Antiepileptic drugs and suicidality: An expert consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission on Neuropsychobiology

Authors


Address correspondence to Marco Mula, Division of Neurology, University Hospital Maggiore della Carità, C.so Mazzini, 18, 28100 Novara, Italy. E-mail: marco.mula@med.unipmn.it

Summary

In 2008, the U.S. Food and Drug Administration (FDA) issued an alert to health care professionals about an increased risk of suicide ideation and suicide behavior in people treated with antiepileptic drugs (AEDs). Since then, a number of retrospective cohort and case–control studies have been published that are trying to address this issue, but gathered results are contradictory. This report represents an expert consensus statement developed by an ad hoc task force of the Commission on Neuropsychobiology of the International League Against Epilepsy (ILAE). Although some (but not all) AEDs can be associated with treatment-emergent psychiatric problems that can lead to suicidal ideation and behavior, the actual suicidal risk is yet to be established, but it seems to be very low. The risk of stopping AEDs or refusing to start AEDs is significantly worse and can actually result in serious harm including death to the patient. Suicidality in epilepsy is multifactorial, and different variables are operant. Clinicians should investigate the existence of such risk factors and adopt appropriate screening instruments. If necessary, patients should be referred for a psychiatric evaluation, but AED treatment should not be withheld, even in patients with positive suicidal risks. When starting an AED or switching from one to other AEDs, patients should be advised to report to their treating physician any change in mood and suicidal ideation. Data on treatment-emergent psychiatric adverse events need to be collected, in addition to general safety information, during controlled studies in order to have meaningful information for patients and their relatives when a new drug is marketed.

In 2008, the U.S. Food and Drug Administration (FDA) issued an alert to health care professionals about an increased risk of suicide ideation and behavior in people treated with antiepileptic drugs (AEDs) (FDA 2008a). Such a conclusion came from a meta-analysis of multicenter-randomized placebo controlled trials of 11 AEDs. Pharmaceutical companies had been previously asked to submit data from these trials, with at least 30 patients involved, regardless of indication. Spontaneously reported suicidality occurring during double-blind trials with an AED (or within 1 day of stopping) were sought and categorized. Data were provided on the use of carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide used for epilepsy (25% patients), psychiatric indications (27% patients), and “other conditions” (48% patients). In the main analysis, almost 28,000 people taking AEDs and >16,000 people taking placebo were considered. There were four completed suicides altogether, all in people taking AEDs and none in those taking placebo. The FDA concluded that patients receiving AEDs were significantly more likely to experience suicidal behavior or ideation compared with placebo (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.24–2.66). In addition, they observed that the relative risk (RR) versus placebo was higher in patients treated for epilepsy (RR 3.6; 95% CI 1.3–12.1) than for selected psychiatric illnesses (RR 1.6; 95% CI 1–2.4) or other conditions (e.g., migraine and neuropathic pain; RR 2.0; 95% CI 0.8–4.8) (FDA 2008b) where RR were not significant. As a result of the analysis, the FDA required that all manufacturers of drugs in this class include a warning in their labeling and develop a medication guide for patients, informing them of the risks of suicidal thoughts or actions. The FDA also suggested that the warning language be carefully worded and that it mention the risk of not treating the underlying condition (Busco, 2008).

The FDA data was received with great skepticism by clinicians and the professional societies, including the American Epilepsy Society, and some investigators questioned the validity of its findings, after identifying serious methodologic flaws (Hesdorffer & Kanner, 2009) and suggested that the FDA’s concern might have been excessive (Hesdorffer & Kanner, 2009; Mula et al., 2010), and that the risk of stopping (or not even starting) AEDs in people with epilepsy would be far greater than this hypothetic small increased risk of suicidality (Mula & Sander, 2010). The International League Against Epilepsy (ILAE) appointed a Task Force under the Commission on Neuropsychobiology to formulate a proposal for a consensus on treatment issues in patients with epilepsy and psychiatric problems. Members of this task force (MM, BS, AMK) have been selected according to the following criteria: (1) to be boarded in both adult neurology and adult psychiatry with certified clinical practice in adult neurology and adult psychiatry; (2) to work in an epilepsy center as an epileptologist as main clinical practice; (3) to have published relevantly in epileptology and neuropsychiatry of epilepsy. An additional member (SS) has been included as a liaison with the ILAE Commission on Therapeutic strategies. The present article represents an expert consensus statement on the issue of suicide during treatment with AEDs. References were identified by searches of Medline/PubMed using the terms “epilepsy,”“antiepileptic drugs,”“suicide.” Only articles published in English in international peer-reviewed journals were considered. The reference list of relevant articles was hand-searched for additional publications (e.g., book chapters or review papers) if relevant to the discussion. Abstracts of presentations, even from international congresses, have not been included. Discussions at international workshops have been considered (Kanner et al., 2012).

Limits of the FDA Meta-Analysis

An analysis of the FDA document demonstrates several methodologic flaws, which include:

  • 1 The assessment of suicidality was based on “spontaneous” reports of patients and not gathered in a systematic prospective manner in every patient who was randomized to study drug or placebo (Hesdorffer & Kanner, 2009; Hesdorffer et al., 2010).
  • 2 The FDA’s warning indicates an increased risk of suicide with all AEDs, despite the fact that statistical significance was found in only 2 (i.e., topiramate and lamotrigine) of the 11 AEDs studied. Furthermore, inclusion of three additional studies of lamotrigine resulted in the loss of statistical significance for this AED. Two other AEDs, valproic acid and carbamazepine, actually yielded a “small protective effect.” The FDA’s decision to present the risk as involving all AEDs stemmed from a concern that singling out specific AEDs might have changed prescribing practices, rather than emphasize the suicide risk, a reasoning that was not based on scientific facts.
  • 3 Most epilepsy trials (92%) included patients taking adjunctive therapy (compared with 14% of psychiatric trials and 15% of other medical trials). It is, thus, unclear whether the higher suicidality rates in the epilepsy trials were due to drug interactions, given the high proportion of epilepsy trials designed with polytherapy, or whether they potentially were due to the low suicidality risk associated with carbamazepine and valproate—both drugs are the most common comparison drugs in these trials and demonstrated favorable psychotropic properties (Ettinger, 2006).
  • 4 Suicidal behavior was greater in certain geographic regions. For example, the odds ratio of suicidality was 1.38 (95% CI 0.9–2.13) in North American studies and 4.53 (95% CI 1.86–13.18) in studies done elsewhere. Such differences strongly suggest serious methodologic errors in data gathering (Hesdorffer & Kanner, 2009; Hesdorffer et al., 2010).

Available Evidence on AEDs and Suicide

In the last 3 years, a number of retrospective cohort and case–control studies, using observational study methodology, investigated whether or not there is an association between AEDs and suicidality (Gibbons et al., 2009, 2010; Andersohn et al., 2010; Arana et al., 2010; Olesen et al., 2010; Patorno et al., 2010; VanCott et al., 2010; Redden et al., 2011). The majority of studies included data from patients with epilepsy, whereas some authors focused on psychiatric subjects only (Gibbons et al., 2009). In general terms, results are contradictory among the studies, with some studies reporting an increased suicidality risk (Andersohn et al., 2010; Olesen et al., 2010; Patorno et al., 2010; VanCott et al., 2010) and others observing no increased risk (Arana et al., 2010; Gibbons et al., 2010). However, all of these studies are being affected by a number of limitations (Hesdorffer et al., 2010; Mula & Hesdorffer, 2011) such as the failure to adjust for past suicidal behaviors (Andersohn et al., 2010; Olesen et al., 2010). In one study, the authors adjusted for a history of self-harm that does not imply suicidal behavior, being two different entities from a psychopathologic point of view (Mula & Hesdorffer, 2011). Another study took into account past suicidality but over an unspecified period of time (VanCott et al., 2010), whereas other authors (Arana et al., 2010; Patorno et al., 2010) excluded subjects with a past history, or family history (Arana et al., 2010), of suicidality before the study entry. The issue of a past history of suicide behavior represents an important variable because suicide is a highly recurrent phenomenon (between 14% and 17% after 1 year and >30% over 10 years) (Owens et al., 2002; Kapur et al., 2006) and because prescribing practices may be influenced by prior suicidal behaviors (Hesdorffer et al., 2010; Mula & Hesdorffer, 2011), considering that some AEDs are thought to have positive effects on mood and others negative (Ettinger, 2006). Therefore, in the absence of adjustment for prior suicidal behavior, it is impossible to determine, from the published studies, whether AEDs are associated with suicidal behavior (Mula & Hesdorffer, 2011).

The Issue of Suicide in Epilepsy

In the general population, suicide represents the 11th cause of death and the second in the group aged 25–34 years (Gelder, 2009). It is more common in men than in women, particularly in developed countries, whereas attempted suicide is more represented among females (Sadock et al., 2009). In patients with epilepsy, the overall risk of committing suicide is about three times higher than that of the general population (Harris & Barraclough, 1997; Christensen et al., 2007; Bell et al., 2009). Several studies have attempted to identify reasons for such an increased risk. In fact, suicidality and epilepsy have a complex relation, based on several variables. In the general population, about 90% of people who successfully commit suicide have at least one psychiatric disorder at that time (Barraclough, 1987). Epilepsy can be complicated by psychiatric comorbidities, but it is unlikely that such comorbidity is the only responsible element. A Danish study pointed out that the rate ratio of suicide in people with epilepsy is still doubled even after excluding people with psychiatric comorbidity and adjusting for various factors and that it increases by 32-fold in the presence of comorbid mood disorders and by 12-fold in the presence of anxiety disorders and schizophrenia. Some have suggested a link with temporal lobe epilepsy (Harris & Barraclough, 1997). However, a recent study, using retrospective and prospective methods, found no epilepsy-related factors (Hara et al., 2009). Postictal suicidal ideation is relatively frequent in patients with treatment-resistant partial epilepsy, having been identified in 13% of 100 consecutive patients with a median duration of 24 h (Kanner et al., 2004). Furthermore, a bidirectional relation has been identified between suicidality and epilepsy, whereby patients with a history of suicidal behavior have a fivefold higher risk of developing epilepsy in a population-based study conducted in Iceland (Hesdorffer et al., 2006). This bidirectional relation raises the question of common pathogenic mechanisms operant in both conditions such as serotonin dysfunction, a hyperactive hypothalamic-pituitary-adrenal axis, as well as glutamate and γ-aminobutyric acid (GABA)-ergic disturbances (Hecimovic et al., 2011).

In conclusion, all the complexities of the relation between epilepsy and suicide are still far from being elucidated, but they are clearly multifactorial with biologic, constitutional, and psychosocial variables being implicated. Yet, given the increased risk of suicide in patients with epilepsy, screening for suicide is a relevant issue.

Psychiatric Adverse Events of AEDs in Patients with Epilepsy

The psychotropic potential of AEDs in patients with epilepsy is related to direct and indirect mechanisms (Mula & Sander, 2007). A number of studies suggest that treatment with some AEDs is associated with the occurrence of symptoms of depression (Table 1), whereas other compounds have positive psychotropic properties. As far as first-generation compounds are concerned, authors agree that there is a link between barbiturates and depression, whereas carbamazepine probably has mood stabilizing and antimanic effects (Rodin et al., 1976; Dodrill & Troupin, 1977; Robertson & Trimble, 1983). Among second-generation AEDs, vigabatrin (Levinson & Devinsky, 1999), tiagabine (Trimble et al., 2000), and topiramate (Mula et al., 2003a) have been linked to treatment-emergent depressive symptoms, whereas levetiracetam with dysphoria and mood lability (Mula et al., 2003b).

Table 1.   Treatment-emergent psychiatric adverse events of AEDs in patients with epilepsy
DepressionPsychosesIrritability/Emotion lability
Barbiturates
Tiagabine
Topiramate
Vigabatrin
Zonisamide
Ethosuximide
Levetiracetam
Phenytoin (toxic levels)
Topiramate
Vigabatrin
Zonisamide
Felbamate
Lamotrigine
Levetiracetam

In some cases, treatment-emergent depressive symptoms are associated with a sudden complete control of seizures (the forced normalization phenomenon) (Ring et al., 1993), whereas in others they are unrelated to this. Nevertheless, a rapid titration of the drug (Mula et al., 2009) in patients with drug-refractory mesial temporal lobe epilepsy and a past history of depression (Mula et al., 2007) have been identified as major determinants in the majority of cases. Particularly, several studies pointed out that the development of psychiatric adverse events (which could potentially facilitate the occurrence of suicidal ideation and behavior) is more likely in patients at risk of developing psychiatric disorders, either because of a past psychiatric history or a family psychiatric history (Kanner et al., 2003; Mula et al., 2007).

Conclusions

  • 1 Although some (but not all) AEDs can be associated with treatment-emergent psychiatric problems that can lead to suicidal ideation and behavior, the actual suicidal risk is yet to be established, but it seems to be very low. The risk of stopping AEDs or refusing to start AEDs is significantly worse and can actually result in serious harm including death to the patient (Hesdorffer et al., 2011; Ryvlin et al., 2011).
  • 2 Suicidality in epilepsy is multifactorial. Major operant variables include the following: (1) postictal suicidal ideation; (2) a past and/or current history of psychiatric disorders, particularly mood and anxiety disorders (and above all when associated with prior suicidal attempts); (3) a family history of mood disorder complicated with suicidal attempts. Notably, suicide attempts preceding the onset of the epilepsy need to be taken into account. Given the above risks, clinicians should investigate the existence of such risk factors and if necessary, refer the patient for a psychiatric evaluation, but not withhold treatment even in patients with positive suicidal risks.
  • 3 When starting an AED or switching from one to other AEDs, patients should be advised to report any changes in mood and suicidal ideation to their treating physician. In fact, despite the uncertainty, the FDA alert remains active and clinicians need to screen patients they start on AEDs. The Columbia Suicide Severity Rating Scale (C-SSRS) represents a suitable and reliable instrument to evaluate suicidality (Posner et al., 2011) and it is available in several languages (Korean, Japanese, Chinese, Afrikaans, French, Bulgarian, Czech, Dutch for Belgium, Dutch for The Netherlands, English, English for South Africa, Estonian, Finnish, German for Austria, Korean, Lithuanian, Turkish, Swedish, Spanish for U.S.A., Spanish for Mexico, Polish, Malay, Greek, Hungarian, Italian, German, and Romanian).
  • 4 Data on treatment-emergent psychiatric adverse events need to be collected, in addition to general safety information, during controlled studies in order to inform patients and their relatives when drugs are marketed. A detailed family and personal history of psychiatric disorders, a previous history of suicidal behaviors (even before the onset of the epilepsy), and a screening for suicide using the C-SSRS need to be included in any controlled trial of new AEDs in epilepsy.

Acknowledgments

This report was written by experts selected by the International League Against Epilepsy (ILAE) and was approved for publication by the ILAE. Opinions expressed by the authors, however, do not necessarily represent official policy or position of the ILAE.

Disclosure

MM has received consultancy fees from Pfizer, UCB Pharma, and Janssen. AMK has received research funding from Pfizer, Novartis, and GlaxoSmithKline. BS has received consultancy fees from GlaxoSmithKline, UCB Pharma, Janssen, Desitin, Pfizer, Eisai, Novartis, and Sanofi. SS has been compensated by Cyberonics, Insero Health, and Sage therapeutics for giving scientific guidance for the further clinical development of devices and compounds for the diagnosis and treatment of epilepsy. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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