2026 ECNP Congress

PS04-4196

Effects of 4 weeks of serotonergic treatment on emotional processing in individuals with low vs high neuroticism: a neuroimaging study

Lena Lisa Maria Beckers — B.M. Vissel, L.P. Capitão, S.E. Murphy, M. Di Simplicio, C.J. Harmer · University of Oxford, Department of Psychiatry, Oxford, United Kingdom

2026 ECNP Congress

Neuroticism is a personality trait characterised by negative emotional processing biases similar to those seen in depression and has been linked to increased vulnerability for depression [1]. However, although depressed people show an increased amygdala response to fearful faces, which is decreased after seven days of selective serotonin reuptake inhibitor (SSRI) treatment [2, 3], a previous study found a reduced amygdala response to fearful stimuli in highly neurotic individuals, which increased following seven days of SSRIs [4]. One potential explanation for this is that highly neurotic people initially avoid negative emotional cues [5], which gets reversed by sub-chronic SSRI treatment, subsequently allowing for habituation to negative cues and thereby leading to the expected amygdala response after some delay. Therefore, this study aimed to characterise the effects of sub-chronic citalopram (SSRI) treatment on emotional processing neural responses in participants with low versus high neuroticism.

Sixty-three healthy participants, stratified into low (<5) and high (>16) neuroticism groups (Eysenck Personality Questionnaire), were randomised in a double-blind design to receive citalopram (20 mg) or placebo for 28 days. Participants then completed a covert emotional faces task during 3T fMRI. Data were analysed using FSL’s tool for non-parametric permutation testing ‘randomise’ (5000 permutations; TFCE-corrected, p<0.05), including amygdala region-of-interest (ROI) as well as whole-brain analyses. Different emotion conditions (fear, happy) were contrasted to each other and to neutral faces. A parametric modulator was included to account for the different levels of emotion intensity of the fear and happy conditions.

Parametric analyses of fear intensity revealed widespread reductions in neural responses across fronto-cingulate and parietal regions in participants taking citalopram compared to those taking placebo, which was similar across both neuroticism groups. However, ROI analyses of the bilateral amygdala showed a treatment by trait neuroticism interaction effect for fearful > happy faces in the right amygdala (80 voxels, x=34, y=64, z=25, p=0.006, t-max=3.83). This interaction effect was driven by increased activation to fearful > happy faces following citalopram treatment in the low but not high neuroticism group (66 voxels, x=34, y=64, z=25, p=0.002, t-max=4.47; high neuroticism: all ps>0.05). Additionally, whole-brain analyses revealed increased activation to happy > neutral faces in the orbitofrontal cortex in individuals with low relative to high neuroticism taking placebo (73 voxels, x=70, y=77, z=31, p=0.029, t-max=5.93) and reduced activation to happy > neutral faces in bilateral cerebellar areas following citalopram treatment in only the low neuroticism group (100 voxels, x=61, y=24, z=18, p=0.039, t-max=4.72; 26 voxels, x=49, y=18, z=22, p=0.044, t-max=4.25; 19 voxels, x=22, y=27, z=21, p=0.044, t-max=4.46; 13 voxels, x=38, y=18, z=21, p=0.047, t-max=4.01; high neuroticism: p=0.87).

These results underscore the importance of individual differences in shaping SSRI effects on emotional processing and suggest that personality traits like neuroticism may be critical for understanding variability in treatment mechanisms and outcomes. Specifically, paradoxical effects of SSRI treatment (reduced response to happy and increased response to fear) may be observed across an interconnected network of emotional processing areas in individuals with very low trait neuroticism.

References

  1. Lahey, B. B., 2009. Public health significance of neuroticism. American Psychologist, 64(4), 241–256. https://doi.org/10.1037/a0015309
  2. Godlewska, B. R., Norbury, R., Selvaraj, S., Cowen, P. J., & Harmer, C. J., 2012. Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients. Psychological Medicine, 42(12), 2609–2617. https://doi.org/10.1017/s0033291712000591
  3. Harmer, C. J., Mackay, C. E., Reid, C. B., Cowen, P. J., & Goodwin, G. M., 2006. Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biological Psychiatry, 59(9), 816–820. https://doi.org/10.1016/j.biopsych.2005.10.015
  4. Di Simplicio, M., Norbury, R., Reinecke, A., & Harmer, C. J., 2013. Paradoxical effects of short-term antidepressant treatment in fMRI emotional processing models in volunteers with high neuroticism. Psychological Medicine, 44(2), 241–252. https://doi.org/10.1017/s0033291713000731
  5. Di Simplicio, M., Doallo, S., Costoloni, G., Rohenkohl, G., Nobre, A. C., & Harmer, C. J., 2014. ‘Can you look me in the face?’ Short-term SSRI Administration Reverts Avoidant Ocular Face Exploration in Subjects at Risk for Psychopathology. Neuropsychopharmacology, 39(13), 3059–3066. https://doi.org/10.1038/npp.2014.159