7-day Atorvastatin and Emotional Processing

November 30, 2020 updated by: University of Oxford

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

50

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 46 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Participants will receive lactose placebo tablets, encapsulated in opaque capsules, and will be asked to take one capsule daily for seven days at night-time, by mouth
Other: Lactose placebo
oral dose, once daily for 7 days
Other Names:
  • placebo
Experimental: Atorvastatin
Participants will receive 20mg atorvastatin tablets, encapsulated in opaque capsules, and will be asked to take one capsule daily for seven days at night-time, by mouth
Drug: Atorvastatin 20mg
oral dose, once daily for 7 days
Other Names:
  • Lipitor
  • Atorva

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Accuracy and reaction times during facial expression recognition task
Time Frame: 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
Faces representing varying degrees [from "neutral" (0%) to "full prototypical emotion" (100%) of basic emotions (happiness, fear, anger, disgust, sadness, surprise)] are displayed on the screen and participants are asked to quickly and correctly classify them. Accuracy and reaction times on positive vs negative stimuli are compared between those receiving drug and placebo.
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
Accuracy and reaction times during faces dot-probe task
Time Frame: 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
Faces acting as positive or negative emotional stimuli (happy or fearful facial expressions) are presented together with a matched neutral face. One is presented above and one below a central fixation point. Subsequently, a probe appears behind one of the two faces and participants are asked to quickly indicate the position of the probe. Accuracy and reaction times on positive vs negative stimuli are compared between those receiving drug and placebo.
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
Accuracy and reaction times during emotional categorisation task
Time Frame: 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
Words describing positive and negative personality characteristics are presented, and participants are asked to quickly indicate whether they would like or dislike being described with the presented word. Accuracy and reaction times on positive vs negative stimuli are compared between those receiving drug and placebo.
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
Accuracy during emotional recall task
Time Frame: 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
After a delay from the Emotional categorisation task, participants are asked to recall and write down as many words as possible from it. Accuracy in recall of positive vs negative stimuli are compared between those receiving drug and placebo.
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
Accuracy and reaction times during emotional recognition memory task
Time Frame: 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
The original personality descriptors in the Emotional categorisation task, plus an equal number of matched distractor words, are presented, and participants are asked to indicate whether they recognise it from the Emotional categorisation task. Accuracy and reaction times on positive vs negative stimuli are compared between those receiving drug and placebo.
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Accuracy and reaction times during reward processing
Time Frame: 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
During a computer-based task, participants are instructed to learn and select which images are associated with wins rather than losses. Accuracy and reaction times are assessed and compared between those receiving drug and placebo.
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
Changes in C-Reactive Protein levels
Time Frame: 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)
Changes in high sensitivity-C Reactive Protein (hs-CRP) from baseline to seven-day, comparing those receiving drug and placebo
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)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oxford

Collaborators

Wellcome Trust

Investigators

  • Principal Investigator: Philip J Cowen, MBBS, MD, FRPsych, University of Oxford, Medical Sciences Division, Department of Psychiatry

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 19, 2019

Primary Completion (Actual)

February 1, 2020

Study Completion (Actual)

February 1, 2020

Study Registration Dates

First Submitted

May 20, 2019

First Submitted That Met QC Criteria

May 24, 2019

First Posted (Actual)

May 29, 2019

Study Record Updates

Last Update Posted (Actual)

December 1, 2020

Last Update Submitted That Met QC Criteria

November 30, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • R61966/RE001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

To comply with the General Data Protection Regulation (GDPR) and the new Data Protection Act, personal data will be deleted as soon as possible after it is no longer needed for the study.

Screening information: For volunteers who do not wish to be contacted for future studies, screening information (including contact details) will be stored for up to one year of completing study analyses, and then destroyed by shredding. Contact details may be retained after the end of the study for participants who have agreed to be contacted for future studies.

Consent forms: Consent forms will be kept for 10 years after the end of the study, and then destroyed by shredding.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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