GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

[Anxiety disorders: which psychotherapy for whom?] / Angsterkrankungen: Welche Psychotherapie für wen?

According to the Federal Healthcare Survey (Bundesgesundheitssurvey), approximately 15% of the German population fulfil the diagnostic criteria for at least one anxiety disorder within (any) 1 year. Women are affected approximately twice as often as men. The study by the Robert Koch Institute included the systematic assessment of panic disorder, agoraphobia, generalized anxiety disorder, social anxiety disorder and specific phobias; therefore, the question for both those affected and the treating therapist is "anxiety disorders: which psychotherapy for whom?" is of great clinical and healthcare political importance. We therefore review the available literature for answering three more specific questions: 1) what are the most suitable forms of psychotherapy, 2) which psychotherapy is most promising for an individual patient and diagnosis (differential evaluation of indications) and 3) what is the best approach to nonresponse or avoidance of the treatment offered? National and international guidelines agree that cognitive behavioral therapy is the psychotherapy of first choice in most patients with anxiety disorders. In cases of nonresponse or lack of availability of the appropriate therapy, psychodynamic therapy or pharmacotherapy can also be recommended. For individualized treatment recommendations we do not have empirical evidence. Also, no evidence-based (individual) recommendations are available for non-responders;however, there are some preferred strategies based on a clinical consensus.

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing.

Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here we aimed to evaluate CRHR1 as a risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk allele of rs17689918 led to less flight behavior during fear-provoking situations but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus reduced gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.

Dimensional structure of bodily panic attack symptoms and their specific connections to panic cognitions, anxiety sensitivity and claustrophobic fears.

BACKGROUND: Previous studies of the dimensional structure of panic attack symptoms have mostly identified a respiratory and a vestibular/mixed somatic dimension. Evidence for additional dimensions such as a cardiac dimension and the allocation of several of the panic attack symptom criteria is less consistent. Clarifying the dimensional structure of the panic attack symptoms should help to specify the relationship of potential risk factors like anxiety sensitivity and fear of suffocation to the experience of panic attacks and the development of panic disorder. METHOD: In an outpatient multicentre study 350 panic patients with agoraphobia rated the intensity of each of the ten DSM-IV bodily symptoms during a typical panic attack. The factor structure of these data was investigated with nonlinear confirmatory factor analysis (CFA). The identified bodily symptom dimensions were related to panic cognitions, anxiety sensitivity and fear of suffocation by means of nonlinear structural equation modelling (SEM). RESULTS: CFA indicated a respiratory, a vestibular/mixed somatic and a cardiac dimension of the bodily symptom criteria. These three factors were differentially associated with specific panic cognitions, different anxiety sensitivity facets and suffocation fear. CONCLUSIONS: Taking into account the dimensional structure of panic attack symptoms may help to increase the specificity of the associations between the experience of panic attack symptoms and various panic related constructs.

Mental health needs and availability of mental health care for children and adolescents with intellectual disability in Berlin.

BACKGROUND: The increased risk of mental health problems in children and adolescents with intellectual disability (ID) has been reported in several studies. However, almost no research has been conducted on parents' experiences with the general mental health system. We have investigated the prevalence of emotional and behavioural problems in children with ID as well as the availability and quality of mental health care from the parents' point of view. METHODS: Teachers of specialised schools for ID in Berlin were asked to complete the Teacher's Report Form (TRF) of the Child Behavior Checklist. Information was collected for 1226 children and adolescents aged 6-18 years with mild to profound ID (response 70.5%). The availability and quality of mental health care was assessed by a questionnaire given to parents who had already been seeking help for their children. A total of 330 parents completed the questionnaires (response 62.0%). In addition to univariate analysis, we conducted multiple logistic regressions regarding the psychopathology reported by teachers (TRF-syndrome scales) and difficulties concerning mental health care reported by parents for a paired sample of 308 children. RESULTS: Overall, 52.4% of the children and adolescents with ID had a total problem score on the TRF in the deviant range (47.1% when eliminating four items reflecting cognitive deficits). Compared with the general population normative sample of children, this is a three-time higher prevalence. The most striking problems were thought problems (schizoid and obsessive-compulsive), aggressive behaviour, attention problems and social problems. Parents whose children had more severe behavioural or emotional dysfunction reported more difficulties with the mental health system. From the parents' point of view, mental health professionals frequently did not feel responsible or were not sufficiently skilled for the treatment of children with ID. As a consequence, 96% of all parents were longing for specialised in- and outpatient services. CONCLUSIONS: This study confirms the findings from other studies regarding the high rate of co-occurrence of ID and mental health problems in youths. Results indicate that both are strongly requested by parents: specialised in- and outpatient services, as well as more professional general services and equitable treatment for all children, with and without ID.

Anticipating agoraphobic situations: the neural correlates of panic disorder with agoraphobia.

BACKGROUND: Panic disorder with agoraphobia is characterized by panic attacks and anxiety in situations where escape might be difficult. However, neuroimaging studies specifically focusing on agoraphobia are rare. Here we used functional magnetic resonance imaging (fMRI) with disorder-specific stimuli to investigate the neural substrates of agoraphobia. METHOD: We compared the neural activations of 72 patients suffering from panic disorder with agoraphobia with 72 matched healthy control subjects in a 3-T fMRI study. To isolate agoraphobia-specific alterations we tested the effects of the anticipation and perception of an agoraphobia-specific stimulus set. During fMRI, 48 agoraphobia-specific and 48 neutral pictures were randomly presented with and without anticipatory stimulus indicating the content of the subsequent pictures (Westphal paradigm). RESULTS: During the anticipation of agoraphobia-specific pictures, stronger activations were found in the bilateral ventral striatum and left insula in patients compared with controls. There were no group differences during the perception phase of agoraphobia-specific pictures. CONCLUSIONS: This study revealed stronger region-specific activations in patients suffering from panic disorder with agoraphobia in anticipation of agoraphobia-specific stimuli. Patients seem to process these stimuli more intensively based on individual salience. Hyperactivation of the ventral striatum and insula when anticipating agoraphobia-specific situations might be a central neurofunctional correlate of agoraphobia. Knowledge about the neural correlates of anticipatory and perceptual processes regarding agoraphobic situations will help to optimize and evaluate treatments, such as exposure therapy, in patients with panic disorder and agoraphobia.

Comparing augmentation with non-antidepressants over sticking to antidepressants after treatment failure in depression: a naturalistic study.

INTRODUCTION: Non-response to an antidepressant monotherapy in unipolar depression is quite common. Therefore strategies for subsequent treatment steps are necessary. However, there is a lack of direct comparisons of these different strategies. In this naturalistic study we compared the outcome to different strategies after failure of the primary antidepressant treatment. METHODS: Failure of primary antidepressant monotherapy occurred in 135 patients. 98 of these patients have been administered 4 treatment strategies of the physicians' choice: lithium augmentation (Li-Augm), switching to another antidepressant (AD-Switch), combination of 2 antidepressants (AD-Comb) or augmentation with second generation antipsychotic (SGA-Augm). Primary outcome measure was the 17-item Hamilton rating scale for depression (HRSD). RESULTS: Patients who received Li-Augm or augmentation with SGAs showed significantly greater improvement in HRSD and BDI compared to patients with antidepressant switch or antidepressant combination. Remission rates for Li-Augm and SGA-Augm were 89.3% and 86.2% compared to 40.7% for AD-Switch and 42.9% for AD-Comb. DISCUSSION: Changing to another pharmacological class (Li-Augm or augmentation with SGAs) showed better treatment results than sticking to the class of antidepressants (AD-Switch and AD-Comb) after primary failure in response to antidepressant monotherapy in unipolar depression. The lack of randomization and absence of a non-response definition are design flaws. Controlled studies are required to confirm the findings of this trial.

Physical fitness is associated with neural activity during working memory performance in major depressive disorder.

BACKGROUND: Deficits in cognition like working memory (WM) are highly prevalent symptoms related to major depressive disorder (MDD). Neuroimaging studies have described frontoparietal abnormalities in patients with MDD as a basis for these deficits. Based on research in healthy adults, it is hypothesized that increased physical fitness might be a protective factor for these deficits in MDD. However, the relationship between physical fitness and WM-related neural activity and performance has not been tested in MDD, to date. Understanding these associations could inform the development of physical exercise interventions in MDD. METHODS: Within a larger project, 111 (53female) MDD outpatients and 56 (34female) healthy controls performed an n-back task (0-, 1-, 2-, 3-back) during functional Magnetic Resonance Imaging. Physical fitness from a graded exercise test on a cycle ergometer was performed by 106 MDD patients. RESULTS: Patients showed reduced performance particularly at high loads of the n-back WM task and prolonged reaction times at all n-back loads. A whole-brain interaction analysis of group by WM load revealed reduced neural activity in six frontoparietal clusters at medium and high WM loads in MDD patients compared to healthy controls. Analysis of covariance within the MDD sample showed that physical fitness was associated with neural activity in right and left superior parietal lobules. Externally defined Regions of Interest confirmed this analysis. CONCLUSIONS: Results indicate frontoparietal hypoactivity in MDD at high demands, arguing for decreased WM capacity. We demonstrate a parietal fitness correlate which could be used to guide future research on effects of exercise on cognitive functioning in MDD.

A new paradigm (Westphal-Paradigm) to study the neural correlates of panic disorder with agoraphobia.

Agoraphobia (with and without panic disorder) is a highly prevalent and disabling anxiety disorder. Its neural complexity can be characterized by specific cues in fMRI studies. Therefore, we developed a fMRI paradigm with agoraphobia-specific stimuli. Pictures of potential agoraphobic situations were generated. Twenty-six patients, suffering from panic disorder and agoraphobia, and 22 healthy controls rated the pictures with respect to arousal, valence, and agoraphobia-related anxiety. The 96 pictures, which discriminated best between groups were chosen, split into two parallel sets and supplemented with matched neutral pictures from the International Affective Picture System. Reliability, criterion, and construct validity of the picture set were determined in a second sample (44 patients, 28 controls). The resulting event-related "Westphal-Paradigm" with cued and uncued pictures was tested in a fMRI pilot study with 16 patients. Internal consistency of the sets was very high; parallelism was given. Positive correlations of picture ratings with Mobility Inventory and Hamilton anxiety scores support construct validity. FMRI data revealed activations in areas associated with the fear circuit including amygdala, insula, and hippocampal areas. Psychometric properties of the Westphal-Paradigm meet necessary quality requirements for further scientific use. The paradigm reliably produces behavioral and fMRI patterns in response to agoraphobia-specific stimuli. To our knowledge, it is the first fMRI paradigm with these properties. This paradigm can be used to further characterize the functional neuroanatomy of panic disorder and agoraphobia and might be useful to contribute data to the differentiation of panic disorder and agoraphobia as related, but conceptually different clinical disorders.

[Comorbidity of chronic somatic illness and psychological disorders. Problems in outpatient mental health care]. / Komorbidität chronischer somatischer Erkrankung und psychischer Störungen. Problem in der ambulanten psychotherapeutischen Versorgung.

Especially when chronic, the presence of a somatic disorder is accompanied by various levels of psychological stress, which can range up to comorbidity with mental disorders. In addition, chronic somatic diseases and mental disorders are often interdependent. Treatment for persons with mental and somatic comorbidity is frequently offered in the context of medical rehabilitation. As skills of psychotherapists are concerned, comorbidity needs a bio-psychosocial approach in which knowledge of medicine, psychology, and social sciences is integrated. In addition to the expert skills of psychotherapists, interprofessional training, basic knowledge, and communication with physicians are necessary. The present article outlines conditions for outpatient psychotherapeutic care of persons with chronic somatic diseases and addresses central problems in the differential diagnosis of mental and somatic disorders as well as treatment indications when comorbidity is present. Selected examples for the diagnosis and treatment of patients with cardiovascular disorder and diabetes, respectively, illustrate these aspects.

Mechanism of action in CBT (MAC): methods of a multi-center randomized controlled trial in 369 patients with panic disorder and agoraphobia.

Cognitive behavioral therapy (CBT) is efficacious for panic disorder with agoraphobia (PD/A). Nevertheless, the active ingredients of treatment and the mechanisms through which CBT achieves its effects remain largely unknown. The mechanisms of action in CBT (MAC) study was established to investigate these questions in 369 patients diagnosed with PD/A. The MAC study utilized a multi-center, randomized controlled design, with two active treatment conditions in which the administration of exposure was varied, and a wait-list control group. The special feature of MAC is the way in which imbedded experimental, psychophysiological, and neurobiological paradigms were included to elucidate therapeutic and psychopathological processes. This paper describes the aims and goals of the MAC study and the methods utilized to achieve them. All aspects of the research design (e.g., assessments, treatment, experimental procedures) were implemented so as to facilitate the detection of active therapeutic components, and the mediators and moderators of therapeutic change. To this end, clinical, behavioral, physiological, experimental, and genetic data were collected and will be integrated.

[Diagnostic of personality disorders in adolescence according to SCID-II]. / Diagnostik von Persönlichkeitsstörungen im Jugendalter nach SKID-II.

OBJECTIVES: The aim of the present study was to ascertain whether the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II) is applicable for use with adolescents. Furthermore, the diagnostic concordance between SCID-II and the clinicians' estimations of personality disorders (PD) is assessed. In addition, we identified predicting factors for personality disorders in adolescent psychiatric inpatients. METHODS: 110 adolescent psychiatric inpatients aged 14-18 years were assessed by means of SCID-II and a personality and disorder inventory (PSSI). RESULTS: 32.7% of the inpatients met the criteria for PD according to SCID-II. While agreement between the presence of any PD based on SCID-II and that found according to clinicians' estimations was low, moderate and very good agreement between SCID-II and clinicians' estimations was found with regard to borderline PD and histrionic PD. Logistic regression analyses identified "anorexia nervosa (binge-purging)", "attention-deficit/hyperactivity disorder/conduct disorder (ADHD/CD)" and "socioeconomic status" as good predictors for PD. CONCLUSIONS: The SCID-II - which was primarily developed for use with adults - is suitable for use among adolescents. Anorexia nervosa (binge-purging type) and ADHD/CD are closely associated with the development of PD in adolescents.

Learn to forget: Does post-exposure administration of d-cycloserine enhance fear extinction in agoraphobia?

The use of d-cycloserine (DCS) to augment exposure based therapy for anxiety disorders has shown mixed, although overall positive effects. Aim of the present study was to examine post-exposure administration of DCS in patients with agoraphobia with or without panic disorder. 73 patients with agoraphobia (with or without panic disorder) were treated with 12 sessions of cognitive behavioral therapy (CBT) including 3 exposures. Following successful exposure patients were given double blind either placebo or 50 mg of DCS. Primary outcome criterion was change in the Panic and Agoraphobia Scale (PAS) between CBT session t1, t4 (+∼2 months), t10 (+∼3 months) und t11 (+∼4 months). During the course of CBT the patients' symptomatology decreased significantly as measured by primary and secondary outcome criteria, however, without an additional benefit for DCS treated patients. Exploratory sub-group analyses for severely ill patients and patients with high anxiety and strong habituation during exposure showed that DCS administration was associated with increased improvement during the 1-month follow-up period (t10 - t11) with medium to large effect sizes (range in effect size η2p from .06 to .25). Our study results are consistent with recent research on DCS, indicating a beneficial augmentative effect for sub-groups of anxiety patients. The lack of an overall DCS effect for the whole patient sample might be explained by a dual mechanism in fear conditioning and extinction with different cognitive processes being involved during exposure depending on the degree of anxiety experienced by the patient.

A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety.

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

Behavioral assessment of social performance: a rating system for social phobia.

The Social Performance Rating Scale (SPRS) is a modification of the rating system for behavioral assessment of social skills, originally developed by Trower, P., Bryant, B., & Argyle, M. (1978). Social skills and mental health. Pittsburgh: University of Pittsburgh Press) and subsequently adapted by Turner and colleagues (e.g., Turner, S.M., Beidel, D.C., Dancu, C.V., & Keys, D.J. (1986). Psychopathology of social phobia and comparison to avoidant personality disorder. Journal of Abnormal Psychology, 95, 389-394). Designed to yield ratings of social performance appropriate for use in a socially phobic population and based on videotaped role plays, the five SPRS ratings are gaze, vocal quality, speech length, discomfort, and conversation flow. The sum of these ratings provides an internally consistent total score. In an initial study of the psychometric properties of the SPRS, three groups were assessed: individuals with social phobia, another anxiety disorder, or no psychological disorder. Inter-rater reliability for individual items and the total score proved excellent, and positive evidence for convergent, divergent, and criterion-related validity was obtained.

The functional -1019C/G HTR1A polymorphism and mechanisms of fear.

Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n=185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n=245; after CBT: n=171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n=39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT-induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders.

[The Explanatory Model-Interview in the diagnosis of orthopaedic pain patients]. / Das Erklärungsmodell-Interview in der Diagnostik von orthopädischen Schmerzpatienten.

AIM: This study aims to clarify weather the Explanatory Model Interview (EMIC, Weiss, 1997) can detect differences between pain patients with somatoform disorders and pain patients without any psychiatric disorder. We consider the importance of psychological symptom reporting, somatic illness attribution and the subjective experience of exhaustion. METHODS: The (EMIC) and the Structured Clinical Interview for DSM-IV (SKID) were administered to 87 in-patients recruited from the pain therapy ward of the Orthopaedic Clinic in Heidelberg, Germany. The analysis of the EMIC strongly reflects interactional factors and the subjective importance for the patients. RESULTS: Patients with somatoform disorders reported more psychological distress than patients without psychiatric disorder, especially after inquiry. Physical exhaustion was clearly more important in the symptom attribution of somatic pain patients, but an exclusive somatic illness attribution did not appear more often in this group of patients. CONCLUSIONS: Most pain patients with somatoform disorders report psychological distress when they are encouraged. In spite of this emotional strain, most of the pain patients with somatoform disorders attribute their pain complaints to somatic causes. The conspicuous importance of exhaustion in the attribution of patients with somatoform disorders confirms clinical observations and requires further research.