2026 ECNP Congress

EP02-2040

Enhanced sensitivity to esketamine in elderly treatment-resistant depression: marked response to low-dose intranasal therapy

Lorenna Pereira da Rocha Farias — N.C.D.F. Martinelli, R.P. Valentim, A.S.D. Souza, I.R.B.D.O. Pereira · Hospital Potiguar de Saúde Mental, Psychiatry, Natal, Brazil

2026 ECNP Congress

Background

Treatment-resistant depression (TRD) in older adults frequently co-occurs with neurocognitive disorders, contributing to increased morbidity, functional decline and limited therapeutic responsiveness. Age-related changes in pharmacokinetics and pharmacodynamics, including reduced metabolic clearance, altered receptor sensitivity, reduced protein binding and increased central nervous system vulnerability, may substantially modify response to psychotropic agents. Esketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects through modulation of glutamatergic neurotransmission, increased synaptic plasticity and downstream activation of brain-derived neurotrophic factor (BDNF) signalling pathways [1,2].

Despite these advances, frail elderly individuals with low body weight remain underrepresented in clinical trials, and optimal dosing strategies in this population are not well defined. Whether reduced exposure may preserve efficacy while improving tolerability is clinically relevant but insufficiently explored, particularly in the presence of neurocognitive comorbidity and polypharmacy.

Case Presentation

We report a 73-year-old woman (41 kg; height 1.54 m) presenting with severe TRD, characterised by anhedonia, avolition, anergia, apragmatism, persistent rumination, hypersomnia and reduced appetite, resulting in marked functional impairment. She had a diagnosis of mild neurocognitive disorder, stable under treatment with donepezil and memantine. Previous antidepressant trials with venlafaxine (150 mg/day) and vortioxetine (20 mg/day) were ineffective. At admission, depressive severity was high (MADRS 32), with preserved insight and no psychotic features.

Intranasal esketamine was initiated. Standard induction dosing (three devices twice weekly) was not tolerated, with early overstimulation, dizziness, transient dissociative sensations and subjective discomfort. A reduced regimen consisting of one device once weekly was therefore implemented. Despite substantially lower cumulative exposure, treatment adherence was maintained and clinical improvement was both rapid and sustained. After two months, MADRS decreased from 32 to 10, with parallel improvement in motivation, behavioural activation, emotional reactivity, social engagement and overall daily functioning.

Importantly, no clinically relevant adverse effects were observed, including persistent dissociation, haemodynamic instability or cognitive worsening. Neurocognitive status remained stable throughout follow-up, and the patient demonstrated increased engagement in structured activities and improved interpersonal functioning. No treatment interruptions or dose escalations were required during the observation period.

Conclusions

This case provides clinically relevant evidence of enhanced sensitivity to NMDA receptor antagonism in a frail elderly patient with TRD, suggesting that therapeutic effects of esketamine may be achieved at substantially lower doses in selected individuals. Age-related pharmacokinetic and pharmacodynamic factors, including altered glutamatergic signalling, receptor-level responsiveness, reduced distribution volume and increased brain exposure, may underlie this effect [1–3].

These findings support the concept of individualised, precision-informed dosing strategies in late-life depression, particularly in patients with low body weight and neurocognitive comorbidity. The absence of cognitive deterioration in the context of concurrent NMDA modulation and cholinergic treatment further supports the tolerability of this approach [4,5].

Although causal inference is limited, this observation generates a testable hypothesis that reduced-dose esketamine protocols may optimise the balance between efficacy and tolerability in vulnerable populations and may inform future dose-adaptation strategies in geriatric psychopharmacology.

References

  1. Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338(6103):68–72.
  2. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23:801–811.
  3. Schatzberg AF. A word to the wise about intranasal esketamine. Am J Psychiatry. 2019;176(6):422–424.
  4. Parsons CG, Danysz W, Dekundy A, Pulte I. Memantine and ketamine: similarities and differences. Neuropharmacology. 2013;62:1125–1132.
  5. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression. Am J Psychiatry. 2021;178(5):383–399.