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Abstract Background Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. Methods Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker. Results Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28–124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment. Conclusion Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function. Trial registration NCT00742911 , first posted 28/08/2008.

Abstract Background Climate change has psychological impacts but most of the attention has been focused on the physical impact. This study was aimed at determining the association of climate change with adolescent mental health and suicidality as reported by Kenyan high school students. Methods This was a cross sectional study with a sample size of 2,652. The participants were high school students selected from 10 schools in 3 regions of Kenya. A questionnaire was used to assess climate change experiences, mental health problems, and suicidality of the youth. Data were analyzed descriptively and with logistic regression to determine various associations of the different variables and the predictors of the various scores of SDQ and suicidality at 95% CI. Results Significant differences were observed between gender and two of the threats of climate change – worry and being afraid as subjectively experienced by the participants. Females were more worried and afraid of climate change than males. On univariate and multivariate logistic regression, we found that various experiences of climate change were significantly associated with various scores of SDQ and much fewer of the experiences predicted SDQ scores. The same pattern was reflected in suicidality. Conclusion Climate change appears to be associated with mental health concerns and suicidality according to Kenyan high school students’ reports with gender differences in some associations.

Background Most evidence on suicidal thoughts, plans and attempts comes from Western countries; prevalence rates may differ in other parts of the world. Aims This study determined the prevalence of suicidal thoughts, plans and attempts in high school students in three different regional settings in Kenya. Method This was a cross-sectional study of 2652 high school students. We asked structured questions to determine the prevalence of various types of suicidality, the methods planned or effected, and participants’ gender, age and form (grade level). We provided descriptive statistics, testing significant differences by chi-squared and Fisher's exact tests, and used logistic regression to identify relationships among different variables and their associations with suicidality. Results The prevalence rates of suicidal thoughts, plans and attempts were 26.8, 14.9 and 15.7%, respectively. These rates are higher than those reported for Western countries. Some 6.7% of suicide attempts were not associated with plans. The most common method used in suicide attempts was drinking chemicals/poison (18.8%). Rates of suicidal thoughts and plans were higher for older students and students in urban rather than rural locations, and attempts were associated with female gender and higher grade level – especially the final year of high school, when exam performance affects future education and career prospects. Conclusion Suicidal thoughts, plans and attempts are prevalent in Kenyan high school students. There is a need for future studies to determine the different starting points to suicidal attempts, particularly for the significant number whose attempts are not preceded by thoughts and plans.

Abstract Background Hundreds of youth psychotherapy randomized trials have generated scores of helpful empirically supported treatments (ESTs). However, the standardized structure of many ESTs and their focus on a single disorder or homogeneous cluster of problems may not be ideal for clinically referred youths who have comorbidity and whose treatment needs may shift from week to week. This concern has prompted development of flexible transdiagnostic, modular youth psychotherapies. One of these, designed for efficient training and implementation, is FIRST—a transdiagnostic intervention built on five empirically supported principles of change (i.e., feeling calm, increasing motivation, repairing thoughts, solving problems, and trying the opposite) and targeting common internalizing and externalizing youth mental health disorders and problems. FIRST has shown promise in improving youth mental health in three open trials. Now, in a more rigorous test, we seek to (1) conduct a randomized controlled trial comparing FIRST to usual care in real-world clinical practice settings; (2) examine a promising candidate mediator of change—regulation of negative emotions; and (3) explore variables that may influence clinicians’ treatment implementation. Methods This is an assessor-naïve randomized controlled effectiveness trial in youth outpatient community clinics in New England and Texas. Using double randomization, clinic-employed clinicians and treatment-referred youths (7–15 years old) are independently randomly allocated (1:1) to FIRST or usual care. We aim to recruit 212 youth participants, all referred through normal community pathways, with elevated symptoms of anxiety, depression, conduct problems, or post-traumatic stress. This study will test the effectiveness of FIRST compared to usual care on mental health outcomes, examine whether those outcomes are mediated by regulation of negative emotions, and explore clinician factors that may be associated with FIRST implementation and outcomes. Session recordings are coded to assess treatment fidelity. Discussion This study will evaluate the effectiveness of FIRST in youth community mental health settings, relative to the care usually provided in those settings. If FIRST is found to be effective, it could offer an efficient and practical method to increase use of empirically supported treatment principles in real-world practice contexts. Trial registration NIH Clinical Trials Registry, NCT04725721. Registered 27 January 2021, https://clinicaltrials.gov/ct2/show/study/NCT04725721

Abstract Background Low- and middle-income countries (LMICs) have the highest socio-economic burden of mental health disorders, yet the fewest resources for treatment. Recently, many intervention strategies, including the use of brief, scalable interventions, have emerged as ways of reducing the mental health treatment gap in LMICs. But how do decision makers prioritize and optimize the allocation of limited resources? One approach is through the evaluation of delivery costs alongside intervention effectiveness of various types of interventions. Here, we evaluate the cost-effectiveness of Shamiri, a group– and school–based intervention for adolescent depression and anxiety that is delivered by lay providers and that teaches growth mindset, gratitude, and value affirmation. Methods We estimated the cost-effectiveness of Shamiri using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guidelines for economic evaluations. Changes in depression and anxiety were estimated using the Patient Health Questionnaire (PHQ-8) and Generalized Anxiety Disorder questionnaire (GAD-7) at treatment termination and 7-month follow-up using two definitions of treatment benefit. Cost-effectiveness metrics included effectiveness-cost ratios and cost per number needed to treat. Results Base case cost assumptions estimated that delivering Shamiri cost $15.17 (in 2021 U.S. dollars) per student. A sensitivity analysis, which varied cost and clinical change definitions, estimated it cost between $48.28 and $172.72 to help 1 student in Shamiri, relative to the control, achieve reliable and clinically significant change in depression and anxiety by 7-month follow-up. Conclusions Shamiri appears to be a low-cost intervention that can produce clinically meaningful reductions in depression and anxiety. Lay providers can deliver effective treatment for a fraction of the training time that is required to become a licensed mental health provider (10 days vs. multiple years), which is a strength from an economic perspective. Additionally, Shamiri produced reliable and clinically significant reductions in depression and anxiety after only four weekly sessions instead of the traditional 12–16 weekly sessions necessary for gold-standard cognitive behavioral therapy. The school setting, group format, and economic context of a LMIC influenced the cost per student; however, broader conclusions about the cost-effectiveness of Shamiri have yet to be determined due to limited economic evaluations of mental health programs in LMICs. Trial registration This study was registered prior to participant enrollment in the Pan-African Clinical Trials Registry (PACTR201906525818462), registered 20 Jun 2019, https://pactr.samrc.ac.za/Search.aspx .

Abstract This study aimed at determining the prevalence of stress, different types of stress, their severity and their determinants in Kenyan university, college and high school students. The following tools were administered to 9741 students: (1) Researcher-designed socio-demographic tool, (2) Psychiatric Diagnostic Screening Questionnaire (PDSQ) for psychiatric disorders, (3) WERC Stress Screen for stress, (4) Washington Early Recognition Center Affectivity and Psychosis (WERCAP) screen for psychosis and affectivity, (5) Wealth Index Questionnaire for economic indicators. Descriptive analysis for the prevalence of different types of stress and inferential analysis for stress and independent variables were done. Significant variables (p

Abstract Background Adolescents in low- and middle-income countries in need of mental health care often do not receive it due to stigma, cost, and lack of mental health professionals. Culturally appropriate, brief, and low-cost interventions delivered by lay-providers can help overcome these barriers and appear effective at reducing symptoms of depression and anxiety until several months post-intervention. However, little is known about whether these interventions may have long-term effects on health, mental health, social, or academic outcomes. Methods Three previous randomized controlled trials of the Shamiri intervention, a 4-week, group-delivered, lay-provider-led intervention, have been conducted in Kenyan high schools. Shamiri teaches positively focused intervention elements (i.e., growth mindset and strategies for growth, gratitude, and value affirmation) to target symptoms of depression and anxiety and to improve academic performance and social relationships, by fostering character strengths. In this long-term follow-up study, we will test whether these mental health, academic, social, and character-strength outcomes, along with related health outcomes (e.g., sleep quality, heart-rate variability and activity level measured via wearables, HIV risk behaviors, alcohol and substance use), differ between the intervention and control group at 3–4-year follow-up. For primary analyses (N anticipated = 432), youths who participated in the three previous trials will be contacted again to assess whether outcomes at 3–4-year-follow-up differ for those in the Shamiri Intervention group compared to those in the study-skills active control group. Multi-level models will be used to model trajectories over time of primary outcomes and secondary outcomes that were collected in previous trials. For outcomes only collected at 3–4-year follow-up, tests of location difference (e.g., t-tests) will be used to assess group differences in metric outcomes and difference tests (e.g., odds ratios) will be used to assess differences in categorical outcomes. Finally, standardized effect sizes will be used to compare groups on all measures. Discussion This follow-up study of participants from three randomized controlled trials of the Shamiri intervention will provide evidence bearing on the long-term and health and mental health effects of brief, lay-provider-delivered character strength interventions for youth in low- and middle-income countries. Trial registration PACTR Trial ID: PACTR202201600200783 . Approved on January 21, 2022.

Abstract Background The earlier younger people begin to use drugs, the more vulnerable they become to both their short term and long-term harmful effects. The overall aim of this study is to determine the prevalence of alcohol and drug abuse, the socio-demographic characteristic, perception of abuse and associated economic indicators and mental disorders and how they inform potential intervention in a cohort of Kenyan students. Methods This was a cross-sectional study on a total of 9742 high school, college and university students. We used tools to document socio-demographic characteristics, economic indicators, drug and alcohol use and related perceptions and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) related psychiatric disorders. Basic descriptive statistics (means and standard deviations for numerical variables and frequencies for nominal and ordinal variables) were done. Logistic regression models were used to assess the association and odds ratios between the use of a given substance and the use of the other substances, as well as associations with the various available socio-demographic factors and economic indicators. Chi-squared tests were used in socio-economic characteristics disaggregated by current alcohol use. Results The mean age was 21.4 ± 2.4; median = 21.3 (range 15–43) years. We found a wide range of different drugs of abuse. Alcohol abuse was the commonest and inhalants were the least, with different perceptions.Both alcohol and drug abuse were associated with various economic indicators and various mental disorders. Conclusion This study has established for the first time in Kenya the multifaceted associations and predictors of alcohol and drug abuse in a cross-sectional student population ranging from high school to college and university levels. In the process, the study contributes to global data on the subject. These associations call for an integrated and multifaceted approach in addressing alcohol and substance abuse. This approach should take into account various associations and predictors as part of holistic approach in both public awareness and clinical interventions.

Abstract Background Treatments for youth mental disorders are a public health priority, especially in sub-Saharan Africa (SSA), where treatment options remain limited due to high cost, elevated stigma, and lack of trained mental health professionals. Brief, accessible, and non-stigmatizing community-based interventions delivered by lay providers may help address treatment needs in SSA. One such intervention, the Shamiri Intervention, consisting of three elements (growth mindset, gratitude, and value affirmation) has been tested in randomized controlled trials with school-going Kenyan adolescents. This three-element Shamiri Intervention has been shown to significantly reduce depression and anxiety symptoms and improve social support and academic performance relative to a control group. In this trial, we aim to investigate the effects of each element of the Shamiri Intervention. Methods In this five-arm randomized controlled trial, we will test each of the intervention components (growth mindset, gratitude, and value affirmation) against the full Shamiri Intervention and against a study skills control intervention. Students (N planned = 1288) at participating secondary schools who are interested in participating in this universal intervention will be randomized in equal numbers into the five groups. The students will meet in groups of 8–15 students led by local high school graduate lay providers. These lay providers will receive a brief training, plus expert supervision once a week throughout the intervention delivery. Multi-level models will be used to compare trajectories over time of the primary outcomes (depressive symptoms, anxiety symptoms, academic performance, and wellness) and secondary outcomes in each intervention group to the control group. Multi-level models will also be used to compare trajectories over time of the primary outcomes (depressive symptoms, anxiety symptoms, academic performance, and wellness) and secondary outcomes of participants in the single-element interventions compared to the full Shamiri Intervention. Finally, effect sizes (calculated as mean gain scores) will be used to compare all groups on all measures. Discussion This trial will shed light on the mechanisms and outcomes targeted by each individual intervention, helping prioritize which mental health interventions are most important to disseminate. Trial registration PACTR Trial ID: PACTR202104716135752 . Approved on 4/19/2021.

Abstract Background Treatment of a child who has an anxiety disorder usually begins with the question of which treatment to start first, medication or psychotherapy. Both have strong empirical support, but few studies have compared their effectiveness head-to-head, and none has investigated what to do if the treatment tried first isn’t working well—whether to optimize the treatment already begun or to add the other treatment. Methods This is a single-blind Sequential Multiple Assignment Randomized Trial (SMART) of 24 weeks duration with two levels of randomization, one in each of two 12-week stages. In Stage 1, children will be randomized to fluoxetine or Coping Cat Cognitive Behavioral Therapy (CBT). In Stage 2, remitters will continue maintenance-level therapy with the single-modality treatment received in Stage 1. Non-remitters during the first 12 weeks of treatment will be randomized to either [1] optimization of their Stage 1 treatment, or [2] optimization of Stage 1 treatment and addition of the other intervention. After the 24-week trial, we will follow participants during open, naturalistic treatment to assess the durability of study treatment effects. Patients, 8–17 years of age who are diagnosed with an anxiety disorder, will be recruited and treated within 9 large clinical sites throughout greater Los Angeles. They will be predominantly underserved, ethnic minorities. The primary outcome measure will be the self-report score on the 41-item youth SCARED (Screen for Child Anxiety Related Disorders). An intent-to-treat analysis will compare youth randomized to fluoxetine first versus those randomized to CBT first (“Main Effect 1”). Then, among Stage 1 non-remitters, we will compare non-remitters randomized to optimization of their Stage 1 monotherapy versus non-remitters randomized to combination treatment (“Main Effect 2”). The interaction of these main effects will assess whether one of the 4 treatment sequences (CBT➔CBT; CBT➔med; med➔med; med➔CBT) in non-remitters is significantly better or worse than predicted from main effects alone. Discussion Findings from this SMART study will identify treatment sequences that optimize outcomes in ethnically diverse pediatric patients from underserved low- and middle-income households who have anxiety disorders. Trial registration This protocol, version 1.0, was registered in ClinicalTrials.gov on February 17, 2021 with Identifier: NCT04760275 .

Background: Severe irritability is a common, impairing problem among youth referred for mental health services, but evidence to guide care is limited. Treatment research can be advanced by adopting a transdiagnostic perspective, leveraging existing evidence-based treatment (EBT) techniques, and situating irritability within the context of emotion dysregulation. Accordingly, this study examined treatment outcomes for youth with different levels of irritability and dysregulation who received cognitive-behavioral therapy (CBT) or behavioral parent training (BPT) in a modular EBT framework.Method: We analyzed data from a community-based implementation trial of a transdiagnostic youth psychotherapy. Two-hundred treatment-referred youths (7-15 years; 47% female; 33% White, 28% Black, 24% Latinx, 14% multiracial, 2% other) and their caregivers completed measures of clinical problems and emotion dysregulation at baseline, with repeated outcomes assessments over 18 months. First, latent profile analysis was applied to baseline irritability and emotion dysregulation data; then, latent growth curve models were used to examine outcome trajectories, controlling for covariates.Results: A two-class solution fit well, differentiating youth with high (n = 54) vs. low (n = 146) levels of dysregulation and irritability at baseline. Nearly all high-dysregulation youth received either BPT (n = 26) or CBT-Depression (n = 23). Across measures, both groups showed statistically and clinically significant improvements over time. High-dysregulation youth had greater baseline severity than low-dysregulation youth, but otherwise their longitudinal trajectories were mostly similar, with few between-group slope differences. There was virtually no evidence of differential effects for BPT vs. CBT on clinical outcomes.Conclusions: Youth with severe irritability and dysregulation, treated with a transdiagnostic, modular, EBT approach, showed significant within-person improvements over time. Their outcome trajectories did not differ according to whether they received BPT or CBT. Findings extend the literature on modular, transdiagnostic, and EBT approaches for irritability and dysregulation, suggesting comparable benefits associated with BPT and CBT when treatment selection is guided by comprehensive assessment.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03153904.

Introduction: Schools have become a primary setting for providing mental health care to youths in the U.S. School-based interventions have proliferated, but their effects on mental health and academic outcomes remain understudied. In this study we will implement and evaluate the effects of a flexible multidiagnostic treatment called Modular Approach to Therapy for Children with Anxiety, Depression, Trauma, or Conduct Problems (MATCH) on students' mental health and academic outcomes.Methods and Analysis: This is an assessor-blind randomized controlled effectiveness trial conducted across five school districts. School clinicians are randomized to either MATCH or usual care (UC) treatment conditions. The target sample includes 168 youths (ages 7–14) referred for mental health services and presenting with elevated symptoms of anxiety, depression, trauma, and/or conduct problems. Clinicians randomly assigned to MATCH or UC treat the youths who are assigned to them through normal school referral procedures. The project will evaluate the effectiveness of MATCH compared to UC on youths' mental health and school related outcomes and assess whether changes in school outcomes are mediated by changes in youth mental health.Ethics and Dissemination: This study was approved by the Harvard University Institutional Review Board (IRB14-3365). We plan to publish the findings in peer-reviewed journals and present them at academic conferences.Clinical Trial Registration:ClinicalTrials.gov ID: NCT02877875. Registered on August 24, 2016.

Mental health disorders are prevalent among youth and adolescents in low- and middle-income countries, and access to evidence-based treatments is poor. Although there is a great need for high-quality research to serve young people in low- and middle-income countries, there is limited guidance available for researchers who wish to conduct such work. Here, we describe our process of conducting school-based youth mental health work in Kenya over the last several years. We focus on five key lessons we learned that could guide future global mental health work with youth: (a) reducing stigma with strengths-focused interventions, (b) expanding access by working in schools, (c) generating buy-in from local stakeholders, (d) adapting the intervention via multicultural collaboration, and (e) applying insights from low- and middle-income countries to serve young people in high-income countries. We conclude by discussing how these lessons, and those shared by other teams, can be applied to help reduce the treatment gap for young people around the world.