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.     

Lamotrigine Monotherapy Improves Depressive Symptoms in Epilepsy: A Double-Blind Comparison with Valproate

Depressive symptoms are highly prevalent in patients with epilepsy. The antiepileptic drug lamotrigine has been shown to be an effective treatment for the depressive phase of bipolar disorder and to enhance mood and well-being in epilepsy patients. The effects of lamotrigine monotherapy on depressive symptoms in epilepsy have not been evaluated to date in a controlled clinical trial. A recently completed double-blind epilepsy trial comparing the effects of lamotrigine monotherapy and valproate monotherapy on weight change incorporated a battery of standard mood assessments. Mean screening Beck Depression Inventory scores showed that both lamotrigine and valproate groups suffered from mild depression at baseline. Lamotrigine monotherapy was reliably associated with earlier and larger improvements than valproate in mood assessed with the Beck Depression Inventory, the Cornell Dysthymia Rating Scale, and the Profile of Mood States. Considered in the context of other data showing lamotrigine's antidepressant efficacy in bipolar depression, these results suggest that lamotrigine improves mood in mildly depressed patients with epilepsy. Lamotrigine may be particularly useful in treating epilepsy patients with comorbid depression, the most common psychiatric illness in epilepsy.     

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.     

Lamotrigine therapy in elderly patients with epilepsy, bipolar disorder or dementia

INTRODUCTION: In spite of circumstances that precipitate high use of anticonvulsants in geriatric populations, there is a paucity of data on the use of antiepileptic drugs in elderly patients with psychiatric and neurological disorders. METHODS: Reports of lamotrigine therapy in elderly patients with epilepsy, bipolar disorder (BD), or dementia were identified by conducting an electronic search of major publication databases. Abstracts and presentations from professional meetings were searched as were the bibliographies of relevant articles. RESULTS: Fourteen reports were identified, and included well-controlled prospective trials, retrospective analyses, and case reports of lamotrigine treatment. Controlled trials in elderly patients with epilepsy demonstrate efficacy and tolerability comparable to gabapentin. Improvement in bipolar depressive symptoms, improvement in core manic symptoms, and delay in mood relapse was reported in geriatric patients with BD. Preliminary case studies in patients with dementia note improvement in cognition and symptoms of agitation and depression. CONCLUSION: Review of the available literature suggests lamotrigine is effective and well tolerated in elderly patients with epilepsy and relatively well-tolerated and may be effective in delaying mood relapse, particularly in the depressive pole, in patients with BD. While very limited literature suggests that lamotrigine may be effective and relatively well-tolerated in patients with dementia, further studies are needed.     

Interictal mood and personality disorders in temporal lobe epilepsy and juvenile myoclonic epilepsy.

BACKGROUND: Mood disorders have been described as the commonest psychiatric disorders in patients with temporal lobe epilepsy. Secondary depression in temporal lobe epilepsy could be interpreted either as an adjustment reaction to a chronic disease or as a limbic dysfunction. To clarify this issue, a controlled study of psychiatric disorders was conducted in different forms of epileptic and non-epileptic chronic conditions. METHODS: Twenty outpatients with temporal lobe epilepsy, 18 outpatients with juvenile myoclonic epilepsy--a primary generalised seizure disorder--20 matched type I diabetic patients, and 20 matched normal controls were assessed by a structured interview (SADS) and by self rating scales (Beck depression inventory (BDI) and the state and trait anxiety scales STAIX1 and STAIX2). RESULTS: Sixteen (80%) patients with temporal lobe epilepsy fulfilled the criteria for a psychiatric diagnosis at the SADS interview with a significantly higher frequency than patients with juvenile myoclonic epilepsy (22%) and diabetic patients (10%) (P < 0.0001). The most frequent disorder in temporal lobe epilepsy was a mood disorder: 11 (55%) patients with temporal lobe epilepsy had depression compared with three patients with juvenile myoclonic epilepsy and two diabetic patients (P < 0.001). Eight patients with temporal lobe epilepsy with an affective disorder also had a comorbid personality or anxiety disorder. Patients with temporal lobe epilepsy scored significantly higher on BDI, STAIX1, and STAIX2 than the three control groups (P < 0.001, P < 0.01, P < 0.001). CONCLUSIONS: Patients with temporal lobe epilepsy have a higher incidence of affective and personality disorders, often in comorbidity, than patients with juvenile myoclonic epilepsy and diabetic patients suggesting that these psychiatric disorders are not an adjustment reaction to a chronic disease but rather reflect a limbic dysfunction.     

The Interictal Dysphoric Disorder of Epilepsy: a Still Open Debate

Mood disorders represent a frequently encountered comorbidity in epilepsy, but the issue of phenomenology of depression is still matter of debate, having relevant implications in terms of treatment and prognosis. The interictal dysphoric disorder has been described by pre-modern psychiatry and recently revitalized by behavioral neurology identifying a pleomorphic pattern of symptoms claimed to be typical of patients with epilepsy. The present paper reviews current literature on this subject. A number of variables seem to be implicated in the complex and pleomorphic nature of interictal dysphoric disorder such as the high comorbidity between mood and anxiety, the pathophysiology of epilepsy with peri-ictal behavioral symptoms, and the psychotropic effect of antiepileptic drugs. Further studies identifying specific behavioral endophenotypes may have practical implications in terms of prognosis and tailored treatment strategies.     

Clinical experience with anticonvulsant medication in pediatric epilepsy and comorbid bipolar spectrum disorder

Anticonvulsant drugs are first-line treatments for both bipolar mood disorder and epilepsy; however, few studies have explored treatment options when these disorders co-occur. The aim of this study was to identify bipolar disorder symptoms common in pediatric epilepsy and to determine whether anticonvulsant monotherapy might be a practical treatment consideration. A retrospective chart review identified 38 children with bipolar spectrum disorder and epilepsy comorbidity. Two mental health clinicians independently assessed psychiatric diagnoses, symptoms, and assigned retrospective CGI-I ratings for psychiatric symptoms. Common bipolar symptoms included impulsivity, psychomotor agitation, and explosive rage. Forty-two medication trials with 11 different anticonvulsants were identified. Of the 30 instances in which anticonvulsant monotherapy was attempted, carbamazepine, divalproex sodium, lamotrigine, and oxcarbazepine were associated with better psychiatric CGI-I ratings than other monotherapies (P<0.01). Results suggest that in many cases, selected anticonvulsants appeared to simultaneously treat both epilepsy and mood disorder. Controlled trials are necessary to further ascertain optimal anticonvulsant usage.     

Symptoms profile of mixed anxiety and depressive disorder

The paper describes symptoms of mixed depressive and anxiety disorder (ICD-10). The study was carried out in three medical dispensaries: two psychiatric (42 persons) and one primary care (62 persons). Patients with or without anxiety and depressive symptoms were included. Exclusion criteria was: psychoactive substance abuse, physical diseases affecting mental state, and mental disorders other than anxiety or mood disorders. A total of 104 patients (65 women and 39 men in mean age of 41.1 years) were inquired with General Health Questionnaire (GHQ-30), Global Assessment of Functioning (GAF) and diagnostic questionnaire based on Schedules for Clinical Assessment in Neuropsychiatry, Version 2.0. There was no pattern of symptoms specific for mixed disorder that could be a basis for operational criteria. The most frequent were symptoms of generalised anxiety disorder (GAD), depression and dysthymia. The most specific symptoms, selected using discriminant analysis were: (1) difficulty in concentrating, (2) feeling mentally tense, (3) feeling of hopelessness or despair, (4) shortening of breath, (5) lowered mood, (6) feeling dizzy, unsteady, faint, or light headed; (7) early waking up, (8) nightmares, (9) dry mouth, (10) hot flushes or cold chills, (11) frequent tearfulness. The results contribute to the concept that mixed depression and anxiety disorder is closely related to generalised anxiety disorder (GAD).     

癫(疒间)患者焦虑抑郁情绪研究

目的:探讨癫(疒间)患者焦虑抑郁情绪的有关因素. 方法:80例成年癫疒间患者,前期诊疗不规范,采用焦虑自评量表(SAS)和抑郁自评量表(SDS)评估. 结果:癫疒间合并焦虑情绪者25%,合并抑郁情绪者45%.多因素回归分析结果显示,病程越长,发作程度越严重,男性患者更易产生焦虑情绪,而居住在农村的癫疒间患者更易产生抑郁情绪. 结论:癫疒间患者焦虑抑郁情绪明显高于正常人群,性别、病程、发作严重程度和生活居住地是影响癫疒间患者焦虑抑郁情绪的独立危险因素.     

癫患者焦虑抑郁情绪研究

目的：探讨癫癎患者焦虑抑郁情绪的有关因素。方法：80例成年癫癎患者，前期诊疗不规范，采用焦虑自评量表（SAS）和抑郁自评量表（SDS）评估。结果：癫癎合并焦虑情绪者25％，合并抑郁情绪者45％。多因素回归分析结果显示，病程越长，发作程度越严重，男性患者更易产生焦虑情绪，而居住在农村的癫癎患者更易产生抑郁情绪。结论：癫癎患者焦虑抑郁情绪明显高于正常人群，性别、病程、发作严重程度和生活居住地是影响癫癎患者焦虑抑郁情绪的独立危险因素。     

Lamotrigine in motor and mood symptoms of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by midlife onset, progressive course and a combination of motor, cognitive and psychiatric symptoms. Since dysregulation of the glutamate/calcium signalling pathway is beginning to emerge as a potential cause of neuron degeneration, antagonists of glutamate pathways such as lamotrigine, may have beneficial value for treatment of HD. We describe the use of lamotrigine in the treatment of an HD patient with motor abnormality (choreoathetoidic movements) complicated by psychiatric abnormalities (depression, severe mood swing and recurrent high risk of suicidal attempts). The patient's depression, severe mood swing and choreoathetoidic movements significantly improved with 300 mg/day of lamotrigine. Experience from our patient suggests that lamotrigine might be effective in treating HD patients with motor and mood symptoms. Further controlled studies are warranted to confirm its efficacy in patients of this type.     

Lamotrigine in the Treatment of Unipolar Depression with and Without Comorbidities: A Literature Review

To review the available data behind the use of lamotrigine in unipolar depression and common comorbid conditions. A PubMed based literature review was conducted using keywords related to lamotrigine, depression, anxiety, post traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and personality disorders. A large number of trials using lamotrigine for unipolar depression and various comorbid conditions were reviewed. A major limitation behind the majority of studies was a limited course of the treatment phase. The most robust data was found among studies that followed patients for over 8?weeks, and used higher dosages. Patients with comorbid anxiety states appeared to benefit. Patients with borderline personality disorder also appeared to benefit. The benefits of lamotrigine in unipolar depression have been inconsistently noted in a number of studies. This is due in part to short treatment phases, atypical domains of benefit and different patient populations across studies. Patients with more treatment-resistance, comorbid anxiety and borderline personality disorder may be more able to benefit from lamotrigine.     

Burden of illness in bipolar depression

Bipolar depression is the underrecognized and unappreciated phase of bipolar disorder. Nevertheless, bipolar depression is responsible for much of the morbidity and mortality associated with the disorder. Depressive symptoms are far more prevalent than hypomanic or manic symptoms in bipolar patients, and they are associated with a heavier burden of illness, including reduced functioning, increased risk of suicidal acts, and high economic costs. Because most patients with bipolar disorder present with depression, misdiagnoses of major depressive disorder are common, even typical. Comorbid psychiatric disorders are also prevalent and may obscure the diagnosis and complicate treatment strategies. Depressed patients should be carefully assessed for manic or hypomanic symptoms to help reveal possible bipolar disorder. In addition to evaluation of psychiatric symptoms, a close examination of family history, course of illness, and treatment response will aid the clinician in making an accurate diagnosis. Treatment of acute depression in bipolar patients may require therapy combining agents such as lithium, divalproex, lamotrigine, carbamazepine, and atypical antipsychotics or using such agents in combination with an anti-depressant. Olanzapine/fluoxetine combination is the only medication currently approved for the treatment of bipolar depression. Antidepressant monotherapy should not be used, because there is evidence that such treatment increases the risk of switching into mania/hypomania and could induce treatment-refractory conditions such as mixed or rapid-cycling states. Maintenance therapy will be required by most patients, since discontinuation of mood stabilizers or antidepressants frequently leads to relapses in depressive symptoms. Prompt diagnosis and the use of specific therapeutic agents with evidence of efficacy may help reduce the disease burden associated with bipolar depression.     

Recognition of the Various Expressions of Anxiety, Psychosis, and Aggression in Epilepsy

Summary:  Anxiety, psychosis, and aggressive behavior are among the frequent comorbid psychiatric disorders identified in patients with epilepsy. Often the clinical manifestations of these disorders vary according to their temporal relation relative to seizure occurrence. Thus, postictal symptoms of anxiety or psychosis differ in severity, duration, and response to treatment with interictal symptomatology. Psychiatric symptomatology in epilepsy can appear concurrently with the seizure disorder and improve or remit on the abolition of epileptic activity. We refer to these as paraictal psychiatric phenomena. Such is the case of aggressive disturbances associated with gelastic seizures caused by hypothalamic hamartomas. In this article, three case studies are presented to illustrate the importance of distinguishing psychiatric symptoms of anxiety, psychosis, and aggression, with respect to their temporal relation with seizure occurrence.     

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.     

Correlation between Cognition and Behavior in Epilepsy

Summary:  Cognitive function is more frequently impaired in people with epilepsy than in the general population, and the degree of cognitive impairment varies according to the epilepsy syndrome. Behavioral disorders are also more frequent in people with epilepsy than in individuals who do not have epilepsy. Behavioral disturbance is observed more frequently in people with drug-resistant epilepsy, frequent seizures, and/or associated neurological or mental abnormalities. In children and adolescents, many data suggest a close link between behavior/cognition and some specific epilepsy syndromes. For example, aspects of mood, behavior, personality, and cognition may be related to temporal lobe epilepsy or juvenile myoclonic epilepsy. Behavioral disorders may precede, occur with, or follow a diagnosis of epilepsy; they differ between children and adults. Predictors of behavioral disorders in children with epilepsy are the epilepsy itself, treatment, the underlying lesion, and personal reactions to epilepsy. More specifically, conditions in which behavioral disorders may be associated with epilepsy include depression, psychosis, particular personality traits, aggression, anxiety, and attention deficit and hyperactivity disorder.     

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 anxiety disorders in pediatric epilepsy

PURPOSE: This study examined affective disorders, anxiety disorders, and suicidality in children with epilepsy and their association with seizure-related, cognitive, linguistic, family history, social competence, and demographic variables. METHODS: A structured psychiatric interview, mood self-report scales, as well as cognitive and language testing were administered to 100 children with complex partial seizures (CPSs), 71 children with childhood absence epilepsy (CAE), and 93 normal children, aged 5 to 16 years. Parents provided behavioral information on each child through a structured psychiatric interview and behavior checklist. RESULTS: Significantly more patients had affective and anxiety disorder diagnoses (33%) as well as suicidal ideation (20%) than did the normal group, but none had made a suicide attempt. Anxiety disorder was the most frequent diagnosis among the patients with a diagnosis of affective or anxiety disorders, and combined affective/anxiety and disruptive disorder diagnoses, in those with suicidal ideation. Only 33% received some form of mental health service. Age, verbal IQ, school problems, and seizure type were related to the presence of a diagnosis of affective or anxiety disorder, and duration of illness, to suicidal ideation. CONCLUSIONS: These findings together with the high rate of unmet mental health underscore the importance of early detection and treatment of anxiety disorders and suicidal ideation children with CPSs and CAE.     

Safety and tolerability of lamotrigine: results from 12 placebo-controlled clinical trials and clinical implications

The mechanism of action of lamotrigine depends on voltage-sensitive sodium channels by which the neuronal membrane is stabilized and the release of excitatory neurotransmitters, such as glutamate and aspartate, is inhibited. Lamotrigine is indicated for maintenance treatment of bipolar I disorder to delay the time to the occurrence of mood episodes for those treated for acute mood episodes with standard therapy. There are significant gaps between clinical practices and research settings; data from controlled clinical trials of lamotrigine provide essential information about safety in bipolar populations because they result from large samples of patients with a specific disease and include comparisons with placebo or other comparators with randomized designs. In addition, lamotrigine's safety and tolerability data differ slightly in relation to disease entities, age ranges of the patients taking lamotrigine, and treatment conditions. For example, the incidence of serious rashes, including Stevens-Johnson syndrome, is approximately 0.8% (8/1000) in pediatric patients (2-16 years of age) receiving lamotrigine as adjunctive therapy for epilepsy and 0.3% (3/1000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08% (0.8/1000) in adult patients receiving lamotrigine as initial monotherapy and 0.13% (1.3/1000) in adult patients receiving lamotrigine as adjunctive therapy. Hence, in this study, we focus on the data regarding the safety and tolerability of lamotrigine in the treatment of bipolar disorder gathered from 12 placebo-controlled trials, regardless of publication status, that were sponsored by GlaxoSmithKline. We also inform clinicians of practical issues in safety and tolerability in the use of lamotrigine in the treatment of bipolar disorders.     

Painful physical symptoms in depression: a clinical challenge

Painful physical symptoms are common elements within mood disorders and provide a therapeutic challenge when such patients attribute their pain to causes other than the mood disorder. These somatic presentations may lead to under-diagnosis and inappropriate treatment of patients with mood disorders. Antidepressant agents that inhibit both serotonin and norepinephrine reuptake effectively remit mood disorders, thereby providing relief of painful physical symptoms often associated with these disorders. They may also provide analgesia for neuropathic pain, such as that caused by diabetic neuropathy, which are associated with mood disorders. Newer generation dual acting antidepressants such as duloxetine and venlafaxine offer a well-tolerated and safe alternative to tricyclics. Concurrent with medication and management, the physician must educate the patient about the nature of both depressed mood and painful physical states that are augmented by and inherent in the depressive disorders. This mini review addresses the problems inherent to the treatment of painful physical symptoms in depression.