In a frail older adult with depression unresponsive to two SSRI trials, what's your next step in management?

This is certainly a longer and nuanced conversation.

Depends on the intensity of symptoms. Ensuring the diagnosis is accurate, reviewing the role of co-morbid cognitive disorders, organic issues masquerading as depression, and so on. Augmentation of an SSRI, e.g., mirtazapine, stimulating medication, Cytomel, or lithium could be considered if there is an inadequate response. If you want to change meds completely, switching to an SNRI to address neurovegetative symptoms could be helpful.

If frailty is the primary concern with worsened severity of symptoms, interventional options such as TMS (SAINT) or ECT, if indicated.

If 2 SSRIs didn’t work, a third is unlikely. Best to switch, after ruling out an occult bipolar disorder or other medical reasons for the depression (thyroid, other abnormal labs, occult malignancy presenting with depression, CNS event, etc.), switch to a different class. If not sleeping, low-dose mirtazapine, possibly Viibryd, perhaps an SNRI or Wellbutrin, depending on the symptom profile.

Hope this is helpful.