Alzheimer's disease patients who were showing vexing social behaviors were two to three times likely to relapse after being taken off of risperidone.
ALTERNATIVES TO ANTIPSYCHOTICS? Neurologists, geriatricians and psychiatrists who treat Alzheimer's disease patients, like the nursing home patient seen here, try behavioral strategies to calm and comfort patients who may become agitated or have psychotic behaviors.
Alzheimer's disease (AD) patients being treated for difficult behaviors — agitation or psychosis — are two to three times more likely to relapse when taken off of a common, second-generation antipsychotic — risperidone, according to an Oct. 18 paper published in the New England Journal of Medicine.
Experts say that this is the first rigorous study to test the benefits of continuing versus discontinuing the drug in elderly patients with psychosis, aggression and/or agitation who have improved with this treatment. And they say the data may help neurologists and other prescribers make important decisions about the ongoing care of their patients.
The study was conducted by scientists at Columbia University College of Physicians and Surgeons.
DR. DAVANGERE P. DEVANAND: “We planned to address the need to continue treatment used for these common behavioral symptoms. Do patients need to stay on these medicines long-term? Our findings suggest that there is a high rate of relapse when patients who have improved are taken off these medicines, even several months later.”
Federal regulations on the use of anti-psychotic drugs “urge early discontinuation within three to six months in nursing homes,” said Davangere P. Devanand, MD, professor of clinical psychiatry and neurology at Columbia.
Dr. Devanand, a geriatric psychiatrist, and his colleagues set out to test whether or not discontinuation of the drugs increased the risk that these troubling behavioral symptoms would return.
The Columbia researchers said that they chose risperidone because it is more widely used than the other second-generation antipsychotics and had been shown to be superior to placebo in earlier treatment trials, but Dr. Devanand said that it is likely that the findings would apply to all drugs in this class.
DR. LON SCHNEIDER: “There is still a sizeable proportion of patients who did not relapse and a sizeable proportion of people on medication who did relapse. I would be concerned if this study is interpreted to mean that patients should not be discontinued indefinitely.”
For the current study, the researchers recruited patients from memory clinics and nursing homes in eight states throughout the United States. They enrolled 180 patients who received risperidone for four months; only those who responded to the treatment — a reduction in psychosis and agitation — were continued in the study, which would go on in several phases over an additional eight months.
Patients who had already responded to risperidone were randomly assigned to one of three groups: continued risperidone therapy for 32 weeks (group 1), risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2), or placebo for 32 weeks (group 3). They were followed closely throughout the study with a range of assessments. When the patients relapsed, their participation in the study ended.
At the end of the first four months, the relapse rate was 60 percent (24 out of 40 patients) for those on placebo (group 3) versus 33 percent (23 out of 70 patients, groups 1 and 2) in those on the active medication (p = 0.004). Over the next four months (weeks 17–32), 48 percent of those who were blindly taken off the drug and placed on a placebo pill (13 out of 27 patients, group 2) relapsed versus 15 percent (two of 13 patients, group 1) who continued on risperidone (p = 0.02).
The findings answered the question of the risk for relapse following discontinuation. The investigators knew going into the study that the numbers would not be sufficient or the study long enough to pick up differences in the rates of adverse effects (strokes and deaths) that led to the black box warning.
“We planned to address the need to continue treatment used for these common behavioral symptoms,” said Dr. Devanand. “Do patients need to stay on these medicines long-term? Our findings suggest that there is a high rate of relapse when patients who have improved are taken off these medicines, even several months later.”
He said that they found the same relapse rates in those treated in the community and those already living in nursing homes.
It is estimated that anywhere between ten to 40 percent of patients in the mild to moderate stages of AD have agitation, aggression or psychosis and the number can increase to over 50 percent as the disease progresses.
The risk of death must still be considered when using these medications, Dr. Devanand said. The risk of death is 1.7 times higher in AD patients on antipsychotic medicines. No one knows exactly why the use of these drugs increases the risk of death, he added.
The study was funded by the National Institute on Aging and Janssen Pharmaceuticals, makers of risperidone, donated free drugs and placebo for the study but was otherwise uninvolved in the study, said Dr. Devanand.
“This is a very important paper,” said Jeffrey L. Cummings, MD, director of the Cleveland Clinic Lou Ruvo Center for Brain Health and the Andrea and Joseph Hahn chair of neurotherapeutics of the Neurological Institute. Dr. Cummings created the Neuropsychiatric Inventory used to characterize behavioral disturbances in AD and other dementia syndromes. “The use of a withdrawal design was strong enough to answer the exact question the investigators were interested in.”
“The increased risk of mortality has put us in a position of trying to get patients off these drugs as soon as possible,” said Dr. Cummings. “But these findings show that the risk of relapse is quite high when the patient was chosen appropriately to begin with. If anything, this reinforces the conundrum we are in. We have an effective therapy with serious side effects.”
“We need better drugs with fewer side effects,” he added.
Lon Schneider, MD, a professor of psychiatry, neurology, and gerontology at the Keck School of Medicine of the University of Southern California, and director of the Alzheimer's Disease Research and Clinical Center, said that it is not surprising that a discontinuation study would show an effect “after you load the patient up on medicine and then quickly take it away.” Dr. Schneider is principal investigator of the National Institute of Mental Health's CATIE program, a multicenter effectiveness trial of atypical antipsychotics in Alzheimer's disease.
He also pointed out that a large percentage of patients did well during the placebo dose part of the study. “There is still a sizeable proportion of patients who did not relapse and a sizeable proportion of people on medication who did relapse.” He added: “I would be concerned if this study is interpreted to mean that patients should not be discontinued indefinitely.”
“Patients, their families, and their doctors are caught between a rock and a hard place,” said Howard Fillit, MD, a geriatric psychiatrist and executive director and chief executive officer of the Alzheimer's Drug Discovery Foundation. “There are some patients who are psychotic or extremely agitated and for their own safety and well-being we need medical or pharmaceutical interventions. Our options are limited.”
DR. JEFFREY L. CUMMINGS: “The increased risk of mortality has put us in a position of trying to get patients off these drugs as soon as possible. But these findings show that the risk of relapse is quite high when the patient was chosen appropriately to begin with. If anything, this reinforces the conundrum we are in. We have an effective therapy with serious side effects. We need better drugs with fewer side effects.”
Neurologists, geriatricians and psychiatrists who treat AD patients also try behavioral strategies. Many work with caregivers to help them identify things in the environment that could trigger behavioral outbursts and then learn to redirect the patient's attention.
Dr. Fillit, has found that the best strategy in managing these symptoms is to do an assessment to determine the causes and intervene appropriately. Distracting patients helps to reduce symptoms of agitation and aggression, he said.
Dr. Fillit contends that the antipsychotics were initially overprescribed in these elderly patients but the black box warning has led to more judicious prescribing patterns. “The value of these medicines is that it could help a patient remain in their home longer,” he said.
The US Food and Drug Administration (FDA) approved risperidone in 1993 to treat the vexing psychotic symptoms in patients with schizophrenia, and subsequently other atypical antipsychotics, including olanzapine and quetiapine, were approved for this purpose.
Shortly after, several studies, mainly supported by the pharmaceutical industry, were conducted to examine this class of drug's potential use for elderly patients with Alzheimer's disease who can be psychotic, agitated, and aggressive. These medicines showed modest success in some placebo-controlled trials and physicians began to prescribe them in patients with AD and other dementias though these drugs remained off-label and have not received FDA approval for this purpose.
But a decade into its growing, widespread use among Alzheimer's patients, federal regulators picked up a troubling signal: an increased risk of stroke and death that was not identifiable in individual drug trials but was present for all anti-psychotics when placebo-controlled trials were pooled together.
In 2005, the FDA introduced a black box warning about increased mortality risk. Physician prescribing in patients with dementia declined only to a moderate degree because of the clinical emergencies often occurring in these patients requiring medication treatment and the lack of any other effective available treatments.
For the Neurology Today archive on risperidone and other antipsychotics for elderly demented patients, see http://bit.ly/SxtEXr .
LISTEN UP, TUNE IN: Davangere P. Devanand, MD, professor of clinical psychiatry and neurology at Columbia, discusses results from a clinical trial finding that Alzheimer's disease patients were two to three times more likely to relapse with vexing social behaviors when they are taken off risperidone. How should this impact treatment options? Dr. Devanand discusses the implications for neurologists. http://bit.ly/dy2KLx .