Statins decrease aggression in men but increase it in women

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Nelson Vergel

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PLoS One. 2015 Jul 1;10(7):e0124451. doi: 10.1371/journal.pone.0124451. eCollection 2015.

Statin Effects on Aggression: Results from the UCSD Statin Study, a Randomized Control Trial.

Golomb BA1, Dimsdale JE2, Koslik HJ1, Evans MA1, Lu X3, Rossi S4, Mills PJ2, White HL3, Criqui MH5.



Abstract

BACKGROUND:
Low/ered cholesterol is linked to aggression in some study designs. Cases/series have reported reproducible aggression increases on statins, but statins also bear mechanisms that could reduce aggression. Usual statin effects on aggression have not been characterized.

METHODS:
1016 adults (692 men, 324 postmenopausal women) underwent double-blind sex-stratified randomization to placebo, simvastatin 20mg, or pravastatin 40mg (6 months). The Overt-Aggression-Scale-Modified-Aggression-Subscale (OASMa) assessed behavioral aggression. A significant sex-statin interaction was deemed to dictate sex-stratified analysis. Exploratory analyses assessed the influence of baseline-aggression, testosterone-change (men), sleep and age.

RESULTS:
The sex-statin interaction was significant (P=0.008). In men, statins tended to decrease aggression, significantly so on pravastatin: difference=-1.0(SE=0.49)P=0.038. Three marked outliers (OASMa-change &#8805;40 points) offset otherwise strong significance-vs-placebo: statins:-1.3(SE=0.38)P=0.0007; simvastatin:-1.4(SE=0.43)P=0.0011; pravastatin:-1.2(SE=0.45)P=0.0083. Age&#8804;40 predicted greater aggression-decline on statins: difference=-1.4(SE=0.64)P=0.026. Aggression-protection was emphasized in those with low baseline aggression: age<40-and-low-baseline-aggression (N=40) statin-difference-vs-placebo=-2.4(SE=0.71)P=0.0016. Statins (especially simvastatin) lowered testosterone, and increased sleep problems. Testosterone-drop on statins predicted aggression-decline: &#946;=0.64(SE=0.30)P=0.034, particularly on simvastatin: &#946;=1.29(SE=0.49)P=0.009. Sleep-worsening on statins significantly predicted aggression-increase: &#946;=2.2(SE=0.55)P<0.001, particularly on simvastatin (potentially explaining two of the outliers): &#946;=3.3(SE=0.83)P<0.001. Among (postmenopausal) women, a borderline aggression-increase on statins became significant with exclusion of one younger, surgically-menopausal woman (N=310) &#946;=0.70(SE=0.34)P=0.039. The increase was significant, without exclusions, for women of more typical postmenopausal age (&#8805;45): (N=304) &#946;=0.68(SE=0.34)P=0.048 - retaining significance with modified age-cutoffs (&#8805;50 or &#8805;55). Significance was observed separately for simvastatin. The aggression-increase in women on statins was stronger in those with low baseline aggression (N=175) &#946;=0.84(SE=0.30)P=0.006. No statin effect on whole blood serotonin was observed; and serotonin-change did not predict aggression-change.

CONCLUSION:
Statin effects on aggression differed by sex and age: Statins generally decreased aggression in men; and generally increased aggression in women. Both findings were selectively prominent in participants with low baseline aggression - bearing lower change-variance, rendering an effect more readily evident.

TRIAL REGISTRATION:
Clinicaltrials.gov NCT00330980.
 
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