An online experimental medicine trial on the effect of 28-day simvastatin administration on emotional processing, reward learning, working memory and salivary cortisol in healthy volunteers at risk for depression: OxSTEP protocol.

BACKGROUND: Evidence suggests inflammation may be a key mechanism by which psychosocial stress, including loneliness, predisposes to depression. Observational and clinical studies have suggested simvastatin, with its anti-inflammatory properties, may have a potential use in the treatment of depression. Previous experimental medicine trials investigating 7-day use of statins showed conflicting results, with simvastatin displaying a more positive effect on emotional processing compared with atorvastatin. It is possible that statins require longer administration in predisposed individuals before showing the expected positive effects on emotional processing. AIMS: Here, we aim to test the neuropsychological effects of 28-day simvastatin administration versus placebo, in healthy volunteers at risk for depression owing to loneliness. METHOD: This is a remote experimental medicine study. One hundred participants across the UK will be recruited and randomised to either 28-day 20 mg simvastatin or placebo in a double-blind fashion. Before and after administration, participants will complete an online testing session involving tasks of emotional processing and reward learning, processes related to vulnerability to depression. Working memory will also be assessed and waking salivary cortisol samples will be collected. The primary outcome will be accuracy in identifying emotions in a facial expression recognition task, comparing the two groups across time.

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

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.

Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis.

Reduced gut-microbial diversity ("gut dysbiosis") has been associated with an anhedonic/amotivational syndrome ("sickness behavior") that manifests across severe mental disorders and represent the key clinical feature of chronic fatigue. In this systematic review and meta-analysis, we investigated differences in proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue vs. controls and the association of these biomarkers with sickness behavior across diagnostic categories. Following PRISMA guidelines, we searched from inception to April 2020 for all the studies investigating proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue. Data were independently extracted by multiple observers, and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. Thirty-three studies were included in the systematic review; nineteen in the meta-analysis (N = 2758 patients and N = 1847 healthy controls). When compared to controls, patients showed increased levels of zonulin (four studies reporting data on bipolar disorder and depression, SMD = 0.97; 95% Cl = 0.10-1.85; P = 0.03, I2 = 86.61%), lipopolysaccharide (two studies reporting data on chronic fatigue and depression, SMD = 0.77; 95% Cl = 0.42-1.12; P < 0.01; I2 = 0%), antibodies against endotoxin (seven studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.99; 95% CI = 0.27-1.70; P < 0.01, I2 = 97.14%), sCD14 (six studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.54; 95% Cl 0.16-0.81; P < 0.01, I2 = 90.68%), LBP (LBP, two studies reporting data on chronic fatigue and depression, SMD = 0.87; 95% Cl = 0.25-1.48; P < 0.01; I2 = 56.80%), alpha-1-antitripsin (six studies reporting data on bipolar disorder, depression, and schizophrenia, SMD = 1.23; 95% Cl = 0.57-1.88; P < 0.01, I2: 89.25%). Elevated levels of gut dysbiosis markers positively correlated with severity of sickness behavior in patients with severe mental illness and chronic fatigue. Our findings suggest that gut dysbiosis may underlie symptoms of sickness behavior across traditional diagnostic boundaries. Future investigations should validate these findings comparing the performances of the trans-diagnostic vs. categorical approach. This will facilitate treatment breakthrough in an area of unmet clinical need.