Start with the direct answer. If you have taken at least two different antidepressants — each at a proper dose, each for long enough — during your current episode and neither has helped, medicine has a name for that situation: treatment-resistant depression, usually defined as an inadequate response to at least two different antidepressant treatments of adequate dose and duration during the current moderate-to-severe episode (EMA). The name sounds final. It is the opposite: it is the label that unlocks the next set of options — including some your prescriber may not have mentioned yet. This guide walks through all of them, honestly, with what the evidence and the European guidelines actually say about each.
Two reassurances before the list. First, "resistant" describes how this episode has responded to particular drugs, not who you are, and it is common — a meaningful share of people treated for depression meet the definition at some point. Second, nothing here is a recommendation of one option over another. Which step fits you depends on your history, your diagnosis and your preferences, and it is a decision to make with a clinician who knows you. What this page can do is make sure you walk into that conversation knowing the full menu.
TL;DR Two failed antidepressants is not the end of the road; it is a defined clinical situation with a defined set of next options. European guidelines list switching antidepressants, adding a second medicine such as lithium, psychotherapy, rTMS and — for severe depression — ECT. Beyond those, esketamine nasal spray (Spravato) is EU-approved precisely for this situation and reimbursed in much of continental Europe; ketamine infusions are an off-label private-clinic route; psilocybin and MDMA remain in clinical trials. The key that opens every one of these doors is the same: a written record of what you have tried, at what dose, for how long, with what result.
What the options actually are
The fact box above compresses the whole landscape; here is the same list with the honest detail.
Staying on the medication path. The standard playbook has not run out just because two drugs have. The UK's NICE depression guideline and Germany's Nationale VersorgungsLeitlinie for unipolar depression — the two reference documents this page leans on for the non-psychedelic options — both set out further steps when depression has not responded: switching to a different antidepressant, sometimes from a different class; adding a second medicine to the antidepressant, a strategy called augmentation, with lithium the classic example and some atypical antipsychotics also used; and combining medication with psychological therapy rather than treating them as either/or. These are guideline-recommended clinical decisions, not self-serve choices: augmentation in particular involves specialist input and monitoring. If nobody has walked you through this menu, that conversation — with your prescriber or a psychiatrist — is a reasonable next appointment to ask for.
Psychotherapy, on its own terms. If your treatment so far has been tablets only, adding a structured psychological therapy is itself a guideline option for depression that has not responded — not a consolation prize (NICE NG222). The reverse combination also holds: therapy alone not working is a reason to discuss medication, and the two together are, for many situations, what the guidelines actually recommend.
Brain stimulation. Two options sit here, at very different intensities. Repetitive transcranial magnetic stimulation (rTMS) is non-invasive — magnetic pulses through the scalp, no anaesthesia, done awake in a chair. The UK's assessment found no major safety concerns and adequate evidence of short-term efficacy, with clinical response that varies from person to person (NICE IPG542); the practical constraint in much of Europe is simply finding a provider, since availability differs widely between countries and often between cities. Electroconvulsive therapy (ECT) is a different order of intervention: a hospital treatment under general anaesthesia that guidelines reserve for severe depression — when a rapid response is needed or when other treatments have failed (NICE NG222). It carries decades of clinical use, close regulation, and side effects (particularly around memory) that the treating team is obliged to discuss with you. It is nobody's first step, and for the severest depression it remains one of the most effective treatments medicine has.
Esketamine — the approved door most people haven't heard of. Here is the option this site exists to explain. Esketamine nasal spray (Spravato) is not an experimental substance: it has held an EU-wide marketing authorisation since December 2019, and its main approved indication is precisely the situation this page describes — adults with treatment-resistant major depressive disorder "who have not responded to at least two different treatments with antidepressants in the current moderate to severe depressive episode," taken in combination with an SSRI or SNRI (EMA EPAR). It works on a different brain system from conventional antidepressants — the NMDA glutamate receptors — which is why it can help people for whom standard drugs have not, and why it can act within days rather than weeks. It is a prescription-only medicine, started by a psychiatrist, and self-administered by the patient under direct supervision in a clinic — never taken at home — with blood-pressure monitoring and a post-dose observation period, because dissociation and a temporary blood-pressure rise are common during sessions. The effect is real but moderate, and it is maintained by continued treatment, not by a one-off cure. The full picture — trial results, limitations, the suicidality question — is in our esketamine evidence review; crucially for this page, esketamine is publicly reimbursed in much of continental Europe for exactly the two-failed-antidepressants situation, which makes it, in several countries, an ordinary insurance-funded next step rather than an exotic purchase.
Ketamine infusions — related, but a different route. Racemic ketamine is a licensed anaesthetic used off-label for depression: legal, but outside the licence, and delivered mostly in private clinics. Its rapid antidepressant effect has been replicated since 2006 and confirmed by Cochrane and later meta-analyses — and the benefit of a single infusion usually fades within one to two weeks, which is why clinics treat in series. Off-label also means public funding is uncommon and protocols are clinic-defined, so quality varies more than with the approved medicine. The evidence, honestly weighed, is in our ketamine evidence review, and the practical differences between the two routes — approval, setting, cost, supervision — are set out in Spravato vs ketamine infusions.
Psilocybin, MDMA and the rest — trials, with narrow exceptions. No classic psychedelic holds an EU marketing authorisation for depression. Outside a handful of narrow national programs — Switzerland's limited medical use framework and Germany's two-site compassionate-use program for psilocybin — the only legal route is a clinical trial. That is a real option, and it gets its own section below; what it is not is a treatment you can book. (And if the condition you are actually treating is PTSD rather than depression, the equivalent overview is PTSD treatment isn't working: your options.)
How to work out where you are
The options above sort themselves quickly once two questions are answered — and both are answerable this week, without an appointment.
First: what have you actually tried? Write it down, in one document: every antidepressant, with its name, the highest dose you reached, how long you took it at that dose, what it did, what side effects it caused, and why it stopped; any second medicine added to an antidepressant; any psychotherapy, with type and rough number of sessions. Old prescriptions, pharmacy records and discharge letters are the raw material, and your GP's records can fill gaps. This is not busywork. "Adequate dose for an adequate duration" is what every assessor — psychiatrist, insurer, trial screener — looks for, and a written history determines eligibility more than anything said in an appointment. If two adequate courses are in that document, the treatment-resistant door is already open; it just has not been documented until now. (If you are reading this for someone else, our guide for family members covers how to help without pushing.)
Second: where are you now? A validated two-question screener — the PHQ-2, the same first-pass instrument clinicians use — asks how often, over the last two weeks, you have been bothered by "little interest or pleasure in doing things" and "feeling down, depressed, or hopeless." It takes under a minute, and the fuller PHQ-9 gives a severity picture worth bringing to an appointment. Both run privately in your browser via our eligibility check — which will also, once you add your country and treatment history, tell you which of the routes on this page are realistically open to you. A screener result is conversation material for a clinician, never a diagnosis.
And one question worth asking about the drugs themselves: why didn't they work? Non-response has many causes — the diagnosis, the dose, the duration, sleep, thyroid, adherence — and one of them is pharmacological: how fast your liver clears a particular medicine. Two enzymes, CYP2D6 and CYP2C19, do most of that work, and the genes behind them vary enough that some people never reach a working blood level of a given drug while others hit side effects at doses that look low on paper. That is a real, guideline-recognised phenomenon — and also the thing consumer genetic tests most exaggerate. Our guide to genetic testing and antidepressants sets out what the tests can and cannot tell you, how strong the evidence is, and how to get one in Germany, the UK and the Netherlands.
If the esketamine route fits: country by country
Because esketamine's approval is EU-wide but health systems are national, what "getting it" means depends entirely on where you live. Germany has one of Europe's most solid routes: statutory insurance covers it, and since a dedicated billing code for the observation period it is increasingly offered in ordinary office-based psychiatric practices, not only hospital outpatient units. In the UK, Scotland funds it on the NHS under treatment-resistance criteria while England and Wales remain essentially private-only. Spain runs it through hospital psychiatry, publicly financed but with criteria stricter than the EU label. Poland reimburses it through a dedicated drug program with its own eligibility list. And if your country is not among those four, the Europe-wide comparison maps every system — who reimburses, who is private-only, and where the genuine gaps are.
Trials as an option
For psilocybin, MDMA and other unapproved substances, clinical trials are the only legal route in most of Europe — and for any of the options on this page, including esketamine and ketamine, trials exist that may fit your situation. The honest frame: trials are free, voluntary and ethics-committee supervised; you may be randomly assigned to a placebo or comparison arm; you can withdraw at any time without losing your regular care; and most applicants are screened out, which is the norm rather than a judgment on you. Some psychedelic trials also require supervised tapering of serotonergic antidepressants, which is its own decision to weigh with your clinician. Treat a trial as an option to check while keeping other care moving, not as a plan to rely on. Our trials guide explains phases, placebo and consent, and how to search ClinicalTrials.gov and the EU's CTIS register.
Frequently asked questions
Is treatment-resistant depression treatable?
Yes. "Treatment-resistant" means the episode has not responded to at least two antidepressants — it does not mean nothing works. Guideline options after that point include switching medication, augmentation with a second medicine, psychotherapy, rTMS and ECT, and esketamine nasal spray is EU-approved specifically for this situation. Many people who meet the definition go on to respond to a later option.
What if nothing works?
"Nothing has worked so far" almost always means "some of the options have been tried" — the full list on this page is longer than most people's treatment history. If you genuinely have tried most of it, the remaining moves are a specialist reassessment (diagnosis, thyroid, sleep, comorbidity — non-response sometimes has reasons a fresh pair of eyes catches), the intensive options like ECT that guidelines reserve for exactly this point, and clinical trials. If the question behind the question is despair, tell someone today: in an emergency, call 112 or your local crisis line — no planned treatment is the answer to a crisis.
Is ketamine a last resort?
No — neither ketamine nor esketamine is positioned as a last resort. Esketamine's EU approval sits at the two-failed-antidepressants point, which for many people is years before "last resort" territory; in several countries it is an ordinary reimbursed next step. Ketamine infusions are an off-label option some people reach for at the same stage, usually privately. Last-resort framing belongs, if anywhere, to treatments guidelines reserve for the severest cases — and even ECT is better described as a specific tool for a specific situation.
How many antidepressants do I need to have tried before esketamine?
The EU label requires non-response to at least two different antidepressants, at adequate dose and duration, in the current episode. Some national systems ask for slightly more — Spain and the Netherlands, for example, add an augmentation attempt to the count. Your written treatment history is what settles the question; our eligibility check walks you through the criteria country by country.
Do I need to know anything about psychedelics for any of this?
No. Esketamine and ketamine are dissociative medicines administered in supervised clinical settings — no journey framing, no ceremony, and the session experience, while sometimes strange, is a monitored side effect rather than the point. The classic psychedelics (psilocybin, MDMA) remain in trials. Everything on this page is ordinary, regulated European medicine.
Sources
- EMA — Spravato European Public Assessment Report
- NICE NG222 — Depression in adults: treatment and management
- NVL Unipolare Depression — German national care guideline (AWMF nvl-005)
- NICE IPG542 — Repetitive transcranial magnetic stimulation for depression
- Dean et al. (2021), Cochrane Database of Systematic Reviews — ketamine and other glutamate receptor modulators for depression in adults
- CTIS — the EU Clinical Trials Information System
This guide is for general information only and is not medical advice, a diagnosis, or a recommendation of any treatment. Treatment decisions at this stage are specialist decisions: discuss your options with a licensed clinician who knows your history. If you are in crisis, contact your local emergency number (112 in the EU) or a crisis line immediately.