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Are antiepileptic drugs (AEDs) associated with an increased risk of attempted or completed suicide?
5 130 795 people enrolled with a general practice for ≥6 months during the study period identified using The Health Improvement Network (THIN) database. People with a history of one or more suicide attempts or a family history of suicide were excluded. The THIN database includes the anonymised medical records of more than 6.7 million people collected by their general practitioner and is representative of the general population of the UK. For the case–control part of the study, for each case with suicide-related events five age-, gender- and practice-matched controls were selected. When looking at the effect of AED use within specific diagnostic groups, another set of controls was selected and matched to cases for psychiatric or neurological diagnosis.
General population, UK; 1 July 1988 to 31 March 2008.
Use of AEDs available in the UK and included in a previous Food and Drug Administration meta-analysis on the effects of AEDs on suicidality (carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate and zonisamide). Current use was defined as having a prescription for AEDs in the past 75 days; previous use was defined as a prescription before this time; and non-use as no recorded prescription of AEDs. People were also classified according to their diagnosis: epilepsy, bipolar disorder, depression or none of these diagnoses. The analyses were controlled for potential confounders including age; duration of disease; previous use of AEDs, lithium, antipsychotic drugs or antidepressants; presence or absence of a history of alcohol abuse or a mental disorder; and chronic disease score.
Incidence of suicide-related events (based on medical codes for suicide, attempted suicide and intentional self-inflicted injuries plus suicide). Completed suicide was defined as recorded suicidality followed by recorded death in the following month and final administrative activity in the database or disenrollment from the database within 6 months of the recorded suicidality, or having a last medical or other health-related code recorded within 1 month after the suicide date.
Cohort and nested case-control study (registry based).
Mean follow-up 6.2 years.
During follow-up, 8212 people attempted and 464 people completed suicide. The crude incidence rates of suicide-related events are summarised in the table 1. The adjusted case–control analysis showed that compared with people without epilepsy, depression or bipolar disorder who were not using AEDs, the risk of suicidality was increased among people with epilepsy, depression or bipolar disorder, regardless of whether they were taking AEDs. When comparisons were made among people with the same diagnosis, current use of AEDs among people with depression alone or among peoplewas associated with an increased risk of suicidality compared with non-use (OR 1.65, 95% CI 1.24 to 2.19). However, the current use of AEDs was not associated with an increased risk of suicidality in people with epilepsy alone or bipolar disorder alone compared with non-users (epilepsy alone: OR 0.59, 95% CI 0.35 to 0.98; bipolar disorder alone: OR 1.13, 95% CI 0.35 to 3.61).
The current use of AEDs is associated with an increased risk of attempted or completed suicide in patients who have depression. There is no increased risk associated with antiepileptic medication for patients with epilepsy or bipolar disorder.
After reviewing 199 placebo-controlled trials of antiepileptic drugs (AEDs) in 2008, the US Food and Drug Administration (FDA) issued a warning that usage of the drugs could result in heightened risk of suicidality. They also added a public health advisory requiring that “health care professionals should notify patients and caregivers of the potential for an increase in the risk of suicidal thoughts or behaviors so that patients may be closely observed.” The meta-analysis found that the absolute risk of suicidal thinking or behaviour was 0.43% in those taking AEDs versus 0.24% in the group on placebo. That equates to one additional case of suicidal thoughts or behaviour for every 500 patients taking an AED.
The limitations of randomised trials in evaluating uncommon adverse effects are well known. Short duration of follow-up and lack of accurate data on outcomes are reasons why large observational studies offer an important alternative perspective. In this case control study, Arana and colleagues make use of a UK database of primary care attenders to provide an analysis of risk by indication for prescription. They found that AEDs were not associated with an increased risk of attempted or completed suicide among patients with epilepsy (OR 0.59, 95% CI 0.35 to 0.98) or bipolar disorder (1.13, 95% CI 0.35 to 3.61). However, there was an increased risk in depressed patients (OR 1.65, 95% CI 1.24 to 2.10) and notably in those without epilepsy, depression or bipolar disorder (2.57, 95% CI 1.78 to 3.71). A plausible explanation for this latter finding is that AEDs may have been prescribed for chronic pain, which itself is associated with an increased risk of suicide.
This study indicates that the underlying illness provides a greater risk of suicidal behaviour than the prescription of AEDs. Advisory warnings may promote monitoring for suicidal thoughts, but this must be set against the risk of people with epilepsy declining or stopping treatment, as was the case with the FDA warnings on antidepressants.1 Unlike depression, there are no ready alternative treatments for epilepsy.
Source of funding Sepracor.
Competing interests None.
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