7-day Atorvastatin and Emotional Processing
Condition: Healthy
Study type: Interventional

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 atorvastatin
      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 atorvastatin will have positive effects on emotional and
      reward processing.
    

Detailed description: 
      Depression is common and associated with considerable health disability. Traditional
      antidepressants mainly work by modulating monoamine levels in the synaptic cleft; however,
      the evidence that depression is caused by impaired serotonin or noradrenaline activity is
      weak and inconsistent, and indeed current antidepressant strategies remain burdened by
      partial efficacy, poor side-effects profile, and a slow onset of therapeutic action.
      Therefore, there is a pressing need to develop antidepressant medications with novel
      non-monoaminergic mechanisms of action - 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.

      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.
      Overall, robust evidence suggests that early changes in emotional processing can serve as
      valid surrogate markers of antidepressant efficacy; 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. 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.
      Furthermore, depression associated with inflammation is characterised by significant symptoms
      of anhedonia, which has been linked to diminished neural responses to reward anticipation.
      Such reward-deficit is particularly refractory to conventional serotoninergic and
      noradrenergic antidepressants, and even the antidepressant bupropion (a noradrenaline and
      dopamine reuptake inhibitor), whilst inducing positive changes in emotional processing,
      appears to worsen reward processing. 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.

      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. It is now established that these medications have significant anti-inflammatory
      effects that are independent from their lipid-lowering properties, as well as appearing early
      in treatment only after seven day of administration. 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, especially at doses lower than 80mg/day and when used for less than 52 weeks.
      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, as well as clinically in
      observational and interventional studies. Although their anti-inflammatory and anti-oxidant
      properties have been involved, the mechanisms underlying the antidepressant effects of
      statins remain unclear, therefore further translational studies have been advocated in order
      to elucidate this aspect.

      In this exploratory study, we will investigate the effect of seven-day administration of
      atorvastatin 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 atorvastatin will
      have positive effect on emotional and reward processing.
    

Intervention name(s): Atorvastatin 20mg; Lactose placebo
Intervention type(s): Drug; Other
Intervention description(s): oral dose, once daily for 7 days; oral dose, once daily for 7 days
Other intervention name(s): Lipitor; Atorva; placebo
Intervention MeSH terms: Atorvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be randomised, in a double-blind fashion, to either placebo or atorvastatin. The randomisation code will be drawn up by a researcher not involved in the study using an online randomisation tool (https://www.sealedenvelope.com/simple-randomiser/v1/lists).
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: Atorvastatin; Emotional processing; Reward processing; Inflammation (C-Reactive Protein)