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.     

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.     

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.     

Detection and management of depression and/or anxiety for people with epilepsy in primary health care settings in Zambia

PurposeAmong the 50 million people with epilepsy (PWE) worldwide ～15 to 60% likely also suffer from depression and/or anxiety and 80% reside in low-income regions where human and technological resources for care are extremely limited.MethodsIn Zambia, we carried out a retrospective chart review of 200 randomly selected files of PWE using a structured abstraction form to systematically collect socio-demographic data and clinical details on the detection and treatment of depression and/or anxiety.ResultsOnly 2 PWE (1%) had depression diagnosed and none were given a diagnosis of an anxiety disorder. Complaints suggestive of underlying depressive and/or anxiety disorders were documented in 120 (60%), but no diagnoses were made and no referrals, investigations or treatment were offered.ConclusionsFurther research is required to establish the prevalence of depression and anxiety among PWE in sub-Saharan Africa and efforts are needed to improve screening and treatment for common, treatable psychiatric comorbidities in PWE in resource limited settings.     

Identification of three distinct groups of patients with both epilepsy and psychogenic nonepileptic seizures

Psychogenic nonepileptic seizures (PNES) can be observed in patients with or without epilepsy (mixed and pure PNES). Patients with mixed PNES are usually considered to be a homogeneous group characterized by the coexistent epilepsy. Our study found that patients with mixed PNES were not homogeneous, but could be divided into three groups based on epilepsy type, mental level, comorbid psychiatric disorders, and history of traumatic experiences. Group 1 patients have pharmacoresistant epilepsy, normal cognition, and comorbid anxiety and/or depressive disorders. Here, PNES etiology is the epilepsy-related problems. In group 2 patients, the epilepsy is associated with mental retardation and dependent personality traits. PNES etiology is represented by the reduction or cessation of seizures. The PNES allow patients to continue receiving attention from caregivers. Group 3 patients have epilepsy, normal cognition, comorbid cluster B personality disorders and anxiety disorders, and psychic trauma. Here, PNES etiology is not related to the epilepsy, but to the psychic trauma.     

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.     

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.     

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.     

Psychiatric comorbidity and hostility in patients with psychogenic nonepileptic seizures compared with somatoform disorders and healthy controls

PURPOSE: To investigate the prevalence of psychiatric comorbidity and level of anxiety, depression, and aggression in patients with psychogenic nonepileptic seizures compared with those in patients with somatoform disorders and healthy controls. METHODS: Twenty-three patients with psychogenic nonepileptic seizures (PNESs) and 23 age- and sex-matched patients with somatoform disorders (SDs) underwent a clinical and a semistructured psychiatric interview (MINI) and filled in the Hospital Anxiety and Depression scale (HAD) and the Aggression Questionnaire (AQ). Twenty-three sex- and age-matched controls without psychopathology also underwent a clinical interview and completed the HAD and AQ. RESULTS: PNES reported more minor head injuries in the past than did the two comparison groups, and more unspecific EEG dysrhythmias were observed on EEG. Twenty-one PNES patients and 18 with SDs had comorbid psychiatric diagnoses. However, the mean number of comorbid psychiatric diagnoses was higher in the PNES group (1.9 +/- 0.3 compared with 1.5 +/- 0.5 in the SD group; p = 0.003). Ten PNES patients additionally had a somatoform pain disorder, and seven had an undifferentiated somatoform disorder. Both patient groups reported significantly higher levels of anxiety, depression, and anger than did the healthy controls, but the PNES patients had significantly higher level of hostility than both comparison groups. CONCLUSIONS: Increased psychiatric comorbidity is known to be associated with poorer response to regular interventions, and hostility is associated with more hostile coping patterns, often interfering with treatment compliance. Thus the increased prevalence of soft neurologic signs and comorbid psychiatric disorders and increased hostility as well in the PNES group, emphasizes that assessment and treatment of patients with PNES referred to a tertiary center requires an integrated approach involving both neurologic and psychiatric resources.     

Anxiety and depression in children and adolescents with sickle cell disease

A growing body of evidence suggests that depressive disorders and anxiety disorders are much more prevalent among medically ill children and adolescents when compared with the general population, and that the presence of comorbidity may adversely affect medical outcomes and quality of life. Whereas the prevalence and impact of anxiety and depressive disorders have been described in chronic conditions such as asthma, diabetes, and epilepsy, much less is known about sickle cell disease (SCD), a disorder that affects more than 70,000 Americans, primarily those of African and Mediterranean descent. A hallmark of this disorder is recurrent, acute, and chronic pain that often requires emergency management and hospitalization. Medical advances in the treatment of this illness have transformed SCD from a condition associated with very early morbidity and mortality into a chronic condition of adulthood. This article reviews the evidence describing our knowledge of anxiety and depression in children and adolescents with SCD, its clinical impact, and effectiveness of interventions.     

Comorbidity of anxiety and depressive disorders: issues in conceptualization, assessment, and treatment

OBJECTIVES: The purpose of this review is to provide a clinically relevant analysis of issues concerning comorbidity among anxiety and depressive disorders. The co-occurrence of social anxiety disorder (SAD) and generalized anxiety disorder (GAD) with depressive disorders is highlighted as an illustration. Data on prevalence, rates of comorbidity, order of onset, course, and functional impairment associated with these disorders, in both the general population and clinical samples, are examined. The second half of the review focuses on discussion of practical issues concerning assessment and treatment of comorbid anxiety and depressive syndromes. CONCLUSIONS: Available evidence suggests that comorbidity among SAD, GAD, and the depressive disorders is substantial and pervasive. Co-occurrence of these syndromes is typically characterized by a chronic course with clinically significant impairment in social and occupational functioning. SAD and GAD precede the onset of major depression in a majority of cases and appear to be risk factors for developing major depression. Clinicians encountering patients with primary complaints of anxiety or depression should carefully assess for the presence of comorbid symptoms and syndromes. Treatment outcome research suggests that pharmacotherapy and psychosocial therapy (cognitive-behavior therapy in particular) both represent viable first-line treatment alternatives. However, with increasing severity of depression, pharmacotherapy is indicated as a primary intervention. The authors recommend increased efforts in screening and detection, more clinical trials that include patients with comorbid syndromes and symptoms, and continued research on the integration of pharmacological and psychotherapeutic treatments.     

Depressive, anxiety, and somatoform disorders in primary care: prevalence and recognition

Recent studies emphasize the negative impact of comorbidity on the course of depression. If undiagnosed, depression and comorbidity contribute to high medical utilization. We aimed to assess (1) prevalences of depression alone and with comorbidity (anxiety/somatoform disorders) in primary care, (2) coexistence of anxiety/somatoform disorders in depressive patients, and (3) diagnostic validity of two screeners regarding depression with versus without comorbidity. We examined 394 primary care outpatients using the Composite International Diagnostic Interview (CIDI), the General Health Questionnaire (GHQ-12), and the Well-Being Index (WHO-5). We conducted configurational frequency analyses to identify nonrandom configurations of the disorders and receiver operating characteristic (ROC)-analyses to assess diagnostic validity of the screeners. Point prevalence of any depressive disorder was 22.8%; with at least one comorbid disorder, 15%; and with two comorbid conditions, 6.1%, which significantly exceeded expected percentage (0.9%, P< or =.0001). Depression without comorbidity occurred significantly less often than expected by chance (P< or =.0007). Comorbidity of depressive and anxiety or somatoform disorders was associated with a high odds ratio (6.25). The screeners were comparable regarding their diagnostic validity for depression with [GHQ-12: area under the curve (AUC)=0.86; WHO-5: AUC=0.88] and without comorbidity (GHQ-12: AUC=0.84; WHO-5: AUC=0.86). It can be concluded that comorbidity between depression and anxiety/somatoform disorders in primary care may occur much more frequently than expected. These results confirm assumptions that the current division between depression and anxiety might be debatable. Validity of screeners tested in our study was not affected by comorbid conditions (e.g., anxiety or somatoform disorders).     

Anxiety and depression in later life: Co-occurrence and communality of risk factors

OBJECTIVE: The purpose of this study was to examine the comorbidity of and communality of risk factors associated with major depressive disorder and anxiety disorders in later life. METHOD: A random age- and sex-stratified community-based sample (N=3,056) of the elderly (age 55-85 years) in the Netherlands was studied. A two-stage screening design was used, with the Center for Epidemiologic Studies Depression Scale as a screening instrument and the National Institute of Mental Health Diagnostic Interview Schedule as a criterion instrument. Risk factors were measured with well-validated instruments and represented a broad range of vulnerability and stress-related factors associated with anxiety and depression. Multivariate analyses examined risk factors associated with pure major depressive disorder, pure anxiety disorders, and comorbid conditions. RESULTS: Comorbidity was highly prevalent: 47.5% of those with major depressive disorder also met criteria for anxiety disorders, whereas 26.1% of those with anxiety disorders also met criteria for major depressive disorder. While the only variables associated with pure major depressive disorder were younger age and external locus of control, risk factors representing a wide range of both vulnerability and stress were associated with pure anxiety disorders. External locus of control was the only common factor. The group with anxiety disorders plus major depressive disorder had a distinct risk factor profile and may represent those with a more severe disorder. CONCLUSIONS: Although high levels of comorbidity between major depressive disorder and anxiety disorders were found, comparing risk factors associated with pure major depressive disorder and pure anxiety disorders revealed more differences than similarities. Anxiety disorders in later life merit separate study.     

The FDA alert on suicidality and antiepileptic drugs: Fire or false alarm?

In January 2008, the U.S. Food and Drug Administration (FDA) issued an alert about an increased risk for suicidality in 199 clinical trials of 11 antiepileptic drugs (AEDs) for three different indications, including epilepsy. An advisory panel voted against a black-box warning on AED labels, and the FDA has accepted this recommendation. We discuss three potential problems with the alert. First, adverse event data were used rather than systematically collected data. Second, the 11 drugs grouped together as a single class of AEDs have different mechanisms of action and very different relative risks, many of which were not statistically significant and some of which were smaller than one. These facts suggest that they should not be grouped as a class. Third, the risk of adverse effects from uncontrolled seizures almost certainly outweighs the small risk of suicidality. We place our comments in the context of a review of the literature on suicidality and depression in epilepsy and the sparse literature on AEDs and suicidality. We recommend that all patients with epilepsy be routinely evaluated for depression, anxiety, and suicidality, and that future clinical trials include validated instruments to systematically assess these conditions to determine whether the possible signal observed by the FDA is real.     

The Comorbidity of Major Depression and Anxiety Disorders: Recognition and Management in Primary Care

BACKGROUND: Depressive and anxiety disorders commonly occur together in patients presenting in the primary care setting. Although recognition of individual depressive and anxiety disorders has increased substantially in the past decade, recognition of comorbidity still lags. The current report reviews the epidemiology, clinical implications, and management of comorbidity in the primary care setting. METHOD: Literature was reviewed by 2 methods: (1) a MEDLINE search (1980-2001) using the key words depression, depressivedisorders, and anxietydisorders; comorbidity was also searched with individual anxiety diagnoses; and (2) direct search of psychiatry, primary care, and internal medicine journals over the past 5 years. RESULTS: Between 10% and 20% of adults in any given 12-month period will visit their primary care physician during an anxiety or depressive disorder episode (although typically for a nonpsychiatric complaint); more than 50% of these patients suffer from a comorbid second depressive or anxiety disorder. The presence of depressive/anxiety comorbidity substantially increases medical utilization and is associated with greater chronicity, slower recovery, increased rates of recurrence, and greater psychosocial disability. Typically, long-term treatment is indicated, although far less research is available to guide treatment decisions. Selective serotonin reuptake inhibitor antidepressants are the preferred treatment based on efficacy, safety, and tolerability criteria. Knowledge of their differential clinical and pharmacokinetic profiles can assist in optimizing treatment. CONCLUSION: Increased recognition of the high prevalence and negative psychosocial impact of depression and anxiety disorder comorbidity will lead to more effective treatment. While it is hoped that early and effective intervention will yield long-term benefits, research is needed to confirm this.     

Depressive episodes–evidence for a causal role of primary anxiety disorders?

Anxiety and depressive disorders are common mental disorders in general population, imposing tremendous burden on both affected persons and society. Moreover, comorbidity between anxiety and depressive conditions is high, leading to substantial disability and functional impairment. Findings consistently suggest that anxiety disorders are primary to depression in the majority of comorbid cases. Yet, the question of whether anxiety disorders are risk factors for depression, and potentially even causal risk factors for the first onset of depression, remains unresolved. Recent results have shown that anxiety disorders increase the risk for subsequent depression, and also affect the course of depression, resulting in a poorer prognosis. Further, some results suggest a dose-response-relationship in revealing that a higher number of anxiety disorders and more severe impairment associated with anxiety disorders additionally increase the risk for subsequent depression. The goal of this paper is to review recent literature, summarize implications of previous findings, and suggest directions for future research regarding preventive and intervention strategies.     

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.