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Background: Increased total brain volume (TBV) has been reported for children with autism spectrum disorder (ASD) but studies in older ASD subjects have been contradictory. Similarly, studies of corpus callosum (CC) area in ASD differ with regard to inclusion criteria, age, and IQ. Methods: In the present study, TBV, gray matter (GM), and white matter (WM) volume as well as midsagittal CC area were compared between 15 medication-naïve, high-functioning adolescent and young adult ASD subjects and 15 healthy control individuals, and correlations with visuomotor coordination and imitation abilities were explored. In addition, computational surface-based methods were implemented to encode callosal thickness at high spatial resolution. Results: Total brain volume, GM, and WM were increased and CC area was decreased in ASD subjects, a finding that was predominantly due to ASD subjects with lower IQ. Positive correlations of IQ with volume measures were observed only in control subjects. Autism spectrum disorder subjects showed reduced thickness in the posterior part of the CC. White matter volume showed a trend for negative correlation with dynamic balance and imitation abilities across groups. Conclusions: This study replicates previous structural magnetic resonance imaging (MRI) findings in ASD, emphasizes the role of IQ differences, and adds some evidence for functional implications of structural findings. [Copyright &y& Elsevier]

Summary: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common child psychiatric disorders. Previous studies have reported a blunted cortisol response to challenging situations and a decreased cortisol awakening response (CAR) in children with ADHD. As ADHD often is comorbid with oppositional defiant disorder (ODD), conduct disorder (CD), or anxiety disorder (AnxD), and changes in hypothalamic–pituitary–adrenal (HPA) axis activity have also been reported for these disorders, the present study aimed to compare the CAR in children with ADHD with and without comorbid disorders. Data on the CAR were obtained in 128 children with ADHD (aged 6–13 years) and in 96 control children (aged 6–12 years). Children with ADHD+ODD showed an attenuated CAR (area under the curve, AUC) compared to children with ADHD without ODD/CD and control children. Findings point towards either disinhibition or pervasive underarousal in children with ADHD+ODD, and seem to be specific for children with ADHD+ODD, as the attenuated CAR–AUC was not observed in children with ADHD without comorbid disorders or children with ADHD+CD or ADHD+AnxD. In addition, current adverse parenting conditions, family conflicts, and acute life events were associated with mean increase in CAR, emphasizing the role of psychosocial risk factors in mediating HPA axis activity in children with ADHD. [Copyright &y& Elsevier]

Abstract: In individuals with autism or autism-spectrum-disorder (ASD), conflicting results have been reported regarding the processing of biological motion tasks. As biological motion perception and recognition might be related to impaired imitation, gross motor skills and autism specific psychopathology in individuals with ASD, we performed a functional MRI study on biological motion perception in a sample of 15 adolescent and young adult individuals with ASD and typically developing, age, sex and IQ matched controls. Neuronal activation during biological motion perception was compared between groups, and correlation patterns of imitation, gross motor and behavioral measures with neuronal activation were explored. Differences in local gray matter volume between groups as well as correlation patterns of psychopathological measures with gray matter volume were additionally compared. On the behavioral level, recognition of biological motion was assessed by a reaction time (RT) task. Groups differed strongly with regard to neuronal activation and RT, and differential correlation patterns with behavioral as well as with imitation and gross motor abilities were elicited across and within groups. However, contrasting with the initial hypothesis, additional differences between groups were observed during perception and recognition of spatially moving point lights in general irrespective of biological motion. Results either point towards difficulties in higher-order motion perception or in the integration of complex motion information in the association cortex. This interpretation is supported by differences in gray matter volume as well as correlation with repetitive behavior bilaterally in the parietal cortex and the right medial temporal cortex. The specific correlation of neuronal activation during biological motion perception with hand-finger imitation, dynamic balance and diadochokinesis abilities emphasizes the possible relevance of difficulties in biological motion perception or impaired self-other matching for action imitation and gross motor difficulties in individuals with ASD. [Copyright &y& Elsevier]

Abstract: Although attention-deficit/hyperactivity disorder (ADHD) is highly heritable, environmental conditions play an important role in its manifestation during childhood development. Here, we report the results of an investigation on the interaction of adverse childhood environment with a functional polymorphism of the serotonin transporter promoter gene (5-HTTLPR) and its impact on ADHD psychopathology in young adult delinquents. Standardized instruments were used to assess childhood and current ADHD and adverse childhood environment in 184 male delinquents. Each subject was genotyped for 5-HTTLPR long (L) and small (S) alleles. Logistic regression analysis revealed independent effects of high childhood environmental adversity and the 5-HTTLPR LL-genotype on self-reported childhood ADHD and on persistent ADHD. In addition, a significant gene by environment interaction was found, indicating that carriers of at least one 5-HTTLPR short allele are more sensitive to childhood environment adversity than carriers of the LL-genotype. The results support prior findings of association between ADHD and 5-HTTLPR LL-genotype and adverse childhood environment, and they underline the need for further investigation of gene by environment interaction with respect to ADHD. [Copyright &y& Elsevier]

• ASD show reduced activation in the human middle temporal complex (hMT+). • Decreased PMC activation reflects reduced preparedness for social interaction in ASD. • No global MNS or MZS deficit can be found for ASD. Deficits in social communication and interaction are among the core symptoms of Autism Spectrum Disorder (ASD). Intention understanding in particular has been shown to be impaired in ASD. However, only one previous study has explicitly assessed the understanding of communicative intentions in ASD. Thus, the aim of the present study was to compare neural activation during the observation of communicative and non-communicative actions in participants with ASD and typically developing (TD) controls using functional magnetic resonance imaging (fMRI). Based on recent findings that show that the degree of involvement of the observer has an impact on neural activation, the present study included first- and third-person perspective stimuli. Twenty-five male TD (mean age 20.41 ± 3.39) and twenty-two male participants with ASD (mean age 18.60 ± 3.55) were included. Stimuli consisted of videos in which actors performed an action with an everyday object. Actions were either private or communicative; communicative actions were either directed at the observer (first-person) or at a third person. The ASD group showed reduced activation in the human middle temporal complex (hMT+) across all conditions. However, modulation of activation in response to different conditions remained intact in ASD. Additionally, while TD showed an increase in premotor cortex (PMC) activation in response to communicative actions directed at them, the ASD group showed a decrease in activation. These findings suggest an early processing deficit with regard to human biological motion in ASD. Furthermore, results reflect a reduced preparedness for social interactions in ASD compared to TD when addressed directly. [ABSTRACT FROM AUTHOR]

Conduct disorder (CD) has been associated with deficits in the use of punishment to guide reinforcement learning (RL) and decision making. This may explain the poorly planned and often impulsive antisocial and aggressive behavior in affected youths. Here, we used a computational modeling approach to examine differences in RL abilities between CD youths and typically developing controls (TDCs). Specifically, we tested 2 competing hypotheses that RL deficits in CD reflect either reward dominance (also known as reward hypersensitivity) or punishment insensitivity (also known as punishment hyposensitivity). The study included 92 CD youths and 130 TDCs (aged 9-18 years, 48% girls) who completed a probabilistic RL task with reward, punishment, and neutral contingencies. Using computational modeling, we investigated the extent to which the 2 groups differed in their learning abilities to obtain reward and/or to avoid punishment. RL model comparisons showed that a model with separate learning rates per contingency explained behavioral performance best. Importantly, CD youths showed lower learning rates than TDCs specifically for punishment, whereas learning rates for reward and neutral contingencies did not differ. Moreover, callous-unemotional (CU) traits did not correlate with learning rates in CD. CD youths have a highly selective impairment in probabilistic punishment learning, regardless of their CU traits, whereas reward learning appears to be intact. In summary, our data suggest punishment insensitivity rather than reward dominance in CD. Clinically, the use of punishment-based intervention techniques to achieve effective discipline in patients with CD may be a less helpful strategy than reward-based techniques. [ABSTRACT FROM AUTHOR]

Highlights from the article: B Overall Abstract: b Many early, childhood onset chronic psychiatric disorders show a mixed genetic and environmental etiology. Epigenetic studies on highly prevalent psychiatric disorders with onset in childhood and adolescence, such as Conduct Disorder (CD), aggressive behavior and anxiety disorders are then presented. The last talk will report multilevel data on DNA methylation of the oxytocin receptor gene (OXTR) and the monoamine oxidase A gene (MAOA) in anxiety disorders with regard to their impact on neuronal networks, neuroendocrinological measures and treatment response to cognitive-behavioral psychotherapy.

Objective: Conduct disorder (CD) involves aggressive and antisocial behavior and is associated with blunted cortisol stress response in male youths. Far less is known about cortisol stress responsivity in female youths with CD or other neuroendocrine responses in both sexes. Although CD is linked to early adversity, the possibility that neuroendocrine alterations may mediate the relationship between early adversity and CD has not been systematically investigated.Method: Within the European FemNAT-CD multi-site study, salivary cortisol, testosterone, the testosterone/cortisol ratio, oxytocin, and psychological stress response to a standardized psychosocial stress test (the Trier Social Stress Test [TSST]), together with common pre- and postnatal environmental risk factors, were investigated in 130 pubertal youths with CD (63% female, 9-18 years of age) and 160 sex-, age-, and puberty-matched healthy controls (HCs).Results: The TSST induced psychological stress in both CD and HCs. In contrast, female and male youths with CD showed blunted cortisol, testosterone, oxytocin, and testosterone/cortisol stress responses compared to HCs. These blunted stress responses partly mediated the relationship between environmental risk factors and CD.Conclusion: Findings from this unique sample, including many female youths with CD, provide evidence for a widespread attenuated stress responsivity of not only stress hormones, but also sex hormones and neuropeptides in CD and its subgroups (eg, with limited prosocial emotions). Results are the first to demonstrate blunted neuroendocrine stress responses in both female and male youths with CD. Early adversity may alter neuroendocrine stress responsivity. Biological mechanisms should be investigated further to pave the way for personalized intervention, thereby improving treatments for CD. [ABSTRACT FROM AUTHOR]

• Non-mental diseases over the lifespan are associated with ADHD. • Epilepsy, migraine, elimination disorders, asthma and obesity are significantly associated with ADHD over the lifespan. • Diagnosing non-mental diseases in ADHD patients is important for optimizing the treatment of both conditions. Several non-mental diseases seem to be associated with an increased risk of ADHD and ADHD seems to be associated with increased risk for non-mental diseases. The underlying trajectories leading to such brain-body co-occurrences are often unclear - are there direct causal relationships from one disorder to the other, or does the sharing of genetic and/or environmental risk factors lead to their occurring together more frequently or both? Our goal with this narrative review was to provide a conceptual synthesis of the associations between ADHD and non-mental disease across the lifespan. We discuss potential shared pathologic mechanisms, genetic background and treatments in co-occurring diseases. For those co-occurrences for which published studies with sufficient sample sizes exist, meta-analyses have been published by others and we discuss those in detail. We conclude that non-mental diseases are common in ADHD and vice versa and add to the disease burden of the patient across the lifespan. Insufficient attention to such co-occurring conditions may result in missed diagnoses and suboptimal treatment in the affected individuals. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To elucidate the contributions of modality-dependent post-processing in auditory, motor and visual cortical areas to short-term memory. Methods: We compared late negative waves (N700) during the post-processing of single lateralized stimuli which were separated by long intertrial intervals across the auditory, motor and visual modalities. Tasks either required or competed with attention to post-processing of preceding events, i.e. active short-term memory maintenance. Results: N700 indicated that cortical post-processing exceeded short movements as well as short auditory or visual stimuli for over half a second without intentional short-term memory maintenance. Modality-specific topographies pointed towards sensory (respectively motor) generators with comparable time-courses across the different modalities. Lateralization and amplitude of auditory/motor/visual N700 were enhanced by active short-term memory maintenance compared to attention to current perceptions or passive stimulation. The memory-related N700 increase followed the characteristic time-course and modality-specific topography of the N700 without intentional memory-maintenance. Conclusions: Memory-maintenance-related lateralized negative potentials may be related to a less lateralised modality-dependent post-processing N700 component which occurs also without intentional memory maintenance (automatic memory trace or effortless attraction of attention). Encoding to short-term memory may involve controlled attention to modality-dependent post-processing. Significance: Similar short-term memory processes may exist in the auditory, motor and visual systems. [ABSTRACT FROM AUTHOR]

• Heterogeneous results of cortisol stress response are reported in ADHD and MDD. • Blunted cortisol stress response is consistently reported for CD and/or ODD. • If altered, cortisol stress response in ADHD is driven by comorbidity with CD and/or ODD. • More, and sex-specific research is needed to clarify differences in cortisol stress response. • *ADHD = Attention-deficit/hyperactivity Disorder, CD = Conduct Disorder, MDD = Major Depressive Disorder, ODD = Oppositional Defiant Disorder. BERNHARD, A., J. S. Mayer, N. Fann, and C. M. Freitag. Cortisol response to acute psychosocial stress in ADHD compared to Conduct Disorder and Major Depressive Disorder: A systematic review. NEUROSCI BIOBEHAV REV XX(X) XXX-XXX, 2020. – Heterogeneous alterations of the cortisol stress response in Attention-deficit/hyperactivity Disorder (ADHD) were recently reported by a systematic literature review. To investigate the moderating effect of frequent psychiatric comorbidities, we systematically searched for studies on cortisol stress response to psychosocial stress in ADHD compared to Conduct Disorder (CD) and Major Depressive Disorder (MDD) following PRISMA guidelines. EBSCOhost and PubMed databases were searched in July 2020, employing relevant keywords. Nineteen studies met inclusion criteria. While blunted cortisol stress response was consistently reported in individuals with CD and/or Oppositional Defiant Disorder (ODD), alterations of cortisol stress response were less pronounced in ADHD. Consistently blunted cortisol stress response in ADHD was only found in children with comorbid CD/ODD. Results on cortisol stress response in children and adolescents with MDD were mixed, and no indication for influence of comorbid MDD on cortisol stress response in ADHD was found. Taken together, altered cortisol stress response in ADHD is driven by comorbidity with disruptive behavior disorders. Limitations of previous research and suggestions for future studies are discussed. [ABSTRACT FROM AUTHOR]

• Young adults with ADHD have an increased risk for co-morbid depression. • This systematic review specifies shared neurocognitive impairments of ADHD and MDD. • Impairments of executive functions and memory are candidate risk markers of MDD. • Shared neurocognitive risk mechanisms may mediate pathways from ADHD to MDD. • Low IQ may not confer risk for MDD among patients with ADHD. The risk for major depressive disorder (MDD) is considerably increased in young adults with attention-deficit/hyperactivity disorder (ADHD) but underlying mechanisms are poorly understood. This review explores ADHD-specific neurocognitive impairments as possible underlying mechanisms for ADHD-depression comorbidity. Two systematic literature searches were conducted in EBSCOhost, PubMED, and Cochrane Reviews databases according to PRISMA guidelines. The first search identified 18 meta-analyses of cross-sectional and longitudinal studies on cognitive dysfunctions in MDD across the lifespan. The second search identified six original studies on reaction time variability in MDD. During acute depression, children and adults showed cognitive deficits that overlapped with some of the ADHD-related impairments. Findings from remitted patients, high-risk individuals, and few prospective studies suggest that a subset of these shared impairments, specifically executive dysfunctions (selective attention, verbal fluency, working memory) and long-term memory problems, are candidate pre-existing risk markers of depression. We discuss if and how these specific neurocognitive mechanisms may mediate developmental pathways from ADHD to depression. If replicated by longitudinal studies, these findings may guide future prevention strategies. [ABSTRACT FROM AUTHOR]

Objective: Studies using diffusion tensor imaging (DTI) to investigate white matter (WM) microstructure in youths with conduct disorder (CD) have reported disparate findings. We investigated WM alterations in a large sample of youths with CD, and examined the influence of sex and callous-unemotional (CU) traits.Method: DTI data were acquired from 124 youths with CD (59 female) and 174 typically developing (TD) youths (103 female) 9 to 18 years of age. Tract-based spatial statistics tested for effects of diagnosis and sex-by-diagnosis interactions. Associations with CD symptoms, CU traits, a task measuring impulsivity, and the impact of comorbidity, and age- and puberty-related effects were examined.Results: Youths with CD exhibited higher axial diffusivity in the corpus callosum and lower radial diffusivity and mean diffusivity in the anterior thalamic radiation relative to TD youths. Female and male youths with CD exhibited opposite changes in the left hemisphere within the internal capsule, fornix, posterior thalamic radiation, and uncinate fasciculus. Within the CD group, CD symptoms and callous traits exerted opposing influences on corpus callosum axial diffusivity, with callous traits identified as the unique clinical feature predicting higher axial diffusivity and lower radial diffusivity within the corpus callosum and anterior thalamic radiation, respectively. In an exploratory analysis, corpus callosum axial diffusivity partially mediated the association between callous traits and impulsive responses to emotional faces. Results were not influenced by symptoms of comorbid disorders, and no age- or puberty-related interactions were observed.Conclusion: WM alterations within the corpus callosum represent a reliable neuroimaging marker of CD. Sex and callous traits are important factors to consider when examining WM in CD. [ABSTRACT FROM AUTHOR]

In children and adolescents, 1 mA transcranial direct current stimulation (tDCS) may cause “paradoxical” effects compared with adults: both 1 mA anodal and cathodal tDCS increase amplitude of the motor evoked potential (MEP) as revealed by a single pulse transcranial magnetic stimulation (TMS) of the motor cortex. Here, EEG based evoked potentials induced by a single pulse TMS, particularly the N100 component as marker of motor cortex inhibition, were investigated in order to explain effects of tDCS on the developing brain. In nineteen children and adolescents (11–16 years old), 1 mA anodal, cathodal, or sham tDCS was applied over the left primary motor cortex for 10 min. The TMS-evoked N100 was measured by 64-channel EEG before and immediately after stimulation as well as every 10 min after tDCS for one hour. 1 mA Cathodal stimulation suppressed the N100 amplitude compared with sham stimulation. In contrast, anodal tDCS did not modify the N100 amplitude. It seems likely that the increase of the motor cortex activity under cathodal tDCS in children and adolescents as shown in previous studies can be attributed to a reduce inhibition. Based on TMS evoked N100, the study provides an insight into neuromodulatory effects of tDCS on the developing brain. [ABSTRACT FROM AUTHOR]

Deficient facial emotion recognition has been suggested to underlie aggression in individuals with antisocial personality disorder (ASPD). As the neuropeptide oxytocin (OT) has been shown to improve facial emotion recognition, it might also exert beneficial effects in individuals providing so much harm to the society. In a double-blind, randomized, placebo-controlled crossover trial, 22 individuals with ASPD and 29 healthy control (HC) subjects (matched for age, sex, intelligence, and education) were intranasally administered either OT (24 IU) or a placebo 45 min before participating in an emotion classification paradigm with fearful, angry, and happy faces. We assessed the number of correct classifications and reaction times as indicators of emotion recognition ability. Significant group × substance × emotion interactions were found in correct classifications and reaction times. Compared to HC, individuals with ASPD showed deficits in recognizing fearful and happy faces; these group differences were no longer observable under OT. Additionally, reaction times for angry faces differed significantly between the ASPD and HC group in the placebo condition. This effect was mainly driven by longer reaction times in HC subjects after placebo administration compared to OT administration while individuals with ASPD revealed descriptively the contrary response pattern. Our data indicate an improvement of the recognition of fearful and happy facial expressions by OT in young adults with ASPD. Particularly the increased recognition of facial fear is of high importance since the correct perception of distress signals in others is thought to inhibit aggression. Beneficial effects of OT might be further mediated by improved recognition of facial happiness probably reflecting increased social reward responsiveness. [ABSTRACT FROM AUTHOR]

Background Conduct problems (CP) comprise abnormal behaviors associated with aberrant aspects of affective empathy as well as learning. However, behavioral measures for affective empathy are challenging, and previous results concerning learning in patients with CP are inconsistent. Methods Nineteen boys with CP and 24 typically developing (TD) boys aged 11–17 years (M = 14.34, SD = 1.93) participated in the study. An ultimatum-game was applied in order to elicit the feeling of like or dislike towards the opponent for a subsequent gambling task, which was played by the opponents (OTHER-condition) and by the participants themselves (SELF-condition). Functional MRI data were recorded throughout the experiment. Results In accordance with the model of insensitivity to punishment, hypo-activation of the left amygdala, left anterior insula, ventral medial prefrontal cortex (MPFC), and bilateral temporo-parietal junction (TPJ) was observed as a response to losing in participants with CP during the SELF-condition. Callous-unemotional (CU)-traits correlated negatively with activation of amygdala and right TPJ. During the OTHER-condition, TD participants showed activation in brain areas associated with theory of mind (right TPJ, left IFG), and affect regulation (right DLPFC) rather than areas associated with affective empathy. This pattern was not found in adolescents with CP. Moreover, and independently of individual characteristics of their opponents, adolescents with CP demonstrated reward-associated activation (ventral striatum) observing others win, which was positively correlated with CU-traits. This may be interpreted in line with the theory of reward dominance. Conclusions The current study provides support for the theory of abnormal learning processing in adolescents with CP which yields implications for further research as well as clinical practice. The gambling task did not activate affective empathy networks, but was specific for cognitive empathy, inhibition, and affect regulation. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) is a promising and well-tolerated method of non-invasive brain stimulation, by which cortical excitability can be modulated. However, the effects of tDCS on the developing brain are still unknown, and knowledge about its tolerability in children and adolescents is still lacking. Safety and tolerability of tDCS was assessed in children and adolescents by self-reports and spectral characteristics of electroencephalogram (EEG) recordings. Nineteen typically developing children and adolescents aged 11–16 years participated in the study. Anodal and cathodal tDCS as well as sham stimulation were applied for a duration of 10 min over the left primary motor cortex (M1), each with an intensity of 1 mA. Subjects were unable to identify whether they had received active or sham stimulation, and all participants tolerated the stimulation well with a low rate of adverse events in both groups and no serious adverse events. No pathological oscillations, in particular, no markers of epileptiform activity after 1 mA tDCS were detected in any of the EEG analyses. In summary, our study demonstrates that tDCS with 1 mA intensity over 10 min is well tolerated, and thus may be used as an experimental and treatment method in the pediatric population. [ABSTRACT FROM AUTHOR]

Objective The aim of the present study was to investigate the effect of the transcranial direct current stimulation (tDCS) on motor cortex excitability in healthy children and adolescents. Methods We applied 1 mA anodal or cathodal tDCS for 10 min on the left primary motor cortex of 19 healthy children and adolescents (mean age 13.9 ± 0.4 years). In order to prove whether the effects of tDCS may be attributed to the stimulation intensity, 10 children and adolescents were studied again using 0.5 mA anodal and cathodal tDCS. Sham stimulation was used as a control. Results Compared with sham stimulation, both 1 mA anodal and cathodal tDCS resulted in a significant increase of Motor evoked potentials (MEP) amplitudes which remained to be prominent even one hour after the end of stimulation. Interestingly, the 0.5 mA cathodal tDCS decreased cortico-spinal excitability whereas the 0.5 mA anodal stimulation did not result in any effect. Conclusion For the first time, the study demonstrates age-specific influences of tDCS on cortical excitability of the primary motor cortex. Significance Thus, the stimulation protocols of the tDCS have to be optimized according to age by planning studies in pediatric population. [ABSTRACT FROM AUTHOR]

Abstract: Atomoxetine (ATX), a selective norepinephrine reuptake inhibitor, is a non-stimulant approved for the treatment of attention deficit/hyperactivity disorder (ADHD). Little is known about the molecular basis for its therapeutic effect. The objective of this animal study was to determine alterations in gene expression patterns in the prefrontal cortex after long-term administration of atomoxetine. Rats were treated for 21days during childhood and early adolescent stages of development with a once-daily oral application of 0.05g/kg atomoxetine, which resulted in plasma levels similar to those described in children. A whole genome RNA-microarray of rat prefrontal cortical gene expression after administration of atomoxetine versus sterile water revealed an mRNA increase in 114 genes (≥2-fold) while 11 genes were down-regulated (≤0.5-fold). By applying quantitative real-time PCR (qRT-PCR) and Western Blot we confirmed a significant increase in the expression of GABA A receptor subunits as well as ubiquinol–cytochrome c reductase complex core protein 2 (Uqcrc2). SNAP-25 (synaptosomal-associated protein of 25kDa), which is an ADHD candidate gene and an important vesicle protein involved in axonal growth, synaptic plasticity and regulation of neurotransmitter release was also significantly upregulated on RNA- and protein level after atomoxetine treatment. In summary, we could show that long-term treatment with the ADHD drug atomoxetine induces the regulation of several genes in the prefrontal cortex of young rats. Especially the increased expression of SNAP-25 and GABA-A receptor subunits may indicate additional active therapeutic mechanisms for atomoxetine. [Copyright &y& Elsevier]

Abstract: Adenosine A2A receptors are suggested to play an important role in different brain circuits and pathways involved in anxiety reactions. A variant within the corresponding ADORA2A gene (rs5751876) increased the risk for panic disorder (PD), for elevated anxiety during challenge tests in healthy probands and for anxiety-related arousal in blood-injury phobia. These multiple effects may mirror a more general effect of the SNP on basic personality traits. In the present study we therefore aimed to replicate the original finding in a large PD sample and extend it by investigating an additional proband sample characterized for different anxiety-related personality scores. In addition, as rs5751876 is assumed not to be the disease variant itself but to be in linkage disequilibrium (LD) with the true functional polymorphism other SNPs of potentially functional relevance were identified by re-sequencing the whole gene including several newly identified regions of putative regulatory potential and analysed for their impact on PD and anxious personality. We were indeed able to replicate rs5751876 as risk factor for PD, particularly PD with agoraphobia. Rs5751876 and several other variants in high LD (rs5751862, rs2298383 and rs3761422) as well as the corresponding haplotypes were also associated with different anxiety-related personality scores (Bonferroni corrected P all < 0.05). Of these variants, rs2298383 shows functional potential based on in silico analyses and might therefore represent the true underlying causal variant. Our data provide further support for an important role of ADORA2A variants in the pathogenesis of anxiety disorders and anxious personality reflecting their potential as basic susceptibility factors. [ABSTRACT FROM AUTHOR]

Abstract: Several biochemical and pharmacological studies suggest that the catecholaminergic system involving the norepinephrine transporter (NET) is relevant for the pathogenesis of panic disorder. Three single nucleotide polymorphisms in the promoter or untranslated 5′ region of the NET gene were investigated by means of RFLP analysis in a sample of 115 German patients with panic disorder and 115 matched controls. Statistical analysis failed to show association with the overall diagnosis of panic disorder. In the subgroup of patients with panic disorder without agoraphobia, however, two polymorphisms were found to be associated with the disease (G/C (rs2397771): p &#60;0.05; T/C (rs2242446): p &#60;0.01). While our data do not support a major function of the NET gene in the development of panic disorder, it may play a role in the subgroup of panic disorder without agoraphobia. [Copyright &y& Elsevier]