het Rot 2010 and Murrough 2013. It is delivered intravenously over about 40 minutes, with anesthesia-level monitoring throughout the infusion. The mechanism is the same NMDA-glutamate pathway. The route, the dose, the bioavailability profile, and the regulatory status all differ.

Neither is inherently better. The right tool depends on insurance coverage, response to prior trials, comfort with the route, and clinical fit. We compare the two head-to-head in our IV-versus-Spravato breakdown, and we summarize the regulatory side in our FDA-and-ketamine piece. For some patients, Spravato through insurance is the right answer. For others, IV racemic ketamine fits better. We will say so honestly in the consultation.

What response and durability really look like

Response rates around 50 to 70% in the published TRD literature are real. They are also one number out of context, and context matters here. Most of those numbers refer to acute response within 24 to 72 hours of an infusion. Single-infusion benefit typically fades over one to two weeks. The aan het Rot data suggested that a six-infusion induction series can extend response, but that even responders relapsed at a median of about 19 days post-series without additional treatment.

That is why most modern protocols, ours included, use an induction series followed by individualized maintenance dosing. The maintenance schedule is not standardized. Some patients do well with a booster every four to six weeks. Others go longer. Some need adjunctive psychotherapy, lifestyle changes, or continued antidepressant medication to consolidate gains. Research suggests that combining ketamine with structured psychological support extends benefit, but the optimal protocol is still being worked out.

We hedge here on purpose. Studies indicate that ketamine helps a clear majority of TRD patients, and the data supports rapid onset. Evidence does not yet support a one-size protocol. Durability is the open question across the entire field.

Who is and isn’t a candidate

Most adults with TRD are reasonable candidates for a consultation. Strongest fit, based on the published literature and our clinical experience:

Two or more failed antidepressant trials of adequate dose and duration. This is the textbook TRD threshold and the population the research was built around.
Acute symptoms where waiting six to eight weeks for a new SSRI to take hold is not the right plan. Ketamine’s faster onset is one of its most valuable features.
Co-occurring features that overlap with ketamine’s evidence base, including features explored in our ketamine-versus-ECT comparison and our ketamine-versus-TMS comparison.
People who want a treatment with a different mechanism than what they have already tried rather than a third or fourth monoamine drug.

Ketamine is not appropriate for everyone. We are cautious in patients with active psychosis, untreated severe hypertension, recent cardiovascular events, or active substance-use disorder involving dissociatives. Pregnancy is a high-caution context that requires direct conversation with a prescribing OB and the patient’s mental-health team. We do not provide diagnostic guidance, and we will never tell you to stop, start, or change any medication; those decisions belong with your prescribing provider.

What to expect at a Nashville TRD consultation

The first step is a no-cost conversation. We review your diagnostic history, prior medication trials, current medication list, and any other treatments you have tried. We are looking for two things: whether ketamine is a clinically reasonable next step, and whether there are red flags that argue against it.

If we move forward, the standard induction is a series of six IV infusions over two to three weeks, dosed by weight. Marla Peterson, CRNA, oversees every infusion at our Franklin clinic, with anesthesia-level monitoring of heart rate, blood pressure, oxygen saturation, and clinical status throughout each session. Our safety overview walks through the monitoring stack. If you want more on the role itself, our CRNA explainer covers it.

You will need a driver after each session, and you should plan to take the rest of the day light. Most patients return to normal activity the next morning. After the induction, we plan maintenance individually based on your response, your symptoms, and your preferences. Many patients want to know about how it works at our clinic from a logistical standpoint and the broader depression page for the treatment context. Cost is transparent: $475 per session, no surprise add-ons.

Ketamine is not a miraculous reset and we will not describe it that way. What the evidence supports is a meaningful response in roughly half to two-thirds of treatment-resistant patients, often within days, with durability that depends on a thoughtful maintenance plan. — Based on Murrough et al., Am J Psychiatry 2013; aan het Rot et al., Biol Psychiatry 2010; FDA Spravato approval 2019

The honest summary: TRD is real, the evidence for ketamine is genuinely strong by the standards of psychiatric research, and the durability question is open. If your last two or three antidepressants have not done the job, ketamine deserves a conversation, not as a last resort but as a reasonable next step.