Older people are the largest consumers of prescription medications, yet they are consistently under-represented in drug regulatory trials. This is true even for diseases that almost exclusively occur in the elderly, such as arthritis, dementia and Parkinson‘s disease. For example, in an analysis involving 9664 subjects who were enrolled in trials studying arthritis, it was found that although more than half of the studies included patients over the age of 65 years, there were only 207 patients (2.1%) in this age group, and only 14 of the 9664 patients studied were aged between 75 and 84 years, with none older than 85 years Citation[1]. Similarly, it was demonstrated that the exclusion criteria for two regulatory trials for cholinesterase inhibitors would have eliminated more than 90% of a community sample of 3470 subjects with possible or probable Alzheimer‘s disease; overall, only 4.4 or 7.9% would have been provisionally eligible for each of these two trials Citation[2]. Patients provisionally eligible were younger, relatively under-represented by women, better educated, wealthier and were more likely to be White than ineligible patients Citation[2].
One of the major problems encountered by those treating older patients is a critical lack of clinically useful drug data. Over the past decade, clinicians and pharmacoepidemiologists have found significant age-associated side effects as well as the need for dose reductions after drug approvals. For widely used antidepressants, such as the selective serotonin reuptake inhibitors, adverse effects that are unique to older patients include hyponatremia, extrapyramidal symptoms, gastrointestinal bleeding and fragility fractures Citation[3].
In particular, patients suffering from dementia-related psychoses and aggression are in dire need of safe and effective treatments. The heavily used first- and second-generation antipsychotics have been unequivocally demonstrated to increase mortality Citation[4] and this issue has rightly captured public attention with major news stories, including one published last year in The New York TimesCitation[101]. While antipsychotics currently still have a role in treating severe psychiatric symptoms accompanying dementia, clinicians must assess their potential risks and benefits and advise family members. We must advocate for continued research to develop improved pharmacological as well as nonpharmacological interventions for dementia-related agitation and aggression.
To address the public health need for safe and effective treatments for dementia-related agitation and aggression, a consensus development conference, including participants from academic centers, the pharmaceutical industry, the FDA, the Centers for Medicare and Medicaid Services (CMS), the NIH, leaders in the nursing home industry and advocates for patients with dementia was held and the group‘s ‘Consensus Statement on Treatment Options, Clinical Trials Methodology, and Policy’ was published last year Citation[5].
After reviewing the data from previous industry-sponsored registration trials of drug treatments for persons with dementia, the conference group concluded that, “a number of methodological flaws limit the conclusions that can be drawn from these studies and indicate a need for better-designed future research.” Study participation requirements eliminated the most severe cases and allowed for much variation in type and severity of symptoms. Investigators should use a repeated-measures design to rate a patient‘s symptoms over time, examine the balance between harm and benefit as the primary outcome, and after each randomized clinical trial they should examine possible moderators of treatment response and baseline variables that differentiate between responders and nonresponders. The consensus paper also included 18 recommendations to improve clinical trial methodology. These include examining the rating instruments used in previous studies, implementing pilot studies to test new methods of assessment and attempting nonpharmacologic interventions before study enrollment.
Commenting on nonpharmacologic treatment of dementia-related agitation and aggression, the group said that given the promising results demonstrated by some studies, additional scientifically sound, adequately powered studies are needed in order to allow clinicians to recommend evidenced-basd treatment. Regarding postmarketing drug safety surveillance, the conference group stated that, “it is critical that a better system of monitoring be established to supplement the limited data collected prior to drug approval.” The group encouraged collaboration between the FDA and CMS in order to allow observational studies to be conducted from existing databases and to incorporate an active drug surveillance system. Collaboration with drug registries in Western Europe and the development of nursing home staff rater standardization was also recommended. The group‘s paper also outlined ideas for improving current practice. For example, a stepped-care algorithm suggests assessing the patient; talking with family members and other caregivers; evaluating for drug interactions, medical conditions, and environmental factors; and considering cognitive enhancers and antidepressants, as well as nonpharmacologic protocols, in addition to antipsychotics and close monitoring. With no approved drug therapy for severe agitation and aggression in patients with dementia, there is a clear need for more research into pharmacologic and nonpharmacologic treatments. Our patients and their families can no longer wait for the pharmaceutical industry alone to provide solutions.
Financial & competing interests disclosure
Bruce G Pollock receives research support from the National Institute of Health. Within the past 2 years he has been a member of the advisory boards of Forest Laboratories (last meeting was March 2008) and Lundbeck Canada and has served one time as a consultant for Wyeth Pharmaceuticals (October 2008). Bruce G Pollock is currently a faculty member of the Lundbeck International Neuroscience Foundation (LINF).
The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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Bibliography
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- Tarkan L: Doctors say medication is overused in dementia. New York Times. June 24 2008. www.nytimes.com/2008/06/24/health/24deme.html