The Effect of Seven-day Simvastatin Administration on Emotional Processing, Reward Processing, and Inflammation in Healthy Volunteers

Depression is common and associated with considerable health disability (Kassebaum-2016). Traditional antidepressants mainly work by modulating monoamine levels in the synaptic cleft (Harmer-2017); however, the evidence that depression is caused by impaired serotonin or noradrenaline activity is weak and inconsistent (Cowen-2015), and indeed current antidepressant strategies remain burdened by partial efficacy, poor side-effects profile, and a slow onset of therapeutic action (Penn-2012). Therefore, there is a pressing need to develop antidepressant medications with novel non-monoaminergic mechanisms of action (Jha-2018) - or, conversely, to identify alternative pathophysiological pathways leading to depression that can be targeted with new drugs. Intriguingly, there is growing evidence that both peripheral and central inflammation play a role in the pathophysiology of depression (Miller-2017).

Patients with depression consistently show negative biases in emotional processing, which are believed to play a key role in the aetiology and maintenance of their clinical symptoms (Roiser-2013). Overall, robust evidence suggests that early changes in emotional processing can serve as valid surrogate markers of antidepressant efficacy (Harmer-2017); for example, seven days' treatment with selective serotonin and noradrenaline reuptake inhibitors (citalopram and reboxetine respectively) compared to placebo decreases the recognition of negative facial expressions and recall of negative versus positive stimuli in healthy volunteers (Harmer-2004). Conversely, another study using the pro-inflammatory cytokine interferon-α showed that inflammatory-mediated depression can be associated with an increased recognition of negative facial expressions (Cooper-2017). Furthermore, depression associated with inflammation is characterised by significant symptoms of anhedonia (Miller-2017), which has been linked to diminished neural responses to reward anticipation (Felger-2017). Such reward-deficit is particularly refractory to conventional serotoninergic and noradrenergic antidepressants (McCabe-201), and even the antidepressant bupropion (a noradrenaline and dopamine reuptake inhibitor), whilst inducing positive changes in emotional processing, appears not to improve reward processing (Walsh-2018). However, the reversal of this deficit in reward processing is still considered as a valuable marker of target engagement for anti-inflammatory drugs in depression, as a more sensitive outcome measure than traditional rating scales designed to capture the global clinical symptomatology (Miller-2017).

The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or statins are recommended and have been widely used since the '80s for the primary and secondary prevention of cardiovascular diseases (NICE 2014). It is now established that these medications have significant anti-inflammatory effects that are independent from their lipid-lowering properties (Jain-2005), as well as appearing early in treatment only after seven day of administration (Macin-2011). Statins are considered extremely safe drugs: their more common side-effect are muscle pain or weakness (usually mild and quickly responding to stopping or switching medication) and elevation of liver transaminases (significant only in case of pre-existing hepatic disease), whereas more serious adverse events include rhabdomyolysis (very rare but severe myopathy associated with elevated creatine kinase and myoglobinuria), new-onset diabetes mellitus (in predisposed individual with pre-existing hyperglycaemia), and haemorrhagic stroke (in patients with prior haemorrhagic stroke or lacunar infarct); however, clinical trials have ultimately concluded that such adverse events attributed to statin therapy in routine practice are not actually caused by it (Collins-2016). Other common (≥ 1/100, < 1/10) but usually mild side-effects include: nasopharyngitis, pharyngo-laryngeal pain, epistaxis, headache, and gastrointestinal disturbances (constipation, diarrhoea, flatulence, dyspepsia, nausea). Importantly, a potential antidepressant effect for statins has been confirmed in animals (Kilic-2012), as well as clinically in observational (Parsaik-2014) and interventional studies (Salagre-2016). Although their anti-inflammatory and anti-oxidant properties have been proposed, the precise mechanisms underlying the antidepressant effects of statins remain unclear, therefore further translational studies have been advocated in order to elucidate this aspect (Köhler-Forsberg-2017).

In this exploratory study, we will investigate the effect of seven-day administration of simvastatin 20mg once daily compared to placebo on emotional and reward processing tasks in 50 healthy volunteers. In view of the previous evidence that statins may exert antidepressant effects via anti-inflammatory and anti-oxidant pathways, we predict that simvastatin will have positive effect on emotional and reward processing.