Duration of the episode: the longer the episode of depression, the greater the atrophy in specific brain regions (eg, hippocampus); the cognitive and behavioral changes that take place during long episodes make a return to previous well-being difficult
Severity of the episode: both ends of the depression spectrum (most severe, mildest) are hypothesized to increase the risk of poor response—severe depression is associated with biological unbalances; mild depression, with lower drug versus placebo response
Melancholic features: TRD is more prevalent in bipolar depression than in MDD; the specific investigation of subthreshold manic symptoms is pivotal
Lack of symptomatic improvement within the first couple of weeks since the start of treatment
Comorbidity: anxious symptoms and full anxiety disorders (especially generalized anxiety disorder) were found to be predictors of lower rates of response and remission; personality disorders, especially avoidant and borderline, are negative prognostic factors
Old age, long duration of an episode, anxiety symptoms, and major life events can contribute to TRD.