Contribution of the μ-opioid receptor system to affective disorders in temporal lobe epilepsy: A bidirectional relationship?

Objective

Affective disorders are frequent comorbidities of temporal lobe epilepsy (TLE). The endogenous opioid system has been implicated in both epilepsy and affective disorders, and may play a significant role in their bidirectional relationship. In this cross-sectional study, we investigated the association between μ-opioid receptor binding and affective disorders in patients with TLE.

Methods

Nine patients with TLE and depression/anxiety underwent ¹¹C-carfentanil positron emission tomography (CFN PET) and neuropsychiatric assessment, including the Hospital Anxiety and Depression Scale and the Positive and Negative Affect Schedule. The normalized CFN PET scans were compared with those of 26 age-matched healthy controls. Correlation analyses with affective symptoms were performed by region of interest-based analysis focusing on the limbic circuit and orbitofrontal cortex.

Results

We observed widely reduced CFN binding potential (BP) in bilateral frontal lobes and striata in patients with TLE compared to healthy controls. In the TLE group, more severe anxiety and negative affect were associated with decreased CFN BP in the posterior cingulate gyrus.

Significance

In patients with TLE, interictally reduced binding in the opioid system was associated with higher levels of anxiety and negative affect. We speculate that seizure-related agonist-driven desensitization and downregulation of opioid receptors could be a potential underlying pathomechanism.     

Is interictal EEG activity a biomarker for mood disorders in temporal lobe epilepsy?

Objective

Psychiatric comorbidities are frequent in temporal lobe epilepsy (TLE), and symptoms of these comorbidities may be related to epilepsy activity. Here we evaluated interictal EEG activity in TLE patients with or without psychiatric comorbidities.

Methods

A cohort study of 78 patients with TLE, with evaluation of wake/sleep interictal scalp EEG. All subjects were submitted to a psychiatric structured clinical interview (SCID) for the diagnosis of lifetime psychiatric comorbidities. Three major diagnostic categories were studied: mood disorders, anxiety disorders, and psychosis. We then evaluated differences in interictal EEG activity between patients with and without these psychiatric comorbidities.

Results

Infrequent EEG interictal spikes, defined as less than one event per minute, were significantly associated with mood disorders in TLE (p = 0.02).

Conclusions

Low intensity seizure disorder has been associated with a decrease in interictal EEG discharges and with an increase in psychiatric symptoms in TLE, a phenomenon known as forced normalization. In our study, we observed a low interictal spike frequency on EEG in TLE patients with mood disorders.

Significance

A low spike index might be a neurophysiological marker for depression in temporal lobe epilepsy.     

The association of depression and anxiety with medical symptom burden in patients with chronic medical illness

BACKGROUND: Primary care patients with anxiety and depression often describe multiple physical symptoms, but no systematic review has studied the effect of anxiety and depressive comorbidity in patients with chronic medical illnesses. METHODS: MEDLINE databases were searched from 1966 through 2006 using the combined search terms diabetes, coronary artery disease (CAD), congestive heart failure (CHF), asthma, COPD, osteoarthritis (OA), rheumatoid arthritis (RA), with depression, anxiety and symptoms. Cross-sectional and longitudinal studies with >100 patients were included as were all randomized controlled trials that measure the impact of improving anxiety and depressive symptoms on medical symptom outcomes. RESULTS: Thirty-one studies involving 16,922 patients met our inclusion criteria. Patients with chronic medical illness and comorbid depression or anxiety compared to those with chronic medical illness alone reported significantly higher numbers of medical symptoms when controlling for severity of medical disorder. Across the four categories of common medical disorders examined (diabetes, pulmonary disease, heart disease, arthritis), somatic symptoms were at least as strongly associated with depression and anxiety as were objective physiologic measures. Two treatment studies also showed that improvement in depression outcome was associated with decreased somatic symptoms without improvement in physiologic measures. CONCLUSIONS: Accurate diagnosis of comorbid depressive and anxiety disorders in patients with chronic medical illness is essential in understanding the cause and in optimizing the management of somatic symptom burden.     

Diagnosis and treatment of temporal lobe epilepsy

Of the 1,200,000 Americans with partial epilepsy, temporal lobe epilepsy (TLE) occurs in more than 400,000. Temporal lobe seizures are usually stereotypic in their symptoms and duration. A typical sequence is an aura followed by arrest of motor behavior, blank stare, and automatisms. Patients with TLE often show impairments in attention, memory, mental processing speed, executive functions, mood, personality, and drive-related behaviors. Interictal depression occurs in approximately one third of TLE patients. TLE is diagnosed by a history of characteristic partial seizure symptoms. The diagnosis is confirmed by the capture of a typical episode during an electroencephalogram (EEG) or video-EEG, with epileptiform activity over one or both temporal regions. Video-EEG monitoring has revolutionized diagnosis and should be considered in patients in whom diagnosis is uncertain. TLE is treated with medications, resective surgery, and vagus nerve stimulation. Epilepsy surgery should be considered in all patients with refractory partial epilepsy.     

Equality of the psychological model underlying depressive symptoms in patients with temporal lobe epilepsy versus heterogeneous neurological disorders

Controversy surrounds the question of whether there is a specific pattern of psychopathology or personality style observed in patients with temporal lobe epilepsy (TLE) or whether the symptoms of psychological distress reflect a common disorder such as depression. Measurement equivalence was examined to test the hypothesis that the latent variable model underlying scores on the Beck Depression Inventory (BDI) was equivalent across samples of patients with TLE (n = 187) and patients with heterogeneous neurological disorders (n = 150). A well-replicated model of depression or psychological distress comprising three related variables, negative attitude, performance difficulty, and somatic elements, displayed a pattern of strict metric invariance. This result suggests that the same set of latent variables is measured with the same metric relationship between item scores and latent variables in patients with TLE and in patients with heterogeneous neurological disorders.     

Depression and Anxiety in Patients with Epilepsy

The aim of this investigation was to study the interaction between depression/anxiety and epilepsy. One hundred fifty individuals with partial epilepsy, 70 with idiopathic generalized epilepsy, and 100 controls were administered two self-rating mood questionnaires (Zung and Stai) for the evaluation of depression and anxiety, respectively. The group with epilepsy was much more severely impaired than the controls according to both mood questionnaires; the patients with partial epilepsy, especially those with temporal lobe epilepsy (TLE), were more depressed and anxious than the patients with generalized epilepsy. The group with left TLE appeared to have the highest levels of depression and anxiety. The final results of our study confirmed that some mood disorders are common throughout the epilepsy population, especially in patients with left TLE. No correlation was noted between the frequency of seizures and onset of epilepsy and the results of the mood questionnaires. Moreover, no differences were found in depression and anxiety between males and females among both left focus and right focus epilepsy patients.     

Coping measurement and the state effect of depression and anxiety in psychiatric outpatients

The relationship between coping styles and mental health has received considerable attention, but the state effects on coping measures in a clinical sample are not well known. This study investigated changes in scores on the Coping Inventory for Stressful Situations between two treatment phases (acute and remitted phase) in 49 outpatients with major depression or anxiety disorders. Task-oriented coping changed significantly between the treatment phases in both depressive and anxious patients, as analyzed by two-way multivariate analysis of variance. Results from repeated measures of multivariate analysis of covariance indicated that task-oriented coping was influenced by depression and emotion-oriented coping was influenced by anxiety. Avoidance-oriented coping did not change significantly over time in either depressive or anxiety disorders controlled for depressive and anxiety symptoms. The results of this study suggest that depressive or anxiety symptoms and treatment phase affect coping measurement.     

The relation between anger management style, mood and somatic symptoms in anxiety disorders and somatoform disorders

The objective of this study was to examine the relationship between anger management style, depression, anxiety and somatic symptoms in anxiety disorder and somatoform disorder patients. The subjects comprised 71 patients with anxiety disorders and 47 with somatoform disorders. The level of anger expression or anger suppression was assessed by the Anger Expression Scale, the severity of anxiety and depression by the Symptom Checklist-90-Revised (SCL-90-R) anxiety and depression subscales, and the severity of somatic symptoms by the Somatization Rating Scale and the SCL-90-R somatization subscale. The results of path analyses showed that anger suppression had only an indirect effect on somatic symptoms through depression and anxiety in each of the disorders. In addition, only anxiety had a direct effect on somatic symptoms in anxiety disorder patients, whereas both anxiety and depression had direct effects on somatic symptoms in somatoform disorder patients. However, the anxiety disorder group showed a significant negative correlation between anger expression and anger suppression in the path from anger-out to anger-in to depression to anxiety to somatic symptoms, unlike the somatoform disorder group. The results suggest that anger suppression, but not anger expression, is associated with mood, i.e. depression and anxiety, and somatic symptoms characterize anxiety disorder and somatoform disorder patients. Anxiety is likely to be an important source of somatic symptoms in anxiety disorders, whereas both anxiety and depression are likely to be important sources of somatic symptoms in somatoform disorders. In addition, anger suppression preceded by inhibited anger expression is associated with anxiety and somatic symptoms in anxiety disorders.     

Depressive Symptomatology in a General Hospital Sample of Outpatients with Temporal Lobe Epilepsy: A Controlled Study

Summary: We compared temporal lobe epilepsy (TLE) outpatients attending a general hospital with depressed psychiatric patients and normal control subjects to investigate depressive symptomatology. Both clinicianrated measures and self-report questionnaires were used. Rates of depressive and anxious symptomatology in TLE subjects were higher than those in a normal control sample, but TLE subjects did not differ significantly from controls on anxiety measures. The depressed psychiatric group scored higher than the TLE and control groups on both depression and anxiety measures. Rates of depressive symptomatology in the TLE group were lower than those reported in previous studies for persons attending specialist epilepsy clinics, but similar to the findings of one community study.     

Relationships among pain, anxiety, and depression in primary care

Pain, anxiety, and depression are commonly seen in primary care patients and there is considerable evidence that these experiences are related. This study examined associations between symptoms of pain and symptoms and diagnoses of anxiety and depression in primary care patients. Results indicate that primary care patients who endorse symptoms of muscle pain, headache, or stomach pain are approximately 2.5-10 times more likely to screen positively for panic disorder, generalized anxiety disorder, or major depressive disorder. Endorsement of pain symptoms was also significantly associated with confirmed diagnoses of several of the anxiety disorders and/or major depression, with odds ratios ranging from approximately 3 to 9 for the diagnoses. Patients with an anxiety or depressive disorder also reported greater interference from pain. Similarly, patients endorsing pain symptoms reported lower mental health functioning and higher scores on severity measures of depression, social anxiety, and posttraumatic stress disorder. Mediation analyses indicated that depression mediated some, but not all of the relationships between anxiety and pain. Overall, these results reveal an association between reports of pain symptoms and not only depression, but also anxiety. An awareness of these relationships may be particularly important in primary care settings where a patient who presents with reports of pain may have an undiagnosed anxiety or depressive disorder.     

The NR1 N-methyl-D-aspartate subunit and brain-derived neurotrophic factor in temporal lobe epilepsy hippocampus: a comparison of patients with and without coexisting psychiatric symptoms

PURPOSE: The glutamate N-methyl-D-aspartate (NMDA) receptor and the neurotrophin brain-derived neurotrophic factor have been implicated in the pathophysiology of schizophrenia and depression. Since these psychiatric disorders are common in temporal lobe epilepsy (TLE), a comparison of TLE patients with and without coexisting psychiatric symptoms may be useful to unravel pathophysiologic mechanisms for psychosis or depression. METHODS: We used immunoautoradiography to assess the NR1 NMDA receptor subunit and brain-derived neurotrophic factor in resected TLE hippocampus. RESULTS: No changes relative to comparison controls were found for TLE patients with schizophrenia-like psychosis or depression. Increased NR1 was found in the dentate molecular layer in the dysphoria group and unmedicated depressed patients. CONCLUSIONS: An increase in NR1 protein in the dentate molecular layer suggests an upregulation of NMDA receptors in granule cells in TLE patients with dysphoria and depression. This finding is compatible with the theory that increased NMDA receptor function is involved in the pathogenesis of depression and that antidepressants may act by opposing this mechanism.     

Psychiatric disorders in temporal lobe epilepsy: An overview from a tertiary service in Brazil

PurposeTo evaluate the frequency and intensity of psychiatric disorders in a group of temporal lobe epilepsy (TLE) patients from a tertiary-care center.MethodsClinical and sociodemographic data of 73 patients were collected and a neuropsychiatric evaluation was performed with the following instruments: Mini-Mental State Examination (MMSE), structured clinical interview (MINI-PLUS), Hamilton Anxiety Scale (HAM-A), Hamilton Depression Scale (HAM-D), Brief Psychiatric Rating Scale (BPRS).ResultsPatients with TLE showed a high frequency of lifetime psychiatric disorders (70%), the most frequent being mood disorders (49.3%). At assessment, 27.4% of the patients were depressed and 9.6% met criteria for bipolar disorder. Nevertheless, depression had not been properly diagnosed nor treated. Anxiety disorders were also frequent (42.5%), mainly generalized anxiety disorder (GAD) (21.9%). Obsessive compulsive disorder (OCD) was present in 11.0% and psychotic disorders in 5.5% of the sample. Patients with left mesial temporal sclerosis (LMTS) exhibited more psychopathologic features, mainly anxiety disorders (p = 0.006), and scored higher on HAM-A and HAM-D (p < 0.05 in both).ConclusionTLE is related to a high frequency of psychiatric disorders, such as anxiety and depression, which are usually underdiagnosed and undertreated. Damage to the left mesial temporal lobe, seen in LMTS, seems to be an important pathogenic lesion linked to a broad range of psychopathological features in TLE, mainly anxiety disorders. The present study prompts discussion on the recognition of the common psychiatric disorders in TLE, especially on the Brazilian setting.     

Symptomatic and syndromal anxiety in chronic forms of major depression: effect of nefazodone,cognitive behavioral analysis system of psychotherapy,and their combination

BACKGROUND: Limited information is available on treatment response of anxiety symptoms in chronic forms of major depression. Concurrent anxiety disorders are prevalent in chronic depression, but the responsiveness of patients with such comorbidity to different treatments is largely unknown. This study investigated the comparative efficacy of nefazodone, Cognitive Behavioral Analysis System of Psychotherapy (CBASP), and their combination in improving anxiety symptoms in patients with chronic forms of major depression, including those with a concurrent anxiety disorder. METHOD: 681 patients with chronic major depressive disorder (DSM-IV criteria) participated in a multicenter study of 12 weeks of acute treatment with nefazodone (N = 226), CBASP (N = 228), or the combination (N = 227). The Hamilton Rating Scale for Anxiety (HAM-A), the HAM-A psychic anxiety factor, and the anxiety/arousal subscale of the 30-item Inventory for Depressive Symptomatology-Self Report (IDS-SR-30) were used to assess anxiety symptoms. RESULTS: In the full sample. without controlling for change in depressive symptoms, combination therapy was superior to both monotherapies on all 3 anxiety measures both in the rate of change and at endpoint. When change in depressive symptoms was controlled for, there were no treatment differences in rate of change from baseline to week 12 on any of the 3 anxiety measures. In those patients with a concurrent anxiety disorder, however, the combination was superior to CBASP on the HAM-A and the IDS-SR-30. Nefazodone alone and combination therapy were both superior to CBASP on the HAM-A psychic anxiety factor. CONCLUSION: For patients with chronic depression, combination therapy is superior to CBASP or nefazodone alone. Among patients with a concurrent anxiety disorder, nefazodone. either alone or in combination with CBASP, improves anxiety symptoms faster than CBASP alone, independent of depressive symptom reduction.     

Impulsivity and internalizing disorders in childhood

Impulsivity has often been related to externalizing disorders, but little is known about how it is related to symptoms of internalizing disorders. This study aims to examine the relationship between impulsivity and depression and anxiety symptoms of depression and anxiety in childhood, and compare it with its relationship with a measure of aggressive behavior, which is present in many externalizing disorders. We administered the Barratt Impulsiveness Scale-11 for children, the Children's Depression Inventory and the Screen for Children's Anxiety Related Emotional Disorders to a case-control sample of 562 children aged between 9 and 13 who were selected from an epidemiological study of anxiety and depression and whose teachers provided information about their proactive and reactive aggression. Impulsivity was related to measures of anxiety, depression and aggressive behavior, and showed higher relationships with measures of internalizing symptoms than with aggression. Motor impulsivity, a component of impulsivity related to inhibition deficits, was the component most related to anxiety and depression. Cognitive impulsivity, on the other hand, was negatively related to anxiety and depression. The relationships between impulsivity and symptoms of internalizing disorders seem to indicate that impulsivity should be taken into account not only in externalizing problems, but also in depression and anxiety in children and adolescents.     

Depression and anxiety before and after temporal lobe epilepsy surgery.

PURPOSE: To examine the course of depression and anxiety in patients with temporal lobe epilepsy (TLE) treated with epilepsy surgery (and anticonvulsant drugs) or medical means alone. METHODS: Of 94 TLE patients evaluated for epilepsy surgery, 76 underwent a resective procedure, 18 continued on medical treatment alone. Depression (Beck Depression Inventory (BDI)) and anxiety scores (Self-Rating Anxiety Scale (SRAS)) were examined during presurgical evaluation (T1) and after a mean of 16 months (T2), or 12 months after surgery. Depression and anxiety scores were related to type of intervention, underlying epileptogenic lesion, change of seizure control and anticonvulsant therapy. RESULTS: At T1, depression and anxiety scores were higher in patients with TLE than scores in published normal populations. At T2, depression but not anxiety scores were significantly lower than at T1. Change of depression scores interacted with improvements of seizure control. CONCLUSIONS: Evidence of depression and anxiety is commonly found in patients with TLE. Depression improves not because of epilepsy surgery per se, but because of improved seizure control. This is more commonly achieved by surgery than medical treatment. The results are consistent with the hypothesis that depression in TLE is caused by pathological epileptic activity rather than a fixed structural defect.     

Clinical correlates of pathological gambling symptoms in patients with epilepsy

Pathological gambling symptoms (PGS), that is, the subjective urge to gamble and the actual gambling behaviors, are currently acknowledged as relatively common symptoms among Western countries, with an estimated point prevalence of 0.6–1.1% in the general population. Converging evidence suggests that PGS are overrepresented in patients with neurological conditions affecting dopaminergic reward pathways, and can be expressed in both impulse control disorders and obsessive-compulsive spectrum disorders. This study explored the clinical correlates of PGS in patients with epilepsy. Eighty-eight consecutive adult outpatients recruited at three epilepsy clinics in northern Italy were assessed using the Gambling-Symptom Assessment Scale (G-SAS), along with a battery of psychometric instruments to index depression (Beck Depression Inventory [BDI]), anxiety (Spielberger State-Trait Anxiety Inventory [STAI]), and obsessionality (Yale-Brown Obsessive Compulsive Scale [YBOCS]) symptoms. On the G-SAS, patients with a diagnosis of temporal lobe epilepsy (TLE) reported a mean [sd] G-SAS score of 2.0 [5.7], significantly higher than patients with frontal lobe epilepsy (FLE) (0.6 [1.7]) and idiopathic generalized epilepsy (IGE) (0.4 [1.4]). Moreover, multiple regression analysis showed that G-SAS scores were selectively predicted by YBOCS scores, thus suggesting an association between the expression of obsessional spectrum symptoms and PGS in patients with TLE. Alterations in the mesolimbic reward system could represent the putative neuropathological substrate for this multifaceted clinical picture.     

Migraine, psychiatric disorders, and suicide attempts: an epidemiologic study of young adults

To determine the prevalence of migraine and the risks for psychiatric disorders and suicide attempts associated with it, we studied a random sample of 1,007 young adults from a large Health Maintenance Organization in the Detroit, MI area. The lifetime prevalence of migraine was 7% in males and 16.3% in females. The rate of migraine was higher in persons with lower education and was equal in whites and blacks. Persons with migraine were at increased risk for affective and anxiety disorders, nicotine dependence, and alcohol or illicit drug abuse or dependence. There was a consistent trend toward higher psychiatric comorbidity in migraine with aura than in migraine without aura. Coexisting anxiety, which generally preceded migraine, was associated with a marked increase in the odds of major depression. Persons with migraine had higher rates of suicide attempts than persons without migraine. The odds ratio for suicide attempts, adjusted for coexisting major depression and other psychiatric and substance use disorders, in migraine with aura was 3.0 (95% confidence interval, 1.4-6.6). The coexistence of migraine with major depression, anxiety disorders, and suicide attempts has important clinical and research implications.     

Pilot study of anxiety and depression in prepubertal children

Early detection of anxiety and depression is important because of the relationship between these disorders, suicide and other problems (i.e. social, phobias, learning problems). This study screened prepubertal students in a school setting for symptoms of anxiety and depression using self-report measures (Revised Children's Manifest Anxiety Scale and the Children's Depression Inventory). Controls and children who scored high on measures of anxiety or depression or both were interviewed with their parents and were tested using the Diagnostic Interview for Children and Adolescents (computer version) and the Peabody Individual Achievement Test. Initial results indicated that anxiety is more prevalent in prepubertal children than depression. The correlation between different diagnostic measurements used in this project was calculated. A correlation was found between low scores of self-esteem and high scores of anxiety and depression on self-reports. It is concluded that self-report measures are good screening tools.     

Mixed anxiety depression should not be included in DSM-5

Subthreshold anxiety and subthreshold depressive symptoms often co-occur in the general population and in primary care. Based on their associated significant distress and impairment, a psychiatric classification seems justified. To enable classification, mixed anxiety depression (MAD) has been proposed as a new diagnostic category in DSM-5. In this report, we discuss arguments against the classification of MAD. More research is needed before reifying a new category we know so little about. Moreover, we argue that in patients with MAD symptoms and a history of an anxiety or depressive disorder, symptoms should be labeled as part of the course trajectories of these disorders, rather than calling it a different diagnostic entity. In patients with incident co-occurring subthreshold anxiety and subthreshold depression, subthreshold categories of both anxiety and depression could be classified to maintain a consistent classification system at both threshold and subthreshold levels.     

Factors associated with generic and disease-specific quality of life in temporal lobe epilepsy

PURPOSE: We aimed at further elucidating the association between quality of life (QOL) and sociodemographic factors, clinical seizure factors, depression and anxiety in drug-resistant temporal lobe epilepsy (TLE). METHODS: We studied 106 consecutive adult right-handed patients (mean age 35.4 +/- 9.7; 50% males; IQ> or = 70) with drug-resistant unilateral (59% right) TLE (70% hippocampal sclerosis, 30% tumors or other lesions), who underwent a comprehensive non-invasive pre-surgical protocol. They completed the Beck Depression Inventory (BDI) and the State Form of the Spielberger State-Trait Anxiety Inventory (STAI). To measure QOL, we used both a generic instrument, the WHOQOL-100, and a disease-specific instrument, the 31-item quality of life in epilepsy (QOLIE-31). Multiple linear regression analysis was used to examine the relationship between each QOL domain and age, gender, education, side of TLE, duration of epilepsy, seizure frequency, and level of depression and anxiety. RESULTS: Severity of depressive symptoms was significantly associated with lower scores across most QOL domains. Depression was consistently the strongest predictor of lower scores on almost all QOL domains. Also, severity of anxiety symptoms was significantly associated with lower scores across many QOL domains. Independent significant relationships between QOL and sociodemographic or clinical epilepsy variables were limited in number and strength. CONCLUSIONS: Our findings suggest that QOL in TLE might be substantially affected by the presence and severity of depressive symptoms and, to a lesser degree, of anxiety symptoms. While clinical seizure variables had a weaker association with QOL, the absence of seizure-free patients might have obscured a relation between seizure frequency and QOL. Healthcare professionals should be aware of the significance of patients' emotional state and of the role it plays for their QOL. Adopting a biopsychosocial approach might be useful to address patients' needs.