Pedro ZuzartePsychiatry · Lisbon
PTENG

Treatment-resistant depression

Treatment-resistant depression is a depressive episode that has not improved enough after at least two different antidepressants, taken at an adequate dose and for an adequate time.1,2 It describes a stage in the course of treatment, not a different kind of depression, and it calls for a review of the diagnosis and a stepwise plan.

Drawing by Vincent van Gogh: a long, straight road lined with bare pollarded willows, with a man holding a broom and other people walking in the distance

A long, straight road, walked on foot. The path continues beyond what can be seen.

Vincent van Gogh, Road in Etten, 1881. Chalk, pastel and watercolour on paper. The Metropolitan Museum of Art, New York. Public domain. Artwork record (external site)

What does “resistant” mean?

It means that the treatments tried so far have not been enough to bring remission. The most widely used criterion, adopted by the European and US medicines agencies, is an inadequate response to at least two antidepressants, at an adequate dose and duration and with good adherence.1 The European Medicines Agency guideline for clinical trials, in force since September 2025, uses the same threshold.2

Research is still looking for a consensus definition with proven predictive value.1,3 In clinical practice, resistance is described in degrees: how many treatments have been tried, of what kind and with what response. That record guides the next choice.

Could it be pseudo-resistance?

It could, and it is one of the first possibilities to check. A significant share of depressions labelled resistant are pseudo-resistant: treatment was not given under conditions in which it could work.1 The most common causes are:

  • Insufficient dose or duration. An antidepressant generally needs 4 to 6 weeks at an optimised dose before it can be judged.1
  • Irregular use. Partial adherence is common and worth discussing openly, without judgement.1
  • A diagnosis to revisit. In bipolar disorder, depression may respond poorly to successive antidepressants; a history of elevated mood changes the plan.1
  • Associated conditions. Alcohol or other substance use, an anxiety disorder, a personality disorder or physical illnesses such as hypothyroidism can hold back the response and need their own treatment.1
  • Imprecise measurement of response. Without rating scales and records over time, a partial improvement can be missed or overestimated.1

UK guidance recommends that, when the response is insufficient, the diagnosis is reviewed and alternative or comorbid conditions are considered before changing strategy.5

What is assessed before changing the plan?

The full history of the episode and of every treatment tried is assessed. A careful reassessment usually covers:

  • the list of previous treatments, with the class, the highest dose reached, the length of treatment, the response and the side effects;
  • the lifetime history of mood, including periods of unusually high energy, and the family history;
  • sleep, alcohol and other substance use, anxiety, and life events that keep the symptoms going;
  • physical health and other medication, with blood tests when indicated, for example thyroid function;
  • suicide risk, reviewed at every appointment;
  • repeated symptom scales, so that response is always measured in the same way.

With this information, the next options are discussed together: what each one may offer, its risks, and what it requires in time and travel.

What options are there, and in what order?

The options are organised in steps. The 2023 Canadian guidelines and the 2022 UK guidelines follow a similar sequence:4,5

  1. Optimise. Adjusting the dose of the current antidepressant and giving it time is the first step.4
  2. Switch. Moving to an antidepressant from another class or with another mechanism of action.4
  3. Combine. Adding a second medicine, such as an antidepressant from another class, a second-generation antipsychotic or a mood stabiliser, by shared decision.4,5
  4. Psychotherapy. Added to medication, structured psychotherapy brings further benefit in treatment-resistant depression.1
  5. Neuromodulation. Transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) generally come in after switches and combinations of medicines have not helped enough.4
  6. Esketamine nasal spray. Approved in the European Union for treatment-resistant depression, together with an antidepressant and under clinical supervision.10
  7. Ketamine. Studied in treatment-resistant depression in randomised trials; for this indication its use is outside the approved indications.9
  8. Psychedelics. Psilocybin with psychological support is under investigation.12

The order is a guide. Severity, urgency, personal preference, previous response and access to each treatment can justify another sequence; ECT, for example, is considered earlier when a rapid response is needed.5 In the large STAR*D study, the more steps were needed, the lower the chance of remission and the higher the risk of relapse: an organised plan from the start avoids lost time.6

Ketamine and esketamine have a page of their own: Ketamine and esketamine in treatment-resistant depression. Research with psychedelics is summarised in Psychedelics for depression.

How do TMS and ECT work?

Repetitive transcranial magnetic stimulation stimulates the cerebral cortex with magnetic fields applied to the surface of the head, in repeated sessions. It needs no anaesthesia and has no cognitive side effects, and the response varies from person to person.4,13 In meta-analyses, several forms of TMS were more effective than sham stimulation.8

Electroconvulsive therapy is given under general anaesthesia and muscle relaxation, in repeated sessions. It is one of the most effective options in treatment-resistant and severe depression and can cause temporary memory changes.4,7,9 In a 2023 randomised trial in treatment-resistant depression without psychosis, intravenous ketamine was non-inferior to ECT.9

Where does each option stand?

The table summarises the state of the evidence in treatment-resistant depression, to separate established practice from what is still under investigation.

State of the evidence, without figures: where each approach has been studied and at what stage it is.
ApproachWhere it has been studiedEvidenceStage
Optimising, switching or combining medicinesMajor depression and treatment-resistant depressionClinical guidelines; mixed evidence for some switching and combination strategies1,4Approved · available
Psychotherapy added to medicationTreatment-resistant depressionBenefit when added to antidepressants1Established clinical practice
Transcranial magnetic stimulation (TMS)Major depression and treatment-resistant depressionMeta-analyses of trials controlled with sham stimulation8,13Approved · available
Electroconvulsive therapy (ECT)Severe and treatment-resistant depressionMeta-analysis of randomised trials; one of the most effective options4,7Approved · available
Esketamine nasal spray, with an SSRI or SNRITreatment-resistant depressionPositive phase 3 trials14Approved in the EU (2019) · funded in Portuguese NHS hospitals (2025)
Intravenous ketamineTreatment-resistant depressionPositive randomised trials; non-inferior to ECT in a 2023 trial9Studied · outside approved indications
Psilocybin with psychological supportTreatment-resistant depressionPositive phase 2 trial; phase 3 trials reported by the company12Investigational · US regulatory submission under way

What is the position in Portugal and the EU?

Esketamine nasal spray has held a marketing authorisation valid throughout the European Union since 18 December 2019, for adults with treatment-resistant depression, together with an SSRI or SNRI antidepressant.10 In Portugal, Infarmed approved public funding in May 2025 for hospital use in the national health service, for a narrower group of patients than the European authorisation covers.11

Ketamine is authorised as an anaesthetic, and its use in depression is outside the approved indications (“off-label”). Off-label use means prescribing an authorised medicine for a situation not included in its summary of product characteristics. It is an individual clinical decision, made with informed consent, and it may not be advertised.15

Psilocybin has no marketing authorisation in the European Union; in Portugal, its clinical use is limited to clinical trials.16

What is still unknown?

  • The best sequence for each person: the evidence on extending, switching or combining antidepressants is mixed.1
  • How to tell in advance who will respond to each option: a definition of resistance with proven predictive value is still missing.1
  • The place of ketamine and esketamine in treatment algorithms and how they compare directly with other options.17
  • The long-term efficacy and safety of psilocybin, which call for larger and longer trials.12

What should I ask my psychiatrist?

  • Has the diagnosis been reviewed, including the possibility of bipolar disorder?
  • Were previous treatments given at a sufficient dose and for long enough?
  • Is any associated condition, physical or mental, holding back the response?
  • What is the next step, and why this one before the others?
  • How will we measure the response, and when will we review it?
  • In my case, is it worth considering TMS, ECT or esketamine?

In summary

  • Treatment-resistant depression is generally defined as no adequate response to at least two suitable antidepressants in the current episode.
  • Before changing strategy, pseudo-resistance is ruled out: dose, duration, adherence, diagnosis and associated conditions.
  • Options are organised in steps: optimise, switch, combine, add psychotherapy and then neuromodulation.
  • Esketamine nasal spray is approved in the EU for treatment-resistant depression; ketamine is studied outside its approved indications; psilocybin is investigational.
  • The choice is individual, made together and followed with regular measurement of the response.

References

  1. McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394–412. doi:10.1002/wps.21120 PubMed (external site)
  2. European Medicines Agency, CHMP. Guideline on clinical investigation of medicinal products in the treatment of depression (EMA/CHMP/185423/2010 Rev. 3). In force since 30 September 2025. Source (external site)
  3. Gaynes BN, Lux L, Gartlehner G, et al. Defining treatment-resistant depression. Depress Anxiety. 2020;37(2):134–145. doi:10.1002/da.22968 PubMed (external site)
  4. Lam RW, Kennedy SH, Adams C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 update on clinical guidelines for management of major depressive disorder in adults. Can J Psychiatry. 2024;69(9):641–687. doi:10.1177/07067437241245384 PMC (external site)
  5. National Institute for Health and Care Excellence. Depression in adults: treatment and management (NG222). 2022. Source (external site)
  6. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–1917. doi:10.1176/ajp.2006.163.11.1905 PubMed (external site)
  7. UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet. 2003;361(9360):799–808. doi:10.1016/S0140-6736(03)12705-5 PubMed (external site)
  8. Brunoni AR, Chaimani A, Moffa AH, et al. Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes: a systematic review with network meta-analysis. JAMA Psychiatry. 2017;74(2):143–152. doi:10.1001/jamapsychiatry.2016.3644 PubMed (external site)
  9. Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med. 2023;388(25):2315–2325. doi:10.1056/NEJMoa2302399 PubMed (external site)
  10. European Medicines Agency. Esketamine nasal spray: European public assessment report (EPAR, EMEA/H/C/004535); marketing authorisation valid throughout the EU since 18 December 2019. Source (external site)
  11. Infarmed (Portuguese medicines authority). Public funding assessment report: esketamine (nasal spray) in treatment-resistant depression. Approval decision of 7 May 2025; report of 12 May 2025. Source (external site)
  12. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387(18):1637–1648. doi:10.1056/NEJMoa2206443 PubMed (external site)
  13. National Institute for Health and Care Excellence. Repetitive transcranial magnetic stimulation for depression (HTG396, formerly IPG542). 2015. Source (external site)
  14. Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428–438. doi:10.1176/appi.ajp.2019.19020172 PubMed (external site)
  15. Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use, Article 87(2) (all parts of the advertising of a medicinal product must comply with its summary of product characteristics). Source (external site)
  16. European Medicines Agency, medicines register (accessed 10 October 2026): no marketing authorisation for psilocybin, MDMA, LSD or DMT; European Medicines Agency, report of the multi-stakeholder workshop on psychedelics (2024). Source (external site)
  17. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383–399. doi:10.1176/appi.ajp.2020.20081251 PubMed (external site)

Clinical review: Pedro Zuzarte, psychiatrist · Published: · Reviewed: .

How a psychiatry consultation works