Treatment-Resistant Depression

TRD is conventionally defined as failure to achieve a meaningful response to at least two adequate trials of different antidepressants from distinct classes, each at therapeutic dose for a typical treatment duration. Inadequate trials—subtherapeutic dose, short duration, poor adherence—are common pitfalls. Always confirm diagnosis with reassessment: rule out bipolar spectrum disorder, medical causes (e.g., hypothyroidism), or substance effects before labeling TRD.

Before escalating to neuromodulation, ensure no overlooked contributors exist: polypharmacy interactions, unresolved anxiety or insomnia, psychosocial stressors, or comorbid personality patterns. A full medication history including OTC and herbal products is essential. If bipolarity is suspected, avoid antidepressant monotherapy, which can induce switches or rapid cycling. Evidence supports trying at least two trials of evidence-based augmentations (e.g., lithium, atypical antipsychotics) before neuromodulation.

Neuromodulation referral (e.g., rTMS, ECT) is indicated when two adequate medication trials fail, especially with severe functional impairment, high suicide risk, or catatonia. rTMS is often first-line neuromodulation due to tolerability; ECT is preferred in psychosis,catatonia, or rapid deterioration. Genetic tests lack sufficient validity to guide TRD treatment selection—clinical assessment remains the cornerstone.