An experimental medicine study of the effects of simvastatin on emotional processing, reward learning, verbal memory, and inflammation in healthy volunteers

Riccardo De Giorgi, Alice M G Quinton, Shona Waters, Philip J Cowen, Catherine J Harmer, Riccardo De Giorgi, Alice M G Quinton, Shona Waters, Philip J Cowen, Catherine J Harmer

Abstract

Rationale: Clinical studies suggest that the highly lipophilic, anti-inflammatory molecule, simvastatin, might be an ideal candidate for drug repurposing in the treatment of depression. The neuropsychological effects of simvastatin are not known, but their ascertainment would have significant translational value about simvastatin's influence on mood and cognition.

Objectives: We aimed to investigate the effects of simvastatin on a battery of psychological tests and inflammatory markers in healthy volunteers.

Methods: Fifty-three healthy subjects were randomly assigned to 7 days of either simvastatin (N = 27) or sucrose-based placebo (N = 26) given in a double-blind fashion. Then, participants were administered questionnaires measuring subjective rates of mood and anxiety, and a battery of tasks assessing emotional processing, reward learning, and verbal memory. Blood samples for C-reactive protein were also collected.

Results: Compared to placebo, participants on simvastatin showed a higher number of positively valenced intrusions in the emotional recall task (F1,51 = 4.99, p = 0.03), but also an increase in anxiety scores (F1,51 = 5.37, p = 0.02). An exploratory analysis of the females' subgroup (N = 27) showed lower number of misclassifications as sad facial expression in the simvastatin arm (F1,25 = 6.60, p = 0.02). No further statistically significant changes could be observed on any of the other outcomes measured.

Conclusions: We found limited evidence that 7-day simvastatin use in healthy volunteer induces a positive emotional bias while also being associated with an increase in anxiety, potentially reflecting the early effects of antidepressants in clinical practice. Such effect might be more evident in female subjects. Different drug dosages, treatment lengths, and sample selection need consideration in further experimental medicine and clinical studies.

Trial registration: Clinicaltrials.gov: NCT04652089.

Keywords: Depression; Emotional processing; Experimental medicine; Healthy volunteers; Inflammation; Precision psychiatry; Reward learning; Simvastatin; Verbal memory.

Conflict of interest statement

CJH has received consultancy fees from P1vital, Janssen, Sage Pharmaceuticals, Zogenix, Pfizer, and Lundbeck outside of the current work. The other authors declare that they have no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Effect of simvastatin on the State-Trait Anxiety Inventory-State (STAI-s) score. Values are mean differences between visits ± standard error of the mean bars, and an asterisk (*) represents a statistically significant difference between the simvastatin (grey) and placebo (white) groups
Fig. 2
Fig. 2
Effect of simvastatin on emotional recall (EREC), false alarms. Values are means ± standard errors of the mean bars, and an asterisk (*) represents a statistically significant difference between the simvastatin (grey) and placebo (white) groups

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