01/08/2009

Cerca de 15% dos efeitos adversos das estatinas se referem a distúrbios psiquiátricos.

Statin-associated psychiatric adverse events: a case/non-case evaluation of an Italian database of spontaneous adverse drug reaction reporting Tuccori M, Lapi F, Testi A, Coli D, Moretti U, Vannacci A, Motola D, Salvo F, Rivolta AL, Blandizzi C, Mugelli A, Del Tacca M. Drug Saf. 2008;31(12):1115-23.
Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Pisa, Italy. m.tuccori@ao-pisa.toscana.it
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.

Psychiatric adverse reactions with statins, fibrates and ezetimibe: implications for the use of lipid-lowering agents Tatley M, Savage R. Drug Saf. 2007;30(3):195-201
New Zealand Pharmacovigilance Centre, Department of Preventative and Social Medicine, University of Otago, Dunedin, New Zealand. michael.tatley@stonebow.otago.ac.nz
The HMG-CoA reductase inhibitors ('statins') have come into widespread use internationally. There has been a long history of their use in New Zealand and this use has increased in recent years. There has also been an increase in the number of reports to the New Zealand Centre for Adverse Reactions Monitoring (CARM) of suspected psychiatric adverse reactions associated with statins. The reactions mentioned in these reports include depression, memory loss, confusion and aggressive reactions. Convincing reports to CARM of recurrence of these reactions upon rechallenge add weight to recent studies reporting serious psychiatric disturbances in association with statin treatment. Aggressive reactions associated with statins are poorly documented in the literature. These observations emphasise the need to be vigilant in looking for these reactions as they can have a significant personal impact on a patient. The observation that other lipid-lowering agents have similar adverse effects supports the hypothesis that decreased brain cell membrane cholesterol may be important in the aetiology of these psychiatric reactions.

Statins--the pattern of adverse effects with empahsis on mental reactions. Data from a national and an international database Buajordet I, Madsen S, Olsen H. Tidsskr Nor Laegeforen. 1997 Sep 20;117(22):3210-3. [Article in Norwegian]

Medisinsk avdeling, Statens legemiddelkontroll, Oslo.
We report on adverse drug reactions to statins recorded internationally and in Norway. The use of HMG-CoA reductase inhibitors (statins) has increased with a factor of 30 in Norway over the period 1989-96. Recently published clinical trials conclude that statins are safe; adverse drug reactions being infrequent and non-serious. The reactions observed are mostly increased hepatic enzymes and myopathy. Data from the Norwegian spontaneous reporting system, and from WHO's international database covering the period of 1988-95, includes reports of adverse drug reactions relating to other organ systems, such as the nervous system, the gastrointestinal tract, skin and cardiovascular organs. Psychiatric disorders represent 15% of the reactions to statins in the Norwegian database. Reactions include aggression, nervousness, depression, anxiety, sleeping disorders and impotence. The pharmacological mechanisms are not elucidated, but may be an effect of falling serum cholesterol.

Behavioral changes with paranoia in an elderly woman taking atorvastatin Peters JT, Garwood CL, Lepczyk M. Am J Geriatr Pharmacother. 2008 Mar;6(1):28-32
Department of Pharmacy Practice, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan 48201, USA.
BACKGROUND: There have been a number of published reports of central nervous system (CNS) adverse effects with statins. CASE SUMMARY: A 79-year-old woman developed paranoia, anxiety, and behavioral changes approximately 2.5 weeks after starting atorvastatin 10 mg/d. The patient had no other medication changes at this time. After 2 months of therapy, the patient discontinued atorvastatin, and her symptoms fully resolved after 4 days. CONCLUSIONS: This is the first case report, to our knowledge, describing paranoia as one of the symptoms associated with statin therapy. Our report suggests an adverse reaction due to the initiation of atorvastatin via the temporal relationship between the start of atorvastatin and symptom onset, as well as termination of therapy and subsequent symptom disappearance. Use of the Naranjo adverse drug reaction probability scale to assess causality revealed a "probable" association (score, 5) for this adverse event. This report emphasizes the possibility of paranoia as a CNS adverse effect due to statin therapy. Statins are frequently used in older populations and should therefore be considered when such CNS adverse effects occur during therapy.