April 16

Specific Anticonvulsants Increase Suicide Risk

The Harvard study,  published in the Journal of the American Medical Association, evaluated 827 suicidal acts (801 attempts and 26 completed suicides) and 41 violent deaths (868 combined suicidal acts or violent deaths) in 297 620 patients newly treated with an anticonvulsant ( median follow-up was 60 days).

The analysis includes ALL anticonvulsants :
carbamazepine (Tegretol), ethosuximide (Zarontin), felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), oxcarbazepine (Trileptal), primidone (mysoline), tiagabine (Gabitril), topiramate (Topamax), valproate (Depakote), and zonisamide (Zonegran).

The study found significant differences in the relative suicide risk that each drug poses for patients.

The study (termed "exploratory")  included a heterogeneous patient cohort:and  the analysis factored in patients’ diverse diagnoses–which is "consistent with the wide spectrum of uses of anticonvulsant drugs." 

Topamax (topiramate, the second most widely prescribed anticonvulsant) was prescribed prescribed overwhelmingly for women (82.6%)  mostly for migraine or headaches–in less than 3% (combined) was it prescribed for epilepsy or seizures.

The authors found an increased risk for suicide and violent deaths in new users of Neurontin, Lamictal, Trileptal, and Gabitril compared with Topamax.

In particular, they note, that "gabapentin [Neurontin] treatment was significantly associated with higher risk of suicidal events and combined suicidal acts or violent deaths in adults and young adults" 
The authors found that although Neurontin and Lamictal can have anxiolytic and mood stabilizer properties, these drugs

"have also been associated with behavioral problems such as aggression and hyperactivity, particularly in children and adults with learning disabilities and cognitive impairment."

Furthermore, the study found that Neurontin continued to pose a suicide risk for younger and older patients, for patients with mood disorder, and patients with epilepsy or seizure disorders:

"The risk remained increased for gabapentin [Neurontin] in subgroups of younger and older patients, patients with mood disorder, and patients with epilepsy or seizure disorders"

The authors conclusion: The study suggests that "the use of gabapentin [Neurontin], lamotrigine [Lamictal], oxcarbazepine  [Trileptal] , and tiagabine [Gabitril], compared with the use of topiramate [Topamax] or carbamazepine [Tegretol], may be associated with an increased risk of suicidal acts and combined suicidal acts or violent deaths."

The researchers emphasize the importance of these findings for clinical practice:

 "the fact that no previous studies have directly evaluated the relationship between different anticonvulsant medications and risk of suicide in routine care, the large sample size used, and the access to detailed patient information make this investigation valuable to clinical practice."

Furthermore, the results, said the lead author, Dr. Elisabetta Patorno "argue that the risk was derived from the specific drug that the patient was taking and not their underlying conditions."

The question is, will clinicians be guided by the evidence or will their prescribing practices continue to be influenced by Pharma’s hype and "incentives"?

Vera Hassner Sharav


JAMA. 2010; 303(14):1401-1409
Anticonvulsant Medications and the Risk of Suicide, Attempted Suicide, or Violent Death
Elisabetta Patorno, MD, MPH; Rhonda L. Bohn, MPH, ScD; Peter M. Wahl, MLA, MS; Jerry Avorn, MD; Amanda R. Patrick, MS; Jun Liu, MD, MS; ebastian Schneeweiss, MD, ScD


Context: In 2008, the US Food and Drug Administration mandated warning labelin for anticonvulsant medications regarding the increased risk of suicidal thoughts and
behaviors. The decision was based on a meta-analysis not sufficiently large to investigate individual drugs.

Objective: To evaluate the risk of suicidal acts and combined suicidal acts or violent death associated with individual anticonvulsants.

Design A cohort study of the risk of suicidal acts and combined suicidal acts or violent death in patients beginning use of anticonvulsant medications compared with patients initiating a reference anticonvulsant drug.

Setting and Patients: Patients 15 years and older from the HealthCore Integrated Research Database (HIRD) who began taking an anticonvulsant between July 2001and December 2006.

Main Outcome Measures: Cox proportional hazards models and propensity score–matched analyses were used to evaluate risk of attempted or completed suicide and combined suicidal acts or violent death, controlling for psychiatric comorbidities and other risk factors, among individual anticonvulsants compared with topiramate and secondarily carbamazepine.

Results: The study identified 26 completed suicides, 801 attempted suicides, and 41 violent deaths in 297 620 new episodes of treatment with an anticonvulsant (overall edian follow-up, 60 days). The incidence of the composite outcomes of completed suicides, attempted suicides, and violent deaths for anticonvulsants used in at least 100 treatment episodes ranged from 6.2 per 1000 person-years for primidone to 34.3 per 1000 person-years for oxcarbazepine.

The risk of suicidal acts was increased for gabapentin (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.11-1.80), lamotrigine (HR, 1.84; 95% CI, 1.43-2.37), oxcarbazepine (HR, 2.07; 95% CI, 1.52-2.80),  tiagabine (HR, 2.41; 95% CI, 1.65-3.52), and valproate (HR, 1.65; 95% CI, 1.25-2.19), compared with topiramate.
The analyses including violent death produced similar results. Gabapentin users had increased risk in subgroups of younger and older patients, patients with mood disorders, and patients with epilepsy or seizure when compared with carbamazepine.

Conclusion: This exploratory analysis suggests that the use of gabapentin, lamotrigine, oxcarbazepine, and tiagabine, compared with the use of topiramate, may be associated with an increased risk of suicidal acts or violent deaths.


Popular anticonvulsant drugs raise suicide risks
Julie Steenhuysen
Apr 13, 2010

CHICAGO (Reuters) – Widely used anticonvulsant drugs, including Pfizer’s Neurontin and Novartis’ Trileptal, may increase the risk of suicide, attempted suicide and violent death in patients taking them for the first time, U.S. researchers said on Tuesday.

Compared with Johnson & Johnson’s generic epilepsy drug topiramate or Topamax, the team found an increased risk for suicide in new users of Neurontin, sold generically as gabapentin, GlaxoSmithKline’s Lamictal or lamotrigine, Novartis’ Trileptal or oxcarbazepine and Cephalon’s Gabitril or tiagabine.

In one analysis, the team also found an increased risk of suicide with the drug valproate sold by Sanofi-Aventis as Epilim and as Depakine in the United States by Abbott Laboratories Inc.

In 2008, the U.S. Food and Drug Administration required that all drugs in the anticonvulsant class carry a warning that they double the risk of suicidal thoughts and behaviors, based on a so-called meta-analysis of nearly 200 clinical trials.

But the analysis was not large enough to show which drugs in the class were risky. And they are prescribed for a range of conditions.

"We all know the range of uses of these medications is very, very wide," said Dr. Elisabetta Patorno of Brigham and Women’s Hospital and Harvard Medical School in Boston, whose study appears in the Journal of the American Medical Association.

Anticonvulsant drugs are chiefly used for patients with epilepsy, but the drugs have been aggressively promoted, in some cases for conditions they are not approved to treat, such as bipolar disorder, pain and migraine headaches.

While doctors are free to prescribe medicines as they see fit, drugmakers are only allowed to promote them for uses approved by the FDA.

Last month, a Boston jury found Pfizer guilty of improperly marketing Neurontin. And in January, Novartis said it would plead guilty to violating U.S. laws relating to potential off-label marketing and promotion of Trileptal.

To study the risks of suicidal thoughts and acts, Patorno and colleagues analyzed prescription and clinical data on nearly 300,000 patients 15 and older who had been given an anticonvulsant drug for the first time between July 2001 and December 2006.

"We found increased risk for suicidal acts beginning within the first 14 days after treatment initiation, opening the possibility that anticonvulsant medications could induce behavioral effects prior to the achievement of their full therapeutic effectiveness," Patorno and colleagues wrote.

The study identified 827 suicidal acts, including 801 attempted suicides and 26 completed suicides. They also found an additional 41 violent deaths.

They said compared with topiramate, the risk of suicidal acts was higher in those who took gabapentin, lamotrigine, oxcarbazepine, tiagabine and valproate.

Among these, the risks were "pretty much even," Patorno said in a telephone interview. "It’s not easy to draw conclusions about which one is the most risky," she said.

Patorno said patients should continue taking their medications, but the findings do suggest that patients need to be watched carefully, and doctors need to consider whether the benefits of the drug outweigh the risks, particularly when given for an unapproved use.

(Editing by Maggie Fox and Cynthia Osterman)

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