Antidepressant holds promise in treating Alzheimer's agitation

When non-medication options fail, it may prove to be an alternative treatment for this common, distressing symptom Feb. 19, 2014 (Toronto) - An antidepressant medication has shown potential in treating symptoms of agitation that occur with Alzheimer's disease and in alleviating caregivers' stress, according to a multi-site U.S.- Canada study. "Up to 90 per cent of people with dementia experience symptoms of agitation such as emotional distress, restlessness, aggression or irritability, which is upsetting for patients and places a huge burden on their caregivers," said Dr. Bruce G. Pollock, Vice President of Research at the Centre for Addiction and Mental Health (CAMH), who directed research at the CAMH site. "These symptoms are a major reason why people go into long-term care prematurely." The antidepressant citalopram, sold under the brand names Celexa and Cipramil, significantly relieved agitation in a group of Alzheimer's disease (AD) patients as reported in the February 19 issue of the Journal of the American Medical Association. "When agitation occurs, it's paramount to try non-medication approaches first, such as looking for underlying physical discomfort in a patient, reducing external triggers such as noise or overstimulation, and encouraging light exercise," said Dr. Pollock, Director of CAMH's Campbell Family Mental Health Research Institute. When these approaches don't work, antipsychotic medications are commonly used to treat agitation. "Antipsychotics are not an ideal therapy and significantly increase the risk of strokes, heart attacks and sudden death," he said. Based on promising early findings from Europe, Dr. Pollock began conducting studies on citalopram, which suggested it might be a viable treatment alternative to antipsychotics. To provide stronger evidence, the Citalopram for Agitation in Alzheimer's Disease Study (CitAD) was initiated with eight leading Alzheimer's research centres across the United States and Canada, including the Geriatric Program at CAMH. The study included 186 patients with Alzheimer's disease who showed symptoms of agitation. Their average age was in the late 70s. None had experienced symptom relief with non-medication therapies, and some had failed treatment with antipsychotic drugs. The study measured both patients' agitation levels as well as their caregivers' stress levels, a factor strongly linked to Alzheimer's patients' well-being. Patients were then randomly assigned to receive either citalopram for nine weeks, up to a dose of 30 milligrams per day, or an identical-looking placebo. At the end of the study period, the tests were repeated. Patients on the drug had significant relief from their agitation symptoms. In one measure of agitation, about 40 percent of patients who took citalopram had "considerable relief" compared to 26 percent of patients who took the placebo. In addition, caregivers for these patients had significantly lower levels of stress. ### Other CAMH collaborators were Dr. Tarek Rajji, Chief of Geriatric Psychiatry and Physician-in-Chief Dr. Benoit Mulsant. The other academic centres involved with the study were the University of Rochester, Johns Hopkins University, Columbia University, University of Calgary, Roper St. Francis Health Care, University of Southern California, University of Pennsylvania and Stanford University. This research was supported by a grant from the U.S. National Institute on Aging and National Institute of Mental Health. For further information, please contact Kate Richards, CAMH Media Relations at (416) 595-6015. The Centre for Addiction and Mental Health (CAMH) is Canada's largest mental health and addiction teaching hospital, and one of the world's leading research centres in the field. CAMH combines clinical care, research, education, policy development and health promotion to help transform the lives of people affected by mental health and addiction issues CEUs For Nurses CAMH is fully affiliated with the University of Toronto, and is a Pan American Health Organization/World Health Organization Collaborating Centre.

Aging and gene expression -- possible links to autism and schizophrenia in offspring

Advanced paternal age has been associated with greater risk for psychiatric disorders, such as schizophrenia and autism. With an increase in paternal age, there is a greater frequency of certain types of mutations that contribute to these disorders in offspring. Mutations are changes in the genetic code. Recent research, however, looks beyond the genetic code to "epigenetic effects", which do not involve changes in the genes themselves, but rather in how they are expressed to determine one's characteristics. Such epigenetic changes in sperm, related to ageing, have been linked with psychiatric disorders in offspring. Maria Milekic, PhD, reported today, at the American College of Neuropsychopharmacology annual meeting in Hollywood Florida, that old mice have an epigenetic change ‒ a loss of DNA methylation at the locations where the genetic code starts being transcribed. DNA methylation is a biochemical process that plays an important regulatory role in development and disease. The work was done by a research team in the Department of Psychiatry at Columbia University. Offspring of old fathers showed the same deficit in DNA methylation, and they differed in their behavior from the offspring of the young fathers. They showed less exploratory activity and differed in the startle response and in habituation. Two groups, with 10 breeder mice per group, were tested. The breeders were either old (12 month) or young (3 month) males, each bred with two young (3 month) female mice. Then the behavior of the offspring was tested when they were 3 months old. DNA methylation also was tested in the young and old fathers' sperm, and brains of the offspring were tested for DNA methylation as well as gene expression. "We were interested in understanding the mechanism of the paternal age effect", said Dr. Milekic."The risk for schizophrenia increases 2-fold when a father is over 45 years of age, and the risk for autism increases 2-5-fold. It seemed unlikely that mutation alone could account for this. We therefore speculated that DNA methylation could provide an alternative mechanism." Not only did the offspring of the old fathers differ from their counterparts with young fathers in DNA methylation, they also showed significant differences in the expression of genes that have been implicated in autism spectrum disorders and that are known to regulate the development and function of the brain. These findings point to possible factors that can lead to autism spectrum disorders and schizophrenia, and ultimately may lead to more effective therapeutic interventions. With respect to studies in the immediate future, Dr. Milekic said,"We are trying to evaluate changes in different brain regions. Our studies before did not compare brain regions. Most of the genes that have altered expression are in the cerebellum. We are interested in how DNA methylation in the cerebellum is affected by paternal age." Social Worker CEUs ### The work was supported by grants from NIMH and the Simon Foundation to Jay Gingrich, MD, PhD, and a NARSAD Young Investigator Awa rd from the Brain and Behavior Research Foundation to Dr. Milekic.