Treatment-resistant Depression in the Post-ketamine Era: Unmet Needs beyond Rapid Response

The introduction of ketamine and its S-enantiomer, esketamine, has been one of the most consequential advances in treatment-resistant depression (TRD) in recent decades, demonstrating that rapid and clinically meaningful antidepressant effects can occur within hours, even in patients who have not responded to conventional treatments. However, this advance has not resolved the clinical problem of TRD. Rather, it has shifted the field's most important unmet needs from the induction of short-term symptom improvement to the management of what follows. The central questions now concern the post-response trajectory: how durable the initial benefit is, how relapse should be prevented, how maintenance treatment should be structured and eventually tapered, whether symptomatic improvement translates into functional recovery, which patients are most likely to benefit, why clinically useful predictive biomarkers remain elusive, and what the long-term safety and abuse-liability profile of repeated glutamatergic treatment will prove to be. This clinically oriented review examines these unresolved problems in the post-ketamine era, considers whether emerging rapid-acting antidepressants may address some of them, and argues that durability, functional recovery, patient selection, long-term safety, and implementation value, rather than acute efficacy alone, should now guide research priorities and bedside decision-making in TRD.