Hydroxymethyl glutaryl-coenzyme A reductase (HMG-CoA) inhibitors (also called statins) are the most commonly prescribed first-line medications for lowering serum cholesterol.1

Statins also have other pleiotropic effects, including anti-inflammatory properties (eg, a reduction of C-reactive protein [CRP], tumor necrosis factor [TNF]-alpha, and interleukin [IL]-6 levels).2 They have been found effective in reducing cardiovascular risk, including stroke, and in patients suffering from diabetes.3,4

It has even been suggested that since statins reduce deleterious oxidative and inflammatory effects, they might also have utility in treating depression,5 which is thought to be associated with elevated levels of proinflammatory cytokines in the brain.6,7

RELATED: Psychiatric Disorders Resource Center

A recent article by You et al2 calls into question the potentially beneficial effects of statins in the treatment of depression, and even more significantly, the article suggests that statins prescribed for cholesterol reduction may actually cause depression. Since cholesterol plays an important role in neuroprotection, low cholesterol may adversely impact neurotransmission, thereby increasing the risk of depression.

Earlier research has demonstrated that patients may be vulnerable to depression, violence, or suicidality during the first month of statin use, with a reduction in risk following that initial period.8 You et al challenge this contention, stating that depression risk may increase with long-term statin use.

Mechanisms by Which Low Cholesterol Might Cause Depression

Low cholesterol may lead to depression by disrupting the serotonin system (which consists of serotonin, serotonin transporters [SERTs], and serotonin receptors).2 A well-functioning serotonin system is key to maintain euthymia.

Disruptions in the serotonin system have been implicated in the etiology of numerous psychiatric conditions, including depression. Increasing evidence suggestions that membrane cholesterol is a requirement in the function of serotonin receptors9,10 and that reduction in cholesterol levels in the plasma membrane reduces serotonin binding and signaling.11

It is also possible that low cholesterol contributes to depression by disrupting neurosteroid production. Neurosteroids are potent neuromodulators synthesized from cholesterol or cholesterol precursors. Their aberrant synthesis may contribute to defects in neurotransmission, causing affective disorders. However, as of now, no clear evidence exists to show that cholesterol-lowering drugs can cause depression by affecting neurosteroid synthesis.2

Do All Statins Cause Depression?

The blood–brain barrier (BBB) maintains homeostasis within the brain microenvironment.2 Statins differ in their ability to cross the BBB, as seen in the table below. Simvastatin and lovastatin, both lipophilic, have been found to be associated with depression, raising the possibility that lipophilic statins may pass through the BBB, affecting brain cholesterol synthesis and synaptic homeostasis.12

However, the association between lipophilic statins and depression is not clear. Hydrophilic statins can also be linked with depression.13 The authors recommend further research into this issue.

Name of Drug Lipophilicity Impact on BBB



Highly hydrophilic

Barely crosses the BBB




Relatively lipophilic

Easily passes through BBB


Highly lipophilic

Cannot pass through BBB

Are All Statin Users Vulnerable to Depression?

The authors note that no “clear boundary” has been set to guide clinicians in determining a cutoff point, when low cholesterol levels warrant discontinuation or lowering of statin treatment. They recommend that patients with extremely low cholesterol or depressive symptoms should avoid statins or use them with caution.