Beyond Monoamines: Ketamine and Interventional Psychiatry

Ben Yudkoff, MD, discussed the evolving role of ketamine and esketamine in the treatment of refractory mood disorders and the limitations of traditional antidepressant paradigms. Yudkoff described his clinical background in interventional psychiatry and emphasized the need for novel approaches for patients who do not respond adequately to standard pharmacologic treatments.

Yudkoff explained that modern antidepressant development has historically been grounded in the monoamine hypothesis of depression. Over decades, treatment strategies progressed from monoamine oxidase inhibitors and tricyclic antidepressants to selective serotonin reuptake inhibitors and related agents. Although these medications remain effective for many patients, Yudkoff noted that they target a relatively narrow neurochemical framework. As he explained, “they work, but they work by manipulating a very specific set of tools and very specific portions of the brain.” For a substantial subset of patients, this mechanism does not adequately address the complex biological and psychological factors underlying depressive illness.

He highlighted ketamine as a fundamentally different therapeutic modality. Rather than acting primarily on monoamine neurotransmitters, ketamine influences glutamatergic signaling through NMDA receptor modulation and downstream pathways associated with synaptic plasticity, including brain-derived neurotrophic factor.¹ According to Yudkoff, “what ketamine has offered is a categorically different way of approaching the same disorder,” representing a shift toward mechanisms that may rapidly alter neural circuitry implicated in depression.

Yudkoff also referenced findings from the STAR*D Trial, which demonstrated decreasing response rates with each successive antidepressant trial.² He described this pattern as a “law of diminishing returns,” reinforcing the need for alternative therapeutic strategies when conventional treatments fail.

Within this context, Yudkoff positioned interventional treatments—including ketamine and esketamine—as part of a broader, evolving toolkit for treatment-resistant depression. He suggested that these therapies may complement existing pharmacologic and psychotherapeutic approaches, particularly for patients whose clinical presentation does not align well with monoaminergic treatment models.

Dr Yudkoff is a psychiatrist and chief medical officer at Lumin Health.

References

1. Niciu MJ, Henter ID, Luckenbaugh DA, et al. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds. Annu Rev Pharmacol Toxicol. 2014;54:119-139.

2. Questions and answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study — all medication levels. National Institute of Mental Health. November 2006. Accessed March 5, 2026. https://www.nimh.nih.gov/funding/clinical-research/practical/stard/allmedicationlevels