The direct answer first. If antidepressants have not helped in your current episode, the evidence-based next steps in Europe in 2026 are: a structured clinical reassessment, then, depending on what it finds, optimising or changing medication, augmentation (adding a second medicine such as lithium), structured psychotherapy such as CBT or interpersonal therapy, rTMS, ECT (which can be considered early in severe depression), esketamine nasal spray (Spravato, an EU-authorised medicine for treatment-resistant depression), off-label ketamine infusions in some clinics, and clinical trials. Every one of these is walked through below, with what the evidence and the European guidelines say about each. None of them is presented here as the best choice; which fits you is a decision for you and your clinician.
Behind that list is a definition worth understanding precisely. Treatment resistance commonly refers to inadequate benefit from two adequate antidepressant trials, but definitions and access criteria vary. It prompts a clinical review; it does not establish eligibility for every treatment. One specific place the two-trials threshold does appear is the EU licence for esketamine nasal spray, which covers adults with a current moderate-to-severe major depressive episode who have not responded to at least two different antidepressant treatments in that episode, used together with an SSRI or SNRI (EMA). The other options on this page do not require you to wait until two drugs have failed: psychotherapy, medication changes and, in severe depression, even ECT can be appropriate earlier.
Two reassurances before the detail. 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 a definition of it at some point. Second, nothing here is a recommendation of one option over another. Which step fits you depends on your diagnosis, severity, previous response and 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 main options.
TL;DR Antidepressants not working is a defined clinical situation with a defined set of responses, and the first of them is a review, not a new prescription: diagnosis, dose, duration, adherence, interactions, bipolar symptoms, other conditions and suicide risk all need checking. After that, European guidelines describe several options chosen by response and tolerability rather than in a fixed order: optimising or switching medication, augmentation with a second medicine, psychotherapy such as CBT or interpersonal therapy, rTMS, ECT and esketamine nasal spray (an EU-authorised medicine whose funding and availability vary by country). Off-label ketamine infusions and trial-stage substances such as psilocybin and MDMA sit in separate categories with their own rules. A written record of what you have tried, and screening results, can help your clinician assess possible next steps.
Start with a review, not a menu
Before any new treatment, guidelines ask a set of questions, and this review should not be postponed until most treatments have failed (NICE NG222). Is the diagnosis right, and could this be bipolar depression, which changes the medication logic entirely (what is and is not known about ketamine there: ketamine for bipolar depression)? Was each antidepressant taken at an adequate dose, for long enough, consistently? Is another medicine or substance interacting with it? Is a physical condition (thyroid disease, sleep apnoea, anaemia) or another mental health condition contributing? And, always, what is the current suicide risk, because that shapes both urgency and setting. Non-response sometimes has a reason a fresh assessment catches, and finding it can matter more than any item on the list below.
A written treatment history is useful preparation for that review, not a substitute for it. How to build one is covered further down; the point here is order. Assessment first, options second.
What the main options are
These are the main options rather than an exhaustive menu, and they are alternatives selected with a clinician according to response and tolerability, not rungs on a compulsory ladder.
Staying on the medication path. 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) describe several medication strategies when depression has not responded: optimising the current treatment (dose, duration, adherence); switching to a different antidepressant, sometimes from a different class; augmentation, meaning adding a second medicine such as lithium or certain atypical antipsychotics; and combining medication with psychological therapy rather than treating them as either/or. These are alternatives chosen case by case, not an identical sequence endorsed by both guidelines: the German guideline, for instance, specifically discourages repeated antidepressant switches within the same episode. Every change needs a prescriber-led plan; none of this is self-serve. Augmentation in particular adds a medicine with its own potential harms and concrete monitoring requirements: lithium needs regular serum-level, kidney, thyroid and calcium checks, and antipsychotics need monitoring for metabolic effects (weight, glucose, lipids) and movement side effects. That monitoring burden is worth weighing alongside the clinic visits that treatments like esketamine or rTMS require; no option on this page is burden-free.
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 main evidence-based forms include cognitive behavioural therapy (CBT) and interpersonal psychotherapy (IPT); a typical course means weekly or fortnightly sessions with a trained therapist over roughly three to six months, and changing the type of therapy after a course that has not helped is a legitimate move, just as switching medicines is. 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. Alongside formal treatment, guidelines also include structured exercise and support for social connection within the care plan; they are complements to treatment, not replacements for it.
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, typically as daily weekday sessions over several weeks. The UK's assessment found no major safety concerns and adequate evidence of short-term efficacy (NICE HTG396), but that is not a guarantee: response varies, lack of benefit is possible, and how any improvement is maintained (and what longer-term outcomes look like) is something to discuss with the provider before starting. The practical constraint in much of Europe is finding a provider at all, 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. It is not only a treatment of last resort: ECT can be considered early in severe depression when a rapid response is needed, including life-threatening situations such as a person stopping eating or drinking, or when a patient prefers it after benefiting from it before (NICE NG222). It carries decades of clinical use and close regulation, alongside real risks (those of general anaesthesia, and side effects particularly around memory) that the treating team is obliged to discuss with you as part of informed consent. For the severest depression it remains one of the most effective treatments medicine has. How each of these stimulation routes compares with ketamine on evidence, availability and cost is in our two head-to-head comparisons: TMS vs ketamine and ECT vs ketamine.
Esketamine nasal spray (Spravato). This is a licensed medicine, and being approved does not make it more effective than the options above; approval defines who may be treated and under what conditions, not a ranking. It has held an EU-wide marketing authorisation since December 2019 for adults with a current moderate-to-severe major depressive episode who have not responded to at least two different antidepressant treatments in that episode, and it is taken in combination with an SSRI or SNRI (EMA EPAR). Esketamine acts on glutamate signalling and may reduce symptoms rapidly in some people; a different pharmacological target does not, by itself, explain why previous treatments did not work or predict that you will respond. For a sense of the benefit: in the ESCAPE-TRD trial, remission at eight weeks occurred in 27.1% of people on esketamine versus 17.6% on quetiapine extended release, both added to an SSRI or SNRI (Reif et al., NEJM 2023). That was an industry-funded, open-label trial with blinded raters, and it supports a benefit over that comparator, not superiority over every option on this page. The treatment burden is real: esketamine is prescription-only, started by a psychiatrist, and self-administered under direct supervision in a clinic, never at home. Sessions commonly cause dissociation, a temporary blood-pressure rise and sedation; respiratory depression is rare but has occurred, so patients remain under observation until clinically stable, and driving is restricted until the following day after a restful sleep. Cardiovascular risk is assessed beforehand, because the medicine is contraindicated in people with aneurysmal vascular disease, a history of intracerebral haemorrhage or a recent cardiovascular event. Supervision reduces risk; it does not remove it. Continued treatment is conditional on benefit and tolerability, with a review after the induction phase and periodic reassessment: visits start twice weekly, then become weekly or fortnightly if treatment continues, and not everyone benefits or stays on it indefinitely. The full picture (trial results, limitations, the suicidality question) is in our esketamine evidence review; funding and availability vary by country and are covered below.
Ketamine infusions, related, but a different route. Racemic ketamine is a licensed anaesthetic used off-label for depression: legal in that sense, but outside the licence, and delivered mostly in private clinics. The evidence deserves a careful description. A Cochrane review supported a short-term antidepressant effect, but rated much of the ketamine evidence low or very low certainty; the benefit of a single infusion typically fades within roughly one to two weeks, an approximate figure rather than a reliable individual duration; and the evidence for a single infusion is not the same as the evidence for repeated courses, maintenance treatment or long-term safety, which is thinner. One guideline position worth knowing: recommendation 7-25 of the German NVL advises against IV ketamine for depression outside an inpatient psychiatric setting. That is German guidance, not a Europe-wide legal prohibition, and legal availability is a separate question from guideline endorsement. Off-label status also means public funding is uncommon and protocols are clinic-defined; that says nothing automatic about any clinic's quality, so judge a service directly on its screening, monitoring, follow-up and clinical governance. The evidence, with its limits, is in our ketamine evidence review, and the practical differences between the two routes (approval, setting, cost, supervision) are in Spravato vs ketamine infusions. How ketamine may fit within an individual care plan alongside antidepressants is in Ketamine vs antidepressants; note that the requirement to combine treatment with an SSRI or SNRI is specific to the EU esketamine licence, not a general rule, and the German guideline includes supervised non-pharmacological continuation as an option after repeated medication failure, so nobody is obliged to stay on an oral regimen that has not helped without discussing the alternatives.
Psilocybin, MDMA and the rest: research routes, with narrow exceptions. No classic psychedelic holds an EU marketing authorisation for depression, and the same is true of MDMA, which is an entactogen rather than a classic psychedelic; its major phase III trials concern PTSD, not depression (Mitchell et al., 2021). MDMA depression research exists but is preliminary: a proof-of-principle study treated 12 participants without a control group (BJPsych 2025), which is not evidence comparable with the established treatments above, and a suitable recruiting MDMA depression trial may simply not exist near you. For psilocybin, the national exceptions are narrow but real: Switzerland runs a limited medical-use framework; Germany's psilocybin compassionate-use listing is current but remains a restricted two-site programme; and from 2026 Czechia operates a regulated medical-prescribing framework, under which the Ministry of Health's rules specify the eligible indications, prescriber requirements, dosing limits and supervision (Czech Ministry of Health framework). None of these is an EU marketing authorisation, and none guarantees availability or reimbursement in practice. Everywhere else, the legal route is a clinical trial, which gets its own section below. (If the condition you are actually treating is something else, this series has equivalent maps for PTSD, OCD and addiction.)
How to work out where you are
Two pieces of preparation make the clinical review above more productive, and both are doable 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. "Adequate dose for an adequate duration" is what assessors look at, and a clear written history saves weeks of reconstruction. (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. These records and screening results can help your clinician assess possible next steps; they are one component of assessment, and cannot by themselves establish a diagnosis, confirm that a treatment is safe for you, or settle funding entitlement. 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 contributing factor can be pharmacological: how fast your body handles a particular medicine. Variants in the enzymes CYP2D6 and CYP2C19 affect the handling of some antidepressants, and CYP2B6 also matters for sertraline; other pathways and interactions contribute too (CPIC guideline). Genetic variation does not explain most non-response and does not reliably identify an effective drug, which is why testing is used selectively rather than as a routine next step. Our guide to genetic testing and antidepressants sets out what the tests can and cannot tell you, and how to get one in Germany, the UK and the Netherlands.
Country by country: approval, funding and availability are separate
Esketamine's marketing authorisation is EU-wide, but the EMA authorisation is not a funding source: approval, reimbursement criteria and actual service availability are three separate questions, answered differently in every country. In Germany, statutory insurance can cover esketamine and a billing code exists for the supervised observation period; whether a practice or hospital near you offers it is a separate, local question. In the UK, the position differs by nation: the SMC accepts esketamine for its reviewed indication under an approved Patient Access Scheme, and local NHS arrangements determine access (SMC2258); NICE does not recommend it for routine treatment-resistant depression use, though TA854 preserves existing NHS funding arrangements for people already receiving treatment before the guidance, so an absolute private-only reading of England and Wales is too strong; see our UK access guide. Spain runs it through hospital psychiatry, publicly financed but with criteria stricter than the EU label. Poland reimburses it through a dedicated drug programme with its own eligibility list. For any other country, the Europe-wide comparison links each system's current payer rules; check the country page rather than assuming that EU approval, or a reimbursement decision on paper, means a service is actually running near you.
Trials as an option
For psilocybin, MDMA and other unapproved substances, clinical trials are the main legal route in most of Europe, and for the options on this page, including esketamine and ketamine, trials also exist that may fit your situation. The terms are worth knowing, and they are study-specific rather than universal: trials are voluntary and ethics-committee supervised, the investigational treatment is typically provided without charge, but travel costs, time commitments, eligibility criteria, risks and follow-up arrangements differ from study to study and are exactly what to ask about at screening. You may be randomly assigned to a placebo or comparison arm; you can withdraw at any time without losing your regular care; eligibility criteria are strict and being screened out is common, not a judgment on you; and participation offers no guarantee of personal benefit (NHS clinical trials guidance). Some psychedelic trials require tapering of serotonergic antidepressants; that, like any change to existing medication, needs clinical supervision. 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, in the sense that evidence-based options remain: it means the episode has not responded to previous antidepressant trials, not that nothing works. Guideline options after that point include a full clinical reassessment, medication changes, augmentation, psychotherapy, rTMS and ECT, and esketamine nasal spray is EU-authorised for this situation. Many people who meet the definition improve with a later option, though responses vary and no option is guaranteed.
What if nothing works?
Sometimes the list genuinely has been worked through, and it is important to say plainly: some people remain unwell despite extensive, appropriate care. That is not a personal failure, and it does not mean care ends. Reasonable moves at that point are a specialist reassessment (diagnosis, physical health, sleep, comorbidity: persistent non-response sometimes has a reason a fresh pair of eyes catches), the intensive options such as ECT, ongoing care focused on functioning and quality of life, and clinical trials. If the question behind the question is despair, do not wait for a booked treatment: seek urgent assessment now, via 112, your local crisis line, or an emergency department. Effective treatments can form part of emergency care, but no scheduled therapy replaces urgent help, and esketamine has not been shown to prevent suicide.
Is ketamine a last resort?
No option on this page is formally ranked as a last resort, and none is the automatic next step either. Esketamine's EU licence applies from the two-failed-antidepressants point, where funding rules allow; ketamine infusions are an off-label route some people consider at a similar stage, usually privately and, under German guidance, recommended only in inpatient psychiatric settings. Even ECT, often imagined as the end of the line, can be considered early in severe depression. The order that fits you is a clinical decision, not a fixed sequence.
How many antidepressants do I need to have tried before esketamine?
The EU licence requires non-response to at least two different antidepressant treatments, at adequate dose and duration, in the current moderate-to-severe episode, with esketamine then used alongside an SSRI or SNRI. Some national systems ask for more: Spain and the Netherlands, for example, add an augmentation attempt to the count. A written treatment history helps your clinician assess this, but eligibility, safety and funding are established through clinical assessment, not paperwork alone; our eligibility check walks you through the criteria country by country as preparation for that conversation.
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. Psilocybin (a classic psychedelic) and MDMA (an entactogen, not a classic psychedelic) remain in research settings for depression, apart from the narrow national programmes described above. Everything on this page is ordinary, regulated European medicine.
Sources
- EMA - Spravato European Public Assessment Report and product information
- NICE NG222 - Depression in adults: treatment and management
- NVL Unipolare Depression - German national care guideline (AWMF nvl-005), chapter 7
- NICE HTG396 - Repetitive transcranial magnetic stimulation for depression
- Reif et al. (2023), NEJM - Esketamine nasal spray versus quetiapine for treatment-resistant depression (ESCAPE-TRD)
- Dean et al. (2021), Cochrane Database of Systematic Reviews - ketamine and other glutamate receptor modulators for depression in adults
- SMC2258 - esketamine (Spravato): Scottish Medicines Consortium advice
- NICE TA854 - Esketamine for treatment-resistant depression
- Czech government regulation on psilocybin for medical use (Ministry of Health material, ODok portal)
- Mitchell et al. (2021), Nature Medicine - MDMA-assisted therapy for severe PTSD (phase 3)
- BJPsych (2025) - MDMA-assisted therapy for major depressive disorder: proof-of-principle study
- CPIC - guideline for SSRIs/SNRIs and CYP2D6, CYP2C19 and CYP2B6
- NHS - Clinical trials: what they are and what taking part involves
- 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.