Editorial
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Antiepileptic drugs and suicide risk: could stopping medications pose a greater hazard? Expert Rev. Neurother. 10(12), 1775–1776 (2010)
“…a subgroup of people with epilepsy seems to be prone to
Marco Mula Author for correspondence: Division of Neurology, University Hospital Maggiore della Carità, Amedeo Avogadro University, Novara, Italy Tel.: +39 321 373 3371 Fax: +39 321 373 3298
[email protected]
Josemir W Sander Department of Clinical & Experimental Epilepsy, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, UK and SEIN – Epilepsy Institutes in the Netherlands Foundation, SW Heemstede, The Netherlands
develop psychiatric adverse events whenever a new AED is introduced…”
More than 2 years after the US FDA issued an alert to healthcare professionals regarding an increased risk of suicidal thoughts and increased suicidality in people taking antiepileptic drugs (AEDs), the debate is still simmering over the agency’s decision [1,2] . Drug companies had previously been asked to submit data from placebo-controlled trials of AEDs, regardless of indication, when at least 30 people were enrolled. A total of 11 compounds were involved in 199 placebo-controlled trials, with over 27,000 individuals taking AEDs and 16,000 on placebo. The overall odds ratio (OR) for spontaneously reported suicidal behavior or ideation in those taking active drugs was 1.8 (95% CI: 1.24–2.66) [3] . It has been suggested that the concern of the FDA might have been excessive, and the methodology of using only spontaneously reported suicidality events has been questioned [4] . Others commented that when analyzing the data by indication, the OR was significantly raised in people with epilepsy (OR: 3.53; 95% CI: 1.28–12.10), but not for those taking AEDs for psychiatric conditions (OR: 1.51; 95% CI: 0.95– 2.45) or other medical problems (OR: 1.87; 95% CI: 0.81–4.76), thus reflecting only the known increased risk of suicide in people with epilepsy [5] . At any rate, all seem to agree that the risks associated with stopping, or not even starting, AEDs in epilepsy might well be in excess of the socalled risk of suicide [4,5] . Lack of seizure
control and its potential and often fatal consequences are responsible for this. The rate of suicide is almost certainly raised in people with epilepsy [6] , but the number of deaths due to suicide seem to be much smaller than those due to accidents or sudden unexpected death in epilepsy, which are related to uncontrolled seizures [7–9] . It has been demonstrated that nonadherence to AEDs can have serious or fatal consequences for people with epilepsy, with a threefold increase in mortality risk compared with those who comply with the treatment [10] . Many other drugs have been named as potentially risky for suicide. The British National Formulary lists several individual drugs and classes of drugs for which suicidal ideation is given as a potential side effect; five of these include a specific caution [5] . It has been argued that neither observational studies nor clinical trials of drugs for nonpsychiatric conditions are suitable for investigating suicide or suicidality [5] . Observational studies may generate hypotheses but they are complicated by a number of confounding factors. It also has to be acknowledged that, in clinical trials, while suicide is recorded as a serious adverse event, suicidal behavior or ideation is not usually sought [11] . Thus, it is clear that the etiology of suicide and suicidal behavior is complex and that the relationship between suicidal behavior and drugs is unclear.
Keywords : antiepileptic drugs • depression • epilepsy • suicide • US FDA
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Editorial
Mula & Sander
What is becoming clear is that a subgroup of people with epilepsy seems to be prone to develop psychiatric adverse events whenever a new AED is introduced, despite the different pharmacological properties [12] . These individuals are usually drug refractory, with a previous history and a family history of psychiatric disorders and may have functional abnormalities in the limbic system. In other words, there might be a genetic and biologic substrate on which the psychotropic properties of AEDs may have their deleterious effects. Such a biological substrate is probably interlinked with the biology of the epilepsy, as such effects are less frequent in people with primary psychiatric disorders where AEDs are commonly and successfully used. In these cases, the choice of the AEDs is of outmost relevance to avoid further complications.
“…tailored treatment strategies in epilepsy are mandatory.” It has to be acknowledged that tailored treatment strategies in epilepsy are mandatory. In particular, when choosing the appropriate AED for an individual, physicians need to take into consideration not only epilepsy syndrome, but also a number of individual circumstances, such as age, gender, somatic comorbidities, learning status, body type and not least, the mental state of the person. In agreement with others, we would suggest that early medical treatment with AEDs could potentially reduce the suicide risk of people with epilepsy in view of the mood-stabilizing properties of some compounds [13] . Indeed, upcoming studies seem to suggest that AED treatment may even prevent suicide in patients with epilepsy. A study using the UK General Practice Research Database investigated patients with incident epilepsy (defined as a diagnostic code of epilepsy and at least two AED prescriptions) and up to four matched controls for each individual with incident epilepsy. With over 3000 people with epilepsy and 11,000 controls, the incidence rate ratio was significantly increased for suicide References 1
Mula M, Bell GS, Sander JW. Suicidality in epilepsy and possible effects of antiepileptic drugs. Curr. Neurol. Neurosci. Rep. 10(4), 327–332 (2010).
2
Mula M, Sander JW. Antiepileptic drugs and suicidality. Much ado about very little? Neurology 75(4), 300–301 (2010).
3
US Food and Drug Administration. Antiepileptic drugs and suicidality. May 23 (2008).
4
Hesdorffer DC, Kanner AM. The FDA alert on suicidality and antiepileptic drugs: fire or false alarm? Epilepsia 50(5), 978–986 (2009).
5
Bell GS, Mula M, Sander JW. Suicidality in people taking antiepileptic drugs: what is the evidence? CNS Drugs 23(4), 281–292 (2009).
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attempts before the diagnosis of epilepsy and for the first year after the diagnosis [14] . Looking at suicide recurrence in individuals with a previous history of suicide attempt, however, the incidence rate ratio was actually reduced after epilepsy diagnosis and starting AED treatment, suggesting that treating epilepsy may actually reduce the risk of suicide. A US pharmacoepidemiologic study using the PharMetrics medical claims database (IMS Health, CT, USA) clearly suggests that AEDs do not increase the risk of suicide attempts in people with bipolar disorder compared with those not treated with AEDs or lithium [15] . Conversely, the use of AEDs seemed to reduce suicide attempt rates both relative to patients not receiving any psychotropic medication and relative to their pretreatment levels. Taken together, these findings seem to suggest that benefits from an appropriate treatment of seizures in people with epilepsy clearly overcome potential disadvantages, making AEDs potentially protective against suicide. The prognosis of epilepsy and the occurrence of severe complications, including suicide, may be made worse by missing important comorbidity and by delaying or withholding treatment. These issues may be compounded by the lack of input from professionals, such as psychologists, social workers and psychiatrists. A multidisciplinary approach to people with epilepsy is warranted. Financial & competing interests disclosure
Marco Mula has received travel grants or consultancy fees from various pharmaceutical companies including Novartis, Pfizer, UCB Pharma, Eisai, Janssen-Cilag and Sanofi-Aventis. Josemir W Sander has received travel grants or consultancy fees from various pharmaceutical companies including UCB Pharma, Eisai, Janssen-Cilag,and GSK – involved in the manufacture of antiepileptic drugs. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
6
Christensen J, Vestergaard M, Mortensen PB, Sidenius P, Agerbo E. Epilepsy and risk of suicide: a population-based case–control study. Lancet Neurol. 6(8), 693–698 (2007).
7
Bell GS, Gaitatzis A, Bell CL, Johnson AL, Sander JW. Suicide in people with epilepsy: how great is the risk? Epilepsia 50(8), 1933–1942 (2009).
8
Forsgren L, Hauser WA, Olafsson E et al. Mortality of epilepsy in developed countries: a review. Epilepsia 46(Suppl. 11), 18–27 (2005).
9
Surges R, Thijs RD, Tan HL, Sander JW. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms. Nat. Rev. Neurol. 5(9), 492–504 (2009).
10
Faught E, Duh MS, Weiner JR, Guérin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM study. Neurology 71(20), 1572–1578 (2008).
11
Reith DM, Edmonds L. Assessing the role of drugs in suicidal ideation and suicidality. CNS Drugs 21(6), 463–472 (2007).
12
Mula M, Trimble MR, Sander JW. Are psychiatric adverse events of antiepileptic drugs a unique entity? A study on topiramate and levetiracetam. Epilepsia 48(12), 2322–2326 (2007).
13
Ettinger AB. Psychotropic effects of antiepileptic drugs. Neurology 67(11), 1916–1925 (2006).
14
Hesdorffer DC, Ishihara-Paul L, Mynepalli L et al. Epilepsy and psychiatric disorders: evidence for a bidirectional relationship. Epilepsia 50(Suppl. 11), 220–221 (2009).
15
Gibbons R, Hur K, Brown CH, Mann JJ. Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch. Gen. Psychiatry 66, 1354–1360 (2009).
Expert Rev. Neurother. 10(12), (2010)
