Posted by Phillipa on August 5, 2010, at 18:27:47
In reply to Heard on the news...., posted by bleauberry on August 5, 2010, at 16:57:11
Here is what I found on today's newsletter. Didn't edit out the email or forward part. Phillipa
From Medscape Medical News
Underlying Illness May Be More Important Than Antiepileptic Use for Suicide Risk
Megan BrooksAuthors and Disclosures
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August 4, 2010 New research suggests that it might not be antiepileptic drugs (AEDs) themselves that raise the risk for suicide but the underlying disease for which these drugs are prescribed, according to the study's authors.Analyzing observational data on more than 5 million people in the United Kingdom, the researchers report that current use of AEDs was not associated with an increased risk for suicide-related events in patients with epilepsy.
AED treatment was, however, associated with an increased risk for such events in patients with depression, as well as in a reference population without epilepsy, depression, or bipolar disorder. Patients in these subgroups may have been undergoing AED therapy for pain, which may increase the risk for suicide, the study authors note.
"Our results, stratified according to the indication for drug use, suggest that illness carries more importance than the use of AEDs," first study author Alejandro Arana, MD, from Risk MR Pharmacovigilance Services in Zaragoza, Spain, and colleagues write in the August 5 issue of The New England Journal of Medicine.
"This new study outlines the importance of understanding the safety of anticonvulsants in relevant patient subgroups to develop risk management plans," Sebastian Schneeweiss, MD, ScD, who was not involved in the current study but who has also published research on AED treatment and suicidality, noted in an email to Medscape Medical News.
Dr. Schneeweiss is associate professor of medicine and epidemiology at Harvard Medical School and vice chief of the Division of Pharmacoepidemiology, Department of Medicine, Brigham & Women's Hospital, in Boston, Massachusetts.
AEDs and Suicide Risk: A Brief History
In January 2008, the US Food and Drug Administration (FDA) issued a safety alert on the risk for suicidality in people taking AED medications. The alert stemmed from a meta-analysis of 199 placebo-controlled AED trials of 11 AEDs.
The analysis found a 2-fold increased risk for suicidal thoughts or actions among AED-treated patients compared with placebo-treated patients (0.4% vs 0.2%) and suggested that the risk was increased regardless of AED type and indication for use.
However, the assessment of suicidality in the meta-analysis was "subject to several limitations such as the lack of systematic or standardized language to define suicidal ideation and behavior across clinical trials," Dr. Arana and colleagues note in their report.
To investigate further, Dr. Arana's team used observational data from The Health Improvement Network database, collected as part of clinical practice in the United Kingdom to study the association between AEDs and "harder" endpoints (attempted and completed suicides) in patients with epilepsy, depression, or bipolar disorder.
The total cohort comprised 5,130,795 individuals, broken down as follows:
4,514,366 individuals without epilepsy, depression, bipolar disorder, or use of AEDs (reference category)
77,319 individuals who received AEDs but did not have epilepsy, depression, or bipolar disorder. The indications for AED use in these patients were not known, although pain and pain-related diagnoses were documented in the records of 18.7% of patients in the month before AED prescription.
16,120 individuals with epilepsy but not depression or bipolar disorder who did not receive AEDs.
39,325 individuals with epilepsy and AED use.
During an average follow-up of 6.2 years, 8212 individuals attempted suicide, including 464 who succeeded.The crude incidence of suicide-related events per 100,000 person-years was 15.0 (95% confidence interval [CI], 14.6 15.5) in individuals without epilepsy, depression, bipolar disorder, or AED treatment. It was 38.2 (95% CI, 26.3 53.7) among patients with epilepsy who did not receive AED treatment, and it was only slightly higher (48.2; 95% CI, 39.4 58.5) among patients with epilepsy who received AED treatment.
Adjusted Case-Control Analysis
The investigators conducted a case-control analysis adjusting for age; duration of disease; previous use of AEDs, lithium, antipsychotic drugs, or antidepressants; presence or absence of a history of alcohol abuse or a mental disorder; and chronic disease score. In this analysis, current use of AEDs was not associated with an increased risk for suicide-related events in patients with epilepsy (odds ratio [OR], 0.59; 95% CI, 0.35 0.98) or bipolar disorder (OR, 1.13; 95% CI, 0.35 3.61).
"Treatment with AEDs helps to control the psychiatric syndromes that are at the root of suicidal behavior in these patients," Dr. Arana commented in an email to Medscape Medical News. "In our opinion, in the long term, it might not be the drugs themselves that raise the risk of suicide, but the underlying disease for which these drugs are prescribed."
Current use of AEDs was associated with a greater than 2-fold increased risk for suicide-related events among individuals free of epilepsy, depression, or bipolar disorder (OR, 2.57; 95% CI, 1.78 3.71) and in patients with depression (OR, 1.65; 95% CI, 1.24 2.19). Pain, as mentioned, may have been the reason for AED treatment in these patients, and pain, especially chronic pain, has been associated with an increased risk for suicide, they note.
Still, it is not known whether the link to suicide-related events observed is attributable to the use of antiepileptic drugs per se "or to the nature or severity of the disease that indicates treatment with antiepileptic drugs," Dr. Arana said.
In the current study, "the underlying illness was more strongly associated with suicide-related events than was the use or nonuse of antiepileptic drugs," he and colleagues write.
Variation by AED Type?
Dr. Arana's team notes that their analysis of individual AEDs was "imprecise, with wide confidence intervals," but points to differences in risk associated with AEDs for various indications.
In the July 27 issue of Neurology, Frank Andersohn, MD, from Charite University Medical Center in Berlin, Germany, and colleagues reported evidence that not all AEDs may increase the risk for suicidal behavior. They found that certain newer AEDs known to have a high potential for causing depression may indeed increase the risk for self-harm or suicidal behavior in people with epilepsy. These drugs include levetiracetam, tiagabine, topiramate, and vigabatrin.
However, for the most commonly used other groups of AEDs barbiturates, conventional AEDs, and newer AEDs with low potential of causing depression no increase in risk was observed. These drugs include lamotrigine, gabapentin, pregabalin, oxcarbazepine, valproate, and phenytoin. (Neurology. 2010;75:300-301, 335-340).
Dr. Andersohn's team and Dr. Arana's team both conclude that their respective studies do not support the January 2008 FDA blanket safety alert of an excess risk for suicidality in people taking AED medications.
But Dr. Schneeweiss sees the current study findings differently.
Contrary to the authors' statement, this new study supports the findings of the FDA meta-analysis of an overall increase in suicidality.
"In patients free of epilepsy, depression, or bipolar disorder," he noted in an email to Medscape Medical News, Dr. Arana and colleagues "found a 2.5 times increased risk for suicidal acts in patients using anticonvulsants and in 3 of 4 analyzable patient subgroups, they found a numerically increased risk for suicidal acts."Due to their large study size they were able to investigate important patient subgroups," Dr. Schneeweiss added. This study contributes to "the growing evidence about the likely association between antiepileptic drugs and suicidal acts," he concludes.
"Contrary to the authors' statement," Dr. Scheeweiss adds, "this new study supports the findings of the FDA meta-analysis of an overall increase in suicidality. Such a risk," he emphasized, "needs to be seen in light of the agents' benefits in patients suffering from often debilitating chronic conditions."
Dr. Arana's study also confirms that epilepsy in itself is a risk factor for suicidal acts, Dr. Schneeweiss noted.
The study was supported by an unrestricted grant from Sepracor, and Dr. Arana and coauthor Dr. Felix Arellano have worked for Pfizer in the past. Disclosures for coauthors appear at www.nejm.org . Dr. Schneeweiss has disclosed no relevant financial relationships. He discloses having also published research on anticonvulsant medications and risk for suicide (JAMA. 2010;303:1401-1409).
N Engl J Med. 2010;363:542-551.
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