Does lipid-lowering treatment increase the risk of depression?

Fråga: Does lipid-lowering treatment increase the risk of depression?

Sammanfattning: There is conflicting evidence regarding whether statin treatment increases the risk of depression. One randomised controlled study demonstrates increased depressive symptoms in statin-treated patients, while others fail to show such an effect. There are also epidemiological studies showing a reduced risk of depression in association with statin treatment. Taken together, there seem to be little evidence to support the idea that statin treatment increases the risk of depression.

Svar: Similar questions have previously been answered by the drug information centres (1,2,3). It has been concluded that epidemiological studies indicate a connection between low serum cholesterol and depression or violent death. However, large randomised studies have not demonstrated an increased risk of depression in statin-treated patients. Notably, a connection between low cholesterol levels and depression does not necessarily imply that cholesterol-lowering treatment would increase the risk of depression. If e.g. low cholesterol levels in depressed patients were a result of the depression itself, one would not expect an increased depression risk in patients treated with lipid-lowering drugs.

An updated Medline search revealed several new publications on the subject (4,5,6,7). In one 24-week placebo-controlled, crossover study (n=120), simvastatin 20 mg/d significantly increased somatization, depression and aggressiveness scores in the Brief Symptom Inventory. Although lipid levels were measured, their influence on the psychological outcome measures was not mentioned in the report. Furthermore, the large number of statistical tests performed (nine inventory items in two treatment groups, simvastatin and Mediterranean diet) would seem to increase the risk of spurious mass significance (4).

The results of the cross-over study were contradicted by two observational studies, associating statin use with a significantly reduced risk of depression (5,6). In the first of these, 371 patients with coronary artery disease were followed for up to seven years with annual psychometric assessments (Kellner Symptom Questionnaire). After adjustment for a range of possible confounders, continuous statin users had lower scores on all three questionnaire items (depression, anxiety, and hostility), compared with non-users. Baseline cholesterol did not influence the psychological outcome measures (5).

The second observational study had a case-control design where 458 depressed and 105 suicidal patients were compared to hyperlipidemic controls with regard to lipid-lowering therapy. After adjustment for a number of confounders, the risk of depression was significantly lower in current statin users compared to hyperlipidemic non-users (OR 0.4, 95% CI 0.2-0.9). Statins had no significant effects on suicidal behaviour (OR 0.5, 95% CI 0.1-1.5). The use of hyperlipidemic controls eliminates the problem of statin non-users generally being normolipidemic and thereby at a higher risk of depression, provided that high cholesterol levels reduce the risk of depression. On the other hand, the choice not to give this subset of hyperlipdemics pharmacological treatment might in turn depend on unknown confounding factors related to depression risk (6).

Finally, a sub-study of twelve patients in a larger statin clinical trial demonstrated a small but significant increase in impulsivity (Barrett Impulsivity Scale) after four weeks of lovastatin or atorvastatin treatment, as compared to baseline values. However, the small number of patients, the multiple testings performed, and the lack of placebo group make these findings very uncertain (7).

No conclusive information was found regarding the use of lipid-lowering drugs other than statins and the risk of depression. Drugline no 13872 (year 1996) Drugline no 15637 (year 1998) Drugline no 19565 (year 2002) Hyyppa MT, Kronholm E, Virtanen A, Leino A, Jula A. Does simvastatin affect mood and steroid hormone levels in hypercholesterolemic men? A randomized double-blind trial. Psychoneuroendocrinology 2003;28:181-94. Young-Xu Y, Chan KA, Liao JK, Ravid S, Blatt CM. Long-term statin use and psychological well-being. J Am Coll Cardiol 2003;42(4):690-7. Yang CC, Jick SS, Jick H. Lipid-lowering drugs and the risk of depression and suicidal behavior. Arch Intern Med 2003;163:1926-32. Ormiston T, Wolkowitz OM, Reus VI, Manfredi F. Behavioral implications of lowering cholesterol levels: a double-blind pilot study. Psychosomatics 2003;44:412-4.