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 Citation[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) Citation[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 Citation[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 Citation[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 so-called risk of suicide Citation[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 Citation[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 Citation[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 Citation[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 Citation[5]. It has been argued that neither observational studies nor clinical trials of drugs for nonpsychiatric conditions are suitable for investigating suicide or suicidality Citation[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 Citation[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.
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 Citation[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.
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 Citation[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 attempts before the diagnosis of epilepsy and for the first year after the diagnosis Citation[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 Citation[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.
References
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