Mood disorder and epilepsy: a neurobiologic perspective of their relationship

Mood disorders are the most frequent psychiatric comorbidity in epilepsy, and in particular in temporal lobe epilepsy For a long time, depressive disorders were considered to be the expression of a reactive process to the obstacles of a life with epilepsy. Data obtained in the last two decades, however, have demonstrated biochemical, neuropathological, and neurophysiologic changes mediating the development of mood disorders, which in fact can be tested in animal models. Furthermore, there is also evidence that mood disorders and epilepsy have a complex relationship which is bidirectional; that is, not only are patients with epilepsy at greater risk of developing depression, but patients with depression have a higher risk of developing epilepsy. Such a relationship can only be explained by the existence of common pathogenic mechanisms that are operant in both conditions. These include changes in neurotransmitters, such as serotonin, norepinephrine, glutamate, and y-aminobutyric acid. Such a bidirectional relationship also appears to have important clinical consequences. Indeed, patients with a history of mood disorders are twice as likely to develop pharmacoresistant epilepsy as those without such a history. These data are reviewed in this article.     

Biomarkers of Epileptogenesis: Psychiatric Comorbidities (?)

The last decade has witnessed a significant shift on our understanding of the relationship between psychiatric disorders and epilepsy. While traditionally psychiatric disorders were considered as a complication of the underlying seizure disorder, new epidemiologic data, supported by clinical and experimental research, have suggested the existence of a bidirectional relation between the two types of conditions: not only are patients with epilepsy at greater risk of experiencing a psychiatric disorder, but patients with primary psychiatric disorders are at greater risk of developing epilepsy. Do these data suggest that some of the pathogenic mechanisms operant in psychiatric comorbidities play a role in epileptogenesis? The aim of this article is to review the epidemiologic data that demonstrate that primary psychiatric disorders are more frequent in people who develop epilepsy, before the onset of the seizure disorder than among controls. The next question looks at the available data of pathogenic mechanisms of primary mood disorders and their potential for facilitating the development and/or exacerbation in the severity of epileptic seizures. Finally, we review data derived from experimental studies in animal models of depression and epilepsy that support a potential role of pathogenic mechanisms of mood disorders in the development of epileptic seizures and epileptogenesis. The data presented in this article do not yet establish conclusive evidence of a pathogenic role of psychiatric comorbidities in epileptogenesis, but raise important research questions that need to be investigated in experimental, clinical, and population-based epidemiologic research studies.     

Depression and epilepsy, pain and psychogenic non-epileptic seizures: clinical and therapeutic perspectives

The clinical manifestations of depression in people with epilepsy (PWE) are pleomorphic, often associated with anxiety symptoms and anxiety disorders. The ongoing debate of whether the clinical presentation of depression in PWE is unique to this neurologic disorder is reviewed. Comorbid depression can impact the recruitment of PWE for pharmacologic trials with antiepileptic drugs (AEDs). Yet, the impact of depression on the response of the seizure disorder to pharmacotherapy with AEDs and its impact on worse adverse events may bias the interpretation of the trial findings, particularly when depressed patients are included in the AED trials. PWE have a greater suicidal risk than the general population. This risk is mediated by multiple factors, and recent data from the FDA have imputed a potential pathogenic role to all AEDs. The recognition of patients at risk is reviewed. Yet, the validity of the FDA data has been questioned, and the status of this controversial question is analyzed. As in the case of epilepsy, depression and pain syndromes have a relatively high comorbidity. The negative impact of depression on pain is reminiscent of that of depression in PWE; furthermore, the high comorbidity may be also associated with the existence of common pathogenic mechanisms. Neurologists and in particular, epileptologists establish the diagnosis of psychogenic non-epileptic seizures (PNES) in whom a comorbid depressive disorder is very often identified. The role of depression in the course of PNES and its treatment are discussed. Scarce data are available on the treatment of depression in PWE. Thus, clinicians have had to adopt data from patients with primary depressive disorders. We outline a consensus strategy on the identification and treatment of depressive disorders in adult and pediatric patients with epilepsy.     

Epilepsy and mood disorders

Summary   Mood disorders (MD) are a frequent comorbidity of epilepsy with a negative impact on quality of life. The higher prevalence of MD in people with epilepsy (PWE) is most likely a reflection of a bidirectional relation between the two conditions, and common pathogenic mechanisms. Treatment of MD in PWE is safe with selective serotonin reuptake inhibitor (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), but nonpsychiatrists need to know when to refer these patients to a psychiatrist for further evaluation and treatment.     

Is depression associated with an increased risk of treatment-resistant epilepsy? Research strategies to investigate this question

Persons with epilepsy (PWE) have a higher risk of developing depressive disorders (DDs), and people with primary DD have an increased risk of developing epilepsy. Furthermore, a lifetime history of DD has been associated with a worse response of the seizure disorder to pharmacotherapy and epilepsy surgery. The first part of this article reviews the literature of this problem with the intention of highlighting the neurobiologic pathogenic mechanisms operant in DD with a potential to facilitate the epileptogenic process and/or cortical hyperexcitability in humans and experimental animal studies of depression. They include the following: (i) a hyperactive hypothalamic–pituitary–adrenal axis and the associated structural and functional abnormalities of limbic structures, (ii) increased glutamatergic activity and decreased GABAergic and serotonergic activity, and (iii) immunologic disturbances. In the second part of this article, we suggest research strategies to test the hypothesis of whether depression worsens the course of epilepsy and identify the pathogenic mechanisms operant in this process.This article is part of a Special Issue entitled “NEWroscience 2013”.     

Bipolar disorder and epilepsy: a bidirectional relation? Neurobiological underpinnings, current hypotheses, and future research directions.

A number of studies have demonstrated that affective disorders in epilepsy represent a common psychiatric comorbidity; however, most of the classic neuropsychiatric literature focuses on depression, which is actually prominent, but little is known about bipolar depression, and very little about mania, in epilepsy. Biochemical, structural, and functional abnormalities in primary bipolar disorder could also occur secondary to seizure disorders. The kindling paradigm, invoked as a model for understanding seizure disorders, has also been applied to the episodic nature of bipolar disorder. In bipolar patients, changes in second-messenger systems, such as G-proteins, phosphatidylinositol, protein kinase C, myristoylated alanine-rich C kinase substrate, or calcium activity have been described, along with changes in c-fos expression. Common mechanisms at the level of ion channels might include the antikindling and the calcium-antagonistic and potassium outward current-modulating properties of antiepileptic drugs. All these lines of research appear to be converging on a richer understanding of neurobiological underpinnings between bipolar disorder and epilepsy. Mania, which is the other side of the coin in affective disorders, may represent a privileged window into the neurobiology of mood regulation and the neurobiology of epilepsy itself. Future research on intracellular mechanisms might become decisive for a better understanding of the similarities between these two disorders.     

Depression and epilepsy: Do glucocorticoids and glutamate explain their relationship?

Depression is the most common psychiatric comorbidity in people with epilepsy, but it remains underrecognized and undertreated. In addition to its negative impact on quality of life, depressive disorders are predictive of a worse response to pharmacologic and surgical treatment of seizure disorders. This phenomenon is probably an expression of a bidirectional relationship between epilepsy and depression, which in turn is indicative of common pathogenic mechanisms that are operant in the two conditions. The abnormal role of the hypothalamic-pituitary-adrenal axis is one of the common pathogenic mechanisms that explains why patients with depression are at greater risk for developing epilepsy and vice versa.     

Systematic Literature Review of Psychiatric Comorbidities in Adults with Epilepsy

Background and PurposeMental illness is disproportionately common in people with epilepsy (PWE). This systematic literature review identified original research articles that reported the prevalence of psychiatric comorbidities based upon clinical assessments in a sample of PWE and assessed the clinical features of the populations found in studies included in our review of mental health comorbidity.MethodsThe included articles were written in English and published from 2008 to 2018, and focused on adults aged ≥18 years who had psychiatric diagnoses determined in clinical assessments, such as those found in medical records, clinician psychiatric evaluations, structured diagnostic interviews, and mental health screening questionnaires specific for a psychiatric disorder. The primary outcome was the prevalence of psychiatric comorbidities as a percentage of the total sample of PWE. Additional data included the overall sample size, mean age, epilepsy type, study design, and method of diagnosis. A modified Newcastle Ottawa Scale was used to assess the quality of the studies. All 23 articles that were consistent with the inclusion criteria were related to observational studies.ResultsMood disorders and anxiety disorders were the most common psychiatric comorbidities, with prevalence rates of 35.0% and 25.6%, respectively. Major depressive disorder was the most common mood disorder, with a prevalence of 24.2%. Post-traumatic stress disorder (PTSD) had the highest reported prevalence among anxiety disorders, at 14.2%, followed by general anxiety disorder at 11.1%. Other comorbidities included psychosis (5.7%), obsessivecompulsive disorder (3.8%), schizophrenia (1.7%), bipolar disorder (6.2%), and substance abuse (7.9%). The pooled prevalence of suicidality, as reported for two studies, was 9.3%. Temporal lobe epilepsy (TLE) was associated with higher levels of psychiatric comorbidity. Two (8.7%) of the 23 studies compared psychiatric comorbidities in TLE with that of extratemporal lobe epilepsy (ETLE), and one of these two studies found that depression was more common in TLE (53.8%) than in ETLE (25%). Regarding seizure types, partial seizures were associated with a higher prevalence of depression vs generalized seizures.ConclusionsThis systematic literature review of recent original research found a relatively high prevalence of mental health comorbidities in PWE. Mood and anxiety disorders are the most common comorbidities, while psychotic spectrum conditions such as schizophrenia and bipolar disorder are much rarer. The prevalence of comorbidity may vary with the epilepsy type and treatment responsiveness. These findings suggest that screening tools for depression and anxiety should be included as part of the training for epilepsy care, while resources for other relatively common conditions such as PTSD and substance abuse disorders should be readily available to neurology specialists who treat PWE.     

Mechanisms underlying altered mood and cardiovascular dysfunction: the value of neurobiological and behavioral research with animal models

A bidirectional association between mood disorders and cardiovascular diseases has been described in humans, yet the precise neurobiological mechanisms that underlie this association are not fully understood. This article is focused on neurobiological processes and mediators in mood and cardiovascular disorders, with an emphasis on common mechanisms including stressor reactivity, neuroendocrine and neurohumoral changes, immune alterations, autonomic and cardiovascular dysregulation, and central neurotransmitter and neuropeptide dysfunction. A discussion of the utility of experimental investigations with rodent models, including those in rats and prairie voles (Microtus ochrogaster), is presented. Specific studies using these models are reviewed, focusing on the analysis of behavioral, physiological and neural mechanisms underlying depressive disorders and cardiovascular disease. Considered in combination with studies using human samples, the investigation of mechanisms underlying depressive behaviors and cardiovascular regulation using animal models will enhance our understanding of the association of depression and cardiovascular disease, and will promote the development of improved interventions for individuals with these detrimental disorders.     

Reevaluating the prevalence and diagnostic subtypes of depressive disorders in epilepsy

ObjectiveDepressive disorders are common among patients with epilepsy (PWE). The aim of this study was to estimate the prevalence of different forms of depressive disorders among PWE treated in the outpatient setting.MethodsA group of consecutive PWE that visited the epilepsy outpatient clinic was invited to participate in the study. Ninety-six patients met inclusion criteria and were examined by a trained psychiatrist using standardized measures.ResultsA diagnosis of a current major depression was established in 21 (22.3%) out of 96 participants. Furthermore, almost 20% of the study group fulfilled criteria for mood disorder categories other than MDD, adding up to over 40% of PWE suffering from any mood disorder category. Older age and later age at seizure onset, as well as unemployment, were associated with an increase in the odds of MDD diagnosis.Study limitationsA number of limitations are to be considered: the sample size is relatively small, and the findings may not be representative of PWE in general because our population represents a sample coming from a single outpatient clinic with a higher ratio of drug-resistant epilepsy.ConclusionsMajor depression as well as other forms of depressive disorders are common among PWE. Unemployment, age, and age at seizure onset are important factors associated with major depression among PWE.     

Preclinical models: status of basic research in depression.

Approximately one half-century ago several classes of medications, discovered by serendipity, were introduced for the treatment of depression and bipolar disorder. These highly effective medications revolutionized our approach to mood disorders and helped launch the modern era of psychiatry. Yet our progress since those serendipitous discoveries has been disappointing. We still do not understand with certainty how those medications produce their desired clinical effects. We have not introduced newer medications with fundamentally different mechanisms of action than the older agents. We have not identified the genetic and neurobiological mechanisms underlying depression and mania, nor do we understand the mechanisms by which nongenetic factors influence these disorders. We have only a rudimentary understanding of the circuits in the brain responsible for the normal regulation of mood and affect, and of those circuits that function abnormally in mood disorders. In approaching these gaps in our knowledge, this workgroup highlighted four major areas for future investment. These include developing better animal models of mood disorders; identifying genetic determinants of normal and abnormal mood in humans and animals; discovering novel targets and biomarkers of mood disorders and treatments; and increasing the recruitment of investigators from diverse backgrounds to mood disorders research.     

Depression and Anxiety in People with Epilepsy

Many recent epidemiological studies have found the prevalence of depression and anxiety to be higher in people with epilepsy (PWE) than in people without epilepsy. Furthermore, people with depression or anxiety have been more likely to suffer from epilepsy than those without depression or anxiety. Almost one-third of PWE suffer from depression and anxiety, which is similar to the prevalence of drug-refractory epilepsy. Various brain areas, including the frontal, temporal, and limbic regions, are associated with the biological pathogenesis of depression in PWE. It has been suggested that structural abnormalities, monoamine pathways, cerebral glucose metabolism, the hypothalamic-pituitary-adrenal axis, and interleukin-1b are associated with the pathogenesis of depression in PWE. The amygdala and the hippocampus are important anatomical structures related to anxiety, and γ-aminobutyric acid and serotonin are associated with its pathogenesis. Depression and anxiety may lead to suicidal ideation or attempts and feelings of stigmatization. These experiences are also likely to increase the adverse effects associated with antiepileptic drugs and have been related to poor responses to pharmacological and surgical treatments. Ultimately, the quality of life is likely to be worse in PWE with depression and anxiety than in PWE without these disorders, which makes the early detection and appropriate management of depression and anxiety in PWE indispensable. Simple screening instruments may be helpful for in this regard, particularly in busy epilepsy clinics. Although both medical and psychobehavioral therapies may ameliorate these conditions, randomized controlled trials are needed to confirm that.     

Antiepileptic drugs in the treatment of psychiatric disorders

The clinical interface between psychiatry and neurology is epilepsy; the pharmacological expression of this interface is antiepileptic drugs (AEDs), as they are used to treat both epilepsy and psychiatric disorders, especially bipolar disorders. The prevalence of psychiatric comorbidity and the risk of suicidal behavior/ideation/suicide are markedly increased in patients with epilepsy (PWE). Though AEDs receive initial indications for the treatment of epilepsy, currently the majority of AEDs are used to treat pain and psychiatric disorders. Thus in selecting the appropriate AEDs for treatment of PWE, consideration should be given to which AEDs best treat the epileptic disorder and the psychiatric comorbidity. This review is an overview of 21 AEDs in which negative psychotropic properties, approved indications in psychiatry, off-label studied uses in psychiatry, and principal uses in psychiatry are presented with literature review. A total of 40 psychiatric uses have been identified. Of the 21 AEDs reviewed, only 5 have U.S. Food and Drug Administration and/or European Medicines Agency psychiatric approval for limited uses; the majority of AEDs are used off-label. Many of these off-label uses are based on case reports, open-label studies, and poorly controlled or small-sample-size studies. In some instances, off-label use persists in the face of negative pivotal trials. Further placebo-controlled (augmentation and monotherapy) parallel-arm research with active comparators is required in the complex field of AED treatment of psychiatric disorders to minimize the treatment gap not only for PWE with psychiatric disorders, but also for psychiatric patients who would benefit from properly studied AEDs while minimizing adverse effects.     

Anxiety in patients with epilepsy: systematic review and suggestions for clinical management

Up to 50 or 60% of patients with chronic epilepsy have various mood disorders including depression and anxiety. Whereas the relationship between epilepsy and depression has received much attention, less is known about anxiety disorders. It is now recognized that anxiety can have a profound influence on the quality of life of patients with epilepsy. The relationship between anxiety disorders and epilepsy is complex. It is necessary to distinguish between different manifestations of anxiety disorder: ictal, postictal, and interictal anxiety. Preexisting vulnerability factors, neurobiological factors, iatrogenic influences (antiepileptic drugs, epilepsy surgery), and psychosocial factors are all likely to play a role, but with considerable individual differences. Despite the high prevalence of anxiety disorders in patients with epilepsy, there are no systematic treatment studies or evidence-based guidelines for best treatment practice. Nevertheless, a practical approach based on the temporal relationship between anxiety and epileptic seizures allows clinicians to consider appropriate treatment strategies to reduce the psychiatric comorbidity in patients with epilepsy.     

Comorbidity of depression in children and adolescents: models and evidence from a prospective high-risk family study.

Despite abundant research demonstrating the magnitude of comorbidity and its importance in understanding childhood psychopathology, there has been limited empirical research designed to examine the nature and causes of comorbidity among youth. This article reviews the current literature on the magnitude and mechanisms of depressive comorbidity and presents data to exemplify the application of high-risk and longitudinal study designs to investigate patterns and explanations for comorbidity. A prospective family study of offspring at high and low risk for the development of anxiety was used to examine the specificity of familial comorbidity of depression and anxiety and the longitudinal stability of "pure" and comorbid disorders over an 8-year period. Findings suggest some specificity of familial expression, as well as longitudinal specificity, of depression and anxiety. The onset of depression follows the onset of most anxiety subtypes, suggesting the sequential nature of depressive comorbidity. Evaluation of mechanisms for comorbidity is important for the identification of homogeneous syndrome categories that will inform research designed to gain understanding of the pathogenesis of mood or anxiety disorders.     

Magnetic resonance volumetry reveals focal brain atrophy in transient epileptic amnesia

Psychiatric complaints afflict many patients with epilepsy, and these contribute significantly to the impaired quality of life experienced by sufferers of this common group of neurological conditions. Psychiatric disorders in epilepsy patients are under-diagnosed and under-treated. Moreover, evidence suggests that the psychiatric disorders may act as risk factors for some types of epilepsy and exacerbate disease progression in established cases, promoting the case for a bidirectional relationship between epilepsy and psychopathology. While cause and effect relationships can be difficult to establish in human studies, appropriate animal models provide valuable tools with which to study the interactions between epilepsy and stress‐related disorders. Indeed, many epilepsy models exhibit behavioral phenotypes which are reflective of psychiatric disorders, and, conversely, stressful environments appear to promote a vulnerability to developing epilepsy. This review summarizes this research area, exploring the behavioral phenotypes in animal models of epilepsy and then examining the influence of stressful environments on susceptibility to seizures and epilepsy. The ultimate goal of this line of research is to be able to translate these findings to humans. Understanding the relationships between epilepsy and associated psychiatric disorders will facilitate effective treatment of mood disorders in epilepsy, inform about the pathophysiology of each individually, and potentially open up novel therapeutic disease‐modifying strategies for patients with epilepsy.This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.     

Conséquences psychopathologiques de l'épilepsie. À partir de l'analyse de 10 observations

From the analysis of clinical data and the viewpoint of the bibliographic data, bringing out the comorbidity epilepsy/mental health, frequency of personality disorders during epilepsy and constancy of behavioural troubles are outlined. However, results of works, dealing with behavioural disorders, are often contradictory. Association with mental retardation shows a problem of imputability. Depressive mood, often concomitant with anxiety disorders, represent the psychiatric comorbidity frequently associated with epilepsy; recent works assess the factors of seriousness of depression. As for the relationship between psychosis and epilepsy, the term ”epileptic psychosis” indicates today specific entity. Psychotic patients who suffer from epilepsy are not in that concept frame. Alcoholism does not seem more frequent in people suffering from epilepsy than in general population. The social disqualification assessed by the scales of quality of life is frequent with people suffering from epilepsy.     

Suicidality and epilepsy: a neuropsychobiological perspective

People with epilepsy (PWE) are at increased risk of experiencing suicidal ideation, displaying suicidal behavior, and committing suicide than the general population. The relationship between suicidality and epilepsy is complex and multifactorial in which operant pathogenic mechanisms include epilepsy-related variables, personal and familial psychiatric history, and iatrogenic effects. Furthermore, a bidirectional relationship between suicidality and epilepsy has suggested the existence of common neurobiological pathogenic mechanisms operant in both conditions and including disturbances of several neurotransmitters, in particular, serotonin (5HT), norepinephrine (NE), glutamate (GTE), and γ-aminobutyric acid (GABA), and disturbances of the hypothalamic–pituitary–adrenal axis (HPAA), which, in turn, can result in abnormal secretion of some of these neurotransmitters. The purpose of this article is to review these common neurobiological pathogenic mechanisms.     

Consensus statement: the evaluation and treatment of people with epilepsy and affective disorders

Affective disorders in people with epilepsy (PWE) have become increasingly recognized as a primary factor in the morbidity and mortality of epilepsy. To improve the recognition and treatment of affective disorders in PWE, an expert panel comprising members from the Epilepsy Foundation's Mood Disorders Initiative have composed a Consensus Statement. This document focuses on depressive disorders in particular and reviews the appearance and treatment of the disorder in children, adolescents, and adults. Idiosyncratic aspects of the appearance of depression in this population, along with physiological and cognitive issues and barriers to treatment, are reviewed. Finally, a suggested approach to the diagnosis of affective disorders in PWE is presented in detail. This includes the use of psychometric tools for diagnosis and a stepwise algorithmic approach to treatment. Recommendations are based on the general depression literature as well as epilepsy-specific studies. It is hoped that this document will improve the overall detection and subsequent treatment of affective illnesses in PWE.