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Antiepileptic Drugs May Increase Suicidal Thoughts, Says FDA

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The U.S. Food and Drug Administration (FDA) today issued new information to health care professionals to alert them about an increased risk of suicidal thoughts and behaviors (suicidality) in patients who take drugs called antiepileptics to treat epilepsy, bipolar disorder, migraine headaches, and other conditions.

An FDA analysis of suicidality reports from placebo-controlled studies of 11 antiepileptic drugs shows that patients taking these drugs have about twice the risk of suicidal thoughts and behaviors (0.43 percent), compared with patients receiving placebo (0.22 percent). This risk corresponds to an estimated 2.1 per 1,000 more patients in the drug treatment groups who experienced suicidality than in the placebo groups.

"We want health care professionals to have the most up to date drug safety information," said Russell Katz, M.D., director of the Division of Neurology Products in FDA’s Center for Drug Evaluation and Research. "This is an example of FDA working with drug manufacturers throughout products’ lifecycles to keep health care professionals informed of new safety data."

Patients who are currently taking antiepileptic medicines should not make any changes without first talking to their health care provider. Health care providers should notify patients, their families, and caregivers of the potential for an increase in the risk of suicidal thoughts or behaviors so that patients may be closely observed for notable changes in behavior.

Following a preliminary analysis of data from several antiepileptic drugs that suggested an increased risk of suicidality, in March 2005 FDA requested this type of data from manufacturers of marketed antiepileptic drugs for which there were adequately designed controlled clinical trials. FDA received and reviewed data from 199 placebo-controlled studies of 11 drugs.

The analysis included 27,863 patients in drug treatment groups and 16,029 patients in placebo groups. There were four suicides among patients in the drug treatment groups and none among patients in placebo groups. There were 105 reports of suicidal thoughts or behaviors in the drug-treated patients and 35 reports in placebo-treated patients.

The higher risk of suicidal thoughts and behaviors was observed at one week after starting a drug and continued to at least 24 weeks. The results were generally consistent among all the different drug products studied and were seen in all demographic subgroups. There was no clear pattern of risk across age groups.

Antiepileptic drugs in the analyses included the following:

  • Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
  • Felbamate (marketed as Felbatol)
  • Gabapentin (marketed as Neurontin)
  • Lamotrigine (marketed as Lamictal)
  • Levetiracetam (marketed as Keppra)
  • Oxcarbazepine (marketed as Trileptal)
  • Pregabalin (marketed as Lyrica)
  • Tiagabine (marketed as Gabitril)
  • Topiramate (marketed as Topamax)
  • Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
  • Zonisamide (marketed as Zonegran)

Some of these drugs are also available in generic form.

Although only the drugs listed above were part of the analysis, the FDA expects that all medications in the antiepileptic class share the increased risk of suicidality.

FDA will be working with manufacturers of marketed antiepileptic drugs to include this new information in the labeling for these products. The agency anticipates that labeling changes will be applied broadly to the entire class of drugs. FDA is also planning to discuss these data at an upcoming advisory committee meeting.

Source: FDA, January 31, 2008

One in Seven Americans Over 70 Has Dementia

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A new analysis suggests that about 3.4 million Americans over 70 years of age—one in seven people in that age group—has dementia, and 2.4 million of them have Alzheimer’s disease (AD).

The study was published online this week in Neuroepidemiology, and is the first to estimate rates of dementia and AD using a nationally representative sample of older adults across the United States.

The study highlights the nationwide reach of dementia, which affects not only those with the disease, but their families and communities as well. "As the population ages during the next few decades, the prevalence of Alzheimer’s disease will increase several-fold unless effective interventions are discovered and implemented," said National Institute on Aging Director Richard J. Hodes, M.D. "These data underscore the urgency of research in this area."

The study included 856 HRS participants over the age of 70 from 42 states in 2001-2003. Aging, Demographics and Memory Study (ADAMS) interviewers from Duke University Medical School conducted at-home evaluations to gather information about each participant’s cognitive and functional status and symptoms, neuropsychiatric symptoms, current medications, medical history and family history of memory problems. Prior neuroimaging and laboratory results were also obtained.

A team of clinicians reviewed the evaluation information and made a preliminary assessment of each person’s cognitive status. A consensus panel of other medical experts then used well-accepted diagnostic criteria to determine if the participant had normal cognitive function, cognitive impairment without dementia, or dementia. Such criteria further were used to discern the type of dementia, including AD or vascular dementia, the second most common cause of dementia in older adults.

Based on the experts’ classifications, Drs. Plassman and Langa and co-authors estimated the national prevalence and total numbers of people age 71 and older, by age group, with any dementia and with AD or vascular dementia in 2002. According to their calculations, 13.9 percent of Americans age 71 and older have some type of dementia, 9.7 percent of Americans in that age group have AD, and 2.4 percent have vascular dementia. AD accounted for about 70 percent of all dementia cases among people 71 and older.

As in other studies, the ADAMS analysis showed that the prevalence of dementia increases significantly with age. Five percent of people ages 71 to 79, 24.2 percent of people 80 to 89, and 37.4 percent of those 90 years or older were estimated to have some type of dementia. The estimated rate of Alzheimer’s also rose greatly with older age — from 2.3 percent of people ages 71 to 79 to 18.1 percent of people 80 to 89 to 29.7 percent of those age 90 and older. The ADAMS investigators found fewer years of education and the presence of at least one APOE e4 allele, a genetic risk factor for AD, to be strong predictors of AD and other dementias.

Richard Suzman, Ph.D., director of NIA’s Behavioral and Social Research Program, which jointly directs the HRS, said the ADAMS data will prove particularly valuable not only in assessing the prevalence of dementia, but also its impact. "ADAMS, with its link to the data about the health, economic, and family resources of individuals in the study, will help us to characterize more fully the burden of dementia on individuals, caregivers and the nation’s health care system," he says.

The ADAMS report is the latest published study to estimate the prevalence of dementia and AD among older Americans. "These assessments have provided a range of estimates, based on differing methodologies and approaches," explains Dallas Anderson, Ph.D., program director for population studies in NIA’s Dementias of Aging Branch.

For example, some studies have included lower age ranges than ADAMS or broader characterizations of dementia, or have sampled participants in a specific community as a base for national extrapolations. A study reported in 1998 (Brookmeyer et al., 1998) combined incidence data from four community-based studies, estimating that national Alzheimer’s prevalence among individuals age 60 years or older would rise from 2.3 million in 1997 to 8.6 million in 2047. Widely cited estimates based on the prevalence of Alzheimer’s disease in a Chicago-based community (Hebert et al., 2003), and an earlier comparable study using data from East Boston (Evans et al., 1990) forecast the number of those age 65 or older with AD to be 5.1 million in 2010.

Despite the varied approaches and findings, however, NIA experts point out, the numbers of people with dementia, and Alzheimer’s specifically, will certainly increase until ways to delay the progression or prevent the dementia are found. Advancing age is the most common known risk factor for Alzheimer’s disease.

The HRS is an ongoing national survey of 22,000 adults age 51 and older that began in 1992, providing data that helps researchers, policy makers and others understand the life circumstances of older adults and help address the challenges of the nation’s rapidly aging population.

NIA leads the federal effort supporting and conducting research on aging and the medical, social and behavioral issues of older people, including AD and age-related cognitive change.

The National Institutes of Health (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. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases.

Brenda L. Plassman, Ph.D., of Duke University Medical Center, with Kenneth M. Langa, M.D., Ph.D., and David R. Weir, Ph.D., of the University of Michigan, Robert B. Wallace, Ph.D., of the University of Iowa, and others, conducted the analysis as part of the Aging, Demographics and Memory Study (ADAMS). ADAMS is a sub-study of the larger Health and Retirement Study (HRS), the leading resource for data on the combined health and economic circumstances of Americans over age 50. ADAMS and the HRS are sponsored by the National Institute on Aging, a component of NIH, under a cooperative agreement with the University of Michigan.

Source: National Institutes of Health, October 30, 2007

Researchers Find Major Clues on How Schizophrenia Develops

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Scientists have found some major clues in learning more about why schizophrenia develops. The new research may lead to better medications to correct gene-related problems that can lead to schizophrenia.

The researchers found that a gene called GAD1, which makes an enzyme essential for production of the chemical messenger called GABA, is turned on at increasingly high rates during normal development of the prefrontal cortex, but that this normal increase may not occur in people with schizophrenia. The prefrontal cortex is involved in higher functions like thinking and decision-making.

While scientists have known that abnormalities in brain development and in GABA synthesis play a role in schizophrenia, this study shows that defects in specific biochemical reactions that regulate gene activity—such as turning genes on and off so that they can make substances like the GAD1 enzyme—are also involved.

"This discovery opens a new area for exploration of schizophrenia," said NIMH Director Thomas R. Insel, MD. "Studies have yielded very strong evidence that schizophrenia involves a decrease in the enzymes, like GAD1, that help make the neurotransmitter GABA. Now we’re starting to identify the mechanisms involved, and our discoveries are pointing to potential new targets for medications."

The researchers also found that people with three different variations of the GAD1 gene that have been associated with schizophrenia also were more likely to have indicators of a malfunction in brain development. Among them were indicators of altered epigenetic actions related to GABA synthesis.

Clozapine and other antipsychotic medications are effective for many patients, but some patients choose to discontinue treatment because of the side effects they experience on these drugs. For this reason, scientists are working to find more precise molecular targets for the development of new medications that can correct the epigenetic flaws.

"We’ve known that schizophrenia is a developmental disease, and that something happens in the maturation of the prefrontal cortex during this vulnerable period of life. Now we’re beginning to find out what it is, and that sets the stage for better ways of preventing and treating it," says the study’s lead author, Schahram Akbarian, MD, PhD.

Results of the research were published in the October 17 issue of the Journal of Neuroscience, by Schahram Akbarian, MD, PhD, Hsien-Sung Huang, PhD student, and colleagues at the University of Massachusetts Medical School and Baylor College of Medicine. The study was funded by the National Institutes of Health’s National Institute of Mental Health (NIMH) and National Institute of Child Health and Human Development.

Sources:

  • National Institutes of Health
  • Journal of Neuroscience, October 17, 2007