Epilepsy and Major Depressive Disorder

By: Natalie Bailey

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Epilepsy and Major Depressive Disorder 

When compared to the general population, there is a discernible increase in the prevalence of depression among individuals with epilepsy. Major Depressive Disorder (MDD) is classified as a mood disorder distinguishable by recurrent depressive episodes, feelings of worthlessness, the absence of pleasure, thoughts of death, and abnormal physiological changes (fluctuations in weight, insomnia, fatigue, etc.) that are enduring for a minimum of two weeks. The correlation between epilepsy and MDD exists within a bidirectional relationship that is mutually facilitating, providing a foundation that increases the chances of both disorders eventually developing. Patients with a history of MDD exhibit an approximate 4 to 7-fold heightened susceptibility to epileptogenesis and the development of epilepsy (Kanner, 2006). Conversely, individuals with diagnosed epilepsy possess an approximately 4 to 5-fold increased proclivity for developing MDD and experiencing depressive episodes (Baki et al., 2004). 

Biological Similarities in Epilepsy and MDD

  Several pathogenic mechanisms, as well as neuroanatomical abnormalities, are prevalent and consistent in patients experiencing both epilepsy and MDD. These aberrations contribute to the bidirectional nature of their relationships and explain their comorbid manifestations. These disorders exhibit shared dysregulation and abnormal levels of specific neurotransmitters. Affected neurotransmitters include serotonin, norepinephrine, dopamine, γ-aminobutyric acid, and glutamate (Kanner, 2005). Furthermore, they commonly manifest unprecedented structural alterations within various regions of the brain that affect the temporal and frontal lobes, amygdala, hippocampus, temporal lateral neocortex, entorhinal cortex, medial-frontal cortex, orbitofrontal cortex, prefrontal cortex, thalamic nuclei, and the basal ganglia (Kanner, 2006).

More specifically, certain shared features pertaining to epilepsy and MDD consist of diminished serotonin and noradrenergic activity within the brain, specifically in regions of the hippocampus (Kanner, 2005). These neurotransmitters assume pivotal roles in mood disorders and impact seizure severity. It is essential for serotonin and noradrenaline to both be present, where elevated levels of transmission act as deterrents to seizures, while the reduced levels are contributors to recurrent onsets and remission failure (Jobe et al., 1999). Additionally, a prevalent serotonin deficit observed in brain tissue, platelets, plasma, and various regions of the dorsal raphe nuclei and hippocampus is associated with patients with epilepsy and MDD who commit suicide (Kanner, 2005).

Suicide Rate  

   As a result of the elevated prevalence of MDD within the epileptic patient demographic, there is an emerging association with heightened frequencies of suicidal ideation and behaviors. The ubiquity of suicidality within the epileptic cohort surpasses that of the general population, with numbers being up to 5 times greater (Hesdorffer et al., 2005). A substantial proportion of patients with epilepsy who experience depressive thoughts and turmoil have reported the contemplation of suicide, with approximately 70% admitting to such considerations. Moreover, 50% of identified cases presenting both MDD and epileptic seizures have been hospitalized, voluntarily and involuntarily, due to explicit ideation, while 25% proceeded to attempt suicide (Hague et al., 2023). 

Despite the seemingly daunting statistics, the incidence of suicidal ideation aligns with and is comparable with that observed in the general population grappling with MDD and depressive disorders without epilepsy. While individuals with epilepsy are faced with an elevated risk of suicide, the casual relationship does not inherently reside in the variable of epilepsy itself, but rather in the severity of depressive symptoms (Hague et al., 2023). The association with MDD is the factor that categorizes epileptic individuals within the at-risk demographic on account of feelings of worthlessness and hopelessness. Epilepsy, in isolation, does not independently heighten the risk of suicidality on its own; however, its co-occurrence and mutually facilitating relationship with MDD is the direct constant that contributes to the increased likelihood of ideation and attempts. 

Nevertheless, the mortality rate attributed to suicide among individuals with epilepsy remains significantly high relative to the general population. While the commonly cited suicide rate for epilepsy is generally reported to be around 5% (Sirven, 2013), Tian et al. (2016) published a detailed account delving into aspects of suicidality among epileptic patients. Their investigation revealed that between 2003-2011, the suicide rate for individuals with epilepsy was approximately 22% higher than that of the general populace. Notably, individuals with epilepsy were found to be more likely to utilize prescription medication overdose, predominantly involving antiepileptic drugs (6%), typically within the confines of their residences. Moreover, the prevalence of suicide in epileptic individuals is significantly elevated among individuals aged 40-49, unmarried men, and women whose marriages have dissolved for various reasons (Tian et al., 2016). 

Risk Factors 

There are numerous prevalent factors contributing to the heightened susceptibility of individuals with epilepsy to developing MDD. Variables encompassing age, gender, educational attainment, employment status, and the specific characteristics of an individual’s epileptic condition all introduce variability in the severity and duration of depressive symptoms. The prevalence of MDD in the context of epilepsy exhibits a higher rate of prevalence among females in comparison to males, a phenomenon which currently possesses no definite answers. Proposed hypotheses suggest several influences such as diminished levels of estrogen, a greater willingness among female patients to report mental health concerns, and higher levels of stigma surrounding male vulnerability and emotional psyche (Kim et al., 2018).

Additionally, the advancement of age emerges as another risk factor in the genesis of depressive symptoms and MDD in those with epilepsy. However, this observation may potentially reflect a generation shift in the development of depression with the aging population. Moreover, educational background and employment security also exert notable implications on MDD in epilepsy. Epileptic individuals from a lower socioeconomic status and limited educational attainment in addition to individuals lacking a stable work environment possess increased vulnerability to developing MDD. A hypothesized connection between low status facilitating MDD suggests declines in mental health is due to a reduced prevalence of security and stability in one’s life (Yang et al., 2020). 

Furthermore, one factor possessing a paramount significance is drug treatment. Antiepileptic drug (AED) response is a strong signifier that lends itself to the relationship between epilepsy and MDD. A patient’s resistance to AEDs is significantly and positively correlated to negative affect and emotional states. Individuals resistant to these vital medications used to diminish the frequency and intensity of seizures often exhibit a highly elevated likelihood of developing MDD (Yang et al., 2020). 

Drug Treatment 

Several commonly used AEDs in the treatment of epileptic conditions encompass carbamazepine, oxcarbazepine, valproic acid, and lamotrigine (Kanner, 2005). However, in addition to MDD’s association with negative influences impacting an individual’s quality of life, there exists an adverse correlation between MDD and epilepsy and the functioning ability of pharmacological medication interventions, including AEDs. The antecedent development of MDD preceding epileptogenesis and the heightened neural excitability associated with seizures is associated with resistance to AEDs. Beyond drug resistance, the progression of depression in the epileptic brain has the potential to exacerbate adverse side effects associated with the prescribed medication (Kim et al., 2018). These effects include but are not limited to, suicidal ideation, alterations in body weight, sleep disorders, etc. Moreover, individuals possessing psychiatric disorders and mental illnesses, particularly those with MDD, exhibit a significantly elevated likelihood of failure to enter seizure remission with the use of AEDs. Epileptic individuals with coexisting MDD are more than 3 times as likely to manifest drug treatment resistance aimed to repress seizure onset (Kanner, 2006). 

Surgery Treatment 

In instances of severe epilepsy, a viable therapeutic approach involves the surgical disconnection of the brain through severing the corpus callosum. This treatment aims at suppressing seizures by decreasing neuronal hyperexcitability and limiting the connection between the left and right cerebral hemispheres. There is an observed 60-70% seizure remission rate among patients post-surgical intervention. Nevertheless, the manifestation and onset of MDD proceeding the corpus callosum severance emerge as a noteworthy risk factor, potentially amplifying the susceptibility to adverse seizure outcomes and associated effects (de Araújo Filho et al., 2012). The existence of a preoperative history of depression is significantly associated with the failure to achieve seizure remission following surgery (Kanner, 2006). The enduring persistence of depression and MDD in individuals with epilepsy severely constrains a patient’s options for treatment and therapeutic intervention. Given the significant decrease in favorable surgical outcomes among these individuals, the inherent risks associated with an invasive procedure may outweigh the prospective benefits, particularly as the probability of attaining sustained seizure alleviation diminishes. 


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