Certain epilepsy drugs may increase risk of suicide, study suggests

While the Food and Drug Administration (FDA) requires a warning of an increased risk of suicide for all epilepsy drugs, a new study shows that only certain drugs may increase the risk.

The study is published in the July 27, 2010, issue of Neurology®, the medical journal of the American Academy of Neurology.

Newer drugs with a higher risk of causing depression than other epilepsy drugs, such as levetiracetam, topiramate and vigabatrin, were found to increase the risk of self-harm or suicidal behavior among people with epilepsy.

In contrast, newer drugs that have a low risk of causing depression and conventional epilepsy drugs did not have any increased risk of self-harm or suicidal behavior. These groups include drugs such as lamotrigine, gabapentin, carbamazepine, valproate and phenytoin.

"These results may be helpful for doctors and people with epilepsy as they decide which drugs to use," said study author Frank Andersohn, MD, of Charité University Medical Center in Berlin, Germany. "An earlier analysis of data by the FDA grouped all of the epilepsy drugs together and found an increased risk of suicidal thoughts and behavior, but could not address the question of whether there were differences among the various classes of epilepsy drugs."

In an editorial accompanying the article, Josemir Sander, MD, PhD, of the University College London in the United Kingdom and the Epilepsy Institute of the Netherlands Foundation and Marco Mula, MD, PhD, of the University Hospital Maggiore della Carità in Novara, Italy, noted that some researchers have been concerned that the risks of people stopping taking their epilepsy drugs or not starting to take a drug due to worries about the risk of suicide would be greater than the risk of suicidal behavior.

The study looked at all of the people in the United Kingdom General Practice Research Database who had epilepsy and had at least one prescription for an epilepsy drug from 1989 through 2005. The participants were followed for an average of five and a half years. Of the 44,300 people, 453 had harmed themselves or attempted suicide; 78 people died at the time or within four weeks of the initial attempt. The 453 people were compared to 8,962 in the larger group who had not harmed themselves or attempted suicide.

People who were currently using the newer drugs with a higher risk of depression, such as levetiracetam, topiramate and vigabatrin, were three times more likely to harm themselves or attempt suicide than those who were not currently taking any epilepsy drugs. A total of six of the 453 people, or 1.3 percent, who harmed themselves or attempted suicide were taking the newer drugs with the higher risk of depression, compared to 45 of the 8,962 people, or 0.5 percent, of those who did not harm themselves.

According to the authors, the number of people taking some of the drugs was small, so the results need to be confirmed by additional studies. People should not abruptly stop or change their epilepsy medication based on the findings of this study but should discuss this issue with their physician, Andersohn noted.

Afraid of a broken heart? Feeling insecure in relationships may predispose people to later cardiovascular problems, says research

People who feel insecure about their attachments to others might be at higher risk for cardiovascular problems than those who feel secure in their relationships, according to a new study published by the American Psychological Association.

"This is the first study to examine adult attachment and a range of specific health conditions," said lead author Lachlan A. McWilliams, PhD, of Acadia University in Nova Scotia, Canada. He and a colleague examined data on 5,645 adults age 18 to 60 from the National Cormorbidity Survey Replication and found that people who felt insecure in relationships or avoided getting close to others might be at a higher risk of developing several chronic diseases.

Ratings of attachment insecurity were positively associated with a wide range of health problems, they found. "Much of the health research regarding attachment has focused on pain conditions, so we were initially surprised that some of our strongest findings involved conditions related to the cardiovascular system," said McWilliams.

Participants rated themselves on three attachment styles — secure, avoidant, and anxious. Secure attachment refers to feeling able to get close to others and being willing to have others depend on you. Avoidant attachment refers to difficulty getting close to others and trusting others. Anxious attachment refers to the tendency to worry about rejection, feel needy and find others are reluctant to get close to you.

The participants answered a questionnaire about their histories of arthritis, chronic back or neck problems, frequent or severe headaches, other forms of chronic pain, seasonal allergies, stroke and heart attack. They also disclosed whether a doctor had told them they had heart disease, high blood pressure, asthma, chronic lung disease, diabetes or high blood sugar, ulcers, epilepsy, seizures or cancer. They were also questioned regarding their history of psychological disorders.

After adjusting for demographic variables that could account for the health conditions, the authors found that avoidant attachment was positively associated with conditions defined primarily by pain (e.g., frequent or severe headaches). Anxious attachment was positively associated with a wider range of health conditions, including some defined primarily by pain and several involving the cardiovascular system (e.g., stroke, heart attack or high blood pressure).

The authors also adjusted for lifetime histories of common psychological disorders and found that people with anxious attachments were at a higher risk of chronic pain, stroke, heart attack, high blood pressure and ulcers.

"These findings suggest that insecure attachment may be a risk factor for a wide range of health problems, particularly cardiovascular diseases. Longitudinal research on this topic is needed to determine whether insecure attachment predicts the development of cardiovascular disease and the occurrence of cardiovascular events, such as heart attacks,"said McWilliams. "The findings also raise the possibility that interventions aimed at improving attachment security could also have positive health outcomes.


Journal Reference:

  1. Lachlan A. McWilliams and S. Jeffrey Bailey. Associations Between Adult Attachment Ratings and Health Conditions: Evidence From the National Comorbidity Survey Replication. Health Psychology, Vol. 29, No. 4 DOI: 10.1037/a0020061

FDA Accepts Historical Controls for Epilepsy Monotherapy Studies

 New York University researchers revealed that data from previously completed withdrawal to monotherapy studies for antiepileptic drugs (AEDs) provide a valid control for future studies, obviating the need for placebo/pseudo-placebo trials to demonstrate the efficacy of these drugs as monotherapy. Results of this study are now available online in Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.

According to a National Institute of Neurological Disorders and Stroke workshop, monotherapy is the ultimate treatment strategy for newly-diagnosed and many long-term epilepsy patients because of fewer side effects, better compliance, less risk of fetal malformations (teratogencity) and lower cost compared with polytherapy.

However, in the U.S., it is difficult to get monotherapy approval for AEDs because the FDA, in accordance with the International Conference on Harmonization (ICH), requires an internal, interpretable control group in which the test drug shows superiority over the control. New AEDs, while offering improvements in safety and efficacy, rarely demonstrate superiority compared to standard AEDs, leaving placebo or pseudo-placebo as the only acceptable internal controls.

The pseudo-placebo withdrawal to monotherapy study model assigns treatment-resistant patients to receive a study drug or a suboptimal maintenance dose of a safe and effective active drug. Once patients are randomized and standardized to the intended dose, they undergo a withdrawal phase (when background AEDs are removed over a specified time frame) followed by a monotherapy phase. The trial continues until either all phases are completed or patients reach pre-specified endpoints.

Study leader Dr. Jacqueline French explains why this clinical trial model isn't suited for epilepsy patients. "Epilepsy is different from other conditions where placebo may be utilized (such as hypertension), since there is no way to exit a patient at a warning stage, before harm can occur. In a hypertensive patient, one can withdraw a patient on placebo if blood pressure increases, before it gets dangerously high. But with an epilepsy patient, the escape criteria consist of an increase or worsening of seizures, which by itself can be considered an adverse outcome."

The study authors proposed that a historical control, based on an evaluation of prior pseudo-placebo withdrawal to monotherapy studies, would provide a valid alternative to an actual control group. The team analyzed 8 separate studies of similar design and escape criteria, with randomized patients of common demographic characteristics. The primary endpoint was the same for all trials: percent of patients exiting the trial due to seizure worsening. All 8 studies had consistent outcomes, with the percentages of patients exiting their respective trials ranging from 74.9%-95.9%.

Dr. French concludes, "These trials would appear to meet the criteria set forth by ICH for use of historical control. Therefore, this group of trials might reasonably be used as historical controls for future trials of withdrawal to monotherapy using a similar design in a similar population."

The historical control design allows all patients to receive a promising AED at an effective dose, making the study more attractive to patients and to physicians. Dr. Emilio Perucca agreed with these findings, stating in this month's Epilepsia Commentary, "The New York University team should be commended for their scholarly work…in setting the stage for a new conversion-to-monotherapy design in which patients are no longer required to receive suboptimal, and therefore, potentially hazardous, treatments."

Based upon this French et al. study, the FDA has accepted the concept of historical controls in this setting, a major milestone in AED development. Several trials utilizing this design planned for regulatory submission have begun.


Journal Reference:

  1. Jacqueline A. French, Steven Wang, Bob Warnock, Nancy Temkin. Historical control monotherapy design in the treatment of epilepsy. Epilepsia, 2010; : no DOI: 10.1111/j.1528-1167.2010.02650.x