A Sequential, Multiple Assignment Randomized Trial (SMART) for Non-specialist Treatment of Common Mental Disorders in Kenya: Leveraging the Depression And Primary-care Partnership for Effectiveness-implementation Research (DAPPER) Project
Phase: NA
Conditions: Depression, Unipolar, Posttraumatic Stress Disorder, Trauma
Sponsor: University of California, San Francisco

 
 
Project Title: SMART-DAPPER: Leveraging the Depression And Primary-care Partnership for 
Effectiveness-implementation Research Project (SMART-DAPPER) 
 
Clinicaltrials.gov number: NCT03466346 
 
 
 
Title of Document: Protocol (version 7.0)  
Date of Document: October 27, 2021 
 
 

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A SEQUENTIAL, MULTIPLE ASSIGNMENT RANDOMIZED TRIAL 
(SMART) FOR  NON-SPECIALIST TREATMENT OF COMMON 
MENTAL DISORDERS IN KENYA: LEVERAGING THE DEPRESSION  
AND PRIMARY-CARE PARTNERSHIP FOR EFFECTIVENESS-
IMPLEMENTATION RESEARCH (DAPPER) PROJECT (SMART-
DAPPER) 
 
 
 
 
 
By  
MUTHONI MATHAI MMed (Psychiatry) PhD 
SUSAN MEFFERT MD, MPH 
LINNET ONGERI MMed (Psychiatry) 
 
 
 
 
 
©  October 2021 

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 ABSTRACT 
Introduction:  
Dominated by depression, mental disorders are a leading cause of global disability. 
Most of the disease burden is in Low and Middle Income Countries (LMICs), where 
75% of adults with mental disorders have no service access. Despite nearly 15 years of 
efficacy studies showing that local non-specialists can provide evidence-based care for 
depression in LMICs, few studies have advanced to implementation research. As 
emphasized by a recent World Health Organization (WHO) initiative, integration of 
depression treatment into existing systems of care is critical to achieving public health 
impact. Kenyan leaders recently launched an initiative to scale-up treatment for mental 
disorders in primary healthcare, prioritizing depression. Yet, they lack an evidence base 
for the two essential treatments – psychotherapy and second-generation antidepressants 
- without which the scale-up will fall short of its potential. The proposed research 
responds to this need and builds on our current work in Kisumu, showing that 
Interpersonal Psychotherapy (IPT) can be delivered by trained non-specialists with high 
efficacy for the treatment of depression and/or PTSD using fluoxetine or Interpersonal 
therapy. In the context of the ongoing COVID-19 pandemic, and to adequately respond 
to and provide additional care for new or worsening mental health needs, we will 
integrate a phone based screening, assessment and treatment options. Additionally, the 
study applies a SMART design to manage non-responsiveness to the given treatment 
by switching or combination. 
Objectives: We propose to partner with local and national mental health stakeholders 
in Kenya to evaluate: (1) non-specialist delivery of evidence-based depression and/or 
PTSD treatment integrated within existing healthcare centers and by telephone in regard 
to clinical effectiveness and implementation parameters; including (2) costs and cost-
benefit ratios for depression and/or PTSD care.   Given that evidence-based 
psychotherapy and second-generation antidepressants are the two leading first-line 
treatments for depression and/or PTSD   and are feasible to deliver in Kenya, our goal 
is to test an implementation strategy for improving equitable access to these treatments 
by integrating them with primary care.  
Methodology:  
Given the novelty of non-specialist depression care and primary care integration for 
Kenya, we will use an effectiveness-implementation hybrid design type I, which 
emphasizes effectiveness outcomes for the new setting and study population, while 
also gathering implementation data for future scale up. In collaboration with the 80-
member FACES team currently providing integrated HIV care to Kisumu County 
Hospital (KCH) primary care outpatient clinics (~10,000 patients/month), we will 
randomize 2000 adult KCH and other Kisumu County Ministry of Health primary 
care patients with Major Depressive Disorder (MDD) to receive IPT delivered in 
person or by telephone by non-specialists trained in the study or fluoxetine delivered 
by fluoxetine trained providers in the study and follow them for 30 months. We will 
use the Exploration, Preparation, Implementation and Sustainment (EPIS) framework 
to inform the research and incorporate positive findings into practice. Given the high 
prevalence of MDD-PTSD co- morbidity, we will leverage the R01 to support a 
Sequential, Multiple Assignment Randomized Trial (SMART) by recruiting an 
additional 710 participants with MDD and/or PTSD (irrespective of HIV status) for a 

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total of 2710 participants.  Local non-specialists will be trained in mental health care 
for the SMART and hired through the Kenyan Ministry of Health to work at KCH and 
other Kisumu County Ministry of Health facilities. After the study, Kisumu County 
will continue their payroll and the fluoxetine supply.   
 
 
Data analysis: the study will compare short and long term (relapse) outcomes for IPT 
versus fluoxetine treatment (Aim 1), and calculate costs and cost-benefit ratios for each 
treatment arm (Aim 2). 
Results: 
The results of the proposed research will (1) produce a scalable strategy for delivering 
depression treatments in sub-Saharan Africa using non-specialists integrated within 
existing primary care structures and (2) offer policy makers short and long-term cost-
benefit options for integrated depression care with corresponding effectiveness and 
implementation values. 
 

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TABLE OF CONTENTS 
 
 
ABSTRACT .................................................................................................................. iii 
TABLE OF CONTENTS ............................................................................................... v 
ABBREVIATIONS AND ACRONYMS .................................................................... vii 
OPERATIONAL DEFINITIONS ............................................................................... viii 
LIST OF TABLES ........................................................................................................ ix 
LIST OF FIGURES ....................................................................................................... x 
LIST OF APPENDICES ............................................................................................... xi 
INTRODUCTION ......................................................................................................... 1 
Background ................................................................................................................ 1 
Expertise and experience in training nurses in East Africa to administer 
fluoxetine for depression: ....................................................................................... 5 
Hypothesis and Specific Aims: .................................................................................. 5 
Significance ................................................................................................................ 7 
LITERATURE REVIEW .............................................................................................. 8 
RESEARCH METHODOLOGY AND PROCEDURES ............................................ 12 
Study location:.......................................................................................................... 12 
Figure 1: Map of study area .................................................................................. 12 
Study Design: ........................................................................................................... 12 
Assessment schedule and rationale: ......................................................................... 19 
Data collection. ..................................................................................................... 29 
Effectiveness outcomes ............................................................................................ 30 
Fidelity .................................................................................................................. 34 
Acceptability and Appropriateness ....................................................................... 35 
Service delivery mechanism: availability and affordability ................................. 36 
Human participants in the project ............................................................................ 39 
Target population. ................................................................................................. 39 
Sample size calculations ....................................................................................... 39 
Eligibility criteria ..................................................................................................... 42 
Inclusion criteria: .................................................................................................. 42 
Exclusion criteria: ................................................................................................. 42 

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Recruitment .............................................................................................................. 43 
Mental health crisis. .............................................................................................. 44 
Research Ethics ........................................................................................................ 45 
Institutional Review Process ................................................................................ 45 
Voluntariness: ....................................................................................................... 47 
Confidentiality ...................................................................................................... 47 
Risks and benefits of the study ............................................................................. 48 
Risks to the Subject .............................................................................................. 48 
Potential Risks ...................................................................................................... 48 
Adequacy of Protection against Risks .................................................................. 50 
Potential adverse events and proposed interventions ............................................... 53 
Nature and Degree of Risk: .................................................................................. 53 
Minimization of Risk: ........................................................................................... 53 
Additional information ............................................................................................. 58 
Audio Recording................................................................................................... 58 
TIMELINE ................................................................................................................... 58 
REFERENCES ............................................................................................................ 63 
BUDGET ..................................................................... Error! Bookmark not defined. 
APPENDICES ............................................................. Error! Bookmark not defined. 
 
 

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ABBREVIATIONS AND ACRONYMS 
AUDIT: alcohol use disorder identification test 
ASQ: Ask Suicide-Screening Questions 
BDI: Beck Depression Inventory 
CAG: Community Advisory Groups 
CTS: Conflict Tactics Scale 
CHW/CHV: Community Health Worker/ Community Health Volunteer  
DAP: Dynamic Adaptation Process 
DAPPER: Depression And Primary-Care Partnership For Effectiveness-
Implementation Research 
DAS: Dyadic Adjustment Scale 
DAST: Drug Abuse Screening Test 
DM: Diabetes Mellitus DSM-V: Diagnostic and Statistical Manual of Mental 
Disorders-V 
EPIS: Exploration, Preparation, Implementation and Sustainment  
FACES: Family Aids Care and Education Services 
GBD: Global Burden of Disease 
HIC: High Income Countries 
HIV: Human Immune Deficiency Virus 
HSE: Baseline Household Socio-Economic Survey 
HTN: Hypertension  
IPT: Interpersonal Therapy 
KCH: Kisumu County Hospital 
KEMRI: Kenya Medical Research Institute 
KNH: Kenyatta National Hospital 
LMIC: Low and Middle Income Countries 
MDQ: Mood Disorder Questionnaire  
MDSPSS: Multi-dimensional Scale of Perceived Social Support 
MDD: Major Depressive Disorder  
MINI: Mini International Neuropsychiatric Interview 
NACOSTI: National Commission for Science, Technology and Innovation 
NIMH: National Institute of Mental Health 
PCL: Posttraumatic Stress Checklist 
PHQ-2: Patient Health Questionnaire-2 
PPB: Pharmacy & Poisons Board 
PTSD: Post traumatic stress disorder 
RDoC: Research Domain criteria 
REDCap: Research Electronic Data Capture 
SAM: Self-Assessment Manikin 
SMART: Sequential, Multiple Assignment Randomized Trial 
THQ:  Trauma History Questionnaire 
UCSF: University of California, San Francisco   
UoN: University of Nairobi 

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WB: World Bank 
WHO: World Health Organisation 
WHODAS: World Health Disability Assessment Schedule  
 
 
OPERATIONAL DEFINITIONS 
 
Interpersonal therapy: a form of psychotherapy (talking treatment) in which the 
health provider works with the patient to improve interpersonal and intrapersonal 
communication skills within relationships and to develop social support network  
 
 
 
 
 
 
 
 
 
 

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LIST OF TABLES 
 
Table 1: List of SMART-DAPPER measures 
Table 2: Calculating RE-AIM from an Effectiveness-Implementation Hybrid Type III 
(SMART-DAPPER)  
Table 3: Research timeline 
Table 4: Budget  
 
 
 

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LIST OF FIGURES 
 
Figure 1: Map of Kisumu County  
Figure 2: Exploration, Preparation, Implementation, Sustainment (EPIS) model  
Figure 3: SMART-DAPPER Study design  
Figure 4: Interpersonal Psychotherapy Phases 
 
 
 
 
 
 

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LIST OF APPENDICES 
 
Study explanation  
 
Consent  
Consent to Participate in a Research Study 
Consent to Participant in a Research Study:  In-Depth Interview Assessments 
of Interventions 
Consent to Participant in a Research Study:  Focus Group Assessment of 
Implementation 
Consent to Participant in a Research Study:  In-Depth Interview Assessments 
of Implementation 
Consent for in-depth Assessment Of Implementation Luo 
 
Questionnaires 
Alcohol Use Disorders Identification Test (AUDIT) 
Ask Suicide-Screening Questions (ASQ) 
Beck Depression Inventory (BDI) 
Conflicts Tactics Scale-2 (CTS-2) 
Drug Abuse Screening Test (DAST) 
Dyadic Adjustment Scale (DAS) 
HSE: Baseline Household Socio-Economic Survey 
Mini International Interview (MINI)  
Trauma History Questionnaire (THQ) 
Posttraumatic Checklist (PCL) 
Mood Disorder Questionnaire (MDQ) 
Multi-dimensional Scale of Perceived Social Support (MSPSS)  
Self-Assessment Manikin (SAM)  
World Health Organization Disability Assessment Schedule (WHODAS)  
Patient Health Questionnaire-2 (PHQ-2) 
Healthcare utilization, Income and Employment, Education and School Fees, 
and Time Allocation (SEARCH) 
Demographic Health Survey (DHS) – selected questions  
Affordability and Access for Treatment  
Demographics  
Concomitant Medications  
Health Co-morbidities  
 

 
 
INTRODUCTION 
 
Background 
Led by depression, untreated mental disorders are the largest global cause of 
disability.(Christopher J L Murray et al., 2015),(Ferrari et al., 2013),(Thornicroft et al., 
2016) Most of this burden is in Low and Middle Income Countries (LMICs), where 75% 
of adults with mental disorders have no access to treatment.(Organization, 2008) Despite 
15 years of efficacy research demonstrating that evidence-based, low-cost depression 
treatments can be successfully delivered by non-specialist personnel in low resource 
settings,(Hyman, 2014),(Vikram Patel et al., 2013),(van Ginneken et al., 2013) morbidity 
from mental disorders continues to escalate.(Bloom et al., 2011),(Kassebaum et al., 
2016),(Shidhaye, Lund, & Chisholm, 2015),(Chisholm et al., 2016) It is vital that global 
mental health treatment researchers now focus on implementation science to inform 
scale-up of evidence-based depression care to lower mental health burden. As 
emphasized by a recent World Health Organization (WHO) initiative,(“WHO | 
Framework on Integrated People-Centred Health Services,” n.d.) integration of 
depression treatment into existing systems of care is critical to achieving public health 
impact. With high prevalence of Major Depressive Disorder (MDD) in Kenyan primary 
care populations (26.3%,(Aillon et al., 2014) 3-5 times higher than in the U.S.(Katon, 
2003)), treatment for depression is a top concern for Kenya mental health leaders. 
Knowledge gaps in Kenyan mental health care implementation thwart current scale up 
efforts. Kenyan mental health leaders recently launched a government-funded initiative to 
scale-up treatment for mental disorders in primary healthcare, prioritizing 

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depression.(Bukusi, 2015) Yet, they lack an evidence base to guide programs for the two 
essential treatments –psychotherapy and second generation antidepressants(Gelenberg et 
al., 2010)—without which Kenyan care scale-up will fall short of its potential.(Kiima, 
2015),(Ndetei et al., 2009) The proposed research responds to this need. 
Implementation research on depression treatment within existing LMIC health care 
systems must consider not only individual treatment benefits in culturally distinct 
populations, but also barriers affecting access to care, healthcare system capacities, and 
budget.(Cabassa & Baumann, 2013) Hence, we propose to partner with local and national 
mental health stakeholders in Kenya to evaluate: (1) non-specialist delivery of evidence-
based depression treatment integrated within existing healthcare centers in regards to 
clinical effectiveness and healthcare system implementation parameters; including (2) 
costs and cost-benefit ratios for depression care. In collaboration with Family Aids Care 
and Education Services (FACES), we are already conducting an effectiveness-
implementation hybrid type I study (Curran, Bauer, Mittman, Pyne, & Stetler, 2012) 
(n=300) of Interpersonal Psychotherapy (IPT) delivered by non-specialists for HIV-
positive women with co-morbid MDD and posttraumatic stress disorder (Onu et al., 
2016),(Meffert, Neylan, Chambers, & Verdeli, 2016). In preliminary analyses, IPT 
delivered by non-specialists achieves remission in 38% of participants–similar to U.S. 
effectiveness studies with specialists (36.8%) (Rush et al., 2006) Given that evidence-
based psychotherapy and second-generation antidepressants are now considered the two 
leading first-line treatments for depression(Gelenberg et al., 2010) and are feasible to 
deliver in Kenya, our goal is to test an implementation strategy for improving equitable 
access to these treatments by integrating them with primary care. We will leverage 

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research suggesting that antidepressants and psychotherapy have equivalent short-term 
results for depression, and that psychotherapy better protects against relapse (long-term 
result).(Schneier et al., 2012),(Lee et al., 2016),(Hien et al., 2015) We propose an 
effectiveness-implementation hybrid design type III (Curran et al., 2012) (Depression 
And Primary-care Partnership for Effectiveness-implementation Research [DAPPER]) to 
determine the outcomes of non-specialist delivered Interpersonal Psychotherapy (IPT) 
compared to fluoxetine, including assessment of the service delivery mechanism in 
regards to availability to attend required treatment schedule and affordability.(Obrist et 
al., 2007),(Penchansky & Thomas, 1981),(Khanassov et al., 2016),(Levesque, Harris, & 
Russell, 2013)  
Preliminary studies  
 
We are currently conducting an effectiveness-implementation hybrid type I study of 
depression treatment delivered by non-specialists, integrated with HIV care services at a 
government primary healthcare center (n=300). We have used individual IPT delivered 
by non-specialist personnel for MDD and Posttraumatic Stress Disorder (PTSD) in three 
LMICs, including Darfur refugees in Cairo,(Jiang et al., 2014) Sichuan earthquake 
survivors (absolute risk reduction of greater than 50% and effect sizes of 2.37 (p=0.018) 
and 1.94 (p=0.056) for MDD and PTSD, respectively)(Jiang et al., 2014) and our current 
NIMH-funded randomized, controlled effectiveness-implementation hybrid type I trial of 
IPT for HIV+ women affected by gender based violence integrated within the FACES-
supported Kisumu County primary care clinic at Lumumba health center (enrolment 
complete [n=300], study ongoing).(Zunner et al., 2015),(Onu, Ongeri, Rota, Atewa, & 
Meffert, n.d.) 

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In our current study: 
• Clinical outcome domains include mental health (MDD and PTSD diagnostic and 
symptom measures), HIV (viral load and self-reported anti-retroviral adherence), 
intimate partner violence, interpersonal functioning, disability, quality of life and 
neurocognition.  
•  Implementation and economic domains include human resources for integrating 
mental health care within the HIV clinic (implementation officer, peer supervision, 
clinic staff advisory team), treatment protocol adherence (a random 20% of IPT 
sessions are externally reviewed for IPT adherence), repeated stakeholder 
engagement (local and national) and a detailed economics core assessing patient-level 
benefits, formal and informal productivity gains and overall returns on mental health 
care investment.  
In preliminary analyses of post-treatment data (n=194) in the current study in Kisumu, 
Kenya, non-specialist delivered IPT achieves MDD remission in 38% and PTSD 
remission in 52% of participants – greater than treatment as usual and higher than U.S. 
effectiveness studies (30%) with physician-delivered depression care. In a subsample 
with HIV viral load data (n=116), we have a nearly significant effect (p=0.09) on un-
detectability of HIV viral load (clinical goal): 82% of those in IPT have undetectable 
viral loads after their 12-week treatment, versus only 68% of those in usual care, despite 
the fact that all participants received usual HIV care, throughout. 

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Expertise and experience in training nurses in East Africa to administer fluoxetine 
for depression:  
Our team has experience with training nurses and clinical officers to integrate with 
existing healthcare systems and successfully prescribe fluoxetine for depression, 
including HIV clinics in a neighbouring region of Uganda. In preliminary analyses 
of Dr. Akena and Wagner’s INDEPTH study (n=415), 66% (n=272) completed a 9 
month course of antidepressant therapy. Only 15% (n=61) had prematurely 
discontinued treatment —a higher rate of adherence than with SSRIs in High 
Income Countries (HICs). 78% of completers were in full remission at treatment 
conclusion and 66% in the intent to treat analysis, which classified those who 
prematurely discontinued treatment as non-responders. The majority of the treatment 
gains were achieved early in treatment (weeks 6-12), with a 68.5% average 
reduction on the Patient Health Question 9 item (PHQ-9) from baseline and little 
further gain with additional treatment. 
Hypothesis and Specific Aims: 
Aim 1:  
Determine the effectiveness of non-specialist-delivered Interpersonal Psychotherapy 
(IPT), fluoxetine, or combination for MDD and PTSD.  
Hypothesis 1a: Initial randomization to IPT or fluoxetine will have similar efficacy for 
post-treatment remission.   
Hypothesis 1b: Participants who remit with IPT or combination treatment will have fewer 
relapses over follow-up than those who remit with  fluoxetine.    

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Aim 2:  
Investigate key presumed mediators of the relationship between treatment and remission 
Hypothesis 2a: For initial treatment with IPT, change in social support will mediate the 
relationship between treatment and remission—improved social support will be 
associated with remission 
Hypothesis 2b:  For initial treatment with fluoxetine, change in emotional reactivity will 
mediate the relationship between treatment and remission—decreased emotional 
reactivity will be associated with remission.    
Aim 3: Identify demographic and clinical moderators of the relationship between 
treatment and remission.   
Hypothesis 3a: Time or cost for transport between participants’ residences and KCH, 
and other Kisumu County Ministry of Health facilities will moderate the relationship 
between treatment and remission—higher time/cost will decrease the effect of initial 
treatment with IPT relative to fluoxetine (more treatment visits required for IPT versus 
fluoxetine treatment).   
Hypothesis 3b: Severity of MDD and/or PTSD symptoms among non-remitters will 
moderate the relationship between subsequent treatment and remission, such that higher 
severity will decrease the effect of treatment on remission for treatment switch relative to 
treatment combination.  
 Hypothesis 3c:  Q learning will produce personalized treatment algorithms using the 
above or other moderators.    

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Aim 4. Estimate the costs and cost-benefit ratios for fluoxetine and IPT treatment of 
depression and PTSD.   
Hypothesis 4a: Pooled cost-benefit ratios will show that depression and/or PTSD 
treatment leads to net economic gain for individuals and households at month 6; 
Hypothesis 4b: Separate analyses will find that  IPT has a more favorable cost-benefit 
than fluoxetine at month 30. 
Aim 5. Determine the acceptability and feasibility of delivering SMART-DAPPER 
treatments by telephone.   
Hypothesis 5a. Telephone IPT will be acceptable and feasible.  
Hypothesis 5b. Telephone fluoxetine provider appointments will be acceptable and 
feasible. 
Aim 6. Determine the effect of telephone treatment delivery on retention in care.  
Hypothesis 6a. Participants who elect to receive telephone treatment will have higher 
retention in care than those who receive face-to-face care. 
Significance  
The results of the proposed research will be significant in two ways:  
(1) They will produce a scalable strategy for delivering evidence-based depression 
treatments in sub-Saharan Africa using non-specialists integrated within existing primary 
care structures and  

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(2) They will produce a practical, policy maker “menu” of short and long-term cost-
benefit options for integrated depression care with corresponding effectiveness and 
implementation values. 
 
 
 
LITERATURE REVIEW 
 
Depression is now the leading cause of disability in eastern sub-Saharan 
Africa(Thornicroft et al., 2016),(“Global, regional, and national incidence, prevalence, 
and years lived with disability for 301 acute and chronic diseases and injuries in 188 
countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 
2013,” 2015) and among the top 5 diseases driving the overall increase of global 
morbidity and disability.(Christopher J L Murray et al., 2015),(C.J.L. Murray & Lopez, 
1996) The 1996 global burden of disease (GBD) report by World Health Organization 
(WHO) and the World Bank (WB) was the first to put mental disorders on the list of 
highly disabling conditions.(C.J.L. Murray & Lopez, 1996) Twenty years later, the global 
disability attributed to mental disorders has increased by 45%. 
 Depression is higher in primary care populations compared with general populations.  In 
primary care populations of high income countries, 29% of adult outpatients have major 
depressive disorder, compared with approximately 6.7% of the general population.(Roca 
et al., 2009),(“NIMH » Major Depression Among Adults,” n.d.)  Preliminary data from 

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our studies in Kenya indicates an even heavier burden among primary care patients in 
Kenya, with approximately 50% meeting criteria for major depressive disorder, compared 
approximately 2.6-5.6% of the general population—a 10-19 fold difference.(Ongeri et al., 
n.d.),(Jenkins, Othieno, Ongeri, Sifuna, et al., 2015),(Hanlon et al., 2014) 
Integration of depression treatment with primary care is beneficial to patients and 
healthcare systems. For more than ten years, it has been established that integrating 
depression treatment with primary care services produces better results for patients in 
both the short term and the long term (5 years).(Gilbody, Bower, Fletcher, Richards, & 
Sutton, 2006)More recent studies have shown that integrated depression care effectively 
improves depression symptoms, adherence and response to treatment, remission of 
symptoms, quality of life, function and satisfaction with care.(Thota et al., 2012)  
Integrated depression care has been shown to be cost-effective.(Jacob et al., 2012)   
Integrated depression care in LMICs has been advocated for many years, and a completed 
large scale treatment study in an LMIC shows positive results.(Vikram Patel et al., 2016) 
In sub-Saharan Africa, numerous studies show that adequate resources for integration of 
depression and primary care services exist,(Hanlon, Wondimagegn, & Alem, 
2010),(Mugisha et al., 2017),(V. Patel et al., 2016) with some of the clearest findings in 
Kisumu County (below).  
 
Integration of depression treatment with primary care is feasible and acceptable at 
Kisumu County Hospital (KCH) and other Kisumu County Ministry of Health facilities.  
Kisumu County is one of the more advanced regions of Kenya for research on integration 
of mental health and primary health care.  Our team has shown that interventions to 

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improve mental health care for primary care outpatients are feasible,(Jenkins, Othieno, 
Okeyo, Kaseje, et al., 2013) and acceptable to patients(Jenkins, Othieno, Ongeri, Ogutu, 
et al., 2015) as well as primary health care providers.(Jenkins, Othieno, Okeyo, Aruwa, et 
al., 2013) Integration of depression care with adult medical outpatient clinics at KCH and 
other Kisumu County Ministry of Health facilities or over the telephone will benefit from 
our collaboration with FACES, which currently has large teams at KCH and other 
Kisumu County Ministry of Health facilities, integrated with the primary care clinics to 
provide HIV services and ready to partner with this study to facilitate its integration.  
Furthermore, both local and national mental health policy leaders, as well as the directors 
of KCH and other Kisumu County Ministry of Health facilities are highly enthused about 
integration of depression treatment with primary care clinics at KCH and other Kisumu 
County Ministry of Health facilities given its high prevalence in the region and the 
burden that untreated depression places on regional primary care systems. 
In light of the COVID-19 pandemic, Kenya has appropriately responded with strict stay-
home and curfew orders to limit transmission. Yet, these restrictions are likely to worsen 
symptoms for those already living with Major Depressive Disorder (MDD) and 
Posttraumatic Stress Disorder (PTSD), the focus of SMART-DAPPER treatment. In 
order to adapt to the community’s mental health care implementation needs, participants 
will have the option to have their treatment visits (Interpersonal Psychotherapy [IPT] and 
fluoxetine initiation and management) and assessment visits by telephone.   
Prior to randomization, participants will chose if they would prefer to receive their 
treatment at the health facility in person or by telephone.  Participants who are 
randomized to fluoxetine will collect their medication at the health facility.  If 

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participants do not collect their medication at the health facility, fluoxetine may be 
delivered to participants in the community.   
 

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RESEARCH METHODOLOGY AND PROCEDURES 
Study location:  
Kisumu County is in western Kenya near Lake Victoria and the county capital is Kisumu, 
the third largest city in Kenya. With its high prevalence of HIV, the region has been a 
focus of national and international healthcare efforts, with robust research infrastructure 
(Figure 1). 
Kisumu County Hospital is a county government run facility situated at the centre of 
Kisumu city, just next to Kisumu Bus Park. The facility still hosts the only county 
psychiatric ward, which serves the whole former Nyanza region. The outpatient 
department is headed by a physician, 2 Medical Officers, 3 Clinical Officers and Nurses. 
On estimate 10,000 adult primary care outpatients are seen per month.   
Figure 1: Map of study area  
 
 
 
 
Study Design: 
Effectiveness-implementation study designs are a transformative tool for making 
evidence-based depression care disorders equitably available in LMICs. Recently, Curran 
Kisumu County Hospital (KCH): 
10,000 adult primary care outpatients seen per month 

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and colleagues defined effectiveness-implementation hybrid study designs.(Curran et al., 
2012) These designs include both effectiveness and implementation outcomes, allowing 
for the collection of data on individual clinical outcomes as well as system-level data on 
provider training, supervision, financing and workflow in real-world settings. 
Effectiveness-implementation hybrid designs are a key advancement for global mental 
health implementation research because they allow monitoring of clinical outcomes with 
culturally diverse populations, while advancing research to support mental health care 
scale up.(Meffert et al., 2016) Our team has shown that effectiveness-implementation 
study designs are feasible in Kisumu County.(Meffert et al., n.d.; Onu et al., 2016) See 
details in preliminary data, below.  
Effectiveness-implementation hybrid designs.  Type I effectiveness-implementation 
hybrid designs prioritize clinical effectiveness outcomes (the design that we propose), 
type II balances effectiveness and implementation outcomes, and type III emphasizes 
implementation outcomes. Given that effectiveness research using non-specialist 
integrated care is in the early stages in this region, we will use a type I design. 
Randomizing at the participant level, we will emphasize collection of effectiveness data 
while gathering implementation data to advance an evidence base for sustainable, 
integrated depression care in LMICs  
Research team: Based on our work in the region, we are aware that implementation 
research that achieves a sustained positive impact after study conclusion must include key 
stakeholders at national and local levels who make final decisions on the allocation of 
healthcare funds, and directors, providers, staff, patients and community liaisons at the 
proposed clinic(s). Therefore, we have in place a team with (1) academic and research 

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expertise in implementation science, healthcare economics, integration of mental health 
services within large Kenyan healthcare settings and task-shifting for delivery of 
evidence based depression care; (2) national and local healthcare policy and economics, 
including decision-makers for the allocation of healthcare funds (Drs. Simon Kahonge, 
David Bukusi and Dickens Onyango) (3) KCH and other Kisumu County Ministry of 
Health facilities directors and FACES KCH and other Kisumu County Ministry of Health 
facilities staff who have successfully integrated with primary care to provide over a 
decade of sustained service, and FACES’ roster of contacts, including KCH and other 
Kisumu County Ministry of Health facilities providers, staff, patients and community 
advisory groups. See discussion of the EPIS model, below, for details on how we will 
form collaborative stakeholder implementation teams to plan and adapt the study (as 
needed) and strategy for incorporating positive findings into policy and practice. 
Overview of our approach: The EPIS model will be our primary vehicle for engaging 
key stakeholders to plan the proposed research, adapt/optimize depression care and 
identify strategies for incorporating positive findings into policy and practice. The EPIS 
model balances engagement of the inner context (e.g., clinic staff, patients, providers) 
and outer context (e.g., local health policy and community leaders, regional stakeholders, 
national mental health policy experts) stakeholders (Figure 2). We will use the DAP to 
make contextually required adaptations in order to optimize the fit of depression care 
delivered by non-specialists and integrated with primary care without sacrificing fidelity 
to evidence based practice. The DAP process will be carried out by an implementation 
resource team (IRT) composed of stakeholders from the inner and outer settings and 

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representing the spectrum of collaborators, including community, academic and 
policy/government leaders. 
Building on our team’s experience with integration of mental health care services in 
Kenya,(Zunner et al., 2015),(Verdeli et al., 2003) our first step will be to identify the key 
stakeholders from the “inner”(e.g. clinic staff, patients and providers) and “outer”(e.g. 
county and national health policy makers, community leaders and regional leaders) 
context of the proposed study.  From these stakeholders, we will identify a diverse core 
implementation resource team, which will serve as liaisons and will participate in 
monthly adaptation process meetings to (1) review study protocols and trouble shoot 
implementation (e exploration phase); (2) prepare for study launch with communications 
and logistical preparations (EPIS preparation phase); (3) review study progress, deepen 
engagement with key stakeholders,  monitor fidelity to protocol and identify areas in need 
of further adaptation (EPIS implementation); (4) as results accumulate, discuss best 
strategies for local dissemination of findings, and collaborative strategies to produce the 
most useful  of final results to achieve maximal public mental health impact in Kenya and 
regionally (EPIS sustainment). 
 To explore optimal logistics for integration of depression screening and care into the 
adult outpatient  clinics at Kisumu County Hospital (KCH) and other Kisumu County 
Ministry of Health facilities we will meet with patients, patient representatives, staff and 
heads of staff to identify optimal strategies for integrating depression care services within 
outpatient clinics in KCH and other Kisumu County Ministry of Health facilities, and by 
telephone.  We will also collaborate with and learn from the experiences of the FACES 
teams at KCH and other Kisumu County Ministry of Health facilities, which currently 

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integrates with outpatient medical clinics to provide HIV services – drawing on the 
successes of their model.  FACES also has a strong assemblage of community advisory 
groups (CAGs) composed of local religious leaders, patients of community health care 
and village chiefs who are experienced with review and advising on new healthcare 
endeavors.  CAGs meet monthly, and we will put the addition of depression screening 
and care for KCH and other Kisumu County Ministry of Health facilities adult 
outpatients on the agenda, soliciting feedback on best strategies for communicating about 
the change, decreasing stigma and maximizing participation. In addition, we will leverage 
our current relationships with the local director of medical services and the national 
director of mental health in the MOH as well as the medical superintendents of KCH and 
other Kisumu County Ministry of Health facilities soliciting feedback on best strategies 
for optimizing public health impact.  As preparation for the study launch proceeds, we 
will hire study personnel that are experienced with KCH and other Kisumu County 
Ministry of Health facilities adult outpatient clinics and can function as liaisons for 
sustainment.  We will also work with Community Health Workers (CHWs) and 
Community Health Volunteers (CHVs) to mobilize and sensitize the community about 
mental health services and refer community members to one of the health facilities for 
screening for the SMART-DAPPER study.  During implementation, we will meet 
regularly with local stakeholders, as well as the  regional and national health policy 
leaders to share study progress.  In the sustainment phase, we will discuss study findings  
and next steps for scale up of primary care integrated depression care services in Kenya. 
The implementation resource team will meet quarterly in person or by telephone with PIs 
and Co-Is and serve as liaisons from stakeholder groups on study launch, logistics, 

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findings and/or dissemination of results, with the goal of optimizing the utility of the final 
results for maximal public mental health impact in Kenya and regionally. 
Study Procedures. 
Participants in our proposed study – A sequential, multiple assignment randomized trial 
(SMART) for non-specialist treatment of common mental disorders in Kenya: 
Leveraging  the Depression And Primary-care Partnership for Effectiveness-
implementation Research (DAPPER) – will be initially randomized to 12 weekly  one-
hour sessions of IPT (3 months) or 6 months of fluoxetine (tapering up to 60mg). Those 
participants who are not in remission with at the conclusion of initial treatment will be re-
randomized to second-line treatment (see below). Prior to randomization, participants 
will be given the option to receive their treatment at the health facility or by telephone. 
Participants who are randomized to fluoxetine and conduct their visits by telephone will 
need to collect their medication at the health facility.  If participants do not collect their 
medication at the health facility, fluoxetine may be delivered to participants in the 
community.  A smaller, Part 2, of the study will consist of qualitative interviews and 
focus groups to assess the overall implementation strategy and gather feedback on the 
specific interventions.  Please see "Part 2," below (and additional consent for this aspect 
of the study, attached).  
Randomization and blinding: Randomization will take place after baseline measures 
are complete. Randomization will be done in blocks of 10 and stratified by sex and 
telephone vs in-person treatment to ensure that the treatment groups are approximately 
equal in size and in gender distribution and telephone vs in-person treatment. See below 

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for second randomization information. Clinical evaluators who conduct follow-up 
assessments will be blinded to treatment assignment. Participants, IPT therapists, 
fluoxetine providers cannot be blinded because they will either be providing or receiving 
the IPT and/or Fluoxetine treatment and therefore they will know their treatment status.  
In addition, at least one study coordinator will not be blinded to assist with tracking of 
participants.  
Study visits: To characterize the trajectory of symptom change during treatment, participants 
will be re-evaluated at the mid-point of treatment (month 1.5 for IPT and month 3 for 
fluoxetine). Treatment mid-point data is valuable because it can inform the minimum duration 
of treatment necessary to optimize mental health gains in a setting of scarce mental health 
resources. For example, if 90% of all observed treatment gains are achieved in the first half of 
treatment, subsequent implementation efforts might  consider shortened courses of treatment. 
Participants will be assessed at month 3 (end of IPT treatment, mid-point of fluoxetine 
treatment) and at month 6 (end of fluoxetine treatment). For those participants who are in 
remission from depression and/or PTSD, follow up assessments will then continue at 9 month, 
12 month and then at six month  intervals until month 30 to assess for maintenance of gains and 
relapse.  Assessments may be done at the health facility or by telephone. We are defining 
remission as absence of disease as defined by threshold criteria for Diagnostic and Statistical 
Manual of Mental Disorders-V (DSM-V) for PTSD and MDD. Those participants who have not yet 
remitted will be re-randomized to: switch of treatment (from IPT to fluoxetine  or vice versa) or 
combination treatment (addition of IPT to fluoxetine or vice versa).  See Figure 3.  
  

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Assessment schedule and rationale:  
In order to characterize the trajectory of symptom change during treatment, participants 
will be re-evaluated at the mid-point of treatment (month 1.5 for IPT and month 3 for 
fluoxetine).  Treatment mid-point data is valuable because it can inform the minimum 
duration of treatment necessary to optimize mental health gains in a setting of scarce 
mental health resources.  For example, if 90% of all observed treatment gains are 
achieved by month 1.5, subsequent implementation efforts might consider shortened 
courses of treatment.  Participants will be assessed at end of treatment (month 3 for IPT 
and month 6 for fluoxetine) and fluoxetine recipients will be tapered off the medication.   
At six months, participants will be re-assessed and then monitored at 6-month intervals 
until month 30 (Figure 3).  Assessment visits may be done at the health facility or over 
the telephone. 
 
Measures (Table 1): Demographics. We will obtain usual demographic measures, 
education, including individual income, assets, education and school fees, healthcare 
utilization, and time allocation.  
 Physical health co-morbidities.  Given the strong association of depression with physical 
disorders, we will assess such as major medical co-morbidities in this population:  HIV, 
malaria, hypertension and diabetes.   We will also collect concomitant medication.  
Accessibility. We will evaluate accessibility as defined above (geographic proximity to 
clinic, type and severity of challenge for attending depression appointments).  
Affordability. We will assess cost of transportation to KCH and other Kisumu County 

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Ministry of Health facilities, and costs of treatment by telephone and opportunity costs 
for each treatment session.  
Mental health. We are aware of the current discussions regarding categorical versus 
dimensional (RDoC) measures in mental health research.(Insel et al., 2010) However, to 
efficiently integrate mental health with KCH and other Kisumu County Ministry of 
Health facilities primary care outpatient clinics treating specific diseases (HIV, malaria, 
hypertension, diabetes), our procedures must be disease-specific. We will use a threshold 
criteria for DSM-V for MDD which we are currently using in our IPT study at the 
FACES-Lumumba site in Kisumu (Table 1).  We will also use the Self-Assessment 
Manikin (SAM) (Bradley MM, 1994), Patient Health Questionnaire (PHQ-2) (Kroenke 
K, 2003) Primary Care PTSD Screen (Prins A, 2015), the Ask Suicide-Screening 
Questionnaire (ASQ)(Horowitz, L.M, 2020), the Mood Disorder Questionnaire (MDQ) 
(Hirschfeld R, 2000) and The Pandemic Emotional Impact Scale (Palsson O, 2020).  
Given the high rates of domestic violence, alcohol use disorders, and deaths due to 
disease such as HIV and the influence of traumatic events on depression etiology and 
treatment response,e.g.,(Cattaneo et al., 2015) we will measure domestic violence, alcohol 
and drug use disorders, general trauma history and perceived social support (Zimet GD, 
1988). Health-related disability. We will use WHO standard measures. All of the Table 1 
measures have been translated into local languages (Luo and Kiswahili) as part of our 
current study, using a standardized process of measure adaptation and translation.(Bhui, 
Mohamud, Warfa, Craig, & Stansfeld, 2003; Bolton, 2001; de Jong & van Ommeren, 
2002; Smit, van den Berg, Bekker, Seedat, & Stein, 2006; Sousa & Rojjanasrirat, 
2011)The Trauma History Questionnaire and the Conflict Tactics Scale have both been 

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used in 2 ongoing studies in Kisumu, Kenya.(Onu et al., n.d.) These are a mixed method 
study whose main objective is to identify the mental health impact of providing testimony 
to FIDA legal providers for women with claims related GBV and a capacity Building 
Randomized Controlled Trial of Interpersonal Psychotherapy for HIV+ Women Affected 
by Gender Based Violence. The studies are not formal psychometric 
evaluation/validation studies, but show acceptability and convergent validity. As the 
results of those measures were corroborated by qualitative assessments.  The BDI also 
showed convergent validity in Luo (as well as the Kiswahili) with the MINI MDD 
diagnosis. 
 
Table 1: SMART-DAPPER Measures 
Variable 
Description 
Demographics 
Age, gender, marital status 
Highest education 
(1) None; (2) primary; (3) secondary; (4) 
tertiary and beyond 
Individual income and employment, 
education, assets, school fees, and 
time allocation  
Assessment of individual formal and informal 
income and employment, assets, education, and 
time allocation  
Health co-morbidities 
HIV, Malaria, HTN, DM  
Proximity to clinic* 
Location of residence relative to KCH and other 
Kisumu County Ministry of Health facilities 
Overall challenges for attending 
depression care appointments at 
KCH and other Kisumu County 
Ministry of Health facilities, and by 
telephone and identification of top 
challenge* 
(1) easy challenge (2) moderate challenge (3) 
difficult challenge (4) impossible or nearly 
impossible challenge; (5) Identify source of the 
greatest challenge in text (e.g., money, logistics, 
stigma, etc.) 
Cost of transport from residence to 
KCH and other Kisumu County 
Ministry of Health facilities, and 
any associated telephone costs ** 
(1) 0-100KSH (2) 100-300KSH (3) 300-
500KSH (4) more than 500KSH 

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Opportunity costs per depression 
treatment session: lost wages, 
dependent care** 
(1) 0-100KSH (2) 100-300KSH (3) 300-
500KSH (4) more than 500KSH 
Major Depressive Disorder (MDD) 
Beck Depression Scale (BDI)(Beck, Ward, 
Mendelson, Mock, & Erbaugh, 1961), MINI 
MDD module (D V Sheehan, 1998) 
Post-traumatic Stress Disorder 
(PTSD) 
Posttraumatic Stress Checklist (PCL-5), MINI 
PTSD module (D V Sheehan, 1998),  Primary 
Care PTSD Screen for DSM-5 (PC-PTSD-5) 
(Prins A, 2015) 
Suicidality, mania/hypomania 
(exclusion-referral) 
Beck Depression Scale (BDI)(Beck, Ward, 
Mendelson, Mock, & Erbaugh, 1961), MINI 
suicidality, (hypo) mania modules (D V 
Sheehan, 1998), Mood Disorder Questionnaire 
(Hirschfeld R, 2000), ASK Suicide-Screening 
Questionnaire (ASQ)(Horowitz, L.M., 2020) 
Depression symptoms 
Beck Depression Scale (BDI)(Beck, Ward, 
Mendelson, Mock, & Erbaugh, 1961), Patient 
Health Questionnaire-2 (PHQ-2) (Kroenke K, 
2003) 
Emotional reactivity 
Self-Assessment Manikin (SAM) (Bradley MM, 
1994) 
Domestic violence 
Revised conflict tactics scale (CTS2) (STRAUS, 
HAMBY, BONEY-McCOY, & SUGARMAN, 
1996)  
Trauma history 
Trauma History Screen (THS)(Carlson et al., 
2011)  
PTSD symptoms 
 
Posttraumatic Stress Checklist (PCL-5) 
Detailed alcohol use (exclusion-
referral) 
Alcohol Use Disorders Identification Test 
(AUDIT)(Babor, Higgins-Biddle, Saunders, 
Monteiro, & World Health Organization, 2001) 
Drug use (exclusion-referral) 
Drug Abuse Screening Test (DAST-
10)(Skinner, 1982) 
Social Support 
Multi-dimensional Scale of Perceived Social 
Support (MSPSS) (Zimet GD, 1988) 
Health-related disability 
World Health Organization Disability 
Assessment Schedule (WHODAS)(Üstün et al., 
2010) 
Wellbeing and functioning changes 
due to COVID-19 pandemic 
The Pandemic Emotional Impact Scale (Palsson 
O, et al., 2020) 
Depression And Primary care Partnership for Effectiveness-implementation Research 
(DAPPER); Diabetes Mellitus (DM); Human Immunodeficiency Virus (HIV); 
Hypertension (HTN); Kenyan Shillings (KSH) (100KSH~1USD); Major Depressive 

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Non-specialist training and treatment refinements for context  
● IPT: Based on our experience training local community members to deliver IPT in the 
proposed region of research and other LMICs,(Jiang et al., 2014; Meffert et al., n.d.; Onu 
et al., 2016; Zunner et al., 2015) we have developed a process of combining training in 
IPT with cultural adaptations, as needed, from IPT trainees.  
Prospective IPT therapists will be identified according to the following criteria: (1) 
fluency in all local languages (Luo, Kiswahili) and English; (2) plans to remain in the 
area for the duration of the study with continuous availability to provide weekly therapy; 
(3) strong interest in providing mental health care; and (4) a promising background for 
effective communication regarding emotions (e.g., community healthcare workers, 
teachers, church leaders, women’s group leaders, village chiefs, village elders, traditional 
healers, HIV treatment adherence counselors, formal health or mental health care 
training/experience). While primary care physicians, clinical officers and available 
mental health specialists will be actively recruited and welcomed, their level of 
healthcare experience will not be required for IPT therapists. 
Prospective IPT therapists will be invited to join a 10-day IPT training course. The first 3 
days of the course will consist of an introduction to mental disorders, focused on 
depression and trauma-related conditions and emphasizing a medical model. Patient-
provider interactions will be reviewed, including the fundamental importance of 
confidentiality and respect. Basic tenets of psychotherapy and its evidence will be 
Disorder (MDD); Mini International Neuropsychiatric Interview version 5.0 (MINI v. 
5.0). * Accessibility measures; **Affordability measures. 

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introduced, followed by introduction to IPT and an overview of its initial, middle and 
concluding phases (Figure 4).  
Refinements for use of IPT in primary care: [Note: We have already adapted IPT for 
non-specialist, integrated delivery within a FACES HIV care setting in our current study. 
Here, we describe minor refinements to optimize logistics and content fit for primary care 
adult outpatient clinic served at Kisumu County Hospital, a FACES-supported clinic]. 
Following the introductory training, we will begin an iterative process of more IPT 
training, using the trainee therapists (including local health care providers) as our primary 
resources. We will review the sequence of work, including tasks and techniques for each 
session and phase of IPT (Figure 4). During this detailed review, we will solicit feedback 
from local IPT trainees on cultural or logistical adaptations or additions needed to 
improve the acceptability and relevance of IPT for the target population. 
An iterative group process will be used to integrate input from trainee therapists on 
adaptations of IPT content and process with ensuing modification if consensus is reached 
that not doing so would negatively affect outcomes or engagement. The adaptations 
defined through the above processes will be incorporated with the standard IPT manual to 
create adaptations tailored to the needs of KCH and other Kisumu County Ministry of 
Health facilities adult primary care outpatients. We will also develop standard operating 
procedures and provide training on adaptations for conducting IPT over the telephone 
including how to address a mental health crisis. Primary care physicians, clinical officers 
and available mental health specialists will be invited to participate as providers during 
the run in period of the study. Those showing consistently high protocol adherence and 

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interest will be recruited as onsite IPT supervisors, with oversight by the study PIs and 
Co-Is. 
IPT therapist competency testing: When the IPT training concludes, prospective study 
therapists will be asked to articulate the fundamental tenets of IPT and to successfully 
model an example of an initial, middle, and concluding IPT session through role play 
with other trainees. If they demonstrate competency, therapists will be assigned an IPT 
practice case. If sessions are successfully completed with the training case, as 
demonstrated by scores of 9 or 10 on our 10-12 item IPT adherence measures, DAPPER 
IPT study participants will be gradually added to therapists’ caseloads with a maximum 
of 10 clients per therapist. 
● Fluoxetine 
Antidepressants for MDD and PTSD: Research team members Drs. Wagner and Akena 
developed a clinical guide for non-specialists to provide antidepressant care on HIV 
platforms in a nearby region of Uganda.(Wagner, Ngo, Glick, et al., 2014; Wagner, Ngo, 
Akena, & Seggane, 2014) Drawing heavily on that protocol, we will train all interested 
nurses and clinical officers at the KCH and other Kisumu County Ministry of Health 
facilities adult primary care clinic and additional study providers to deliver fluoxetine to 
SMART-DAPPER participants.  
Prospective fluoxetine providers will be invited to attend a 10 day training course. We 
will begin with an introduction to mental disorders, focused on depression. Patient-
provider interactions will be reviewed, including the fundamental importance of 
confidentiality and respect. The use of antidepressants to treat depression and/or PTSD 
will be taught, with a focus on the role of fluoxetine. The dosing protocol will be 

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introduced, followed by review of potential side effects and required provider responses 
for each effect, including any uncertainty regarding existence or type of side effect. The 
importance of ruling out bipolar affective disorder before initiating fluoxetine (see 
exclusion criteria), will be emphasized and symptoms/signs of mania/hypomania will be 
reviewed. Role plays and case studies will be used to practice assessment, dosing and 
evaluation of side effects and/or mania/hypomania. We will also develop standard 
operating procedures and will also provide training on adaptations for conducting 
fluoxetine treatment visits over the telephone including how to address a mental health 
crisis. Primary care physicians will also be trained in fluoxetine treatment of MDD and/or 
PTSD, and recruited as providers during the run in period of the study. Those showing 
consistently high protocol adherence and interest will be invited to assist with onsite 
fluoxetine treatment supervision, with oversight by the study PIs and Co-Is. 
Fluoxetine provider competency testing: The course will conclude with 10-20 case 
studies, in which prospective fluoxetine providers will be asked to apply the fluoxetine 
treatment protocol and respond to case scenarios including contraindications, side effects 
and dosing challenges. If they demonstrate competency on these tests, fluoxetine 
providers will be assigned training cases including starting and monitoring fluoxetine 
treatment. If they successfully complete training cases, as demonstrated by scores of 9-10 
on fluoxetine protocol adherence measures, fluoxetine participants will be gradually 
added to the trained fluoxetine provider caseloads, to a maximum of 10 cases. 
IPT and fluoxetine treatment schedule and location: IPT and fluoxetine appointments 
will be conducted at confidential location within the KCH and other Kisumu County 
Ministry of Health facilities, or over the telephone. IPT will be administered by an IPT 

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therapist (see therapist selection and training procedures, above), in 12 weekly 60-minute 
sessions. Participants randomized to receive fluoxetine will meet or speak with fluoxetine 
trained provider at baseline, 2 weeks, 4 weeks, 2, 3, 4, 5, and 6 months, for a total of 
eight appointments. Participants will be assessed for initiation of fluoxetine and 
advisement on common side effects. Fluoxetine participants will be started on 20mg (1 
capsule per day) and will return for assessment of initial efficacy/tolerability at week 2. If 
the participant does not have any prohibitive side effects, dose will be maintained at 
20mg (1 capsule). Participant will return for re-assessment at week 4, if the participant 
does not have any prohibitive side effects and does not have improvement on the Patient 
Health Questionnaire-2 (PHQ-2), dose will be increased to 40mg (2 capsule). At month 2, 
if the participant does not have any prohibitive side effects and does not have 
improvement on the PHQ-2, the dose will be increased to 60mg (3 capsule).  Participants 
receiving treatment by telephone may be able to receive a 3 month supply at the 
minimum dose (20 mg per day).  If the dose is increased during the intervening treatment 
visits, the participant will need to receive additional medication.  Participants receiving 
treatment by telephone will be asked to pick up their medication within two days of their 
treatment call.  If they do not collect their medication within 2 days, the medication will 
be delivered in the community.  Studies support that higher fluoxetine doses do not show 
additional benefit.(Jakubovski, Varigonda, Freemantle, Taylor, & Bloch, 2016)  See 
Protection of Human Subjects section for details on fluoxetine side effect management.  
The participant will be maintained at 20, 40 or 60 mg at the month 3, 4, and 5 visits, if the 
participant does not have any prohibitive side effects. At the month 6 visit, participants 
will be given instructions for tapering off fluoxetine, with decrease of the dose by 20mg 

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increments each week until reaching zero. Participants who were maintained on 20 mgs 
throughout the treatment period will have fluoxetine discontinued at the end of 6 months.  
IPT therapists and fluoxetine-trained providers will be compensated per IPT/medication 
session/day completed, at the local currency equivalent of 10usd. 
Fluoxetine treatment duration: Participants treated with fluoxetine will be tapered off 
fluoxetine at month 6.  
Retention: Based on previous work, retention is not expected to be a problem. Our pilot 
study of IPT for Sudanese refugees in Cairo had a 93% retention rate; our study of IPT 
for survivors of the Sichuan earthquake had an 85% retention rate and our ongoing study 
of integrated IPT care with HIV+GBV+ women in Kisumu has 300 enrollees with 20 
dropouts (93% retention, to date). However, given uncertainty regarding generalizability 
to the KCH and other Kisumu County Ministry of Health facilities adult primary care 
clinics, the more conservative estimate of 20% drop-out will be used. However, provision 
of treatment over the telephone may improve retention rates.  As part of retention efforts, 
participants will be asked to provide the name and phone number of a trusted adult who 
can be contacted if the study has concerns about participants’ welfare or whereabouts.  
Therapists and fluoxetine providers will be asked to provide study cell phone numbers to 
study participants. Missed appointments will be followed with at least two efforts to 
reach the participant directly and/or through their contact (80% cell phone coverage). 
Likewise, at least two efforts will be made to reach drop-out participants for remaining 
measures. 

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Acute mental health care: IPT therapist and fluoxetine training will include risk 
assessment and referral procedures for acute mental health care needs. See Protection of 
Human Subjects section for details.  
Clinical evaluators: Clinical evaluators will be blind to treatment group and will conduct 
baseline screening at the primary care clinic prior to initiating treatment, as well as re-
assessments at months 1.5 (mid-treatment for IPT), 3 (mid-treatment for fluoxetine), 6, 9 
month 12, 18, 24 and 30. Candidate clinical evaluators will undergo a two day training 
during which they will be introduced to the study measures and their proper application. 
At the conclusion of the training, the candidates will be observed in their administration 
of the measures, assessing for accuracy and completeness. If successful, they will be 
evaluated for reliability by conducting a group interview and comparing measure results. 
Those who demonstrate both accuracy and inter-rater reliability will be invited to join the 
study. Monetary compensation will be provided for completed measures at the local 
currency equivalent of 7usd. 
 
Data collection. Data collection will use tablets programmed with Research Electronic 
Data Capture (REDCap), similar to the electronic data system that we are currently using 
in Kisumu, Kenya (Online Data Kit [ODK]). REDCap now has an offline feature which 
does not require internet connectivity for data entry and can be later connected to the 
internet for upload to secure server.  

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Effectiveness outcomes  
Clinical evaluators. Clinical evaluators will consent and screen study participants, 
complete baseline measures and then refer participants to (un-blinded) study coordinators 
for randomization.  Blinded to group assignment, clinical evaluators will conduct 1.5 
month (IPT treatment mid-point), 3 month (IPT end-of-treatment, fluoxetine-mid-
treatment), and follow-up assessments.  Candidate clinical evaluators will undergo a two 
day training during which they will be introduced to the study measures and their proper 
application. At the conclusion of the training, the candidates will be observed in their 
administration of the measures, assessing for accuracy and completeness. If successful, 
they will be evaluated for reliability by conducting a group interview and comparing 
measure results. Those who demonstrate both accuracy and inter-rater reliability will be 
invited to join the study. Monetary compensation will be provided for completed 
measures at the local currency equivalent of 7usd. 
 Data analysis plan  
For Hypothesis 1a the analysis is standard intention to treat for 3 month (end of 
treatment) data. Our basic analysis strategy will be to fit logistic regression models for 
the outcome of MDD and/or PTSD remission, in this case with the predictor of group 
assignment (IPT or fluoxetine), demographics and severity of baseline depression and/or 
PTSD symptoms (BDI and PCL) . Hypothesis 1b will be analyzed for the sub-group of 
participants who are in remission from MDD and/or PTSD at months 1.5 or 1.5 and 3 and 
will use weighted generalized estimating equations logistic regression to accommodate 
the repeated measures on this subgroup through month 30.   
 

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As identified by RDoC, current mental disorder disease categories may allow for 
diversity among psychological constructs of negative/positive valence, cognition, social 
processes and arousal/regulatory systems, undermining the utility of current disease 
definitions and average treatment responses for some individuals.  Based on this concern, 
we will evaluate for heterogeneity in treatment response trajectories for individuals with 
MDD and/or PTSD using X2 tests (binary outcome, [threshold for DSM-V for MDD 
yes/no; PCL yes/no]) and t tests (continuous outcome, [depression symptoms, BDI/ 
PTSD Symptoms PCL]) on key study outcomes.  Next, we will use mixed-mode latent 
regression modeling to identify heterogeneous sub-group trajectories.(Haviland & Nagin, 
2005) We will use the Bayes Information Criterion to identify the appropriate number of 
subgroups, deriving the smaller number.(Raftery, 1995) 
Procedures and measurements to assess implementation approach (EPIS) and 
outcomes. 
EPIS strategy. The feasibility, acceptability and utility of this study’s EPIS strategy, 
including its use of a DAP to integrate the feedback from the implementation resource 
team (IRT) members into the delivery of evidence based depression treatment will be 
evaluated using semi-structured individual interviews and focus groups with inner and 
outer context IRT members, providers and study participants. Domains of interest. IRT 
members will be asked: (1) to identify positive and negative aspects of the EPIS model, 
IRT and DAP strategies, including content and process; (2) to identify ways to improve 
the DAP process. Providers (mental health and primary care) will be asked: (1) their 
awareness and understanding of the use of the EPIS model; (2) satisfaction or 
dissatisfaction with the EPIS, IRT and DAP strategies for adaptation of evidence-based 

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depression treatments in DAPPER; (3) suggestions for improvement. Study 
participants will be asked: (1) their awareness and understanding of the use of the EPIS 
model; (2) satisfaction or dissatisfaction with the EPIS, IRT and DAP strategies for 
adaptation of evidence-based depression treatments in DAPPER; (3) suggestions for 
improvement. Enrollment (n=112) and study procedures. 16 focus groups will be 
conducted with five participants each (n=80). Focus groups will include: (1) inner context 
IRT members at each EPIS stage (4 groups); (2) outer context IRT members at each EPIS 
stage (4 groups); (3) study participants in the implementation and sustainment phases (2 
groups each phase, 4 total) and (4) study providers in the implementation and sustainment 
phases (2 groups each phase, 4 total). Thirty-two individual interviews (n=32) will be 
conducted with IRT members (2 interviews with inner and outer IRT members at each 
EPIS phase [n=16]), participants and providers (2 interviews with each group at each 
EPIS phase [n= 16]). 
 
Implementation outcomes and mechanisms of action 
Acceptability and appropriateness. The acceptability and appropriateness of 
IPT/fluoxetine for treatment of MDD and/or PTSD in primary care clinics will be 
assessed through semi-structured closing and post-implementation of tele-mental health 
interviews and focus groups with participants, IPT therapists, providers delivering 
fluoxetine, KCH and other Kisumu County Ministry of Health facilities primary care 
clinics and FACES personnel and FACES CAGs. Domains of Interest. Participants will 
be asked: (1) to identify positive and negative aspects of IPT and fluoxetine treatment, 
including content, delivery, logistics; (2) if they would refer other people to the treatment 

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and why; (3) if they prefer IPT or fluoxetine treatment of MDD and why; (4) to identify 
suggestions for improvements; (5) feedback on tele-mental health. IPT therapists and 
providers delivering fluoxetine will be asked: (1) if they believed IPT/fluoxetine 
benefitted participants and why; (2) whether they would like to continue providing 
IPT/fluoxetine; (3) what suggestions they have to improve the intervention; and (5) 
feedback on tele-mental health. Primary care clinic personnel, KCH and other Kisumu 
County Ministry of Health facility directors, KCH and other Kisumu County Ministry of 
Health facility-based FACES personnel, local and national healthcare policy makers, 
will be asked: (1) to identify positive and negative aspects of IPT and fluoxetine 
treatment, including delivery, logistics; (2) to identify positive and negative impacts of 
treatment on primary care clinic and community; (3) whether or not they would like 
continuation of IPT and/or fluoxetine treatment for MDD and/or PTSD in their 
community and why/why not; (5) feedback on tele-mental health; and (6) suggestions for 
improvement of either treatment.  
Enrollment (n=65) and Study Procedures. Nine focus groups will be conducted with five 
participants each (n=45). Focus groups will include: (1) Study participants who 
completed IPT or fluoxetine (one group each); (2) Prospective participants who declined 
enrollment; (3) enrolled participants who dropped out during treatment; (4) IPT therapists 
and fluoxetine providers (one group each); (5) primary care personnel; (6) FACES-KCH 
and other Kisumu County Ministry of Health facilities staff; (7) health policy leaders at 
the county level. Twenty individual interviews (n=20) will be conducted with participants 
(including those who decline enrollment, drop out of treatment and treatment-
completers), depression care providers, primary care clinic personnel, KCH and other 

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Kisumu County Ministry of Health facilities directors and local and national policy 
makers.  
Concept Mapping. We will use the IRT and extended IRT members to inform study 
related implementation questions using concept mapping methods.  Concept Mapping is a 
process that allows stakeholders to express their ideas on a given topic, examine how 
these ideas relate to one another, and determine what ideas are judged to be most 
important or critical for a particular goal or initiative.  Concept Mapping has three 
activities all to be completed online: 1) begins with a brainstorming process in which 
participants respond to a focus statement, 2) each participant is provided with a complete 
set of the statements and asked to sort them into categories based on similarity, and 3) 
each participant will rate statements. 
Feasibility. Attrition from the study will be evaluated in regards to both timing (active 
treatment or follow-up phase) and reason (e.g., symptom remission, move out of the 
region, lost wages/dependent care, cost/burden of transport, displeased with treatment).  
With the exception of those who leave the study because their symptoms remit (“cured”), 
the IPT/fluoxetine will be considered feasible if fewer than 20% of participants leave 
during treatment and if one or fewer therapists/fluoxetine provider voluntarily leave the 
study. 
Fidelity 
Therapist Adherence to IPT Protocol. Therapists will discuss each IPT session with a 
supervising clinician. During supervision, therapists will be assisted with their adherence 
to and application of IPT. Adherence will be scored using a 10 point Likert scale 
assessing adherence in each IPT phase (used in our current IPT study). Sessions will be 

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considered adherent to the IPT protocol if they average a score of 5 or higher and do not 
employ off-protocol interventions. All sessions will be audio-taped and 20% of sessions 
will be selected using blocked randomization to ensure both early and late sessions are 
included, then transcribed and translated for IPT adherence scoring by an independent 
rater.  
Fluoxetine Provider Adherence to Fluoxetine Protocol. In collaboration with the study 
coordinators, Drs. Ongeri and Akena (co-Is) will randomly select 10 charts of treated 
patients each month to assess compliance with the fluoxetine treatment protocol 
(eligibility, dosing and monitoring of side effects). Treatment will be considered adherent 
if there are no deviations from protocol. 
Acceptability and Appropriateness. Interview material will be recorded in audio files, 
transcribed and translated. Dedoose software will be used to analyze the resulting text 
using grounded theory. Grounded theory sorts data in three ways: through concepts, 
categories and propositions. Concepts are identified by seeking conceptual similarities 
among focus groups/interviews. These concepts are grouped to develop categories of 
concepts. Categories are then compared and grouped to develop propositions or 
theoretical constructs about the phenomena of interest. Dedoose software facilitates 
coding of observations to work toward the theoretical construct. Data will be collected 
using a “triangulation” technique that compares information from various sources (focus 
groups, individual interviews) in order to increase the reliability and validity of the 
findings. Feasibility and Fidelity. Feasibility and fidelity measures will be assessed by 
sample means and proportions, with 95% confidence intervals, and compared to pre-
specified benchmarks (above).   

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Service delivery mechanism: availability and affordability.  Hypothesis 1c will be 
addressed by calculating RE-AIM for IPT and fluoxetine according to the procedures 
outlined in Glasgow et al.(Glasgow, Vogt, & Boles, 1999)  Then, we will then evaluate 
how RE-AIM scores correlate with availability and affordability measures (Table 2) for 
IPT versus fluoxetine.  Finally, we will evaluate for mediation by treatment completion.  
Specifically, we will begin with logistical regression models of RE-AIM score including 
availability factors and affordability factors.  If any significant relationships exist, we will 
construct figures of hypothetical relationships between variables that are significantly 
associated with RE-AIM score and create path diagrams, using effect sizes to identify 
potential causal pathways between availability, affordability and RE-AIM scores for IPT 
versus fluoxetine. 
 
 
Table 2: Calculating RE-AIM from an Effectiveness-Implementation Hybrid Type I (SMART-
DAPPER)(Farris, Will, Khavjou, & Finkelstein, 2007; Glasgow, Klesges, Dzewaltowski, Estabrooks, & 
Vogt, 2006) 
1 
Reach will be calculated as the ratio of study participants who are eligible for SMART-DAPPER 
compared with those who choose to participate.    Reach is the first assessment of RE-AIM. 
Effectiveness Outcomes 
2a MDD and/or PTSD remission from IPT or fluoxetine at month 3 (IPT) and month 6 (fluoxetine). 
2b MDD and/or PTSD   remission at month 1.5 (treatment mid-point) for IPT and at 3 months (treatment 
mid-point) for fluoxetine to identify the proportion of treatment gain achieved at mid-point compared 
with end of treatment (month 3). 
Treatment Effectiveness is a key aspect of RE-AIM. 
3 
Maintenance of month-3 remissions from IPT or and month 6 remissions from fluoxetine at follow-up 
assessments (months 6 (for IPT), 9, 12, 18, 24 and 30). 
Maintenance of gains is an individual level measure of Maintenance in RE-AIM. 
Implementation Outcomes 
4 Both IPT and fluoxetine will be acceptable treatments for delivery in primary care as determined by 
qualitative interviews. 
5 Both IPT and fluoxetine will be appropriate treatments for delivery in primary care as determined by 
qualitative interviews. 

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Measurement of implementation costs. We will measure the full resources and 
associated costs of implementing the screening for MDD and/or PTSD in the KCH and 
other Kisumu County Ministry of Health facilities primary care adult clinics as well as 
the IPT and fluoxetine treatments for those who screen positive. Costs will include staff 
time as well as supplies (including drugs), services, telephone expense, and infrastructure 
used to deliver the interventions. Data on costs will be collected using two methods. The 
first will be micro-costing to quantify resources used and unit costs, with data extracted 
from project expenditure and management records, including purchase logs and human 
resource records. This information will be recorded in structured costing spreadsheets 
that capture each resource (e.g., space for IPT sessions and fluoxetine monitoring, 
telephone expenses), category (e.g., personnel, supplies), quantity (e.g., hours), and unit 
costs. A second method will be time and motion logs will record how staff divide time 
among multiple roles to allow us to reliably apportion effort to the mental health 
screening and treatment activities. Cost per person treated will be computed for IPT and 
also for fluoxetine treatments. 
Measurement of economic effects on patients. We will also measure patient-level costs 
and benefits, including costs associated with transportation to clinics (included as part of 
treatment) and costs of using the telephone, and benefits such as increased labor supply 
and income. These measures will come from surveys administered at baseline and at 
follow-up (months 1.5, 3, 6, 12, 24 and 30). We will use a measure (Table 1) similar to 
6 Both IPT and fluoxetine will be feasible treatments as determined by completion rates.  With the 
exception of those who leave the study because their symptoms remit, completion rate will be used as an 
individual level measure of Adoption in RE-AIM. 
7 Both IPT and fluoxetine will have strong treatment fidelity as determined by protocol adherence to IPT 
and fluoxetine administration. Fidelity is a key component of Implementation in RE-AIM. 

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that which we are using to assess informal and formal income in our current 
effectiveness-implementation study in Kisumu, and that our research team is using across 
East Africa to assess the economic impacts of other health interventions. Employment 
gains in the informal and agricultural sectors will be converted to monetary values using 
imputed wages in the local labor market. Based on prior research that shows a strong 
linkage between mental health and economic outcomes,(Lund et al., 2011) we believe 
that assessing the economic benefits of depression treatment is essential for conducting a 
comprehensive cost-benefit analysis. To the extent that treatment results in changes in 
mortality (all-cause, whether or not suspected as suicide), we will incorporate these 
effects using the “full income” approach(Jamison et al., 2013), which attaches a financial 
value to each year of life lost. 
Estimation of non-intervention control. For ethical reasons, our study does not include 
a non-treatment control. However, for complete cost-benefit analysis, we will compare 
the interventions to current (mainly absent) depression management. We cannot compare 
patients to their own baseline condition, since the natural history of untreated depression 
involves (at least episodic) clinical resolution in a substantial subset of 
individuals.(Whiteford et al., 2013) Instead, we will apply findings on the association of 
evolving clinical status and economic status in the intervention arms to historical data on 
the natural history of depression in these settings. In other words, we will make the 
conservative assumption that the changes in productivity associated with clinical 
resolution of the depression episode following treatment can be applied to untreated 
patients who eventually remit.  

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Cost-benefit analyses. An important question for policymakers concerns the economic 
returns to investments in treating and improving mental health. We will use data obtained 
on the economic status of those treated to calculate the economic benefits associated with 
treated mental health disorders (both pooled analyses of IPT or fluoxetine treatment and 
separate analyses of IPT and fluoxetine treatment). We will also incorporate data on 
health care utilization and hospitalizations (Table 1). The value of these economic 
benefits will be summarized on a per-person basis and then combined with the 
implementation cost data to generate a rate of return on mental health expenditures (in 
general and by treatment type –IPT or fluoxetine). This rate of return is net gains in all 
economic measures divided by implementation costs, x 100 to yield % return. Cost and 
income measures will be adjusted for inflation and discounting during the 3 year study 
period. 
Human participants in the project  
Target population. Adult primary care outpatient clinic attendees at Kisumu County 
Hospital (KCH) and other Kisumu County Ministry of Health facilities.  
Sample size calculations: SMART designs are used to inform the construction of 
optimal Adaptive Treatment Strategies (ATS), which is our goal. Therefore, we will 
power our study to detect the smallest difference between the various ATS included in 
the study design. The proposed SMART examines (1) first line treatment strategies with 
IPT or fluoxetine, including long-term relapse risk for participants who remit with initial 
treatment and (2) second line treatment strategies for non-remitters—specifically, 
treatment “switch” (from IPT to fluoxetine or vice versa) versus treatment “combination” 
(addition of IPT to fluoxetine or vice versa). Based on the current evidence base, we 

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expect that differences between switching or combining treatment will be smaller than 
other ATS comparisons in the study and we will therefore power the study to detect this 
difference. 
 
As it pertains to antidepressants and psychotherapy, the evidence base comparing 
“switching” versus “combining” treatment for non-remitters (second line treatment) is 
still developing. However, the field does have meta-analytic data on the differences 
between treating depression with antidepressants or psychotherapy alone, versus their 
combination. A 2009 meta-analysis (n=2036) which compared combination treatment 
(psychotherapy and pharmacotherapy) to pharmacotherapy alone for depression found an 
effect size of 0.31 (Cohen’s d).27A 2007 meta-analysis (n=903) found that the remission 
rate for major depression treated with psychotherapy and pharmacotherapy was better 
than psychotherapy alone, with an odds ratio of 1.5928, which when converted to a 
Cohen’s d is 0.25.29 While specific studies have not yet been completed for IPT and 
PTSD, we leveraged the above-referenced meta-analyses of the effects of general 
psychotherapy and general pharmacotherapy to estimate sample size for the proposed 
study. Based on those studies, we would need approximately 164 per treatment arm to 
compare combined psychotherapy-medication treatment with medication alone, and 242 
to compare combined psychotherapy-medication with psychotherapy, alone (using a two-
sided alpha of 0.05 and power of 0.80). Using the conservative estimate, we will need 
242 for each of the four treatment arms (968, total) after the second randomization 
(switch to fluoxetine, switch to IPT, combination after fluoxetine, combination after IPT). 
Note, this strategy uses fluoxetine treatment for 6 months as a first line treatment, 

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consistent with the original R01 submission and responsive to reviewers’ comments 
(summary statement response) on our funded U01 (DAPPER) study. While effectiveness 
data on treatment of depression in HICs (STAR*D) indicate that only approximately one-
third remit with first line treatment, preliminary data from our current IPT study in 
Kisumu indicate remission rates over two-thirds. We will use a conservative estimate of 
the numbers entering the second randomization phase (non-remitters) and assume that 
half of study participants will need second-line treatment. Based on that estimate, the 968 
participants randomized to the second stage of the SMART should represent 50% of 
those enrolled at the start of the trial, or 1936. Allowing for a 40% drop out rate across 
the 33 month duration of the study (domestic migration is common in Kenya30), we will 
need 2710 participants for the SMART.  
 
The additional number required for integration of the SMART design is 710 participants. 
Making a conservative assumption of ~20% prevalence of MDD and/or PTSD among 
primary care patients, we will screen 3,550 individuals to enroll 710 participants. While 
KCH and other Kisumu County Ministry of Health facilities see over 10,000 adult 
primary care patients per month, we will assume that only 20% of clinic attendees will 
undergo screening, and we will budget 3 months for recruitment. In order to avoid 
overwhelming mental health care providers, these 3 months of recruitment will be 
dispersed across a 18 month period: enrollment will halt when providers’ caseloads are 
full and resume when at least 20% availability is regained.  We will also work with 
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mobilize and sensitize the community about mental health services and refer community 
members to one of the health facilities for screening for the SMART-DAPPER study. 
 
Eligibility criteria 
Inclusion criteria:  
(1) KCH and other Kisumu County Ministry of Health facilities adult primary 
care outpatient clinic attendees who meet the threshold criteria for DSM-V for 
MDD and/or PTSD. . 
(3) Ability to attend weekly IPT sessions/fluoxetine monitoring in person or by 
telephone;  
(4) 18 years or older. 
Exclusion criteria:  
(1) Cognitive dysfunction compromising ability to participate in IPT or accurately 
take fluoxetine (lack of orientation to person, place, time and situation);  
(2) Acute suicidality (moderate or high score on the MINI suicidality module or 
Ask Suicidality-Screening Questionnaire (ASQ)) requiring higher level of care;  
(3) drug/alcohol use disorders requiring substance use treatment (AUDIT score of 
8 or higher or DAST score of 3 or higher);  
(4) History of mania or requiring treatment for bipolar affective disorder 
hypomania (positive score on MINI mania/hypomania module or on the Mood 
Disorder Questionnaire (MDQ));  

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(5)  Outside mental health treatment during the SMART-DAPPER treatment 
phases (any mental health treatment is allowed during follow-up phases and is 
recorded by study team). Participants will be asked to not start new mental health 
treatment during the SMART-DAPPER treatments, but will be assured that this is 
not prohibited. Participants who do will be treated as dropouts. 
(6) Pregnant or breastfeeding 
 
Recruitment  
Working closely with clinic directors, providers and staff, we will integrate with the KCH 
and other Kisumu County Ministry of Health facilities primary care adult outpatient 
clinics. Waiting times for primary care medical outpatients at KCH and other Kisumu 
County Ministry of Health facilities can last many hours, creating an opportunity for 
study recruitment. As with our current study, we will provide health talks to waiting room 
attendees regarding emotional distress and the availability of treatment services for 
eligible participants through SMART-DAPPER, inviting interested individuals to meet 
with our study team in a private area for more information, consent and screening, as 
desired.  A recruitment poster, brochure, and/or cards will be made available with key 
information about the study including the contact information to reach for further 
information.  If individuals wish to undergo study screening while waiting for their 
appointment, we will work with the clinic to provide them with a card that will allow 
them to enter back in the waiting line without losing their place, or moving them to head 
of the line if their name was called during their time with our team.  Prospective 

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participants who consent, meet study criteria, and wish to enroll will be provided with an 
appointment date and time for baseline measures. If they do not consent, meet criteria 
and/or wish to enroll, they will be provided with information on alternative treatments 
(see Human Subjects). Per below sample calculations, allowing for holidays and time to 
integrate study procedures with primary care activities, we estimate that recruitment will 
last 18 months.  
Given the large unmet need for depression and PTSD treatment, we will allow other 
public sector primary care centers and CHWs to refer individuals to the SMART-
DAPPER study at KCH and other Kisumu County Ministry of Health facilities to receive 
mental health services, if eligible.  Other recruitment strategies may be utilized to reach 
our recruitment targets. These other recruitment strategies may include sending text 
messages to patients receiving HIV care and treatment services at Kisumu County 
Ministry of Health facilities notifying them about the study and study requirements. We 
also may use social media and traditional media to inform the community about the 
study.  Patients at other public sector primary care centers can also self-refer to the 
SMART-DAPPER study.  All screening and enrollment will be conducted at KCH and 
other Kisumu County Ministry of Health facilities, or by telephone. 
Mental health crisis. During recruitment, participants who report suicidality will be 
administered a Risk Assessment. Participants who are acutely suicidal will be escorted to 
KCH or another Kisumu County Ministry of Health facility psychiatric clinic for further 
evaluation.   

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Tracking team. FACES has a robust tracking team of employees who are highly 
knowledgeable of the local communities. FACES HIV patients who do not present for 
scheduled visits are contacted by the tracking team to assist with access to care. 
Leveraging their community contacts and the highly interconnected nature of 
communities served by FACES, efforts to contact the patient include phone calls, 
community and home visits, contacting relations and seeking out the individual at other 
medical appointments.  For the proposed study, we will add similarly qualified SMART-
DAPPER team members and CHW/CHVs to the ongoing KCH FACES tracking teams, 
to track SMART-DAPPER study participants who do not present for appointments. 
 
Research Ethics 
Institutional Review Process: This proposal will be reviewed by the KNH-UoN ERC 
the University of California San Francisco Institutional Review Board, National 
Commission for Science, Technology and Innovation (NACOSTI), and the Pharmacy & 
Poisons Board and granted approval before implementation.  
Consenting Process:  
All Participants: Informed consent will be obtained from prospective participants.  
Consenting will be performed without undue pressure or coercion. Only those who 
provide consent will be recruited in the study. Once the participant has been recruited, the 
clinical evaluator will explain the study and if s/he has accepted to be consented, the 
consenting process will be begin. We shall ask the participant the language they will 
prefer to use. We shall answer all the questions that the participants asks to help them 

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make informed decision. Those who decline to participate after reading the consent 
document will be thanked for their time, and those who agree to participate will be sign 
the consent form (if in person), or if we are unable to meet face to face to sign the consent 
form due to COVID19, the clinical evaluator will sign the consent form on their behalf. 
The written consent procedures are as follows 
1. The clinical evaluator will ask whether they want assistance in reading or they 
would do it themselves.  The clinical evaluator or potential participant 
will read the entire consent form in its entirety (same information for written and 
verbal consent) in their preferred language;  
2. Through the consent process, the clinical evaluator will ensure that the 
prospective participant understands each section in the consent before moving on 
by asking her or him to repeat it in his or her own words.  The prospective 
participant must understand the nature of the procedure, the risks, benefits, and 
has the opportunity to ask and have questions answered;  
3. Given the variable literacy levels, participants consenting will provide either a 
signature or a thumbprint to indicate their agreement with the consent.  The 
clinical evaluator will also sign and date the consent form.  
4. The participant will be offered a copy of the paper consent form. 
5. Document in the research file (REDCap) where (in person) and when the consent 
discussion took place and if there were any issues. 
Verbal consent procedures are as follows: 

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1. The clinical evaluator reads the entire consent form to the potential participant in 
its entirety in their preferred language (same information for written and verbal 
consent);  
2. Through the consent process, the clinical evaluator will ensure that the 
prospective participant understands each section in the consent before moving on 
by asking her or him to repeat it in his or her own words.  The prospective 
participant must understand the nature of the procedure, the risks, benefits, and 
has the opportunity to ask and have questions answered;  
3. The prospective participant gives verbal agreement for study participation and the 
clinical evaluator will sign and date the verbal consent form. 
4. The participant will be offered a copy of the paper consent from to be retrieved at 
the KCH and other Kisumu County Ministry of Health participating in the 
SMART-DAPPER study. 
5. Document in the research file (REDCap) where (over the telephone) and when the 
consent discussion took place and if there were any issues. 
Voluntariness: The participants will be informed that they will be free to withdraw from 
the study at any point without any untoward consequences and that participation is 
voluntary. Those who withdraw will still benefit from necessary care that will be 
available. 
Confidentiality: All the interviews will be conducted individually and confidentially. 
Information collected will not obtain participants identifiers. Information entered in the 

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computers will be password protected. All hard copy documents with identifiers will be 
kept in lockable cabinets and will only be accessible to the study investigators. 
Risks and benefits of the study 
Risks to the Subject 
Potential Risks 
Risks and solutions related to inclusion/exclusion criteria at primary care referral clinics: 
Inclusion: 
If prospective participants meet the DSM-V threshold for MDD and/or PTSD, but no 
longer meet criteria when they present for SMART-DAPPER treatment, the common 
process of spontaneous remission will be discussed and they will be provided with 
contact information for the study coordinator, should their symptoms re-emerge. They 
will also be alerted to alternative mental health treatment options (see below).- If 
participants are unable to attend weekly appointments for 12 weeks for IPT or 8 sessions 
for fluoxetine (6 months), they will be alerted to alternative mental health treatment 
options in the area. 
- If participants are not over the age of 18 years, they will be alerted to alternative mental 
health treatment options in the area.   
 
Exclusion: 
- Prospective participants who are identified as having cognitive dysfunction will be 
referred to primary care providers for work-up and treatment. 

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- Prospective participants with acute suicidality, will be escorted by our study team to the 
psychiatric facility for further evaluation and treatment. 
- Prospective participants with substance use disorders with elevated scores on the 
AUDIT (8 or higher) or DAST (3 or higher) will be escorted by our study team to the 
nearest psychiatric facility for further evaluation and treatment. 
- Prospective participants who have a history of mania or bipolar affective disorder will 
be screened for a current or past manic and hypomanic episode. If they have current 
symptoms, they will be escorted by our study team to the nearest psychiatric facility for 
further evaluation and treatment. 
- Participants will be asked to not engage in mental health care outside the study during 
active treatment, but will be assured that they are not prohibited from doing this. They 
will also be told that they can use whatever type of mental health care they would like 
during the monitoring and follow-up phases of the study. They will be asked to alert 
study care provider and/or study coordinator if they begin receiving care outside the 
study and describe the type of care. If subjects do engage in outside mental health 
treatment during the SMART-DAPPER trial, they will be handled as a dropout at the 
point of engagement with the additional treatment. 
- Pregnant and breastfeeding women will be excluded from the study given risk of 
fluoxetine in pregnancy and breastfeeding.  These women will be invited to be screened 
for the study again after the conclusion of pregnancy and/or breastfeeding. 
 
 

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Adequacy of Protection against Risks 
Recruitment and Consent Procedures: 
Aim 1.  
KCH and other Kisumu County Ministry of Health facilities primary care patients age 18 
or older will be recruited to participate in mental health screening using procedures 
adapted from our current mental health treatment studies in the same city, including a 
“health information talk” in which information on the study will be provided to primary 
care patients waiting to be seen by KCH and other Kisumu County Ministry of Health 
facility providers, or referred by CHWs. Other recruitment strategies may be used 
including sending text messages to patients receiving HIV care and treatment services at 
Kisumu County Ministry of Health facilities notifying them about the study and study 
requirements. Social media and traditional media to inform the community about the 
study.  Those who express interest will be invited to a private room for more information 
and a card system with KCH and other Kisumu County Ministry of Health facility 
providers will be used to ensure their place in the primary care patient cue. The first part 
of the meeting will be devoted to explaining the content and purpose of the study and 
completing a written, informed consent, if the prospective participant is interested and 
over the age of 18. Prospective participants may also be screened and verbally consented 
over the phone during the COVID-19 pandemic. Prospective participants will be alerted 
that, if they meet the threshold for DSM-V for MDD and/or PTSD and meet other 
eligibility criteria, they will be offered a referral to the SMART-DAPPER study for 
treatment, which will involve randomization to one of two evidence-based treatments 
delivered by a non-specialist. Those who meet inclusion criteria will be provided with an 

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appointment time and travel voucher (if conducting the visit in person) for completion of 
screening and baseline measures, as indicated. 
When prospective participants who meet the threshold for DSM-Vfor MDD and/or PTSD 
present for care at the primary care referral clinic or by phone, they will again meet with 
our study staff in a private space before initiating treatment. Prospective participants will 
be informed that the process begins with a screening procedure which includes questions 
about their age, their ability to attend weekly 60-minute treatment sessions in person or 
by telephone and symptoms of depression. They will be informed that if they do not meet 
the eligibility criteria, they will not be enrolled in the study and if they have certain 
mental health risk factors, such as acute suicidality, bipolar affective disorder, or 
substance use disorders, they will be referred for higher level or different care. Potential 
participants will be informed that some of the questions may remind them of traumatic 
life experiences, emotional distress and problems in their relationships, and it is possible 
that these questions could be upsetting. They will be informed that they have the right to 
ask for a halt of the questions or treatment at any time. If the participant agrees to  
participate, the last stage of the interview will be devoted to completing the screening 
procedure and baseline measures (as indicated), providing further information regarding 
the study and answering questions about the study. The principles for overriding 
confidentiality will be made clear as defined below. 
B. Protection Against Risk 
Safety of Participants 

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Potential participants will be advised of the study principles of overriding confidentiality 
for the purposes of acute mental health care in three situations: risk of self-harm, risk of 
harm to others and grave disability (inability to provide for one’s own food, clothing or 
shelter) secondary to mental illness. The personal safety of prospective study participants 
will be assessed during the completion of the screening process.. Any participants who 
respond affirmatively to suicidality will be further assessed using a suicidality screen. 
Those scoring moderate or high will be referred to by the PI, Co-I or designated crisis 
evaluation representative, who will be onsite for the duration of the study. Our current 
study with Family AIDS, Care and Education Services (FACES) has developed a robust 
mental health crisis response team composed of senior IPT therapists and study 
coordinators, with crisis protocols and referral channels, supported by the current study’s 
PI and site PI (Drs. Meffert and Ongeri, respectively) and has operated without any 
adverse events, handling 1-2 crises per month over the last 1.5 years at the FACES-
supported primary care clinic in Kisumu. Funds have been allocated to assist with 
immediate transport for urgent mental health care needs, with study team escort.   
Mental Health Safety during Screening.  
If the initial measures completed at KCH and other Kisumu County Ministry of Health 
facility primary care clinics or by phone suggest that a potential participant is at risk of 
self-harm, risk of harm to others or grave disability (inability to provide for one’s own 
food, clothing or shelter) secondary to mental illness, or needs a different type of mental 
health care, he/she will be evaluated by our mental health crisis team and referred to 
higher level or alternative treatment, as needed. Potential participants will be informed 
that their mental health status will be evaluated at every IPT or fluoxetine monitoring 

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session. If their mental health status worsens during treatment such that they are at risk of 
self-harm, harm to others or grave disability, they will be re-evaluated, referred and 
escorted to a higher level of care/alternate care, as indicated. 
Potential adverse events and proposed interventions  
Nature and Degree of Risk:   It is possible, that screening questions and/or additional 
measures applied at the primary care clinic could lead to emotional distress by reminding 
prospective participants of negative events or emotions. 
While fluoxetine is considered a safe and well-tested selective serotonin reuptake 
inhibitor (SSRI), it is possible that subjects will have side effects or adverse effects from 
the medication, if they are randomized to receive it. Side effects of fluoxetine include 
nausea, sleepiness, headache, tremor, diarrhoea, nervousness, dry mouth, inability to 
sleep, and transient increase in suicide ideation. 
While IPT is an evidence-based treatment for MDD and/or PTSD, with any 
psychotherapy some recipients can experience transient, initial elevation of symptoms as 
they begin acknowledging negative emotions. 
Minimization of Risk:   
Mental Health Safety during treatment 
As part of study enrolment, potential participants will be asked “If we think you are in 
serious mental health trouble, whom we should call?” Name and number of supportive 
friend or family member will be gathered and used in the event of mental health crisis, in 
addition to mental health referrals. If the need for acute mental health care arises during 
screening or later in the treatment, this individual will be contacted to provide additional 
support. IPT and fluoxetine are expected to decrease psychiatric symptoms. IPT and 

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fluoxetine have been safely and successfully delivered by non-specialists in East Africa. 
IPT therapist and fluoxetine training will include evaluation of suicidality using the MINI 
suicidality module. Additional protections for urgent mental health care for participants 
receiving treatment over the telephone have been integrated.  Protections include 
contacting the trusted contact, follow-up in person meeting with the treatment provider, 
and utilizing the treatment provider, retention tracker, and other study personnel if 
immediate tracking is needed. 
Monitoring and response to fluoxetine side effects  
Participants will be advised on common side effects with fluoxetine, including the 
potential for weight gain, sexual dysfunction and transient, initial nausea. They will be 
advised of less common, but possible side effects including suicidal thoughts, 
activation/agitation, insomnia, or sedation. 
If participants experience severe side effects such as anxiety/activation, insomnia, 
suicidality, disabling sedation or significant weight gain/sexual dysfunction, their dose 
will be reduced to the lowest tolerable or they will be tapered off fluoxetine and they will 
be monitored with twice weekly visits and interim phone contact until stabilization is 
achieved, or they are referred for a higher level of care. Funds have been allocated to 
assist with immediate transport for urgent mental health care needs, with study team 
escort. 
Potential benefits of the proposed study to participants and others: 
 Introducing the concept of mental disorders and screening primary care patients for 
depression may help to normalize the disorder and reduce stigma for affected individuals, 

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allowing them to access care with fewer social barriers.  Providing referral appointments 
for those who screen positive for depression disorders may instill hope in the idea that the 
disorders are not shameful and that symptoms can be relieved with medical treatment. 
Training local non-specialists to provide IPT and fluoxetine for MDD and/or PTSD may 
normalize the disorders for KCH and other Kisumu County Ministry of Health facility 
primary care providers. This could reduce stigma for affected individuals. Training local 
non-specialists to deliver evidence based care could demonstrate the feasibility of local, 
effective treatment of mental disorders and instill hope for patients and providers. 
Adverse Events Treatment:   
If participants experience severe side effects from Fluoxetine treatment such as 
anxiety/activation, insomnia, suicidality, disabling sedation or significant weight 
gain/sexual dysfunction, their dose will be reduced to the lowest tolerable or they will be 
tapered off fluoxetine and they will be monitored with twice weekly visits and interim 
phone contact until stabilization is achieved, or they are referred for a higher level of 
care. 
Adverse Events Facilities:  Resources for mental health crisis and alternative mental 
health care.  
Resources for mental health care needs include evaluation and treatment with medication 
through KCH and other Kisumu County Ministry of Health facilities medical 
professionals and local resources for psychiatric care across a spectrum of diagnoses and 
severity (domestic violence crisis clinic, outpatient psychiatric clinic, inpatient 
psychiatric hospital ward). If the need arises for psychiatric hospitalization or mental 

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health care needs exceeding local resources in Kisumu county, Drs. Linnet Ongeri (Co-I), 
David Bukusi (Co-I) and Muthoni Mathai (PI), all of whom are practicing psychiatrists in 
Kenya with referral access to the nation’s largest inpatient unit in Nairobi at Mathari 
Teaching and Referral Hospital, will be contacted for facilitation of specialist services.  
 
a) Financial Responsibilities:  Funds will be allocated to assist with immediate 
transport for urgent mental health care. Participant will be accompanied to the 
referral site by study staff.   
 
Confidentiality of research data 
The study records will be kept as confidential as is possible under the law. No individual 
identities will be used in any reports or publications resulting from the study. All 
participants will be assigned a unique participant identification number that will only be 
known to the PI and research staff. The key, with numbers corresponding to first and last 
names of participants, will be kept in a locked office and uploaded to a secure server on a 
Research Electronic Data Capture (REDCap) server hosted at UCSF, accessible only to 
study coordinators and PIs. REDCap’s capability for offline data entry will be used with 
encrypted tablets, with later use of a secure internet connection to upload data to local, 
servers and a secure UCSF server. No participant personal identifiers will be entered in 
the REDCap data base 
 

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Ethical consideration:  
Institutional Review Process: This proposal will be reviewed by the KNH-UoN ERC and 
the University of California San Francisco Institutional Review Board and the National 
Commission for Science, Technology and Innovation (NAOSTI) and granted approval 
before implementation. The study has also been approved by the Kenya Pharmacy & 
Poisons Board (PPB). 
Consenting Process: Written Informed consent will be obtained from all prospective 
participants.  Verbal consent may be conducted during the COVID-19 pandemic to avoid 
disease transmission. Consenting will be performed without undue pressure or coercion. 
Only those who provide consent will be recruited in the study.  
Voluntariness: The participants will be informed that they will be free to withdraw from 
the study at any point without any untoward consequences and that participation is 
voluntary. Those who withdraw will still benefit from necessary care that will be 
available. 
Confidentiality: All the interviews will be conducted individually and confidentially. 
Information collected will not obtain participants identifiers. Information entered in the 
computers will be password protected. All hard copy documents with identifiers will be 
kept in lockable cabinets and will only be accessible to the study investigators. 
 

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Additional information  
Audio Recording 
The in-depth interviews and focus group will be digitally recorded (sound, only), 
transcribed and translated so that we can study the in-depth interviews and focus group 
discussion and compile its findings with the other focus groups and interviews in this 
study.  You will be assigned a study number and only the study number will be used in 
the audio-recording. Your name will not be used by the interviewer and participants will 
be asked not to refer to one another by name.  After the focus group, the digital file will 
be uploaded on a computer to a secure server and the file will be erased from the 
recorder. 
 
TIMELINE 
Table 3: Research Timeline 
 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Processing IRBs and sub-contracts 
 
 
EPIS model for collaborative 
implementation research with key 
stakeholders  
 
Aim 1: Hiring and training for 
SMART-DAPPER 
  
   
 
Aim 1: Recruitment to SMART- 
DAPPER through primary care clinic 
 
 
 
Aim 1: SMART-DAPPER, including 
follow-up  
 
  
 
 
Aim 2: Estimate the costs and cost-
benefit ratios for fluoxetine and IPT 
treatment of depression. 
 
 
Data analysis 
 
 
Manuscript preparation 
                        

October 27, 2021 
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Sequential, Multiple Assignment Randomized Trial (SMART) Depression And Primary care Partnership 
for Effectiveness-implementation Research (DAPPER); Exploration, Preparation, Implementation and 
Sustainment (EPIS); Internal Review Board (IRB); Interpersonal Psychotherapy (IPT). 

 
 
Figure 2 - Exploration, Preparation, Implementation, Sustainment (EPIS) model  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sociopolitical context 
Community health organizations 
Professional organizations 
 
Community Advisory Group (CAG); Dynamic Adaptation Process (DAP); Family AIDS, Care education and Services (FACES); Implementation Resource Team (IRT); 
Kisumu County Hospital (KCH). NOTE: Adapted from Aarons et al (2011). Advancing a conceptual model of evidence-based practice implementation in public 
service sectors. Adm Policy Ment Health. 38: 4–2 (Figure 2).  
Exploration 
Outer context 
Inner context 
Sociopolitical context 
Community health organizations 
Professional organizations 
KCH directors 
FACES staff and CAGs 
KCH Primary care clinic(s) 
Healthcare providers 
Staff, Patients, Volunteers 
Preparation 
Outer context 
Inner context 
Sociopolitical context 
 
Primary care clinic(s) 
Healthcare providers 
Staff, Patients, Volunteers 
 
Implementation 
Outer context 
KCH directors 
FACES staff and CAGs 
KCH Primary care clinic(s) 
Healthcare providers 
Staff, Patients, Volunteers 
 
Identify and convene IRT 
Regular IRT meetings and DAP as 
needed 
Inner context 
Sustainment 
Outer context 
Sociopolitical context 
Community health organizations 
Professional organizations 
 
KCH directors 
FACES staff and CAGs 
KCH Primary care clinic(s) 
Healthcare providers 
Staff, Patients, Volunteers 
 
IRT – Review data, discuss findings, 
collaborate for next steps in scale up 
 
Inner context 
IRT DAP for study launch 
Establish schedule for study 
updates to key stakeholders 

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Figure 3. SMART DAPPER Study Design
 

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Figure 4: Interpersonal Psychotherapy Phases 
 
 

 
 
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