Although AEDs are not the only option for treatment of psychiatric disorders and pain, currently there are no alternative treatments for epilepsy. Therefore, assessment of the risk–benefit balance for epilepsy may be more important than for the other disorders for which AEDs are prescribed. The FDA advisory panel recommended that information about the potential risk for suicidality be sent to doctors and detailed within the package insert. In addition, the FDA has recommended that patients receive a medication guide detailing the potential for suicidality each time a prescription is filled. It is too early to tell what effect this may have on AED prescription rates or on adherence to AEDs in epilepsy. However, after the black-box warning was issued for SSRIs, prescription rates fell among children and adolescents younger than 19 years of age (Gibbons et al., 2007; Nemeroff et al., 2007). This suggests the possibility of two consequences with AEDs that have already been observed for SSRIs: doctors may issue fewer prescriptions (Bhatia et al., 2008), and patients or their caretakers may decide that the drugs are not worth the potential risk for suicidality (Bhatia et al., 2008).
Although the issue of suicidality with AEDs is controversial, the adverse effects of failing to control epilepsy are not. If AEDs are less frequently prescribed or taken, seizure frequency will increase with associated increases in accidents (Buck et al., 1997; Van den Broek et al., 2004) and mortality, including sudden unexplained death in epilepsy (SUDEP) (Sander & Bell, 2004). Seizure frequency is an important predictor of both accidents and SUDEP. The risk for these serious adverse outcomes of epilepsy is more severe than the 3.4/1,000 suicidality rate reported by the FDA in the AED-treated group, especially since 64.4% of the suicidality incidents were ideation rather than attempts. Among people with active epilepsy who had had at least one seizure during the previous year (Buck et al., 1997), 24% experienced at least one head injury, 16% were burned or scalded, 10% had a dental injury, and 6% had a fracture. Seizure severity and seizure frequency were strong predictors of experiencing such injuries. Another large study of people with epilepsy reported that 21% had an accident during the study, of which 24% were seizure-related (Van den Broek et al., 2004). SUDEP occurs in 0.35–2.7 per 1,000 people with epilepsy in population-based studies (Annegers & Coan, 1999), and is more common in people with uncontrolled seizures (Annegers & Coan, 1999; Nilsson et al., 1999; Sander & Bell, 2004), and among those with a generalized tonic–clonic seizure in the preceding 3 months (Langan et al., 2005). But even if the FDA is correct, the risk for suicidality, predominantly suicidal ideation, is only 3.4/1,000 in people with epilepsy treated with the 11 AEDs. Therefore, AED treatment protects people with epilepsy from severe adverse outcomes associated with the occurrence of seizures.
What should clinicians look for?
Psychiatric disorders in the general population and in epilepsy are more often than not unrecognized and untreated (Simon et al., 1999; Kanner et al., 2004; Olfson et al., 2005), even if they are severe. In a study of 100 consecutive patients with a depressive episode sufficiently severe to warrant pharmacologic treatment, 63% of patients with spontaneous depressive episodes and 53% of “iatrogenic” episodes had been symptomatic for more than one year before they were identified (Kanner et al., 2004). Yet good medical practice demands an early identification of comorbid depressive and anxiety disorders in patients with epilepsy, not only because of the significant negative impact they have on patients’ quality of life (Gilliam, 2002) but also because of their association with an increased risk of suicidal ideation and behavior (Jones et al., 2003; Tellez-Zenteno et al., 2007).
At a minimum, clinicians should obtain the following clinical data: (1) Current or past history of the principal depressive and anxiety disorders (e.g., major depressive disorder, generalized anxiety disorder, panic disorder); (2) current or past history of suicidal ideation or behavior, both during the interictal and postictal periods; and (3) family psychiatric history of mood disorders and suicidal behavior. When clinicians treating epilepsy identify current psychiatric symptoms or suicidality, they should refer the patient to a mental health professional for care.
The acquisition of such data need not be a taxing demand on clinicians who can initially inquire if patients are experiencing anhedonia, that is, the inability to find pleasure in most activities. This symptom is a very good predictor of current depression (Mohr et al., 2007). Anhedonia is not usually related to physical complaints secondary to drugs or underlying illness, and it is a barometer of the intensity of the depression in the medically ill. Similar single questions are not possible for anxiety and suicidality.
Clinicians could also use screening instruments to identify current symptoms of depression. These include a six-item self-rating screening instrument, the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), that takes less than 3 min to complete and is validated to identify major depressive episodes in patients with epilepsy (Gilliam et al., 2006). This instrument was specifically constructed to minimize the potential that symptoms reported are not adverse events related to AEDs (e.g., fatigue or experiencing cognitive problems), whereas other instruments do not make this distinction. A score of 15 and higher is suggestive of a major depressive disorder and serves as a red flag referral to a psychiatrist for further evaluation. The Beck Depression Inventory (BDI-II) (Beck et al., 1996) is another self-rating screening instrument developed to identify symptoms of depression in the general population that has been validated in patients with epilepsy (Jones et al., 2005). It has 21 items and it takes 5–10 min to complete. A score of 14–19 suggests a depressive episode of mild severity; 20–28 moderate, and 29–63 severe. Both the NDDI-E and the BDI-II have items that identify suicidal ideation.
Several validated self-rating instruments to identify symptoms of anxiety are available, although none has been validated in patients with epilepsy. The recently developed the Patient’s Health Questionnaire-Generalized Anxiety Disorder-7 (PHQ-GAD7) (Kroenke et al., 2007), is a seven-item self-rating instrument that takes 3 min to administer and was developed to identify symptoms of generalized anxiety disorders. None of the items can be confounded with adverse events of AEDs or cognitive symptoms associated with the underlying neurologic insult that caused the epilepsy.
The identification of any current or past symptoms of depression and anxiety or suicidality as well as family history of these conditions should never be considered a reason to delay the start of AED therapy, as the likelihood of seizure recurrence poses a greater safety risk for patients, as previously discussed. The identification of such a prior or current history may help the clinician in the choice of AED, such as avoiding drugs that are known to increase the risk of psychiatric adverse events (barbiturates, levetiracetam, topiramate, zonisamide), particularly in the presence of these factors.
The development of psychiatric symptoms after the start of an AED should not be automatically considered causally related to the AED. Indeed, several mechanisms may be involved in the development of AED-related psychiatric symptoms and each should always be carefully considered. These include: (1) the administration of an AED with negative psychotropic properties. In such cases, the AED should be discontinued; (2) during a switch to a new AED, the discontinuation of the previous AED with mood-stabilizing properties (e.g., carbamazepine, valproic acid, lamotrigine) or anxiolytic ones (e.g., benzodiazepines, pregabalin, gabapentin), in patients with a prior mood or anxiety disorder that had been in remission with the discontinued AED. In such cases, an AED with similar psychotropic properties should be selected, or the previous AED restarted; and (3) the introduction of AEDs with enzyme-inducing properties in patients with a psychiatric disorder treated with a psychotropic drug metabolized in the liver. In such patients, the psychiatric symptoms result from an increased metabolism of the concurrent psychotropic drug, leading to lower serum concentrations associated with loss of efficacy. In such cases, the dose of the psychotropic drug must be adjusted to compensate for its increased clearance.
It is not rare for some patients with refractory epilepsy to become seizure-free or experience a significant reduction of seizure frequency with a new AED that can also cause psychiatric adverse events. If no other AEDs are available, the clinician can discuss with the patient the option to treat the psychiatric symptoms with a psychotropic drug without having to discontinue the AED.
Obviously, the presence of suicidality requires an immediate in-depth evaluation and treatment of the underlying psychiatric disorder ideally by a psychiatrist, and if not available (e.g., in rural areas) by another mental health professional. Likewise, current depressive and anxiety symptoms call for a more detailed evaluation by a mental health professional and a change to therapy more likely to yield total remission of symptoms (e.g., pharmacotherapy or cognitive behavior therapy, or both). Patients with current psychiatric symptoms not associated with suicidal ideation should be followed closely after the start of an AED and advised to contact their physician if their symptoms worsen or if they start experiencing suicidal ideation. Finally, patients with a family psychiatric history or a past psychiatric history should be advised of the increased risk of psychiatric symptoms in association with some AEDs. They should be told to contact their physician as soon as they occur.
What is the expected impact of the FDA alert on AED regulatory trials?
It is very likely that the FDA in the U.S.A., and at some future time the European Agency for the Evaluation of Medicinal Products (EMEA), will require a prospective investigation of suicidality in every regulatory AED trial. It is also possible that patients will need to be screened for suicidality, depression, and anxiety before randomization and during the course of future trials. In our opinion, an appropriate evaluation should include: the identification of suicidality, using the suicide module of the Mini International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998)), as well as a brief structured interview to identify current and past history of depression and anxiety disorders, such as the depression and anxiety modules of the Structured Clinical Interview for Axis I DSM-IV Diagnosis (SCID) (First et al., 1999); and self-rating screening instruments like the NDDI-E (Gilliam et al., 2006), the BDI-II (Beck et al., 1996), and the PHQ-GAD7 (Kroenke et al., 2007). In addition, the Columbia Suicide Severity Rating Scale (C-SSRS), a new instrument, has been developed specifically to identify current and past suicidal ideation and behavior and is being used in trials for antidepressants (Posner K., personal communication).