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.

Bradley Hospital researchers link lack of sleep in teens to higher risk of illness

Study also finds consistent sleep pattern can reduce risk of illness EAST PROVIDENCE, R.I. – Newly released findings from Bradley Hospital published in the Journal of Sleep Research have found that acute illnesses, such as colds, flu, and gastroenteritis were more common among healthy adolescents who got less sleep at night. Additionally, the regularity of teens' sleep schedules was found to impact their health. The study, titled "Sleep patterns are associated with common illness in adolescents," was led by Kathryn Orzech, Ph.D. of the Bradley Hospital Sleep Research Laboratory CEUs For Nurses Orzech and her team compared three outcomes between longer and shorter sleepers: number of illness bouts, illness duration, and school absences related to illness. The team found that bouts of illness declined with longer sleep for both male and female high school students. Longer sleep was also generally protective against school absences that students attributed to illness. There were gender differences as well, with males reporting fewer illness bouts than females, even with similar sleep durations. Orzech's team analyzed total sleep time in teens for six-day windows both before and after a reported illness and found a trend in the data toward shorter sleep before illness vs. wellness. Due to the difficulty of finding teens whose illnesses were spaced in such a way to be statistically analyzed, Orzech also conducted qualitative analysis, examining individual interview data for two short-sleeping males who reported very different illness profiles. This analysis suggested that more irregular sleep timing across weeknights and weekends (very little sleep during the week and "catching up" on sleep during the weekend), and a preference for scheduling work and social time later in the evening hours can both contribute to differences in illness outcomes, conclusions that are also supported in the broader adolescent sleep literature. "Some news reaches the general public about the long-term consequences of sleep deprivation, such as the links between less sleep and weight gain," said Orzech. "However, most of the studies of sleep and health have been done under laboratory conditions that cannot replicate the complexities of life in the real world. Our study looked at rigorously collected sleep and illness data among adolescents who were living their normal lives and going to school across a school term." "We showed that there are short-term outcomes, like more acute illness among shorter-sleeping adolescents, that don't require waiting months, years or decades to show up," Orzech continued. "Yes, poor sleep is linked to increased cardiovascular disease, to high cholesterol, to obesity, to depression, etc., but for a teenager, staying healthy for the dance next week, or the game on Thursday, may be more important. This message from this study is clear: Sleep more, and more regularly, get sick less." Mary Carskadon, Ph.D., director of the Bradley Hospital Sleep Research Laboratory, commented on Orzech's study, "We have long been examining the sleep cycles of teenagers and how we might be able to help adolescents - especially high school students - be better rested and more functional in a period of their lives where sleep seems to be a luxury." Carskadon continued, "In the future, these findings identifying specific issues in individual sleep patterns may be a useful way to help adolescents begin to prioritize sleep." ### Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under award numbers MH45945 and MH79179, and T32 training grant MH19927. Direct financial and infrastructure support for this project was received through the Lifespan Office of Research Administration. The principal affiliation of Carskadon is Bradley Hospital (a member hospital of the Lifespan health system in Rhode Island). She is also a professor of psychiatry and human behavior at The Warren Alpert Medical School of Brown University. Orzech was a postdoctoral fellow in the Bradley Hospital Sleep Research Laboratory at the time of the research, and is currently a postdoctoral fellow with the Charting the Digital Lifespan project based at the University of Dundee in Scotland, UK. About Bradley Hospital Founded in 1931, Bradley Hospital, located in East Providence, R.I., was the nation's first psychiatric hospital devoted exclusively for children and adolescents. It remains a nationally recognized center for children's mental health care, training and research. Bradley Hospital was awarded the distinction of 'Top Performer on Key Quality Measures' for both 2011 and 2012 by The Joint Commission, the leading accreditor of health organizations in the U.S. Bradley Hospital is the only hospital in Rhode Island and the only psychiatric hospital in New England to receive this designation. Bradley Hospital is a member of the Lifespan health system and is a teaching hospital for The Warren Alpert Medical School of Brown University. Follow us on Facebook and on Twitter (@BradleyHospital).

Study provides roadmap for delirium risks, prevention, treatment, prognosis and research

INDIANAPOLIS -- Delirium, a common acute condition with significant short- and long-term effects on cognition and function, should be identified as an indicator of poor long-term prognosis, prompting immediate and effective management strategies, according to the authors of a new systematic evidence review ceus for nurses "Delirium is extremely common among older adults in intensive care units and is not uncommon in other hospital units and in nursing homes, but too often it's ignored or accepted as inevitable. Delirium significantly increases risk of developing dementia and triples likelihood of death. It can't be ignored," said Regenstrief Institute investigator Babar A. Khan, M.D., M.S., assistant professor of medicine at the Indiana University School of Medicine and an Indiana University Center for Aging Research scientist, the first author of the review. The authors reviewed 45 years of research encompassing 585 studies to provide a roadmap for the identification of risks, prevention and treatment options as well as prognoses related to delirium. "As an intensive care unit physician, I have seen that about 80 percent of ICU patients who need mechanical assistance to breathe develop delirium," Dr. Khan said. "That's because in addition to being on a respirator, they have multiple risk factors that can predispose and precipitate delirium, including but not limited to serious illness, restraints and pre-existing cognitive impairment." According to the American Delirium Society, more than 7 million hospitalized Americans suffer from delirium each year, and more than 60 percent of delirium cases are not recognized or treated. "Having delirium prolongs the length of a hospital stay, increases the risk of post-hospitalization transfer to a nursing home, increases the risk of death and may lead to permanent brain damage," said Regenstrief Institute investigator Malaz Boustani, M.D., MPH, associate professor of medicine at IU School of Medicine and associate director of the IU Center for Aging Research. Dr. Boustani, senior author of the new study, is medical director of the Wishard Healthy Aging Brain Center and president of the American Delirium Society. How to lower the likelihood of delirium and increase recognition of cases that occur? Drs. Khan and Boustani recommend eliminating restraints, treating depression, ensuring that patients have access to eyeglasses and hearing aids, and prescribing classes of antipsychotics that do not negatively affect the aging brain. They and the other study authors note the need for a more sensitive screening tool for delirium, especially when administered by a non-expert. "Delirium in Hospitalized Patients: Implications of Current Evidence on Clinical Practice and Future Avenues for Research -- A Systematic Evidence Review" was published in the September issue of Journal of Hospital Medicine. In addition to presenting evidence for clinical practice, it identifies areas for future delirium research. ### The study was supported by the National Institute on Aging (grant AG054205-02) and the National Institute of Mental Health (grant MH080827-04). In addition to Drs. Khan and Boustani, authors of the paper are Mohammed Zawahiri, M.D., of the Regenstrief Institute and IU Center for Aging Research; Regenstrief Investigator Noll L. Campbell, Pharm.D., of Purdue University and Wishard Health Services; George C. Fox, M.D., MRCPsych, University of East Anglia, Norfolk, U.K.; Eric J. Weinstein, M.D., of Tri-State Pulmonary Associates, Cincinnati, Ohio; Arif Nazir, M.D., Mark O. Farber, M.D., and John D. Buckley, M.D., MPH, of the IU School of Medicine; and Alasdair MacLullich, Ph.D., of the University of Edinburgh.

Survey Finds More Evidence That Mental Disorders Often Begin in Youth

About 8 percent of U.S. teens meet current criteria for having a serious emotional disturbance, according to two NIMH-funded studies published in the April 2012 issue of the Archives of General Psychiatry. Background A September 2010 study using data from the NIMH-funded National Comorbidity Survey-Adolescent Supplement (NCS-A) found that about 20 percent of youth are affected by a mental disorder sometime in their lifetime. The NCS-A is a nationally representative, face-to-face survey of more than 10,000 teens ages 13 to 18. Parents or caregivers were also asked to complete a corroborating questionnaire after teens were interviewed. The NCS-A used criteria established by the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM-IV) to assess for a wide range of mental disorders including mood and anxiety disorders, behavior disorders like attention deficit hyperactivity disorder (ADHD), eating disorders, and substance use disorders. In this most recent analysis, Kathleen Merikangas, Ph.D., of NIMH, Ron Kessler, Ph.D., of Harvard University, and colleagues examined the prevalence of mental disorders, as well as the severity of the disorders, within a 12-month period to estimate the rate of serious emotional disturbances (SED) in youth. SED was defined by the Substance Abuse and Mental Health Administration (SAMHSA) as a “mental, behavioral, or emotional disorder … that resulted in functional impairment which substantially interferes with or limits the child’s role or functioning in family, school, or community activities.” Results of the Study The researchers found that about 8 percent of all respondents had SED. Those with behavior disorders were most likely to be considered to have a severe disorder. Those with three or more coexisting disorders were also more likely to be severely affected. Similar to adults, anxiety disorders were the most common conditions in adolescents. Echoing many other studies, girls were more likely to have a mood or anxiety disorder or eating disorder, while boys were more likely to have a behavior disorder like ADHD or substance use disorder. Contrary to regional studies, this report showed a lower rate of depression among Hispanics compared to whites. Significance The findings in this study reflect the widely held belief that most psychiatric disorders first manifest in childhood or adolescence and tend to persist or recur throughout a person’s life. The researchers conclude that the high prevalence rate of mental disorders in U.S. adolescents underscores the need for more research focused on changing the trajectory of mental disorders in youth. What’s Next More research is needed to better understand the differences in prevalence rates among cultural and ethnic groups in different regions of the country ceus for nurses Citations Kessler R, Avenevoli S, Costello J, Georgiades K, Green JG, Gruber M, He J, Koretz D, McLaughlin K, Petukhova M, Sampson N, Zaslavsky A, Merikangas K. Prevalence, persistence and Sociodemographic correlates of DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement. Archives of General Psychiatry. April 2012; 69(4):372-380. Kessler R, Avenevoli S, Costello J, Green JG, Gruber M, McLaughlin K, Petukhova M, Sampson N, Zaslavsky A, Merikangas K. Severity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement. Archives of General Psychiatry. April 2012; 69(4):381-389.

Spontaneous Gene Glitches Linked to Autism Risk with Older Dads

Non-Inherited Mutations Spotlight Role of Environment – NIH-Supported Study, Consortium ceus for nurses

Researchers have turned up a new clue to the workings of a possible environmental factor in autism spectrum disorders (ASDs): fathers were four times more likely than mothers to transmit tiny, spontaneous mutations to their children with the disorders. Moreover, the number of such transmitted genetic glitches increased with paternal age. The discovery may help to explain earlier evidence linking autism risk to older fathers.

The results are among several from a trio of new studies, supported in part by the National Institutes of Health, finding that such sequence changes in parts of genes that code for proteins play a significant role in ASDs. One of the studies determined that having such glitches boosts a child’s risk of developing autism five to 20 fold.

Taken together, the three studies represent the largest effort of its kind, drawing upon samples from 549 families to maximize statistical power. They reveal sporadic mutations widely distributed across the genome, sometimes conferring risk and sometimes not. While the changes identified don’t account for most cases of illness, they are providing clues to the biology of what are likely multiple syndromes along the autism spectrum.

“These results confirm that it’s not necessarily the size of a genetic anomaly that confers risk, but its location – specifically in biochemical pathways involved in brain development and neural connections. Ultimately, it’s this kind of knowledge that will yield potential targets for new treatments,” explained Thomas, R. Insel, M.D., director of the NIH’s National Institute of Mental Health (NIMH), which funded one of the studies and fostered development of the Autism Sequencing Consortium, of which all three groups are members.

Multi-site research teams led by Mark Daly, Ph.D., of the Harvard/MIT Broad Institute, Cambridge, Mass., Matthew State, M.D., Ph.D., of Yale University, New Haven, Conn., and Evan Eichler, Ph.D., of the University of Washington, Seattle, report on their findings online April 4, 2012 in the journal Nature.

The study by Daly and colleagues was supported by NIMH – including funding under the American Recovery and Reinvestment Act. The State and Eichler studies were primarily supported by the Simons Foundation Autism Research Initiative. The studies also acknowledge the NIH’s National Human Genome Research Institute, National Heart Lung and Blood Institute, and National Institute on Child Health and Human Development and other NIH components.

All three teams sequenced the protein coding parts of genes in parents and an affected child – mostly in families with only one member touched by autism. One study also included comparisons with healthy siblings. Although these protein-coding areas represent only about 1.5 percent of the genome, they harbor 85 percent of disease-causing mutations. This strategy optimized the odds for detecting the few spontaneous errors in genetic transmission that confer autism risk from the “background noise” generated by the many more benign mutations.

Like larger deletions and duplications of genetic material previously implicated in autism and schizophrenia, the tiny point mutations identified in the current studies are typically not inherited in the conventional sense – they are not part of parents’ DNA, but become part of the child’s DNA. Most people have many such glitches and suffer no ill effects from them. But evidence is building that such mutations can increase risk for autism if they occur in pathways that disrupt brain development.

State’s team found that 14 percent of people with autism studied had suspect mutations – five times the normal rate. Eichler and colleagues traced 39 percent of such mutations likely to confer risk to a biological pathway known to be important for communications in the brain.

Although Daly and colleagues found evidence for only a modest role of the chance mutations in autism, those pinpointed were biologically related to each other and to genes previously implicated in autism.

The Eichler team turned up clues to how environmental factors might influence genetics. The high turnover in a male’s sperm cells across the lifespan increases the chance for errors to occur in the genetic translation process. These can be passed-on to the offspring’s DNA, even though they are not present in the father’s DNA. This risk may worsen with aging. The researchers discovered a four-fold marked paternal bias in the origins of 51 spontaneous mutations in coding areas of genes that was positively correlated with increasing age of the father. So such spontaneous mutations could account for findings of an earlier study that found fathers of boys with autism were six times – and of girls 17 times – more likely to be in their 40’s than their 20’s.

“We now have a path forward to capture a great part of the genetic variability in autism – even to the point of being able to predict how many mutations in coding regions of a gene would be needed to account for illness,” said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, which funded the Daly study and helped to create the Autism Sequencing Consortium. “These studies begin to tell a more comprehensive story about the molecular underpinnings of autism that integrates previously disparate pieces of evidence.”

References

Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. April 5, 2012. Nature.

O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. April 5, 2012.

Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shair K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 5, 2012.

###

The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.