7-day Simvastatin and Emotional Processing
Condition: Depression; Inflammation
MeSH terms: Inflammation; Depression
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Work in our group has revealed that short-term (7-day) administration of antidepressants
      produces positive biases in the processing of emotional information in healthy volunteers.
      Such effect might be an important neuropsychological mechanism of antidepressant action.

      The current study will investigate the effect of seven-day administration of simvastatin 20mg
      on emotional and reward processing tasks in healthy volunteers. There is evidence that
      statins may exert antidepressant effects via anti-inflammatory and anti-oxidant pathways, and
      it is therefore predicted that simvastatin will have positive effects on emotional and reward
      processing.
    

Detailed description: 
      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.
    

Intervention name(s): Simvastatin 20mg; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Simvastatin 20mg once a day for 7 days; Placebo once a day for 7 days
Intervention MeSH terms: Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Parallel Assignment Participants will be randomly allocated to one of two groups (simvastatin or placebo) and take the assigned medication for 7 days
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Depression; Inflammation