Edward J. Mills

Background:Depression is a critical public health issue among youth in Uganda, with limited access to mental health services. This pilot randomized controlled trial (RCT) evaluated the mechanisms and cost-effectiveness of mobile phone-based Tele-Support Psychotherapy (TSP) delivered by lay counselors for youth with depression in Kampala. Methods: We randomized 300 youth aged 15–30 with mild to moderate depression to TSP combined with Standard Mental Health Services (SMHS) or SMHS alone. Assessments at baseline, 6, and 12 months measured depression (Mini International Neuropsychiatric Interview), stigma, and income generation. Generalized structural equation modeling (GSEM) explored mediation pathways, and a provider-perspective cost-effectiveness analysis calculated the incremental cost-effectiveness ratio (ICER) using disability-adjusted life years (DALYs). Results: TSP significantly reduced depression through stigma reduction and increased income generation (total effect β = -3.736, p<0.001, 95% CI [-4.273, -3.198]). The ICER was US$2,293 per DALY averted, cost-effective compared to Uganda’s GDP per capita (US$1,002). Conclusions: TSP is an effective and cost-effective intervention for youth depression in low-resource settings, with potential for integration into national mental health strategies. Trial Registration: PACTR202201684613316.

In response to the rise in mental health problems among youth during the COVID-19 pandemic, we conducted a qualitative study in March 2022, using a user-centered design approach guided by ecological theories, to adapt group support psychotherapy into tele-support psychotherapy (TSP) via mobile phones. The development of a call platform, informed by the unified theory of acceptance and use of technology, was integrated into the Medical Concierge Group’s (TMCG) telehealth services under Rocket Health Africa. This platform included a dedicated toll-free line for psychotherapy, connecting users with lay counselors. An open-label randomized controlled trial (PACTR202201684613316) was conducted to assess the feasibility, acceptability, and effectiveness of TSP in combination with standard mental health services (n = 154) compared with standard mental health services alone (n = 146) among youth with mild to moderate major depression in Kampala. Participants commonly equated mental health with mental illness and reported significant challenges, including financial stress, substance abuse, and family dysfunction. Although digital interventions were largely accepted, some participants preferred in-person services. The adapted TSP maintained gender sensitivity and used folk tales, stories, riddles, and creative visualizations to facilitate emotional expression, acquisition of coping strategies, and income-generating skills, addressing both emotional and socio-economic needs.

After successfully developing and evaluating group support psychotherapy (GSP) as a first-line treatment for mild-to-moderate depression in adults, we aimed to adapt and assess this approach for children and adolescents (CA) (ages 10–18) living with HIV. In June 2021, 30 young people and 30 caregivers participated in separate GSP sessions. Data on psychosocial issues and GSP effectiveness were collected through focus groups and interviews. Insights were guided by the ecological validity and culturally sensitive framework. An open-label randomized controlled trial in Kitgum, with 120 participants, registered with PACTR, number 202006601935462, compared GSP plus intensive adherence counseling (IAC) to IAC alone, assessing feasibility, acceptability, depression, anxiety, and HIV treatment outcomes. We found that CA with HIV struggled with self-esteem issues, suicidal thoughts, medication adherence, and food insecurity, alongside stigma, discrimination, and limited mental health programs. The adult GSP model was adapted for CA by creating gender- and age-specific groups, simplifying language, and incorporating play and expressive art activities. Caregivers were concurrently engaged with the adult GSP model. GSP participants showed a significantly greater reduction in depression symptoms compared to IAC participants.

Randomized clinical trials (RCTs) are essential for establishing evidence of comparative efficacy since prognostic factors (known or unknown) are more equally distributed across treatment groups after randomization compared with nonrandomized populations. Placebo-controlled RCTs in which the placebo intervention has been matched to the characteristics of the experimental intervention (eg, route of administration, frequency, and visual appearance) are considered the standard.¹

Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424). 12 clinical sites in Brazil. Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. Low event rate overall, consistent with contemporary trials in vaccinated populations. Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. Latona Foundation, FastGrants, and Rainwater Charitable Foundation.

Clinical trial endpoints must be carefully and intentionally selected so that the results of the trial can be used to inform policy- and decision-making. The relative importance of potential endpoints often depends on the stakeholder, with patients having different preferences to policymakers and regulators. The set up of clinical trials for COVID-19 was problematic, as endpoints that could be reasonably measured did not always match the efficacy endpoints usually required by guideline panels. Thus, different endpoints were used, which made the timely comparison and evaluation of interventions difficult. Here we discuss the evolution of the COVID-19 landscape and the effect this is having on the selection of consistent and measurable clinical trial endpoints. Using appropriate endpoints is crucial for researchers to offer the most reliable, valid, and interpretable results possible.

Approximately 20% of people infected with COVID-19 develop at least one persistent condition potentially attributable to their SARS-CoV-2 infection. We sought to determine the effectiveness of early COVID-19 treatment interventions on long COVID symptoms. We conducted a multi-arm multi-stage adaptive platform trial at 12 public health clinics in Brazil between June 2020 and July 2022. Participants were followed for 60. Patients received one of six interventions (doxazosin, fluvoxamine, fluvoxamine in combination with inhaled budesonide, interferon-lambda, ivermectin, or metformin) or matching placebo. The primary outcome was persistence of COVID-19 symptoms at 60 days after randomization. We analyzed data from 5,700 participants across study cohorts. Overall, approximately 22% of patients reported at least one ongoing symptom 60 days after randomization, regardless of the early treatment they received. At day 60, we did not find any statistical benefit of any intervention on recovery, cure fractions, or PROMIS scores (mental and physical).

To date, two published randomized trials have indicated a clinical benefit of early treatment with fluvoxamine versus placebo for adults with symptomatic COVID-19. Using the results of the largest of these trials, the TOGETHER trial, we conducted a cost–consequence analysis to assess the health system benefits of preventing progression to severe COVID-19 in outpatient populations in the United States. A decision-analytic model in the form of a decision tree was constructed to evaluate two treatment strategies for high-risk patients with confirmed, symptomatic COVID-19 in the primary analysis: treatment with a 10-day course of fluvoxamine (100 mg twice daily) and current standard-of-care. A secondary analysis comparing a 5-day course of nirmatrelvir–ritonavir was also conducted. We used a time horizon of 28 days. Reported outcomes included cost-savings and hospitalization days avoided. The results of our analysis indicated that administration of fluvoxamine to symptomatic outpatients at high risk of progressing to severe COVID-19 was substantially cost-saving, in the amount of $232 per eligible patient and prevented an average of 0.15 hospital days per patient treated, compared with standard of care. Nirmatrelvir–ritonavir was also shown to be cost-saving despite its higher acquisition cost and provided savings to the healthcare system of $625 per patient treated. These findings suggest that fluvoxamine is likely to be a cost-effective addition to frontline COVID-19 mitigation strategies in many settings, particularly where access to nirmaltrevir–ritonavir or monoclonal antibodies is limited.