2026 ECNP Congress

PS04-4110

Metabolism meets mind: intranasal insulin modulates facial emotion recognition

Aicha Bouzouina — P. Forbes, J. Lee, T. Zhao, V. Schack, R. Jacoby, C. Uckermark, M. Aichholzer, C. Schiweck, H. Sochor, S. Dastagir, A. Hellmann, R. Hanssen, S. Matura, J. Repple, A. Reif, S. Edwin Thanarajah · Goethe University Frankfurt, Department of Psychiatry- Psychotherapy and Psychosomatics, Fankfurt, Germany

2026 ECNP Congress

Background

Type 2 diabetes (T2D) and major depressive disorder (MDD) frequently co-occur, suggesting shared underlying biological mechanisms [1]. One key candidate mechanism is insulin resistance (IR), which has been implicated not only in metabolic dysregulation but also in altered brain function [2]. Insulin receptors are widely distributed in the central nervous system, with particularly high densities in regions involved in emotional and reward processing, such as the amygdala, striatum, and prefrontal cortex [3]. Insulin signaling in the brain modulates dopaminergic neurotransmission and affective pathways, thereby influencing mood, motivation, and emotional reactivity. Intranasal insulin administration provides a non-invasive method to selectively target central insulin pathways while largely bypassing peripheral metabolic effects. This approach enables the direct investigation of insulin’s role in human brain function [4]. In the present study, we examined how intranasal insulin modulates emotional processing across neural, behavioral, and subjective domains, and whether these effects differ between individuals with MDD and healthy controls.

Methods

:In a double-blind randomized crossover design, participants received intranasal insulin (160 IU) or placebo. Emotional processing was assessed using (i) a facial emotion recognition task (FERT), (ii) visual analogue scales (VAS) of mood, and (iii) functional MRI during a faces task (Hariri paradigm). The total sample included 43 patients with MDD and 79 healthy controls, each tested under both conditions. Due to quality control and preprocessing criteria, the final fMRI analyses were conducted in a subsample of 92 participants. Linear mixed-effects models were applied to assess condition effects and interactions.

Results

:Insulin effects on emotional processing differed as a function of diagnosis. In the fMRI task, region-of-interest analyses revealed a significant condition × diagnosis interaction in the amygdala (p = 0.008), which was further qualified by a condition × diagnosis × hemisphere interaction (p = 0.045). Post-hoc analyses showed that this effect was driven by the right amygdala, where insulin showed a trend by increasing responses to faces in healthy controls (p = 0.068) and significantly decreased responses in patients with MDD (p = 0.0058), indicating opposing and lateralized neural effects. No significant insulin effects were observed in the left amygdala (all p > 0.30). Consistent with this interaction, patients with MDD exhibited higher amygdala activation than controls under placebo (p = 0.018), whereas this group difference was not present under insulin (p = 0.276). Behaviorally, insulin modulated emotion recognition in the FERT, with a significant condition-by-valence interaction (p = 0.048), reflecting improved recognition of positive facial expressions. Subjectively, VAS ratings showed a significant condition × group × timepoint interaction (p = 0.026), indicating differential mood effects of insulin across groups.

Conclusion:Intranasal insulin modulates emotional processing across neural, behavioral, and subjective domains, with diagnosis-dependent and lateralized effects in the amygdala. The opposing insulin effects in the right amygdala of healthy individuals and patients with MDD suggest altered central insulin signaling in depression. These findings highlight a mechanistic link between metabolic signaling and affective brain function.

References

  1. I. Holt et al. (2014): Diabetes and depression. Curr Diab Rep 14, 491
  2. P . Belujon, A. A. Grace, Dopamine System Dysregulation in Major Depressive Disorders. Int J Neuropsychopharmacol 20, 1036-1046 (2017)
  3. D. P . Figlewicz, S. B. Evans, J. Murphy, M. Hoen, D. G. Baskin, Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res 964, 107-115 (2003).
  4. S. E. Thanarajah et al., Food Intake Recruits Orosensory and Post-ingestive Dopaminergic Circuits to Affect Eating Desire in Humans. Cell Metab 29, 695-706 e694 (2019).