Depression is usually called "treatment-resistant" when at least two different antidepressants, each taken properly, have not worked in the current episode. That is the definition European and US regulators use. It is common: a 2023 expert review estimated at least 30% of people with depression meet it.
It is not a verdict. There are many next steps. These include changing the dose or drug, adding therapy, adding a second medicine, esketamine nasal spray, ketamine, electroconvulsive therapy (ECT) and brain stimulation.
What you can get depends on where you live. The HSE agreed to reimburse esketamine in Ireland, and Scotland accepted it, but NICE does not recommend it in England and Wales. This page sets out the options, the evidence and the access rules.
Get help now
If you are thinking about suicide: in Ireland or the UK, freephone Samaritans on 116 123, any time. In Ireland you can also text 50808. In the US, call or text 988.
If you might act on those thoughts, phone 112 or 999 in Ireland, or 999 in the UK. Or go to an emergency department. In the UK you can also call NHS 111.
Suicidal thoughts can increase in the early weeks of a new antidepressant. NICE advises an earlier review for people aged 18 to 25. Tell your prescriber straight away.
There is no single agreed definition. A 2023 international consensus paper counted many competing ones. The most used is the one adopted by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA). It means an inadequate response to at least two antidepressants. Each must be at an adequate dose, for long enough, and actually taken.
NICE's depression guideline for England (NG222) does not set a strict cut-off. It talks about depression that has had "no or a limited response" to treatment. NICE says that if an antidepressant is going to work, it usually does so within four weeks.
The same 2023 paper says many people labelled treatment-resistant are "pseudo-resistant". The dose was too low, the trial too short, or the medicine was not taken as prescribed.
NICE advises your doctor to ask:
Underactive thyroid, iron or B12 deficiency, sleep apnoea, alcohol and some medicines can all look like, or worsen, depression. Our guide to what works for depression covers what to rule out.
NICE lists these options when an antidepressant alone has not worked:
Switching may need a cross-taper, where one drug is reduced as the other starts. Never stop suddenly. NICE warns that stopping abruptly can cause withdrawal symptoms, and our page on coming off antidepressants explains why.
You may also have heard of bupropion. Whether it is licensed for depression differs by country, as our bupropion explainer sets out.
If medicine alone has not worked, NICE suggests adding group exercise, switching to a psychological therapy, or combining medicine with therapy such as CBT. If therapy alone has not worked, it suggests a different therapy, or adding or switching to an SSRI.
If you are willing to accept more side effects, NICE suggests a specialist may add:
Some of these are "off-label" for depression. That means the doctor uses a licensed medicine outside its listed use. NICE noted this applied to some antipsychotics, lamotrigine and liothyronine in 2022.
Lithium needs regular blood tests. NICE advises checking kidney and thyroid function, weight and calcium before starting and at least every six months. Lithium levels are checked often at first.
Esketamine is a form of ketamine, given as a nasal spray. In the EU and UK it is licensed for adults with moderate to severe depression. It is for when at least two antidepressants have not worked in the current episode. It is used alongside an SSRI or SNRI.
The evidence. The EMA summarises it like this:
A 2023 trial compared esketamine with quetiapine, an antipsychotic added to an antidepressant. At week 8, 27.1% on esketamine were in remission, against 17.6% on quetiapine. Patients knew which treatment they were having, though raters did not. The manufacturer funded it.
How it is given. You take it yourself under direct supervision in a clinic. Blood pressure is checked before and after. Common side effects include dizziness, nausea, feeling disconnected (dissociation), headache, sleepiness and vertigo. Because of misuse risk, it needs a special prescription.
Ketamine is a licensed anaesthetic. Giving it as a drip for depression is off-label.
The Royal College of Psychiatrists supports ketamine only in specialist settings with oversight and long-term monitoring. It does not recommend take-home ketamine. It lists possible long-term harms, mostly seen in heavy recreational use: bladder damage, liver and gall bladder problems, memory problems and dependence.
ECT is given under general anaesthetic. NICE says to consider it for severe depression if:
The main risks are those of an anaesthetic and memory problems. A 2019 analysis of 113 trials found two forms of ECT had the highest odds of response among brain stimulation treatments. The confidence intervals were wide.
After a good response, NICE advises continuing an antidepressant or therapy to prevent relapse.
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Esketamine in Ireland. An Irish review in 2026 said uptake remains limited even after reimbursement. It pointed to cost, clinic space, trained staff and monitoring. Ask your psychiatrist whether your service offers it.
Esketamine in England and Wales. NICE found the evidence uncertain and the cost-effectiveness unreliable. People already on NHS treatment when the guidance came out can continue. A separate NICE appraisal for people at imminent risk of suicide was terminated in 2023, because the company did not submit evidence.
ECT in Ireland. The Mental Health Commission publishes yearly figures. In 2024, 236 people in approved centres had ECT. Most treatments (about 91%) were given with consent. Strict rules apply to treatment without consent.
In the US, esketamine is approved on its own or with an oral antidepressant. Patients must be monitored for at least two hours after each dose.
Clinical trials. On ClinicalTrials.gov on 3 November 2026, we found no recruiting trials listed under treatment-resistant depression in Ireland. A psilocin-based drug trial for major depression is recruiting in Dublin and Galway. Several UK studies were listed. Trials are research, not treatment. Ask your psychiatrist if one might suit you.
Usually two, each at an adequate dose for an adequate time in the current episode. That is the EMA and FDA definition. Some researchers use different definitions.
No. In the EU, a psychiatrist should decide to start it. It is given under supervision in a clinic, not at home.
We found no HSE or NCPE decision on ketamine infusions for depression. In the UK, it is off-label, and the Royal College of Psychiatrists says it should only be used in specialist settings.
Memory problems are the main known side effect. In one large trial, memory scores dropped at three weeks and then gradually recovered. Your team should talk through your own risks before you consent.
No. NICE tells doctors to reassure people that other treatments can be tried and may work.
This article is general information, not medical advice. Do not change or stop any medicine without talking to your prescriber.
Reviewed by: Proco Team
Last updated: November 2026