EPILEPSY & DEPRESSION: NAVIGATING THE NEUROPSYCHOLOGICAL INTERPLAY
By Ceren Ozkartal (PhD in Pharmacology)
Oct, 2024
Epilepsy, a prevalent neurological disorder characterized by recurrent seizures, significantly impacts mental health, with depression emerging as a frequent comorbidity. Examining the interplay between epilepsy and depression is crucial for understanding the comprehensive needs of individuals living with epilepsy. This article will explore clinical studies, co-prevalence rates, and shared neurobiological mechanisms between these two conditions, drawing upon evidence.
Clinical Studies and Co-Prevalence: Unveiling the Burden
Clinical studies consistently demonstrate a heightened risk of depression in individuals with epilepsy. A meta-analysis revealed that epilepsy is associated with an increased risk of depression, with a random effects model odds ratio/relative risk of 2.05. Subgroup analyses further revealed a consistent association across various study designs (case-control and cohort studies) and diverse populations, including Asian, African, and Caucasian populations.
The prevalence of depression among individuals with epilepsy is considerably higher than in the general population. The pooled period prevalence of depression in individuals with epilepsy was reported to be 27% in population-based settings and 34% in clinical settings. This significant co-occurrence underscores the importance of recognizing and addressing mental health concerns in epilepsy management.
Understanding the Bidirectional Relationship
There is a clear bidirectional relationship between epilepsy and depression. This means that not only is depression more common in individuals with epilepsy, but those with a history of depression are also at a higher risk of developing epilepsy. This interrelationship underscores the potential for shared underlying mechanisms that contribute to the development of both conditions:
Neurotransmitter Imbalances: Serotonin and Norepinephrine
Abnormalities in neurotransmitter systems, particularly serotonin and norepinephrine, as pivotal pathogenic mechanisms in both epilepsy and depression have been accumulated. Reduced serotonergic activity is implicated in both animal models of epilepsy and in human depression. In epilepsy-prone rats, enhancing serotonin transmission has been shown to reduce seizure frequency. Conversely, in individuals with depression, deficits in serotonin transmission are well-documented. Deficiencies in norepinephrine transmission have also been identified in both epilepsy-prone rats and individuals with major depressive disorder. Studies suggest that increasing norepinephrine transmission can prevent seizures in animal models.
The fact that certain antiepileptic drugs (AEDs), such as carbamazepine, valproic acid, and lamotrigine, have demonstrated both antiepileptic and psychotropic properties further supports the notion of shared neurotransmitter pathways. These AEDs are known to increase serotonin levels, suggesting that their therapeutic effects in both epilepsy and depression might be mediated through modulation of serotonergic and noradrenergic systems.
Structural and Functional Brain Abnormalities: Temporal and Frontal Lobes
Specific brain regions are involved in both epilepsy and depression:
● Temporal Lobe: Hippocampal atrophy, a frequent finding in temporal lobe epilepsy (TLE), has also been observed in individuals with major depressive disorder (MDD). This suggests a potential link between hippocampal dysfunction and the development of both conditions.
● Frontal Lobe: Both functional disturbances and structural changes in frontal lobe structures, especially the orbitofrontal cortex, have been reported in TLE and MDD. These alterations can contribute to the cognitive and emotional dysregulation observed in both disorders. In TLE, functional neuroimaging studies have revealed reduced metabolism in the frontal lobes, particularly in individuals with comorbid depression.
Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation
The HPA axis, responsible for regulating stress response, is known to be dysregulated in both epilepsy and depression. Studies in animal models of TLE have shown exaggerated corticosterone responses, indicative of HPA axis hyperactivity. This dysregulation can lead to elevated levels of circulating glucocorticoids, which have been linked to hippocampal damage and impaired neurogenesis.
Integrating Neuroinflammation: A Potential Missing Link
Interleukin-1β (IL-1β): IL-1β is a pro-inflammatory cytokine that has been implicated in both epilepsy and depression. Studies have demonstrated elevated IL-1β levels in the hippocampus of animals with TLE. Notably, chronic infusion of an IL-1β receptor antagonist into the hippocampus of these animals resulted in a reduction in depressive-like behaviors, suggesting that IL-1β signaling in the hippocampus might contribute to the development of depression in TLE.
IL-1β and HPA Axis Dysregulation: IL-1β is known to activate the HPA axis, potentially leading to the exaggerated corticosterone responses observed in TLE. This suggests that neuroinflammation, through IL-1β signaling, might play a role in the HPA axis dysregulation seen in both epilepsy and depression.
IL-1β and Serotonin: Research indicates that IL-1β can also impact serotonin transmission. In animal models of TLE, blocking IL-1β signaling in the hippocampus led to partial restoration of impaired serotonin release. This finding further supports the potential for neuroinflammation to disrupt serotonergic pathways, a key neurotransmitter system implicated in depression.
Risk Factors: A Complex Interplay
Several risk factors contribute to the development of depression in individuals with epilepsy. The main factors have been identified are seizure frequency, socioeconomic factors (low income, unemployment), perceived stigma, anxiety, female gender, unmarried status, disease course, impaired quality of life, higher disability scores, and focal-impaired awareness seizures as potential risk factors.
Implications for Treatment and Future Directions
The evidence underscores the significant interplay between epilepsy and mental health, particularly depression. The increased risk, high co-prevalence, shared neurobiological mechanisms, and contributing risk factors highlight the need for a holistic approach to epilepsy management that addresses both neurological and psychological well-being.
Integrated Care: Understanding the interconnectedness of these conditions emphasizes the need for integrated care that addresses both neurological and psychological aspects.
AED Selection: Careful consideration should be given to the selection of AEDs with minimal impact on mood. Some AEDs, while effective in controlling seizures, may exacerbate depressive symptoms.
Psychological Therapies: The integration of psychological therapies, such as cognitive behavioral therapy (CBT), is crucial for managing depression in individuals with epilepsy.
By better understanding the underlying common neurobiological mechanisms, we can move towards more comprehensive and effective treatment approaches that improve the overall well-being of individuals living with epilepsy and depression.
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