[Neuropsychiatric manifestations in Tuberous Sclerosis Complex (TSC): diagnostic guidelines, TAND concept and therapy with mTOR inhibitors]. / Neuropsychiatrische Manifestationen bei Tuberöser Sklerose (TSC): Diagnostische Leitlinien, TAND-Konzept und Therapie mit mTOR-Inhibitoren.

Neuropsychiatric manifestations in Tuberous Sclerosis Complex (TSC): diagnostic guidelines, TAND concept and therapy with mTOR inhibitors Abstract. Tuberous sclerosis complex (TSC), albeit a rare autosomal-dominant multisystem disease with an incidence of 1:6,000, is one of the most important monogenetic disorders in child and adolescent psychiatry. In up to 90 % of patients, neurological disorders such as epilepsy and psychiatric disorders such as autism spectrum disorder, ADHD, affective disorders, and intellectual disability are observed. In recent years, significant progress has been made in understanding the molecular mechanism as well as in the clinical diagnosis and treatment of the disease. Here, we review these recent developments. In the first part, we describe the need for psychiatric assessment and treatment of patients and analyse challenges in interdisciplinary work between child and adolescent psychiatry, child neurology, and other professional groups. In the second part, we introduce the concept of TSC-associated neuropsychiatric disorders (TAND), developed by the TSC Neuropsychiatry Panel as a guide to help clinical teams, families, and individuals with TSC via screening, assessment, and treatment of neuropsychiatric symptoms and disorders as well as with a novel screening instrument, the TAND Checklist. Finally, we report findings from recent clinical trials of mTOR-inhibitors to treat TAND. The paper includes the German translation of the TAND Checklist as an electronic supplement.

Review: How should child mental health services respond to the refugee crisis?

BACKGROUND: Child mental health services and related agencies are faced with an increasing challenge in responding to the influx of refugee children around the world. There is strong evidence on the prevalence and complexity of these children's mental health problems and broader needs. AIMS: To review the research literature on risk and protective factors, and associated mental health interventions for refugee children. METHODS: Peer-reviewed studies were included for the period 2004-2017; if they included refugee, asylum-seeking or internally displaced children under 18 years; and adopted a quantitative design. Vulnerability and protective factors for refugee children were considered in this context, followed by the respective types of interventions at pre-, peri- and postmigration stage, and across high- and low-/middle-income countries. Eighty-two peer-reviewed studies fulfilled the selection criteria. RESULTS: The existing body of literature is largely based on identifying risk factors among children with mental health problems and predominantly designing trauma-focused interventions to reduce their symptomatic distress. Recent research and services have gradually shifted to a broader and dynamic resilience-building approach based on ecological theory, that is at child, family, school, community and societal level. There is increasing evidence for the implementation and effectiveness of multimodal interventions targeting all these levels, despite the methodological constraints in their evaluation. CONCLUSIONS: In high-income countries, child mental health services need to collaborate with all agencies in contact with refugee children, establish joint care pathways, and integrate trauma-focused interventions with family and community approaches. In low- and middle-income countries, where specialist resources are sparse, resilience-building should aim at maximising and upskilling existing capacity. A six-dimensional psychosocial model that applies to other children who experience complex trauma is proposed.

Experiences of Domestic and School Violence Among Child and Adolescent Psychiatric Outpatients.

The experience of cumulative childhood adversities, such as exposure to domestic violence or abuse by caregivers, has been described as risk factor for poor mental health outcomes in adolescence and adulthood. We performed an investigation of experience of violence in all patients aged 6 to 20 years who had consulted the Department of Child and Adolescent Psychiatry, Medical University of Vienna, as outpatients during the period of one year. We were using the Childhood Trauma Interview (CTI) in order to obtain information on the kind of violence. Seventy-five percent of all patients had reported experiences of violence. These youth were significantly more often involved in acts of school violence, thus a significant correlation between experience of domestic violence and violence at school could be revealed. The results of our study emphasize the need for interventions preventing violence both in domestic and in school environments.

Additive gene-environment effects on hippocampal structure in healthy humans.

Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G × E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n = 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G × E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD).

Adolescent Defense Style as Correlate of Problem Behavior.

OBJECTIVE: Adolescent problem behaviors are often the visible results of intrapsychic distress. Defensive reactions are the unconscious means of managing intrapsychic distress. This cross-sectional study examines the strength of defensive style as measured by self-report on the Response Evaluation Measure (REM-71) relative to age, sex, and SES, as a correlate of internalizing and externalizing problem behaviors, as assessed by the Youth Self Report (YSR). METHODS: A sample of 1,487 students from two suburban high schools completed self-report measures of defense style, self-esteem, and internalizing and externalizing problem behaviors. Demographic variables (age, sex, and SES) were included as covariates. RESULTS: Mature and immature defense style correlated as expected with problem behaviors. Demographic variables contributed minimally to the variance in the outcome variable. CONCLUSIONS: Defense style, as assessed by the REM-71, is a significant correlate of clinically elevated internalizing and externalizing problem behaviors in youth as in adults. This study adds to the convergent validity of the REM-71.

Defensive functioning and psychopathology: a study with the REM-71.

OBJECTIVES: The aim of the present study is to explore the association between defensive functioning (as assessed through the REM-71) and psychiatric symptoms in a large sample from the community, and the moderating role of age and gender on that association. Furthermore, we explored the concurrent validity of REM-71 as compared with "caseness" (SCL-90-R). METHODS: The REM-71 was administered together with SCL-90-R to a community sample of 1,060 Italian high-school and university students (mean age=19.01±3.85 years; 66.7% females). RESULTS: Factor 1 defenses were by far the primary contributors to the predictor synthetic variable (i.e. association between defenses and psychopathology). Gender proved to moderate the association between immature defenses and symptoms. Using ROC analysis, we derived a cut-off score for Factor 1 defenses. CONCLUSIONS: Our results support the adoption of the REM-71 as a useful instrument for the assessment of defensive array and psychopathological liability in adolescents and adults.

Detecting and treating adult attention deficit hyperactivity disorder in a patient with schizophrenia.

BACKGROUND: The comorbidity of attention deficit hyperactivity disorder (ADHD) and schizophrenia poses a considerable diagnostic challenge due to significant symptom overlap, and represents a highly debilitating condition for the patient. This case report aims to present the history of a 19-year-old patient suffering from these two diagnostic entities, and thereby seeks to elucidate diagnostic and therapeutic approaches for this condition. METHODS: The Diagnostic and Statistical Manual of Mental Disorders (fourth edition) criteria for ADHD and schizophrenia were used to establish clinical diagnoses. Furthermore, an in-depth clinical interview with the patient's mother was carried out. Finally, a clinical interview was conducted with the patient and the Wender Utah Rating Scale was applied to assess ADHD symptoms retrospectively. RESULTS: Outcomes of the mentioned diagnostic approaches confirmed the diagnosis of ADHD in the patient suffering from schizophrenia. As amphetamines would be contraindicated in the described patient, atomoxetine, a drug approved for the treatment of ADHD due to its efficacy as a selective norepinephrine reuptake inhibitor, was chosen. Following a 6-week interval after treatment initiation, a clinical re-evaluation was carried out, which showed an improvement of symptoms according to the International Classification of Diseases (tenth revision) criteria. CONCLUSION: The present case report indicates that atomoxetine may be effective in treating symptoms of ADHD in patients with schizophrenia, without increasing psychotic symptoms. Results are discussed in terms of diagnostic and therapeutic implications.

Responses to conflict, family loss and flight: posttraumatic stress disorder among unaccompanied refugee minors from Africa.

OBJECTIVE: To investigate African unaccompanied refugee minors (URMs) living in Austria for posttraumatic stress disorder (PTSD) prevalence and related symptoms, comorbidity, demographics and coping strategies. METHOD: "UCLA PTSD Index and inventories" and "Scales for Children Afflicted by War and Persecution (SCWP)" were used to assess 41 African URMs. RESULTS: The study revealed lower PTSD rates than measured among URMs in previous studies. Girls were more likely to develop PTSD. PTSD was significantly correlated with single war-related traumatic events. The depression score for the sample was above the clinical cut-off value. CONCLUSIONS: Trauma-specific psychopathology was less severe than reported in other studies. These findings could be explained by concepts of resilience. Other implications, such as response bias, are discussed.

Personality and psychopathology in African unaccompanied refugee minors: repression, resilience and vulnerability.

Examining personality and psychopathological symptoms among unaccompanied refugee minors (URMs), we measured intra-individual dimensions (repression and correlates thereof) usually associated with resilience. Forty-one URMs completed the Weinberger Adjustment Inventory (WAI), assessing personality, and the Youth Self-Report (YSR), describing current symptoms. URMs endorsed high levels of Repressive Defensiveness, Denial of Distress, and Restraint; unexpectedly, URMs reported high Distress and reduced Happiness (WAI, p's < 0.05). Although YSR symptoms were below clinical cut points, there were notable correlations between Distress and Attention Problems, Self-destructive, and Aggressive Behavior (all on the YSR), correcting for multiple comparisons (p's < 0.004). URMs exposed to non-normative stressors reported non-symptomatic outcomes, and high levels of personality dimensions correlating with resilience. However, URMs also endorsed high Distress and low Happiness, calling their resilience into question. Positive correlations between WAI Distress and YSR symptom subscales suggest that URMs harbor vulnerabilities of clinical and forensic significance.

Perception of autonomy and connectedness prior to the onset of anorexia nervosa and bulimia nervosa.

OBJECTIVE: This study examines retrospective correlates of nonshared family environment prior to onset of disease, by means of multiple familial informants, among anorexia and bulimia nervosa patients. METHODS: A total of 332 participants was included (anorexia nervosa, restrictive type (AN-R): n = 41 plus families); bulimic patients (anorexia nervosa, binge-purging type; bulimia nervosa: n = 59 plus families). The EATAET Lifetime Diagnostic Interview was used to establish the diagnosis; the Subjective Family Image Test was used to derive emotional connectedness (EC) and individual autonomy (IA). RESULTS: Bulimic and AN-R patients perceived significantly lower EC prior to onset of disease compared to their healthy sisters. Bulimic patients perceived significantly lower EC prior to onset of disease compared to AN-R patients and compared to their mothers and fathers. A low family sum - sister pairs sum comparison - of EC had a significant influence on the risk of developing bulimia nervosa. Contrary to expectations, AN-R patients did not perceive significantly lower levels of IA compared to their sisters, prior to onset of disease. Findings of low IA in currently ill AN-R patients may represent a disease consequence, not a risk factor. CONCLUSIONS: Developmental child psychiatrists should direct their attention to disturbances of EC, which may be present prior to the onset of the disease.

Effect of obesity on plasma clusterin, [corrected] a proposed modulator of leptin action.

Clusterin, a protein constituent of HDL, was recently shown to bind plasma leptin in vitro and has been proposed to modulate leptin activity. To gain insight into a possible role for plasma clusterin in human obesity, we measured plasma clusterin, leptin, soluble leptin receptor (sObR), and lipoproteins in 70 obese adolescents (12.4 ± 1.6 y; BMI-SD score (SDS-BMI) 2.35 ± 0.47) before and after 3 wk of weight reduction in a dietary camp and in 44 normal weight controls. Binding of plasma leptin to HDL or clusterin was studied using ultracentrifugation and immunoaffinity chromatography. During weight reduction, clusterin decreased from 14.6 ± 4.1 to 10.3 ± 2.9 mg/dL, p < 0.001) in obese adolescents, whereas sObR increased. However, baseline plasma clusterin in obese adolescents did not differ from controls. Clusterin did not correlate with SDS-BMI, weight loss, leptin, or lipoproteins. Only ∼ 1% of plasma leptin was associated with clusterin/apoA-I complexes or with HDL. Our results do not support a role for plasma clusterin as an important leptin-binding protein or modulator of leptin action. The decrease of plasma clusterin during weight reduction may be an effect of the hypocaloric diet rather than being directly linked to weight loss.

Migraine in patients with eating disorders: a study using a sister-pair comparison design.

OBJECTIVE: To evaluate the relationship between migraine and eating disorders by applying a special study design. BACKGROUND: To date, only a few studies have assessed eating disorders and eating behavior in patients with migraine. METHODS: The distinctive feature of this design is the comparison of sister pairs with one sister suffering from an eating disorder according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition and the other being free of such disease. RESULTS: We investigated 120 female patients with a median age of 24 years (interquartile range 20-31) as well as their non-eating-disordered sisters with a median age of 24 (20-31) years. Headache was diagnosed according to the International Classification of Headache Disorders, Second Edition. Thirteen sister pairs were concordant for the presence of migraine, 67 were concordant for the absence of migraine and 40 were discordant. Among the latter, 21 patients and 19 controls had migraine. The prevalence of migraine was virtually identical in patients (28%) and controls (27%). CONCLUSION: This clinic-based controlled study using a sister-pair comparison design showed no evidence of an increased prevalence of migraine among patients with eating disorder.

Symptomatic response to divalproex in subtypes of conduct disorder.

To investigate response to Divalproex sodium (DVPX) with respect to Reactive/Affective/Defensive/Impulsive (RADI) and Proactive/Instrumental/Premeditated (PIP) aggression among adolescent males with conduct disorder (CD), using results from a randomized, double-blind, placebo-controlled trial. It was hypothesized that DVPX response among participants with RADI aggression would be greater than among those with PIP aggression. Fifty-eight ethnically diverse males with severe CD were assigned to High Distress (HDCD) or Low Distress (LDCD) Conduct Disorder, corresponding with RADI and PIP aggression, respectively. Following a 1-week washout, all subjects were randomized to a high dose (up to 1,500 mg/day) or low dose (up to 250 mg/day) of DVPX. Baseline and endpoint assessments included Clinical Global Impression (CGI), Achenbach Self Report (YSR), and Weinberger Adjustment Inventory (WAI-62). Response to DVPX was significantly higher in the HDCD group (64%) than in the LDCD group (22%) in the high-dose treatment group (p = 0.03). Mean weekly WAI-62 distress scores declined significantly among the HDCD subjects than among LDCD subjects in the high-dose group. These results support the utility of mood stabilizing agents such as DVPX in treating patients with disorders characterized by the RADI pattern of aggression, including those with severe CD.

Psychopathology in African unaccompanied refugee minors in Austria.

We assessed the prevalence of a range of psychopathology among African unaccompanied refugee minors (URMs) in Austria. Additionally, the predictive value of war exposure on PTSD symptoms was examined. Forty-one URMs were assessed with the Mini-International Neuropsychiatric Interview for children and adolescents, the Youth Self-Report, the UCLA PTSD Reaction Index and Facts About You. As expected, 56% of youth had at least one diagnosis by structured clinical interview. The most common diagnoses were adjustment disorder, PTSD and dysthymia. War affliction marginally predicted (p = 0.065) PTSD controlling for age and gender. URMs had high levels of psychopathology compared to norms. Their PTSD rates were somewhat lower than found in previous studies. We discuss methodological and substantive reasons for this finding. Future studies need to examine URMs across the entire diagnostic spectrum and employ multi-method designs to yield valid results. The psychopathology in URMs has clinical and forensic implications.

Overt and covert aggression in college women with bulimia nervosa.

OBJECTIVE: This study examines the prevalence of overt and covert aggression in women with bulimia nervosa (BN) as well as the relationship between the severity of BN and the frequency of aggressive acts. PATIENTS AND METHODS: 20 female college students with BN and 20 control subjects completed self-report measures of aggressive behavior and eating disorder pathology. They also completed the Juvenile Health and Wellness Survey-76 to assess general risk taking and indices of sexual behavior and mental health. RESULTS: BN subjects reported higher levels of both overt and covert aggression (p < .001). Overt aggression tended to be more premeditated, while the self-report of covert aggression behavior was more impulsive. Levels of aggressive behavior were significantly correlated with severity of BN (p < .01). Subjects with BN reported higher levels of risk-taking and sexual behaviors. CONCLUSIONS: Aggression is an important clinical issue in BN. Subtypes of aggression suggest different pathways for overt and covert aggressive acts with impulsive covert aggression being more closely related to the binge-purge cycle. Awareness of subtypes of aggression in BN may have important clinical and treatment implications.

Correction to: Knock-on effect of periodontitis to the pathogenesis of Alzheimer's disease?

The original version of this article unfortunately contained a mistake. There was an error in Fig. 2. The original article has been corrected. We apologize for the mistake.The correct Fig. 2 is given ….

Knock-on effect of periodontitis to the pathogenesis of Alzheimer's disease?

BACKGROUND: Alzheimer's disease has chronic inflammatory components, which can be enhanced by systemic immune activation resulting in inflammation or vice versa. There is growing evidence that chronic periodontitis drives systemic inflammation and finally Alzheimer's disease. Thus, a link might exist between oral pathogens and Alzheimer's disease. This may be of special significance as there is an age-related incidence of chronic periodontitis. METHODS: In this study, 20 consecutive patients with probable Alzheimer's disease were investigated. Diagnosis was established by cognitive tests, routine laboratory tests and cerebral magnetic resonance tomography. In 35% of these patients with cognitive impairment pathogenic periodontal bacteria were found. RESULTS: The presence of Porphyromonas gingivalis, the key pathogen and one of the species involved in chronic periodontitis, was found to be associated with lower mini mental state examination scores (p < 0.05) and with a tendency to lower scores in the clock drawing test (p = 0.056). Furthermore, association between lower serum concentrations of the immune biomarker neopterin and the presence of Treponema denticola (p < 0.01) as well as of kynurenine were found in Alzheimer patients positive vs. negative for Tannerella forsytia (p < 0.05). CONCLUSIONS: Data indicate a possible association of specific periodontal pathogens with cognitive impairment, Treponema denticola and Tannerella forsytia may alter the host immune response in Alzheimer's disease. Albeit still preliminary, findings of the study may point to a possible role of an altered salivary microbiome as a causal link between chronic periodontitis and cognitive impairment in Alzheimer's disease.

Identification of Common Neural Circuit Disruptions in Emotional Processing Across Psychiatric Disorders.

OBJECTIVE: Disrupted emotional processing is a common feature of many psychiatric disorders. The authors investigated functional disruptions in neural circuitry underlying emotional processing across a range of tasks and across psychiatric disorders through a transdiagnostic quantitative meta-analysis of published neuroimaging data. METHODS: A PubMed search was conducted for whole-brain functional neuroimaging findings published through May 2018 that compared activation during emotional processing tasks in patients with psychiatric disorders (including schizophrenia, bipolar or unipolar depression, anxiety, and substance use) to matched healthy control participants. Activation likelihood estimation (ALE) meta-analyses were conducted on peak voxel coordinates to identify spatial convergence. RESULTS: The 298 experiments submitted to meta-analysis included 5,427 patients and 5,491 control participants. ALE across diagnoses and patterns of patient hyper- and hyporeactivity demonstrated abnormal activation in the amygdala, the hippocampal/parahippocampal gyri, the dorsomedial/pulvinar nuclei of the thalamus, and the fusiform gyri, as well as the medial and lateral dorsal and ventral prefrontal regions. ALE across disorders but considering directionality demonstrated patient hyperactivation in the amygdala and the hippocampal/parahippocampal gyri. Hypoactivation was found in the medial and lateral prefrontal regions, most pronounced during processing of unpleasant stimuli. More refined disorder-specific analyses suggested that these overall patterns were shared to varying degrees, with notable differences in patterns of hyper- and hypoactivation. CONCLUSIONS: These findings demonstrate a pattern of neurocircuit disruption across major psychiatric disorders in regions and networks key to adaptive emotional reactivity and regulation. More specifically, disruption corresponded prominently to the "salience" network, the ventral striatal/ventromedial prefrontal "reward" network, and the lateral orbitofrontal "nonreward" network. Consistent with the Research Domain Criteria initiative, these findings suggest that psychiatric illness may be productively formulated as dysfunction in transdiagnostic neurobehavioral phenotypes such as neurocircuit activation.

Global connectivity and local excitability changes underlie antidepressant effects of repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a commonly- used treatment for major depressive disorder (MDD). However, our understanding of the mechanism by which TMS exerts its antidepressant effect is minimal. Furthermore, we lack brain signals that can be used to predict and track clinical outcome. Such signals would allow for treatment stratification and optimization. Here, we performed a randomized, sham-controlled clinical trial and measured electrophysiological, neuroimaging, and clinical changes before and after rTMS. Patients (N = 36) were randomized to receive either active or sham rTMS to the left dorsolateral prefrontal cortex (dlPFC) for 20 consecutive weekdays. To capture the rTMS-driven changes in connectivity and causal excitability, resting fMRI and TMS/EEG were performed before and after the treatment. Baseline causal connectivity differences between depressed patients and healthy controls were also evaluated with concurrent TMS/fMRI. We found that active, but not sham rTMS elicited (1) an increase in dlPFC global connectivity, (2) induction of negative dlPFC-amygdala connectivity, and (3) local and distributed changes in TMS/EEG potentials. Global connectivity changes predicted clinical outcome, while both global connectivity and TMS/EEG changes tracked clinical outcome. In patients but not healthy participants, we observed a perturbed inhibitory effect of the dlPFC on the amygdala. Taken together, rTMS induced lasting connectivity and excitability changes from the site of stimulation, such that after active treatment, the dlPFC appeared better able to engage in top-down control of the amygdala. These measures of network functioning both predicted and tracked clinical outcome, potentially opening the door to treatment optimization.

Listening for avoidance: narrative form and defensiveness in adolescent memories.

We describe a linguistic clue to speakers' states of mind that has utility for psychotherapists and counselors, and summarize the theoretical and empirical support for using this clue in clinical practice. Specifically, we posit that the degree to which people relate stressful episodes from their lives as a chronological sequence of events is negatively associated with the extent to which they self-protectively avoid experiencing negative affect. We review relevant discussions and findings from linguistics and psychology, and then present a new study that replicates previous research. In this study of the relationship between defensive avoidance and the narrative structure of stressful memories in non-clinical adolescents, 168 high school students spoke for 10 min into a tape recorder about "your most stressful life event." Transcribed interviews were analyzed for narrative immersion, the extent to which the past is retold in chronological order, using a method adopted from Labov and Waletzky. A negative association was found between narrative immersion and avoidance (as operationalized by scores on the Marlowe Crowne Social Desirability Scale). Listening for narrative immersion in the speech of clients discussing past stressful times may therefore represent a useful tool in exploring defensive avoidance of stressful episodic memories.