Integrating a Stepped Care Model of Screening and Treatment for Depression Into Malawi's National HIV Care Delivery Platform
Phase: PHASE4
Conditions: Depressive Disorder
Sponsor: RAND

 
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Integrating a Stepped Care Model of Screening and Treatment for 
Depression into Malawi's National HIV Care Delivery Platform 
 
20 September, 2021 – v2 
 
(ID: R01MH117760) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Stepped Care for Depression at Integrated Chronic Care Centers (IC3D) in Malawi:  
Study Protocol for a Stepped Wedge Cluster Randomized Controlled Trial 
 
 
INTRODUCTION 
In low- and middle-income countries (LAMICs), mental health conditions like major 
depression often account for a larger burden of disease than HIV and malaria combined;1 yet, 
three-quarters of affected individuals receive no treatment.2 The funding landscape accounts for 
much of this discrepancy: In 2017, international funding for HIV was $US9.5 billion, compared 
to $US130M for mental health conditions—roughly a 70-fold difference.3 The economic impact 
of this under-investment, in terms of lost human capital, is expected to reach $30 trillion 
worldwide over a 20-year period.4 Malawi represents a paradigm case: despite being the second 
poorest country in the world5 and having one of the ten highest HIV incidences,6 collective 
efforts by the Ministry of Health and international donors have successfully built a system of 
care to address the HIV epidemic. Nevertheless, over 90% of those requiring treatment for 
depression have yet to receive care,7 even though depression is one of the leading causes of 
disability in Malawi.8 One recent study estimated the point prevalence of depression in Malawi 
at 19%.9 
Underlying the paucity of depression care is a perception that, relative to treatments for 
infectious disease, treatments for mental health conditions are more time-intensive and less 
cost-effective.10 However, research to-date has two major shortcomings: First, evaluations often 
study the cost of stand-alone programs, rather than leveraging existing infrastructure to 
integrate care, which would reduce costs.11 The HIV care platform in Malawi, comprising a 
network of community and  facility based care, represents one such example.12  Second, past 

 
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interventions have underestimated total benefits of depression care, making treatment appear 
less cost-effective. For example, our past work has shown that depression treatment can lead to 
physical health improvements for comorbid conditions such as HIV through improved 
medication adherence.13,14 These indirect benefits should be quantified. Likewise, we have found 
household-level benefits, such as reduced need for emotional and financial supports,15 that have 
been overlooked.16–18 
Integrating depression care into the national HIV platform has the potential to represent 
a cost-effective, scalable solution in Malawi, consistent with best practices. Over the past 10 
years, Malawi has enrolled over a million individuals in antiretroviral therapy. While many 
have passed away, current enrollment levels stand at 580,000.19 Over this same timeframe, HIV 
has evolved from an acute condition with poor prognosis, to a chronic condition with vastly 
improved survival rates.20 Given this context, the HIV system is a strategic point of entry for 
screening and treating non-communicable diseases (NCDs) such as depression, as it represents 
a leverageable chronic care system that manages patients at high risk of mental health 
conditions.21 In Neno District, HIV facilities have already transitioned into an integrated chronic 
care (IC3) platform for treating NCDs such as diabetes, hypertension, asthma and epilepsy.22–24 
Likewise, community health screenings, routine in Malawi,25 could be leveraged to screen for 
NCDs such as depression.  
We plan to evaluate an evidence-based stepped care model of depression treatment 
integrated into Neno District’s IC3 system, assessing health outcomes and cost-effectiveness, 
inclusive of direct and indirect benefits. Specifically, the depression care model will recommend 
behavioral therapy for those with moderate depression, and a combination of behavioral 

 
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therapy and pharmacological therapy for those with severe depression—aligned with Malawi’s 
aspirational guidance for mental health.26 The behavioral therapy, group-based Problem 
Management Plus (PM+), has been recently developed by the World Health Organization 
(WHO) for delivery by lay health workers in resource-limited settings such as Malawi.27 
Preliminary evidence indicates substantial effects on reducing depression symptoms.28 The 
antidepressant therapy protocol, in accordance with international guidelines, will utilize 
fluoxetine as a first-line treatment and amitriptyline as second-line. Ultimately, this framework 
is intended to apply best practices in a delivery format that places significant consideration on 
the existing physical and human resources infrastructure available in rural Malawi. Moreover, 
while these represent evidence-based treatments, their implementation and effectiveness within 
a real-world low-resource setting such as Neno have not been studied.  
Using a stepped-wedge cluster randomized trial (RCT), we will evaluate the effects of 
this stepped care depression model, the protocol of which this paper describes in detail. The 
primary objective of the study is to assess whether the integrated depression care model is 
superior to usual care on (1) reducing depression symptoms and functional impairment 
(primary outcomes); (2) improving physical health for those with HIV, diabetes and/or 
hypertension (secondary outcomes); and (3) reducing perceived mental health stigma and 
increasing retention in IC3 care (care processes). We will also evaluate the incremental cost-
effectiveness of integrating evidence-based depression care, relative to usual care, and track 
mental health-related outcomes among household members of patients. If efficacious and cost-
effective, this study will provide a model for integrating depression care into HIV clinics in 
Malawi, and the study will promote social wellbeing among household members.  

 
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METHODS 
Study Design  
This is a prospective, stepped-wedge cluster randomized trial to evaluate the effects of an 
evidence-based depression care model, relative to usual care, on mental and physical health 
outcomes of patients seeking care at integrated chronic care centers (IC3) in Neno, Malawi. The 
study will take place at fourteen health clinics in Neno District, which will constitute our 
clusters. Clinics will be randomized to one of five arms, each comprising 2-3 health clinics, such 
that that the clinics receive the intervention in a random order and all clinics receive the 
intervention by the end of the study (Figure 1).  
Figure 1. Stepped wedge design of IC3D clinical trial 
 
 
 
Footnote: Each arm represents 2-3 health clinics that have been randomized to that particular arm.  
 
 
A schedule of trial activities is shown in Table 1. Within each cluster, we will use an 
open cohort design of individual participants who screen positive for potential depression. All 
attendees at each clinic will be screened at each time point and screen-positive patients will 
enter the cohort and be followed for the rest of the study—including after initiation of 
depression care at their site to assess how depression and depression alleviation relate to our 
primary (depression symptom alleviation; alleviation of functional impairment) and secondary 

 
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(HIV patients: viral load; hypertension patients: systolic blood pressure; diabetes patients: A1C 
or blood glucose levels; all patients: health utility index) outcomes, as well as processes of care 
(treatment uptake; adherence; perceived mental health stigma). Furthermore, prior to receipt of 
depression care, as well as six months later, one household member per participant will be 
interviewed in order to examine changes in their mental and physical health status. A cost-
effectiveness analysis will be used to examine the incremental cost of integrated depression care 
(IC3D) over and above usual care within the IC3 framework. 
Randomization, Allocation and Blinding 
Health clinics will be randomly allocated to the five arms, the roll-out of which is spaced 
apart at 3-month intervals, with one exception: 13 potential combinations will be restricted from 
this algorithm, due to logistical considerations in the geographical layout of Neno District (note 
that over a quadrillion theoretical permutations are retained). This randomization will be 
executed by the project principal investigators using a random sequence generator in Stata 15.29 
There is no way to blind the participants on whether or not they have received the 
intervention; this could potentially influence the outcomes, as clients may feel more or less 
incentivized to report feeling well in light of whether or not they have received the intervention.  
We do not see a way to prevent this potential bias, nor a way to distinguish such effects from 
actual intervention effects, but this limitation will be cited in reports of study findings. 

 
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Study Setting  
The study will take place at fourteen health facilities and five outreach clinics in Neno 
District. Ten health facilities are run solely by the Ministry of Health and the remaining four by 
the Christan Health Association (CHAM) of Malawi in collaboration with the Ministry of 
Health. Partners In Health -—a health nonprofit organization, accompanies the Ministry of 
Health in the district. The project will receive technical implementation assistance from the 
RAND Corporation, Blantyre College of Medicine, Harvard Medical School, and University of 
Birmingham. Each of the participating health facilities provide HIV and NCD care and 
treatment, and range in size—from dispensaries that serve 50-250 patients per year to health 

 
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centers serving roughly 250-500 patients per year to secondary-level hospitals providing care to 
over 1,000 patients per year.  
Patients in Neno District, Malawi with chronic health conditions are enrolled and 
treated at Integrated Chronic Care Clinics (IC3)—an integration of Malawi’s national HIV 
system with NCD care—at regular intervals.30 IC3 provides treatment for a broad array of 
chronic care conditions, including HIV, hypertension, diabetes and epilepsy. The clinic is staffed 
by clinical officers, nurses and support staff employed both by PIH and MOH. IC3 
implementation assumes a modular framework, in which patients proceed station-by-station for 
screening and treatment administered by nurses, after which they receive a concluding 
consultation with a clinical officer. Supervision and mentorship are performed by district MOH 
coordinators and physicians along with support from PIH. In total, the IC3 model served 
approximately 13,000 patients with chronic care conditions in 2020. 
A core group of staff for IC3 are based at the health facilities, while an additional group 
of staff travel to the health facilities four-to-five days a week to join these facility-based staff. 
This IC3 model leverages the existing HIV care and treatment model and is a solution for 
staffing shortages at smaller facilities given high volumes of patients with other acute needs. 
Study Participants and Eligibility Criteria 
Initial eligibility criteria include: (1) active patients at an IC3 in Neno District, and (2) age 
18 or older. Given complexities associated with pediatric depression care, as well as age-related 
differences in the mode and content of behavioral and pharmacological interventions for 
depression among those in this age group, we are limiting the trial to adults.31  
 

 
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Figure 2. Trial Flow Chart 
 

 
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Screening will be administered by data clerks and counsellors trained on the PHQ-2 and 
PHQ-9,32 which have been locally validated in Malawi.33 The PHQ-2 assesses frequency of 
depressed mood and anhedonia, and it has been implemented throughout Africa.35–37 
Administration of the PHQ-2 by data clerks as a first step has the potential to save time, given 
the number of attendees at IC3. Those who score 0 will not advance to the remaining PHQ-9 
questions. Patients who screen positive with the PHQ-2 (score > 0; range: 0-6) will immediately 
receive remaining PHQ-9 questions from a counsellor. A PHQ-9 score > 10 (range: 0-27) 
represents a possible depressive disorder.32,38 Those with PHQ-9 <10 (PHQ-9 score of 5-9 
indicates mild depressive symptoms) will receive a brief, manualized psychoeducation session, 
and counsellors will inform patients that screening will continue at IC3 on an ongoing basis. 
Those with PHQ > 10 (moderate/severe depression) will proceed to receive A brief diagnostic 
interview adapted from the Composite International Diagnostic Interview (CIDI) 3.0, a 
structured diagnostic interview designed for the assessment of mental disorders by lay 
interviewers.1,2 This has been widely used throughout sub-Saharan Africa as part of the World 
Mental Health Survey.1–4 The depression module of the CIDI 3.0 corresponds to DSM-IV 
diagnostic criteria, on which 5 or more depressive symptoms for > 2 weeks and functional 
impairment indicates a diagnosis of depression.1 Counselors will be trained to administer the 
brief diagnostic interview and—analogous to the PHQ-9—those for whom a diagnosis of 
depression is not concluded will receive a brief, manualized psychoeducation session.  
 
 
 

 
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Figure 3. Care Pathways for Control and Intervention Arms  
Treatment: Usual Care 
In most of Malawi, including in Neno District, the usual care procedure for addressing 
depression is for patients who self-present with significant symptoms such as psychosis, 
suicidal ideation or attempt or potential harm to others receive a referral either to a mental 
health clinical officer or nurse within the district (in Neno District there are three), or else to a 
mental health specialist at a regional hospital. Due to the limited supply of mental health 
clinicians in Neno District, those with comorbid conditions such as schizophrenia or more 
complex mood disorders such as bipolar disorder are prioritized for immediate intervention. Of 
those who presently receive treatment for overt mood disorders, treatment typically comprises 
pharmacotherapy—including fluoxetine or amitriptyline for depressive symptoms with 
individual counseling if time and staff is available. There is currently no system-wide model in 
IC3 or primary services for screening for depression. However, Neno District has begun 

 
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screening and treatment for peripartum depression at one antenatal clinic—a system separate 
from the IC3 system which is the focus of this work. The inclusion of depression screening and 
psychoeducation, features of the control arm of this study, represent modest enhancements of 
the existing system from which the full IC3 model will be introduced.     
With regard to IC3, services are condition-specific. To provide an example: HIV/AIDS is 
the most common chronic care condition treated at IC3, constituting approximately 70% of 
enrollees. Patients receiving antiretroviral therapy attend clinic every three to six months for 
evaluation (e.g. screening, adherence, viral load) and are provided with a necessary supply of 
antiretroviral medications until their scheduled return date. Patients with non-suppression, 
missed appointments or poor adherence are evaluated on a monthly basis. Non-communicable 
disease (NCD) patients attend clinic every 3 months with 1-month appointments with poor 
disease control or missed appointments. They are screened for comorbid disease (e.g. HIV, 
tuberculosis [TB], other NCDs) and provided with necessary supply of medications to their 
schedule return date. 
Treatment: IC3D 
 
The Integrated Chronic Care Clinics Depression (IC3D) module draws from best 
evidence on collaborative care models for depression in low-resource settings.40,41 We will use a 
gold standard, stepped-care approach to offering psychological and pharmacologic treatment 
across all treatment facilities and clinics. Usual care will be augmented with evidence-based 
Problem Management Plus (PM+) through provision of manualized, group-based counseling 
sessions, and antidepressant therapy (ADT) for those with severe depression (or if PM+ is 

 
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declined), which is consistent with WHO mhGAP guidelines42 for use of ADT.  The primary 
components of the depression care model are described below. 
Psychoeducation and treatment selection: If eligible for treatment, the counsellor will 
inform the client of the availability of PM+ and ADT as treatment options, in addition to 
encouraging the client to access general supports—such as peer support groups—within 
Neno. Psychoeducation on depression, treatment course, possible side effects, and benefits of 
treatment will be provided. Clients will have the autonomy to select their preferred treatment, 
but the counsellor will encourage clients with moderate depression (PHQ-9 < 15) to consider 
group-based PM+ counseling given its established efficacy and absence of significant side effect 
concerns, while adults with moderate-to-severe and severe depression (PHQ-9 > 15) will be 
encouraged to consider joint ADT and group-based PM+. If the client remains depressed after 
12 weeks of receiving either depression treatment modality (as measured by PHQ-9 at quarterly 
visits), s/he will be offered to switch to or add the other form of treatment. 
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, we 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.43 

 
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Problem Management Plus (PM+): Psychosocial counsellors with a diploma from a 
Malawian university will receive a one-week training course to administer group-based PM+ 
sessions, with ongoing mentorship and supportive supervision. PM+ is a cognitive-behavioral 
intervention that trains recipients to improve their management of practical problems, and uses 
the term “problem management” rather than “problem solving” to emphasize that many 
problems encountered by individuals living in adverse circumstances may not be “solvable”.27 
The “plus” in PM+ underscores additional evidence-based behavioral strategies incorporated 
into the model, including: stress management strategies, behavioral activation,44 and social 
support strengthening.45 In total, PM+ comprises five sessions held once per week for 1.5. to 2.5 
hours per session. The model has shown success in reducing depression symptoms in low-
resource settings such as Nepal46 and Pakistan.28  
 
Antidepressant therapy (ADT): We expect 20-25% of study participants—i.e. those who 
meet diagnostic criteria—to have severe depression and opt to enroll in ADT.47,48 Fluoxetine, a 
serotonin selective reuptake inhibitor (SSRI), and amitriptyline, a tricyclic antidepressant (TCA), 
are part of Malawi’s national formulary.49 Neno District supply chain is supported by PIH, 
which reduces stock-outs relative to those observed in other Malawian settings. Potential side 
effects of ADT are modest but include nausea, insomnia, and nervousness50 and will be 
communicated to participants prior to initiation. There is modest evidence ADT may increase 
risk of suicidality;51 this risk will be stated in informed consents, counselors will be trained to 
identify this risk, and patients will be formally assessed during outcome assessments, with the 
potential to trigger protocol for suicide assessment.  Benefits of ADT often outweigh risk of 

 
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harm and negative impact of untreated depression.  Fluoxetine is typically the first drug of 
choice because it is safer and better tolerated.53 
Daily dose will commence at 20 mg of fluoxetine, or 25 mg of amitriptyline, 
administered by trained clinical officers.49 At monthly follow-up visits, a dose increment or 
medication change may be considered based on measures of treatment response and side 
effects, using an Antidepressant Side Effect Checklist—also administered by clinical officers.54 
This algorithm-based process will be repeated every other week until the patient is fully 
responding to treatment (PHQ-9 < 5) for a period of three months. Dose escalations of more 
than one increment and medication changes will be reviewed by a supervising mental health 
clinician with greater expertise. 
 
Treatment monitoring: Schedule of follow-up visits to monitor side effects and treatment 
response will vary based on the treatment; for PM+, visits will be weekly for all five sessions, 
whereas for ADT, the first two visits will be every other week, and then the remainder will be 
monthly. A Depression Registry will be maintained by a project manager to record treatment 
data for each visit, which will facilitate future visits, supervision, and fidelity monitoring. 
Discontinuation will be considered if symptoms are in remission for 9 months.55 If on ADT at 
end of study, it will be sustained as part of usual care.  
 
Training, supervision and fidelity: All counsellors will be trained to implement the 
depression care model so that related burden is balanced, and to prevent interruptions caused 
by staff changes. When possible, counsellors will have received prior certification in 
psychosocial counseling from a local university; however, depending on recruitment success, 
other counsellors will have no prior mental health training and served in a former capacity as a 

 
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community health worker or similar position. Clinical officers responsible for administering 
ADT will have a  degree in clinical medicine (mental health)  from a university in Malawi (or 
equivalent) and will receive additional training on manualized ADT protocols prior to trial 
initiation.56 
 
Supervision will be conducted one-on-one with counselors and clinical officers – and 
provided by a lead clinician. Supervision will be weekly for first month, then every other week 
for 3 months, and then monthly thereafter. Supervisors will be available 24/7 for suicide or 
emergency consultations. Regarding fidelity, supervisors will review charts of clients receiving 
ADT, and at each monthly supervision meeting assess adherence to the treatment protocol. For 
PM+, we will develop a checklist for the supervisors to use to rate fidelity to each component of 
the protocol for PM+.  
Primary Outcomes 
Measures will include surveys, laboratory assays, pharmacy data, and data abstracted 
from medical charts. 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 prevalence and severity. Depression symptoms will be measured with the PHQ-
9,38 which has been translated previously and locally-validated.33 We 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.7,57–61 It contains nine four-point ordinal response items on topics such as hopelessness, 
psychosomatic response (e.g. sleeplessness, loss of appetite) and anhedonia. We will derive two 

 
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outcome measures from this: (i) depression prevalence among patients attending the clinic; and 
(ii) depression severity among those with depression. The numerator for the former is all those 
who screen positive as on the PHQ-9 (PHQ-9 > 10), the denominator is all active adult patients 
at IC3. The latter measure will be the PHQ-9 score.  
Functional impairment. Functional impairment including aspects of daily functioning, 
correspond to DSM diagnostic criteria.62 We will evaluate this using the 12-item WHO Disability 
Assessment Schedule 2.0 (WHODAS).63 The WHODAS has been validated in a diverse range of 
sub-Saharan African contexts, including Malawi,64,65 and covers topics like completing 
household chores, concentrating, and maintaining relationships.  
Overall health. A health profile will be generated for each individual enrolled in IC3D, 
using the EQ-5D-5L66—previously validated in Malawi.67 This survey determines patients’ 
overall health at time of interview and offers a cross-walk to quality-adjusted life years 
(QALYs).68 
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 or else 
defaulted, an approach considered more reliable than self-reports.69,70 This interval overlays 

 
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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.71  
 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.72   
 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 adherence to clinic visits with 
medication dispersing) will be measured among those with hypertension. Among those with 
type-2 diabetes, adherence to quarterly visits with medication dispersement and A1C (or 
random blood sugar) levels will be abstracted. Among those with epilepsy, we 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),15 previously implemented by the team.17 The survey assesses dimensions of emotional 
and functional burden of care, including missed work, guilt and worry.  
Mediators and Moderators 

 
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Our analyses will also include three mediators/moderators 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+.73 This will be 
measured with the Multidimensional Scale of Perceived Social Support (MSPSS),74 previously 
validated,75 to assess support before and after care. 
 Perceived stigma. Self-perceived stigma is associated with HIV status76 and 
depression,77,78 including in Malawi.79,80 We will adapt the AIDS-Related Stigma Scale (ARSS) 
and Internalizing Stigma of Mental Illness (ISMI) scale81 in Year 1 of the project—both designed 
for use in community-based settings in sub-Saharan Africa.82  
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.83  
Household Interviews 
Adult household members of participants—one per household—will be identified for 
participation based referral by the study participant and/or 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-5L (primary outcomes). In addition, household 
members will complete the BAS, as described above.  

 
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Process Evaluation 
In the final year of the project, we 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, we will interview up to 10 providers including clinical 
officers who prescribed ADT, as well as psychosocial counsellors who led PM+ sessions. In 
addition to discussing perceived strengths and weakness of the intervention and its 
implementation, we 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.  
 
Sample Size 
We assumed n=30 enrollees per facility (total n=420) during each three month “step”, 
based on an estimated 10% depression prevalence in Malawi.7,84 We further assumed loss to 
follow-up of 15%, based on intervention trials we have conducted in similar settings.11,85  
The power calculation is based on the model described in the analysis section (see 
below) and a two-sided null value of no effect.86 To indicate the precision of the study design, 
we report “minimum detectable effect” sizes across the range of our primary outcomes at 80% 

 
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power, with a type I error rate of 0.05, and conservative intraclass correlation coefficient (ICC) 
of 0.05, a cluster autocorrelation coefficient (CAC) of 0.80, and an individual autocorrelation 
coefficient (IAC) 0.80. Table 2 reports these effect sizes. 
Analysis of Intervention Effects 
The data from the trial will be analyzed using a generalized linear mixed model 
framework, which is standard for stepped-wedge cluster designs.87,88 The patients participating 
form an open cohort with repeated measures, as it will be possible to link each patient taking a 
PHQ-9 screening and any subsequent exams over time. The models will be at the patient-level, 
nested within clinic-months and clinics. The primary outcomes are: (i) prevalence of depression; 
(ii) depression severity (PHQ-9 score) conditional on having depression; (iii) WHODAS score 
conditional on having depression; and (iv) utility score (0 to 1) from the EQ-5D-5L. The first 
outcome is a dichotomous event for if the patient has depression or not, while the remaining 
outcomes are treated as continuous. For the principal analysis of the trial, we used the 
“complete” stepped-wedge of data from months 1 to 18; long-term follow-up will constitute a 
secondary analysis. 
We specify the following model for patient ! = 1, … , & in clinic ' = 1, … , ( at time period 
) = 1, … *: 
+!"#~- ./01!"#23 
1!"# = 4 + 6!"#
$ 7 + 8"#
$ 9 + :;(!)"# + <! + =" + >"# + ?# 
where +!"# is the outcome, -(. ) is an appropriate likelihood and /(. ) is a suitable link 
function, 6!"# and 8"# are respectively patient and clinic level covariates, ?# are monthly fixed 
effects, and <!~&00, D'
(2, ="~&(0, D)(), and >"#~&00, D*
(2 patient-, clinic-, and clinic-time random 

 
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effects term. We will take both intention to treat (ITT) and per protocol approaches. For the ITT 
analysis, the variable ;"# is an indicator equal to one if cluster ' is in the intervention state at 
time ) and zero otherwise, thus : represents our estimated treatment effect. For per protocol 
analysis ;!"# will be a patient-level variable equal to one if the clinic was in the intervention 
state and the patient completed the treatment as defined above, and zero otherwise. For 
dichotomous outcomes, we will use a Bernoulli distribution with logistic link function, for 
continuous outcomes a normal distribution with identity link function. The same models will be 
used for secondary outcomes. 
All models will be estimated using restricted maximum likelihood using the R package 
lme4. We will report point estimates, confidence intervals, and p-values but not make any 
claims of “statistical significance” given recent strong arguments against doing so.89 P-values 
will be based on the null hypotheses E+: : = 0 versus the two-sided alternatives E,: : ≠0 in 
each of the models. Given there are multiple primary outcomes, we will adjust reported p-
values for multiple testing using a stepdown method, which provides an efficient means of 
controlling the family-wise error rate.90 We will derive the exact distributions of the test 
statistics to perform the stepdown procedure using a (pseudo-)permutation test approach, by 
re-randomizing clusters to different sequences in the stepped-wedge design 100,000 times.91 
This method ensures appropriate control of the family-wise error rate and avoid potential 
biases resulting from small numbers of clusters. 
Cost and cost-effectiveness analysis 
The research team will employ time-driven activity-based costing (TDABC) to gather 
program costs before (Year 1) and after (Year 4) intervention roll-out. TDABC is a gold 

 
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standard, patient-centered approach: It begins by studying flow of patients through the health 
system, and then measuring human and other resources expended. Baseline costs, gathered in 
Y1, will assess cost of care as usual for individuals utilizing IC3s. A cycle of care will be 
annualized as four quarterly IC3 visits, inclusive of testing and labs, according to diagnosis. 
Itemized expenditures will be accrued from PIH’s financial software system.92 To assess 
economic costs, such as subsidized ARVs by PEPFAR, we will use external cost sources such as 
management Science for Health’s International Medical Product Price Guide (MSH-IMPPG).93 
As the cost comparator, we will replicate the cost exercise in Year 4, when depression care is 
operating at scale, again tracing individuals according to service type—now including 
depression care. 
Health measures will be converted to quality-adjusted life years (QALYs) using the EQ-
5D-3L cross-walk between domain-specific outcomes.11 QALY estimates will be related to base 
case and treatment cost estimates. For formal CEA, we will use a gold standard Markov chain 
Monte Carlo (MCMC) simulation-based approach94 in TreeAge,95 from a societal perspective.96 
For sensitivity analyses, we will vary discount rates from 0-5%, based on health-adjusted life 
expectancy.97 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. 
Ethics  
The study protocol has been reviewed and approved by the National Health and Science 
Research Council administered by the Government of Malawi, and by the RAND Corporation 
in Santa Monica, California. Any protocol modifications will be submitted to the IRB for review, 

 
24 
and participants will be informed if warranted. The trial is registered with the NIH clinical trial 
registry (clinicaltrials.gov) and assigned the number NCT04777006. 
We do not expect any medication-related adverse events beyond that of routine medical 
care and use of antidepressant therapy. All potential side effects will be outlined to patients 
during the informed consent process.  Patients will be assessed and monitored with regards to 
psychiatric symptoms and treatment side effects by their provider on a standardized schedule 
using the Antidepressant Side Effect Checklist. 
 
Given the potential severity of depression among those in the sample, some will express 
suicidal thoughts. Counsellors will be trained to implement a standardized protocol when 
patients report suicidal thoughts, including assessment of the severity of the ideation, intent 
and means for carrying out any intent for suicide; and activation of a plan to keep the patient 
safe. In order to maintain the scientific integrity of this human subject research project, and to 
protect the safety of its research participants, we will assemble a Data Safety Monitoring Board 
(DSMB) comprising members with appropriate clinical and technical expertise. The DSMB will 
have the responsibility of assuring that participants are not being exposed to unnecessary or 
unreasonable risks as a result of the pursuit of the study’s scientific objectives. All data collected 
over the course of the trial—including from study participants and household members—will 
be stored on an encrypted, password protected server to which only research study staff 
(including clinical staff providing depression care) have access.  
Availability of Data 
For dissemination purposes, reporting results will be documented on ClinicalTrials.gov 
in accordance with NIH requirements. Information submitted will occur no later than 12 

 
25 
months after the primary completion date. Results produced by this investigation will be 
presented at conferences where applicable and published in a timely fashion. In the final year of 
the project, we will also host a conference  and invite government officials to discuss findings in 
the broader context of Malawian policy initiatives. All final peer-reviewed manuscripts that 
arise from this proposal will be submitted to PubMed Central for open access. When applicable, 
deidentified analytic code and the associated datasets will be deposited in public repositories—
including Harvard University’s Dataverse database: https://dataverse.harvard.edu.  
 
DISCUSSION 
 
This study will conduct a district-wide stepped-wedge cluster randomized trial to assess 
the effects of an evidence-based stepped care depression treatment model vs. usual care on 
depression symptom alleviation as well as quantifying improvements in physical health and 
household dynamics. While there is evidence of the deleterious effects of depression on mental 
health, this will be one of the first studies to quantify treatment benefits on physical health 
outcomes and household-level outcomes, and to incorporate these knock-on effects in cost-
effectiveness estimates.  We anticipate that by leveraging the existing infrastructure of the 
robust HIV care delivery system, the IC3 model and by quantifying these knock-on effects, 
expansion of depression care will be highly cost-effective and financially feasible for scale-up in 
Malawi.     
 
Building on our research with task-shifted evidence-based depression care for HIV 
clients in Uganda, and our use of problem solving therapy (PST) and ADT in low-resource 
settings such as Rwanda and Haiti,98,99 this study is specifically designed to test a group-based 

 
26 
model of PM+ that WHO has advocated for broad scale-up. Moreover, the model focuses on an 
existing and growing cadre of counsellors throughout Malawi to deliver group-based PM+ and 
will measure fidelity to protocol execution, among other measures. Through close partnership 
with the Ministry of Health, in the final year of this project we intend to host a conference 
reviewing major findings of this work and to facilitate a discussion—including a technical 
expert panel—to outline potential strategies for wider scale-up.  
 
TRIAL STATUS 
This is Protocol version 1.0, dated February 25, 2021. Recruitment is anticipated to begin July 15, 
2021 and complete on July 14, 2024.  
 
LIST OF ABBREVIATIONS 
• 
A1C: Hemoglobin A1C 
• 
ADT: Antidepressant therapy 
• 
ARSS: AIDS-related stigma scale 
• 
ART: Antiretroviral therapy 
• 
ARVs: Antiretroviruals 
• 
BAS: Burden assessment scale 
• 
CAC: Cluster autocorrelation coefficient 
• 
CIDI: Composite International Diagnostic Interview 
• 
DSMB: Data and safety monitoring board 
• 
EQ-5D-5L: EuroQol 5 dimensions 5 levels 
• 
HIV: Human immunodeficiency virus 
• 
IAC: Individual autocorrelation coefficient 
• 
IC3: Integrated Chronic Care Clinics 

 
27 
• 
IC3D: Integrated chronic care clinics – depression module 
• 
ICC: Intraclass correlation coefficient 
• 
ICER: Incremental cost-effectiveness ratio 
• 
ISMI: Internalized stigma of mental illness scale 
• 
ITT: Intention to treat 
• 
LAMIC: Low- and middle-income county 
• 
MCMC: Markov chain Monte Carlo 
• 
MSPSS: Multidimensional scale of perceived social support 
• 
NCD: Non-communicable disease 
• 
NIMH: National Institute of Mental Health 
• 
PHQ-2: Patient Health Questionnaire – 2-Item 
• 
PHQ-9: Patient Health Questionnaire – 9-Item 
• 
PIH: Partners In Health 
• 
PM+: Problem Management Plus 
• 
QALY: Quality-adjusted life year 
• 
RCT: Randomized controlled trial 
• 
SSRI: Serotonin selective reuptake inhibitor 
• 
TB: Tuberculosis 
• 
TCA: tricyclic antidepressant 
• 
TDABC: Time-driven activity-based costing 
• 
WHO: World Health Organization 
• 
WHODAS: World Health Organization Disability Assessment Schedule 
 
DECLARATIONS 
Ethics approval and consent to participate 
 
This study has received ethics approval from the RAND Human Subjects Protection 
Committee as well as the National Health Science Research Committee of Malawi. The authors 

 
28 
will received verbal or written informed consent to participate in the study from all 
participants.  
Consent for publication 
Publication of findings will not include any identifiable details. A model consent form 
can be provided to individuals upon request.  
Availability of data and materials 
The authorship team will have access to the final trial dataset. All final peer-reviewed 
manuscripts that arise from this proposal will be submitted to PubMed Central for open access. 
When applicable, deidentified analytic code and the associated datasets will be deposited in 
public repositories—including Harvard University’s Dataverse database: 
https://dataverse.harvard.edu.  
Competing interests 
 
The authors declare they have no competing interests.  
Funding 
 
This study is funded by the National Institute of Mental Health (R01 MH117760). The 
funder had no role in the study design or implementation of activities, apart from ensuring 
compliance of ethics guidelines.  
Authors' contributions 

 
29 
RKM and GW are the Principal Investigators; they conceived the study, led the proposal 
and protocol development. EW, EC, TR, WK, MC, and CK contributed to study design and to 
development of the proposal. SM was the lead trial methodologist. All authors read and 
approved the final manuscript. No professional writers were utilized to generate this 
manuscript. 
Acknowledgements 
The authorship team would like to thank the many members of the PIH/APZU family 
for making this project a reality. We would also like to acknowledge the ongoing engagement, 
support, and partnership of the Ministry of Health in Neno District as well as at the national 
level. Their vision to provide exceptional healthcare to meet the mental as well as physical 
needs of patients is a testament to the vision and commitment of these individuals.   
 
 

 
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REFERENCES 
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