Neuropsychiatric disorders from statins

The effects on the central nervous system

Over the years, evidence has emerged supporting the hypothesis that statins, which are effective as primary and secondary prevention of coronary heart disease due to their cholesterol-lowering action,¹ can be beneficial for several diseases affecting the central nervous system, especially Alzheimer's disease.² Although the results of clinical trials evaluating the potential applications of statins in neuropsychiatric disorders have been mixed, there is general agreement that statins may exert pharmacological effects on the central nervous system. These effects could also be harmful and lead to discontinuation of the treatment with statins, a situation that would expose the patient to the risk of cardiovascular events.

The neuropsychiatric damage

A review³ focused on the evidence regarding the neuropsychiatric damage caused by statins. The first evidence of adverse central effects (depressive symptoms, suicidal and obsessive thoughts) associated with the use of statins have emerged from case reports. Subsequently, data from national registers detailing spontaneous reporting of adverse reactions have noted the emergence of a plethora of psychiatric symptoms in relation to the use of statins; in New Zealand in particular,4 there have been 203 reports of psychiatric events associated with statins, which included 67 adverse events classified as mood disorders, 30 as cognitive disorders, 51 as sleep disorders, 14 as disorders of perception and 107 as other reactions (asthenia, fatigue, lethargy, malaise, drowsiness and fatigue).
For Italy, an analysis was made of 60 reports of psychiatric disorders associated with statins in the database of the Italian Medicines Agency (AIFA) (4.3% of total reported reactions to simvastatin, atorvastatin, fluvastatin, pravastatin, rosuvastatin and lovastatin).5 An analysis of the disproportion of these Italian data did not, however, reveal a particular risk of reporting psychiatric events for statins (adjusted ROR: 0.7, 95% confidence interval from 0.6 to 1.0) with the exception of a certain risk of reporting insomnia (adjusted ROR: 3.3, 95% confidence interval from 1.9 to 5.7).
Randomised clinical trials and observational studies have attempted to assess the effects of statins on behaviour and mood using outcomes including aggression, anger, anxiety, depression, hostility, impulsivity and altered moods.3 Most of these studies did not observe positive or negative psychiatric effects, while specific risks for particular statins were only detected in some of them (for example, risk of resorting to the use of antidepressants during treatment with simvastatin: 1.59, 95% confidence interval from 1.08 to 2.45).6 Alteration of cognitive functions was mainly observed in descriptive studies, but only rarely demonstrated in analytical studies. The same considerations also apply to sleep disorders and sexual dysfunction.³
The neuropsychiatric adverse reactions of statins appear to be rare, unpreventable events that are observed more often in sensitive patients who are likely to have subclinical alterations in neurotransmission. The data available do not allow us to determine whether factors such as age or previous history of psychiatric disorders may be considered risk factors for the development of these events.³

The pharmacological explanation

The pharmacological mechanisms hypothesised to explain these effects are multiple, and not mutually exclusive. These effects are class effects and dose-dependent. In some cases, they have been reported for other lipid-lowering drugs. It is likely (but has to be confirmed) that they occur more often with lipophilic statins. In most cases, neuropsychiatric side effects attributed to statins are resolved spontaneously after discontinuation of the treatment or the introduction of a specific diet rich in omega-3.³

What can be done?

When looking at these adverse reactions, it is nevertheless important to ensure the cholesterol lowering medication, especially in secondary prevention. It is therefore appropriate to consider the following possibilities:³

• Since in many cases these events are transient and resolved with the continuation of therapy, in cases where the neuropsychiatric manifestations are mild and the patient appears to be able to tolerate them, the treatment with statins can be maintained at least for a period;
• If the neuropsychiatric symptoms are moderate to severe, an attempt can be made to resolve them by replacing the statin with another statin that is preferably less lipophilic;
• Since there is evidence to support a dose-dependency, reduction of the dose should be considered prior to definitive discontinuation of the statin treatment;
• The use of omega-3 fatty acids can be evaluated both as prophylaxis or treatment;
• There is no evidence that the use of psychotropic drugs can resolve the events. Therefore, it is only appropriate to use medication for particularly serious and persistent symptoms.