Revealing of Treatment Resistant Depression

In this episode, Dr Clayton and other panelists discuss how TRD is revealed.

TRD emerges when standard treatments fail to work, exposing the underlying biological complexity of depression rather than creating it. Dr. Citrome explained that depression involves dysfunction across multiple brain areas, neurotransmitter imbalances, inflammatory processes, dysregulation of the hypothalamic-pituitary-adrenal axis, reduced neuroplasticity, and broader network dysfunction — all interacting through complex gene-environment relationships. Depression is likely not a single unified syndrome, but rather a collection of distinct biological subtypes, which helps explain why one treatment rarely works for everyone.

Panelists highlighted the GABA-glutamate balance as an important and underappreciated mechanism, noting that women may be particularly vulnerable due to differential neuroactive steroid responses and a more prolonged stress-axis activation. When multiple biological pathways are disrupted simultaneously, no single medication is likely to be sufficient.

Critically, clinicians may inadvertently contribute to TRD by repeatedly cycling through monoaminergic drugs — essentially using the same tool expecting different results. As the STAR*D trial demonstrated, each successive medication trial yields diminishing returns. Panelists emphasized that delayed or insufficiently aggressive treatment allows depression to progress in a potentially neurodegenerative manner, making remission increasingly difficult to achieve over time.

In the next episode, “Comorbidities and Diagnosis of Treatment Resistant Depression,” panelists discuss the diagnostic complexity of TRD, emphasizing that comorbid psychiatric and medical conditions, overlapping symptoms, and bidirectional relationships must be carefully evaluated before a TRD diagnosis can be confirmed.