Published
Medically reviewed by Danesh Alam MD, DFAPA, DFASAM
When depression has not improved enough after more than one antidepressant, two newer options often come up: transcranial magnetic stimulation (TMS) and ketamine-based treatment. Both are used when standard treatment has not provided enough relief, but they work differently, ask different things of you, and carry different risks.
No study has directly compared the two in a randomized trial, so there is no evidence-based answer to which one is better. The more useful question is which one fits your health, history, schedule, and goals. This guide explains the differences and the questions to bring to a psychiatrist.
What "treatment-resistant" means
Doctors often describe depression as treatment-resistant when at least two antidepressants, taken at an adequate dose for long enough, have not helped enough during the current episode. Research trials use a similar working definition. NEJM: ESCAPE-TRD trial.
The label describes a treatment history, not a judgment about the person. Before recommending TMS or ketamine, a clinician should review what was tried, for how long, what side effects occurred, and whether something else, such as substance use, a sleep problem, or another medical condition, could be affecting the response.
How TMS works
TMS uses a magnetic coil placed against the scalp to deliver pulses that stimulate nerve cells in a brain region involved in mood. You stay awake, no anesthesia is used, and there is no medication in your bloodstream from the procedure itself. NIMH describes repetitive TMS as FDA-cleared for treatment-resistant depression. NIMH: Brain stimulation therapies.
A standard course involves frequent outpatient visits, typically on weekdays over several weeks. Afterward, most people return to their usual activities. Improvement, when it happens, usually builds gradually over the course rather than appearing after a single session.
Headache and scalp discomfort are the most common side effects. Seizure is a rare but serious risk. People with metal or implanted devices in or near the head need careful screening, and some cannot have TMS. FDA: rTMS special controls guidance. Our guide to the benefits of TMS for treatment-resistant depression covers TMS in more detail.
How ketamine and esketamine work
"Ketamine treatment" can mean two different things:
- Esketamine (Spravato) is a nasal spray that is FDA-approved for treatment-resistant depression in adults. It can only be given in a certified healthcare setting, where the patient uses it under observation and is monitored for at least two hours afterward. Patients cannot drive until the next day, after a restful sleep. DailyMed: Spravato prescribing information.
- Ketamine infusions deliver the medication through an IV. Ketamine is FDA-approved as an anesthetic, and its use for depression is off-label. In a large trial of people already referred for electroconvulsive therapy, IV ketamine performed as well as ECT for treatment-resistant depression without psychosis. NEJM: ELEKT-D trial.
Both act on a different brain chemical system than traditional antidepressants. Their effects can be noticed within hours to days, which is one reason they draw interest. Common side effects during and after a session include dissociation (feeling detached or unreal), sleepiness, dizziness, nausea, and a temporary rise in blood pressure.
Key differences to weigh
How quickly it may work
- TMS: improvement, when it occurs, usually builds over weeks.
- Ketamine and esketamine: some people notice changes within hours to days.
What the schedule asks of you
- TMS: frequent visits over several weeks. You can usually drive yourself home.
- Esketamine: scheduled clinic visits, each with at least two hours of monitoring, and no driving until the next day. IV ketamine also requires a ride home.
Side effects and medical screening
- TMS: headache and scalp discomfort, with rare seizure. Screening covers metal or implanted devices, seizure history, and medications that lower the seizure threshold.
- Ketamine and esketamine: dissociation, sedation, and blood pressure changes. Certain blood vessel conditions, a history of bleeding in the brain, and some other heart and brain conditions can rule them out.
Misuse potential
- TMS: none. It is a device-based procedure, not a medication.
- Ketamine and esketamine: both are controlled substances with potential for misuse. The next section explains why this matters.
Cost and coverage
- TMS and esketamine are often covered by insurance for treatment-resistant depression, usually with prior authorization and proof of earlier treatment.
- IV ketamine for depression is often paid out of pocket because it is off-label. Ask about your specific plan before starting any of these treatments.
If you have a history of substance use
For people in recovery or with a past substance use disorder, this can be the deciding factor.
Esketamine's prescribing information says people with a history of drug abuse or dependence are at greater risk of misuse. It calls for careful consideration before treating someone with a history of substance use disorder, including alcohol, and for monitoring afterward. A history of substance use does not automatically rule ketamine out, but it should lead to careful screening, supervised dosing, and an honest conversation about how long you have been in recovery and what supports you have.
TMS does not carry that misuse risk. But withdrawal, particularly from alcohol, can raise seizure risk, so your team should consider timing if you are drinking heavily, recently stopped, or are going through detox.
If depression and substance use are happening together, both need treatment. Our dual diagnosis care addresses them together rather than one at a time.
What the research can and cannot tell you
Both treatments have been studied against other options:
- In the ESCAPE-TRD trial, esketamine led to remission more often than adding the antipsychotic quetiapine to an antidepressant.
- In ELEKT-D, IV ketamine performed comparably to ECT for people referred for ECT.
- Trials comparing TMS with a sham (inactive) procedure have found that it helps some adults whose depression did not respond to medication. Psychological Medicine: rTMS meta-analysis.
None of these studies compared TMS with ketamine directly. An exploratory 2025 analysis that combined data from separate trials found the two broadly similar at four weeks, and its authors called for head-to-head trials. eClinicalMedicine: rTMS and esketamine comparison. Results vary from person to person, and not everyone responds to either treatment.
Neither treatment replaces urgent help for suicidal thoughts. Esketamine's label states that it has not been shown to prevent suicide or reduce suicidal thoughts, and hospitalization may still be needed. If you are thinking about harming yourself, call or text 988, or call 911 if you are in immediate danger.
Avoid at-home and online ketamine
Ketamine sold online or prescribed for unsupervised use at home is not the same as clinic-based treatment. The FDA has warned that compounded ketamine products are not covered by the safety program that applies to esketamine, and that at-home use carries added risk because no one is monitoring for problems. In June 2026, it sent warning letters to online sellers of unapproved ketamine products. FDA: Compounding risk alerts. For anyone with a substance use history, unsupervised ketamine deserves particular caution.
Questions to ask a psychiatrist
- Is my depression treatment-resistant, or are there other factors we have not addressed?
- Which option fits my medical history, medications, and any implants or devices?
- How does my substance use history affect which option is safer for me?
- What does the schedule look like, and how will I get to and from appointments?
- How will we measure whether it is working, and what happens if it does not?
- What will my insurance require, and what will I pay out of pocket?
- Should my current medications or therapy continue during treatment?
Exploring TMS and ketamine at Ambrosia
Ambrosia's interventional psychiatry services include TMS through our Exomind service and ketamine therapy for mental health. Neither is the right starting point for everyone. A clinical evaluation looks at your diagnosis, treatment history, health, substance use, and goals before any recommendation is made. If you are not sure where to begin, a mental health assessment is a useful first step.
Contact our admissions team to talk through your history and the options worth discussing. Coverage depends on your plan, and the team can verify your insurance benefits before you decide.