Treatment-resistant depression: what it is and which treatments exist
KETAMED is a medically assisted psychedelic therapy clinic, with assessments in Lisbon and sessions in Sintra. Depression is called treatment-resistant when, in the current episode, at least two different antidepressants, at an adequate dose and for an adequate time, have not brought enough improvement. It is not depression without treatment: there are several options, and the choice is made with the doctor.
What treatment-resistant depression is
The most widely used definition, from the European Medicines Agency and a European expert consensus, is no response to at least two different antidepressants, at an adequate dose and for an adequate time [1] [2].
Before speaking of resistance, the doctor reviews the diagnosis, other conditions that may contribute and how the medication is being taken [3].
The Canadian guidelines prefer the term ‘difficult-to-treat depression’, aiming for the best possible improvement in daily life and quality of life, not only the absence of symptoms [3].
Which treatments exist
A comparison of the most used options. The order is decided case by case, with the doctor.
| Option | What it is | How it is given | Usual course | Status in the EU and Portugal | What the evidence says | Main cautions |
|---|---|---|---|---|---|---|
| Adjusting or switching the antidepressant | Raising the dose or changing to another antidepressant. | Tablets, changed gradually when switching. | Improvement is judged after a few weeks. | Authorised medicines, used within their approved indications. | Switching antidepressant has inconsistent results in studies [3]. | Side effects; do not stop suddenly without medical advice. |
| Adding a second medicine | Adding to the antidepressant, for example, a low-dose second-generation antipsychotic or lithium (augmentation). | Tablets; lithium needs blood tests. | Reviewed after a few weeks, keeping the antidepressant. | Authorised medicines; the choice depends on the assessment. | In the Canadian guidelines, second-generation antipsychotics are first line and lithium second line [3]. | Restlessness, weight gain and metabolic effects; with lithium, regular blood-level checks [3]. |
| Psychotherapy | Structured talking therapy, for example cognitive behavioural therapy, alongside medication. | Regular sessions with a psychologist or psychotherapist. | Several months. | Part of usual care. | In a randomised trial, adding cognitive behavioural therapy to medication doubled the proportion of people who responded at six months [8]. | Needs time and regular attendance. |
| Esketamine nasal spray | A medicine derived from ketamine, always given with an antidepressant. | A nasal spray taken by the person, under the direct supervision of a healthcare professional, in a clinical setting. | The most studied schedules range from two sessions a week to one session a week, for a few weeks. [6] [7] The appropriate schedule is decided case by case, after a psychiatric assessment. | Authorised in the European Union since 2019 for treatment-resistant depression; in Portugal, funded for hospital use since 2025, for a narrower indication [9] [10]. | Phase 3 trials; second line in the Canadian guidelines [11] [12] [3]. | Dizziness, a sense of dissociation, nausea and a temporary rise in blood pressure. On the day of the session, we recommend not driving and going home with a companion [7]. |
| Transcranial magnetic stimulation (TMS) | Magnetic pulses applied over the scalp stimulate a brain area linked to mood. | As an outpatient, awake, without anaesthesia; usually alongside medication. | Daily sessions, five days a week, for four to six weeks [3] [13]. | A procedure carried out with a medical device, in centres with the necessary equipment. | A meta-analysis of 81 trials; in the Canadian guidelines, usually offered after medicines and psychotherapy [14] [3]. | Headache and scalp discomfort; daily visits [13]. |
| Ketamine, off-label use | An anaesthetic that, at lower doses, has been studied in treatment-resistant depression. | In a clinical setting, under medical monitoring, after a psychiatric assessment. | The most studied schedules range from two sessions a week to one session a week, for a few weeks. [6] [7] The appropriate schedule is decided case by case, after a psychiatric assessment. | Authorised as an anaesthetic; in depression it is off-label, under the prescribing doctor’s responsibility [4]. | Randomised trials show short-term benefit; the Cochrane review rates the certainty of the evidence as low to very low [6] [15]. | A sense of dissociation, a temporary rise in blood pressure and nausea; the effect may fade weeks after finishing; limited long-term data [6] [5]. |
Who ketamine therapy is for
Ketamine therapy is mainly considered for adults with treatment-resistant depression, when other treatments have not brought enough improvement. It is off-label use and always requires a psychiatric assessment [4] [5].
The most studied schedules range from two sessions a week to one session a week, for a few weeks. [6] [7] The appropriate schedule is decided case by case, after a psychiatric assessment.
This information is educational and the sources are verified. It does not constitute a treatment recommendation or advertising of medicines.
References
15
- European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment of depression, EMA/CHMP/185423/2010 Rev. 3 (in effect since 30 September 2025): treatment-resistant depression typically means failure of at least two antidepressants at an adequate dose and duration. ema.europa.eu (PDF) (opens in a new tab)Guidance
- Sforzini L, Worrell C, Kose M, et al. A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials. Mol Psychiatry. 2022. doi:10.1038/s41380-021-01381-x (opens in a new tab)Guidance
- 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. doi:10.1177/07067437241245384 (opens in a new tab)Guidance
- INFARMED (Autoridade Nacional do Medicamento e Produtos de Saúde), Comissão Nacional de Farmácia e Terapêutica. Utilização de medicamentos em regime off-label (orientação aprovada em Março de 2025). Cita a Circular Informativa n.º 184/CD, de 12 de Novembro de 2010: a utilização fora das indicações aprovadas «é da inteira responsabilidade do médico prescritor». (INFARMED (Portugal’s medicines authority), National Pharmacy and Therapeutics Committee. Guidance on off-label use of medicines (approved March 2025). It cites INFARMED Circular 184/CD of 12 November 2010: use outside the approved indications is the full responsibility of the prescribing physician.) infarmed.pt (PDF) (opens in a new tab)Guidance
- Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017. doi:10.1001/jamapsychiatry.2017.0080 (opens in a new tab)Guidance
- Loo C, Glozier N, Barton D, et al. Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial. Br J Psychiatry. 2023. doi:10.1192/bjp.2023.79 (opens in a new tab)Clinical trial
- European Medicines Agency. Esketamine nasal spray: summary of product characteristics (sections 4.1–4.8). ema.europa.eu (PDF) (opens in a new tab)Regulatory source
- Wiles N, Thomas L, Abel A, et al. Cognitive behavioural therapy as an adjunct to pharmacotherapy for primary care based patients with treatment resistant depression: results of the CoBalT randomised controlled trial. Lancet. 2013. europepmc.org (opens in a new tab)Clinical trial
- European Medicines Agency. European public assessment report (EPAR) and product information for esketamine nasal spray; marketing authorisation in the EU since 18 December 2019. ema.europa.eu (opens in a new tab)Regulatory source
- INFARMED. Public funding assessment report for esketamine nasal spray in treatment-resistant depression (approved for hospital use on 7 May 2025, for a narrower population than the marketing authorisation). infarmed.pt (PDF) (opens in a new tab)Regulatory source
- 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 (opens in a new tab)Clinical trial
- Reif A, Bitter I, Buyze J, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med. 2023;389:1298–1309. doi:10.1056/NEJMoa2304145 (opens in a new tab)Clinical trial
- Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018. europepmc.org (opens in a new tab)Clinical trial
- 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. doi:10.1001/jamapsychiatry.2016.3644 (opens in a new tab)Review
- Dean RL, Hurducas C, Hawton K, et al. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev. 2021;9:CD011612. doi:10.1002/14651858.CD011612.pub3 (opens in a new tab)Review
Frequently asked questions
What is treatment-resistant depression?
It is depression that, in the current episode, has not improved enough with at least two different antidepressants, at an adequate dose and for an adequate time. This is the definition used by the European Medicines Agency.
Can treatment-resistant depression be treated?
Yes. There are several options: adjusting or switching the antidepressant, adding a second medicine, psychotherapy, esketamine nasal spray, transcranial magnetic stimulation and, after a psychiatric assessment, off-label ketamine. The choice is made with the doctor.
Is ketamine approved for depression?
Esketamine nasal spray is authorised in the European Union for treatment-resistant depression, together with an antidepressant. Ketamine is an anaesthetic; its use in depression is off-label and always requires a psychiatric assessment.
How many ketamine sessions are needed?
The most studied schedules range from two sessions a week to one session a week, for a few weeks. The appropriate schedule is decided case by case, after a psychiatric assessment.
Text: KETAMED medical team · Medical review: clinical director, psychiatrist · Last reviewed:
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