The 52-year-old with depression who has not responded to two antidepressants
A 52-year-old woman with a five-year history of recurrent major depressive disorder presents with a nine-month episode. She has had adequate trials of sertraline 150 mg for eight weeks and venlafaxine 225 mg for ten weeks, with documented adherence and therapeutic levels. She scores 24 on the PHQ-9 and reports anhedonia, early waking, 6 kg weight loss and passive thoughts that 'everyone would be better off'. She has no psychotic symptoms and no history of mania. She drinks two glasses of wine most evenings and takes amitriptyline 10 mg at night for insomnia, which she did not mention to her psychiatrist. Physical examination and thyroid function are normal. She asks whether ECT 'will fry my brain' and whether she should just try a third tablet.
1. How do you formulate treatment resistance, and what would you check before escalating?
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This is stage II treatment resistance: failure of two adequate antidepressant trials with verified adherence and dose. Before escalating, systematically exclude pseudo-resistance. Check adherence with dispensing records and a plasma level if available; confirm the diagnosis (bipolarity, psychotic depression, substance-induced mood disorder); screen for comorbid anxiety, personality difficulties and alcohol use - two glasses nightly is above recommended limits and may worsen sleep and mood; review interacting drugs. The undisclosed amitriptyline is important: it is a TCA with anticholinergic and cardiac effects, it may interact with venlafaxine to increase serotonergic and noradrenergic burden, and it signals that she self-medicates, which affects the risk assessment. Check an ECG if considering further QT-prolonging agents. Reassess suicide risk given passive ideation, weight loss and anhedonia, and ask directly about plans and means. Consider thyroid antibodies, B12 and folate if not done. Only after these steps does the question of a third agent, augmentation or ECT become meaningful.
2. Compare the options of a third antidepressant, augmentation, and ECT, and answer her question about ECT.
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Switching within or between classes after two failures has modest evidence; a third agent is reasonable but the expected benefit is smaller with each failed trial, and she has already had two adequate trials. Augmentation - for example with lithium, a second-generation antipsychotic, or liothyronine - has better evidence for treatment-resistant depression, but requires monitoring: lithium needs levels, renal and thyroid checks; antipsychotics carry metabolic risk. ECT is the most effective acute treatment for severe, treatment-resistant depression, particularly with weight loss, psychotic features, catatonia or high suicide risk, and is a reasonable option here given nine months of illness and 6 kg weight loss. Answer her fear honestly: ECT does not 'fry the brain'; it induces a controlled seizure under anaesthesia, and the main risks are transient memory disturbance and confusion, with rare prolonged seizures or cardiac events. Explain the need for pre-ECT workup (ECG, anaesthetic review, cognitive baseline) and that consent can be withdrawn. Present the options with numbers where possible, respect her preference, and document the shared decision. If she lacks capacity and risk is high, the legal route for treatment without consent must be followed.