Depressive symptoms and disorders can be classified according to their temporal relation to seizure occurrence. Depressive symptoms can present during the 48 to 72 hours preceding a seizure (pre-ictal symptoms of depression), they can be an expression of an actual seizure (ictal symptoms of depression) or can occur within 120 hours after a seizure (postictal symptoms of depression). Symptoms that precede or follow are referred to as peri-ictal symptoms. Depression can also occur unrelated to the seizure occurrence (interictal depression). Often, patients experience symptoms of depression during both peri-ictal and interictal periods with an exacerbation in severity of symptoms during the postictal period.
Pre-ictal symptoms. There are a few reports in the literature of pre-ictal depression, which typically presents as a cluster of dysphoric symptoms for hours or up to three days before the onset of seizures. Blanchet and Frommer (1986) studied mood changes over 56 days in 27 patients who were asked to rate their mood daily. Mood ratings pointed to symptoms of dysphoria, anxiety and irritability three days before a seizure in 22 patients. This change in mood was more accentuated during the 24 hours preceding the seizure. It should be noted that in children, these dysphoric moods take the form of irritability, poor frustration tolerance, motor hyperactivity and aggressive behavior.
Ictal symptoms. Ictal symptoms of depression are the expressions of a simple partial seizure (aura) in which the symptoms of depression are its sole (or predominant) semiology. It has been estimated that psychiatric symptoms occur in 25% of auras; 15% of these involve affect or mood changes (Daly, 1958; Mulder and Daly, 1952; Weil, 1959, 1955). Ictal depression ranked second after anxiety/fear as the most common type of ictal affect in one study (Weil, 1959). When mood changes represent the only clinical expression of simple partial seizures, it may be difficult to recognize them as epileptic phenomena. Typically, they are brief, are stereotypical, occur out of context with the patient's activity and are associated with other ictal phenomena. The most common symptoms include feelings of anhedonia (inability to experience pleasure in anything), guilt and suicidal ideation. More typically ictal symptoms of depression are followed by alteration of consciousness as the ictus evolves from a simple to a complex partial seizure.
Postictal symptoms. Recognized for a very long time, postictal symptoms of depression have been recently studied in systematic matter in a study completed in our center, where we investigated the presence of postictal psychiatric symptoms in 100 consecutive patients with poorly controlled partial seizure disorders (Kanner and Balabanov, 2002; Kanner et al., 2004). Patients were given a 42-item questionnaire designed to identify psychiatric symptoms occurring in the postictal period, defined as 72 hours following recovery of consciousness from the last seizure. The following symptoms of depression were investigated: anhedonia, irritability, poor frustration tolerance, feelings of hopelessness and hopelessness, suicidal ideation, feelings of guilt and self-deprecation, and crying bouts. Five neuro-vegetative symptoms (changes in pattern of sleep, appetite and sexual drive) were analyzed separately, as they are common postictal symptoms not associated with symptoms of depression.
A total of 43 patients (43%) experienced a median of five postictal symptoms of depression after more than 50% of their seizures. Patients estimated a median duration of 24 hours in two-thirds of the symptoms they experienced. Thirty-five patients experienced at least two postictal symptoms, with a minimum duration of 24 hours; in 13 of these patients, at least seven symptoms clustered to mimic symptoms of a major depression lasting 24 hours or longer. Thirteen patients reported habitual postictal suicidal ideations. Thirteen patients exclusively experienced symptoms of depression, whereas in the other 30 patients, we identified concurrent postictal symptoms of anxiety and a combination of depression, psychosis and anxiety. It should be noted that postictal symptoms of depression were significantly associated with more postictal cognitive deficits.
Clearly, these data show that postictal symptoms of depression are relatively common in a sample of patients with poorly controlled epilepsy. It remains to be investigated whether this observation applies to patients with rare seizures. It should be kept in mind that the symptoms of postictal depression can last up to two weeks after the seizure occurrence. At times, this can lead to suicide attempts; therefore, close follow up of patients with known postictal depression is necessary.
Interictal depression. Interictal depression is the most commonly recognized presentation of affective disorders among patients with epilepsy (Altshuler et al., 1990; Blumer and Altshuler, 1998; Blumer and Zielinski, 1988; Blumer et al., 1995; Kanner and Palac, 2000). Interictal depression can present as major depressive disorder or any of the other mood disorders included in the DSM-IV classification. In our opinion, however, a large number of patients with epilepsy do not meet DSM-IV criteria for these mood disorders, rather they have pleomorphic cluster of symptoms of depression with a chronic course that is interrupted by recurrent symptom-free periods of hours to several days duration. This clinical presentation closely resembles a dysthymic disorder. Blumer et al. (1995) referred to this atypical form of depression as interictal dysphoric disorder. According to Blumer (1991), almost one-third to one-half of patients with epilepsy suffer from interictal dysphoric disorder of sufficient severity to require pharmacologic treatment. Blumer described the interictal dysphoric disorder as a chronic dysthymic state in which symptoms tend to occur intermittently and are intermixed with brief euphoric moods, explosive irritability, anxiety and somatoform symptoms (e.g., anergia, atypical pain and insomnia), which have been considered as depressive equivalents (Blumer, 1991; Blumer and Zielinski, 1988; Blumer et al., 1995). Despite the fact that interictal depression presenting as interictal dysphoric disorder is so prevalent among our patients, it usually goes unreported by patients and unrecognized by clinicians. Patients eventually assume that their symptoms reflect a natural state that is part of their epilepsy. Physicians overwhelmed with the goal to achieve seizure control very often miss detecting symptoms of depression, even in patients they have followed for a long time. Clinicians should carefully inquire about symptoms of depression as an integral part of their evaluation of seizure disorder.Treatment
Many clinicians are reluctant to use antidepressant medications in patients with known seizure disorder because of fear that the antidepressant drugs can worsen the seizure disorder. However, is that a legitimate concern? Antidepressants have been associated with increased risk of seizure in nonepileptic patients at high plasma serum concentrations or when given at rapid dose increments (Preskorn and Fast, 1992). Other risk factors include known CNS pathology, abnormal EEG, and personal and family history of epilepsy (Curran and de Pauw, 1998; Swinkels and de Jonghe, 1995). If this is the case, then do antiepileptic drugs protect patients with epilepsy from the proconvulsant properties of these drugs?
Blumer and colleagues (1995) have reported using tricyclic antidepressants in combination with selective serotonin reuptake inhibitors in patients with epilepsy, without seizure exacerbation. In a study done in our center by Kanner et al. (2000b), only one of 100 patients had worsening of seizures when treated with sertraline(Drug information on sertraline) (Zoloft). In our opinion, SSRIs should be considered drugs of first choice for treatment of depression in patients with epilepsy (Kanner and Balabanov, 2002). Being inhibitors of the enzymes of the cytochrome P450 system, some SSRIs, such as fluoxetine(Drug information on fluoxetine) (Prozac), fluvoxamine(Drug information on fluvoxamine) (Luvox) and to some degree paroxetine (Paxil), have pharmacokinetic interaction with antiepileptic drugs (Fritze et al., 1991; Grimsley et al., 1991; Pearson, 1990). Of note, citalopram(Drug information on citalopram) (Celexa) does not have any pharmacokinetic impact on the metabolism of the antiepileptic drugs (Kanner and Balabanov, 2002). Selective serotonin reuptake inhibitors also have more favorable adverse-effect profiles and are less likely to result in fatalities after an overdose. They have good efficacy in the treatment of symptoms of irritability and poor frustration tolerance, which are symptoms often seen in patients with epilepsy. Venlafaxine (Effexor), a reuptake inhibitor of norepinephrine(Drug information on norepinephrine) and serotonin, is a drug of choice for patients who failed to respond to SSRIs. Monoamine oxidase inhibitors are not known to cause seizures in nonepileptic patients (Schiwy et al., 1989). Bupropion (Wellbutrin), maprotiline (Ludiomil), amoxapine(Drug information on amoxapine) (Asendin) and clomipramine(Drug information on clomipramine) (Anafranil) are the antidepressant drugs with the strongest proconvulsant properties and should be avoided in patients with epilepsy. Neurotoxicity of lithium(Drug information on lithium) (Eskalith, Lithobid) can cause a change of EEG recordings and has been reported to increase seizure frequency; therefore, it should be used with caution (Bell et al., 1993). Finally, it should be noted that electroconvulsive therapy is not contraindicated in depressed patients with epilepsy (Coffey et al., 1995; Regenold et al., 1998; Sackheim, 1999; Sackheim et al., 1983).
Psychotherapy is an important addition to pharmacological treatment. Counseling and psychotherapy can be very useful in helping the patient deal with the stressors and limitations of living with epilepsy. Patients involved in psychotherapy not only improve in scales of depression and anxiety but also show a decline in seizure frequency (Gillham, 1990).
Clinicians should keep in mind that in patients with refractory epilepsy, mood disorders and adverse events have a greater impact on patients' quality of life than the actual seizure frequency or severity (Boylan et al., 2004). Therefore, treatment of the seizure disorder without treating the eventual comorbid depression is incomplete and inappropriate.Conclusion
Depression is a common comorbidity in patients with epilepsy. Depression is frequently unrecognized and untreated by the physicians taking care of patients with epilepsy. The depression that occurs in patients with epilepsy is not necessarily as easy to recognize when not presenting as major depression; therefore, clinicians have to inquire about symptoms of depression when evaluating patients with epilepsy. The treatment of depression is of high importance for a patient with epilepsy, since it is strongly associated with the patient's quality of life.