Depression is a common and important accompaniment of epilepsy.  Depression in epilepsy is phenomenologically different from the usual forms of depression and it is essential that treating physicians assess for these varied forms as well. Depression in epilepsy may be managed more effectively if the relationship to the ictus is better understood. Other factors such as stressful life events, related or unrelated to epilepsy, may contribute to the depressive symptoms.  Antiepileptic drugs, particularly GABAergic agents such as vigabatrin, tiagabine, topiramate and phenobarbitone are depressogenic in nature.  The newer antidepressants, SSRIs such as sertraline, citalopram and paroxetine do not lower seizure threshold and can be safely used to treat depression in epileptic individuals. Fluoxetine may be avoided because of its longer half-life.

“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 intelligence, melancholy” (Lewis, 1934).Epilepsy is the most common serious, neurological condition, the usual prevalence figure quoted being 5-10 per 1000 persons excluding febrile convulsions, single seizures and inactive cases (Macdonald et al. 2000, Goodridge and Shorvon 1983, Hauser 1975). The risk of having a non-febrile seizure at some point in an average person’s lifetime (lifetime prevalence) ranges between 2 and 5%.Depression is one of the most frequently reported, co-morbid psychiatric conditions in patients with epilepsy. Prevalence figures ranging from 20-55% in patients with recurrent seizures, and 3-9% in patients with controlled epilepsy have been reported (Jacoby et al. 1996). A population-based survey investigating the lifetime prevalence of depression in epilepsy, diabetes and asthma reported 29% of patients with epilepsy having at least one episode of depression, as compared with 16 and 17% prevalence in patients with diabetes and asthma respectively and 8.7% in healthy respondents (Blum 2002).

Historical background
The first organized description of psychiatric disorders in epilepsy was attempted by Falret (Falret 1860/1861) and Morel (Morel 1860). They emphasized the periodicity of mental changes in epilepsy and the prominence of outbursts of anger and fury in their patients. Kraepelin (Kraepelin 1923), in his textbook stated that periodic dysphorias represent the most common psychiatric disorders in epilepsy. These dysphoric episodes are characterized by irritability with or without outbursts of fury. Depressive moods, anxiety, headaches and insomnia were described as frequent accompaniments. Kraepelin also described the dysphoric episodes as beginning and terminating suddenly, recurring at fairly regular intervals in a uniform manner and lasting for a few hours to two days. Interictal hallucinatory and delusional episodes were viewed as a mere expansion of dysphoric moods by Kraepelin. Bleuler (Bleuler 1949) gave a similar description of the dysphoric disorder of epilepsy.

One of the earliest modern investigations to assess psychiatric co-morbidity in patients with epilepsy was carried out by Pond and Bidwell (Pond and Bidwell 1959/60). They found that 29% of patients had psychological disorders of sufficient severity to seek treatment. Subsequently, Jalava and Sillanpaa (Jalava and Sillanpaa 1996) in a prospective, population-based cohort study demonstrated that subjects with epilepsy are at a higher risk of developing co-morbid psychiatric illness when compared with population-based controls. Overall, the available evidence supports the concept of an overrepresentation of common mental disorders in epilepsy (Krishnamoorthy 2001, 2002, 2004).

Phenomenology of depression in epilepsy
Controversy exists regarding the phenomenology of depression in epilepsy. While Betts (Betts 1974) reported a more endogenous presentation, Mulder and Dally (Mulder and Dally 1952) comment on a more reactive nature of depression associated with epilepsy. Mendez (Mendez et al. 1986), on comparing 20, hospitalised, depressed patients with epilepsy with 20 patients suffering from depression alone commented that patients with epilepsy and depression have significantly fewer neurotic traits such as anxiety, guilt, rumination, hopelessness, low self-esteem and somatization. These patients however, had significantly more psychotic symptoms such as paranoia, delusions and persecutory auditory hallucinations. Between episodes of major depression, patients with epilepsy tended to be dysthymic, with irritability and humorlessness. Although it is widely accepted that the phenomenology of depression in epilepsy differs from depression associated with other neurological disorders, confirmatory studies ascertaining are limited in number as well as impact. The phenomenology is also often blurred by the possible side-effects of anti-epileptic agents.

Dietrich Blumer’s description of dysphoric disorders in epilepsy is among the most fascinating (Blumer 2000). According to Blumer, psychiatric symptoms exist along a continuum, from dysphoric disorder with fleeting symptoms, to a more severe dysphoric disorder with prominent but transient psychotic features, to a disorder with more prolonged psychotic states. Blumer also put forward the concept of subictal dysphoric disorders (Morel 1860, had earlier described “masked epilepsy”), a psychiatric symptom complex identical to that observed in patients with epilepsy, but in the absence of seizures. The similarities between premenstrual dysphoric disorder and dysphoric symptoms in epileptic women led him to conclude that premenstrual dysphoric disorder was a variant of subictal dysphoric disorder and needed to be treated with a combination of antidepressants and antiepileptics.

Impact of depression
Co-morbid depression can have significant physical, social and financial consequences, including increased drug use, poor quality of life, social disability, and mortality (Barry et al. 2000). Begley (Begley et al. 2000) studied the lifetime and annual cost of epilepsy in the United States and found that the indirect costs in terms of disabilities and socioeconomic conditions on foregone earnings and household activity account for 85% of the total costs. They further concluded that, “epilepsy is unique in the large proportion of costs that are productivity related”. Cramer, in an assessment of the impact of co-morbid depression on health care utilization and health care coverage by people with epilepsy in US, found that people with untreated depression used significantly more health resources of all types. Patients with untreated depression also varied significantly in terms of health care utilization according to the severity of their depression (Cramer et al. 2004).

Depression or psychological distress have been shown to be the strongest predictors of health-related quality of life, even including seizure frequency and severity, employment, or driving status (Gilliam et al. 2003). Interictal anxiety and depression can exert independent adverse effects on health-related quality of life (HRQOL). In addition, frequent, severe, and chronic seizures also reduce HRQOL, but appear less powerful predictors of HRQOL than interictal psychiatric symptoms. Recognition and treatment of co-morbid depression and anxiety thus form an important consideration in improving quality of life in epilepsy (Johnson et al. 2004).

The suicide rate in epilepsy is five times greater than that in the general population (Harris and Barraclough 1997). Suicides in epilepsy do not necessarily occur when treatment is unsuccessful; but often occur unexpectedly when patients are forced to change their lives when they become seizure-free (Janz 1988). The most common Axis I diagnosis among individuals with current suicidal ideation has been established to be current major depressive episode (Jones et al. 2003).

Classification issues
Although the tradition in modern psychiatry is to adhere to the classification systems such as ICD-10 (WHO, 1992) and DSM-IV (APA, 1994), it is well accepted today that psychopathology in disorders such as epilepsy transcends these conventional descriptions and has unique manifestations that are poorly reflected in these established classifications (Krishnamoorthy 2000). Depressive symptoms and disorders in epilepsy are therefore best classified according to their temporal relationship to the ictus.

1) Pre-ictal depression: prodromal depressive moods or irritability can occur hours to days before a seizure, and are often relieved by the convulsion (Lambert and Robertson 1999, Devinsky and Bear 1991). The 19th century psychiatrist Grule (Grule 1930) quotes “physician and attendants do hope for a seizure in these often very difficult patients, which comes like a salvation for everybody: the patient is much more bearable for weeks thereafter”.

In a prospective study examining prodromal mood changes, Blanchett and Frommer (Blanchett and Frommer 1986) found that most patients reported more depression on the days immediately preceding their seizure than on interictal days, along with an improvement of mood after the seizure. The low mood has been hypothesized to be a symptom of subclinical seizure activity or biological processes involved in the initiation of both depression and seizures.

2) Ictal depression: depression can occur as a part of the ictus itself. Ictal depression classically is of sudden onset and occurs out of context, i.e. is not related to environmental stimuli. It can occur in isolation or within seconds to minutes of a CPS and/or secondarily generalized seizure. Ictal depression appears to be more common in patients with TLE (Williams 1956), in whom rates of over 10% (Weil 1959, Devinsky et al. 1991) have been reported. Williams (Williams 1956) described depression as part of an aura in approximately 1% of his series of 2000 patients. The severity of ictal depression can range from mild feelings of sadness to profound helplessness and despair. Suicide has been reported during ictal depressive episodes (Lim et al. 1986, Betts 1993).

3) Postictal depression: although depression lasting hours to days after seizure has been described in some patients, it is rare to find a patient with postictal depression alone (Blumer 1992). Most patients also experience episodes of interictal depression. Postictal depression occurs more commonly after CPSs originating in the right temporal structures, and more prominently with bilateral limbic dysfunction. It has been postulated that postictal depression is a consequence of the inhibitory mechanisms involved in the termination of the seizures.

Depressive disorders which occur peri-ictally are usually short lasting and self-limiting.

4) Interictal dysphoric disorder: more recently, in 1998, (Blumer, 1998) drew attention to a peculiar mood disorder seen in patients with refractory epilepsy, particularly TLE. Interictal dysphoric disorder is characterized by a constellation of eight symptoms and requires the presence of any three.

Interictal dysphoric disorder is typically of short duration and occurs in various permutation and combinations. These symptoms occur at various intervals and tend to last from hours to two or three days. In women, these symptoms become accentuated in the premenstrual period. Blumer stressed that patients with several of the above symptoms maybe at increased risk of sudden, unexpected suicide attempts and also development of interictal psychosis.

Epileptic Disorders. Volume 9, Number 1, 1-10, March 2007, Review article
Author(s) : R Seethalakshmi, Ennapadam S Krishnamoorthy