MHEI transcript 2 Antiepileptic Drugs and Suicide Risk


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The Mental Health Educational Initiative is an interactive program that utilizes a combination of formal and non-formal learning to provide a multidisciplinary group of health care providers with a unique model for the understanding, identification, and management of actual vs. perceived risk for suicidal ideation and related adverse events.

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MHEI transcript 2 Antiepileptic Drugs and Suicide Risk

  1. 1. PODCAST TRANSCRIPT 2: ANTIEPILEPTIC DRUGS AND SUICIDE RISKNeubauer, David N., M.D.Associate ProfessorPsychiatry and Behavioral SciencesJohns Hopkins Bayview Medical CenterHello, this is David Neubauer and I would like to welcome you back to this podcast seriesfocusing on the issues surrounding the suicide risk associated with the use of medications,particularly antidepressant and antiepileptic agents, and particularly among children,adolescents, and young adults. This is the 2nd of four podcasts. In the first installment wereviewed the history of the concern about medications possibly increasing suicidality – meaningsuicidal ideation, as well as suicide attempts and completed suicides. This concern became amajor topic of discussion following the 2004 FDA Black Box warning requirement forantidepressants prescribed for children and adolescents. In our first podcast we also reviewedthe basis of the FDA warning requirement and the details of C-CASA, the Columbia ClassificationAlgorithm of Suicide Assessment, which was designed to categorize potential cases of suicidality.Now, in this second podcast, we will address the topic of antiepileptic drugs (AEDs) and the FDAactions that did not go so far as a Black Box warning, like with the antidepressants, but didgenerate considerable discussion because of the new warnings that were required in the labelsof many of these medications.The relationship of AEDs and potential suicidality is rather complex, as there are manydimensions to their possible interactions. Some key questions address baseline suicidality ratesin people treated with these medications, whether any medication-induced suicidality varieswith individual AEDs or specific patient populations – for instance different demographic groups– perhaps children and adolescents, or people with particular disorders for which AEDs may beprescribed. We’ll have a closer look at all of these questions, although absolute answers havenot yet been established.Before turning to the FDA warning regarding AEDs, we should consider the bigger issue of risk ofsuicidality and different disorders. Certainly the antiepileptic drugs are prescribed for peoplewith epilepsy, but some also are widely prescribed for bipolar disorder and chronic pain Register here to earn credit for this activity: Presented by The Johns Hopkins University School of Medicine Developed through a strategic educational facilitation by Medikly, LLC. Supported by an educational grant from Lilly USA, LLC.
  2. 2. patients, and some AEDs even have approved indications for these disorders. It is no surprisethat bipolar disorder and chronic pain independently are risk factors for suicide. There also is along history of reports suggesting that people with epilepsy have a suicide rate greater than thegeneral population and also have a greater propensity for depressive episodes.Suicidality in general – particularly suicidal ideation – is very difficult to estimate in anypopulations without quite a lot of effort - interviews and well-defined criteria, so most reportshave focused on the somewhat more definable suicide attempts and completions.Numerous large-scale epidemiologic studies have documented the increased suicide rate amongpeople with epilepsy. One Danish case-controlled study involving over 21,000 suicides andfound the suicide rate in people with epilepsy to be 3.2 times greater than people withoutepilepsy.Generally speaking, in people diagnosed with epilepsy, the risk for suicidality increasessignificantly when there is a comorbid psychiatric disorder. The suicidality risk also is elevatedparticularly during the first six months following the epilepsy diagnosis. It is also elevated inpeople diagnosed with epilepsy before they are 18 years old, and in people with temporal lobeepilepsy, and in individuals treated surgically for their epilepsy.The comorbid psychiatric illness, especially mood disorders, clearly is the strongest risk factorfor suicidality among epilepsy patients. Some authors have speculated that there may becommon underlying mechanisms and that there may be some bidirectionality between epilepsyand depression or suicidal behaviors. Some evidence suggests that not only are epilepsy patientsat higher risk for depression and suicide, but that people with major depression and suicideattempts have a greater probability of subsequently developing epilepsy.Curiously, for a small population of treatment-resistant epilepsy patients, finally achieving aseizure free state may experience increased suicidality. Perhaps the seizures for theseindividuals promote an antidepressant effect analogous to the seizures induced byelectroconvulsive therapy.So, what about the role of antiepileptic medications and further risk of suicidality and the FDAactions.We know that the FDA had examined antidepressant clinical trial data using the C-CASAclassification system and found elevated suicidality in the active medication groups compared Register here to earn credit for this activity: Presented by The Johns Hopkins University School of Medicine Developed through a strategic educational facilitation by Medikly, LLC. Supported by an educational grant from Lilly USA, LLC.
  3. 3. with placebo groups – ultimately leading to the black box warnings for children, adolescents,and young adults taking antidepressants. By 2005, the FDA was concerned about the possibilityof antiepileptic drugs increasing suicidality risk, so they began plans for an AED meta-analysis.The FDA employed the same methodology with the AED clinical trial data and in January 2008issued an alert to healthcare professionals stating that AED groups were associated with nearlydouble the suicidality risk compared with the placebo groups. The FDA analysis pooled datafrom 199 clinical trials involving 11 different AEDs which were studied as mono- and adjunctivetreatments for epilepsy, psychiatric disorders, and other conditions. Among the nearly 44,000subjects, 27% were in treatment studies for psychiatric disorders, 25% were in epilepsytreatment trials, and 48% were in studies for the other possible indications – mostly pain-relatedconditions, such as migraine headaches, but also for insomnia, tremor, and obesity. About 63percent of the subjects were in the active medication groups.Overall the risk for suicidal behavior or ideation was 0.43% for the active drug subjects and0.24% for the placebo groups, representing an overall relative risk of 1.8. The FDA reported thatthe relative suicidality risk was greatest in the epilepsy treatment trials, but that the absoluterisk was similar in the epilepsy and psychiatric disorder trials. The FDA also reported that thesuicidality risk was generally consistent among all eleven AEDs. The increased suicidality wasnoted as early as one week into the clinical trials and continued throughout the trials, whichaveraged about 12 weeks. There were 4 completed suicides in the studies and all were in theAED groups.The January 2008 FDA alert offered specific recommendations for AED prescribers – no matterwhat the indications. Then in July 2008 the FDA convened a public advisory committee meetingfocusing on this issue. The committee recommendation was that the FDA should issue a warningregarding suicidality, but not require a Black Box warning. The FDA did follow thisrecommendation and in December 2008 released a public health advisory regarding theincreased suicidality risk associated with the 11 AEDs and also the details of the requiredmedication label changes and development of an FDA-approved patient medication guide toaccompany the 11 AEDs whenever they were dispensed. Register here to earn credit for this activity: Presented by The Johns Hopkins University School of Medicine Developed through a strategic educational facilitation by Medikly, LLC. Supported by an educational grant from Lilly USA, LLC.
  4. 4. The eleven AEDs involved in the FDA analysis, and subsequently requiring the suicidality labelwarning, were and remain the following: • Carbamazepine • Divalproex sodium • Felbamate • Gabapentin • Lamotrigine • Levetiracetam • Oxcarbazepine • Pregabalin • Tiagabine • Topiramate • ZonisamideAs with the previous antidepressant meta-analysis and warning, the antiepileptic meta-analysisand warning also generated immediate debate that included criticisms of the methodology andconclusions, as well as the potential clinical implications of the label changes. Again there was aconcern that the warnings would lead prescribers or patients to decrease the use of themedications, which could lead to a worrisome increase in the seizure risk among epilepsypatients. It was argued that in epilepsy, the dangers of stopping antiepileptic medications weremuch greater than the very small suicide risk.One of the methodological problems noted was that the FDA excluded all of the trials with nosuicidality reports in either study arm. So, out of the 199 available clinical trials, only 1/3 wereeligible for the main analysis.Another criticism was that, like with the antidepressants, there was no systematic assessment ofsuicidality – the data was dependent on spontaneous adverse event reporting. Accordingly,there was a potential for reporting bias. The idea is that people on active drugs in clinical trialsare more likely to complain of adverse events.Other critics argued that it was inappropriate to lump the widely varying AEDs together as aclass and require the identical warning. Register here to earn credit for this activity: Presented by The Johns Hopkins University School of Medicine Developed through a strategic educational facilitation by Medikly, LLC. Supported by an educational grant from Lilly USA, LLC.
  5. 5. Quite a few epidemiologic studies have provided further insights regarding AED use andsuicidality risk.In a 2010 article in the journal Neurology, Andersohn and colleagues reported the findings of anobservational study based on data from the large United Kingdom General Practice ResearchDatabase. They employed a nested case-control methodology with a population of over 44,000epilepsy patients treated with AEDs. The patients were categorized according to four AEDclasses: Patients taking barbiturates, those prescribed conventional AEDs (phenytoin,carbamazepine, or valproate), individuals on newer AEDs known to have low depression risk(lamotrigine, gabapentin, pregabalin, or oxcarbazepine) and patients on the AEDs known tohave higher risks of depression (levetiracetam, tiagabine, topiramate, and vigabatrin). There wasno increased suicidality risk in the first three categories of AEDs. Only the class including the 4AEDs with the higher depression risk was associated with statistically increased self-harm orsuicidal behavior. When analyzed individually, only levetiracetam was associated with asignificantly elevated self-harm or suicidal behavior risk. Several other studies similarly haveidentified the elevated suicidality risk with levetiracetam.Another very large scale epidemiologic observational study from the UK was published by Aranaand colleagues in the New England Journal of Medicine in 2010. The study database included acohort of over 5 million patients and investigated suicide attempts and completed suicides inpeople with epilepsy, bipolar disorder, and depression. They did find an increased rate ofsuicidal events in people with epilepsy, but treatment with AEDs did not confer greaterstatistically significant risk. People with depression who were taking AEDs did have an elevatedsuicidal event rate. The authors speculated that the AED use could have been a marker forgreater depression severity accounting for the elevated rate of suicidal behavior. Suicidalityassessed in this study was not increased by AED use in the bipolar disorder patients.An even larger study reported in Pharmacoepidemiology and Drug Safety by Olesen andcolleagues in 2010 included the entire Danish population over a 10-year period, during whichthere were 6,780 completed suicides. The authors found an overall increased risk of suicide withAED use with an odds ratio of 1.84. Analyzed individually, where there were a sufficient numberof cases, there was an elevated risk of suicide in those taking clonazepam, valproate,lamotrigine, and phenobarbital, all particularly in the treatment initiation phase.In yet another 2010 publication, this one in JAMA, Patorno and colleagues, presented a large-scale database analysis of AEDs and completed suicides, attempted suicides, and violent deaths. Register here to earn credit for this activity: Presented by The Johns Hopkins University School of Medicine Developed through a strategic educational facilitation by Medikly, LLC. Supported by an educational grant from Lilly USA, LLC.
  6. 6. The study population was nearly 300,000 new treatment episodes of AED use. Using topiramateas a comparator, they found an increased risk of suicidal acts or violent deaths in peopleprescribed gabapentin, lamotrigine, oxcarbazepine, and tiagabine.Has this abundant literature of large-scale epidemiologic studies on suicidality and AED useanswered the questions about whether AEDs actually increases suicidality risk, and if so, aresome of the medications safer than others when it comes to suicide risk? Well, not really. Whilethere is strength in numbers, there also are methodological limitations regarding diagnoses,medication compliance, and effective ascertainment of suicidality.Still, among these many studies, including the clinical trials, there does appear to be a signal ofincreased suicidality, at least for some of the AEDs. Unfortunately, very little research hasclosely investigated suicidality with specific AEDs.The FDA based the alert on the increased suicidality identified with the pooled AED data,although the analyses of individual AEDs demonstrated a non-significant suicidality protectiveeffect from carbamazepine and divalproex . Considered individually, the only AEDS withstatistically significant suicidality increases were lamotrigine and topiramate, which already hadsuicidality risks noted in their labels.A study by Gibbons and colleagues published in 2010 in Pharmacoepidemiology and Drug Safety,examined the relationship of gabapentin and suicide attempts. They used a medical claimsdatabase to compare suicide attempt rates one year before and after gabapentin wasprescribed. The cohort studied represented over 130,000 patients with various diagnoses,including epilepsy, pain disorders, and an assortment of psychiatric disorders. The investigatorsfound no overall increase in suicide attempts following the introduction of gabapentin, and, infact, noted a reduction in suicide attempts in the people with psychiatric disorders.Redden and colleagues in 2011 published an article in the Annals of General Psychiatry ondivalproex sodium and suicidality. Similar to the FDA AED analysis, this was a meta-analysis ofclinical trials including the C-CASA methodology to determine suicidality. The authors concludedthat there did not appear to be an increase in suicide-related adverse events with divalproexrelative to placebo.A few studies have examined suicidality with AEDs in populations of patient with specificdisorders. The majority have been with epilepsy. In a 2012 publication by Leon and colleagues inthe American Journal of Psychiatry, the authors specifically investigated three AEDS approved Register here to earn credit for this activity: Presented by The Johns Hopkins University School of Medicine Developed through a strategic educational facilitation by Medikly, LLC. Supported by an educational grant from Lilly USA, LLC.
  7. 7. for treating bipolar disorder – carbamazepine, lamotrigine, and valproate in relation to suicideattempts and suicides. During a 30-year follow up period, the bipolar patients did not have anincrease in suicide attempts or suicides when exposed to AEDs compared to when they were nottaking them.What about age and suicidality and AED use? Recall that the FDA antidepressant Black Boxwarning refers to increased suicidality in children, adolescents, and young adults. However,further down in the Warning section of the prescribing information, it is noted thatantidepressant use may be associated with increased suicidality in both pediatric and adultpopulations. The AED suicidality warning does not suggest an elevated risk at any particular age.In fact, the required label wording for AEDs notes that the suicidality risk varied little with agesthe pooled analysis, which included an age range of 5 to 100 years.What’s the bottom line? There may be a small increased risk of suicidal thinking and suicideattempts and completed suicides, although with some AEDs appear to be associated withgreater risk while others may be somewhat protective.So, like the AED labels state, educate patients about the suicidality risk and monitor them forsymptoms of suicidality while they are taking these medications.We’ll look more closely at strategies to monitor patients for suicidality in the future podcasts inthis series.Thank you for joining us today. Register here to earn credit for this activity: Presented by The Johns Hopkins University School of Medicine Developed through a strategic educational facilitation by Medikly, LLC. Supported by an educational grant from Lilly USA, LLC.