Allison Gandey

June 22, 2011 — The evidence is limited when it comes to cell phones and cancer risk, but specialists say common-sense measures can come into play until the science catches up with technology.

The issue is back in the news after the World Health Organization’s (WHO’s) recent announcement that cell phone use should be considered “possibly carcinogenic.” There are an estimated 5 billion mobile phones in use around the world.

The working group from the organization’s International Agency for Research on Cancer (IARC) was careful not to make any firm conclusions.

A hands-free device places more distance between the mobile phone and the brain.

“The evidence, while still accumulating, is strong enough to support a conclusion and the 2B classification,” reported Working Group Chair Jonathan Samet, MD, from the University of Southern California in Los Angeles. This category is used for agents when there is limited evidence.

Others have suggested a cancer risk before, but the organization’s consortium is the most significant to classify the radiation emitted by cell phones in this way.

Still, the group, which consists of 31 scientists from 14 countries, avoided calling cell phones carcinogenic and passed on classifying them even as probably cancer causing.

This has left some practicing clinicians shaking their heads in annoyance as cancer fears ripple through the community.

“The classification the working group selected is very weak, and I think people are now focusing too much on the possibly carcinogenic part,” neuro-oncologist Lynne Taylor, MD, from Virginia Mason Medical Center in Seattle, Washington, said in an interview.

Dr. Taylor says she agrees that more research is necessary, but this won’t affect how she uses her cell phone or counsels patients. “This is not anything to worry about,” she said.

“I think that any problems reflect the subtlety of ‘possible,’ which by no means indicates an established carcinogen,” Dr. Samet told Medscape Medical News. Despite some misunderstanding, he added, “many have interpreted the statement correctly.”

However, Dr. Samet acknowledged, “anyone concerned about risk can take steps to reduce exposure by using a hands-free device or texting. Additionally, current phones have lower outputs than the older phones that were investigated in the epidemiological studies.”

The Lancet Oncology published the WHO’s full working group report online June 22. Interestingly, it appears that not all members of the IARC working group were completely in agreement either on how to view the risk for cancer from cell phone use.

Their conclusions were based on several studies, the published report notes. Results of the INTERPHONE study published in 2010 showed that overall those having ever used a cell phone appeared to be at a slightly lower risk of developing glioma than never users. However, when the researchers considered the top 10% of cell phone users, those with a total exposure of 1640 hours or more, there was a 40% increase in risk vs never users. There was also some indication of increased risk for ipsilateral exposure and for tumors in the temporal lobe where radiofrequency exposure was highest.

The working group also reviewed a combined analysis of Swedish studies showing participants who’d used a cell phone for more than a year had a 30% increase in glioma risk vs never users. The risk increased with increasing time since first use and with total call time, reaching a hazard ratio of 3.2 for greater than 2000 hours of use; ipsilateral use was also associated with higher risk.

“Although both the INTERPHONE study and the Swedish pooled analysis are susceptible to bias — due to recall error and selection for participation — the working group concluded that the findings could not be dismissed as reflecting bias alone and that a causal interpretation between mobile phone RF-EMF [radiofrequency electromagnetic field] exposure and glioma is possible.”

However, a Danish study that analyzed cancer rates and subscriptions for cell phones from 1982 and 1995 showed no increased risk for glioma or other brain cancers among users of cell phones. A number of earlier and smaller case-control studies had also shown no connection, the study authors note.

Given these divergent findings, not all members of the group agreed on how to interpret the overall evidence, the study authors acknowledge. “A few members of the working group considered the evidence in humans ‘inadequate,’” the final report notes. “In their opinion, there was inconsistency between the 2 case-control studies and a lack of exposure-response relationship in the INTERPHONE study results; no increase in rates of glioma or acoustic neuroma was seen in the Danish cohort study, and up to now, reported time trends in incidence rates of glioma have not shown a parallel to temporal trends in mobile phone use.”

Still, they conclude that given the limited evidence in humans and experimental animals, RF-EMF should be classified as “possibly carcinogenic to humans” with a Group 2B classification. “The evaluation was supported by a large majority of working group members,” the study authors note.

Cancer Agencies Respond

After initial announcement of the WHO report, several major agencies moved quickly to respond to these new conclusions that have been widely reported in the consumer press. In a statement, the National Cancer Institute pointed out, “This is neither new research nor at odds with previous findings.”

The institute acknowledged it agrees with the working group that continued monitoring of both brain cancer trends and new evidence from studies is called for.

However, they point out that INTERPHONE, “considered the major study on cell phone use and cancer risk, has reported that overall, cell phone users have no increased risk of the most common forms of brain tumors — glioma and meningioma.” The study showed no increased risk associated with progressively increasing number of calls, longer call time, or years since beginning cell phone use, the statement notes. “For the small proportion of study participants who reported spending the most total time on cell phone calls, there was some increased risk of glioma, but the researchers considered this finding inconclusive.”

The National Toxicology Program at the National Institute of Environmental Health Sciences is currently leading the largest laboratory rodent study to date on cell phone radiofrequency exposures and potential health hazards, the institute statement adds. “The studies are designed to mimic human exposure and are based on the frequencies and modulations currently in use in the United States.”

The bottom line is the evidence is enough to warrant concern, but it is not conclusive.

The American Cancer Society has also weighed in. “This report comes from a very credible group and reaches reasonable conclusions about electromagnetic radiation from cell phones and other devices,” Chief Medical Officer Otis Brawley, MD, said in a statement.

“It is critical that its findings be interpreted with great care,” he cautions. “The working group reviewed a large number of studies and concluded that there was limited evidence that cell phones may cause glioma.” The bottom line, Dr. Brawley said, “is the evidence is enough to warrant concern, but it is not conclusive.”

Radiofrequency Exposure

The fear is that radiofrequency electromagnetic fields produced by cell phones may affect the brain and other tissues because handheld devices are usually held close to the head. Researchers are looking at whether radiofrequency energy can cause malignant brain tumors, such as gliomas, as well as benign tumors, including acoustic neuromas and meningiomas. The WHO report notes that third-generation (3G) mobile phones emit about 100 times less radiofrequency energy than global system for mobile communications (GSM) handsets, when signals are strong. They also highlight that the average output power of Bluetooth wireless hands-free kits is estimated to be around 100 times lower than that of mobile phones.

The current concern does not extend to cordless phones. Commonly used in homes, these devices have base units that are plugged into phone jacks that are wired to a local telephone service and operate at about 1/600 the power of cell phones.

The US Food and Drug Administration and the Federal Communications Commission have not linked cell phone use to cancer risk but have long recommended steps that cell phone users can take if they are concerned:

• Reserve cell phone use for shorter conversations or for times when a land line is not available; and
• Use a hands-free device that will place more distance between the mobile phone and the brain.

A cell phone user’s level of exposure to radiofrequency depends on several factors, including the number and duration of calls, the amount of cell phone traffic at a given time, the distance from the nearest cellular base station, the quality of the cellular transmission, the size of the handset, and, for older phones, how far the antenna is extended.

In a recent study published in the Journal of the American Medical Association, investigators found that using a cell phone for as little as 50 minutes at a time appears to affect brain glucose metabolism in the region closest to the phone’s antenna.

The researchers used positron emission tomography during cell phone use in the on and then off positions and found that although whole-brain metabolism was not affected, metabolism was increased in the orbitofrontal cortex and the temporal pole areas of the brain while the cell phone was on — areas close to where the phone’s antenna meets the head.

However, the researchers, with lead author Nora Volkow, MD, from the National Institute on Drug Abuse in Bethesda, Maryland, acknowledge that it’s not clear at this point whether this increase in metabolism is a good or bad thing. Increasing glucose metabolism could potentially have a positive effect in certain therapeutic situations.

Still, like Dr. Samet, Dr. Volkow recommends that cell phone users wanting to play it safe consider hands-free devices or speaker-phone mode to avoid direct contact of the cell phone with the head.

Worse for Children?

According to the National Cancer Institute and the American Cancer Society, there are currently no data on cell phone use and cancer risk in children. Even though cell phone use by children and adolescents is rising rapidly, no published studies to date have included young people.

Children may be at greater risk because their nervous systems are still developing. A large case-control study of childhood brain cancer in several Northern European countries is now under way.

Researchers from the Centre for Research in Environmental Epidemiology in Spain are conducting an international study known as Mobi-Kids to evaluate risk from new communications technologies and other environmental factors in young people ages 10 to 24 years.

There is no consensus among physicians and scientists about the severity of risk, or even if one exists. One of the many hurdles in evaluating a potential connection between cancer and cell phone use is the relatively short period these devices have been heavily used in a large population and the long latency period for many tumors.

Most teenagers are texting, and that’s probably the most appropriate use for mobile phones.

Dr. Taylor says that for younger patients taking precautions makes sense. “Most teenagers are texting, and that’s probably the most appropriate use for mobile phones. It’s the people from my generation who are more likely to be pressing their cells against their ears. With teens, the focus of my attention will be to remind them not to text and drive or use their cell phone at all in the car.”

She adds it probably isn’t appropriate for very small children to be using cell phones anyway. “So that solves that.”

While the evidence remains uncertain, Dr. Brawley added, it is up to each individual to determine what changes they wish to make after weighing the potential benefits and risks of using a cell phone.

“Limiting use among children also seems reasonable in light of this uncertainty. On the other hand, if someone is of the opinion that the absence of strong scientific evidence on the harms of cell phone use is reassuring, they may take different actions, and it would be hard to criticize that.”

Michael O’Riordan

June 21, 2011 (London, United Kingdom) — A meta-analysis of some of the more high-profile statin trials testing the effectiveness of high-dose therapy has revealed a significant increase in the risk of diabetes mellitus associated with statin use in high doses [1]. Compared with moderate-dose therapy across five statin trials, investigators report that treatment with high-dose statins increased the risk of diabetes by 12%.

Senior investigator Dr Kausik Ray (St George’s University of London, UK) said that while there might be consequences from the raised blood glucose levels, researchers do not yet know what these long-term effects mean. The net benefit of high-dose statin therapy “is definitely in favor” of using the drugs, he said.

“One thing we do know is that there does appear to be a dose effect with statin therapy, with the risk of diabetes mellitus increasing with higher doses,” Ray told heartwire . “Statins have multiple effects and cause a number of changes. What we’re seeing is probably an off-target effect, and right now we have no obvious mechanisms. However, lowering LDL-cholesterol levels is probably more important than the increase in blood-sugar levels.”

In their analysis, the number of patients needed to treat with high-dose statin therapy to prevent one cardiovascular event was 155, whereas the number needed to treat to cause one case of new-onset diabetes mellitus was 498. Overall, high-dose statin therapy reduced the risk of cardiovascular events in their meta-analysis by 16% compared with low- or moderate-dose statin therapy.

The results of the study are published in the June 22, 2011 issue of the Journal of the American Medical Association.

Previous Observed Diabetes Risk

Speaking with heartwire , Ray said that the idea for the meta-analysis began two years ago, when the signal for diabetes risk was observed in Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER). The group later performed an analysis of some of the early statin trials comparing the lipid-lowering drugs with placebo in 90 000 individuals and observed a significant 9% increase in the risk of diabetes mellitus. That study was reported in the Lancet in 2010 [2].

In this newest analysis, the researchers included large, randomized, controlled, hard-end-point studies that compared intensive–dose statin therapy with moderate-dose statin therapy followed for more than one year. The trials included in the meta-analysis were PROVE-IT, A to Z, TNT, IDEAL, and SEARCH, five trials that together included 32 752 patients without diabetes mellitus at baseline.

“We wanted to look at the different studies comparing the intensity of statin treatment,” said Ray. “If the diabetes finding was a real finding, we would expect to see it in the statin trials that tested different intensities of treatment in about 33 000 subjects. The trials all ranged from two to five years in duration, and we had information from five trials comparing high versus low/moderate treatment doses. Our results support our initial findings. We observed a 12% increase in risk for those patients treated with high-dose statin therapy.”

In total, 1449 patients treated with high-dose statin therapy developed diabetes compared with 1300 patients assigned to moderate-dose statin therapy. This translated into two additional cases of diabetes mellitus per 1000 patient-years. The odds ratio for new-onset diabetes was 1.12 (95% CI 1.04–1.22). Regarding benefit, 3134 patients treated with high-dose statin therapy and 3550 patients treated with moderate-dose therapy had a cardiovascular event, translating into 6.5 fewer outcomes per 1000 patient-years in the high-dose statin arm, or a relative reduction of 16%.

The investigators did observe differential effects with the different drugs. Whereas atorvastatin 80 mg and simvastatin 80 mg were both associated with similar risks of diabetes mellitus, the benefit differed significantly, with evidence in favor of atorvastatin (22% vs 5% risk reduction for cardiovascular events). The data, said Ray, support the recent Food and Drug Administration (FDA) decision to warn physicians to not start new patients on simvastatin 80 mg and to be vigilant to the risks of muscle toxicity caused by the drug in those who are still taking it.

Getting Patients to Goal

Speaking with heartwire about the results, Dr Brendan Everett (Brigham and Women’s Hospital, Boston, MA), who was not involved in the analysis, agreed with the conclusions of Ray and colleagues, that the signal observed in this latest analysis supports the findings from JUPITER and the Lancet meta-analysis “and supports the idea of a dose effect, that there is an increasing risk of diabetes with increasing doses of statins.”

Everett said the investigators helped clinicians by providing data on the relative benefits and relative harms of high-dose statin therapy. The number needed to treat to prevent one cardiovascular event and number needed to treat to cause one new case of diabetes mellitus clearly support the use of high-dose statin therapy in the patients studied in the five clinical trials.

“The benefits of statins for reducing important macrovascular events is so overwhelming that the balance is clearly on the side of benefit,” said Everett. “This is an important point that shouldn’t be forgotten.”

Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) agreed, stating that while “it makes sense that higher doses [of statins] would have slightly higher adverse effects,” there is still no proposed mechanism for the increased risk of diabetes. Like the others, he told heartwire that the benefits of moderate/high doses of statins outweigh the risks, although he added that some physicians might decide to downgrade the dose based on these new data.

In addition, Dr Steven Nissen (Cleveland Clinic, OH) told heartwire that the effect is likely real as it has been observed in enough trials and analyses. That said, “it is notable that despite the increase in the risk of diabetes mellitus, the reduction in cardiovascular morbidity and mortality is maintained,” he added. “It leads me to believe that the effect is not very clinically significant.”

Everett added that what is currently unknown is how the risks of diabetes mellitus differ in other patient populations. Clinicians need to understand their patients’ baseline risks of cardiovascular disease and diabetes mellitus when making a decision about high-dose statin therapy, and it will be important to determine whether patients at greater risk for adverse side effects can be identified. Researchers will also need to determine what effects high-dose statin therapy has on microvascular complications, such as retinopathy.

“The bottom line is that we need to follow up on the signal, but I don’t believe the results should change treatment goals,” said Everett. A failure to aggressively treat patients at high risk for cardiovascular events will result in an excess of clinical events, he added.

To heartwire , Ray suggested that clinicians monitor Hb_A1c levels when treating patients with high-dose statin therapy.

Like Ray, Everett said the results support the FDA decision regarding simvastatin 80 mg, that the drug is associated with more side effects without a corresponding balance of efficacy. In the interest of getting patients to treatment goal and trying to do so in a cost-efficient manner, some physicians had been using high-dose simvastatin. However, if they are unable to get to goal at 40-mg simvastatin, switching over to other, nongeneric drugs is not difficult, although it does involve extra paperwork when dealing with drug payers, he said.

This Sunday at the American Diabetes Association (ADA) 2011 Scientific Sessions, Dr David Preiss (University of Glasgow, Scotland), the first author of the analysis, will present their data at a special symposium organized by the ADA and FDA. The presentation will highlight the newly observed risks with high-dose statin therapy, as well as their Lancet analysis of 13 randomized trials comparing placebo and standard-therapy trials.

Megan Brooks

June 21, 2011 — Most adults in the United States who have peripheral artery disease (PAD) do not receive secondary preventive treatments that could reduce their risk for myocardial infarction (MI), stroke, and death, according to a report published online June 20 in Circulation.

The authors note that current guidelines for the management of patients with PAD recommend lipid-lowering therapy with a statin to achieve a goal LDL-cholesterol level of less than 100 mg/dL (or <70 mg/dL in high-risk patients), antihypertensive therapy to achieve systolic blood pressure lower than 140 mm Hg, and antiplatelet therapy.

Most studies of secondary prevention have included patients with PAD with previously recognized symptomatic disease, such as intermittent claudication or prior peripheral revascularization. Whether current guidelines can be extended to patients with asymptomatic PAD who have been identified by population screening using ankle-brachial index (ABI) has not been well studied.

“[O]ur data suggest that combination therapy with multiple risk-modifying therapies may be associated with clinical benefit in a population of individuals defined solely by an abnormal ABI,” report Reena L. Pande, MD, and colleagues from Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.

7 Million Americans Have PAD

The researchers analyzed data on 7458 adults aged 40 years and older from the National Health and Nutrition Examination Survey (1999 – 2004), with mortality follow-up through the end of 2006.

The prevalence of PAD, defined as a low ABI of 0.90 or less, was 5.9%, which corresponds to roughly 7.1 million US adults with PAD.

Among these participants, statin therapy was reported in only about 30%, angiotensin-converting enzyme inhibitors/angiotensin receptor blocker therapy in roughly 25%, and aspirin therapy in about 36%. These percentages correspond to 5.0 million adults with PAD not taking statins, 5.4 million not taking an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and 4.5 million not receiving aspirin, the authors calculate.

After adjusting for age, sex, and race/ethnicity, PAD was associated with a greater than 2-fold increased risk for death (hazard ratio, 2.4; 95% confidence interval [CI], 1.9 – 2.9; P < .0001) during an average follow-up of 4.4 years.

Even after excluding adults with known cardiovascular disease, adults with PAD had higher death rates (16.1%) than those without PAD or cardiovascular disease (4.1%), with an adjusted hazard ratio of 1.9 (95% CI, 1.3 – 2.8; P = .001). “Thus, patients with PAD remain at high risk of all-cause mortality even in the absence of established cardiovascular disease,” the authors note.

Importantly, they say, use of 2 or more preventive therapies was associated with a 65% lower rate of death from any cause (hazard ratio, 0.35; 95% CI, 0.20 – 0.86; P = .02) in adults with PAD, but without cardiovascular disease.

“These observational findings highlight the critical need for a large-scale clinical trial to determine whether the implementation of secondary prevention therapies in high-risk individuals identified by ABI screening as having PAD can reduce mortality and cardiovascular events,” the investigators write.

The study was supported in part by grants from the National Heart, Lung and Blood Institute. The study authors are supported via grant funding from the institute and the American Heart Association. The authors have disclosed no relevant financial relationships.

Circulation. Published online June 20, 2011. Abstract

Fran Lowry

June 22, 2011 (Boca Raton, Florida) — Citicoline, a naturally occurring substance found in the brain and liver and marketed as a nutritional supplement, enhanced aspects of cognition in healthy women and may have a role in mitigating the cognitive decline associated with normal aging, new research suggests.

It may also improve the attentional deficits associated with psychiatric disorders, said Erin McGlade, PhD, from the University of Utah Brain Institute, Salt Lake City, who led the study.

“We chose to study citicoline because in prior research it showed cognitive enhancing effects with very few side effects, which is very important when using a supplement,” Dr. McGlade told Medscape Medical News.

“We think these changes in cognition include improvement in attention perhaps due to an increase in brain dopamine levels, but findings regarding dosing in healthy individuals have not been conclusive.”

The study was presented here at the New Clinical Drug Evaluation Unit 51st Annual Meeting, sponsored by the American Society of Clinical Psychopharmacology.

Improvement ‘Noteworthy’

Dr. McGlade and colleagues recruited 60 women between the ages of 40 and 60 years and screened them to rule out Axis 1 or Axis 2 psychiatric disorders and any kind of cognitive deficits beyond the average cognitive decline associated with aging.

The women were divided into 3 groups of 20 and randomized to receive a daily oral dose of 250 mg (low dose) of citicoline, 500 mg (high dose) of citicoline, or placebo for 28 days.

They were evaluated with the Continuous Performance Test II (CPT-II) to measure attention functioning just after randomization and at the end of the study period.

The investigators found that those who received either the low or high dose of citicoline showed improved attention, demonstrating fewer commission and omission errors on the CPT-II test compared with the placebo group.

“Women receiving the supplement made fewer errors in response to nontarget stimuli over the course of the study,” Dr. McGlade said.

“Interestingly, the 250 [mg] dose produced similar results to the larger dose. The improvement was quite noteworthy, with a P value equal to .02 for the 250-mg dose and a P value equal to .03 with the 500-mg dose, and this was just after 28 days, so the effect was relatively rapid as well,” she said.

It is important to know that a supplement such as citicoline can have an effect on attention without adverse effects, she added.

Future work will determine the utility of citicoline in psychiatric disorders to see whether it will lessen some of the associated attentional deficits that are associated with these disorders, Dr. McGlade said.

Large Potential Market

Citicoline is one of the few pyrimidines available as a nutritional supplement in the United States and Canada, noted Perry Renshaw, MD, PhD, professor of psychiatry at the University of Utah, Salt Lake City.

“Among other things, pyrimidines increase brain phospholipid synthesis, which is responsible for the therapeutic efficacy of citicoline as a treatment for stroke and head trauma, and they also increase catecholamine synthesis, which probably is responsible for citicoline’s effect on attention,” said Dr. Renshaw, who was not part of the current study.

“The study by McGlade and colleagues is significant in that it documents proattentional effects at a dose as low as 250 mg. Pharmaceutical doses as high as 4000 mg have been evaluated. If this effect can also be documented in other populations, such as children and teens, it suggests that citicoline would have a large market in the brain health area,” he said.

The study was funded by Kyowa Hakko Bio Co Ltd, the manufacturers of the citicoline that was used in the study. Dr. McGlade has disclosed no relevant financial relationships. Dr. Perry has reported financial relationships with Ridge Diagnostics and Kyowa Hakko.

New Clinical Drug Evaluation Unit (NCDEU) 51st Annual Meeting: Abstract 50. Presented June 14, 2011.

Deborah Brauser

June 22, 2011 (Pittsburgh, Pennsylvania) — A major issue facing the field of psychiatry today may not be that children in the United States are being overdiagnosed with bipolar disorder (BD) but that many clinicians do not truly understand the complexities of this type of diagnosis.

Gabrielle A. Carlson, MD, professor of psychiatry and pediatrics and director of the Child and Adolescent Psychiatry Department at the Stony Brook University School of Medicine in New York, said that no formula currently exists for accurately diagnosing BD in children.

Dr. Gabrielle A. Carlson

“A certain amount of humility is needed, and it is extremely important to clarify symptoms. Remember: context matters,” Dr. Carlson told delegates attending the Ninth International Conference on Bipolar Disorder.

Boris Birmaher, MD, professor of psychiatry and endowed chair in early-onset bipolar disease at the University of Pittsburgh School of Medicine and Western Psychiatric Institute and Clinic in Pennsylvania, agreed.

Dr. Boris Birmaher

During his presentation, he said a diagnosis of BD can be difficult because it is highly comorbid and overlaps with symptoms of other illnesses, including attention-deficit/hyperactivity disorder (ADHD).

“As a field, we’re also looking at the issues of periodicity vs chronicity in bipolar disorder (in our practice we require that a child has definite episodes), the definition of rapid cycling, and the differences between narrow vs broad bipolar disorders.

“The big questions today are: What is the prevalence of bipolar in children? Is it more prevalent in the US than in other countries?” said Dr. Birmaher.

United States on Par With Other Countries

He discussed a new analysis published online May 31 in the Journal of Clinical Psychiatry that assessed 12 epidemiologic studies conducted between 1985 and 2007. The investigators evaluated the prevalence of pediatric BD in children from 8 countries between the ages of 7 and 21 years and found diagnosis rates ranged from 0% (in Ireland) to 3%, the same range found in the United States.

“Another study that included a very broad definition of manic symptoms found that that rate could go up to 5%. But still, all of this shows that we are not very different from other countries,” said Dr. Birmaher.

However, a previous study (Arch Gen Psychiatry. 2007;64:1032-1039) showed that the number of physician visits ending in a diagnosis of pediatric bipolar in the United States increased significantly during 10 years.

“There was a 40-fold increase in the rate of visits for these children compared to adults, but we need to be careful to look at the absolute numbers. For example, if you go from 1 diagnosis to 2, that’s an increase of 100%,” Dr. Birmaher explained.

A 2010 national trends study (Bipolar Disorders. 2010;12:155-162) showed rates of BD diagnoses increased from 1.13 to 1.91 per 100,000 inpatients in Germany from 2000 to 2007.

“This was technically an increase of 68%, but really it was only up from 1 to 2 per 100,000 people,” said Dr. Birmaher.

“It does not seem that the prevalence of bipolar 1 or 2 is higher in the US, but the diagnosis of subsyndromal forms is higher than in other countries.”

Pendulum Can Swing Both Ways

“Pediatric bipolar exists, but we need to be careful because its diagnosis can be difficult,” he said. Dr. Birmaher added that it is especially challenging when trying to identify core symptoms, such as grandiosity and elation in young children.

He noted that although some children are being misdiagnosed as having BD, the opposite is also true. There are many children, he said, who have BD but whose conditions are misdiagnosed and treated inappropriately.

“This is something we need to be aware of because bipolar seriously affects the normal development of a child and increases their risk of suicide, substance abuse, and psychosocial problems. Early recognition and appropriate treatment are most important.”

Dr. Carlson also discussed the difficulties of diagnosing BD.

“It takes me 3 hours to do an evaluation….This is not something that you just take 30 minutes and get the person in and out. Even when it looks like a kid meets the criteria for [BD], time and effort are necessary before you say, ‘I unequivocally know this is bipolar,’ “she said.

‘Profound’ Implications

In a study that has recently been accepted for publication, Dr. Carlson and colleagues assessed the implications of parent and teacher concordance on the Child Mania Rating Scale in 911 children between the ages of 5 and 18 years.

A total of 7.3% of the participating children were found to have a BD. Of these, 20 had BD type 1, 3 had BD type 2, and 43 had BD not otherwise specified.

Although a high parent rating score of manic symptoms (>15) was more associated with a diagnosis of BD than a low score, the child usually ended up having ADHD or oppositional defiant disorder (ODD).

In addition, when the parent rating was high and the teacher rating low, the diagnosis was usually an anxiety disorder, she said.

“The implications are pretty profound. If you think a kid is having a rapidly cycling disorder and in fact they have an anxiety disorder, you’re going to use very different treatments.”

In a 2010 study (Bipolar Disorders. 2010;12:205-212), Dr. Carlson and colleagues also assessed whether rages are actually manic episodes in 130 children between January 2003 and June 2004. Most were hospitalized for parent-reported rages.

Although the parents often reported manic symptoms, the investigators found that BD usually did not explain the episodes because 84.8% of the children had 1 or fewer rages while in the hospital.

“Not surprisingly, community clinicians were more likely to give a diagnosis of bipolar to these kids. But rages are a fairly nonspecific manifestation of a lot of different conditions, such as ODD, autism, posttraumatic stress disorder, schizophrenia, and more.”

She noted that although all of the structured assessments appear useful, “especially in the hands of someone who knows what mania and depression are,” the tools are not easily translated “to people who don’t understand phenomenology, development, and the breadth of child and adolescent assessment.

“It is not just saying, ‘if your parent has bipolar, you must have it too.’ It’s not a simple, quick, and dirty diagnosis.”

9th International Conference on Bipolar Disorder (ICBD): Concurrent Session 3, No. S1. Presented June 11, 2011.

Medscape Medical News © 2011 WebMD, LLC

Fran Lowry

June 22, 2011 (Boca Raton, Florida) — The investigational GABA-B agonist arbaclofen improved irritability and agitation in children with autism spectrum disorder (ASD), new research suggests.

A phase 2, randomized, crossover trial of arbaclofen vs placebo in fragile X syndrome showed improved ratings of social behavior when children were taking arbaclofen, said lead investigator Jeremy Veenstra-VanderWeele, MD, from Vanderbilt University, Nashville, Tennessee.

These promising results prompted the current study, he told Medscape Medical News.

“Fragile X is the most common known inherited cause of autism, but it only accounts for about 5% of kids. In this study, we wanted to see if arbaclofen would be well tolerated and what improvements we might see in children and adolescents with idiopathic autism spectrum disorder,” Dr. Veenstra-VanderWeele said.

The findings were presented here at the New Clinical Drug Evaluation Unit 51st Annual Meeting, sponsored by the American Society of Clinical Psychopharmacology.

Significant Improvement

The 8-week, open-label, flexible-dose trial was performed at 8 sites throughout the United States and included 25 children ages 6 to 17 years. All participants had a diagnosis of ASD according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria and the Autism Diagnostic Interview and had an Aberrant Behavior Checklist irritability (ABC-I) score greater than 16.

The children were allowed to be taking up to 2 concurrent psychoactive medications, with the exception of antipsychotics.

The investigators found that, overall, arbaclofen was well tolerated. Two children discontinued use of the drug because of increased agitation or aggression, and 5 dropped out for other reasons. There was 1 serious adverse event in the form of increased aggression, which occurred during planned taper of arbaclofen.

In the intent-to-treat population, the study found a significant improvement on both parent-rated scales and physician-rated scales, Dr. Veenstra-VanderWeele said.

The ABC-I score went from a mean ± SD of 24.7 ± 8.3 at the start of the study to 17.3 ± 10.5 at 8 weeks, and the Social Withdrawal subscale score went from a mean ± SD of 18.1 ± 8.2 to 12.6 ± 9.3.

In all, 20 children were rated “much improved” or “very much improved” on the Clinical Global Impression for Improvement scale.

Reason for Optimism

“I think there is reason to be optimistic, but I think it’s also important to not overinterpret an open-label study,” Dr. Veenstra-VanderWeele cautioned.

“We did see some participants who showed what looked to us to be pretty dramatic improvements, who seemed more engaged, more talkative, who seemed calmer, but at the same time, until we are able to contrast arbaclofen with placebo, we just don’t know what the specific responses are, and we really can’t say how big the treatment effect might be,” he said.

He stressed that the real message from this work is that it motivates further study.

“In this small trial, arbaclofen showed good tolerability and beneficial effects on the core and associated symptoms of autism spectrum disorder. A double-blind, placebo-controlled, phase 2 trial in ASD is planned,” he said.

Asked by Medscape Medical News to comment on the findings, Heather Cody Hazlett, MD, from the University of North Carolina at Chapel Hill, said she was intrigued by the research.

“I am familiar with drug trials in the fragile X population with arbaclofen, but I was not aware of any studies using this in an autism population, so this is an exciting new avenue,” Dr. Hazlett said.

“This is a strong team of investigators, and as far as I know, this study presented at the conference is the first report looking at arbaclofen in autism. Given the promising results shown with fragile X patients, it seems logical to investigate whether there might be some treatment benefits in autism since the disorders share many behavioral features. I look forward to seeing their double-blind study, which should provide more conclusive data.”

The study was sponsored by Seaside Therapeutics. Dr. Veenstra-VanderWeele reports financial relationships with Novartis, Roche Pharmaceuticals, and Seaside Therapeutics. Dr. Hazlett has disclosed no relevant financial relationships.

New Clinical Drug Evaluation Unit (NCDEU) 51st Annual Meeting: Abstract 43. Presented June 15, 2011.

Laurie Barclay, MD

June 22, 2011 — Long-acting reversible contraceptives (LARCs), namely intrauterine devices (IUDs) and contraceptive implants, are the most effective reversible contraceptives, according to a Practice Bulletin—Gynecologyreleased June 20 by the American College of Obstetricians and Gynecologists (ACOG).

The Bulletin, entitled “Long-Acting Reversible Contraception: Implants and Intrauterine Devices” is published in the July 2011 issue of Obstetrics & Gynecology and offers information regarding appropriate patient selection and management of clinical issues and complications associated with LARC use.

“LARC methods are the best tool we have to fight against unintended pregnancies, which currently account for 49% of US pregnancies each year,” said Eve Espey, MD, MPH, coauthor of the Practice Bulletin, in a news release. “The major advantage is that after insertion, LARCs work without having to do anything else. There’s no maintenance required.”

The 3 LARC methods available in the United States are the copper T380A IUD, the levonorgestrel intrauterine system, and the etonogestrel single-rod contraceptive implant. All must be inserted in the physician’s office. Return of fertility is rapid once the device is removed.

The copper IUD effectively prevents pregnancy for 10 years by releasing a small amount of copper into the uterus, which prevents fertilization or implantation of a fertilized egg to the uterine wall and interferes with sperm motility. When inserted within 5 days of unprotected sex, it can also be used for emergency contraception.

Ovulation continues in women using the copper IUD, which may increase menstrual bleeding and cramping. These symptoms may decrease with time, but heavy menstrual bleeding and dysmenorrhea are the leading causes of IUD discontinuation.

The hormonal IUD releases progestin into the uterus, which thickens cervical mucus, thins the uterine lining, and may reduce sperm motility. Duration of contraception with the hormonal IUD is 5 years. Because the hormonal IUD may make menstrual cycles lighter, it is also approved by the US Food and Drug Administration (FDA) for treatment of menorrhagia.

The contraceptive implant has a pregnancy rate of 0.05%, making it the most effective method of reversible contraception available. A matchstick-sized rod is inserted under the skin of the upper arm, allowing controlled release of an ovulation-suppressing hormone for up to 3 years.

“Women need to know that today’s IUDs are much improved from earlier versions, and complications are extremely rare,” Dr. Espey said. “IUDs are not abortifacients—they work before pregnancy is established—and are safe for the majority of women, including adolescents and women who have never had children. And while upfront costs may be higher, LARCs are much more cost-effective than other contraceptive methods in the long run.”

Recommendations — Level A Evidence

Specific ACOG recommendations and conclusions based on good and consistent scientific evidence (Level A) are as follows:

• Before IUD insertion, routine antibiotic prophylaxis is not recommended to prevent pelvic infection.
• When inserted up to 5 days after unprotected intercourse, a copper IUD is the most effective method of postcoital contraception.

Recommendations — Level B Evidence

Specific ACOG recommendations and conclusions based on limited or inconsistent scientific evidence (Level B) are as follows:

• Women with a history of ectopic pregnancy may be offered IUDs.
• Insertion of the implant is safe at any time after childbirth in women who are not breast-feeding.
• Women who are breast-feeding may be offered implants at 4 weeks after childbirth or later.
• Immediately after either an abortion or miscarriage, insertion of an IUD or implant is safe and effective.
• Immediate postpartum IUD insertion (within 10 minutes of placental separation) appears to be safe and effective.

Recommendations — Level C Evidence

Specific ACOG recommendations and conclusions based primarily on consensus and expert opinion (Level C) are as follows:

• Because of theoretic concerns about milk production and infant growth and development, the US Medical Eligibility Criteria for Contraceptive Use classifies placement of an implant in breast-feeding women less than 4 weeks after childbirth as Category 2.
• Nulliparous women and adolescents can be offered IUDs and other LARC methods.
• When possible, IUDs should be removed from pregnant women without an invasive procedure, according to the FDA and the World Health Organization.
• There are few contraindications to LARCs, and almost all women are eligible for implants and IUDs.
• As long as pregnancy may be reasonably ruled out, an IUD or an implant may be inserted at any time during the menstrual cycle.
• For women at high risk for sexually transmitted infections (STIs), such as those 25 years or younger or women having multiple sex partners, it is reasonable to screen for STIs and place the IUD on the same day (and give treatment if the screen result is positive) or when the test results are available.
• Patients should be counseled about the effects of LARCs on menstrual bleeding.
• Endometrial biopsy or sampling, cervical colposcopy, and cervical ablation or excision may be performed with an IUD left in place.

A performance measure proposed in the Practice Bulletin is the percentage of eligible women seeking contraception who are offered LARC.

“Encouraging the use of LARC methods for appropriate candidates may help lower U.S. unintended pregnancy rates because gaps in use and discontinuation of shorter acting methods are associated with unintended pregnancy rates in high-risk women,” the Bulletin authors write. “Typical-use pregnancy rates for LARCs are lower, and continuation rates are higher, when compared with oral contraceptives. In an economic analysis, both types of IUDs were among the three least expensive contraceptive methods over a 5-year period.”

Obstet Gynecol. 2011;118:184-196. Abstract

Mark Crane

June 22, 2011 — The US Food and Drug Administration (FDA) has approved nitroglycerin ointment 0.4% (Rectiv, ProStrakan Group) for the treatment of moderate to severe pain associated with chronic anal fissures, the company announced today.

The ointment will be the only FDA-approved prescription product for patients with this condition, according to the company. Marketed under the name Rectogesic, the ointment is already approved in the European Union and has been outlicensed outside Europe by ProStrakan to commercial partners in 34 countries worldwide.

“The pain associated with anal fissures can be unrelenting and debilitating. Prompt initiation of treatment by primary care practitioners, gynecologists, gastroenterologists and surgeons alike is critical to a patient’s wellbeing,” Scott Berry, MD, colorectal surgeon and the principal investigator on one of Rectiv’s clinical trials, said in a news release. “Now we have an effective and easy-to-use topical ointment which allows grateful patients to resume their daily lives.”

Approximately 700,000 people in the United States receive a diagnosis of or treatment for an episode of anal fissures each year. An anal fissure is a small tear in the skin that lines the anus, and it can occur in many ways, such as passing large or hard stools, straining during a bowel movement, or following an episode of diarrhea. When an anal fissure occurs, it typically causes severe pain and bleeding with bowel movements. Chronic anal fissure has been shown to significantly affect patients’ quality of life, the company said. An episode can take 6 to 8 weeks to heal, and if healing does not occur surgery may be required.

ProStrakan expects Rectiv to be available in the United States in the first quarter of 2012.

ProStrakan, based in Galashiels, Scotland, and Bedminster, New Jersey, is a subsidiary of Kyowa Hakko Kirin Co. Ltd., a Japan-based global specialty pharmaceutical company.

WASHINGTON (Reuters Health) Jun 21 – More than five million Medicare recipients have used preventive healthcare services to date in 2011 and U.S. health officials are trying to accelerate that trend to combat crippling healthcare costs.

The U.S. Department of Health and Human Services is launching a campaign to encourage Medicare recipients to take advantage of preventive services, including mammograms and prostate cancer screenings, in the hopes that early diagnosis and treatment will help save significant costs for the system.

The Obama administration’s healthcare overhaul, passed in early 2010, eliminated out-of-pocket costs for recommended preventive services and annual checkups at the beginning of this year. Healthcare costs are a central point of negotiation between Democrats and Republicans trying to tame spiraling U.S. debt.

But the uptake of services has been uneven, with one in six Medicare beneficiaries using at least one free service from January 1 through June 10, according to the Centers for Medicare and Medicaid Services (CMS).

“For some services, utilization is slightly higher than in 2010; for some, it is about the same; and for a few services there is a slight drop,” said Ellen Griffith, a CMS spokeswoman. “All of this supports the need for the multi-pronged public awareness campaign we launched today.”

CMS estimates the U.S. could save two-thirds of the $2 trillion it spends on preventable long-term illness by preventing chronic illnesses in Medicare beneficiaries.

BANGALORE (Reuters) Jun 21 – Eli Lilly and Co and Amylin Pharmaceuticals Inc said European health regulators approved their type 2 diabetes drug Bydureon (extended-release exenatide).

The drug, which is a longer-acting, once-weekly version of Lilly’s widely-used diabetes drug Byetta, has not yet been approved by U.S. regulators.

Both drugs compete with Novo Nordisk’s Victoza, which is injected daily.

Bydureon’s U.S. approval application was filed in 2009, but the regulators rejected the drug and asked for more data in late-2010.

The companies plan to submit a response in the second-half of 2011.

The European agency’s expert committee on new drugs had backed Bydureon in April.