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The etio-pathophysiology of obsessive-compulsive disorder (OCD) can be explained using a biopsychosocial model. Little is known about obsessive-compulsive symptoms (OCS) in the context of chromosomal disorders involving the X chromosome. Case studies of two patients with chromosomal disorders involving the X chromosome (Patient 1 with a variant of Turner syndrome and Patient 2 with triple X syndrome). Both patients were treated due to severe OCS. In the research MRI analysis, the most pronounced MRI change in both patients was a gray matter volume loss in the orbitofrontal cortex. Patient 1 additionally showed left mesiotemporal changes. Patient 2 presented with global gray matter volume reduction, slowing in EEG, and a reduced intelligence quotient. OCS could occur in the context of Turner syndrome or triple X syndrome. The detected MRI changes would be compatible with dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD pathophysiology. Further studies with larger patient groups should investigate whether this association can be validated. [ABSTRACT FROM AUTHOR]

Obsessive-compulsive disorder (OCD) can rarely be associated with immunological aetiologies, most notably in Paediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections and possibly in autoimmune encephalitis. As cerebrospinal fluid (CSF) analysis is a sensitive method for assessing neuroinflammation, this retrospective study analysed basic CSF parameters and well-characterised as well as novel neuronal autoantibodies in OCD to screen for signs of autoimmunity. Basic CSF findings of 54 adult OCD patients suspected of an organic aetiology were retrospectively compared to a control group of mentally healthy patients (N = 39) with idiopathic intracranial hypertension. Further subgroup analysis included testing for well-characterised neuronal IgG autoantibodies and tissue-based assays using indirect immunofluorescence to screen for novel brain autoantibodies. Elevated protein in the CSF of OCD patients compared to the control group (p = 0.043) was identified. Inflammatory markers (pleocytosis/oligoclonal bands/increased IgG-index) were detected in 7% of all patients with OCD. Well-characterised neuronal autoantibodies were not found in any OCD patient, whereas 6/18 (33%) CSF samples showed binding on mouse brain sections in tissue-based assays (binding to neuropil in the basal ganglia/brainstem, cilia of granule cells, blood vessels, nuclear/perinuclear structures). While elevated CSF protein is merely a weak indicator of blood CSF barrier dysfunction, the presence of inflammatory CSF changes and novel brain autoantibodies in CSF may indicate OCD subtypes with inflammatory pathomechanism and supports the hypothesis of a rare "autoimmune OCD" subtype. [ABSTRACT FROM AUTHOR]

This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive–Compulsive and Posttraumatic Stress Disorders which was published in 2002 and revised in 2008. A consensus panel of 34 international experts representing 22 countries developed recommendations based on efficacy and acceptability of the treatments. In this version, not only medications but also psychotherapies and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medication treatments. The present paper (Part II) contains recommendations based on published randomised controlled trials (RCTs) for the treatment of OCD (n = 291) and PTSD (n = 234) in children, adolescents, and adults. The accompanying paper (Part I) contains the recommendations for the treatment of anxiety disorders. For OCD, first-line treatments are selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioural therapy (CBT). Internet-CBT was also superior to active controls. Several second-line medications are available, including clomipramine. For treatment-resistant cases, several options are available, including augmentation of SSRI treatment with antipsychotics and other drugs. Other non-pharmacological treatments, including repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS) and others were also evaluated. For PTSD, SSRIs and the SNRI venlafaxine are first-line treatments. CBT is the psychotherapy modality with the best body of evidence. For treatment-unresponsive patients, augmentation of SSRI treatment with antipsychotics may be an option. OCD and PTSD can be effectively treated with CBT and medications. [ABSTRACT FROM AUTHOR]

This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive–Compulsive and Posttraumatic Stress Disorders (published in 2002, revised in 2008). A consensus panel of 33 international experts representing 22 countries developed recommendations based on efficacy and acceptability of available treatments. In total, 1007 RCTs for the treatment of these disorders in adults, adolescents, and children with medications, psychotherapy and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medications. This paper, Part I, contains recommendations for the treatment of panic disorder/agoraphobia (PDA), generalised anxiety disorder (GAD), social anxiety disorder (SAD), specific phobias, mixed anxiety disorders in children and adolescents, separation anxiety and selective mutism. Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line medications. Cognitive behavioural therapy (CBT) is the first-line psychotherapy for anxiety disorders. The expert panel also made recommendations for patients not responding to standard treatments and recommendations against interventions with insufficient evidence. It is the goal of this initiative to provide treatment guidance for these disorders that has validity throughout the world. [ABSTRACT FROM AUTHOR]

There is an emerging role of autoimmune causes related to severe mental disorders (SMD). The clinical approach in patients with chronic SMD and novel anti-central nervous system antibodies is complex. Two corresponding cumulative cases are presented. Cerebrospinal fluid (CSF) and serum were investigated using tissue-based assays. Both patients suffered from chronic SMD and were negative for well-characterized neuronal antibodies. Patient 1 suffered from a dysexecutive and neurocognitive syndrome with mild abnormalities in automated electroencephalography analysis, elevated CSF protein levels, several serum autoantibodies (including antibodies against endothelial cells), and novel antibodies with a "dotted/scalloped" binding against cytoplasmic structures in CSF. Patient 2 with obsessive-compulsive disorder had left temporal abnormalities on automated magnetic resonance imaging analysis, an elevated CSF/serum albumin quotient, and novel atypical cytoplasmic "spotted" antibody staining in the serum. Patient 1 improved with immunotherapy using high-dose steroids, but patient 2 did not improve under the same treatment. The detection of autoantibodies in CSF of chronic SMD may be beneficial in selecting some patients for immunotherapy. The possible impact of novel anti-cytoplasmic antibodies in this context is critically discussed. Further research is needed to establish the underlying pathophysiological processes as well as their diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Temperamental traits as ascertained by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Auto-Questionnaire (TEMPS-A) have been suggested as promising intermediate phenotypes of mental disorders. In anxiety disorders, however, TEMPS scales and their genetic underpinnings are still understudied. TEMPS-A scores in 109 patients with panic disorder (PD) were compared to a sample of 536 healthy probands. All participants were genotyped for serotonin transporter gene variation (5-HTTLPR/rs25531). PD patients displayed significantly increased scores on the dysthymic, cyclothymic, irritable and anxious subscales, and lower scores on the hyperthymic subscale, respectively (all ps < 0.001) compared to healthy probands. In the total sample, the less active 5-HTTLPR/rs25531 S/LG alleles were associated with higher scores on the dysthymic, cyclothymic, irritable and anxious temperaments (all ps < 0.01), but not the hyperthymic subscale. Mediation analyses revealed anxious temperament in particular to mediate the relationship between 5-HTT genotype and PD. Dysthymic, cyclothymic, irritable and notably anxious temperament could serve as valuable intermediate phenotypes in efforts to unravel neurobiological, particularly serotonin system related genetic pathomechanisms associated with PD and potentially contribute to a panel of vulnerability markers guiding early targeted preventive interventions. [ABSTRACT FROM AUTHOR]

Objectives: Childhood emotional neglect (EN) is a predictor for the development of affective disorders. Oxytocin (OXT) may mediate the interplay between EN and changes in stress biological systems, brain development, and mental health outcomes. We investigated, in a cross-sectional study, the associations between EN, (epi)genetic variation in the OXT receptor (OXTR) gene, and amygdalar and hippocampal volumes, two brain regions implicated in emotional processing. Methods: We recruited 63 Caucasian South African adults (35 women) with and without social anxiety disorder. Childhood EN was assessed using the Childhood Trauma Questionnaire. rs53576 and rs2254298 genotypes, as well as methylation status, was determined using DNA purified from whole blood. Bilateral amygdalar and hippocampal volumes were determined by structural magnetic resonance imaging. The relationships between these variables were investigated using linear regression. Results: The interaction of the rs2254298 A risk allele and EN was nominally associated with reduced left hippocampal volume. The rs2254298 A risk allele was independently associated with reduced bilateral amygdalar volumes. We found no association between EN, OXTR methylation and amygdalar or hippocampal volumes. The rs53576 GG risk genotype was, however, associated with decreased OXTR methylation. Conclusions: The rs2254298 A allele may increase susceptibility to the structural brain effects of EN. [ABSTRACT FROM AUTHOR]

Objectives: Complicated grief (CG) following bereavement significantly increases the risk for mood and anxiety disorders. The severity of grief reactions may be interactively influenced by temperamental and psychological factors such as behavioural inhibition (BI) and separation anxiety (SA) as well as biological factors. Given its central role in attachment and stress processing, a genetic variant in the oxytocin receptor (OXTR) gene was thus investigated in order to elucidate the direction of association as well as its interaction with BI and SA in the moderation of CG severity. Methods: Ninety-three patients with mood and anxiety disorders were evaluated for CG by means of the Inventory of Complicated Grief (ICG), for BI using the Retrospective Self-Report of Inhibition (RSRI), and for symptoms of SA during adulthood using the Adult Separation Anxiety Scale (ASA-27). All patients were genotyped for OXTR rs2254298. Results: OXTR genotype interacted with BI and, on a trend-level, with adult SA, to increase CG. Specifically, higher levels on the RSRI and ASA-27 scales, respectively, were related to higher ICG scores in GG genotype carriers. Conclusions: The present study for the first time suggests a gene-environment interaction effect of an OXTR gene variant with BI and possibly also symptoms of adult SA in the moderation of vulnerability for CG. [ABSTRACT FROM AUTHOR]

Objectives: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions.Methods: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated.Results: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine.Conclusions: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment. [ABSTRACT FROM AUTHOR]

Objective:Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). Methods:Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network. Results:The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO2hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics. Conclusions:Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD. [ABSTRACT FROM AUTHOR]

Objectives: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive–compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). Methods: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network. Results: The present article (Part I) summarises findings on potential biomarkers in neuroimaging studies, including structural brain morphology, functional magnetic resonance imaging and techniques for measuring metabolic changes, including positron emission tomography and others. Furthermore, this review reports on the clinical and molecular genetic findings of family, twin, linkage, association and genome-wide association studies. Part II of the review focuses on neurochemistry, neurophysiology and neurocognition. Conclusions: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high-quality research has accumulated that will improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD. [ABSTRACT FROM AUTHOR]

Objectives: Research into the neural basis of social anxiety disorder (SAD) suggests alterations in prefrontal networks, which may in turn disrupt regulation of the limbic system. Better understanding of the disturbed interface between these networks may improve current pathogenic models of this disorder. Methods: Applying group independent component analysis (ICA) to recordings of fMRI resting-state, connectivity in the executive control network was studied in 18 patients with SAD and 15 age- and sex-matched healthy controls. Results: Results revealed a dissociation within the left executive control network, with SAD patients showing decreased connectivity of the orbitofrontal gyrus and increased connectivity of the middle frontal gyrus compared to healthy controls. In a subsequent seed-based functional connectivity analysis, patients with SAD displayed increased connectivity between the left orbitofrontal gyrus and the left amygdala. Conclusions: Findings suggest that hypo-connectivity in the executive control network and hyper-connectivity between the orbitofrontal cortex and the amygdala may reflect a disturbance in the balance between top-down and bottom-up control processes, potentially contributing to the development of SAD. [ABSTRACT FROM AUTHOR]

Objectives: Anxiety sensitivity (AS) has predictive potential for the development of anxiety disorders. We investigated the role that gene–environment (G × E) interactions, focussing on childhood trauma (CT) and selectedSLC6A4variants, play in modulating levels of AS in a South African adolescent population.Methods: All adolescents (n = 951) completed measures for AS and CT. SixSLC6A4polymorphisms were genotyped. G × E influences on AS levels were assessed using multiple linear regression models. Relevant confounders were included in all analyses.Results: Xhosa (n = 634) and Coloured (n = 317) participants were analysed independently of one another. The5-HTTLPR-rs25531L-Ghaplotype associated with reduced AS among Xhosa adolescents (P = 0.010). In addition, the rs1042173CC-genotype protected against increased levels of AS in Xhosa participants who had experienced increased levels of CT (P = 0.038). Coloured males homozygous for theS-allele had significantly increased levels of AS compared to Coloured males with at least oneL-allele (P = 0.016).Conclusions: This is the first study to be conducted on AS in adolescents from two ethnically diverse populations. Results indicate that theL-Ghaplotype confers protection against high AS levels in a Xhosa population. Furthermore, increased CT was found to protect against high levels of AS in Xhosa rs1042173CC-carriers. [ABSTRACT FROM PUBLISHER]

Objectives. The pathogenesis of anxiety is assumed to be interactively influenced by genetic and environmental factors. Thus, a gene-environment interaction (G × E) study of the neuropeptide S receptor gene ( NPSR) A/T polymorphism (rs324981) and life events was conducted with respect to anxiety sensitivity (AS) as an intermediate phenotype of anxiety disorders. Methods. A sample of 475 healthy German subjects was genotyped for NPSR and assessed for AS, childhood maltreatment (CTQ) and recent life events (LTE). Influences on AS and its subdimensions were determined by a step-wise hierarchical regression and a multiple indicator multiple cause (MIMIC) model. Results. Significant main effects of NPSR and CTQ as well as significant G × E were observed, with T/T homozygosity and a high CTQ score resulting in increased anxiety sensitivity. MIMIC modelling yielded association of AS subfactor 'concern about mental/cognitive incapacitation' and the basal somatic subdimension 'concern about physical sensations' to be associated with CTQ and its interaction with NPSR, while the acute somatic subfactor 'concern about heart/lung failure' was associated with NPSR and its interaction with LTE. Conclusions. Results indicate G × E effects of the more active NPSR rs324981 T allele and life events on AS with differential effects of temporally proximal and distal factors on specific AS subdimensions. [ABSTRACT FROM AUTHOR]

Objectives. Clinical and electrophysiological studies suggest that panic disorder (PD) patients show disturbed response inhibition to sensory stimuli. Thus, habituation of neuronal activation after repeated sine tone stimulation was assessed by functional magnetic resonance imaging (fMRI) in patients with PD. Methods. Twenty patients with PD and 20 age- and gender-matched healthy controls were assessed by 3T fMRI for auditory habituation. During three stimulation cycles of digitally generated pulsed (ν=5 Hz) 800-Hz sine tones alternating with silent periods, activation of the auditory cortex and other anxiety- or sensory integration-related regions was assessed. Brain activation was further analyzed dependent on functional serotonin transporter (5-HTT) gene variation (5-HTTLPR). Results. PD patients demonstrated an extended brain activity in the first stimulation block, which normalized during the second stimulation cycle. A positive correlation with anxiety measures (HAMA) and an increased activity of distinct anxiety- or sensory integration-related areas (e.g., BA 22, BA 10) were seen during the third block of auditory stimulation. There was a significant interaction of left amygdala activation and the 5-HTTLPR S allele. Conclusions. Our results support the hypothesis of an aberrant processing of sensory information in PD patients. This phenomenon may underlie an enhanced responsiveness to anxiety-relevant or irrelevant stimuli possibly increasing PD vulnerability. [ABSTRACT FROM AUTHOR]

Family, twin, and segregation analytic studies indicate a complex genetic contribution to panic disorder with an estimated heritability of 48%. Angiotensin-converting enzyme (ACE) degrades substance P, which has been implicated in anxiety-related behaviour. ACE has been suggested as a potential risk factor in the pathogenesis of panic attacks. A functional insertion deletion (I/D) polymorphism in the ACE gene was suggested to be associated with panic disorder in a potentially gender-specific way (Olsson et al. 2004). The present study aimed to replicate this finding and thereby to further elucidate the role of ACE gene variation in the pathomechanism of panic disorder. The ACE I/D polymorphism was genotyped in a sample of 102 German patients with panic disorder with or without agoraphobia as well as a healthy German control group matched with regard to age and sex ( n = 102). In the male subgroup ( n = 43) of panic patients a significant association of the ACE I allele ( P = 0.0474) and genotypes containing the I allele ( P = 0.0195), respectively, was observed. The present results provide further support for a potentially male-specific role of the less active ACE I allele in the pathogenesis of panic disorder, possibly by altering substance P levels. [ABSTRACT FROM AUTHOR]

Previous studies on neuronal activation correlates of panic attacks were mostly based on challenge tests, sensory-related stimulation or fear conditioning in healthy subjects. In the present study, we report on a female patient with panic disorder experiencing a spontaneous panic attack under an auditory habituation paradigm in the last stimulation block with sine tones captured with fMRI at 3T. The panic attack was associated with a significantly increased activity in the right amygdala. This is the first report on neuronal activation correlates of a spontaneous panic attack in a patient with panic disorder as measured by fMRI, which lends further support to a pivotal role of the amygdala in the pathogenesis of the disease. [ABSTRACT FROM AUTHOR]

Hyponatremia is a well-known side effect of antidepressant treatment with serotonin reuptake inhibitors (SSRI) or combined serotonin and noradrenaline reuptake inhibitors (SNRI), and is linked to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in most cases. In contrast, only very few data are available on hyponatremia following treatment with selective noradrenalin reuptake inhibitors (NaRI). In this report, we describe the case of a patient who developed severe hyponatremia after treatment with reboxetine. However, extensive laboratory testing did not reveal inappropriate secretion of ADH, suggesting that SIADH did not account for hyponatremia in our case. Proposing further examination of the underlying pathomechanism of hyponatremia as a side effect of NaRIs, we discuss the importance of careful monitoring of serum sodium levels in patients treated with NaRIs. [ABSTRACT FROM AUTHOR]

Objectives: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions.Methods: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated.Results: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine.Conclusions: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment. [ABSTRACT FROM AUTHOR]