simvastatin for depression

a recent systematic review/meta-analysis assessed the value of statins in depression, finding signficant benefit (see statin depression review jaffectdisord2019 in dropbox, or doi.org/10.1016/j.jad.2019.07.002 Received 15 April 2019).

Details:
--10 articles were included, all randomized controlled trials: 3 were in patients with clinical depression, 7 in non-depressed people
--total sample size 2517 (1348 on statins and 1169 placebo)
--patients were followed from 4 weeks to 4 years
--in the depressed group, statins were add-on therapies (vs placebo) to antidepressants (eg citalopram, fluoxetine)
--statins used: simvastatin in 4, lovastatin in 3, atorvastatin 2, and pravastatin 1 study

Results:
--overall: statins were significantly more effective than placebo in decreasing depressive symptoms, standardized mean difference (SMD) of -0.309 (-0.525 to -0.094), p=0.005 [small effect size]
--subgroup analysis:
    --depressed population: SMD -0.796 (-1.107 to -0.486), p=0.0001 [large effect size]
    --non-depressed population: SM -0.153 (-3.53 to 0.047), p=0.13 [a trend to small benefit, but not statistically significant]

Commmentary:
--depression is remarkably common, as we all know:
    --the WHO estimates that depression affects >300 million people globally
    --a recent study found that major depressive disorder (MDD) has a 12-month prevalence of 10.4% in the US, with lifetime prevalence of 20.6%
--and, about 1/3 of patients with MDD have some degree of refractoriness to the usual meds, psychological treatment or both
--depression and inflammation:
    --depression is observed more commonly in those with inflammatory diseases
    --elevated markers of depression (CRP, IL-6, TNF-a, IL-1 receptor antagonist) are more prevalent in patients with depression; increased levels of oxidative stress are also found in depressed patients
    --infusion of proinflammatory interferon-a and cytokines can induce symptoms of depression
    --anti-inflammatory drugs are effective in treating depressive symptoms, including decreases in both depression and mania, with an effect size similar to antidepressants (see depression anti-inflam helps jpsychopharm2017 in dropbox, or https://doi.org/10.1177/0269881117725711). this review included NSAIDs, N-acetyl cysteine, and minocycline
--statins do decrease inflammation and oxidative stress
    --a purported mechanism of the statin effect on depression is that those statins with high lipophilicity (esp simvastatin, lovastatin) may then cross the blood-brain barrier and decrease cerebral inflammation. a study comparing simvastatin to atorvastatin (which has some lipophilicity as well, much moreso than the hydrophilic rosuvastatin or pravastatin) found that simvastatin improved depression symptoms to a greater degree and more rapidly than atorvastatin
--prior large observational studies have found that the likelihood of depression was 32% lower in statin users; a Swedish cohort study found that those on statins were 5-8% less likely to develop depression; and statins used in conjunction wih SSRIs decreased the risk of hospitalization for depression by 36% over SSRIs alone [observational studies are at high risk of bias because of unaccounted-for confounders: were those on statins more health-conscious and plugged into the health system, and more likely to be diagnosed with depression? or some other factor that led some people to get statins, and it was that factor and not the statin that predicted not getting depressed?)
--it is not so surprising that there was greater statistical significance for statin benefit in those with depression vs the general population: since a small minority of patients in the general population are likely to become depressed (incident cases) during the course of the evaluated studies, there would need to be very large numbers of people in the studies and best followed for a long time to show significant differences in developing depression (though there was a trend to better outcomes even in the non-depressed population even in this small study). also, the non-depressed patients have fewer depressive symptoms (!!) to begin with, so are less able to show much improvement.
--the limitations of this study are as with many meta-analyses: combining different studies with patients of different ages and with different comorbidites (some depressed/some not, some with multpile sclerosis and mild traumatic brain injury, people from different regions of the world). they did try iterative removal of each individual study to see if it affected the results (it didn't), to make sure one study did not distort the aggregate results

so, this study does suggest a few things:
--there may be a clinically significant effect of statins in people who are depressed. and this is likely from their effect on inflammation and oxidative stress. This statin effect implies that the more lipophilic statins (eg simvastatin, lovastatin) are more likely to be beneficial than the hydrophilic ones (pravastatin, rosuvastatin), with atorvastatin in the middle. so, if one sees a depressed patient who might benefit from a statin, probably best to use the lipophilic ones (this study could not assess the different types of statins, given the limited array of statins used and numbers of patients in each group)
--there was a pretty consistent trend over the individual studies for a statin benefit in depressive symptoms in non-depressed patients. which undercuts prior concerns that statins might cause depression

prior related blogs:

http://gmodestmedblogs.blogspot.com/2019/05/statins-dec-dementia-after-concussion.html , finding that in older adults who had a concussion, those on a statin were less likely to develop dementia, moreso if on a hydrophilic statin (!!!), with rosuvastatin doing the best. this blog also reviews some more data on the differential effects of lipophilic vs hydrophilic statins

http://gmodestmedblogs.blogspot.com/2016/01/migraine-prophylaxis-with.html , a small study found that the combo of the lipophilic simvastatin and vitamin D led to decreased migraine recurrences

geoff

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