Clinical trial NCT03966859: 7-day Atorvastatin and Emotional Processing
Official title: The Effect of Seven-Day Atorvastatin Administration on Emotional Processing, Reward Processing, and Inflammation in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Healthy
Keywords: Atorvastatin
Emotional processing
Reward processing
Inflammation (C-Reactive Protein)
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Wellcome Trust
First posted: 2019-05-29
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: BASIC_SCIENCE

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Male or female
* Aged 18-50 years
* Sufficiently fluent English to understand and complete the tasks
* Body Mass Index in the range of 18-30
* Participant is willing and able to give informed consent for participation in the study
* Not currently taking any regular medications (except the contraceptive pill)

Exclusion Criteria:

* Currently any regular medications (except the contraceptive pill)
* History or current significant psychiatric illness
* Current alcohol or substance misuse disorder
* History or current significant hepatic disease
* History or current significant neurological condition (e.g. epilepsy)
* Known hypersensitivity to the study drug (i.e. atorvastatin)
* Pregnant, breast feeding, women of child-bearing potential not using appropriate contraceptive measures
* Participation in a study that uses the same or similar computer tasks as those used in the present study
* Participation in a study that involves the use of a medication within the last three months

Primary outcomes:
measure: Accuracy and reaction times during facial expression recognition task
timeFrame: Assessed during the research visit after the seventh day of atorvastatin or placebo administration, i.e. on the eight day after the patient started taking atorvastatin or placebo
measure: Accuracy and reaction times during faces dot-probe task
timeFrame: Assessed during the research visit after the seventh day of atorvastatin or placebo administration, i.e. on the eight day after the patient started taking atorvastatin or placebo
measure: Accuracy and reaction times during emotional categorisation task
timeFrame: Assessed during the research visit after the seventh day of atorvastatin or placebo administration, i.e. on the eight day after the patient started taking atorvastatin or placebo
measure: Accuracy during emotional recall task
timeFrame: Assessed during the research visit after the seventh day of atorvastatin or placebo administration, i.e. on the eight day after the patient started taking atorvastatin or placebo
measure: Accuracy and reaction times during emotional recognition memory task
timeFrame: Assessed during the research visit after the seventh day of atorvastatin or placebo administration, i.e. on the eight day after the patient started taking atorvastatin or placebo
Secondary outcomes:
measure: Accuracy and reaction times during reward processing
timeFrame: Assessed during the research visit after the seventh day of atorvastatin or placebo administration, i.e. on the eight day after the patient started taking atorvastatin or placebo
measure: Changes in C-Reactive Protein levels
timeFrame: A blood sample will be drawn on the day of randomisation and on the day of the research visit (i.e. after the seventh day on atorvastatin or placebo)
Other outcomes:
Locations:
city: Oxford
country: United Kingdom
facility: Riccardo De Giorgi
Study officials:
affiliation: University of Oxford, Medical Sciences Division, Department of Psychiatry
name: Philip J Cowen, MBBS, MD, FRPsych
role: PRINCIPAL_INVESTIGATOR
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