Different approaches for Management of Treatment Resistant Depression

In this episode, Dr Anita Clayton and experts discuss different approaches for management of TRD.

Panelists outlined a stepwise approach to TRD management, beginning with dose optimization, followed by strategic augmentation with atypical antipsychotics or lithium, combination antidepressant therapy, and ultimately newer interventions such as neuromodulation and esketamine. Exercise was enthusiastically endorsed as a foundational intervention — ideally initiated before or alongside pharmacotherapy — though panelists acknowledged that severely symptomatic patients may first need stabilization before they can engage in physical activity. Concurrent treatment of medical comorbidities was also emphasized throughout.

Regarding FDA-approved pharmacological options, panelists identified the olanzapine-fluoxetine combination and esketamine as the two approved TRD treatments, alongside TMS and ECT. However, the olanzapine-fluoxetine combination was noted to have nearly 50% dropout rates due to adverse effects, particularly weight gain and sexual dysfunction.

Significant concern was raised about the widespread use of atypical antipsychotics — especially quetiapine — given risks of tardive dyskinesia and metabolic syndrome, even at low doses. Clinical cases of quetiapine-induced tardive dyskinesia were shared as cautionary examples. Panelists expressed a clear preference for esketamine over atypical antipsychotics when alternatives exist, citing more favorable response, remission rates, and a superior long-term safety profile.

In the next episode, “Targeting of Glutamatergic Pathway for Management of Treatment Resistant Depression,” panelists discuss how glutamatergic-targeting drugs represent a meaningful mechanistic departure from traditional monoaminergic antidepressants, with esketamine and dextromethorphan-bupropion offering two distinct NMDA receptor-based treatment options for depression.