Impact of safety warnings on antipsychotic prescriptions in dementia: Nothing has changed but the years and the substances

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Abstract

Dementia patients suffering from behavioral and psychological symptoms (BPSD) are often treated with antipsychotics. Trial results document an increased risk for serious adverse events and mortality in dementia patients taking these agents. Furthermore, the efficacy of treating BPSD with antipsychotics seems to be only modest. Using data of a German statutory health insurance company, we examined prescription trends of antipsychotics in prevalent dementia patients in the context of official warnings. The study period is 2004–2009. We studied trends in demographics, age and sex, as well as need of care and the intake of typical and atypical antipsychotics. Seeking for linear trends adjusted for age, sex and level of care between 2004 and 2009, we obtained p-values from a multivariate logistic regression. Prescription volumes were calculated by number of packages as well as defined daily doses (DDDs) using multiple linear regressions for trends in prescriptions amount. We included 3460–8042 patients per year (mean age 80 years). The prescription prevalence of antipsychotics decreased from 35.5% in 2004 to 32.5% in 2009 (multivariate analysis for linear trend: p=0.1645). Overall prescriptions for typical antipsychotics decreased (from 27.2% in 2004 to 23.0% in 2009, p<0.0001) and prescriptions for atypical antipsychotics increased from 17.1% to 18.9% (p<0.0001). The mean DDD per treated patient increased from 80.5 to 91.2 (2004–2009; p=0.0047). Our findings imply that warnings of international drug authorities and manufacturers against adverse drug events in dementia patients receiving antipsychotics did not impact overall prescription behavior.

Introduction

Recently, the World Health Organization (WHO) and the Alzheimer's Disease International (ADI) published the report “Dementia: a public health priority” in order to promote dementia as a public health and social care priority worldwide. Dementia has become the most important age-related disorder in our ageing society. The total number of patients with dementia in 2010 is estimated at 35.6 million and is projected to nearly double every 20 years to 65.7 million worldwide in 2030 (WHO, 2012).

Cognitive impairment is the clinical hallmark of dementia, but non-cognitive neuropsychiatric symptoms such as aggression, agitation and psychosis are common and can dominate disease presentation (Wolter, 2009, Sink et al., 2005). In a consensus statement the International Psychogeriatric Association labeled these symptoms as “behavioral and psychological symptoms of dementia” (BPSD) (Finkel et al., 1996). Up to 90% of dementia patients may experience these symptoms during the course of the disease (Steinberg et al., 2003, Fernandez et al., 2010). The symptoms contribute to caregiver burden, healthcare costs, and they often predict institutional care (Cerejeira et al., 2012, Lyketsos et al., 2000, Steele et al., 1990). Hence, BPSD constitute a major element of the dementia syndrome.

Antipsychotics are the first line pharmacological treatment used in order to meet BPSD (Ballard et al., 2008). Introduced in the 1950s for the treatment of schizophrenia, we distinguish between typical and atypical agents, depending on their pharmacological profile (Ballard and Howard, 2006).

In 2005 and 2008 authorities such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) gave out warnings about prescribing atypical and typical antipsychotics for BPSD in dementia patients because of an increased risk of cerebrovascular events and a higher mortality (FDA, 2005; FDA, 2008;EMA—European Medicines Agency, 2008, Schneider et al., 2005, a-t—arznei-telegramm, 2002). Prior to this, several drug safety mails had been published in Germany (for example Lilly Pharma, 2004, Janssen-Cilag GmbH, 2004). Since then, the atypical agent risperidone has been the only antipsychotic that is officially licensed to treat severe chronic aggression in dementia patients in Germany (DEGAM, 2008).

A recently published cohort study by Huybrechts et al. (2012) has reopened the debate on the use of antipsychotics in dementia, suggesting that the risk of mortality seems to differ between the antipsychotic agents, with the highest risk for Haloperidol.

In addition to the possible adverse drug reactions, the effectiveness of treating BPSD with antipsychotic drugs is only modest (Sink et al., 2005, Schneider et al., 2006a, Schneider et al., 2006b, Ballard et al., 2006). Furthermore, there are only few trials that examine the effects of long-term use of antipsychotics in dementia patients (Ballard et al., 2009). Hence, national and international guidelines emphasize a cautious use of antipsychotics. Even if dementia patients show severe forms of BPSD, antipsychotics should be prescribed only after exploring non-pharmacological treatment options (NICE—National Institute for Health and Clinical Excellence-Social Care Institute for Excellence, 2011, DEGAM—Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin, 2008, DGPPN and DGN—Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde; Deutsche Gesellschaft für Neurologie, 2009, Azermai et al., 2012; AVP, 2004).

Nevertheless, between 18% and 31% of dementia patients receive antipsychotics (Rhee et al., 2011, Laitinen et al., 2011, Guthrie et al., 2010, Kolanowski et al., 2006, Sieberer, 2009). We now raise the question whether prescription behavior changed because of the discussions and warnings of a riskful use of antipsychotics in dementia patients. So far, only little research has dealt with this topic. Valiyeva et al. (2008) examined antipsychotic prescription claims data from the Canadian Ontario Drug Benefit database from 2000 to 2007 for dementia patients. During this period, the overall rate of use of antipsychotics increased. After the publication of FDA advisory in 2005 US studies showed a decrease in the use of atypical antipsychotics (Dorsey et al., 2010). Kales et al. (2011) sought to examine antipsychotic prescription trends applying Veterans Affairs data from 1999 to 2007. They showed an overall decline in usage of antipsychotics from 18% to 12%. However, the predominantly male study population and the limited generalizability of the data have to be taken into consideration. The only European study from Italy summarized a continuous widespread use of antipsychotics in dementia patients with only a slight decrease between 2002 and 2008 (Franchi et al., 2012). However, the authors used only the prescription of cholinesterase inhibitors (ChEI) to identify dementia patients.

We aimed to study the trend in prevalence and amount of antipsychotic prescription in prevalent dementia patients over time from 2004 to 2009 in the context of national and international warnings of drug regulatory authorities and manufacturers against adverse drug reactions.

Section snippets

Database and study cohort

Data for the study were obtained from the Gmünder ErsatzKasse (GEK)—a nationwide operating health insurance company. The period of examination covered the years from 2004 to 2009. During these years the GEK had about 1.7 million members, corresponding to about 2% of the German population. For each year, we included persons aged 65 years and older who were insured at least one day in every quarter of the year. This criterion is used to ensure an (nearly) uninterrupted membership and also to

Characteristics of the study cohort

Baseline characteristics of the prevalent dementia patients in every year from 2004 to 2009 are shown in Table 2. Mean age is approximately 80 in all years. We observed changes over time in the sex-composition and for the care levels in our study population. For example the proportion of patients having no level of care ranged between 38% and 43%.

Prescription prevalences of antipsychotic drugs

The prescription prevalence of antipsychotic drugs in dementia patients showed a slight decline from 35.5% in 2004 to 32.5% in 2009. However, this

Discussion

This study analyzed trends in antipsychotic prescriptions for patients with dementia from 2004 to 2009 and found a slight decrease in the prescription of typical antipsychotics along with an increase for atypical agents. However, overall prescription prevalence for antipsychotics did not change over time (p=0.1645). Furthermore, we found a slight increase in total prescription volumes of antipsychotics over the study period. This indicates that warnings from health authorities and manufacturers

Conclusion

The present study shows that there is a shift in prescriptions from typical to atypical agents, while the overall prescription behavior of antipsychotics in dementia patients has not been changed significantly from 2004 to 2009. Prescription prevalences stay at a level of around 33% and the number of DDDs slightly increased over years. Since 2002 studies showed that antipsychotic usage in dementia patients is associated with a higher risk of adverse drug events (Health Canada, 2002). Moreover,

Role of funding source

This study was supported by grants from the Jackstädt-Stiftung. The Jackstädt-Stiftung had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the manuscript, and in the decision to submit the paper for publication.

Contributors

JS and FH performed the data analysis and JS wrote the manuscript. BW compiled the statistical model strategy. All authors interpreted the data, critically revised the manuscript, read and approved the final manuscript.

Conflict of interest

The authors declare that they have no competing interests.

Acknowledgments

We thank the Gmünder ErsatzKasse (GEK, now BARMER GEK) for providing the data analyzed in our study.

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