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.     

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.     

Psychiatric Comorbidity in Chronic Epilepsy: Identification, Consequences, and Treatment of Major Depression

Summary: The purpose of this article is to review the topic of interictal psychiatric comorbidity among adult patients with chronic epilepsy, focusing specifically on those studies that have used contemporary psychiatric nosology. Five specific issues are addressed: (a) the risk and predominant type(s) of psychiatric comorbidity in chronic epilepsy, (b) adequacy of recognition and treatment of psychiatric comorbidity, (c) the additional burdens that comorbid psychiatric disorders impose upon patients with chronic epilepsy, (d) the etiology of these disorders, and (e) strategies for treatment. Current appreciation for these issues in epilepsy is contrasted to related fields (e.g., primary care, psychiatry, and epidemiology), where considerable attention has been devoted to the identification, consequences, and treatment of psychiatric comorbidity. The issue of psychiatric comorbidity in epilepsy is reviewed with the aim of identifying a clinical and research agenda that will advance understanding of at least one important psychiatric condition associated with epilepsy—namely, major depression.     

Epilepsy in children and adolescents.

Epilepsy is common in the pediatric population and can significantly affect the health and quality of life of the child and family. There are many causes of childhood seizures and many forms of treatment, including pharmacologic and surgical modalities. Psychiatric disease occurs with higher incidence in children with epilepsy, and psychiatric disease in children also must be differentiated from epilepsy. Many medications are used to treat epilepsy and psychiatric disease, all of which interact with each other pharmacodynamically, as well as acting on the clinical manifestations of the disorders. These factors, and the complicated interface between epilepsy and psychiatry, must be considered in the successful management of children with epilepsy.     

Psychiatric comorbidities in epilepsy: Should they be considered in the classification of epileptic disorders?

The prevalence of psychiatric comorbidities is relatively high in people with epilepsy (PWE), as one in three patients will have experienced a psychiatric disorder in the course of their life. The new definition of epilepsy recognizes these comorbidities as part of the seizure disorder, which need to be recognized and treated together with the actual epileptic seizures. Psychiatric comorbidities have a complex relation with epilepsy, being associated with a negative course of the seizure disorder, worse tolerance of pharmacotherapy with AEDs, development of iatrogenic psychiatric complications from pharmacologic and surgical treatments, and increased mortality risks. Given their negative impact at several levels of the lives of PWE, should psychiatric comorbidities be included in a classification of the epilepsies? This question is addressed in this article.This article is part of a Special Issue entitled “The new approach to classification: Rethinking cognition and behavior in 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.     

Concurrent Illnesses in Adults with Childhood-Onset Epilepsy: A Population-Based 35-Year Follow-Up Study

Summary: Purpose: To ascertain the occurrence of concurrent illnesses in adults with epilepsy since childhood.
Method: After a mean follow-up of 35 years of a prospective, population-based long-term followed patient cohort with epilepsy since childhood, comorbidity was examined in 176 surviving (100 of them with epilepsy only) and 44 dead patients and in random and employee controls.
Results: Somatic comorbidity varied from 84 to 95% in patients and from 67 to 74% in controls. No significantly increased risk of somatic diseases could be shown. Psychosomatic disorders were associated in 46-74% of patients and in 42-75% of controls, and psychiatric disorders were associated in 11-23% of patients and in 7% of controls. As compared with random controls, patients with epilepsy had only a 4.0- to 4.2-fold risk of psychiatric disorders or of combinations of somatic, psychosomatic, and/or psychiatric disorders. Patients received psychotropic drugs 8.6 times more frequently than employee controls. The risk for psychiatric and psychsomatic disorders was higher than expected in patients with childhood-onset epilepsy, regardless of whether or not they were still receiving antiepileptic drugs (AEDs).
Conclusion: Epilepsy per se, but not AEDs, has an apparent association with the occurrence of psychiatric and psychosomatic disorders. Risk for somatic comorbidity is not increased.     

Current status of the utilization of antiepileptic treatments in mood, anxiety and aggression: drugs and devices.

Interventions that have been utilized to control seizures in people with epilepsy have been employed by the psychiatric community to treat a variety of disorders. The purpose of this review will be to give an overview of the most prominent uses of antiepileptic drugs (AEDs) and devices like the Vagus Nerve Stimulator (VNS) and Transcranial Magnetic Stimulation (TMS) in the treatment of psychiatric disease states. By far, the most prevalent use of these interventions is in the treatment of mood disorders. AEDs have become a mainstay in the effective treatment of Bipolar Affective Disorder (BAD). The U.S. Food and Drug Administration has approved the use of valproic acid for acute mania, and lamotrigine for BAD maintenance therapy. AEDs are also effectively employed in the treatment of anxiety and aggressive disorders. Finally, VNS and TMS are emerging as possibly useful tools in the treatment of more refractory depressive illness.     

Antidepressants in epilepsy

People with epilepsy (PWE) frequently suffer from comorbid mood and anxiety disorders. Depression is one of the major psychiatric comorbidities having a negative impact on the quality of life in people with epilepsy. A review of the literature indicates that the majority of antidepressant-related seizures have been associated with either ultra-high doses or overdosing and, generally, the risk of antidepressant-associated seizures is low. Correspondingly, there is some evidence indicating that antidepressants of most widely used groups may additionally lower the risk of triggering seizures. Four antidepressants are not recommended for patients with epilepsy, i.e.: amoxapine, bupropion, clomipramine and maprotiline. Clinicians applying first line of depression treatment in patients with epilepsy should consider use of SSRIs or SNRIs, particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine. Implementation of anticonvulsive drugs in depressed patients should include valproate, carbamazepine, lamotrigine, gabapentin, pregabalin. The paper reviews the evidence for the clinical use of antidepressants in PWE.     

The importance of botanical treatments in traditional societies and challenges in developing countries

Epilepsy is one of the most common neurological conditions worldwide, with many affected persons found in Asia, Latin America, and sub-Saharan Africa. Relatedly, the large majority found in these regions does not receive the appropriate therapy with antiepileptic drugs (AEDs), stemming from various reasons among which are lack of access to AEDs, social stigma, and negative cultural attitudes. The presence of epilepsy resistant to the available AEDs coupled with the frequent AED side effects has further fueled the widespread and growing use of botanicals as alternative therapy in several traditional societies in these developing countries since people with epilepsy (PWE) consider them as safe and effective. There have, however, been few botanicals that have been examined for their pharmacological activities related to traditional uses, and there is hardly any conclusive evidence regarding their efficacy in humans or knowledge about the exact mechanism(s) of action. This review discusses some botanical treatments that have been used for epilepsy in developing countries and the challenges faced.This article is part of a Special Issue entitled “Botanicals for Epilepsy”.     

Psychogenic nonepileptic seizures and suicidal behavior on a video/EEG telemetry unit: the need for psychiatric assessment and screening for suicide risk

Patients with epilepsy and psychogenic nonepileptic seizures (PNES) have an increased prevalence of psychiatric illness and risk for suicidal ideation/suicidal behavior/suicide compared with the general population. Recent literature suggests that antiepileptic drugs (AEDs) used to treat epilepsy, pain, and psychiatric disorders increase the risk of suicide and that this increased risk may be AED selective. This case analyzes a suicide attempt on a video/EEG telemetry unit. Specific risk factors associated with increased risk of suicidal behaviors pertinent to this case are reviewed: epilepsy, multiple psychiatric diagnoses including affective disorder, AEDs, PNES, prior medically serious suicide attempt, and suicide attempt within the past month. Specific psychometric rating scales to screen for both psychiatric illness and suicide risk and psychiatric assessment should be integral components of the evaluation and treatment of patients on video/EEG telemetry units.     

Psychogenic nonepileptic seizures and suicidal behavior on a video/EEG telemetry unit: The need for psychiatric assessment and screening for suicide risk

Patients with epilepsy and psychogenic nonepileptic seizures (PNES) have an increased prevalence of psychiatric illness and risk for suicidal ideation/suicidal behavior/suicide compared with the general population. Recent literature suggests that antiepileptic drugs (AEDs) used to treat epilepsy, pain, and psychiatric disorders increase the risk of suicide and that this increased risk may be AED selective. This case analyzes a suicide attempt on a video/EEG telemetry unit. Specific risk factors associated with increased risk of suicidal behaviors pertinent to this case are reviewed: epilepsy, multiple psychiatric diagnoses including affective disorder, AEDs, PNES, prior medically serious suicide attempt, and suicide attempt within the past month. Specific psychometric rating scales to screen for both psychiatric illness and suicide risk and psychiatric assessment should be integral components of the evaluation and treatment of patients on video/EEG telemetry units.     

Off-label gabapentin masking ictal triphasic waves: case analysis of neuropsychiatric and electrographic correlates

Antiepileptic drugs (AEDs) are frequently used off-label for the treatment of psychiatric, pain, and other neurological disorders. Off-label AED use may confound the diagnosis for acute neuropsychiatric changes associated with delirium by fortuitously treating, or partially treating, underlying seizure disorders while masking ictal electrographic patterns on EEGs. Standard video/EEG monitoring includes weaning from AEDs to maximize ictal activity and better determine seizure focus. We report a case of off-label gabapentin use masking ictal electrographic activity, the neuropsychiatric and electrographic consequences of discontinuing gabapentin, and the therapeutic response when gabapentin was re-initiated and titrated to a total daily dose greater than that at time of admission. Weaning from AEDs with concurrent video/EEG monitoring is an important diagnostic tool in these complex cases.     

The interface of psychiatry and irritable bowel syndrome

The interface of psychiatry and irritable bowel syndrome (IBS) is well established, with psychiatric comorbidity approaching 20% to 60%. Anxiety disorders, depressive disorders, and somatoform disorders are the more frequently occurring comorbid conditions. Moreover, psychosocial stressors and history of trauma and abuse play a significant role in the onset and perpetuation of IBS symptoms. The psychiatric management of IBS more effectively uses a collaborative approach between a mental health practitioner and a primary care clinician or gastroenterologist. Psychiatric treatment includes the use of pharmacotherapy with antidepressants or anxiolytics, psychotherapy, and attention to psychosocial stressors. Psychiatric interventions have consistently demonstrated effectiveness in reducing IBS symptoms and improvement of patient functioning.     

Antiepileptic drugs: indications other than epilepsy.

Antiepileptic drugs (AEDs) are increasingly used for the treatment of several non-epileptic neurological conditions and psychiatric disorders. Most of the information available on the use of these agents in clinical disorders outside epilepsy is from case series, uncontrolled studies or small randomised clinical trials, and their apparent efficacy requires confirmation through well designed, large, phase III trials. With regard to neurological conditions other than epilepsy, experimental evidence for the efficacy of AEDs is only available for the treatment of patients with trigeminal neuralgia, neuropathic pain syndromes, migraine and essential tremor. Carbamazepine is commonly prescribed as first-line therapy for patients with trigeminal neuralgia. Gabapentin has been recently marketed for the management of neuropathic pain syndromes, particularly diabetic neuropathy and postherpetic neuralgia. Valproic acid (sodium valproate), in the form of divalproex sodium, is approved for migraine prophylaxis. Primidone can be considered a valuable option for the treatment of essential tremor. AEDs are also used to treat psychiatric conditions, in particular bipolar disorder. So far, the most commonly utilized AEDs in the treatment of this disorder have been carbamazepine and valproic acid, which have showed an antimanic efficacy and a probable long-term, mood-stabilizing effect in many bipolar patients, including those refractory or intolerant to lithium. The availability of a new generation of AEDs has broadened the therapeutic options in bipolar disorder. Lamotrigine, oxcarbazepine, gabapentin and topiramate appear to be promising in the treatment of refractory bipolar disorder, as a monotherapy as well as in combination with traditional mood stabilizers. In addition, newer AEDs appear to have a more favourable tolerability and drug interaction profile as compared to older compounds, so thus improving compliance to treatment.     

Teratogenicity of antiepileptic medications

Antiepileptic drugs (AEDs) are frequently used to treat several conditions that are common in women of childbearing age, including epilepsy, headaches, and mood disorders. Moreover, as in the case of epilepsy and severe psychiatric disease, clinicians frequently do not have the option of stopping these medications or switching to another class of drugs. Overall, AEDs have been associated with an increased risk of major congenital malformations, minor anomalies, specific congenital syndromes, and developmental disorders seen in childhood. However, the differential effects of individual AEDs remain uncertain. Data are accumulating which strongly suggest that these risks are highest in patients receiving polypharmacy and valproate. There is also modest evidence to suggest an increased risk for phenobarbital. While other older AEDs appear to carry some teratogenic risk, there is not adequate evidence to further stratify their risk. Clinical and basic science research regarding newer AEDs suggests equivalent, if not safer, profiles compared with older AEDs, but these data are inconclusive. Management of women with epilepsy should include a discussion of these risks, prophylactic treatment with folic acid, and the minimal use of polypharmacy and valproate needed to maintain optimum seizure control.     

Antiepileptic Drugs in Pediatric Practice

Summary: Several factors characterize the current medical treatment of epilepsy during childhood. Children do not present the same types of seizures or epilepsies as adults, and certain epilepsy syndromes are seen only during childhood. Accordingly, the choice of antiepileptic drugs (AEDs) may differ in children. In addition, certain medical therapies, such as ACTH or pyridoxine, are used only in children. It is also common practice to prescribe AEDs in children for indications that are "off-label," such as the treatment of partial-onset seizures with car-bamazepine before the age of 6 years. The natural history of epilepsy and the risk for seizure recurrence may be different in the pediatric age range, and this may influence the decision to institute chronic prophylactic therapy in children. Similar considerations may apply to the decision to discontinue AED therapy. The pharmacokinetics of several AEDs are age-dependent, and dosages are more variable among patients. The adverse effects of AEDs may be age-dependent, and the pattern of exacerbation of certain seizures by AEDs may be different in children. In addition, several new AEDs are now available, or are about to be released, and the preferential sequence of AEDs of choice in children with epilepsy will need to be reassessed as experience grows and as the results of comparative studies become available.