Study Results
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Basic Information
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COMPLETED
NA
50 participants
INTERVENTIONAL
2019-06-19
2020-02-01
Brief Summary
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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
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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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
BASIC_SCIENCE
TRIPLE
Study Groups
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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
Lactose placebo
oral dose, once daily for 7 days
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
Atorvastatin 20mg
oral dose, once daily for 7 days
Interventions
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Atorvastatin 20mg
oral dose, once daily for 7 days
Lactose placebo
oral dose, once daily for 7 days
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
50 Years
ALL
Yes
Sponsors
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Wellcome Trust
OTHER
University of Oxford
OTHER
Responsible Party
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Principal Investigators
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Philip J Cowen, MBBS, MD, FRPsych
Role: PRINCIPAL_INVESTIGATOR
University of Oxford, Medical Sciences Division, Department of Psychiatry
Locations
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Riccardo De Giorgi
Oxford, , United Kingdom
Countries
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References
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Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016 Nov 19;388(10059):2532-2561. doi: 10.1016/S0140-6736(16)31357-5. Epub 2016 Sep 8.
Cooper CM, et al. Psychological Medicine 2017; Page 1 of 10. doi:10.1017/S00332917170023792017
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Felger JC, Treadway MT. Inflammation Effects on Motivation and Motor Activity: Role of Dopamine. Neuropsychopharmacology. 2017 Jan;42(1):216-241. doi: 10.1038/npp.2016.143. Epub 2016 Aug 2.
Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM. Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. Am J Psychiatry. 2004 Jul;161(7):1256-63. doi: 10.1176/appi.ajp.161.7.1256.
Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017 May;4(5):409-418. doi: 10.1016/S2215-0366(17)30015-9. Epub 2017 Jan 31.
Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. 2005 Dec;4(12):977-87. doi: 10.1038/nrd1901.
Jha MK, Trivedi MH. Personalized Antidepressant Selection and Pathway to Novel Treatments: Clinical Utility of Targeting Inflammation. Int J Mol Sci. 2018 Jan 12;19(1):233. doi: 10.3390/ijms19010233.
GBD 2015 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1603-1658. doi: 10.1016/S0140-6736(16)31460-X.
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Macin SM, Perna ER, Farias EF, Franciosi V, Cialzeta JR, Brizuela M, Medina F, Tajer C, Doval H, Badaracco R. Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study. Am Heart J. 2005 Mar;149(3):451-7. doi: 10.1016/j.ahj.2004.07.041.
McCabe C, Mishor Z, Cowen PJ, Harmer CJ. Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment. Biol Psychiatry. 2010 Mar 1;67(5):439-45. doi: 10.1016/j.biopsych.2009.11.001. Epub 2009 Dec 24.
Miller AH, Haroon E, Felger JC. Therapeutic Implications of Brain-Immune Interactions: Treatment in Translation. Neuropsychopharmacology. 2017 Jan;42(1):334-359. doi: 10.1038/npp.2016.167. Epub 2016 Aug 24.
NICE. NICE Clinical Guidelines 2014; 181:11. Available from: https://www.ncbi.nlm.nih.gov/books/NBK268908
Parsaik AK, Singh B, Murad MH, Singh K, Mascarenhas SS, Williams MD, Lapid MI, Richardson JW, West CP, Rummans TA. Statins use and risk of depression: a systematic review and meta-analysis. J Affect Disord. 2014 May;160:62-7. doi: 10.1016/j.jad.2013.11.026. Epub 2013 Dec 17.
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Walsh AEL, Huneke NTM, Brown R, Browning M, Cowen P, Harmer CJ. A Dissociation of the Acute Effects of Bupropion on Positive Emotional Processing and Reward Processing in Healthy Volunteers. Front Psychiatry. 2018 Oct 16;9:482. doi: 10.3389/fpsyt.2018.00482. eCollection 2018.
Salagre E, Fernandes BS, Dodd S, Brownstein DJ, Berk M. Statins for the treatment of depression: A meta-analysis of randomized, double-blind, placebo-controlled trials. J Affect Disord. 2016 Aug;200:235-42. doi: 10.1016/j.jad.2016.04.047. Epub 2016 Apr 27.
Provided Documents
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Document Type: Informed Consent Form
Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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R61966/RE001
Identifier Type: -
Identifier Source: org_study_id