Anhedonia mediates short-term anti-suicidal effects of intranasal esketamine in major depressive disorder

Background

Intranasal esketamine has demonstrated rapid antidepressant effects in major depressive disorder with acute suicidal ideation, yet its specific impact on suicidal ideation remains inconsistent across randomized trials. In the context of intensive standard-of-care, global suicidal ideation outcomes may lack sensitivity to detect treatment effects. In this framework, examining effects on proximal, suicide-related dimensions may provide more mechanistically informative insights into treatment response. Anhedonia and psychological pain are transdiagnostic constructs, both strongly associated with suicidal ideation across clinical and epidemiological studies, that may be rapidly modulated by ketamine-based interventions.

Aims

We investigated whether reductions in anhedonia and psychological pain mediate the short-term effect of add-on intranasal esketamine on suicidal ideation in patients with major depressive disorder at imminent risk of suicide.

Methods

We conducted secondary analyses of pooled individual participant data from the ASPIRE I and II randomized, double-blind, placebo-controlled trials. The sample included 409 adults aged 18–64 years with major depressive disorder, severe depressive symptoms and imminent suicide risk, randomized to intranasal esketamine 84 mg or placebo, both added to comprehensive standard of care, twice weekly for 4 weeks. Suicidal ideation was assessed using Montgomery-Åsberg Depression Rating Scale item 10, anhedonia using Montgomery-Åsberg Depression Rating Scale item 8, and psychological pain using the Suicide Ideation and Behavior Assessment Tool item “my emotional pain is so great that I would like to end my life”. Mixed-effects models tested treatment effects over time, including visit, treatment, and their interaction, with baseline symptoms adjustment. Parallel mediation analyses were performed using structural equation modelling with maximum likelihood estimation and 5,000 bootstrap samples. To preserve temporal ordering, baseline-to-4-hour changes were tested as mediators of 24-hour suicidal ideation, baseline-to-24-hour changes as mediators of Day 8 suicidal ideation, and baseline-to-Day 8 changes as mediators of Day 25 suicidal ideation. Models were adjusted for baseline depression severity.

Results

Esketamine produced greater reductions in anhedonia than placebo across all assessed time points, from 4 hours to Day 25, whereas psychological pain decreased more strongly under esketamine at 4 hours. In mediation analyses, early reductions in both anhedonia (β = –0.10, 95% CI –0.17 to –0.03, p = 0.009) and psychological pain (β = –0.08, 95% CI –0.14 to –0.02, p = 0.012) significantly mediated the effect of esketamine on suicidal ideation at 24 hours. At Day 8, only reduction in anhedonia at 24 hours significantly mediated suicidal ideation improvement (β = –0.10, 95% CI –0.19 to –0.02, p = 0.024). No significant indirect effects were observed at Day 25.

Conclusions

Add-on intranasal esketamine may reduce suicidal ideation through rapid changes in specific symptom-level dimensions, particularly anhedonia and psychological pain. These findings support an indirect, temporally organized anti-suicidal pathway, with ultra-rapid dampening of psychological pain and a more sustained contribution of anhedonia during the first treatment week.

References

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