Ketamine Applications in Treatment-Resistant Depression

Treatment-resistant depression (TRD) affects a substantial proportion of individuals who fail to achieve remission with standard antidepressant therapies. Ketamine, a dissociative anaesthetic acting primarily as an N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a paradigm-shifting intervention in this context. At subanaesthetic doses, ketamine exerts rapid antidepressant effects, often within hours of administration, contrasting sharply with the delayed onset typical of monoaminergic agents. Mechanistically, ketamine’s blockade of NMDA receptors on inhibitory interneurones leads to a surge in glutamate release, activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and downstream engagement of synaptogenic pathways. Clinically, both single infusions and repeated dosing regimens have demonstrated robust reductions in depressive symptoms, suicidal ideation and anhedonia, with effects persisting for days to weeks. Alternative formulations, including intranasal esketamine and subcutaneous racemic preparations, have broadened the therapeutic toolkit, allowing for tailored delivery in outpatient and supervised settings. Ongoing investigations aim to optimise dosing schedules, mitigate dissociative and cardiovascular side effects, and identify biomarkers predictive of response. The global significance of ketamine in TRD lies not only in its capacity to alleviate severe mood disturbance but also in its potential to reshape our understanding of neuroplasticity and fast-acting psychopharmacology.

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Ketamine Applications in Treatment-Resistant Depression publication trend

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Technical terms

Treatment-resistant depression (TRD): A form of major depressive disorder that does not respond adequately to at least two trials of standard antidepressant treatments.

NMDA receptor antagonist: A compound that blocks the N-methyl-D-aspartate subtype of glutamate receptors, reducing inhibitory interneuron activity and facilitating synaptic potentiation.

Subanaesthetic dose: A drug dosage below the threshold required to induce full anaesthesia, sufficient to elicit therapeutic neuropsychiatric effects without loss of consciousness.

References

1. A meta-analysis of the effects of ketamine on suicidal ideation in depression patients. Translational Psychiatry (2024).
2. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. The BMJ (2022).
3. Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial. The British Journal of Psychiatry (2023).