I take a closer look at treatment-resistant depression (TRD), what the term actually means, why it’s far less useful than people think, and how I approach severe depressive episodes in real practice.

Most definitions of TRD frame it as unipolar major depression without psychotic features that has failed to remit after two adequate trials of first-line antidepressants. But as I discuss in this episode, this “two-step failure” model doesn’t tell us anything meaningful about biology, prognosis, or subtype. It simply reflects that our first-line medications (SSRIs, SNRIs, bupropion, mirtazapine) are not particularly effective to begin with. Data from STAR*D and other large trials reinforce this problem: even responders have high relapse rates.

Instead of rigidly following algorithms designed around weak medications, I argue for a severity-based approach. On the inpatient unit, especially with suicidality or a recent suicide attempt, it often makes more sense to go directly to augmentation rather than waiting six weeks for an SSRI to maybe work. I talk through why agents like aripiprazole can produce meaningful clinical change within days, how I present options to patients, and why we should treat severe MDEs with the same urgency and multimodal strategy we routinely use for manic episodes.

We also cover the broader therapeutic landscape: lithium augmentation, switching antidepressants, TMS, ECT, IV ketamine, intranasal esketamine, and psychotherapy, plus why I’m particularly optimistic about accelerated neuromodulation protocols like SAINT and emerging one-day TMS approaches.

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