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:
The goal of this article is to highlight the importance of recognizing, preventing and treating depression in patients with epilepsy.
Associated Risk FactorsSeizure-related factors. 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(Drug information on 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).
Psychosocial factors. 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.
Iatrogenic factors. Antiepileptic drugs can cause psychiatric symptoms, especially depression. Phenobarbital(Drug information on phenobarbital) (Luminal), felbamate (Felbatol), primidone (Mysoline), tiagabine (Gabitril), vigabatrin (Sabril), topiramate (Topamax) and levetiracetam(Drug information on 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(Drug information on topiramate)) are closely associated with previous or current history of depression (Kanner et al., 2000a). Carbamazepine(Drug information on 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 forced normalization. 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).
