Intranasal Esketamine for Treatment-Resistant Depression

Intranasal esketamine, the S-enantiomer of ketamine, represents a novel rapid-acting intervention for adults whose depressive symptoms have not remitted despite trials of two or more antidepressant regimens. Administered as a nasal spray in conjunction with an oral antidepressant, it exerts its effects through antagonism of N-methyl-D-aspartate (NMDA) receptors, leading to enhanced glutamatergic transmission and synaptic plasticity. Clinical experience has emphasised its capacity to induce symptom relief within hours to days, in contrast to the weeks required by conventional monoaminergic agents. Beyond acute response, esketamine regimens incorporating an induction phase followed by individualised optimisation and maintenance have demonstrated sustained reductions in depressive severity and relapse risk. Commonly observed adverse events include transient dissociation, dizziness, nausea and sedation; these generally resolve within hours of dosing. Its approval by major regulatory authorities has expanded therapeutic options for a condition associated with high morbidity, chronicity and elevated suicide risk.

Research from Nature Portfolio

A large genome-wide association study in individuals of European ancestry has uncovered genetic loci linked to esketamine treatment response. A significant locus in an immune-signalling gene and gene-level associations in pathways related to neuronal development and stress response suggest that both synaptic biology and inflammatory signalling may moderate clinical benefit. Polygenic risk score analyses further hinted that genetic loading for depressive symptom profiles correlates modestly with esketamine efficacy, underscoring the potential for future stratified treatment approaches and the value of integrating genomics into depression therapeutics.

Intranasal Esketamine for Treatment-Resistant Depression publication trend

The graph below shows the total number of articles in intranasal esketamine for treatment-resistant depression across all publications each year (not limited to Nature Index journals).

Technical terms

Treatment-Resistant Depression (TRD): A major depressive episode that fails to improve after at least two trials of different antidepressant classes at adequate dose and duration.

NMDA Receptor Antagonism: The pharmacological blockade of N-methyl-D-aspartate receptors, leading to increased synaptic glutamate release and downstream neuroplastic changes.

Polygenic Risk Score (PRS): A quantitative measure of an individual’s inherited predisposition to a trait or treatment response, calculated from the sum of risk alleles weighted by their effect sizes.

Dissociation: A transient, drug-induced alteration of perception and self-awareness, often manifesting as derealisation or depersonalisation, that typically resolves shortly after esketamine administration.

References

1. Genome-wide association study and polygenic risk score analysis of esketamine treatment response. Scientific Reports (2020).
2. Long-term safety and maintenance of response with esketamine nasal spray in participants with treatment-resistant depression: interim results of the SUSTAIN-3 study. Neuropsychopharmacology (2023).
3. Efficacy of esketamine nasal spray over quetiapine extended release over the short and long term: sensitivity analyses of ESCAPE-TRD, a randomised phase IIIb clinical trial. The British Journal of Psychiatry (2024).
4. Esketamine in treatment-resistant depression patients comorbid with substance-use disorder: A viewpoint on its safety and effectiveness in a subsample of patients from the REAL-ESK study. European Neuropsychopharmacology (2023).