Treatment-resistant depression
Depressive disorder without response to two adequate antidepressant trials. Strategies: switching, augmentation with lithium or atypical antipsychotics, ketamine/esketamine.
ICD-10 F334 drugs
Also known as: TRD
Drugs used for this condition
- BLithiumAdd-on therapy · Psycholeptics. LithiumLithium is used as augmentation in patients with treatment-resistant unipolar depression. NICE and APA recommend adding lithium to an antidepressant when adequate monotherapy fails. Meta-analyses show NNT approximately 5 for remission. Target blood level 0.4–0.8 mmol/L (lower than for bipolar disorder).
- BPhenelzineThird line · Antidepressant, irreversible non-selective monoamine oxidase inhibitor (MAO-A and MAO-B)Phenelzine is a third-line antidepressant for SSRI- and SNRI-resistant depression, especially with atypical features (hypersomnia, hyperphagia, rejection sensitivity). It requires a strict tyramine-free diet because aged cheeses, cured meats, fava beans and red wine can trigger hypertensive crisis. A 2-week SSRI washout (5 weeks for fluoxetine) is needed before starting. EMA and SEPB restrict prescribing to psychiatrists.
- BTranylcypromineThird line · Antidepressant, irreversible non-selective monoamine oxidase inhibitor (MAO-A and MAO-B), amphetamine derivativeTranylcypromine is a third-line antidepressant for treatment-resistant depression. In Spain it is preferred over phenelzine in apathetic or anergic presentations because the amphetamine-like effect adds activation. SEPB restricts prescribing to inpatient or specialist outpatient settings after SSRI/SNRI washout. A tyramine-free diet and blood pressure checks every 2 weeks for the first 2 months are mandatory.
- CL-tryptophanAdd-on therapy · Essential amino acid, precursor of serotonin, melatonin and niacin. In the UK registered by MHRA as Optimax for resistant depressionL-tryptophan is registered in the UK by MHRA as Optimax for adjunctive therapy of resistant depression in patients on MAO-I or lithium under psychiatric supervision. AEMPS does not register L-tryptophan as medicine. Cochrane 2002 (Shaw) reviewed 108 studies of tryptophan and 5-HTP for depression, with only 2 RCTs meeting quality criteria – ambiguous results in 64 patients. NICE 2022 for resistant depression recommends antidepressant combinations, lithium, quetiapine, ketamine/esketamine and ECT; L-tryptophan is not among the main options and is used only under psychiatric supervision, usually after 2–3 failed treatment lines. Self-administration of L-tryptophan supplement for depression is not justified: serotonin syndrome and eosinophilia-myalgia syndrome risk.
How to read tiers A–F
Evidence tiers belong to the drug-indication pair, not to the drug as a whole: the same substance can be A for one condition and F for another.
- AStrong evidence – first or second line in international guidelines
- BRecommended in selected cases
- CStudy data contradict each other
- DBenefit not proven, no documented harm
- FDocumented harm, or risk without benefit