It was suggested some years ago that, although the current view was that people with epilepsy rarely commit suicide, ‘it can be readily appreciated that suicide does occur… rather frequently’ . Many years later, it was reported that three of 107 deaths in a population with epilepsy were due to suicide . Since then, it has been generally accepted that suicide is more common in people with epilepsy than in the general population. A meta-analysis found that the overall standardized mortality ratio (SMR) for suicide in people with epilepsy was 5.1 (95% CI, 3.9–6.6), and the SMR was further raised in those with temporal lobe epilepsy and those treated surgically . Case–control and cohort studies confirm this increase [4,5••]. A report from the United States, however, suggested that there was insufficient evidence to be sure that the rate of suicide is increased in people with treatment-resistant epilepsy .
In whom is the rate of suicide increased?
Individual studies have suggested that up to a third of people with epilepsy in some cohorts may die as a result of suicide , although the overall rate is probably well under 5%. A case–control study from Sweden, with 26 cases of suicide and 23 of suspected suicide in people with epilepsy matched with 171 people with epilepsy from the same population, found a nine-fold increase in the relative risk of suicide associated with psychiatric disease and a 10-fold increase associated with the use of antipsychotic drugs . Onset of epilepsy in the first 17 years of life was associated with a significant increase in risk for suicide compared with those whose epilepsy started at an age of more than 29 years. The risk of suicide appeared to increase slightly with increased seizure frequency but was significantly raised only in those with unknown seizure frequency.
A more recent, and much larger, case–control study from Denmark [5••] used five nationwide registries to obtain information about epilepsy (predominantly inpatients), cause of death, psychiatric diagnoses (predominantly inpatients), socioeconomic data and demographic data. This study investigated only deaths recorded as suicide between 1981 and 1997. Each person who committed suicide was age and sex matched with up to 20 controls who were alive on the day of the relevant suicide. Logistic regression was used to estimate rate ratios. Of the over 21 000 people who committed suicide, 2.3% had a history of epilepsy compared with 0.7% of the 420 000 controls. The rate ratio of suicide in people with epilepsy was 3.2 compared with those without epilepsy. There was an increased risk of psychiatric disease in people with epilepsy (rate ratio, 4.3). Psychiatric history was a strong risk factor for suicide (rate ratio, 12.5 in those without epilepsy), but the rate ratio of suicide in people with epilepsy but without a psychiatric history was almost 2 compared with those without epilepsy. In people both with and without epilepsy, affective disorder was the most common psychiatric disorder associated with the risk of suicide. In people with epilepsy, both with and without comorbid psychiatric disease, the risk of suicide was highest in the first 6 months after diagnosis.
In the general population, the risk of completed suicide seems to be increased by a previous suicide attempt . A questionnaire study from Canada found that lifetime prevalence of suicidal ideation in people with epilepsy (25%) was higher than in people without epilepsy (13%) .
Why is the risk increased?
It was suggested almost 30 years ago that an important reason for the high risk of suicide in people with epilepsy might be social disadvantages, and psychiatric disturbance and the use of antiepileptic drugs (AEDs) might play a role . It was suggested that reducing stigma, as well as seeking and treating psychiatric symptoms in people with epilepsy and treating seizures with the smallest effective dose of AEDs, could be important in suicide prevention.
Psychiatric illness: depression and suicidal behaviour
People with epilepsy may have untreated psychiatric illness, and this has been a consistent finding . Over half of adults admitted to a telemetry unit with treatment-refractory epilepsy were found to have depression as diagnosed by the Beck Depression Inventory (BDI) . Of these, 17% were being treated with antidepressants. Over one-third of those found to have depression had had thoughts of suicide. Interestingly, the only predictor of quality of life (the main aim of the study), again as measured by questionnaire, was the BDI score.
Depression may occur more frequently, and more severely, in people with epilepsy than in people with other neurological diseases , and although reactive depression may not be an unexpected finding in people with epilepsy, in about 40% of people with epilepsy and depression, the depression is endogenous . Bipolar illness seems to be less common in people with epilepsy than depression itself . Additionally, depression in people with epilepsy is sometimes atypical .
A large UK study of adults consulting general practitioners for, or newly diagnosed with, epilepsy over a 4-year period found that psychiatric disorders occurred twice as often in people with epilepsy as in those without a consultation for epilepsy . Over one-third of people with epilepsy were diagnosed with a psychiatric disorder during the study period. People with epilepsy were twice as likely to have depression as those without epilepsy, twice as likely to have neuroses and almost four times as likely to have schizophrenia. In this study, AEDs were not used as a surrogate for epilepsy.
Other studies have suggested that those with treatment-resistant epilepsy are more likely to be depressed (over 20%) than those with fully controlled seizures (8–10%) [17•], the corresponding general population rates are 2–4%. A recent study from Croatia [17•], using the BDI, showed similar results; altogether, one-third of 50 people from an epilepsy centre who completed the questionnaire had symptoms of depression. Three patients had attempted suicide in the past, and two of those had current suicidal ideation; all three had symptoms of severe depression.
A small study from northern Finland investigated epilepsy, suicidal behaviour and depression using death certificates and hospital admission data . Of 1877 people who died as a result of suicide between 1988 and 2002, 25 had hospital-treated epilepsy. People with epilepsy who committed suicide had more often had a hospital-treated psychiatric disorder (76%) than those without epilepsy (44%). The median interval from first hospital-treated epilepsy to death by suicide was 8.8 years, whereas that for first hospital-treated depression to suicide was 7.8 years.
In Italy, 103 patients with temporal lobe epilepsy each completed three questionnaires: the Beck Hopelessness Scale (BHS, in which a cut-off score of nine or more indicates a high risk of suicide), the BDI and the Zung Self-rated Anxiety Scale (SAS) [19•]. Over a quarter of the patients had scores of nine or more on the BHS, suggesting a high risk of suicide. These patients were approximately 9 years older than those with lower scores, and they also scored higher on the BDI and the SAS, suggesting higher general levels of depression and anxiety.
Psychiatric illness: bidirectional causation
There have recently been suggestions that the relationship between depression and suicidal behaviour, and seizures may be two-way, (that is, seizures may be a risk factor for depression and suicidal behaviour, and depression and suicidal behaviour may be risk factors for new onset of seizures). A study from northern Sweden investigated people aged between 17 and 74 years with newly diagnosed unprovoked epileptic seizures . A group of 86 patients was identified, and each was age and sex matched with two controls; those with seizures were evaluated by a neurologist, and they and the controls were asked to complete a questionnaire. Depression in the previous 6 months was found to be significantly more common in those with seizures than in controls.
A study in Iceland investigated all adults and children over 10 years of age who developed unprovoked seizures within a period of just over 3 years; each was matched with two controls . Psychiatric assessment was performed using telephone interviews to arrive at Diagnostic and Statistical Manual of Mental Disorders-IV diagnoses. With 324 patients with new onset of seizures and 647 controls, a history of major depression was almost twice as common in those with seizures and a history of a suicide attempt was five times as common in those with seizures.
More recently, a study in this same population investigated comorbidity with migraine with aura [22•]. Compared with those with neither migraine with aura nor depression, the adjusted odds ratio (OR) for developing seizures for those with migraine with aura alone was 2.5 (95% CI, 1.6–3.9), for major depression alone was 1.4 (95% CI, 0.8–2.4) and for both was 4.6 (95% CI, 1.9–11.4). Similarly, compared with those with neither migraine with aura nor a history of suicide attempt, the adjusted OR for developing seizures in those with migraine with aura alone was 2.4 (95% CI, 1.5–3.9), for suicide attempt alone was 4.7 (95% CI, 1.7–13.0) and for both was 7.9 (95% CI, 1.7–37.3). It is suggested that the associations between these conditions may reflect a causal pathway, in which one brain dysfunction can influence others.
In these studies, biases such as interviewer bias and reporting bias were considered (as some patients and controls reported depression or suicide attempt many years previously) . There was no association of seizures with migraine without aura, suggesting that recall bias does not play a role [22•]. It has also been suggested that, as suicide attempt is a risk factor for epilepsy and as suicide attempt also increases the risk of completed suicide, completed suicide may follow from suicidal tendencies that were present before the onset of seizures .
Further evidence that depression and seizures may be related is provided by a follow-up study of people with newly diagnosed epilepsy from Scotland [24•]. In this study, treatment-resistant epilepsy was associated with, amongst other things, psychiatric comorbidity (mostly depression), which preceded or accompanied the diagnosis of epilepsy. Suicidal behaviour was not considered separately.
Antiepileptic drug usage
It has been suggested that AEDs may also be involved in the increased risk of suicidal behaviour in people with epilepsy. A study from the UK investigated psychiatric adverse events in patients taking topiramate and levetiracetam (both effective AEDs but with different mechanisms of action) [25•]. In the first part of the study, the authors compared demographic and clinical details of patients who developed psychiatric adverse events with both AEDs and those who developed them with neither. Of 108 patients who had taken both AEDs, nine developed psychiatric adverse events with both drugs and 71 with neither. A history of febrile convulsions, a previous psychiatric history and family psychiatric history were all significantly associated with patients who experienced psychiatric adverse events. The study then considered all patients who had tried either levetiracetam or topiramate; those who developed psychiatric adverse events with either drug were similar in most clinical variables. Many patients who developed psychiatric adverse events, however, were completely seizure free during the period of psychopathology. The authors suggest that those with treatment-resistant epilepsy who developed psychiatric adverse events may be likely to do so with any AED; they may be those with a previous and family psychiatric history or a history of febrile convulsions.
Another study reported on four people who developed suicidal ideation while taking levetiracetam . All four developed major depression, one with psychotic features. Onset occurred soon after starting levetiracetam, and all four had significant seizure reduction (three were seizure free). All had a past psychiatric history, but none had a history of a suicide attempt. All resolved after reducing or stopping levetiracetam, and it was suggested that the symptoms of these patients fit with earlier observations that suicide risk may be associated with an interictal dysphoric disorder, a condition in which one key symptom is intermittent depressed mood.
The US Food and Drug Administration recently issued a warning about AEDs and suicidality . Data from pharmaceutical companies regarding placebo-controlled trials with 11 different AEDs was gathered, and a meta-analysis was performed. AEDs were taken for epilepsy, psychiatric conditions or ‘other’ conditions. With almost 28 000 patients in the drug arms and 16 000 in the placebo arms, they found that the OR for suicidal ideation or behaviour in the drug arms was 1.8 (95% CI, 1.24–2.66). ORs for individual AEDs were significantly increased for lamotrigine (29% of patients in these studies were taking lamotrigine for epilepsy) and for topiramate (11% of patients were taking topiramate for epilepsy). The OR was significantly increased in patients taking AEDs for epilepsy (OR, 3.53; 95% CI, 1.28–12.1) but not for the other two groups of indications. Altogether, there were four completed suicides in people taking AEDs and none in the placebo arms. It is important to be aware that no information is available in the report about the state of seizure control in patients with epilepsy, which may be relevant to the discussion.
In the early 20th century, it was suggested that psychosis was rare in people with epilepsy. Others noted that, when certain people with epilepsy became free of seizures, they developed psychotic episodes. This phenomenon, ‘forced normalization’, was thus defined then as ‘the phenomenon characterized by the fact that, with the recurrence of psychotic states, the EEG becomes more normal or entirely normal as compared with previous and subsequent EEG findings’ . This suggests that forced normalization may occur in people with interictal EEGs with epileptiform patterns and in whom seizure reduction, accompanied by EEG normalization, occurs. There are said to be no reliable predictive factors for forced normalization, but it has been suggested that AEDs should be introduced slowly to avoid precipitating psychosis . The condition of alternating abnormal mental states with seizures has also been called ‘alternating psychosis’, a term which does not rely on the use of EEG . It is important to note that, although psychosis is the more usual presentation of forced normalization, depression may also occur .
A recent review has stressed the importance of postictal psychosis . In this situation, a patient with epilepsy has a cluster of tonic–clonic seizures (with or without complex partial seizures). In the initial postictal period, the patient usually improves; this is known as the lucid interval. Psychotic symptoms may then occur, which may last from days to weeks. This situation usually occurs in people with chronic epilepsy, typically 15–22 years after the onset of the epilepsy. It is particularly important as suicide may occur during postictal psychosis.
In a recent review of epilepsy and suicide, it was stated that ‘predicting death caused by suicide is a nearly impossible task’ . It is also suggested, however, that when epilepsy is diagnosed, a psychiatric and psychosocial assessment should be made to determine the risk of suicide. If the risk is thought to be increased, then interventions might include appropriate treatment, referral to psychiatrist or even hospitalization . Appropriate AED therapy might include carbamazepine and valproate as drugs of first choice in patients with mood disorders, but it is suggested that topiramate and levetiracetam should be avoided in these patients. Antidepressant treatment, particularly with selective serotonin reuptake inhibitors (SSRIs), can be used in adults . This has been emphasized by a recent review of treatment of depression in epilepsy, which concludes that, although occasional people with epilepsy and depression treated with SSRIs have worse seizure control, many have no increase in seizure frequency and some have reduced seizure incidence . A discussion about the pharmacological treatment of depression in adults with epilepsy also considers that SSRIs are usually the drugs of first choice in patients with epilepsy and major depression [35•]. There are, however, possible drug interactions between some SSRIs and enzyme-inducing AEDs that need to be considered.
Other advice given is that people with epilepsy should be routinely evaluated for depression, and when this is present, therapeutic interventions should be considered . Few neurologists apparently routinely screen patients for depression. This may be due to a lack of appreciation of its occurrence, failure to consider depression as important in managing people with epilepsy, lack of studies providing definitive treatment strategies and problems in diagnosing depression in people with epilepsy .
It seems conclusive that the risk of suicide is increased in people with epilepsy, but further studies are needed to identify those more at risk. Claims have been made that suitable treatment may prevent suicides in people with epilepsy and dysphoric disorders , but these need to be substantiated.
Josemir W. Sander has received research grants, travel grants or consultancy fees from various pharmaceutical companies, including Novartis, Pfizer, UCB Pharma, Eisai, Janssen-Cilag, Sanofi-Aventis and GSK that are involved in the manufacturing of antiepileptic drugs. Gail S. Bell has no disclosures.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 000–000).
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