Comorbid migraine with aura, anxiety, and depression is associated with dopamine D2 receptor (DRD2) NcoI alleles.

BACKGROUND: Unrelated individuals (n = 242) were interviewed directly for the presence of migraine, anxiety disorders, and major depression. MATERIALS AND METHODS: The data described in this study are derived from a clinical genetic relational database that was developed initially for the genetic analysis of migraine. Genotyping of the DRD2 NcoI C to T polymorphism located in exon 6 (His313His) was performed using previously described primers. RESULTS: A significantly increased incidence of migraine with aura (MWA), major depression, generalized anxiety disorder (GAD), panic attacks, and phobia was observed in individuals with the DRD2 NcoI C/C genotype compared with individuals with an DRD2 NcoI T allele. Specifically, 69% (91/131) of DRD2 NcoI C/C individuals in the present study met criteria for at least one of these neuropsychiatric disorders versus only 22% (4/18) of the DRD2 NcoI T/T individuals (Chi-square = 15.29; p < 0.00005). The DRD2 NcoI C allele frequency is significantly higher (Chi-square = 17.13; p < 0.00002) in individuals with MWA, anxiety disorders, and/or major depression (C allele frequency = 0.80) than in individuals who have none of these disorders (C allele frequency = 0.67). CONCLUSIONS: These data indicate that MWA, anxiety disorders, and major depression can be components of a distinct clinical syndrome associated with allelic variations within the DRD2 gene. Clinical recognition of this genetically based syndrome has significant diagnostic and therapeutic implications.     

Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

The activity‐regulated cytoskeleton‐associated protein (Arc, also known as Arg3.1) regulates glutamatergic synapse plasticity and has been linked to neuropsychiatric illness; however, its role in behaviors associated with mood and anxiety disorders remains unclear. We find that stress upregulates Arc expression in the adult mouse nucleus accumbens (NAc)—a brain region implicated in mood and anxiety behaviors. Global Arc knockout mice have altered AMPAR‐subunit surface levels in the adult NAc, and the Arc‐deficient mice show reductions in anxiety‐like behavior, deficits in social novelty preference, and antidepressive‐like behavior. Viral‐mediated expression of Arc in the adult NAc of male, global Arc KO mice restores normal levels of anxiety‐like behavior in the elevated plus maze (EPM). Consistent with this finding, viral‐mediated reduction of Arc in the adult NAc reduces anxiety‐like behavior in male, but not female, mice in the EPM. NAc‐specific reduction of Arc also produced significant deficits in both object and social novelty preference tasks. Together our findings indicate that Arc is essential for regulating normal mood‐ and anxiety‐related behaviors and novelty discrimination, and that Arc's function within the adult NAc contributes to these behavioral effects.     

Human stiff-person syndrome IgG induces anxious behavior in rats

Background

Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear.

Methodology/Principal Findings

We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient''s amygdala/hippocampus complex. No motor abnormalities were found in recipient rats.

Conclusion/Significance

The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region.     

Cerebrospinal fluid,plasma, and urinary MHPG in children

Cerebrospinal fluid (CSF) free MHPG levels for six autistic and four medicated Tourette Syndrome (TS) patients are in the usual adult range, but levels are elevated in two recently medicated TS patients. Plasma free MHPG levels in unmedicated autistic and TS patients are similar to those in normal boys, but are increased in two of seven medicated TS patients. There is a strong association between plasma free MHPG and urinary total MHPG levels in normal boys. Age and total urinary MHPG are positively correlated in autistic children. MHPG appears to be a useful index of noradrenergic function in childhood neuropsychiatric disorders.     

Biochemical,Histopathological and Morphological Profiling of a Rat Model of Early Immune Stimulation: Relation to Psychopathology

Perinatal immune challenge leads to neurodevelopmental dysfunction, permanent immune dysregulation and abnormal behaviour, which have been shown to have translational validity to findings in human neuropsychiatric disorders (e.g. schizophrenia, mood and anxiety disorders, autism, Parkinson’s disease and Alzheimer’s disease). The aim of this animal study was to elucidate the influence of early immune stimulation triggered by systemic postnatal lipopolysaccharide administration on biochemical, histopathological and morphological measures, which may be relevant to the neurobiology of human psychopathology. In the present study of adult male Wistar rats we examined the brain and plasma levels of monoamines (dopamine, serotonin), their metabolites, the levels of the main excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid and the levels of tryptophan and its metabolites from the kynurenine catabolic pathway. Further, we focused on histopathological and morphological markers related to pathogenesis of brain diseases - glial cell activation, neurodegeneration, hippocampal volume reduction and dopaminergic synthesis in the substantia nigra. Our results show that early immune stimulation in adult animals alters the levels of neurotransmitters and their metabolites, activates the kynurenine pathway of tryptophan metabolism and leads to astrogliosis, hippocampal volume reduction and a decrease of tyrosine hydroxylase immunoreactivity in the substantia nigra. These findings support the crucial pathophysiological role of early immune stimulation in the above mentioned neuropsychiatric disorders.     

Omega-3 fatty acids and neuropsychiatric disorders

Epidemiological evidence suggests that dietary consumption of the long chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), commonly found in fish or fish oil, may modify the risk for certain neuropsychiatric disorders. As evidence, decreased blood levels of omega-3 fatty acids have been associated with several neuropsychiatric conditions, including Attention Deficit (Hyperactivity) Disorder, Alzheimer's Disease, Schizophrenia and Depression. Supplementation studies, using individual or combination omega-3 fatty acids, suggest the possibility for decreased symptoms associated with some of these conditions. Thus far, however, the benefits of supplementation, in terms of decreasing disease risk and/or aiding in symptom management, are not clear and more research is needed. The reasons for blood fatty acid alterations in these disorders are not known, nor are the potential mechanisms by which omega-3 fatty acids may function in normal neuronal activity and neuropsychiatric disease prevention and/or treatment. It is clear, however, that DHA is the predominant n-3 fatty acid found in the brain and that EPA plays an important role as an anti-inflammatory precursor. Both DHA and EPA can be linked with many aspects of neural function, including neurotransmission, membrane fluidity, ion channel and enzyme regulation and gene expression. This review summarizes the knowledge in terms of dietary omega-3 fatty acid intake and metabolism, as well as evidence pointing to potential mechanisms of omega-3 fatty acids in normal brain functioning, development of neuropsychiatric disorders and efficacy of omega-3 fatty acid supplementation in terms of symptom management.     

The complex roles of neurosteroids in depression and anxiety disorders

The role of neurosteroids in neuropsychiatric disorders has been thoroughly investigated in many research studies that have stressed their significant pathophysiological function in neuropsychiatry. In this review, we will focus mainly on the steroids active on the GABA(A) receptors studied in anxiety and depression. The aim is to discuss the controversial results reported in research on anxiety and depressive disorders. We suggest the combined use of biological parameters linked to psychopathological dimensions to make more homogeneous diagnoses and to develop more precise therapies for the treatment of depression and anxiety disorders. We discuss the role of neurosteroids in the pathophysiology and therapy of anxiety and depression. Finally, we consider the possibility of using quantification of mRNA expression of steroidogenic enzymes from peripheral sources in neuropsychiatry.     

Thyrotropin-releasing hormone and cyclo (His-Pro)-like immunoreactivities in the cerebrospinal fluids of 'normal' infants and adults, and patients with various neuropsychiatric and neurologic disorders

Levels of thyrotropin-releasing hormone (TRH) - and cyclo(His-Pro) (CHP)-like immunoreactivities and the activity of enzyme Pyroglutamate aminopeptidase (PAPase) were measured in cerebrospinal fluid (CSF) of over 100 normal adults (NA) and infants, and adult patients with various neurologic and neuropsychiatric disorders (NNDA). Levels of TRH and CHP in CSF of over 70% of the NA group were below 50 and 500 pg/ml respectively. The TRH- and CHP-like immunoreactivities in the remainder of the 30% of NA specimens exhibiting higher peptide concentrations were enzymatically and chromatographically characterized and were found to behave like authentic peptides. The levels of both of these peptides were significantly elevated in the CSF of most of the NNDA patients. An elevation in the CSF level of CHP was significantly correlated with the level of TRH, but not PAPase. Results from this study suggest that CSF elevation of TRH level may be due to a nonspecific response to stress that may be associated with hospitalization, myelogram procedure, and/or the neurologic and neuropsychiatric diseases for which the patients were admitted.     

The Hypersomnic Syndrome: (Classification,Clinical Aspects,Pathogenesis, Treatment)

In neurological practice one often encounters various forms of disturbances of the waking state. Sometimes somnolence is one of the manifestations of a pathological process, and in others it is the major and dominant symptom bringing the patient to the doctor. Our experience in the study of hypersomnia (we have observed 120 patients in recent years) demonstrates that physicians have inadequate familiarity with this problem. Sometimes somnolence is regarded not as the result of pathology, but as a manifestation of excessive fatigue. There is inadequate differentiation of the forms of hypersomnic disorders. One of the causes of these errors is the absence of a logical classification. The most thorough classification is that of A. Epshtein, (1) etiological in nature: 1) random sleep disorders; 2) secondary sleep disorders; 3) constitutional neuropathic; 4) reactive; 5) symptomatic; 6) essential disorders; and 7) sleep disorders associated with psychosis. It has become obsolete, and does not cover the clinical forms of hypersomnia. We have deemed it desirable to make a classification based on clinical principles, with due consideration for etiology.     

Younger and older chronic somatoform pain patients in psycho-diagnostics,physician-patient relationship and treatment outcome

Introduction

Patients with chronic pain are found with highly variable clinical presentation and differing physical complaints. They are seen as a heterogenic group. Based on clinical observations, elderly patients seem to differ from younger patients with chronic pain. We examined whether there were systematic differences between young and old pain patients.

Methods

As part of a routine evaluation of university hospital care, a newly developed psychosomatic treatment model for chronic somatoform pain disorders was examined. The basis for treatment efficacy was a target-oriented, specific somatic and psychological intervention that included a stable physician-patient relationship. Particular attention was paid to differences in treatment outcome with regard to changes in both physical and psychopathological symptom levels. We hypothesised that younger pain patients had higher psychological burden and benefitted more from our treatment than older pain patients.

Results

Overall, 179 inpatients (57.5% women) with chronic pain were examined (age between 16 and 79 years). The group as a whole yielded high scores on the somatisation dimension (SCL-90) and showed a considerable amount of psychopathological symptoms, such as depressive mood and anxiety (HADS) and a great emotional instability (FPI-R). Age differences were only found with regards to patients’ degree of aggression (SCl-90): younger patients showed higher aggressive tendencies than older ones (p< 0.05). The treatment offered helped patients in both age groups especially with regard to reduction of depressive mood (HADS, p< 0.01) and anxiety levels (HADS, p< 0.01). Regression analysis showed different age groups and gender as significant predictors of anxiety reduction under therapy (R²=.108; model: p< 0.01).

Discussion and conclusion

Results show that younger chronic pain patients suffer more from a considerable amount of psychological distress than older ones, but our treatment approach was equally effective in both groups. However, age and gender differences, as well as the patient’s baseline level of anxiety influenced the outcome. These factors need to be studied in future research.

     

Dissociated deficits in attentional networks in social anxiety and depression

A critical cognitive symptom that is commonly involved in social anxiety and depression is attentional deficit. However, the functional relationship between attentional deficit and these two disorders remains poorly understood. Here, we behaviorally disentangled the three key attentional components(alerting, orienting, and executive control) using the established attentional network task(ANT) to investigate how social anxiety and depression are related to deficits in these attention components. We identified a double dissociation between the symptoms of social anxiety and depression and the attentional component deficits when processing non-emotional stimuli. While individuals vulnerable to social anxiety exhibited deficits in the orienting component, individuals vulnerable to depression were impaired in the executive control component. Our findings showed that social anxiety and depression were associated with deficits in different attentional components, which are not specific to emotional information.     

Childhood and persistent ADHD symptoms associated with educational failure and long-term occupational disability in adult ADHD

Few studies have examined the impact of childhood attention deficit hyperactivity disorder (ADHD) symptoms on adult ADHD functional outcomes. To address this issue dimensionally, ADHD symptoms in childhood and adulthood and their relation to educational deficits and work disability are studied in a clinical sample of adult patients with previously untreated ADHD. About 250 adults diagnosed systematically with ADHD according to DSM-IV were prospectively recruited. Primary outcomes were high school dropout and being out of the work last year. Childhood ADHD symptoms, sex differences, comorbidities of other mental disorders, and adult ADHD symptoms were examined by historical data, clinician interviews, and questionnaires. High levels of ADHD symptom severity in childhood were related to dropping out of high school [odds ratio (OR) = 3.0], as were higher numbers of hyperactive–impulsive symptoms in childhood. Significantly, more women than men were long-term work disabled (OR = 2.0). After adjusting for age and gender, persisting high levels of ADHD inattention symptoms in adulthood (OR = 2.5), number of comorbid disorders, and particularly anxiety disorders were significantly related to long-term work disability. Childhood hyperactive–impulsive symptoms and overall severity of childhood ADHD symptoms were associated with high school dropout rates; however, persisting ADHD inattention symptoms and comorbid mental disorders in adulthood were more correlated to occupational impairment. These findings underline proposals for studies on early recognition and interventions for ADHD and psychiatric comorbidity. They further suggest that inattentive symptoms be a focus of adult ADHD treatment and that workplace interventions be considered to prevent long-term work disability.     

Anxious or Depressed and Still Happy?

This study aimed to examine cross-sectionally to what extent persons with higher symptom levels or a current or past emotional disorder report to be less happy than controls and to assess prospectively whether time-lagged measurements of extraversion and neuroticism predict future happiness independent of time-lagged measurements of emotional disorders or symptom severity. A sample of 2142 adults aged 18–65, consisting of healthy controls and persons with current or past emotional disorder according to DSM-IV criteria completed self-ratings for happiness and emotional well-being and symptom severity. Lagged measurements of personality, symptom severity and presence of anxiety and depressive disorder at T0 (year 0), T2 (year 2) and T4 (year 4) were used to predict happiness and emotional well-being at T6 (year 6) controlling for demographics. In particular persons with more depressive symptoms, major depressive disorder, social anxiety disorder and comorbid emotional disorders reported lower levels of happiness and emotional well-being. Depression symptom severity and to a lesser extent depressive disorder predicted future happiness and emotional well-being at T6. Extraversion and to a lesser extent neuroticism also consistently forecasted future happiness and emotional well-being independent of concurrent lagged measurements of emotional disorders and symptoms. A study limitation is that we only measured happiness and emotional well-being at T6 and our measures were confined to hedonistic well-being and did not include psychological and social well-being. In sum, consistent with the two continua model of emotional well-being and mental illness, a ‘happy’ personality characterized by high extraversion and to a lesser extent low neuroticism forecasts future happiness and emotional well-being independent of concurrently measured emotional disorders or symptom severity levels. Boosting positive emotionality may be an important treatment goal for persons personally inclined to lower levels of happiness.     

Design, synthesis, and pharmacological evaluation of azetedine and pyrrolidine derivatives as dual norepinephrine reuptake inhibitors and 5-HT(1A) partial agonists

Compounds with combined norepinephrine reuptake inhibitor (NRI) and serotonin 1A (5-HT_1A) partial agonist pharmacology may offer a new therapeutic approach for treating symptoms of neuropsychiatric disorders including ADHD, depression, and anxiety. Herein we describe the design and optimization of novel chemical matter that exhibits favorable dual NRI and 5-HT_1A partial agonist activity. Lead compounds in this series were found to be devoid of activity at the dopamine transporter and were shown to be brain penetrant with high receptor occupancy.     

Neuropsychiatric symptoms in patients with aortic aneurysms

Background

Emerging evidence suggests that vascular disease confers vulnerability to a late-onset of depressive illness and the impairment of specific cognitive functions, most notably in the domains of memory storage and retrieval. Lower limb athero-thrombosis and abdominal aortic aneurysm (AAA) have both been previously associated with neuropsychiatric symptoms possibly due to associated intracerebral vascular disease or systemic inflammation, hence suggesting that these illnesses may be regarded as models to investigate the vascular genesis of neuropsychiatric symptoms. The aim of this study was to compare neuropsychiatric symptoms such as depression, anxiety and a variety of cognitive domains in patients who had symptoms of peripheral athero-thrombosis (intermittent claudication) and those who had an asymptomatic abdominal aortic aneurysm AAA.

Methodology/Principal Findings

In a cross-sectional study, 26 participants with either intermittent claudication or AAA were assessed using a detailed neuropsychiatric assessment battery for various cognitive domains and depression and anxiety symptoms (Hamilton Depression and Anxiety Scales). Student t test and linear regression analyses were applied to compare neuropsychiatric symptoms between patient groups. AAA participants showed greater levels of cognitive impairment in the domains of immediate and delayed memory as compared to patients who had intermittent claudication. Cognitive dysfunction was best predicted by increasing aortic diameter. CRP was positively related to AAA diameter, but not to cognitive function. AAA and aortic diameter in particular were associated with cognitive dysfunction in this study.

Conclusions/Significance

AAA patients are at a higher risk for cognitive impairment than intermittent claudication patients. Validation of this finding is required in a larger study, but if confirmed could suggest that systemic factors peculiar to AAA may impact on cognitive function.     

Subtypes of Ataques de Nervios: The Influence of Coexisting Psychiatric Diagnosis

The current study assesses the relationship between presenting symptomatology of the self-labeled Hispanic popular diagnosis of ataques de nervios and the specific co-morbid psychiatric diagnoses. Hispanic subjects seeking treatment at an anxiety disorders clinic (n = 156) were assessed with a specially designed self-report instrument for both traditional ataque de nervios and panic symptoms, and with structured or semi-structured psychiatric interviews for Axis-I disorders. This report focuses on 102 subjects with ataque de nervios who also met criteria for panic disorder, other anxiety disorders, or an affective disorder. Distinct ataque symptom patterns correlated with co-existing panic disorder, affective disorders, or other anxiety disorders. Individuals with both ataque and panic disorder reported the most asphyxia, fear of dying, and increased fear during their ataques. People with ataques who also met criteria for affective disorder reported the most anger, screaming, becoming aggressive, and breaking things during ataques. Ataque positive subjects with other anxiety disorders were less salient for both panic-like and emotional-anger symptoms. The findings suggest that (a) ataque de nervios is a popular label referring to several distinct patterns of loss of emotional control, (b) the type of loss of emotional control is influenced by the associated psychiatric disorder, and (c) ataque symptom patterns may be a useful clinical marker for detecting psychiatric disorders. Further study is needed to examine the relationship between ataque de nervios and psychiatric disorders, as well as the relationship to cultural, demographic, environmental, and personality factors.     

Effects of Methamphetamine Exposure on Fear Learning and Memory in Adult and Adolescent Rats

Methamphetamine (meth) use is often comorbid with anxiety disorders, with both conditions predominant during adolescence. Conditioned fear extinction is the most widely used model to study the fear learning and regulation that are relevant for anxiety disorders. The present study investigates how meth binge injections or meth self-administration affect subsequent fear conditioning, extinction and retrieval in adult and adolescent rats. In experiment 1, postnatal day 35 (P35—adolescent) and P70 (adult) rats were intraperitoneally injected with increasing doses of meth across 9 days. At P50 or P85, they underwent fear conditioning followed by extinction and test. In experiments 2a–c, P35 or P70 rats self-administered meth for 11 days then received fear conditioning at P50 or P85, followed by extinction and test. We observed that meth binge exposure caused a significant disruption of extinction retrieval in adult but not adolescent rats. Interestingly, meth self-administration in adolescence or adulthood disrupted acquisition of conditioned freezing in adulthood. Meth self-administration in adolescence did not affect conditioned freezing in adolescence. These results suggest that intraperitoneal injections of high doses of meth and meth self-administration have dissociated effects on fear conditioning and extinction during adulthood, while adolescent fear conditioning and extinction are unaffected.