Andres M. Kanner, MD

Multiple epidemiological studies have shown that depression is the most frequent comorbid psychiatric disorder in patients with epilepsy (Kanner and Balabanov, 2002). Prevalence rates range from 20% to 55% in patents with recurrent seizures and 6% to 8% in patients with well-controlled seizures (Hauser and Kurland, 1975; Kogeorgos et al., 1982; Mendez et al., 1986; Mungas, 1982; Robertson et al., 1987). In addition, suicide is one of the most common causes of death in patients with epilepsy (Barraclough, 1987; Robertson et al., 1987); it was found to be almost 10 times more frequent in these patients than in the general population (Robertson et al., 1987). In a study carried out in a group of patients with refractory epilepsy admitted to a video-electroencephalogram monitoring unit, Boylan and colleagues (2004) found 50% of the patients were depressed, 19% had suicidal ideation, and only 17% were being treated with antidepressant medications. Despite the high prevalence of depression and suicide risk, depression often goes unrecognized and untreated in these patients. Reasons for this include: 

Treating physicians pay attention only to seizure control and fail to inquire about the presence of psychiatric symptoms;

Patients are hesitant to report mood changes, and when they do, they tend to minimize them out of fear of being thought of as crazy;

Physicians and patients often consider symptoms of depression to be a normal adaptation process to epilepsy and its associated problems; and

A fear among clinicians that antidepressant drugs can exacerbate the underlying seizure disorder prevents many patients from receiving treatment even when the need for antidepressant treatment is recognized.

The goal of this article is to highlight the importance of recognizing, preventing and treating depression in patients with epilepsy.

. Many investigators have tried to find an association between depression and epilepsy with respect to age of onset and seizure type, frequency, and duration (Indaco et al., 1992; Kogeorgos et al., 1982). Depression has been identified more frequently in patients with seizures involving limbic structures (predominantly temporal and frontal lobes) and less often in patients with generalized seizure disorders. Laterality of seizure focus also has been considered as a possible risk factor, with seizure disorders of left hemispheric origin being more likely to be associated with depression (Mendez et al., 1986). This association has been questioned by several investigators, however. There is evidence that seizures originating in or propagating to the frontal lobes increase risk of depression. For instance, patients with left temporal focus and depression have been found to display bilateral inferior frontal hypometabolism on both positron emission tomography (PET) and single proton emission computed tomography (SPECT) studies (Bromfield et al., 1992). In fact, decreased frontal metabolism on PET and SPECT has been found in primary depression (Musselman et al., 1998).

Do depression and epilepsy share common pathogenic mechanisms? Twenty-six centuries ago, Hippocrates was the first to suggest a bidirectional relationship between epilepsy and depression when he wrote (Lewis, 1934):

Melancholics ordinarily become epileptics, and epileptics melancholics: what determines the preference is the direction the malady takes; if it bears upon the body, epilepsy, if upon the intelligence, melancholy.

This observation has been supported by population-based, controlled studies published in the past 10 years. Forsgren and Nystrom (1990) conducted a population-based, case-controlled study of patients with newly diagnosed epilepsy in Sweden. They discovered that patients with epilepsy were six times more likely than controls to have experienced a history of depression prior to the onset of the seizure disorder. In a separate study, Hesdorffer et al. (2000) conducted a population-based, case-controlled investigation of the prevalence of new-onset epilepsy among adults ages 55 and older and showed that compared to controls, patients were 3.7 times more likely to have had a history of depression prior to the onset of their seizure disorder. These researchers controlled for the impact of medical therapies for depression on seizure occurrence.

These data do not suggest that depression causes epilepsy or vice versa, but they do suggest that the two disorders may share common pathogenic mechanisms. Indeed, epilepsy and depression may share common pathogenic mechanisms mediated by abnormal serotonergic, noradrenergic, 

-aminobutyric acid (GABA)-ergic and dopaminergic secretion in the central nervous system (Jobe et al., 1999; Ronald and Duman, 1999; Schildkraut, 1973, 1965). In primary depression, decreased activity of these neurotransmitters has been identified as one of the pivotal pathogenic mechanisms and the basis for antidepressant pharmacologic treatment (Garlow et al., 1999; Maes and Meltzer, 1995; Richelson, 1991). In animal models of epilepsy using the genetically epilepsy-prone rat, decreased activities of serotonin and norepinephrine have been shown to facilitate the kindling process (Jobe et al., 1999, 1995; Lehmann, 1967; Meldrum et al., 1982), exacerbate the seizure severity and intensify seizure predisposition. Other common pathogenic mechanisms for primary depression and epilepsy include disturbance of mesial temporal structures, particularly amygdala and hippocampal formation, which have been found to be atrophic in both disorders (Mathern et al., 1997; Sheline, 2003).

. Patients with epilepsy are subjected to discrimination and lack of acceptance. Significant risk factors for the development of depression include the stigma of having epilepsy; the lack of social support; the need to make significant adjustments in lifestyle, such as giving up driving privileges or having to change jobs; and the limited educational and employment opportunities. The individual's sense of lack of control over their life may result in overall fear of seizures and agoraphobic behavior that may not correlate with the actual severity of seizure activity. In addition, sexual dysfunction has been a very prevalent problem among patients with epilepsy, with rates ranging from 14% to 66% (Morrell, 1991). Although biologic and medication factors are largely causative, they clearly facilitate the development of decreased self-esteem and depression.

. Antiepileptic drugs can cause psychiatric symptoms, especially depression. Phenobarbital (Luminal), felbamate (Felbatol), primidone (Mysoline), tiagabine (Gabitril), vigabatrin (Sabril), topiramate (Topamax) and levetiracetam (Keppra) are known to cause depressive episodes (Barabas and Matthews, 1988; Brent et al., 1987; Collaborative Group for Epidemiology of Epilepsy, 1986; Ferrari et al., 1983; McConnell and Duncan, 1998; Ring and Reynolds, 1990; Smith and Collins, 1987). In addition, cognitive side effects associated with some of these drugs (e.g., topiramate) are closely associated with previous or current history of depression (Kanner et al., 2000a). Carbamazepine (Tegretol) and valproic acid (Depakene) are anti-epileptic drugs with mood-stabilizing effects, but can occasionally cause depressive symptoms as well (Smith and Collins, 1987).

Depression and other psychiatric complications have been seen after epilepsy surgery and especially following an anterior temporal lobectomy for the treatment of pharmacoresistant temporal lobe epilepsy (Savard et al., 1998). It is actually not unusual to see mood lability within the initial six weeks after the surgery. Most of the time these symptoms subside, but in up to 30% of the patients, overt symptoms of depression become evident within the first six months. Patients with prior history of depression are at greater risk. The development of this depression is independent of the postsurgical seizure control.

Depression in patients with epilepsy can be the expression of a relatively rare phenomenon known as 

. It consists of the development of psychiatric symptoms following the cessation of seizures in patients whose seizures had failed to be controlled for a long time. Worsening of interictal depression in patients when seizure control is achieved may also be an expression of this phenomenon (Robertson, 1998).

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 

. 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.

. 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 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.

. 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 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 

 classification. In our opinion, however, a large number of patients with epilepsy do not meet 

 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.

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 (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 (Prozac), 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 (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 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 (Asendin) and clomipramine (Anafranil) are the antidepressant drugs with the strongest proconvulsant properties and should be avoided in patients with epilepsy. Neurotoxicity of 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.

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.

 Altshuler LL, Devinsky O, Post RM, Theodore W (1990), Depression, anxiety, and temporal lobe epilepsy. Laterality of focus and symptoms. Arch Neurol 47(3):284-288.
 

 Barabas G, Matthews WS (1988), Barbiturate anticonvulsants as a cause of severe depression. Pediatrics 82(2):284-285.
 

 Barraclough BM (1987), The suicide rate of epilepsy. Acta Psychiatr Scand 76(4):339-345.
 

 Bell AJ, Cole A, Eccleston D, Ferrier IN (1993), Lithium neurotoxicity at normal therapeutic levels. Br J Psychiatry 162:688-692 [see comments].
 

 Blanchet P, Frommer GP (1986), Mood change preceding epileptic seizures. J Nerv Ment Dis 174(8):471-476.
 

 Blumer D (1991), Epilepsy and disorders of mood. In: Neurobehavioral Problems in Epilepsy, Smith DB, Treiman DM, Trimble MR, eds. New York: Raven Press, pp185-194.
 

 Blumer D, Altshuler LL (1998), Affective disorders. In: Epilepsy: A Comprehensive Textbook, Engel J, Pedley TA, eds. Philadelphia: Lippincott-Raven, pp2083-2099.
 

 Blumer D, Montouris G, Hermann B (1995), Psychiatric morbidity in seizure patients on a neurodiagnostic monitoring unit. J Neuropsychiatry Clin Neurosci 7(4):445-456.
 

 Blumer D, Zielinski JJ (1988), Pharmacological treatment of psychiatric disorders associated with epilepsy. J Epilepsy 1:135-150.
 

 Boylan LS, Flint LA, Labovitz DL et al. (2004), Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy. Neurology 62(2):258-261.
 

 Brent DA, Crumrine PK, Varma RR et al. (1987), Phenobarbital treatment and major depressive disorder in children with epilepsy. Pediatrics 80(6):909-917.
 

 Bromfield EB, Altshuler L, Leiderman DB et al. (1992), Cerebral metabolism and depression in patients with complex partial seizures. [Published erratum Arch Neurol 49(9):976.] Arch Neurol 49(6):617-623. 
 

 Coffey CE, Lucke J, Weiner RD et al. (1995), Seizure threshold in electroconvulsive therapy (ECT) II. The anticonvulsant effect of ECT. Biol Psychiatry 37(11):777-788.
 

 Collaborative Group for Epidemiology of Epilepsy (1986), Adverse reactions to antiepileptic drugs: a multicenter survey of clinical practice. Epilepsia 27(4):323-330.
 

 Curran S, de Pauw K (1998), Selecting an antidepressant for use in a patient with epilepsy. Safety considerations. Drug Saf 18(2):125-133.
 

 Daly D (1958), Ictal affect. Am J Psychiatry 115(2):97-108.
 

 Ferrari M, Barabas G, Matthews WS (1983), Psychologic and behavioral disturbance among epileptic children treated with barbiturate anticonvulsants. Am J Psychiatry 140(1):112-113.
 

 Forsgren L, Nystrom L (1990), An incident case-referent study of epileptic seizures in adults. Epilepsy Res 6(1):66-81.
 

 Fritze J, Unsorg B, Lanczik M (1991), Interaction between carbamazepine and fluvoxamine. Acta Psychiatr Scand 84(6):583-584.
 

 Garlow SJ, Musselman DL, Nemeroff CB (1999), The neurochemistry of mood disorders: clinical studies. In: Neurobiology of Mental Illness, Charney DS, Nestler EJ, Bunney BS, eds. New York: Oxford University Press, pp348-365.
 

 Gillham RA (1990), Refractory epilepsy: an evaluation of psychological methods in outpatient management. Epilepsia 31(4):427-432.
 

 Grimsley SR, Jann MW, Carter JG et al. (1991), Increased carbamazepine plasma concentrations after fluoxetine coadministration. Clin Pharmacol Ther 50(1):10-15.
 

 Hauser WA, Kurland LT (1975), The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 16(1):1-66.
 

 Hesdorffer DC, Hauser WA, Annegers JF, Cascino G (2000), Major depression is a risk factor for seizures in older adults. Ann Neurol 47(2):246-249.
 

 Indaco A, Carrieri PB, Nappi C et al. (1992), Interictal depression in epilepsy. Epilepsy Res 12(1):45-50.
 

 Jobe PC, Dailey JW, Wernicke JF (1999), A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders. Crit Rev Neurobiol 13(4):317-356.
 

 Jobe PC, Mishra PK, Adams-Curtis LE et al. (1995), The genetically epilepsy-prone rat (GEPR). Ital J Neurol Sci 16(1-2):91-99.
 

 Kanner AM, Balabanov A (2002), Depression and epilepsy: how closely related are they? Neurology 58(8 suppl 5):S27-S39.
 

 Kanner AM, Faught E, French J et al. (2000a), Psychiatric adverse events caused by topiramate and lamotrigine: a postmarketing prevalence and risk factor study. Epilepsia 41(suppl 7):169A.
 

Articles

The relationship between depression and epilepsy is bidirectional as not only are patients with epilepsy at higher risk of developing depression but patients with depression have a three- to sevenfold higher risk of developing epilepsy. Several studies have found that the presence of depression in patients with intractable epilepsy was a stronger predictor of poor quality of life than the frequency and severity of seizures. The principles of managing depression in epilepsy are reviewed in this article.

Andres M. Kanner, MD

Articles

Unrecognized and Untreated: Preventing and Treating Depression in Patients With Epilepsy