Risk Factors for Treatment Resistant Depression

In this episode, Dr Anita Clayton and panelist discuss risk factors for TRD.

Panelists identified several important risk factors for TRD, beginning with adverse childhood experiences as one of the strongest predictors. Having a first-degree relative with TRD raises an individual's risk ninefold, while women face at least twice the risk of men — potentially linked to differential neuroactive steroid and stress-axis responses. Age plays a bimodal role, with higher TRD rates seen in patients aged 20–40 and again in those 65 and older. Medical comorbidities, as previously discussed, compound these risks further.

A particularly important concept raised was pseudo-resistance — where apparent treatment failure actually reflects non-adherence rather than true biological resistance. Dr. Citrome shared a compelling anecdote illustrating how patients may silently self-adjust doses, underscoring the need for clinicians to routinely and non-judgmentally explore medication-taking habits. Inadequate dosing and insufficient trial duration were also flagged as leading contributors to apparent TRD.

Panelists also emphasized that partial response with persistent residual symptoms — especially anhedonia — should not be mistaken for remission. Anhedonia, encompassing both anticipatory and consummatory dimensions, profoundly eliminates quality of life and warrants explicit screening. Understanding and aligning with each patient's individual priorities was stressed as essential to truly effective depression care.

In the next episode, “Clinical and Functional Impairment in Treatment Resistant Depression,” panelists discuss how quality of life and functional impairment are central to evaluating depression outcomes, emphasizing that depression burden and treatment priorities vary significantly from person to person.