If ketamine didn’t work: what comes next

What does “didn’t work” mean?

Depression studies use two words for success. Response means symptom scores dropped by at least half. Remission means scores fell into the range considered minimal or no depression. Response rates are usually higher than remission rates.

That gives three possible results. No meaningful change is non-response. Feeling better but still clearly depressed may be a partial response. A drop of half or more is a response, even if you have not reached remission. Each one leads to a different conversation with your prescriber, so ask for your scores rather than relying on how a single day felt.

How many sessions before you judge it?

Most IV ketamine programs start with about six infusions over two to three weeks. In one trial of 41 people, those who responded needed a median of three infusions. An international expert review says most responders improve within the first one or two infusions, though some take four to six. If a full series brings no meaningful change, more of the same is unlikely to help.

For Spravato® in treatment-resistant depression, the label says to check for benefit at the end of the four-week induction phase to decide whether to continue. For schedules and maintenance, see how many ketamine treatments.

Questions to ask your prescriber

• What dose and route did I get? Two of the IV trials we cite, ELEKT-D and a 2013 trial, used 0.5 mg per kilogram of body weight, infused over 40 minutes. Ask whether your treatment matched that, and whether the dose was ever adjusted. Ask too whether it was IV, an injection, a nasal spray, or a lozenge.
• How many sessions did I have, and what were my scores? Ask for the rating scale results from your first and last sessions.
• Could one of my medications have blunted it? Observational studies suggest benzodiazepines may blunt ketamine’s antidepressant effect. Never change or stop a medication without your prescriber.
• Should my diagnosis be reviewed? Ask whether anything else could be driving the symptoms, such as another medical or psychiatric condition, substance use, or a medication.
• What do you recommend next, and why? Ask what the evidence is for that option and how you will both know whether it is working.

What are the options after ketamine?

We found no large trial that tested any of these options specifically in people who did not respond to ketamine. The studies below enrolled people whose depression had not responded to antidepressants. That is the closest evidence available, so the choice is a judgment call for you and a psychiatrist.

Spravato (esketamine)

Spravato is a nasal spray of esketamine, a close relative of ketamine. It is FDA-approved for treatment-resistant depression, so insurers publish rules for covering it, often with prior authorization. In a 2023 trial of 676 people with treatment-resistant depression who were taking an SSRI or SNRI antidepressant, 27.1% reached remission at week 8 with esketamine, compared with 17.6% with the added medicine quetiapine. The manufacturer funded that trial, and patients knew which treatment they got, though the raters did not.

We found little research on whether Spravato helps someone who did not respond to IV ketamine. Because the two drugs are so closely related, ask your prescriber what they expect and why. See ketamine vs. Spravato and Spravato insurance coverage.

TMS (transcranial magnetic stimulation)

TMS uses a magnetic coil against the scalp and involves no drug. It has been FDA-cleared for depression since 2008. A standard course is five sessions a week for four to six weeks. In one naturalistic study of 307 patients at 42 U.S. TMS practices, sponsored by the device’s manufacturer, 58% responded and 37% reached remission by clinician rating.

Ketamine and TMS work by different mechanisms, and little research has tested whether not responding to one predicts the other. See ketamine vs. TMS.

ECT (electroconvulsive therapy)

ECT uses an electric current to cause brief seizure activity in the brain while you are under general anesthesia with a muscle relaxant. The National Institute of Mental Health says a typical course is three times a week, usually for 6 to 12 treatments. Common side effects include headache, upset stomach, muscle aches, confusion, and memory loss. The memory problems usually improve in the days and weeks after the course ends. NIMH says ECT is still considered the “gold standard” for treatment-resistant depression.

A large head-to-head trial, ELEKT-D, randomly assigned 403 people with treatment-resistant depression without psychosis, all referred to ECT clinics, to IV ketamine twice a week or ECT three times a week for three weeks. In that trial, 55.4% responded to ketamine and 41.2% to ECT, and ketamine met the trial’s test for being no worse than ECT. ECT appeared to be linked to a drop in memory recall after three weeks, with gradual recovery, and to muscle and joint side effects. Ketamine was linked to dissociation.

That trial has limits. Patients knew which treatment they got, and more people assigned to ECT withdrew before starting (33, against 5 for ketamine). It compared ketamine with ECT directly. It did not test ECT in people for whom ketamine had already failed.

Medication changes

A psychiatrist may suggest switching antidepressants, or adding a second medicine to the one you take (augmentation). One large trial, VAST-D, followed 1,522 veterans whose depression had not responded to at least one antidepressant. After 12 weeks, remission rates were 22.3% after switching to bupropion, 26.9% after adding bupropion, and 28.9% after adding aripiprazole. Only adding aripiprazole beat switching, and the authors called the gain modest. Sleepiness, restlessness (akathisia), and weight gain were more common with aripiprazole.

These results are modest. They come from a mostly male veteran group after at least one failed antidepressant, and it was not a study of people who had tried ketamine.

Psychotherapy

In the CoBalT trial, 469 primary care patients in the UK were still depressed after at least six weeks on antidepressants. Those who added cognitive behavioral therapy (CBT) to their usual care were more likely to respond at six months: 46%, compared with 22% on usual care alone. CBT was added to medication rather than replacing it. Patients and researchers knew who got therapy, and it was not a study of people who had tried ketamine.

If you are a family member

Offer to go to the follow-up visit and help keep the list of past treatments, doses, and scores. The Spravato® label asks family members and caregivers to watch for changes in behavior and to alert the healthcare provider. Our list of warning signs shows what to look for.

Where to go from here

Bring this page to the follow-up visit. If your current program cannot offer the next option, our guide to finding programs to compare lists free locator tools.