Ignite Creation Date:
2024-05-06 @ 3:50 PM
Last Modification Date:
2024-10-26 @ 1:58 PM
Study NCT ID:
NCT04777006
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-04-25
First Post:
2021-02-23
Brief Title:
Integrating a Stepped Care Model of Screening and Treatment for Depression Into Malawis National HIV Care Delivery Platform
Sponsor:
RAND
Organization:
RAND
Study Overview
Official Title:
Integrating a Stepped Care Model of Screening and Treatment for Depression Into Malawis National HIV Care Delivery Platform
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
IC3D
Brief Summary:
Malawi is a low-income country in sub-Saharan Africa that has limited resources to address a significant burden of disease-including HIVAIDS Additionally depression is a leading cause of disability in the country but largely remains undiagnosed and untreated Lack of cost-effective scalable solutions is a fundamental barrier to expanding depression treatment Against this backdrop one major success has been the scale-up of a network of more than 700 HIV clinics with over half a million patients enrolled in ART As a chronic care system with dedicated human resources and infrastructure this presents a strategic platform for integrating depression care and responds to a robust evidence base outlining the bi-directionality of depression and HIV outcomes
The investigators will evaluate a stepped model of depression care that combines group-based Problem Management Plus group PM with antidepressant therapy ADT for 420 adults with moderatesevere depression in Neno District Malawi as measured by the Patient Health Questionnaire-9 PHQ-9 Rollout will follow a stepped-wedge cluster randomized design in which 14 health facilities are randomized to implement the model in five steps over a 15-month period Primary outcomes depression symptoms functional impairment and overall health and secondary outcomes eg HIV viral load ART adherence diabetes A1C levels treatment adherence hypertension systolic blood pressure treatment adherence will be measured every three months through 12-month follow-up The investigators will also evaluate the models cost-effectiveness quantified as an incremental cost-effectiveness ratio ICER compared to baseline chronic care services in the absence of the intervention model
This study will conduct a stepped-wedge cluster randomized trial to compare the effects of an evidence-based depression care model versus usual care on depression symptom remediation as well as physical health outcomes for chronic care conditions The investigators will also look at the indirect effects of the intervention at the household level The investigators hypothesis is that the intervention will be effective at reducing depression symptoms improving physical health and improving household members wellbeing compare to treatment as usual The investigators also hypothesize that the intervention will be highly cost-effective meaning that the cost per QALY gained will be less than Malawis median GDP per capita If determined to be effective and cost-effective this study will provide a model for integrating depression care into HIV clinics in additional districts of Malawi and other low-resource settings with high HIV prevalence
The investigators will evaluate a stepped model of depression care that combines group-based Problem Management Plus group PM with antidepressant therapy ADT for 420 adults with moderatesevere depression in Neno District Malawi as measured by the Patient Health Questionnaire-9 PHQ-9 Rollout will follow a stepped-wedge cluster randomized design in which 14 health facilities are randomized to implement the model in five steps over a 15-month period Primary outcomes depression symptoms functional impairment and overall health and secondary outcomes eg HIV viral load ART adherence diabetes A1C levels treatment adherence hypertension systolic blood pressure treatment adherence will be measured every three months through 12-month follow-up The investigators will also evaluate the models cost-effectiveness quantified as an incremental cost-effectiveness ratio ICER compared to baseline chronic care services in the absence of the intervention model
This study will conduct a stepped-wedge cluster randomized trial to compare the effects of an evidence-based depression care model versus usual care on depression symptom remediation as well as physical health outcomes for chronic care conditions The investigators will also look at the indirect effects of the intervention at the household level The investigators hypothesis is that the intervention will be effective at reducing depression symptoms improving physical health and improving household members wellbeing compare to treatment as usual The investigators also hypothesize that the intervention will be highly cost-effective meaning that the cost per QALY gained will be less than Malawis median GDP per capita If determined to be effective and cost-effective this study will provide a model for integrating depression care into HIV clinics in additional districts of Malawi and other low-resource settings with high HIV prevalence
Detailed Description:
BACKGROUND
Major depressive disorder imposes catastrophic health and economic impacts in Malawi and throughout sub-Saharan Africa Depression is a leading cause of disability in Malawi Yet best evidence suggests that over 90 of individuals with the condition receive no treatment 1 The cost of inaction is liable to have wide-ranging impacts In terms of health depression-when untreated-typically observes a recurrent trajectory across the lifespan and is associated with significant depreciation in quality of life Depression also indirectly impacts other health outcomes including HIV outcomes such as adherence to antiretroviral therapy and health-seeking behavior In terms of social ecology depression affects interpersonal relationships engagement in household activities and labor force participation The World Economic Forum has estimated a 30 trillion loss over a twenty-year span due to neglected treatment of neuropsychiatric conditions largely due to lost labor force participation 2
Integrating depression care into Nenos HIV platform represents a cost-effective scalable solution in Neno District Malawi consistent with best practices Over the past 10 years Malawi has enrolled over a million individuals in antiretroviral therapy Current enrollment levels stand at 580000 This has been achieved by introducing a framework of HIV care delivery the basis of which is a network of 706 HIV clinics throughout the country Over this same timeframe HIV has evolved from an acute condition with poor prognosis to a chronic condition with vastly improved survival rates Given this context the HIV system is a strategic point of entry for screening and treating depression as it represents a leveragable chronic care system In Neno District HIV facilities have already transitioned into an integrated chronic care platform for treating conditions like diabetes hypertension asthma and epilepsy Likewise community health screenings routine in Malawi could be leveraged to screen for depression
Overarching Objective Evaluate a clinical model of screening and treatment for depression in terms of real world effectiveness and cost-effectiveness at reducing depression in Neno District
Objective 1 Determine the implementation strategy effectiveness-in terms of improved depression PHQ-9 daily functioning WHODAS and overall health EQ5D-of introducing a stepped model of depression care behavioral therapy and antidepressant therapy among adults receiving integrated chronic care in Neno District Malawi between July 1 2021-June 30 2025
Objective 2 Determine the cost-effectiveness the stepped model of depression care behavioral therapy and antidepressant therapy among adults receiving integrated chronic care in Neno District Malawi between July 1 2021-June 30 2025
Objective 3 Assess positive externalities associated with depression care including improved wellbeing among household members of treated patients and improved physical health outcomes among patients receiving depression care
Objective 4 Inspect mediators and moderators of improved depression care including a dose effect from level of treatment received number of behavioral therapy sessions reduced internalized mental health stigma and improved perceived social support
RATIONALE
The framework strategically addresses the bi-directionality of depression and HIV outcomes A broad literature throughout sub-Saharan Africa has outlined the impact of HIV-including HIV-related stigma reduced quality of life and ability to maintain employment-on elevated depression levels 3 Depression in turn predicts HIV-related outcomes such as adherence to ART As such targeting depression care among a population that includes HIV individuals in Malawi should yield significant benefits in terms of HIV-related outcomes Outside sub-Saharan Africa there is increasing evidence that integrative health services represents stronger value for money than stand-alone models
Research examining the benefits and costs of treating neuropsychiatric conditions including depression suffers two key limitations First evaluations have only measured individual-level direct treatment effects This approach under-appreciates the social ecology of mental health that individuals are typically situated within families and families within communities From this lens neuropsychiatric disorders have shown adverse effects-in terms of burden of care and emotional wellbeing-on household members Previously the investigators showed that when individuals mental health improves through treatment indirect benefits are observed among household members 4 Likewise measurement limited to direct treatment effects overlooks indirect benefits to overall health including for comorbid conditions such as HIV that may result from mental health intervention A second shortcoming is that evaluations have focused on measuring costs of standalone interventions which are costlier than those that leverage existing systems For instance interventions for youth have often integrated within school systems to lower costs In Malawi the national HIV system-already transitioning to an integrated chronic care platform in Neno District-holds potential to treat depression at lower costs by building on established systems of longitudinal care
In terms of historical objectives a preponderance of mental health evaluations in low-resource settings has stopped at the point of measuring effectiveness rather than cost-effectiveness with a few exceptions by project members The consequences are marked In settings of financial constraint such as Neno District Malawi resources allocated to a particular program necessarily means resources allocated away from another As such assessing intervention costs are fundamental for determining scalability A collaborative care model of treatment for depression and comorbid conditions such as HIV and diabetes has the potential to overcome resource constraints which cost-effectiveness analysis would demonstrate
The investigators will evaluate an evidence-based stepped care model of depression treatment integrated into Nenos HIV system assessing health outcomes and cost-effectiveness inclusive of direct and indirect benefits Partners In Health PIH in collaboration with the Malawian Ministry of Health has operated in Neno District-home to 165000 Malawians-for 12 years The investigators proposed to integrate a stepped care model for depression-combining antidepressant therapy ADT with group-based Problem Management Plus PM the elements of which have been successfully instituted by the research team in low-resource settings ranging from Rwanda to Haiti The proposed study will evaluate a model that trains clinical staff situated in clinics to screen and diagnose depression and administer PM among those with a diagnosis of moderate or severe depression Over five weekly 15-25 hour group sessions the behavioral intervention combines empirically-based treatment components such as psychoeducation strategic problem solving and behavioral activation 5 This will be coupled with antidepressant therapy ADT among those with severe depression
To assess intervention benefits the investigators will measure patient outcomes for depression every 3 months-including baseline post-intervention 6-months and 12-months follow-up-as well as markers of comorbid conditions including viral load and ART adherence among those are HIV 71 of the sample as well as other disease-specific outcomes such as systolic blood pressure for hypertensive patients 17 of sample and hemoglobin A1C for diabetic patients 2 of sample-supported by an electronic medical records system Importantly to quantify indirect benefits of depression care the investigators will also interview household members at baseline and 6-months follow-up to evaluate burden of care including emotional distress and missed days of work The investigators will convert direct and indirect benefits to quality-adjusted life years QALYs
METHODS
Design of Study We will implement a stepped-wedge cluster randomized trial of an evidence-based intervention for depression care within Nenos HIV system currently undergoing transition to a chronic care platform examining depression symptoms and outcomes of comorbid conditions inclusive of HIV across 14 facilities rolled-out clinic-wide in five steps over 15 months 6 This design is a gold standard experimental approach aligned with PIHs clinical goal to implement depression care permanently throughout Neno District and is a methodological framework on which we have unique expertise including locally
Place of Study This study will take place in Neno District a catchment area of 165000 Malawians where 12186 are enrolled in integrated chronic care-including for HIV Five-year retention in ART in Neno District is 80 while five-year mortality is close to 15 The viral suppression rate is 83 These figures signify Neno as high performing but also underscores significant room for improvement-particularly among the most vulnerable such as those with depression As such we do not anticipate a ceiling effect for measuring HIV outcomes among those concurrently enrolled in depression care This is also true for other chronic conditions eg only 60 of hypertensive patients currently have controlled systolic blood pressure 140 mm Hg Successes to-date have been achieved through modest human resource investments such as CHWs suggesting replicability nationally This has been supported by the investigators past cost-effectiveness analyses
Target Population The investigators intend to recruit at least 420 adults with depression for participation in this study beginning July 1 2021 and continuing through June 30 2025 This number is based on the sample size needed for us to determine the effectiveness of the depression treatment as well as the prevalence of depression in Malawi At each ICC clinic 200-1800 patients are seen on a quarterly basis The investigators anticipate 10-12 of all patients n12186 will screen positive for depressive symptoms and 6 will be diagnosed with moderatesevere depression Prior studies in Malawi have found acceptance of research study participation is 90 or higher In addition the investigators will be conducting interviews with 210 households among half of participants-in order to determine whether the intervention improves quality of life within households
Sampling Techniques and Tools The full study period is January 1 2021 through June 30 2025 The first six months will be preparation Beginning July 1 2021 all adults attending integrated chronic care clinics will be screened for depression symptoms using the PHQ-2 by existing clinical officers Consistent with the prior screening literature those with a score 2 will complete remaining questions of the PHQ-9 and a score 9 will trigger administration of a brief diagnostic interview--adapted from the CIDI 30--by a trained counselor Those with PHQ-910 nomild depression will receive a psychoeducation session but will not be enrolled-based on limited availability of health professionals and need-based prioritization Those with moderatesevere depression PHQ-99 corresponding to diagnosis of major depression will be eligible for cohort enrollment Screening diagnosis and enrollment will occur continuously across all facilities over the full trial period those who meet diagnostic criteria will be enrolled Treatment will be rolled-out progressively patients in each clusters cohort will be initiated into the intervention Three facilities will begin treatment immediately Step 1 with remaining facilities will initiate treatment at three- Step 2 six- Step 3 nine- Step 4 or twelve-months Step 5 later The stepped-wedge approach enables all facilities throughout Neno District to implement the model as such maintaining equipoise Assessment of patients on outcome measures will occur at every 3 months
Sample Size Determination The investigators assume n30 enrollees per facility total n420 based on depression prevalence in Malawi The investigators further assume loss to follow-up of 15 based on intervention trials that the investigators have conducted in similar settings To account for clustering the investigators calculated detectable differences using an intracluster correlation coefficient ICC of 005 within treatment group and 001 within rollout step based on depression treatment studies in multiple developing countries including the investigators pilot work Based on this the investigators find n420 enrollees to be sufficient power 080 alpha05 2-tailed for detecting a clinically meaningful standardized effect size of 05 Cohens d for primary outcomes including accounting for cluster autocorrelation This is not separated by modality though the investigators will explore this it is to assess overall effectiveness of the stepped care model
Data Collection Techniques and Tools Over the 15-month roll-out period primary outcomes PHQ-9 WHODAS EQ5D will be measured at three-month intervals among all participants from point of enrollment consistent with the three-month increments between steps see above Three-month increments will coincide with treatment initiation post-intervention 6 months and 12 months follow-up In the event an enrolled individual no longer meets criteria at treatment initiation the individual will leave the cohort and not be eligible for treatment but will continue to be evaluated every three months for future eligibility Given that screening diagnosis and enrollment will occur at all facilities over the full trial period the investigators expect any reduction in patients enrolled in the cohort due to lagged treatment initiation will be offset by newly-identified individuals over this same period This is consistent with an open cohort design for stepped-wedge trials Ultimately this approach enables all facilities to implement the model maintain equipoise and create control sites by randomizing roll-out sequence Measurement intervals are consistent with best practices in outcomes tracking including past trials Interviews with household members will be conducted at treatment initiation and 6-month follow-up among 210 randomized households
Data Analysis Analysis will assume a mixed-effects longitudinal regression framework which the team has implemented in similar contexts To account for nesting of patients within treatment groups and clusters as well as time points autocorrelation patient patient group and cluster will be incorporated as random effects while cluster assignment and covariates are included as fixed effects-using STATAs MIXED command The investigators will run sensitivity analyses to test if data are missing at random MAR and examine stigma and social support as moderators as well as potential mediation using causal mediation analysis
Effectiveness The investigators will use linear mixed-effects regression analysis to test differences between study arms on change in primary outcomes Models will adjust for patient demographics as well as stigma and social support Analysis will assume an intention-to- treat ITT framework with and without multiple imputation analysis In addition to ITT the investigators will perform a completers only analysis to exam outcomes among those who adhered to treatment and examine dose response
Cost-effectiveness Health measures will be converted to QALYs using the EQ5D-3L cross-walk between domain-specific outcomes This approach has been utilized and published on previously QALY estimates will be related to base case and treatment cost estimates For formal CEA the investigators will use a gold standard Markov chain Monte Carlo MCMC simulation-based approach in TreeAge from a societal perspective For sensitivity analyses the investigators will vary discount rates from 0-5 based on health-adjusted life expectancy Unit of interest is the incremental cost-effectiveness ratio ICER of cost per QALY comparing the cost of integrated chronic care before and after introduction of the depression treatment
PROTOCOL
Evidence-based treatment of depression Drawing from a manual-driven framework of enhanced Problem Solving Therapy PST known as Problem Management Plus PM developed by the WHO for low-resource settings the investigators will implement a gold standard stepped approach to treatment for depression The model will follow a group format based on three considerations this lowers costs of human resources which is essential when considering national scalability it provides peer support during treatment and it is culturally appropriate for the setting These considerations have been sources of advocacy for the group model by WHO In settings where group format has been implemented results have been comparable to individual format Local counselors will administer PST in five 15-25 hour sessions with 6-8 participants per group consistent with WHO guidelines Among those with PHQ-915 antidepressant therapy ADT will be offered following WHO mhGAP procedures
Depression screening The investigators will screen patients ages 18 enrolled in ICC clinics in Neno District beginning the first quarter of Y2 Screening diagnosis and enrollment into the treatment cohort will occur continuously across facilities administered by data clerks and counsellors trained on the PHQ-2 and PHQ-9 respectively 6 Screening will also occur every 3 months among individuals in the active cohort to determine current treatment eligibility status The PHQ-2 assesses frequency of depressed mood and anhedonia and has been implemented throughout Africa Use of PHQ-2 as a first step has will save time the investigators are screening 12186 adults The selected threshold allows high sensitivity Patients who screen positive with the PHQ-2 score 2 range 0-6 will immediately receive remaining PHQ-9 questions on which a score 9 range 0-27 represents a possible depressive disorder Those with PHQ-910 will receive a psychoeducation session from the clinical officer using a manual on which they have been trained Those with PHQ9 moderatesevere depression will be referred to a counselor to administer the diagnostic protocol
Depression diagnosis Counselors will review PHQ-9 scores and administer a brief diagnostic interview--based on the Comprehensive International Diagnostic Interview CIDI--to diagnose depression 5 of 9 symptoms present and functional impairment All patients will be evaluated for suicide risk and whether immediate intervention is warranted If so they will be referred to the supervising physician at the health facility triggering an emergency protocol Patients will be assigned to one of three categories mild moderate and severe depression Those with a negative diagnosis will not be eligible for the intervention and will undergo PHQ-2 screenings at subsequent visits for eligibility Those with a positive diagnosis and PHQ-910 will be eligible Those with PHQ-9 10-14 will be offered PST alone Those with PHQ-915 moderate-to-severe depression will be offered PST and ADT as joint treatment with the alternative to choose a single modality Pregnant women with severe depression will also be eligible for ADT Best evidence including recent systematic reviews does not find increased risk for mother or infant with appropriately administered ADT and there are significant potential benefits of improved wellbeing of the mother
Psychoeducation and treatment selection Counselors will inform patients on availability of PST and ADT outline potential benefits and risks provide an overview of the study and acquire informed consent Those who decline care will be offered psychoeducation and referred to available resources Among those who elect PM the first PM session will also incorporate in-depth psychoeducation Patients with a PHQ-9 score of 10-14 will be provided the option of ADT but recommended PM instead given that behavioral therapy has established efficacy and avoids potential side effects of ADT Patients with PHQ-9 15 will also be given the options of PST ADT or both and recommended both At facilities randomized to administer the intervention immediately patients will be informed of date time and location of their first PM session
Problem Management Plus PM Counselors n8 will receive intensive training in Year 1 by to administer PM using a manualized approach Training and supervision are described below PM is a WHO-enhanced framework of Problem Solving Therapy PST for implementation by lay personnel in low-resource settings like Neno designed to be conducted in five weekly 15-25 hour sessions Elements of PM including sequential problem solving have been applied by the research team in numerous settings with marked success including in Lilongwe This district-wide randomized trial leveraging Nenos existing infrastructure would represent a critical evidential support for WHOs agenda to expand the model globally Modules include psychoeducation managing problems behavioral activation social support strengthening and stress reduction
Antidepressant Therapy ADT The investigators expect 20-25 of study participants-ie those who meet diagnostic criteria-to have moderately severe or severe depression and opt to enroll in ADT Fluoxetine a serotonin selective reuptake inhibitor SSRI and amitriptyline a tricyclic antidepressant TCA are part of Malawis national formulary Neno District has a robust supply chain which will reduce stock-out Potential side effects of ADT are modest but include nausea insomnia and nervousness and will be communicated to participants prior to initiation There is modest evidence ADT may increase risk of suicidality this risk will be stated in informed consents counselors will be trained to identify this risk and will be formally assessed during outcome assessments with the potential to trigger protocol for suicidal ideation Benefits of ADT often outweigh risk of harm and negative impact of untreated depression Fluoxetine is typically the first drug of choice because it is better tolerated
Dosing Algorithm Daily dose will commence at 20 mg of fluoxetine or 25 mg of amitriptyline Dose increments and levels are the same for each drug At monthly follow-up visits a dose increment or medication change may be considered based on measures of treatment response and side effects using the Antidepressant Side Effect Checklist This algorithm-based process will be repeated bi-weekly until the patient is fully responding to treatment for a period of three months PHQ-9 5 Dose escalations of more than one increment and medication changes will be reviewed with the doctor-in-charge
MEASUREMENT
Primary Outcomes Measures will include surveys laboratory assays pharmacy data and data abstracted from medical charts and the Depression Care Registry Survey measures that have not been translated into Chichewa in the course of prior research will be translated using standard translation back-translation methods and will be administered at each assessment unless otherwise noted
Depression symptoms Depression symptoms will be measured with the PHQ-9 which has been translated previously and locally-validated The investigators have elected to use PHQ-9 because it has been implemented throughout sub-Saharan Africa including Malawi where the scale has shown high sensitivity responding to treatment as well as concurrent and predictive validity It contains nine four-point ordinal response items on topics such as hopelessness psychosomatic response eg sleeplessness loss of appetite and anhedonia
Functional impairment Functional impairment including aspects of daily functioning correspond to DSM diagnostic criteria The investigators will evaluate this using the 12-item WHO Disability Assessment Schedule 20 WHODAS The WHODAS has been validated in a diverse range of sub-Saharan African contexts including Malawi and covers topics like completing household chores concentrating and maintaining relationships
Overall health A health profile will be generated for each individual using the EQ-5D-3L previously validated in Malawi This survey determines patients overall health at time of interview and offers a cross-walk to quality-adjusted life years QALYs
Secondary Outcomes Secondary outcomes will constitute those measuring indirect benefits and costs of treatment Indirect benefits will be incorporated into cost-effectiveness estimates by internalizing improvements among comorbid conditions such as HIV and hypertension as well as reduced household burden of care
ART adherence ART adherence will be measured in terms of whether HIV enrollees have returned to an IC3 for antiretrovirals ARVs within the past three months an approach considered more reliable than self-reports This interval overlays with clinical protocols throughout Malawi in terms of the duration for which ARVs are supplied
Viral load Viral load will be measured as part of HIV patients clinical assessment pre-intervention post-intervention 6- and 12-month follow-up consistent with ongoing care at IC3s This is considered a key metric for determining treatment plans and is highly sensitive to compliance with prescribed ART regimens
HIV disease staging Staging will be evaluated every three months among HIV enrollees consistent with IC3 visits This approach to tracking disease progression is commonly used in low-resource settings
Chronic care outcomes Chronic care outcomes on hypertension type-2 diabetes and epilepsy will be abstracted from electronic medical records Systolic blood pressure and adherence to antihypertensive medication measured by medicine pickups will be measured among those with hypertension Among those with type-2 diabetes adherence to quarterly visits and A1C or random blood sugar levels will be abstracted Among those with epilepsy the investigators will catalog number of reported seizures in past quarter and adherence to antiepileptics as measured by quarterly medicine pickups
Household burden of care Lastly household burden of care will be evaluated with household members using a locally-adapted version of the Burden Assessment Schedule BAS previously implemented by the team The survey assesses dimensions of emotional and functional burden of care including missed work guilt and worry
Mediators and Moderators Analyses will also include three mediatorsmoderators assessing potential pathways by which depression treatment leads to alleviation of depression symptoms including enhanced social support reduced HIV and depression-related stigma and performance of psychosocial counsellors as quantified by fidelity to PM protocols
Perceived social support Social support strengthening is a focus of PM This will be measured with the Multidimensional Scale of Perceived Social Support MSPSS previously validated to assess support before and after care
Perceived stigma Self-perceived stigma is associated with HIV status and depression including in Malawi The investigators will adapt the AIDS-Related Stigma Scale ARSS and Internalizing Stigma of Mental Illness ISMI scale in Year 1 of the project-both designed for use in community-based settings in sub-Saharan Africa
PM fidelity Fidelity checklist scores will be generated for each counsellor by a lead clinical officer or supervisor Research has shown that fidelity protocols are predictive of patient outcomes in the context of depression care
Household Interviews Adult household members of participants-one per household-will be identified for participation based referral by the study participant andor self-identification as a social support in close contact with the study participant This individual will be informed that the research team is conducting a broad study on the relationship between individual and household health Household interviews will chiefly comprise a subset of the battery administered to participants specifically the PHQ-9 WHODAS and EQ-5D-3L primary outcomes In addition household members will complete the BAS as described above
Process Evaluation In the final year of the project the investigators will conduct qualitative interviews to assess provider and patient experiences on their perceived effects of the intervention as well as implementation barriers and strategies used to solve them The goal is to identify key lessons learned and to ready the intervention tools for scale-up at end of study
Provider experience In Year 5 the investigators will interview 10 clinical officers who prescribed ADT as well as psychosocial counsellors who led PM sessions as well as diagnosed patients In addition to discussing perceived strengths and weakness of the intervention and its implementation the investigators will also discuss the training and supervision process as well as provider job satisfaction and burnout
Patient experience A random sample of 20 participants 10 male 10 female will be interviewed after their final study assessment to assess their experiences with the intervention - including logistical aspect of participation impact on personal mental health and wellbeing as well as changes in relationships at the household level
Major depressive disorder imposes catastrophic health and economic impacts in Malawi and throughout sub-Saharan Africa Depression is a leading cause of disability in Malawi Yet best evidence suggests that over 90 of individuals with the condition receive no treatment 1 The cost of inaction is liable to have wide-ranging impacts In terms of health depression-when untreated-typically observes a recurrent trajectory across the lifespan and is associated with significant depreciation in quality of life Depression also indirectly impacts other health outcomes including HIV outcomes such as adherence to antiretroviral therapy and health-seeking behavior In terms of social ecology depression affects interpersonal relationships engagement in household activities and labor force participation The World Economic Forum has estimated a 30 trillion loss over a twenty-year span due to neglected treatment of neuropsychiatric conditions largely due to lost labor force participation 2
Integrating depression care into Nenos HIV platform represents a cost-effective scalable solution in Neno District Malawi consistent with best practices Over the past 10 years Malawi has enrolled over a million individuals in antiretroviral therapy Current enrollment levels stand at 580000 This has been achieved by introducing a framework of HIV care delivery the basis of which is a network of 706 HIV clinics throughout the country Over this same timeframe HIV has evolved from an acute condition with poor prognosis to a chronic condition with vastly improved survival rates Given this context the HIV system is a strategic point of entry for screening and treating depression as it represents a leveragable chronic care system In Neno District HIV facilities have already transitioned into an integrated chronic care platform for treating conditions like diabetes hypertension asthma and epilepsy Likewise community health screenings routine in Malawi could be leveraged to screen for depression
Overarching Objective Evaluate a clinical model of screening and treatment for depression in terms of real world effectiveness and cost-effectiveness at reducing depression in Neno District
Objective 1 Determine the implementation strategy effectiveness-in terms of improved depression PHQ-9 daily functioning WHODAS and overall health EQ5D-of introducing a stepped model of depression care behavioral therapy and antidepressant therapy among adults receiving integrated chronic care in Neno District Malawi between July 1 2021-June 30 2025
Objective 2 Determine the cost-effectiveness the stepped model of depression care behavioral therapy and antidepressant therapy among adults receiving integrated chronic care in Neno District Malawi between July 1 2021-June 30 2025
Objective 3 Assess positive externalities associated with depression care including improved wellbeing among household members of treated patients and improved physical health outcomes among patients receiving depression care
Objective 4 Inspect mediators and moderators of improved depression care including a dose effect from level of treatment received number of behavioral therapy sessions reduced internalized mental health stigma and improved perceived social support
RATIONALE
The framework strategically addresses the bi-directionality of depression and HIV outcomes A broad literature throughout sub-Saharan Africa has outlined the impact of HIV-including HIV-related stigma reduced quality of life and ability to maintain employment-on elevated depression levels 3 Depression in turn predicts HIV-related outcomes such as adherence to ART As such targeting depression care among a population that includes HIV individuals in Malawi should yield significant benefits in terms of HIV-related outcomes Outside sub-Saharan Africa there is increasing evidence that integrative health services represents stronger value for money than stand-alone models
Research examining the benefits and costs of treating neuropsychiatric conditions including depression suffers two key limitations First evaluations have only measured individual-level direct treatment effects This approach under-appreciates the social ecology of mental health that individuals are typically situated within families and families within communities From this lens neuropsychiatric disorders have shown adverse effects-in terms of burden of care and emotional wellbeing-on household members Previously the investigators showed that when individuals mental health improves through treatment indirect benefits are observed among household members 4 Likewise measurement limited to direct treatment effects overlooks indirect benefits to overall health including for comorbid conditions such as HIV that may result from mental health intervention A second shortcoming is that evaluations have focused on measuring costs of standalone interventions which are costlier than those that leverage existing systems For instance interventions for youth have often integrated within school systems to lower costs In Malawi the national HIV system-already transitioning to an integrated chronic care platform in Neno District-holds potential to treat depression at lower costs by building on established systems of longitudinal care
In terms of historical objectives a preponderance of mental health evaluations in low-resource settings has stopped at the point of measuring effectiveness rather than cost-effectiveness with a few exceptions by project members The consequences are marked In settings of financial constraint such as Neno District Malawi resources allocated to a particular program necessarily means resources allocated away from another As such assessing intervention costs are fundamental for determining scalability A collaborative care model of treatment for depression and comorbid conditions such as HIV and diabetes has the potential to overcome resource constraints which cost-effectiveness analysis would demonstrate
The investigators will evaluate an evidence-based stepped care model of depression treatment integrated into Nenos HIV system assessing health outcomes and cost-effectiveness inclusive of direct and indirect benefits Partners In Health PIH in collaboration with the Malawian Ministry of Health has operated in Neno District-home to 165000 Malawians-for 12 years The investigators proposed to integrate a stepped care model for depression-combining antidepressant therapy ADT with group-based Problem Management Plus PM the elements of which have been successfully instituted by the research team in low-resource settings ranging from Rwanda to Haiti The proposed study will evaluate a model that trains clinical staff situated in clinics to screen and diagnose depression and administer PM among those with a diagnosis of moderate or severe depression Over five weekly 15-25 hour group sessions the behavioral intervention combines empirically-based treatment components such as psychoeducation strategic problem solving and behavioral activation 5 This will be coupled with antidepressant therapy ADT among those with severe depression
To assess intervention benefits the investigators will measure patient outcomes for depression every 3 months-including baseline post-intervention 6-months and 12-months follow-up-as well as markers of comorbid conditions including viral load and ART adherence among those are HIV 71 of the sample as well as other disease-specific outcomes such as systolic blood pressure for hypertensive patients 17 of sample and hemoglobin A1C for diabetic patients 2 of sample-supported by an electronic medical records system Importantly to quantify indirect benefits of depression care the investigators will also interview household members at baseline and 6-months follow-up to evaluate burden of care including emotional distress and missed days of work The investigators will convert direct and indirect benefits to quality-adjusted life years QALYs
METHODS
Design of Study We will implement a stepped-wedge cluster randomized trial of an evidence-based intervention for depression care within Nenos HIV system currently undergoing transition to a chronic care platform examining depression symptoms and outcomes of comorbid conditions inclusive of HIV across 14 facilities rolled-out clinic-wide in five steps over 15 months 6 This design is a gold standard experimental approach aligned with PIHs clinical goal to implement depression care permanently throughout Neno District and is a methodological framework on which we have unique expertise including locally
Place of Study This study will take place in Neno District a catchment area of 165000 Malawians where 12186 are enrolled in integrated chronic care-including for HIV Five-year retention in ART in Neno District is 80 while five-year mortality is close to 15 The viral suppression rate is 83 These figures signify Neno as high performing but also underscores significant room for improvement-particularly among the most vulnerable such as those with depression As such we do not anticipate a ceiling effect for measuring HIV outcomes among those concurrently enrolled in depression care This is also true for other chronic conditions eg only 60 of hypertensive patients currently have controlled systolic blood pressure 140 mm Hg Successes to-date have been achieved through modest human resource investments such as CHWs suggesting replicability nationally This has been supported by the investigators past cost-effectiveness analyses
Target Population The investigators intend to recruit at least 420 adults with depression for participation in this study beginning July 1 2021 and continuing through June 30 2025 This number is based on the sample size needed for us to determine the effectiveness of the depression treatment as well as the prevalence of depression in Malawi At each ICC clinic 200-1800 patients are seen on a quarterly basis The investigators anticipate 10-12 of all patients n12186 will screen positive for depressive symptoms and 6 will be diagnosed with moderatesevere depression Prior studies in Malawi have found acceptance of research study participation is 90 or higher In addition the investigators will be conducting interviews with 210 households among half of participants-in order to determine whether the intervention improves quality of life within households
Sampling Techniques and Tools The full study period is January 1 2021 through June 30 2025 The first six months will be preparation Beginning July 1 2021 all adults attending integrated chronic care clinics will be screened for depression symptoms using the PHQ-2 by existing clinical officers Consistent with the prior screening literature those with a score 2 will complete remaining questions of the PHQ-9 and a score 9 will trigger administration of a brief diagnostic interview--adapted from the CIDI 30--by a trained counselor Those with PHQ-910 nomild depression will receive a psychoeducation session but will not be enrolled-based on limited availability of health professionals and need-based prioritization Those with moderatesevere depression PHQ-99 corresponding to diagnosis of major depression will be eligible for cohort enrollment Screening diagnosis and enrollment will occur continuously across all facilities over the full trial period those who meet diagnostic criteria will be enrolled Treatment will be rolled-out progressively patients in each clusters cohort will be initiated into the intervention Three facilities will begin treatment immediately Step 1 with remaining facilities will initiate treatment at three- Step 2 six- Step 3 nine- Step 4 or twelve-months Step 5 later The stepped-wedge approach enables all facilities throughout Neno District to implement the model as such maintaining equipoise Assessment of patients on outcome measures will occur at every 3 months
Sample Size Determination The investigators assume n30 enrollees per facility total n420 based on depression prevalence in Malawi The investigators further assume loss to follow-up of 15 based on intervention trials that the investigators have conducted in similar settings To account for clustering the investigators calculated detectable differences using an intracluster correlation coefficient ICC of 005 within treatment group and 001 within rollout step based on depression treatment studies in multiple developing countries including the investigators pilot work Based on this the investigators find n420 enrollees to be sufficient power 080 alpha05 2-tailed for detecting a clinically meaningful standardized effect size of 05 Cohens d for primary outcomes including accounting for cluster autocorrelation This is not separated by modality though the investigators will explore this it is to assess overall effectiveness of the stepped care model
Data Collection Techniques and Tools Over the 15-month roll-out period primary outcomes PHQ-9 WHODAS EQ5D will be measured at three-month intervals among all participants from point of enrollment consistent with the three-month increments between steps see above Three-month increments will coincide with treatment initiation post-intervention 6 months and 12 months follow-up In the event an enrolled individual no longer meets criteria at treatment initiation the individual will leave the cohort and not be eligible for treatment but will continue to be evaluated every three months for future eligibility Given that screening diagnosis and enrollment will occur at all facilities over the full trial period the investigators expect any reduction in patients enrolled in the cohort due to lagged treatment initiation will be offset by newly-identified individuals over this same period This is consistent with an open cohort design for stepped-wedge trials Ultimately this approach enables all facilities to implement the model maintain equipoise and create control sites by randomizing roll-out sequence Measurement intervals are consistent with best practices in outcomes tracking including past trials Interviews with household members will be conducted at treatment initiation and 6-month follow-up among 210 randomized households
Data Analysis Analysis will assume a mixed-effects longitudinal regression framework which the team has implemented in similar contexts To account for nesting of patients within treatment groups and clusters as well as time points autocorrelation patient patient group and cluster will be incorporated as random effects while cluster assignment and covariates are included as fixed effects-using STATAs MIXED command The investigators will run sensitivity analyses to test if data are missing at random MAR and examine stigma and social support as moderators as well as potential mediation using causal mediation analysis
Effectiveness The investigators will use linear mixed-effects regression analysis to test differences between study arms on change in primary outcomes Models will adjust for patient demographics as well as stigma and social support Analysis will assume an intention-to- treat ITT framework with and without multiple imputation analysis In addition to ITT the investigators will perform a completers only analysis to exam outcomes among those who adhered to treatment and examine dose response
Cost-effectiveness Health measures will be converted to QALYs using the EQ5D-3L cross-walk between domain-specific outcomes This approach has been utilized and published on previously QALY estimates will be related to base case and treatment cost estimates For formal CEA the investigators will use a gold standard Markov chain Monte Carlo MCMC simulation-based approach in TreeAge from a societal perspective For sensitivity analyses the investigators will vary discount rates from 0-5 based on health-adjusted life expectancy Unit of interest is the incremental cost-effectiveness ratio ICER of cost per QALY comparing the cost of integrated chronic care before and after introduction of the depression treatment
PROTOCOL
Evidence-based treatment of depression Drawing from a manual-driven framework of enhanced Problem Solving Therapy PST known as Problem Management Plus PM developed by the WHO for low-resource settings the investigators will implement a gold standard stepped approach to treatment for depression The model will follow a group format based on three considerations this lowers costs of human resources which is essential when considering national scalability it provides peer support during treatment and it is culturally appropriate for the setting These considerations have been sources of advocacy for the group model by WHO In settings where group format has been implemented results have been comparable to individual format Local counselors will administer PST in five 15-25 hour sessions with 6-8 participants per group consistent with WHO guidelines Among those with PHQ-915 antidepressant therapy ADT will be offered following WHO mhGAP procedures
Depression screening The investigators will screen patients ages 18 enrolled in ICC clinics in Neno District beginning the first quarter of Y2 Screening diagnosis and enrollment into the treatment cohort will occur continuously across facilities administered by data clerks and counsellors trained on the PHQ-2 and PHQ-9 respectively 6 Screening will also occur every 3 months among individuals in the active cohort to determine current treatment eligibility status The PHQ-2 assesses frequency of depressed mood and anhedonia and has been implemented throughout Africa Use of PHQ-2 as a first step has will save time the investigators are screening 12186 adults The selected threshold allows high sensitivity Patients who screen positive with the PHQ-2 score 2 range 0-6 will immediately receive remaining PHQ-9 questions on which a score 9 range 0-27 represents a possible depressive disorder Those with PHQ-910 will receive a psychoeducation session from the clinical officer using a manual on which they have been trained Those with PHQ9 moderatesevere depression will be referred to a counselor to administer the diagnostic protocol
Depression diagnosis Counselors will review PHQ-9 scores and administer a brief diagnostic interview--based on the Comprehensive International Diagnostic Interview CIDI--to diagnose depression 5 of 9 symptoms present and functional impairment All patients will be evaluated for suicide risk and whether immediate intervention is warranted If so they will be referred to the supervising physician at the health facility triggering an emergency protocol Patients will be assigned to one of three categories mild moderate and severe depression Those with a negative diagnosis will not be eligible for the intervention and will undergo PHQ-2 screenings at subsequent visits for eligibility Those with a positive diagnosis and PHQ-910 will be eligible Those with PHQ-9 10-14 will be offered PST alone Those with PHQ-915 moderate-to-severe depression will be offered PST and ADT as joint treatment with the alternative to choose a single modality Pregnant women with severe depression will also be eligible for ADT Best evidence including recent systematic reviews does not find increased risk for mother or infant with appropriately administered ADT and there are significant potential benefits of improved wellbeing of the mother
Psychoeducation and treatment selection Counselors will inform patients on availability of PST and ADT outline potential benefits and risks provide an overview of the study and acquire informed consent Those who decline care will be offered psychoeducation and referred to available resources Among those who elect PM the first PM session will also incorporate in-depth psychoeducation Patients with a PHQ-9 score of 10-14 will be provided the option of ADT but recommended PM instead given that behavioral therapy has established efficacy and avoids potential side effects of ADT Patients with PHQ-9 15 will also be given the options of PST ADT or both and recommended both At facilities randomized to administer the intervention immediately patients will be informed of date time and location of their first PM session
Problem Management Plus PM Counselors n8 will receive intensive training in Year 1 by to administer PM using a manualized approach Training and supervision are described below PM is a WHO-enhanced framework of Problem Solving Therapy PST for implementation by lay personnel in low-resource settings like Neno designed to be conducted in five weekly 15-25 hour sessions Elements of PM including sequential problem solving have been applied by the research team in numerous settings with marked success including in Lilongwe This district-wide randomized trial leveraging Nenos existing infrastructure would represent a critical evidential support for WHOs agenda to expand the model globally Modules include psychoeducation managing problems behavioral activation social support strengthening and stress reduction
Antidepressant Therapy ADT The investigators expect 20-25 of study participants-ie those who meet diagnostic criteria-to have moderately severe or severe depression and opt to enroll in ADT Fluoxetine a serotonin selective reuptake inhibitor SSRI and amitriptyline a tricyclic antidepressant TCA are part of Malawis national formulary Neno District has a robust supply chain which will reduce stock-out Potential side effects of ADT are modest but include nausea insomnia and nervousness and will be communicated to participants prior to initiation There is modest evidence ADT may increase risk of suicidality this risk will be stated in informed consents counselors will be trained to identify this risk and will be formally assessed during outcome assessments with the potential to trigger protocol for suicidal ideation Benefits of ADT often outweigh risk of harm and negative impact of untreated depression Fluoxetine is typically the first drug of choice because it is better tolerated
Dosing Algorithm Daily dose will commence at 20 mg of fluoxetine or 25 mg of amitriptyline Dose increments and levels are the same for each drug At monthly follow-up visits a dose increment or medication change may be considered based on measures of treatment response and side effects using the Antidepressant Side Effect Checklist This algorithm-based process will be repeated bi-weekly until the patient is fully responding to treatment for a period of three months PHQ-9 5 Dose escalations of more than one increment and medication changes will be reviewed with the doctor-in-charge
MEASUREMENT
Primary Outcomes Measures will include surveys laboratory assays pharmacy data and data abstracted from medical charts and the Depression Care Registry Survey measures that have not been translated into Chichewa in the course of prior research will be translated using standard translation back-translation methods and will be administered at each assessment unless otherwise noted
Depression symptoms Depression symptoms will be measured with the PHQ-9 which has been translated previously and locally-validated The investigators have elected to use PHQ-9 because it has been implemented throughout sub-Saharan Africa including Malawi where the scale has shown high sensitivity responding to treatment as well as concurrent and predictive validity It contains nine four-point ordinal response items on topics such as hopelessness psychosomatic response eg sleeplessness loss of appetite and anhedonia
Functional impairment Functional impairment including aspects of daily functioning correspond to DSM diagnostic criteria The investigators will evaluate this using the 12-item WHO Disability Assessment Schedule 20 WHODAS The WHODAS has been validated in a diverse range of sub-Saharan African contexts including Malawi and covers topics like completing household chores concentrating and maintaining relationships
Overall health A health profile will be generated for each individual using the EQ-5D-3L previously validated in Malawi This survey determines patients overall health at time of interview and offers a cross-walk to quality-adjusted life years QALYs
Secondary Outcomes Secondary outcomes will constitute those measuring indirect benefits and costs of treatment Indirect benefits will be incorporated into cost-effectiveness estimates by internalizing improvements among comorbid conditions such as HIV and hypertension as well as reduced household burden of care
ART adherence ART adherence will be measured in terms of whether HIV enrollees have returned to an IC3 for antiretrovirals ARVs within the past three months an approach considered more reliable than self-reports This interval overlays with clinical protocols throughout Malawi in terms of the duration for which ARVs are supplied
Viral load Viral load will be measured as part of HIV patients clinical assessment pre-intervention post-intervention 6- and 12-month follow-up consistent with ongoing care at IC3s This is considered a key metric for determining treatment plans and is highly sensitive to compliance with prescribed ART regimens
HIV disease staging Staging will be evaluated every three months among HIV enrollees consistent with IC3 visits This approach to tracking disease progression is commonly used in low-resource settings
Chronic care outcomes Chronic care outcomes on hypertension type-2 diabetes and epilepsy will be abstracted from electronic medical records Systolic blood pressure and adherence to antihypertensive medication measured by medicine pickups will be measured among those with hypertension Among those with type-2 diabetes adherence to quarterly visits and A1C or random blood sugar levels will be abstracted Among those with epilepsy the investigators will catalog number of reported seizures in past quarter and adherence to antiepileptics as measured by quarterly medicine pickups
Household burden of care Lastly household burden of care will be evaluated with household members using a locally-adapted version of the Burden Assessment Schedule BAS previously implemented by the team The survey assesses dimensions of emotional and functional burden of care including missed work guilt and worry
Mediators and Moderators Analyses will also include three mediatorsmoderators assessing potential pathways by which depression treatment leads to alleviation of depression symptoms including enhanced social support reduced HIV and depression-related stigma and performance of psychosocial counsellors as quantified by fidelity to PM protocols
Perceived social support Social support strengthening is a focus of PM This will be measured with the Multidimensional Scale of Perceived Social Support MSPSS previously validated to assess support before and after care
Perceived stigma Self-perceived stigma is associated with HIV status and depression including in Malawi The investigators will adapt the AIDS-Related Stigma Scale ARSS and Internalizing Stigma of Mental Illness ISMI scale in Year 1 of the project-both designed for use in community-based settings in sub-Saharan Africa
PM fidelity Fidelity checklist scores will be generated for each counsellor by a lead clinical officer or supervisor Research has shown that fidelity protocols are predictive of patient outcomes in the context of depression care
Household Interviews Adult household members of participants-one per household-will be identified for participation based referral by the study participant andor self-identification as a social support in close contact with the study participant This individual will be informed that the research team is conducting a broad study on the relationship between individual and household health Household interviews will chiefly comprise a subset of the battery administered to participants specifically the PHQ-9 WHODAS and EQ-5D-3L primary outcomes In addition household members will complete the BAS as described above
Process Evaluation In the final year of the project the investigators will conduct qualitative interviews to assess provider and patient experiences on their perceived effects of the intervention as well as implementation barriers and strategies used to solve them The goal is to identify key lessons learned and to ready the intervention tools for scale-up at end of study
Provider experience In Year 5 the investigators will interview 10 clinical officers who prescribed ADT as well as psychosocial counsellors who led PM sessions as well as diagnosed patients In addition to discussing perceived strengths and weakness of the intervention and its implementation the investigators will also discuss the training and supervision process as well as provider job satisfaction and burnout
Patient experience A random sample of 20 participants 10 male 10 female will be interviewed after their final study assessment to assess their experiences with the intervention - including logistical aspect of participation impact on personal mental health and wellbeing as well as changes in relationships at the household level
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None