Fluoxetine Increases GABA A Receptor Activity through a Novel Modulatory Site

ABSTRACT Fluoxetine is a selective serotonin reuptake inhibitor used widely in the treatment of depression. In contrast to the proconvulsant effect of many antidepressants, fluoxetine has anticonvulsant activity. This property may be due in part to positive modulation of the GABA A receptors (GABARs), which mediate most fast inhibitory neurotransmission in the mammalian brain. We examined the effect of fluoxetine on the activity of recombinant GABARs transiently expressed in mammalian cells. Fluoxetine increased the response of the receptor to submaximal GABA concentrations but did not alter the maximum current amplitude. Sensitivity did not depend upon the ␤-or ␥-subtype composition of the receptor when coexpressed with the ␣ 1 subunit. Among the six ␣ subtypes, only the ␣ 5 subunit conferred reduced sensitivity to fluoxetine. The metabolite norfluoxetine was even more potent than fluoxetine. Mutations at residues in the ␣ 5 subunit that alter its sensitivity to zinc or selective benzodiazepine derivatives did not affect potentiation by fluoxetine. This suggests that fluoxetine acts through a novel modulatory site on the GABAR. The direct positive modulation of GABARs by fluoxetine may be a factor in its anticonvulsant activity

Predicting the risk of future depression among school-attending adolescents in Nigeria using a model developed in Brazil

Depression commonly emerges in adolescence and is a major public health issue in low- and middle-income countries where 90% of the world's adolescents live. Thus efforts to prevent depression onset are crucial in countries like Nigeria, where two-thirds of the population are aged under 24. Therefore, we tested the ability of a prediction model developed in Brazil to predict future depression in a Nigerian adolescent sample. Data were obtained from school students aged 14–16 years in Lagos, who were assessed in 2016 and 2019 for depression using a self-completed version of the Mini International Neuropsychiatric Interview for Children and Adolescents. Only the 1,928 students free of depression at baseline were included. Penalized logistic regression was used to predict individualized risk of developing depression at follow-up for each adolescent based on the 7 matching baseline sociodemographic predictors from the Brazilian model. Discrimination between adolescents who did and did not develop depression was better than chance (area under the curve = 0.62 (bootstrap-corrected 95% CI: 0.58–0.66). However, the model was not well-calibrated even after adjustment of the intercept, indicating poorer overall performance compared to the original Brazilian cohort. Updating the model with context-specific factors may improve prediction of depression in this setting

Predicting the risk of depression among adolescents in Nepal using a model developed in Brazil : the IDEA Project

The burden of adolescent depression is high in low- and middle-income countries (LMICs), yet research into prevention is lacking. Development and validation of models to predict individualized risk of depression among adolescents in LMICs is rare but crucial to ensure appropriate targeting of preventive interventions. We assessed the ability of a model developed in Brazil, a middle-income country, to predict depression in an existing culturally different adolescent cohort from Nepal, a low-income country with a large youth population with high rates of depression. Data were utilized from the longitudinal study of 258 former child soldiers matched with 258 war-affected civilian adolescents in Nepal. Prediction modelling techniques were employed to predict individualized risk of depression at age 18 or older in the Nepali cohort using a penalized logistic regression model. Following a priori exclusions for prior depression and age, 55 child soldiers and 71 war-affected civilians were included in the final analysis. The model was well calibrated, had good overall performance, and achieved good discrimination between depressed and non-depressed individuals with an area under the curve (AUC) of 0.73 (bootstrap-corrected 95% confidence interval 0.62-0.83). The Brazilian model comprising seven matching sociodemographic predictors, was able to stratify individualized risk of depression in a Nepali adolescent cohort. Further testing of the model's performance in larger socio-culturally diverse samples in other geographical regions should be attempted to test the model's wider generalizability

Adolescent depression beyond DSM definition: a network analysis

Calls for refning the understanding of depression beyond diagnostic criteria have been growing in recent years. We examined the prevalence and relevance of DSM and non-DSM depressive symptoms in two Brazilian school-based adolescent samples with two commonly used scales, the Patient Health Questionnaire (PHQ-A) and the Mood and Feelings Questionnaire (MFQ). We analyzed cross-sectional data from two similarly recruited samples of adolescents aged 14–16 years, as part of the Identifying Depression Early in Adolescence (IDEA) study in Brazil. We assessed dimensional depressive symptomatology using the PHQ-A in the frst sample (n=7720) and the MFQ in the second sample (n=1070). We conducted network analyses to study symptom structure and centrality estimates of the two scales. Additionally, we compared centrality of items included (e.g., low mood, anhedonia) and not included in the DSM (e.g., low self-esteem, loneliness) in the MFQ. Sad mood and worthlessness items were the most central items in the network structure of the PHQ-A. In the MFQ sample, self-hatred and loneliness, two non-DSM features, were the most central items and DSM and non-DSM items in this scale formed a highly interconnected network of symptoms. Furthermore, analysis of the MFQ sample revealed DSM items not to be more frequent, severe or interconnected than non-DSM items, but rather part of a larger network of symptoms. A focus on symptoms might advance research on adolescent depression by enhancing our understanding of the disorder.publishedVersio

Protocol for a systematic review of the development of depression among adolescents and young adults : psychological, biological, and contextual perspectives around the world

Background: Depression is a leading contributor to disability-adjusted life-years because of early onset and chronicity throughout the lifecycle. It is crucial to identify early predictors of depression among adolescents and young people to effectively target prevention. A gap in the literature is a comprehensive systematic review of predictors of depression among adolescents around the globe, especially in low- and middleincome countries LMICs. This review aims to identify evidence for biological, psychological, and contextual risk factors for the development of depression among adolescents and young adults (10–24 years of age) in high-income countries (HICs) and LMICs, ultimately contributing to (a) identification of potential mechanisms underlying depression development, (b) selection of common risk and protective factors as targets for detection, and (c) refinement of risk models that can be evaluated through existing cohorts in HICs and LMICs. Methods: This review will follow the Population, Exposure, Comparison, Outcome (PI(E)CO) model and adheres to the PRISMA-P guidelines. A search strategy was developed by a multidisciplinary research consortium. Seven databases (MEDLINE via Ovid, PsycINFO, Cochrane Database of Systematic Reviews, Web of Science, Lilacs, African Journals Online, Global Health) will be searched to identify articles. Independent raters will screen and retrieve articles for inclusion, conduct quality ratings, and extract data. The Systematic Assessment of Quality in Observational Research adapted for Cultural Psychiatry Epidemiology (SAQOR-CPE) will be used to assess quality of observational studies. We will assess for publication bias using funnel plots and statistical methods. We will use narrative synthesis to present results, addressing the study’s objectives following the Cochrane Handbook guidelines. Meta-analyses will be used to report summary statistics for association of risk factors with development of depression. Discussion: This systematic review will summarize evidence-based research that examines the psychological, biological, and contextual factors contributing to the onset of depression in adolescents across the globe. Results will support the development of a model that can be evaluated in existing cohorts around the world

Mind the brain gap: the worldwide distribution of neuroimaging research on adolescent depression

Adolescents comprise one fourth of the world’s population, with about 90% of them living in low- and middleincome countries (LMICs). The incidence of depression markedly increases during adolescence, making the disorder a leading cause of disease-related disability in this age group. However, most research on adolescent depression has been performed in high-income countries (HICs). To ascertain the extent to which this disparity operates in neuroimaging research, a systematic review of the literature was performed. A total of 148 studies were identified, with neuroimaging data available for 4,729 adolescents with depression. When stratified by income group, 122 (82%) studies originated from HICs, while 26 (18%) were conducted in LMICs, for a total of 3,705 and 1,024 adolescents with depression respectively. A positive Spearman rank correlation was observed between country per capita income and sample size (rs=0.673, p = 0.023). Our results support the previous reports showing a large disparity between the number of studies and the adolescent population per world region. Future research comparing neuroimaging findings across populations from HICs and LMICs may provide unique insights to enhance our understanding of the neurobiological processes underlying the development of depression

What makes it so hard to look and to listen? Exploring the use of the Cognitive and Affective Supervisory Approach with children’s social work managers

This paper reports on the findings of an ESRC-funded Knowledge Exchange project designed to explore the contribution of an innovative approach to supervision to social work practitioners’ assessment and decision-making practices. The Cognitive and Affective Supervisory Approach (CASA) is informed by cognitive interviewing techniques originally designed to elicit best evidence from witnesses and victims of crime. Adapted here for use in childcare social work supervision contexts, this model is designed to enhance the quantity and quality of information available for decision-making. Facilitating the reporting of both ‘event information’ and ‘emotion information’, it allows a more detailed picture to emerge of events, as recalled by the individual involved, and the meaning they give to them. Practice supervisors from Children’s Services in two local authorities undertook to introduce the CASA into supervision sessions and were supported in this through the provision of regular reflective group discussions. The project findings highlight the challenges for practitioners of ‘detailed looking’ and for supervisors of ‘active listening’. The paper concludes by acknowledging that the CASA’s successful contribution to decision-making is contingent on both the motivation and confidence of supervisors to develop their skills and an organisational commitment to, and resourcing of, reflective supervisory practices and spaces