New Mechanisms of Action Explored in Promising Alzheimer’s Disease Therapies
Two new therapies show promise targeting Alzheimer’s disease at little-explored mechanisms of action, researchers announced at the 2008 Alzheimer’s Association International Conference on Alzheimer’s Disease (ICAD). Such treatments may pave the way to safe and effective disease-modifying therapies for Alzheimer’s disease, a goal that has eluded researchers in recent years.
At ICAD, Philip Scheltens, MD, PhD, of the Alzheimer Center of the VU University Medical Centre, Amsterdam, the Netherlands, presented data from a 12-week, randomized, double-blind, placebo-controlled study of Souvenaid, a drink containing the nutrients uridine monophosphate, choline, omega-3 fatty acids, phospholipids, B vitamins, and antioxidants. Souvenaid had been shown to increase synapse formation in preliminary studies by the Massachusetts Institute of Technology. It is believed that the nutrients in Souvenaid impact the synthesis of the membrane phosphatides that compose neural synapses. The provision of these nutrients, it is hypothesized, could promote brain cell outgrowth, synapse formation, and neurotransmitter release, and could also improve cognitive function.
Two hundred twelve subjects with mild Alzheimer’s disease were recruited from the Netherlands, Germany, Belgium, and the United States. Of these, half were assigned to receive 125 ml of Souvenaid per day, and half received a control drink. None of the subjects had received prior treatment for their condition. The primary outcome measures were cognition on the Wechsler Memory Scale-revised and the modified Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). Secondary outcomes included the Mini Mental State Examination (MMSE), the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, Clinician’s Interview Based Impression of Change plus Caregiver Input (CIBIC-plus), the Quality of Life in Alzheimer’s Disease, and the Neuropsychiatric Inventory (NPI). This study also included an optional 12-week extension phase, which 85% of subjects who completed the first phase elected to participate in.
Investigators found a statistically significant benefit on the delayed verbal memory test in the Souvenaid group. There appeared to be no significant effect on the modified ADAS-cog. There was no decline in modified ADAS-cog and verbal memory in the control group during the 12 weeks of the study, however subjects with a higher baseline ADAS-cog score seemed to experience greater cognitive effect with Souvenaid. Souvenaid was well tolerated and showed a good safety profile.
“We believe that medical foods such as Souvenaid can be a valuable part of Alzheimer’s disease management,” said Dr. Scheltens, and this trial showed proof of concept.
Mitochondrial function is another mechanism of action being explored in potential Alzheimer’s disease treatments. Dimebon, a product of Medivation that improves impaired mitochondrial function, showed efficacy in preserving function among subjects with Alzheimer’s disease in an 18-month extension trial. Initially, 183 subjects were randomized to dimebon or placebo for six months, after which subjects could elect to remain in the study for an additional six months. After the completion of both of these periods, an open-label extension was conducted in which 104 participants received dimebon 20 mg TID. Of these participants, 92 had completed 6 months of prior treatment with dimebon.
Jeffrey L. Cummings, MD, director of the Mary S. Easton Centre for Alzheimer’s Disease at the David Geffen School of Medicine at UCLA, Los Angeles, and colleagues found that subjects who received dimebon through all 18 months of the study showed preservation of function close to their baseline measures. They showed benefit compared to projected placebo decline on the ADAS-cog, CIBIC-plus, ADCS-ADL, NPI, and MMSE. Those who had been randomized to placebo during the first 12 months, then to dimebon for open-label trial showed stabilization of their previous decline on all endpoints. Those who received dimebon for 18 months continued to show benefit over those receiving the agent for only six, suggesting this treatment may have disease-modifying properties. However, Dr. Cummings advised that “open-label extensions are not the same as placebo-controlled trials, and extrapolation of the treatment results should be done with caution.” Phase III clinical trials are currently being planned.
Funding for the clinical trial of Souvenaid was provided by the Danone Research Centre for Specialised Nutrition. Funding for the 18-month extension trial of dimebon was provided by Medivation, Inc. (July 29, 2008. Alzheimer’s Association’s International Conference on Alzheimer’s Disease.) –RZ
High Incidence of Psychiatric Disorders in Youths Transferred to Adult Courts
Legal mandates in all states and the District of Columbia allow them to try juveniles in adult courts based on the type of offense, criminal history, and age of the offender. While the transferred youth population steadily climbs, primary care physicians are likely to encounter them, as these young individuals are at high risk for disorder. Jason J. Washburn, PhD, at Northwestern University Feinberg School of Medicine, and colleagues, compared the occurrence of psychiatric disorders among youths tried in adult court to that of youths processed in juvenile court.
They garnered a stratified random sample of 1,829 youths 10–18 years of age arrested in Chicago. One thousand seven-hundred fifteen of them (1,440 processed in juvenile court; 275 processed in adult criminal court) 13–18 years of age underwent version 2.3 of the Diagnostic Interview Schedule for Children.
Results, even after analyses controlled for felony-level violent crime, found males, African Americans, Hispanics, and older youths more likely to be processed in adult criminal court than females, non-Hispanic whites, and younger youths. Sixty-eight percent of youths processed in adult criminal court presented with ≥1 psychiatric disorder, and 43% had ≥2 types of disorders; such figures and findings were essential the same for those processed in juvenile court. However, the most interesting finding concerned juvenile offenders sentenced to prison in adult criminal court.
“These youths [sentenced to prison in adult court] were not only more likely to have disruptive behavior and substance use disorders, as might be expected from more ‘antisocial’ youths, but they were also more likely to have comorbid affective and anxiety disorders,” Washburn said. “These youths who were tried as adults, found guilty, and sentenced to prison had nearly three times the odds of having comorbid affective and anxiety disorders than youths given a lesser sentence.”
It is important to note the study’s dependence on self-report since parents of the offenders could not be interviewed and a majority of them could not be located. Such dependence possibly underestimates actual rates of certain disorders (ie, disruptive behavioral disorders).
Washburn and colleagues’ study outlines the lack of mental health care available for males coming from racial-ethnic minority groups. Psychiatric services within community and correctional systems for youths processed in adult criminal court, particularly those sentenced to prison, are needed.
“Because many of these youths are unlikely to receive appropriate treatment, primary care physicians can be a critical resource for identifying and connecting this vulnerable population with services,” Washburn added.
Funding for this study was provided by grants from the Division of Services and Intervention Research; Center for Mental Health Research on AIDS of the National Institute of Mental Health; Office of Juvenile Justice and Delinquency Prevention, US Department of Justice; National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (NIH); Center for Mental Health Services, Center for Substance Abuse Prevention, and Center for Substance Abuse Treatment of the Substance Abuse and Mental Health Services Administration; National Center on Injury Prevention and Control and National Center for HIV, Sexually Transmitted Disease, and Tuberculosis Prevention of the Centers for Disease Control and Prevention; NIH Office of Research on Women’s Health; NIH Center on Minority Health and Health Disparities; US Department of Housing and Urban Development; NIH Office on Rare Diseases; US Department of Labor; William T. Grant Foundation; Robert Wood Johnson Foundation; John D. and Catherine T. MacArthur Foundation; Open Society Institute; and Chicago Community Trust. (Psychiatr Serv. 2008;59(9):965-973.) –ML
Acute Stress Disorder Not Effective Predictor of Posttraumatic Stress Disorder
Although prior studies have shown evidence that the presence of acute stress disorder can predict the later onset of posttraumatic stress disorder (PTSD), other studies have shown mixed or conflicting results. Additional studies examining the relationship between PTSD and acute stress disorder have also been limited due to single site study locations and small sample sizes. Recently, researchers at the School of Psychology at the University of New South Wales in Sydney, Australia evaluated any possible relationship between the two disorders with a large-scale, multi-site study in order to reduce limitations found with prior studies.
Richard A. Bryant, PhD, and colleagues examined 597 patients admitted to four major trauma hospitals during a 1-year period for presence of acute stress disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Among patients assessed, 62% suffered injury due to automobile accident, 16% due to fall, 8% due to industrial accident, and 5% due to assault; 9% were admitted to trauma hospitals for other reasons. All patients were randomly selected for screening during hospital admission, which occurred within 1 month of trauma exposure, and reassessed for PTSD at 3 months following the initial assessment (N=507). Among patients who met criteria for PTSD at follow-up, the authors studied how many also presented with acute stress disorder at first assessment to determine predictive rates between the disorders.
Bryant and colleagues found that 33 patients met DSM-IV criteria for acute stress disorder and 49 patients met diagnostic criteria for PTSD at 3-month follow-up. Fifteen patients diagnosed with acute stress disorder and 34 patients who were not diagnosed with acute stress disorder were later diagnosed with PTSD at follow-up. For patients who experienced brain injury in addition to other trauma, presence of acute stress disorder predicted later development of PTSD in 58% of all patients with brain injury as compared to 31% among all patients presenting with trauma.
Due to the main findings, the authors concluded that the majority of patients who develop chronic PTSD do not initially present with acute stress disorder. The study’s results are similar to results found in other studies and illustrate that presence of acute stress disorder is not an effective tool to predict chronic PTSD. The authors recommend researchers seek to create improved tools for physicians to determine the development of chronic PTSD among trauma patients as acute stress disorder may be more predictive of PTSD in patients whose trauma occurred due to non-accidental incidence, such as physical assault or military combat. Bryant and colleagues added that patient heart rates or mood states following trauma may be better predictors of subsequent chronic PTSD development.
Funding for this research was provided by the Australian National Health and Medical Research Council. (J Clin Psychiatry. 2008;69(6):923-929.) –CP
Childhood Abuse May Lead to Adult Obesity
Obesity is a continuously spreading global epidemic. While the disease has been linked to mental disorders such as anxiety and depression, whether these conditions truly lead to mid-life obesity is unknown. In addition, historic and contextual factors have been seldom researched. However, a recent study of 9,310 members of the 1958 British birth cohort by Claudia Thomas, PhD, of the University College of London and colleagues found that physical abuse during childhood served as a precursor to mid-life obesity.
Each member was evaluated for negative experiences (ie, verbal, physical, or sexual abuse, parental depression, authoritarian upbringing, parental separation/divorce) at 7, 11, and 16 years of age. At 45 years of age, subjects underwent a biomedical interview, ascertaining their body mass index (BMI), waist circumference, and glycosylated hemoglobin level. Total obesity was defined by a BMI of ≥30, and a waist circumference of ≥102 cm and ≥88 cm indicated central obesity for men and women, respectively. Any individual with a glycosylated hemoglobin level of ≥6 was considered obese. The researchers used the negative-experience findings and the data gathered from the biomedical interviews to determine whether negative childhood experiences were associated with obesity, specifically at 45 years of age.
Results revealed that mid-life obesity risk increased by 20% to 50% for those who experienced negative childhood events. Adverse childhood events most strongly associated with obesity were indicated in members with glycosylated hemoglobin levels of ≥6. However, most associations were explained by adjustment for adulthood mediators (eg, obesity). Effects of other adversities exhibiting milder emotional neglect and less harsh family environments were mostly due to socioeconomic factors during upbringing.
Though findings indicate childhood adversities increase risk of obesity in adulthood, further research is needed to better understand interrelations among the adversities, social contexts in which they occur, and trajectories from harsh childhood circumstances to adult disease. (Pediatrics. 2008;121(5):e1240-e1249.) –ML
Paternal Age and Risk of Bipolar Disorder
Advanced age of fathers or mothers can increase the risk of bipolar disorder in their offspring, although the effect of paternal age is much more significant, especially in the risk of early-onset bipolar disorder. A large, national, case-control study from Sweden suggests that the risk of developing bipolar disorder is higher in the offspring of older fathers.
Emma M. Frans, M.Med.Sc., at the Karolinska Institutet, in Stockholm, Sweden, and colleagues selected 13,428 people with a bipolar disorder diagnosis from the Swedish national databases Multigeneration Register and the Hospital Discharge Register, each of whom were required to have had a bipolar disorder diagnosis on ≥2 separate hospital admissions. For each person in the bipolar disorder group, the researchers chose five random, age- and sex-matched controls without bipolar disorder.
The researchers controlled for parity, maternal age, socioeconomic status, and family history of psychotic disorders, finding that the offspring of men ≥55 years of age were 1.37 times more likely to be diagnosed with bipolar disorder (CI, 1.02–1.84), compared to the offspring of men 20–24 years of age. Advanced maternal age was less significant. The effect of advanced paternal age was much stronger for early-onset cases of bipolar disorder (odds ratio, 2.63; CI, 1.19–5.81), although there was no link with maternal age. (Arch Gen Psychiatry. 2008;65(9):1034–1040.) –LS
Psychiatric Disturbance in Low Birth Weight Children from Urban and Suburban Communities
According to previous research, children born with low weight (≤5.5 pounds), very low weight (≤3.3 pounds), and extremely low weight infants (≤2.2 pounds) may have higher risk of externalizing (ie, delinquent and aggressive behavior), internalizing (ie, withdrawn behavior, anxiety/depression), and attention (ie, symptoms of attention-deficit/hyperactive disorder) problems. Despite advances in neonatal medicine increasing survivorship of low birth weight infants, Naomi Breslau, PhD, and Kipling M. Bohnert, BA, of Michigan State University in East Lansing investigated the long-term effects of low birth weight on psychiatric problems in both socially disadvantaged children and middle-class children.
The study involved a stratified random sample of 823 urban (n=413) and suburban (n=410) low and normal birth weight children from newborn discharge lists (from 1983 through 1985) in two Detroit, Michigan hospitals. Mothers and teachers used the Child Behavior Checklist and Teacher’s Report Form to rate children’s attention, externalizing, and internalizing problems at 6, 11, and 17 years of age. Standard cutoffs were used to identify infants with psychiatric disturbances above normal range.
Results found that psychiatric outcomes of low birth weight did not vary across age. However, low birth weight children had moderate excesses of externalizing (adjust odds ratio [AOR]=1.53; P=.001) and internalizing (AOR=1.28; P=.02) disturbances. Children from the urban cohort demonstrated greater risk of attention problems associated with low birth weight, with very low birth weight infants having higher risk than heavier low birth weight infants. Interestingly, the suburban counterparts showed no increased risk for attention problems associated with low birth weight.
The data indicate that low birth weight effects on psychiatric disturbance are relatively stable during the period of school attendance. However, the differential effect of low birth weight on attention problems between the urban and suburban communities suggests a relationship between prenatal adversity and social environment.
Funding for this research was provided by grants from the National Institute of Mental Health and the National Institute on Drug Abuse. (Arch Gen Psychiatry. 2008;65(9):1080-1086.) –ML
Psychiatric dispatches is written by Michelisa Lanche, Carlos Perkins, Jr, Lonnie Stoltzfoos, and Rebecca Zerzan.