RECENT RESEARCH ARTICLES
Is Environment a Greater Risk Than Genetics in Autism?
Arch Gen Psychiatry. Published July 4, 2011.
The study was funded by grants from the National Institute of Mental Health and from Autism Speaks. The study authors and Dr. Wiznitzer have disclosed no relevant financial relationships.
July 15, 2011 — Environment may play a larger role in susceptibility to an autism spectrum disorder (ASD) than do genetics, new research from a twin study suggests.In the California Autism Twins Study, which included almost 200 pairs, investigators write that shared prenatal and early postnatal environmental factors may explain 55% "of the liability to autism" compared with genetic heritability, which accounted for just 37%.
They add that genetics, while important, "are of substantially lower magnitude than estimates from prior twin studies of autism."
Still, lead author Joachim Hallmayer, MD, from the Department of Psychiatry at Stanford University School of Medicine in Palo Alto, California, told Medscape Medical News that it is important for clinicians to understand that both factors play a role in this disorder.
"In my opinion, knowing if something is genetic or due to environment doesn't say much about whether it is amenable to therapies or not. I think it is more theoretically important so we know where we need to do our research," said Dr. Hallmayer.
"Our study showed more favor towards environmental factors but I think both sides play an equal part. So we need to put a little bit more effort into understanding the interaction between these factors and how they result in the disorder."
The study was published online July 4 in the Archives of General Psychiatry.
Largest Study of Its Kind
According to the researchers, reports of autism prevalence have increased substantially from the 1960s, which had rates of 4% to 5% per 10,000 children, to the current rate of almost 40% per 10,000.
"Autism has changed in the past few years in the way we view the different symptoms. If there really is such an increase, we don't know if this is because of better detection or because the definition has changed or because of other factors," said Dr. Hallmayer.
Past research has shown that monozygotic (identical) twins have a high heritability of autism while dizygotic (fraternal) twins do not.
"However, none of these more recent studies included structured clinical assessments by both parental interview and direct child observation, which is the contemporary standard for establishing the diagnosis of autism or ASD," write the investigators.
For this analysis, they evaluated data from the California Department of Developmental Services on 192 twin pairs, with at least 1 member having an ASD, born between 1987 and 2004.
A total of 54 of the twin pairs were monozygotic (83% male) and 138 were dizygotic (32.5% male, 9.5% female, 58% sex-discordant).
All participants were examined through use of the Autism Diagnostic Interview-Revised (ADI-R), which was given to the parents, and the Autism Diagnostic Observation Schedule (ADOS), which was given to the children.
Verbal and nonverbal abilities were also assessed by using the Stanford-Binet Intelligence Scales, 5th edition.
On the basis of criteria from the ADI-R and ADOS, the researchers defined 2 diagnostic classifications among the twins: narrow/strict autism (n = 143) and broad/ASD (which included all participants).
"To our knowledge, this study is the largest population-based twin study of autism that used contemporary standards for diagnosis," report the study authors.
Environment Over Genetics
Results showed that "the proband-wise concordance rates" for strict autism were similar between male and female twin pairs. However, monozygotic pairs of both sexes showed significantly higher rates than did dizygotic pairs.
Table 1. Concordance Rates for Strict Autism in Twin Pairs
| Subgroup | Concordance Rates (95% CI) |
| Male monozygotic pairs | 0.58 (0.42 - 0.74) |
| Male dizygotic pairs | 0.21 (0.09 - 0.43) |
| Female monozygotic pairs | 0.60 (0.28 - 0.90 |
| Female dizygotic pairs | 0.27 (0.09 - 0.69) |
The concordance rates for the broader category of ASD "were generally higher" for the subgroups compared with strict autism.
Table 2. Concordance Rates for ASD in Twin Pairs
| Subgroup | Concordance Rates (95% CI) |
| Male monozygotic pairs | 0.77 (0.65 - 0.86) |
| Male dizygotic pairs | 0.31 (0.16 - 0.46) |
| Female monozygotic pairs | 0.50 (0.16 - 0.84) |
| Female dizygotic pairs | 0.36 (0.11 - 0.60) |
Although the rates for both strict autism and for ADS found for the monozygotic pairs were similar to those found in prior research, the rates for the dizygotic pairs were higher and "have a significant impact on the heritability analysis," report the investigators.
"A large proportion of the variance in liability can be explained by shared environmental factors (55% for strict autism and 58% for ASD) in addition to moderate genetic heritability (37% for strict autism and 38% for ASD)," they add.
The study authors note that parental age, low birth weight, and maternal infections during pregnancy may be some of the environmental influences for ASD.
In a recent meta-analysis reported on by Medscape Medical News, researchers found that there is currently "insufficient evidence" of perinatal and neonatal risk factors for the disorder.
"Future studies that seek to elucidate such factors and their role in enhancing or suppressing genetic susceptibility are likely to [extend] our understanding of autism," write the investigators of the current study.
"Conclusions Outreach the Data"
"Overall, I think the authors of this study were speculating a lot and their findings go against previous data," Max Wiznitzer, MD, associate professor of pediatrics and neurology at Case Western Reserve University in Cleveland, Ohio, and pediatric neurologist at Rainbow Babies and Children's Hospital in Cleveland, told Medscape Medical News.
"There are wide margins of how to apply the information and the authors appear to be leaning in 1 direction when their data could have easily allowed them to go in another," he added.
"In other words, their conclusions are exceeding what their data can support. It doesn't support their enthusiastic interpretation of the prominence of environmental factors," Dr. Wiznitzer asserted.
Dr. Wiznitzer, who is also the neurology liaison to the Autism Subcommittee for the American Academy of Pediatrics, noted that several older twin studies have shown "a very strong genetic underpinning" whereas only recent ones have suggested a concordance rate "of about 20% or so" for dizygotic twins.
"The first thing that comes to my mind is that we've broadened the definition. If we just had classic autistic disorder, that is one thing, but [ASD] encompasses so many aspects," he cautioned.
He also pointed to a recent twin study by researchers from Johns Hopkins Medical Institutions (Arch Pediatr Adolesc Med. 2009;163:907-914).
"Their raw data looked very similar except that they had a higher concordance rate in the twins than this study shows. And they didn't reach the conclusion that there is a significant environmental factor, which is very interesting," said Dr. Wiznitzer.
"The environmental factors that the authors of the current study are saying might be contributory are things we've known about forever, such as things that affect the egg and the sperm, including parental age. Perhaps the older the egg and sperm, the more likely there are to be mutations on the genetic material."
Other risk factors he called "well known" include those that affect the fetus in the womb, such as toxin effects and the impact extreme premature birth may have on how the brain later develops.
"I don't think they're saying anything new. They're just putting a spin on it. There are a lot of environmental factors out there. But I think all of us would agree that there is still a very strong genetic basis to autism that is different than heritability."
"I think the big question is this: how do environmental factors interact with the child's innate genetic infrastructure? Is it just that those with a specific genetic vulnerability are susceptible to the environment? That's the discussion now," concluded Dr. Wiznitzer.
Diagnosis and Management of Postpartum Depression
Southern Med Journal. 2011
February 14, 2011 — Standard treatment of postpartum depression is still psychotherapy and antidepressant medications, but other modalities may also be beneficial, according to an essential overview for the practitioner reported in the February issue of the Southern Medical Journal.
"PPD [postpartum depression] is a serious medical matter not only because of the suffering it causes women, but because it can negatively affect infants emotionally, socially, and even cognitively, sometimes far beyond the time of the depression," writes Sarah J. Breese McCoy, PhD, from the Department of Physiology, OSU Center for Health Sciences in Tulsa, Oklahoma. "The most severe adverse outcomes of PPD include increased risk of marital disruption and divorce, child abuse and neglect, and even maternal suicide or infanticide. Children of depressed mothers may experience insecurity, low self esteem, and even decreased intellectual skills or language development."
Postpartum depression, which affects approximately 13% of women from all cultural and racial backgrounds, is a serious form of major depressive disorder. Characteristic symptoms include sadness, anhedonia (loss of pleasure in normally pleasurable activities), and other depressive symptoms. Psychomotor agitation, reduced concentration, and anxiety are typically more pronounced in postpartum depression than in women with major depressive disorder.
Although the specific cause of postpartum depression is often poorly understood, various physiological and psychosocial factors may be implicated. Some of the potential psychosocial risk factors include major depressive disorder or anxiety during pregnancy, a history of major depressive disorder, premenstrual dysphoric disorder, undue life stress before conception, lack of social support, marital problems, poverty, and young maternal age. Causes of postpartum depression may be multifactorial, including the rapid decrease in plasma levels of estrogen and progesterone after pregnancy, postpartum hypothyroidism or autoimmune thyroid disease, sleep deprivation, and/or challenging life circumstances.
Because postpartum depression is typically underdiagnosed in more than half of cases, more screening is needed. Available screening tools for postpartum depression are reliable, self-administered, and easy to use in clinical practice. These include the Edinburgh Postnatal Depression Scale, which is a 10-item survey; a 3-item version of this survey to detect anxiety; and a questionnaire for significant others of women with possible postpartum depression.
Although obstetricians and pediatricians are most likely to have a unique opportunity to screen women for postpartum depression, particularly at the postpartum visit or even during the early third trimester, general practitioners may also encounter women with undiagnosed postpartum depression and should be able to recognize this highly prevalent condition. Prompt diagnosis, intervention, and treatment or referral for care as appropriate may be a great benefit to the lives of mothers with postpartum depression and their infants.
Psychotherapy and antidepressant medications are the standard treatments of postpartum depression. For nursing mothers with postpartum depression, interpersonal therapy may be an effective option for first-line treatment. During the short term, other psychological and psychosocial therapies have also been shown to be effective in postpartum depression symptom relief.
Various studies have reported that women receiving IPT [interpersonal therapy] have reduced depressive symptoms over time compared to their wait-listed or control counterparts," Dr. Breese McCoy writes. "Because there is some risk of side effects to nursing infants of mothers who are taking antidepressants, IPT is a logical first line of treatment for depressed, breastfeeding women. Another type of therapy which may also be effective for mild cases of PPD is an abbreviated form of IPT known as Interpersonal Counseling (IPC)."
In pharmacotherapy, the selective serotonin reuptake inhibitor sertraline is considered the drug of choice for women who are breast-feeding. Because few adverse effects have been observed in breast-fed infants, sertraline is thought to be relatively safe. Although other antidepressants, such as paroxetine and nortriptyline, are effective, breast-fed infants are at highest risk from exposure to antidepressants through breast milk during the first 8 weeks of life. Timing of nursing or breast milk expression to coincide with trough serum levels of antidepressants may help lower the prevalence and severity of adverse effects.
Other interventions that may help selected patients include correction of a contributing condition such as thyroiditis or insomnia, as well as regular aerobic exercise and/or massage. The mother's partner giving her a massage for 20 minutes twice weekly or more may be helpful in alleviating postpartum depression, as well as the mother massaging the baby.
Therapy aimed at regulating the release of melatonin may improve altered sleep patterns implicated in postpartum depression, thereby improving outcomes. For example, sleeping in the dark at night and avoiding blue light in particular may help regulate melatonin cycles and help prevent postpartum depression.
"The postpartum period is a stressful time of transition, both physically and psychologically," Dr. Breese McCoy concludes. "PPD makes this phase of life especially burdensome and difficult for some women. Primary care physicians who are aware of this issue, who reach out with compassion and help, are in a unique position to lessen the pain of both mothers and their babies."
Overall Ill Health Predicts Alzheimer's and Dementia Risk
By Barbara Boughton
Neurology. Published July 13, 2011.
July 15, 2011 — For the first time, researchers have found that overall ill health and physical deficits not traditionally associated with cognitive decline — such as poorly fitting dentures, arthritis, bone fractures, or skin problems — may influence the risk for dementia and Alzheimer's disease (AD).
In the Canadian study of 7239 participants without dementia at baseline, a cumulative "frailty index" had a powerful effect on the risk for Alzheimer’s disease or other types of dementia 10 years later. Those who had no health problems at baseline had an 18% risk for developing dementia in 10 years, and those who had 8 or 12 health problems had a 30% or 40% risk for dementia, respectively (P < .001).
The researchers' "frailty index" — adapted from previous research — is a measure of 19 different health deficits that have been seen in the elderly but have not previously been reported to predict dementia. Although higher scores on the cumulative index predicted the development of dementia or Alzheimer’s disease, each health deficit increased risk by only 3.2% (P = .021).
"The message of the study is that while health factors may individually have a small effect on risk of Alzheimer's disease, they can cumulatively have a big important effect," said Kenneth Rockwood, MD, professor of geriatric medicine and neurology at Dalhousie University in Halifax, Nova Scotia, Canada, senior author of the study.
"In our study we were not trying to predict the true risk of Alzheimer's disease. It's a way to draw attention to the idea that an illness such as Alzheimer's disease probably has more than one cause," Dr. Rockwood said.
Their results were published online July 13 in Neurology.
Canadian Study of Health and Aging
The participants in the study were part of the Canadian Study of Health and Aging, a well-characterized epidemiologic cohort. Those free of dementia at baseline were screened for health problems and were assessed for cognitive and health deficits at 5 and 10 years.
After 10 years, 2915 of the participants had died, and of those that remained, 416 had AD and 191 had other types of dementia. According to the study authors, 677 patients had cognitive problems but no dementia after 10 years, and the cognitive status of 1023 people was uncertain.
In an editorial that accompanied the publication of the study in Neurology, Jean Francois Dartigues, MD, PhD, noted that the findings of this novel study should be interpreted cautiously given the wide number of factors evaluated and the possibility that poorly measured confounders could have affected the results.
"In spite of these limitations…these findings showed that general health problems not known to be directly linked to the pathophysiology of AD could be implicated in disease occurrence, expression or progression," Dr. Dartigues writes.
Dr. Rockwood agreed that the findings need to be replicated in future studies. Other limitations of the study included its epidemiologic nature and the lack of autopsy validation and routine neuroimaging. The researchers plan future studies in which imaging will be used to study structural changes in the brain and their possible correlation with traditional and nontraditional risk factors for dementia, he said.
"There's a danger that our work could be overinterpreted," Dr. Rockwood said. "Our research clearly shows that individual risk factors were not associated with Alzheimer's disease risk," he added. To validate the data, replication in a larger database that includes more risk factors is also a necessity.
Dr. Rockwood noted that the physical health deficits that made up the Canadian researchers' "frailty index" may be unrelated, but they may inflict insults to the brain that put into motion similar aberrant repair mechanisms. And the accumulated result may be the damage seen in the brains of patients with AD.
"This study makes perfect sense because all the deficits that the researchers looked at — even problems such as badly fitting dentures — cause inflammation," commented George Bartzokis, MD, professor of psychiatry at the University of California, Los Angeles, David Geffen School of Medicine. "And inflammation can hurt the brain."
Dr. Bartzokis noted that it is now understood that those who are less able to recover after inflammatory insults are more likely to get dementia earlier in life. "They are, simply put, 'bad repairers,' " he said.
"The message for physicians from this study is that they should be insistent with their patients about maintaining overall health," Dr. Barzokis added. "Because once you get Alzheimer's disease, you can't change its course. The only thing you can do is try to change your risk factors."
Healthy habits — whether that means exercising regularly or eating healthily — will not only improve general health in the elderly but have implications for the brain as well, Dr. Barzokis said.
The study was funded by the Canadian Institutes of Health Research, the Nova Scotia Health Research Foundation, and the Alzheimer Society of Canada. Dr. Rockwood has served on a scientific advisory board for Elan Corp./Wyeth; has received speaker honorarium from Bristol-Myers Squibb; and has served as an expert witness for Tory’s LLP, on behalf of Eisai Inc., and for Pfizer Inc. Canada. Dr. Dartigues has served on a scientific advisory board for Janssen, Novartis, and Eisai Inc.; has received honoraria from Novartis, Janssen, Ipsen, and Eisai Inc.; has received funding for travel from Janssen and Pfizer; has served as a consultant for Merck Serono; and has received research support from Novartis, Eisai Inc., and Ipsen. Dr. Bartzokis has disclosed no relevant financial relationships.
Cognitive Therapy Better Than Interpersonal Psychotherapy for Social Anxiety
Arch Gen Psych 2011
NEW YORK (Reuters Health) Jul 08 - Cognitive therapy and interpersonal psychotherapy (IPT) each produce considerable and lasting improvements in symptoms of social anxiety disorder (SAD), new results indicate.
But CT works better than IPT for reducing social anxiety and "should be the preferred psychological treatment" for that indication, said Dr. Ulrich Stangier from University of Frankfurt and colleagues in the July Archives of General Psychiatry.
The researchers say theirs is the first direct comparison of CT and IPT for outpatients with social anxiety disorder. At two research centers in Germany - one specializing in CT, the other in IPT - they randomly assigned 117 patients to either CT (n = 38) or IPT (n = 38) in 16 individual sessions over 20 weeks, plus one booster session, or to a wait-list control group (n = 41).
According to the investigators, both CT and IPT were associated with significantly greater easing of SAD symptoms compared with no treatment (wait list) and CT was considerably more effective than IPT.
On the primary outcome measure, the Clinical Global Impression Improvement Scale, 66% of patients who received CT showed marked improvement in social-phobic symptoms at the 20 week posttreatment assessment, compared with 42% of patients who received IPT and 7% of those in the wait-list control group.
At the one-year evaluation, the CT group still had a significantly higher response rate (68% vs 32%). In addition, patients who received IPT were much more likely to have had additional nonprotocol treatment during follow up.
The pattern was similar when assessors used the Liebowitz Social Anxiety Scale, the Hamilton Rating Scale for Depression, and patient self-ratings of SAD symptoms.
The authors had not expected that CT would be superior to IPT, and they don't know which components of CT might have led to its larger effects.
"Because the two treatments differ with respect to the explicit targets for psychotherapeutic change, CT might tackle aspects that are of greater relevance to the etiology of SAD," they wrote.
They add it's also possible that interpersonal problems may be more likely to resolve when the underlying dysfunctional cognitions and safety avoidance behaviors are effectively modified.
But CT works better than IPT for reducing social anxiety and "should be the preferred psychological treatment" for that indication, said Dr. Ulrich Stangier from University of Frankfurt and colleagues in the July Archives of General Psychiatry.
The researchers say theirs is the first direct comparison of CT and IPT for outpatients with social anxiety disorder. At two research centers in Germany - one specializing in CT, the other in IPT - they randomly assigned 117 patients to either CT (n = 38) or IPT (n = 38) in 16 individual sessions over 20 weeks, plus one booster session, or to a wait-list control group (n = 41).
According to the investigators, both CT and IPT were associated with significantly greater easing of SAD symptoms compared with no treatment (wait list) and CT was considerably more effective than IPT.
On the primary outcome measure, the Clinical Global Impression Improvement Scale, 66% of patients who received CT showed marked improvement in social-phobic symptoms at the 20 week posttreatment assessment, compared with 42% of patients who received IPT and 7% of those in the wait-list control group.
At the one-year evaluation, the CT group still had a significantly higher response rate (68% vs 32%). In addition, patients who received IPT were much more likely to have had additional nonprotocol treatment during follow up.
The pattern was similar when assessors used the Liebowitz Social Anxiety Scale, the Hamilton Rating Scale for Depression, and patient self-ratings of SAD symptoms.
The authors had not expected that CT would be superior to IPT, and they don't know which components of CT might have led to its larger effects.
"Because the two treatments differ with respect to the explicit targets for psychotherapeutic change, CT might tackle aspects that are of greater relevance to the etiology of SAD," they wrote.
They add it's also possible that interpersonal problems may be more likely to resolve when the underlying dysfunctional cognitions and safety avoidance behaviors are effectively modified.
