Statin-associated psychiatric adverse events: a case/non case evaluation of an Italian database of spontaneous adverse drug reaction reporting

BACKGROUND: The inhibitors of HMG-CoA reductase ('statins') are widely prescribed hypolipidaemic drugs, which have been evaluated in several clinical trials involving hundreds of thousands of patients. From a safety perspective, both clinical trials and post-marketing surveillance have demonstrated that statins are generally well tolerated, with rare serious adverse drug reactions (ADRs) that affect mainly muscle, liver and kidney. However, recent interest has been focused on a potential risk of psychiatric ADRs associated with statins, including memory loss, depression, suicidality, aggression and antisocial behaviour. Special attention is currently being paid to the potential for statin-induced sleep disorders. OBJECTIVE: To investigate the hypothesis that statins may be associated with psychiatric adverse events using quantitative and qualitative signal analysis. METHODS: The Interregional Group of Pharmacovigilance database holds reports of suspected ADRs submitted since 1988 from eight Italian regions. In the present analysis, only reports ranked at least 'possible', according to WHO causality assessment criteria, were considered. Association between statins and psychiatric events was assessed by the case/non-case methodology, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. Cases were defined as patients with at least one reported ADR combined with the system organ class (SOC) 'psychiatric disorders'. The non-cases comprised all patients who did not experience an ADR related to the SOC 'psychiatric disorders'. Index reports comprised all ADR reports involving at least one statin, while all ADR reports not involving statins as suspected drugs were used as controls. RESULTS: According to selection criteria, 35,314 reports were included in the analysis. A total of 71 psychiatric preferred terms combined with statins were identified in 60 reports. Among them, 14 reports (23.3%) noted a positive rechallenge. Both the unadjusted (0.8; 95% CI 0.6, 1.1) and adjusted ROR (0.7; 95% CI 0.6, 1.0) suggested a lower rate of reports of psychiatric events for statins as a whole class compared with all other drugs, although the difference was not significant. The five most frequently reported psychiatric events combined with statins were insomnia, somnolence, agitation, confusion and hallucination. Only insomnia was reported with higher frequency for statins compared with all other drugs (ROR = 3.3; 95% CI 1.9, 5.7), while confusion was reported with a lower frequency (ROR = 0.4; 95% CI 0.1, 0.9). Amongst statins available in Italy, only simvastatin (ROR = 0.5; 95% CI 0.2, 0.9) showed a significantly lower rate of reports of psychiatric events compared with all other drugs together. CONCLUSION: A relatively small number of possible statin-associated psychiatric ADRs have been found in our database. No significant risks for a higher overall reporting of psychiatric ADRs associated with statins were identified in comparison with all other drugs combined. However, statin-associated insomnia resulted in a significant ROR that requires further investigation.