The remaining dilemma is the insufficient evidence of effective and safe treatments in the face of increasing prevalence of dementia and coexisting neuropsychiatric symptoms in the United States and around the world. We offer treatments that are modestly effective to our patients and their families as evident from the recent large-scale studies of antipsychotics and valproic acid, as well as behavioral studies, and caregiver trials. The most frequently reported improvement on global scores of multiple behavioral scales commonly used in these trials (e.g., Neuropsychiatric Inventory (NPI) or BPSD) is neither specific nor informative. Although we can successfully manage our patients and help caregivers in our practices, we are unable to provide solid scientific support to back up our clinical successes. The reasons for such state of affairs are not entirely clear, but the four articles published in the current issue reflect this dilemma.
In the current issue, four articles address different aspects of behavioral disturbances of dementia. The article from Selbaek et al.
36 describes the prevalence of behavioral disturbances and the psychotropic drug use in the residents of nursing homes in Norway. The authors found that neuropsychiatric symptoms are common and persistent in a 12-month follow-up study. Agitation and apathy were the most persistent behavioral symptoms that lead to prolonged psychotropic drug use. These findings support the common knowledge that the behavioral disturbances are common and persistent accumulated throughout decades of research. The authors contrast their findings to the fact that the data on the psychotropic drug use for the control of behavioral disturbances in dementia shows only a modest response to psychotropic agents compared with that of a placebo.
The second article by Streim et al.
37 reports the results of the 10-week randomized, double-blind, placebo-controlled, flexible-dose trial of aripiprazole for the treatment of psychosis and agitation in 256 nursing home residents with A.D., and it echoes Selbaeks paper by reporting no drug-placebo difference on primary outcomes of the study that reflect the severity of psychosis and dementia. Nevertheless, a greater improvement occurred in the aripiprazole group in the secondary measures, mostly total scores of several other scales measuring the overall agitation and depression, and improvement over time. The adverse effects were not different between the drug and placebo except for somnolence and the mean dose of aripiprazole was 9 mg. The study was conducted before the FDA warning about the risk of atypical neuroleptic use in the elderly with dementia. The results are comparable with those of other atypical neuroleptic trials and show no advantage of aripiprazole, except possibly in the management of depression associated with A.D. But it mirrors the story of the available psychotropic drugs for treatment of agitation in dementia.
In contrast, Lanctot et al.
38 report contains new information that can advance our understanding of the underlying mechanisms and approaches to management of apathy associated with A.D. that can be present in up to 70% of patients. The authors assessed the use of
d-amphetamine to assess response in apathetic and nonapathetic patients. They found a blunted subjective response to
d-amphetamine, suggesting dysfunction in the Brain Reward System that opens the doors to the use of dopaminergic agents and stimulant drugs that are likely to improve apathy in contrast to serotnergic drugs. Although the reports of cognitive enhancers shows a modest rate of improvement in apathy,
39 the use of dopaminergic agents is also appropriate to correct the dopaminergic deficit in the brain reward system. Perhaps, we should allow a new look at the use of stimulants in dementia that will require new studies of the stimulant use as augmentation of the standard dementia treatments.
Clearly, the field of geriatric psychiatry is in an urgent need of new paradigms of therapeutic development to treat behavioral disturbance in dementia, including new classes of drugs and the new uses of available drugs and other therapeutic agents (e.g., supplements). Although the field is at odds with the state of affairs in pharmacological management, the behavioral research is offering new and better solutions that lie in the development of personalized interventions. The fourth article in this issue by Tune
40 reports behavioral management of sexually inappropriate behaviors of a male patient, in whom mediations were ineffective in controlling his behaviors. The patient responded to a large 3-ft tall pink panther stuffed animal. Although the patient grasped and fondled the Pink Panther, he became less intrusive with fellow patients and staff, and later was discharged to a nursing facility along with the Pink Panther, and continued to refrain from disrupting fellow residents. This proves that while the behavioral approaches do not stop the behavior, they can prevent harm to other patients and staff. This observation calls for creativity in providing individualized approaches.
It is becoming clear that there is not an easy solution to pharmacotherapy of neuropsychiatric symptoms of dementia. The current database exclusively uses averages and group means in documenting response in the drug trials or behavioral studies, which is responsible for the discrepancy between the disappointing results of the research studies and individual successes in clinical practice. We have learned by now that there is not a single prescription for everyone, and creating personalized approaches could be the way to build evidence for our colleagues, and demonstrate to our patients and their families that our treatments work. The question remains whether the pharmaceutical industry and academia can be flexible enough in designing such studies and whether there is an agency that will fund them. The National Institute of Health Roadmap initiative calls for such creative solutions to designing effective treatments using personalized approaches.
41 This is an opportunity to rethink the way research is being conducted in developing effective treatments for neuropsychiatric symptoms of A.D. and related dementias.
In addition to developing effective pharmacotherapy, it would be important to increase evidence base for alternative and complementary approaches that are already widely used by our patients and their families such as spiritual activities, meditation, life style, exercise, energy treatments, light and music therapy, and many others. The use of multiple interventions in an individual patient are likely to replace the use of a single treatment and will need to be tested in research, such as psychosocial treatments, caregiver training and support, antidepressants and acetylcholinesterase inhibitors, as well as other drugs developed for the treatment and prevention of Alzheimer disease.
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