Treatment-resistant depression

What is treatment-resistant depression?

Treatment-resistant depression refers to a depressive episode that has not responded sufficiently to at least two adequately conducted antidepressant treatments, that is, prescribed at an adequate dose, for an adequate duration, and properly followed. This is the definition adopted by the American (FDA) and European (EMA) medicines agencies.

The situation is common: at least 30% of people treated for depression meet these criteria at some point in their care. Treatment-resistant depression is therefore neither a rarity nor a dead end: it is a distinct form of the illness, requiring specialised assessment and specific treatments.

Resistance does not mean incurability. Validated therapeutic options exist beyond conventional antidepressants, and a substantial proportion of so-called “resistant” patients achieve lasting improvement with treatments of recourse.

Is it truly resistance?

Before concluding that depression is resistant, it must be properly assessed. A notable proportion of apparently resistant depression is in fact pseudo-resistance: treatment taken at an insufficient dose or for too short a period, irregular adherence, or a diagnosis that needs to be reconsidered.

Specialised assessment looks in particular for:

• incomplete previous treatments (doses, durations, tolerability);
• unrecognised bipolar disorder, in which antidepressants alone are of limited efficacy;
• comorbidities that maintain the symptoms: anxiety disorders, alcohol or other substance use, physical illness (notably thyroid disease), certain medications;
• a personality disorder, either associated or in the foreground, a frequent situation in practice, which can both maintain the symptoms and explain an apparent non-response to antidepressants; when it is in the foreground, care is primarily a matter of structured psychotherapeutic approaches rather than interventional treatments;
• particular features of the episode (psychotic symptoms, catatonia, marked functional impairment) that point directly towards specific treatments.

This step determines everything that follows: it avoids piling up unnecessary medication trials and allows the most appropriate treatment to be offered directly.

Why not keep trying antidepressants?

The data are clear: the more treatment failures accumulate, the lower the chances of remission with a further antidepressant. In the largest study conducted on this question (STAR*D, over 3,600 patients), remission rates fell from around 37% with the first treatment to around 31% with the second, then dropped below 14% at subsequent steps, with a higher risk of relapse in parallel.

Each unsuccessful trial also prolongs the episode itself, with its consequences for family life, work and physical health.

This is why it is recommended not to wait for a fourth or fifth failure before seeking a specialist opinion in interventional psychiatry: after two adequately conducted treatments without sufficient response, a reassessment is warranted.

What are the options when antidepressants are not enough?

Several validated approaches exist. Some involve pharmacological adjustment (augmentation with lithium or other agents), managed with the treating psychiatrist. Others belong to interventional psychiatry, the core activity of the centre:

Ketamine infusions: a rapid-acting antidepressant, extensively studied in treatment-resistant depression, with a marked anti-suicidal effect. Intravenous ketamine and esketamine are now established treatments for treatment-resistant depression.

Transcranial magnetic stimulation (rTMS): non-invasive neurostimulation, without anaesthesia, validated in treatment-resistant depression and well tolerated.

Electroconvulsive therapy (ECT): the reference treatment for the most severe forms, particularly in the presence of psychotic symptoms, performed on an outpatient basis under brief general anaesthesia.

Anaesthetic treatments (dexmedetomidine, nitrous oxide): recent alternatives and complements to ketamine, tailored to each patient’s profile and tolerability.

The choice between these treatments depends on the severity and features of the episode, previous treatments, contraindications and the patient’s preferences. It is made at an initial in-person assessment at the centre, then discussed with your treating physician.

How does care at LCIP work?

The Centre for Interventional Psychiatry in Lausanne is an independent outpatient clinic entirely dedicated to interventional treatments for depression and related disorders. Care follows three steps:

1. Referral: your psychiatrist or family doctor refers your situation via the dedicated form. Patients may also contact us directly with any questions.
2. Specialised in-person assessment: a full review of your treatment history, diagnosis and comorbidities; the indication is established collegially.
3. Treatment and shared follow-up: treatment takes place on an outpatient basis, in collaboration with your psychiatrist or family doctor, who remains at the centre of your care.

Frequently asked questions

After how many failed treatments is depression considered resistant?

After two adequately conducted antidepressant treatments (adequate dose and duration) without sufficient improvement, within the same episode. A specialist opinion is worthwhile from this point onwards.

Can treatment-resistant depression go into remission?

Yes. Resistance to conventional antidepressants does not mean resistance to all treatment: interventional treatments achieve remission in patients who have failed several lines of treatment. The goal remains the resolution of symptoms, not merely their attenuation.

Do I have to stop my current treatment?

No, not necessarily. Most interventional treatments can be combined with an ongoing antidepressant; any change is a medical decision, never one to make on your own.

Will my psychiatrist remain involved?

Yes. The centre works in collaboration with referring physicians: your usual psychiatric and psychotherapeutic follow-up continues during and after treatment.

What is the first practical step?

Ask your psychiatrist or family doctor to refer your situation via the “Refer a patient” form. The initial consultation takes place in person, in Lausanne.

References

1. McIntyre RS, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023. doi:10.1002/wps.21120
2. Sforzini L, 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
3. Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006. doi:10.1176/ajp.2006.163.11.1905