Bill & Melinda Gates Foundation and Australian National Health and Medical Research Council.

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Findings support the involvement of frontal, striatal, and limbic regions in methamphetamine dependence. Furthermore, they indicate that glucose metabolism and cerebral perfusion in these regions are disrupted in methamphetamine dependent individuals with psychotic symptoms.

Psychiatric disorders present distinct clinical challenges which are partly attributable to their multifactorial aetiology and the absence of laboratory tests that can be used to confirm diagnosis or predict risk. Psychiatric disorders are highly heritable, but also polygenic, with genetic risk conferred by interactions between thousands of variants of small effect that can be summarized in a polygenic risk score. We discuss four areas in which the use of polygenic risk scores in research and clinical contexts could have ethical implications , with a particular focus on potential challenges that could arise with the feedback and interpretation of high polygenic risk for a psychiatric disorder . While there would be extensive overlap with the challenges of feeding back genetic findings in general, the potential clinical use of polygenic risk scoring warrants discussion in its own right, given the recency of this possibility. To this end, we discuss how lay interpretations of risk and genetic information could intersect. Consideration of these factors would be necessary for ensuring effective and constructive communication and interpretation of polygenic risk information which, in turn, could have implications for the uptake of any therapeutic recommendations. Recent advances in polygenic risk scoring have major implications for its clinical potential, however, care should be taken to ensure that communication of polygenic risk does not feed into problematic assumptions regarding mental disorders or support reductive interpretations.

People with B/P-ED show subjective high levels of alexithymia but not an objective deficit in emotional understanding. However, there is an interesting dis-correlation between them and their mothers, which calls for further research.

Recent evidence suggests that the steroid hormone testosterone can decrease the functional coupling between orbitofrontal cortex (OFC) and amygdala. Theoretically this decoupling has been linked to a testosterone-driven increase of goal-directed behaviour in case of threat, but this has never been studied directly. Therefore, we placed twenty-two women in dynamically changing situations of escapable and inescapable threat after a within-subject placebo controlled testosterone administration. Using functional magnetic resonance imaging (fMRI) we provide evidence that testosterone activates the left lateral OFC (LOFC) in preparation of active goal-directed escape and decouples this OFC area from a subcortical threat system including the central-medial amygdala, hypothalamus and periaqueductal gray. This LOFC decoupling was specific to threatening situations, a point that was further emphasized by an absence of such decoupling in a second experiment focused on resting-state connectivity. These results not only confirm that testosterone administration decouples the LOFC from the subcortical threat system, but also show that this is specifically the case in response to acute threat, and ultimately leads to an increase in LOFC activity when the participant prepares a goal-directed action to escape. Together these results for the first time provide a detailed understanding of functional brain alterations induced by testosterone under threat conditions, and corroborate and extend the view that testosterone prepares the brain for goal-directed action in case of threat.

<p>Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.</p>

Behavioural health risks, including substance use, early sexual debut, bullying and suicidality, are common during adolescence, but may be complicated among perinatally HIV-infected adolescents. However, there are few data exploring these behaviours in sub-Saharan Africa. We compared behavioural health risks (any self-report of substance use, sexual activity, bullying others or suicidality, or a positive urine toxicology screen) among perinatally-infected adolescents ages 9-14 years to that of an HIV-uninfected comparator group; and explored the effect of behavioural health risks on adolescent and caregiver report of adolescent suboptimal adherence (missed antiretroviral therapy dose(s) on ≥1 day during the preceding 30 days) and elevated HIV viral load (≥50 and ≥1000 copies/mL in sensitivity analyses) in multivariable logistic regression models. Among 506 HIV-infected and 110 HIV-uninfected adolescents (median age overall: 12 years), 15% and 25% reported any behavioural health risk (p = 0.018), respectively. Tobacco and other drug use was uncommon, while alcohol use was reported by 8% of HIV-infected versus 12% of HIV-uninfected adolescents (p = 0.185). One HIV-infected (0.2%) and 3 HIV-uninfected adolescents (3%) reported any sexual activity (p = 0.019). Among HIV-infected adolescents, report of any behavioural health risk was more common among male adolescents [adjusted odds ratio (aOR): 1.78; 95% confidence interval (CI): 1.08-2.95] and was associated with adolescent report of suboptimal adherence (aOR: 1.66; 95% CI: 0.99-2.78) but not with caregiver report of suboptimal adherence or with elevated viral load. In this group of perinatally-infected youth entering early adolescence, the prevalence of behavioural health risks was lower than that among same-age, HIV-uninfected peers. Longitudinal data are needed to explore the reasons underlying these differences, for example the possibility of more protective caregiving and supportive family environments, or of emotional and physical immaturity, as well as the emergence of risk behaviours over time in this population.

During the last decade, there has been heated debate regarding whether compulsive sexual behaviour should be classified as a mental/behavioural disorder. Compulsive sexual behaviour disorder has been proposed for inclusion as an impulse control disorder in the ICD-111. It is characterized by a persistent pattern of failure to control intense, repetitive sexual impulses or urges, resulting in repetitive sexual behaviour over an extended period (e.g., six months or more) that causes marked distress or impairment in personal, family, social, educational, occupational or other important areas of functioning. The pattern is manifested in one or more of the following: a) engaging in repetitive sexual activities has become a central focus of the person's life to the point of neglecting health and personal care or other interests, activities and responsibilities; b) the person has made numerous unsuccessful efforts to control or significantly reduce repetitive sexual behaviour; c) the person continues to engage in repetitive sexual behaviour despite adverse consequences (e.g., repeated relationship disruption, occupational consequences, negative impact on health); or d) the person continues to engage in repetitive sexual behaviour even when he/she derives little or no satisfaction from it. Concerns about overpathologizing sexual behaviours are explicitly addressed in the diagnostic guidelines proposed for the disorder. Individuals with high levels of sexual interest and behaviour (e.g., due to a high sex drive) who do not exhibit impaired control over their sexual behaviour and significant distress or impairment in functioning should not be diagnosed with compulsive sexual behaviour disorder. The diagnosis should also not be assigned to describe high levels of sexual interest and behaviour (e.g., masturbation) that are common among adolescents, even when this is associated with distress. The proposed diagnostic guidelines also emphasize that compulsive sexual behaviour disorder should not be diagnosed based on psychological distress related to moral judgments or disapproval about sexual impulses, urges or behaviours that would otherwise not be considered indicative of psychopathology. Sexual behaviours that are egodystonic can cause psychological distress; however, psychological distress due to sexual behaviour by itself does not warrant a diagnosis of compulsive sexual behaviour disorder. Careful attention must be paid to the evaluation of individuals who self-identify as having the disorder (e.g., calling themselves “sex addicts” or “porn addicts”). Upon examination, such individuals may not actually exhibit the clinical characteristics of the disorder, although they might still be treated for other mental health problems (e.g., anxiety, depression). Additionally, individuals often experience feelings such as shame and guilt in relationship to their sexual behaviour2, but these experiences are not reliably indicative of an underlying disorder. The proposed diagnostic guidelines also assist the clinician in differentiating compulsive sexual behaviour disorder from other mental disorders and other health conditions. For example, although bipolar disorder has been found at elevated rates among individuals with compulsive sexual behaviour disorder3, sexual behaviours must be persistent and occur independently of hypomanic or manic episodes to provide a basis for a possible diagnosis of the disorder. A diagnosis of compulsive sexual behaviour disorder should not be made when the behaviour can be explained by other medical conditions (e.g., dementia) or by the effects of certain medications prescribed to treat specific medical conditions (e.g., Parkinson's disease)4 or is entirely attributable to the direct effects of illicit substances on the central nervous system (e.g., cocaine, crystal methamphetamine). Currently, there is an active scientific discussion about whether compulsive sexual behaviour disorder can constitute the manifestation of a behavioural addiction5. For ICD-11, a relatively conservative position has been recommended, recognizing that we do not yet have definitive information on whether the processes involved in the development and maintenance of the disorder are equivalent to those observed in substance use disorders, gambling and gaming6. For this reason, compulsive sexual behaviour disorder is not included in the ICD-11 grouping of disorders due to substance use and addictive behaviours, but rather in that of impulse control disorders. The understanding of compulsive sexual behaviour disorder will evolve as research elucidates the phenomenology and neurobiological underpinnings of the condition7. In the absence of consistent definitions and community-based epidemiological data, determining accurate prevalence rates of compulsive sexual behaviour disorder has been difficult. Epidemiological estimates have ranged up to 3-6% in adults8, though recent studies have produced somewhat lower estimates of 1 to 3%9. The more restrictive diagnostic requirements proposed for ICD-11 would be expected to produce lower prevalence rates. In general, men exhibit the disorder more frequently than women, although robust data examining gender differences are lacking. Additionally, higher rates of the disorder have been noted among individuals with substance use disorders. Among treatment seekers, the disorder negatively impacts occupational, relationship, physical health and mental health functioning. However, systematic data are lacking regarding the prevalence of the disorder across different populations and associated socio-cultural and socio-demographic factors, including among non-treatment seekers. Growing evidence suggests that compulsive sexual behaviour disorder is an important clinical problem with potentially serious consequences if left untreated. We believe that including the disorder in the ICD-11 will improve the consistency with which health professionals approach the diagnosis and treatment of persons with this condition, including consistency regarding when a disorder should not be diagnosed. Legitimate concerns about overpathologizing sexual behaviours have been carefully addressed in the proposed diagnostic guidelines. We posit that inclusion of this category in the ICD-11 will provide a better tool for addressing the unmet clinical needs of treatment seeking patients as well as possibly reduce shame and guilt associated with help seeking among distressed individuals. The proposed diagnostic guidelines will be tested in international multilingual Internet-based field studies using standardized case material, which will help to assess the generalizability of the construct across different regions and cultures, and clinicians’ ability to distinguish it from normal variations in sexual behaviour and from other disorders. Additional field studies in clinical settings will provide further information about the clinical utility of the proposed diagnostic guidelines for the disorder among clinical populations. Shane W. Kraus1, Richard B. Krueger2, Peer Briken3, Michael B. First2, Dan J. Stein4, Meg S. Kaplan2, Valerie Voon5, Carmita H.N. Abdo6, Jon E. Grant7, Elham Atalla8, Geoffrey M. Reed9,10 1Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA; 2Department of Psychiatry, Columbia University, College of Physicians and Surgeons and New York State Psychiatric Institute, New York, NY, USA; 3Institute for Sex Research and Forensic Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Department of Psychiatry, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa; 5Department of Psychiatry, University of Cambridge, Cambridge, UK; 6Department of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil; 7Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA; 8Primary Care and Public Health Directorate, Ministry of Health, Manama, Bahrain; 9Department of Mental Health and Substance Abuse, World Health Organization, Geneva, Switzerland; 10Global Mental Health Program, Columbia University Medical Center, New York, NY, USA

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Prenatal exposure to maternal stress and depression has been identified as a risk factor for adverse behavioral and neurodevelopmental outcomes in early childhood. However, the molecular mechanisms through which maternal psychopathology shapes offspring development remain poorly understood. We applied transcriptome-wide screens to 149 umbilical cord blood samples from neonates born to mothers with posttraumatic stress disorder (PTSD; n = 20), depression (n = 31) and PTSD with comorbid depression (n = 13), compared to carefully matched trauma exposed controls (n = 23) and healthy mothers (n = 62). Analyses by maternal diagnoses revealed a clear pattern of gene expression signatures distinguishing neonates born to mothers with a history of psychopathology from those without. Co-expression network analysis identified distinct gene expression perturbations across maternal diagnoses, including two depression-related modules implicated in axon-guidance and mRNA stability, as well as two PTSD-related modules implicated in TNF signaling and cellular response to stress. Notably, these disease-related modules were enriched with brain-expressed genes and genetic risk loci for autism spectrum disorder and schizophrenia, which may imply a causal role for impaired developmental outcomes. These molecular alterations preceded changes in clinical measures at twenty-four months, including reductions in cognitive and socio-emotional outcomes in affected infants. Collectively, these findings indicate that prenatal exposure to maternal psychological distress induces neuronal, immunological and behavioral abnormalities in affected offspring and support the search for early biomarkers of exposures to adverse in utero environments and the classification of children at risk for impaired development.

Background. There is general consensus that methadone maintenance is the gold standard in the management of pregnant heroin users. However, in South African state hospitals, methadone withdrawal is the routine procedure offered to these patients, as methadone maintenance programmes are unavailable in the public sector. Objectives. To conduct a systematic review of the literature on heroin detoxification in pregnancy, and to document pregnancy outcomes in heroin users detoxified with methadone at Groote Schuur Hospital (GSH), Cape Town, from 2006 to 2010. Methods. A literature search was undertaken to identify key publications on the management of heroin addiction in pregnancy. Patients for the study were identified from the GSH methadone registry, and data were collected from the clinical files. Results. A total of 20 relevant publications were identified and reviewed. Early case reports described an increased risk of stillbirths and fetal distress after methadone detoxification, but more recent case series involving larger numbers of patients showed positive outcomes. In our study, six pregnant patients received methadone withdrawal over a 5-year period at GSH, and all the neonates had good Apgar scores and were discharged home within 3 days of delivery. Conclusions. There is limited evidence on the management of heroin addiction during pregnancy, and the only two guidelines identified suggest that methadone maintenance is preferable to methadone withdrawal. The favourable pregnancy outcomes in this small sample of patients managed with methadone withdrawal suggest that it may be safe and deserves further study.