AIM: To characterize the relationship between depression and epilepsy-related seizures, treatment, hormonal and biological variables.

METHODS: Included were 200 Egyptian adults (male = 100, female = 100) with epilepsy (mean age: 30.87 ± 7.88 years; duration of illness: 13.89 ± 7.64 years) and 100 healthy matched subjects for comparison. Psychiatric interview, Beck Depression Inventory (BDI-II) and Hamilton Anxiety Rating Scale (HAM-A) were used to assess depression and anxiety. Blood levels of free testosterone, sex hormone binding globulin, prolactin, free thyroxin and thyroid stimulating hormone, serotonin, noradrenaline and adrenaline neurotransmitters were measured to assess endocrine and biological states.

RESULTS: Patients had higher rates of depressive disorder (25.5% or 51/200), mostly intermixed with anxiety (47.06%), psychotic features (19.61%), aggression (40%) and suicide (55%). Compared to controls, higher scores on the BDI-II were observed with right-sided epileptic foci (P = 0.011), polytherapy (P = 0.001) and lack of control on antiepileptic drugs (AEDs) (P = 0.0001). Patients had lower levels of serotonin (P = 0.001) [marked with depression (P = 0.012)] and adrenaline (P = 0.0001), while noradrenaline was lower with temporal lobe epilepsy (P = 0.039), left-sided foci (P = 0.047) and lack of control on AEDs (P = 0.017). Negative correlations were observed between levels of serotonin and BDI-II (P = 0.048) and HAM-A (P = 0.009) scores, but not with AEDs dose or drug level.

CONCLUSION: Comorbid depressive disorder with epilepsy appears to be closely related to seizure type, focus, side, intractability to medications and neurotransmitter changes. Thus, optimizing seizure control and early recognition and management of depression is necessary to improve patients’ quality of life.

Epilepsy is one of the most common and important chronic medical problems. The prevalence of epilepsy in the general population is approximately 8.2 per 1000[1]. While epilepsy is defined by the presence of recurrent seizures due to sudden electrical misfiring of neurons or nerve cells in the epileptic brain, it is complicated by a high rate of inter-ictal behavioral or psychiatric comorbid symptoms and disorders which include: depression, anxiety, psychosis, obsessive-compulsive disorder, attention-deficit and personality disorders, aggression and suicide[2-10]. Although inter-ictal behavioral manifestations are frequently mild and reversible, some patients with intractable epilepsy may have enduring manifestations that impair their quality of life. Depression is the most frequent psychiatric disorder in patients with epilepsy, with a prevalence of 20%-80%[9,10] compared to 1.5%-19% in the general population[11]. Depression in epilepsy may manifest as: (1) major depressive disorder which meets the Diagnostic and Statistical Manual, 4th edition (DSM-IV)[12]; (2) atypical depression with a fluctuating course and a pleomorphic presentation such as depressive intermixed with euphoric moods, irritability, fear, symptoms of anxiety, insomnia, psychotic features (including hallucinations, paranoia, delusions or bizarre behavior), aggression and suicidal thoughts or even suicide attempts in severe form; and (3) a dysthymic-like disorder that is milder than those of major depression[9,10,13].

The comorbidity of depression and epilepsy have been found to be correlated with a number of variables including psychosocial (such as stigma, learning problems, unemployment, inability to obtain a driving license)[14,15], demographic-, clinical- and epilepsy-related variables (such as age, gender, age at onset, type of seizures, site and side of structural brain lesion, seizure frequency, severity and duration of epilepsy)[16] and iatrogenic variables or adverse effects due to antiepileptic medications (AEDs)[17]. Recent evidence indicated that it seems to be a bidirectional relationship between epilepsy and depression indicating that both disorders share the same common neuroanatomical or structural and biological mechanisms (i.e., neurotransmitters), which include: (1) dysfunctions of the limbic system, frontal-limbic-subcortical circuits, frontal-striatal systems, limbic-brainstem connections or amygdale and its connections (e.g., amygdale-hypothalamic, amygdale-locus ceruleus)[16,18,19]; and (2) dysfunction of cerebral g-amino butyric acid (GABA), catecholamines, dopaminergic, nonadrenergic, and serotonergic systems[20]. In addition, it has been observed that some AEDs are associated with negative psychotropic effects with higher risk reported with phenobarbital (PB)[21], while low risks were associated with phenytoin (PHT)[22], carbamazepine (CBZ)[23], and valproate (VPA)[24]. The mechanisms of negative psychotropic effects with AEDs are complex and may vary dramatically between patients. They seem to be related to the direct and indirect mechanisms of drug action. They are commonly associated with rapid dose titration, slow drug metabolism, polypharmacy and drug-drug interactions, drug toxicity, drug withdrawal and electrolyte and other metabolic derangements (such as folate deficiency)[17,25]. Early recognition of comorbid depression and other psychiatric disorders with epilepsy will have a significant impact on the medical management and quality of life of patients with epilepsy.

This study aimed to determine the frequency of depression in adult patients with epilepsy. This study also aimed to determine the risk variables and correlates of comorbid depression with epilepsy which include: demographic-, clinical-, seizure-, treatment-, hormonal- and biological- (i.e., neurotransmitters) related variables. The relationship between depression and different related variables were determined.

The frequency of comorbid depression in the population with epilepsy was 25.5% (51/200) (male = 20 or 39.22%; female = 31 or 60.78%) compared to 20% (20/100) (male = 7 or 35%; female = 13 or 65%) in healthy control subjects. Based on the psychiatric interview, 95 patients with epilepsy and 32 healthy control subjects had manifestations suggesting a diagnosis other than depression and were thus excluded from the final statistical analysis. The final statistical analysis included 105 patients (male = 51; female = 54) with epilepsy and 68 healthy control subjects (males = 13; female = 55). Patients included in this study (n = 105) had a mean age of 30.87 ± 7.88 years (mean age of control subjects: 31.63 ± 8.55 years; P = 0.559) and mean duration of illness of 13.89 ± 7.64 years (range: 3-35 years). The majority of patients (n = 66; 62.86%) had focal epilepsy (complex partial or partial epilepsy with secondary generalization), while 39 (37.14%) had generalized tonic-clonic convulsions. Twenty six (24.76%) had frontal lobe epilepsy with secondary generalization, 36 (34.29% or 36/105) had temporal lobe epilepsy with secondary generalization and 4 (3.81% or 4/105) had parietal lobe epilepsy with secondary generalization. Thirty seven patients (35.24%) had left-sided foci of epileptic activity, while 29 (27.62%) had right-sided foci. Patients were treated with one or more AED(s) [CBZ (n = 55 or 52.38%), VPA (n = 28 or 26.67%) and polytherapy (n = 22 or 20.95%)] for 2-30 years (mean duration of treatment: 9.08 ± 4.13 years). The majority of patients (n = 54 or 51.83%) were uncontrolled on AEDs (had frequent or very frequent seizures), 23 (21.90%) were partially controlled (had occasional or rare frequency for seizures) and 28 (26.67%) were controlled on treatment or seizure free for ≥ 1 year. Table 1 presents the demographic and clinical features of the patients with epilepsy, patients with comorbid depression and patients without comorbid behavioral disorders.

The results of this study confirm that depression is a common comorbid condition with epilepsy with an estimated frequency of 25.5% which is mostly of a moderate/severe degree (78.43%)[6]. Females with epilepsy had a higher frequency of depression compared to males (60.78% vs 39.22%)[15]. The majority of patients had depression intermixed with symptoms of anxiety, irritability and insomnia (47.06%) or psychotic features such as hallucinations and delusions (19.61%). Patients with depression also had higher scores of HAM-A for anxiety. In addition, scores of BDI-II for depression and HAM-A for anxiety were positively correlated[36]. Nearly 40% of the patients with depression had manifestations of aggression and more than half of the patients with depression (55%) had suicidal thoughts and/or attempts[7,36]. Depression is the most frequent psychiatric disorder in adults with epilepsy, with an estimated prevalence of 20%-80%[6] compared to 1.5%-19% in the general population[11]. Anxiety is the second most common psychiatric disorder in adults with epilepsy with a prevalence estimated to range from 19% to 25% or up to 66%[5] compared to 19.6% in the general population[37]. The coexistence of inter-ictal anxiety and depression is not unusual (73%) in patients with epilepsy[8,36]. The prevalence of aggressive behavior in patients with epilepsy has been estimated to vary between 4.8% and 50%, not taking into account the specific epileptic sub-syndromes, specific socio-economic profile, public and family factors and ethnic social vulnerabilities[4]. Suicide and suicidality (suicidal thoughts and attempts) are also frequent in subjects with epilepsy with an estimated risk of about 13%[7,38] compared to 1.4%-6.9% in the general population[39].

Traditionally, psychosocial variables have been strongly implicated as causes of psychiatric manifestations associated with epilepsy. Depression has been considered a manifestation of a negative effect on effort and attitude about his or her abilities, low self-esteem and reduced well-being, which are the results of poor adjustment to seizures, low socio-economic status, financial stress, poor cultural approach to epilepsy, poorer academic achievement, unemployment (with rates up to 50% in developed countries if seizures are not fully controlled and up to 100% in developing countries), inability to drive, marital stresses, diminished sexual desire and responsiveness. These factors result in social isolation, stigmatization, depression and lower quality of life[14,15]. Anxiety has been considered a response to the unpredictability of seizures and fear of the unknown or fear of death which result in restrictions on normal living and activities, stigmatization and social rejection, misinformation about the disorder and low self-esteem[6]. Aggression and suicidality (thoughts and attempts) have been considered a consequence of decreased adaptive abilities, depression, increased emotional problems and anxiety[7,36]. Several studies reported that depression is one of the psychiatric disorders that increases the risk of suicide which reached approximately 15%-18.9%, and in some studies, it may be as high as 50 times that of the general population[40].

However, the results of this study indicate that not only functional (psychosocial) but also epilepsy itself and its related variables (such as type, focus, side, frequency, severity, intractability to medications and structural brain changes), and epilepsy-associated biological changes (neurotransmitter abnormalities) are important risks which contribute to the comorbidity between epilepsy and depression, depression/anxiety, aggression and suicide. These results also indicated that the risk of epilepsy itself as a cause of psychiatric abnormalities overweighed that of AEDs. Our view is supported by the following: First, in this study, higher scores of BDI-II for depression were observed in patients with right-sided foci of epileptic activity (P = 0.011)[41], those who lacked control on AEDs (P = 0.0001) and those on polytherapy (P = 0.001), indicating epilepsy intractability[42,43]. These findings support the fact that epilepsy itself and its related variables (such as type, focus, side, frequency, severity, intractability to medications and structural brain changes) contribute to the comorbidity between epilepsy and depression, depression/anxiety, aggression and suicide. Further supporting evidence includes: the presence of different patterns of psychiatric symptoms and disorders with different seizure types (i.e., generalized versus localization-related) and lateralization asymmetry. For example: (1) dysfunctions of the limbic system, frontal–limbic–subcortical circuits, frontal-striatal systems, limbic-brainstem connections or amygdale and its connections (e.g., amygdale-hypothalamic, amygdale-locus ceruleus) are the most important causes of epilepsy and its related comorbidities such as depressive and behavioral symptoms[16,19]; and (2) growing evidence in the literature suggests that hippocampal sclerosis appears to be the main factor associated with the occurrence of depression in patients with epilepsy[42,43]. This may explain why some studies found that the frequency of seizures did not correlate with severity of depression, and a seizure-free state did not protect epileptic patients from developing depression and consequently committing suicide. This was further confirmed by the finding that improvement in behavioral manifestations was associated with the disappearance of seizures after temporal lobectomy[44]; (3) The majority of the studies implicate left-sided foci (2-3-fold higher) rather than right-sided foci as a potential risk factor for depression in epilepsy, particularly left-sided temporal lobe epilepsy (TLE) in association with frontal lobe hypofunction[45,46]. However, and in accordance to our findings, some studies implicate the right hemisphere in the risk of depression in epileptic patients and suggest that this might be attributed to the extensive limbic connections compared with the left hemisphere. A few studies found no effect of lateralization [41]; and (4) reduced activity measured with single photon emission computed tomography (SPECT) in bilateral frontal and right temporal regions was associated with higher scores on the BDI in patients with left TLE[47,48].

Second, in this study, lower levels of serotonin (P = 0.001) (particularly in patients with comorbid depression) (P = 0.012) and adrenaline (P = 0.0001) were reported in patients with epilepsy regardless of epilepsy- and treatment-related variables. A significant negative correlation was observed between serum levels of serotonin and scores of BDI-II for depression (P = 0.048) and HAM-A for anxiety (P = 0.009). Lower levels of noradrenaline were observed in patients with focal epilepsy (P = 0.049), particularly with TLE (P = 0.039), left-sided foci of epileptic activity (P = 0.047), and in those who lacked control on AEDs (P = 0.017). These findings indicate that epilepsy-associated biological changes (neurotransmitter abnormalities) are important risks which contribute to the comorbidity between epilepsy and depression, depression/anxiety, aggression and suicide. In support: (1) decreased serotonergic and noradrenergic functions or alterations in dopaminergic activity were identified as pivotal pathogenic mechanisms for comorbid depression in some patients with epilepsy[38]; (2) preclinical and clinical studies suggest that 5-hydroxytryptamine 1A (5-HT1A) receptors play a role in the pathophysiology of both TLE, depression and anxiety disorders[49]; (3) the hypo-perfusion (hypo-metabolism) observed in the limbic frontal regions has been found to be related to inter-ictal inhibitory activity, depletion of substrates with decreased levels of neurotransmitters (such as serotonin, catecholamines and dopamine) and increases in the vulnerability to depression[47]; and (4) analysis of the literature has shown that serotonin metabolism disturbances are involved in the pathogenesis of suicidal behavior irrespective of primary diagnosis. Serotonin disturbances also seem to be a common link between depression, suicidality and even epilepsy itself[38].

Third, in this study, no relationship was identified between the dose and level of AEDs and scores of BDI-II or HAM-A [50]. This indicates that the risk of epilepsy itself as a cause of psychiatric abnormalities overweighed that of AEDs. Although lower levels of noradrenaline were observed in patients on VPA (P = 0.044), however, neither the dose of the drug nor its serum level were correlated with scores of BDI-II or HAM-A as well as serum serotonin levels. This is supported by the finding that VPA is associated with increased synaptic secretion of serotonin, has an antidepressant effect and thus is effective as a mood stabilizer[50]. However, some studies reported sedation and infrequently cognitive impairment, irritability, depression, hyperactivity and aggressive behavior with VPA [24]. This may be related to its mechanism of action[17].

Depressive or depressive/anxiety manifestations associated with epilepsy appear to be more closely related to seizure type, focus, side, severity and intractability to medications as well as epilepsy-related neurotransmitter changes rather than the effect of treatment-related adverse effects. However, it is possible that the overall function and well-being of the patient, the presence of negative, depressed or irritable mood, periods of anxiety and stress in combination with negative life events, may increase the frequency of seizures[39,51]. Attention should be paid to optimizing seizure control and the early recognition of depression and its correlates. Regular psychiatric consultation, psychotherapy and medical treatment are sometimes needed. It is also imperative to properly understand the pathophysiologic mechanisms of comorbid depression with epilepsy. This should move the treatment of patients toward a comprehensive biopsychosocial model that focuses on the whole person rather than on the disease process.

We thank Professor Bruce Hermann, Department of Neurology, University of Wisconsin for his valuable comments, editions, encouragement and assistance in drafting this manuscript.