Depression and epilepsy: A bidirectional relationship and perspective on current thinking with future recommendations

Abstract

Depression is common in epilepsy, but few studies investigate this relationship (Lambert et al, 1999). The purpose of this paper is first to examine the reasons behind the failure to diagnose and treat depressive disorders in epilepsy, and second to identify a clinical and research agenda that will advance understanding of the nature of this comorbid illness. This paper uses literature identified through a non-systematic search in PubMed and the authors own clinical experience with this patient group. Findings indicate epilepsy and depression exist as a co-morbid illness, with the prevalence of depression being almost twice as common in people with epilepsy compared to the general population. Alongside this, episodic seizures and a diagnosis of epilepsy are more common in individuals diagnosed with a depressive disorder than among those undiagnosed. In many of these patients depression affects their quality of life more severely than the seizures themselves, as indicated by increased suicide rates in this population group. Diagnosing depression in epilepsy may be difficult because the symptoms are somewhat atypical and appear episodically. Depressive symptoms may be temporarily related to seizures (ictal or peri-ictal) or more often, independent of seizures (interictal). This phenomenon may be explained by evidence of pathophysiological mechanisms common to both disorders. Antidepressants can, in some cases, reduce the seizure threshold, but SSRI’s do this to a little or negligible extent. Therefore these drugs are recommended as a first line of treatment for depression in people with epilepsy. Overall depression is not found to be simply a reactive process to epilepsy. There appears to be a bidirectional relationship between epilepsy and depression, as both conditions increase the risk of developing the other. Recommendations for future practice are suggested. Implications for future research include the need to investigate treatment modalities with the same scientific rigor used in any neuropsychiatric disorder and its control.

Introduction

Depression is one of the most frequent psychiatric co-morbidity in patients with epilepsy (Kanner, 2005). At the same time, patients with depression are at a greater risk of developing epilepsy than non-depressed individuals are (Kanner, 2005). Such bidirectional relations raise the question of whether both disorders share common pathogenic mechanisms, involving common neurotransmitter and neuroanatomical structure abnormalities (Lambert et al, 1999).Understanding whether this disorder is neurological or neuropsychiatric in nature holds significant implications with regard to the diagnostic and therapeutic approaches applied to patients with epilepsy (Kanner, 2001). A neurological disorder, e.g. pain, seizures or confusion would entail an investigation of areas of the nervous system alone, such as the brain, whereas a neuropsychiatric disorder also includes a comorbid psychiatric illness such as depression or anxiety, and should be investigated as such (Lambert et al, 1999). Indeed, if epilepsy is a neuropsychiatric disorder then patients should undergo a psychiatric evaluation (however brief) as part of their initial diagnosis (Lambert et al, 1999). This paper reviews current research in this area and recommends future actions in order to explore the effects of this distressing co-morbidity.

The correct diagnosis and treatment of depression and depressive disorders (DD’s) is imperative in people with epilepsy (PWE) due to significantly higher suicide rates among this group (Lambert & Robertson, 1999). Astonishingly, 44% to 66% of individuals with epilepsy also have a diagnosis of a depressive disorder according to the diagnostic and statistical manual of mental disorders (DSM-IV, 1994). Although the prevalence of suicide in the literature is varied across studies and samples, it is generally thought to be four to five times greater than in the general population (Barraclough, 1981; Harris & Barraclough, 1997). In a review of the causes of death in epileptic patients, Robertson, Trimble & Townsend (1987) reported a nine to tenfold higher suicide rate in this group. Risk factors for suicide include a history of deliberately self injuries, alcoholism, a family history of suicide, or a co-morbid psychiatric disorder such as depression or psychosis (Lambert et al, 1999; Robertson et al, 1987). Yet whether the high prevalence of depression and suicide rates among the epileptic population is a function of the epilepsy, per se, or reflects the sequel of a “chronic” medical or neurologic disorder continues to be debated (Kanner, 2001).

Background

Epilepsy

Epilepsy is a common disorder seen by neurologists, with an approximate prevalence of 1%, or fifty million people worldwide (Guberman & Bruni, 1999). In most developed countries the incidence of epilepsy ranges from 40 to 70 people per 100,000 per year (Guberman & Bruni, 1999). Epilepsy is usually controlled, but not cured, with medication. However, 30% of individuals with epilepsy do not have seizure control, even with the best available medication (Guidelines for epidemiology and prognosis, 1993). Seizures have a wide variety of etiologies including congenital malformation, head trauma, tumours, degenerative disorders or alcohol abuse (Hopkins & Appleton, 1996). For a diagnosis of epilepsy to be given, individuals must have at least two seizures which cannot be accounted for by drug reactions or other medical enduced causes (Guberman & Bruni, 1999). A seizure may be defined as “an abnormal and excessive discharge of brain neurons involving hypersynchrony accompanied by some behavioural changes” (Guberman & Bruni, 1999, p 23).

Seizures are classified according to their source within the brain, i.e. if the seizure is localised (partial or focal seizures), or distributed (generalised seizures) (Hopkins & Appleton, 1996). Temporal lobe epilepsy (TLE) is the condition of repeated partial seizures in the temporal lobe of the brain. Seizures can be further divided by the extent to which consciousness is affected, and by their overall effect on the body (Hopkins & Appleton, 1996) (see table 1). Partial complex seizures, which involve an alteration of consciousness, and often accompanied by “aura symptoms”, i.e. light-headedness, unusual emotions, altered vision/hearing or hallucinations (Guberman & Bruni, 1999). Partial (simple) seizures involving secondary characteristics occur when the activity spread not only to local neurons, but to cells centrally grouped in the brain, which consequently spread the discharge throughout the brain. This leads to a convulsive (e.g. tonic-clonic or grand mal) seizure if motor neurons are affected (Guberman & Bruni, 1999). Absence (e.g. petit mal) seizures are characterised by brief interruptions in consciousness, during which the individuals generally “cease what they are doing, appear pale, stare, flutter their eyelids and drop their head forward slightly” (Hopkins & Appleton, 1996 p13). These seizures are predominantly seen in children (Hopkins & Appleton, 1996).

In a relatively small percentage of cases genetic factors may play a role in the development of epilepsy (Hopkins & Appleton, 1996). Whatever the cause, epilepsy can have serious psychosocial and neurophysiological ramifications for the individual (Hopkins & Appleton, 1996). Alongside suffering with depression and the increased rates of suicide (Barraclough, 1981; Robertson et al, 1987) research indicates that epilepsy patients are more likely to experience anxiety then the general population (Matthews & Baradas, 1981). The co-morbidity of these psychiatric diagnoses may lead to significant complications in the diagnosis and treatment of epilepsy, as well as associated psychological or social problems (Grabowska-Grzby, Jedrezejczak, Naganska & Fiszer, 2006).

Table 1: Main categories of seizures and their subdivision (Hopkins & Appleton, 1996)

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Impact on Quality of life

Research indicates that epilepsy has important effects on quality of life. Perrine, Hermann, Meador, Vickrey, Cramer et al (1995) investigated 257 epilepsy patients to determine the relationship between neuropsychological function and health related quality of life. Neuropsychological variables included mood, verbal memory, psychomotor function, visual-spatial function, language, and cognitive inhibition. The mood factor had the highest correlation with quality of life in epilepsy, and was also the strongest predictor of poor quality of life in regression analysis, explaining 46% of the variance (Perrine et al, 1995). Lehrner, Kalchmyr, Serles, Olbrich, Patraia et al (1999) investigated individuals with temporal lobe epilepsy (TLE), confirmed by EEG monitoring. Reliable, valid instruments developed for native German speakers assessed health related quality of life (HRQOL) and depression. Findings indicated that depression was the strongest predictor for each domain of HRQOL. The significant negative association between depression and HRQOL continued even after controlling for seizure severity, seizure frequency and other psychosocial variables (Perrine et al, 1995). This study indicates the importance of cross-cultural validation of mood for health outcomes in people with epilepsy (PWE).

Investigating the relationship between mood and health in epilepsy, Gilliam, Kuzniecky, Meador, Martin, Sawrie et al (1999) investigated a group of adults with TLE and also found that mood status was the strongest clinical predictor of the patient’s assessment of their own health status a year after temporal lobe surgery. In a separate cohort study involving adult epilepsy patients Gilliam (2002) found a strong correlation between high depression and poor self-reported health status. These findings further indicate the importance of mood in the subjective health status and quality of life in PWE.

Clinicians and patients alike have the misconception that it is normal to feel depressed when suffering from epilepsy (Kanner, 2003). Clinicians have the misconception that a low mood, feelings of hopelessness or helplessness are due to the diagnosis of epilepsy alone, as do many PWE (Kanner, 2003). Therefore, patients do not seek treatment for these symptoms of depression and clinicians do not inquire about them sufficiently (Kanner, 2003). While the reactive process of facing multiple obstacles associated with a life with epilepsy is undeniable, its impact is mostly prevalent in the initial stages of the disease, but levels off with time (Kanner, 2003). The psychosocial factors that PWE have to endure on a day to day basis include patient’s lack of acceptance and poor adjustment to their epilepsy (Chaplin, Yepez & Shorvon, 1990; Jacoby, 1994). Also, the stigma associated with a diagnosis of epilepsy and the well known discrimination these individuals are subjected to (Dell, 1986; Jacoby, 1994), the lack of control in their lives caused by the random occurrence of epileptic seizures and patients lack of social support (DeVellis, DeVellis & Wallston, 1980; Hermann & Whitman, 1989). The need to make significant adjustments in lifestyle such as giving up driving privileges and changing jobs to maximise seizure precautions, causes much distress (Dell, 1986; Chaplin et al, 1990). More often than not DD’s are an expression of multi-factorial processes acting simultaneously (Kanner, 2003).

The most notable evidence against the impression that patients become depressed every time they have a seizure is found in a study by Gilliam (2002). Variables responsible for poor quality of life were investigated, measured by the Quality of Life in Epilepsy (QOLIE) inventory among 194 adults with refractory partial epilepsy. Gilliam (2002) reported that the high rating of depression and neurotoxicity from antiepileptic drugs were the only independent variables significantly associated with poor quality of life scores. Although patients averaged 9.7 seizures per month (range 0.3-51) the author did not find any correlation between the type and/or the frequency of seizures and poor quality of life scores. This study indicates that in patients with refractory epilepsy, the presence of depression is one of the most important variables to impact on quality of life, even more than seizure frequency and severity. Furthermore, access to health care for patients with co-morbid disorders is hampered by economic factors, as insurance coverage frequently does not include psychiatric services or offers a limited number of visits per year (Kanner, 2006).

Depression in epilepsy

Depression in epilepsy; issues with classification

Depressive disorders (DD’s) include major depression, mania (similar to that in bi-polar disorder) and dysthamia according to ICD-10 (1993) and DSM-IV (1994). However, the clinical picture of depressive disorder in epilepsy does not always correspond to the criteria listed in the organised classification system (Kanner, 1999). When diagnosing a depressive disorder in epileptics, the chronological relation to the seizures must be taken into consideration (Prueter & Norra, 2005). Therefore, the classification into separate DD’s was established. These include peri-ictal, ictal, postictal and interictal and para-ictal depression, and mania (Prueter & Norra, 2005).

Peri-ictal depression

In this form of DD, depressive symptoms frequently precede a seizure (Lambert et al, 1999). Symptoms including dysphoria and depressed-anxious mood, which may last days or hours before the onset of a seizure. When the seizure occurs the symptoms often come to an end. Occasionally they continue for hours or days after the seizure. It is not yet understood if these premonitory depressive symptoms are a subclinical part of the seizure, or if neurobiological activities involved induce a decrease in the convulsion threshold (Lambert et al, 1999). In a study by Hughes, Devinsky & Feldmann, (1993) one-third of people with partial seizures (also known as focal seizures) had peri-ictal depressive symptoms, whereas individuals with generalised seizures did not describe these symptoms.

Ictal depression

Typically, this form of depression is characterised by a sudden onset of symptoms (Betts, 1993). Depression appears to be part of the seizure, with no relationship between the symptoms and stimuli outside the seizure itself (Betts, 1993). This form of depression appears to be more common in individuals with temporal lobe epilepsy; an incidence of 10% is reported in the literature (Devinsky & Bear, 1991; Betts, 1993). In a few case reports, depressive-psychotic symptoms are described as symptoms of a non-convulsive status epilepticus (Betts, 1993). Status epilepticus (SE) is a life threatening condition in which the brain is in a constant state of seizure (Nair, Kalita & Misra, 2011). Accordingly, seizures must last for longer than 30 minutes, without regaining consciousness (Nair et al, 2011). In the case of non-convulsive SE, the brain is in constant partial or simple seizures, characterised by a long-lasting stupor, staring and unresponsiveness (Nair et al, 2011). In some cases impulsive suicidality was observed during an episode (Betts, 1993; Mendez & Doss, 1992).

Postictal depression

This type of DD has been frequently described in the literature, but prevalence figures remain unavailable (Prueter & Norra, 2005). In a study by Soto, Kanner & Hershkowitz (1997) postictal depressive symptoms with an average duration of 37 hours in 56 out of 100 patients were observed at an American epilepsy centre. After a seizure, depressive symptoms appeared to remain for up to 2 weeks and were shown to be able to lead to suicide (Soto et al, 1997; Betts, 1993; Mednez et al, 1992). Blumer (1992) proposed that postictal depression is a consequence of inhibitory mechanisms, which are responsible for the completion of a seizure. Further psychiatric diseases such as anxiety, and a seizure frequency of less than one seizure per month were also significantly associated with postictal depression (Blumer, 1992).

Interictal depression

Interictal depression is the most common type of DD in PWE (Lambert et al, 1999; Kanner et al, 1999). Symptoms appear very similar to that of major depression, dysthamia, or bipolar affective disorder. The prevalence is not fully known, but research estimates it at 20%-70% depending on the patient group investigated. Symptoms similar to those seen in bipolar disorder are rare, whereas episodes of major depression and dysthamia are common. Most researchers agree that interictal depression in PWE, in many cases, cannot be classified according to the operationalised diagnostic systems of the DSM-IV (Lambert et al, 1999; Kanner et al, 1999; Kanner & Palac, 2000). A chronic depressive course is observed in most cases (Lambert et al, 1999). Some of the symptoms observed resemble those of dysthamia, such as depressed mood or anergia, while others are specific for interictal depression (see table 2). Blumer, Montouris & Hermann (1995) suggested calling this affective disorder interictal mood disorder due to its unorthodox nature, and Kanner (2001) referred to this DD as a dysthymic-like disorder of epilepsy. Aside from depressive symptoms, pleomorphic symptoms may also occur (Blumer et al, 1995). These may include atypical pain and phases during which a euphoric or dysphoric affect, anxiety or phobias are predominant. Short periods of symptoms may also occur (Blumer et al, 1995). In an investigation by Kanner et al (2000), criteria for an interictal mood disorder were met in 70% of patients with interictal depression. This research reported how, during the course of a chronic depressive phase, individuals may become accustomed to the depressive state, which may be considered normal and therefore may not be reported to the physician. Since some of the symptoms involved are not as obvious as major depression, the physician may not recognise them as depressive symptoms, and treatment is therefore not commenced (Kanner et al, 2000). In a review by Wiegartz, Seidenberg & Woodland, (1999), major depression was diagnosed in 30% of subjects, and interictal mood disorder in 25%. None of the patients received anti-depressive therapy when symptoms were first reported to the physician.

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