SMART-DAPPER: Leveraging the Depression And Primary-care Partnership for Effectiveness-implementation Research Project

Study Overview
=================
Brief Summary
-----------------
Despite carrying the vast majority of the global mental disorder burden, 75% of adults with mental disorders in Low and Middle Income Countries have no access to services. This study will test strategies for integrating first and second line evidence-based depression and trauma-related disorder treatments with primary care services at a large public sector hospital and conduct robust cost and cost-benefit analyses of each treatment to produce a menu of cost-benefit options for personalized, integrated mental health care with corresponding effectiveness and implementation values.

Detailed Description
-----------------
Mental disorders are a leading cause of global disability, driven by depression and anxiety. 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 research showing that local non-specialists can provide evidence-based care for depression and anxiety in LMICs, few studies have advanced to the critical next step: identifying strategies for sustainable real world non-specialist treatment including integration with existing healthcare platforms and response to common clinical dilemmas, such as what treatment to start with and how to modify it. Given the need to personalize treatment to achieve remission (absence of disease) and the scarcity of mental health specialists in LMICs, successful reduction of population-level disability caused by depression and anxiety requires (1) evidence-based strategies for first-line and second-line (non-remitter) treatment delivered by non-specialists, with (2) confirmation of presumed mechanism of action and (3) patient-level moderators of treatment outcome to inform personalized, non-specialist treatment algorithms. The research team has worked in western Kenya for 6 years with a UCSF-Kenya collaboration that supports integrated HIV services at over 70 primary healthcare facilities in Kisumu County (Family AIDS Care and Education Services [FACES]). Primary care populations in Kenya have high prevalence of Major Depressive Disorder (MDD) (26%) and Posttraumatic Stress Disorder (PTSD) (35%). Kenyan leaders lack an evidence base for two essential treatments - psychotherapy and second generation antidepressants- without which scale-up will fall short of its potential. We conducted a randomized, controlled trial in Kisumu County of Interpersonal Psychotherapy (IPT) delivered by non-specialists for HIV-positive patients with MDD and PTSD. In our study, IPT achieved full remission of MDD and PTSD in the majority of participants. Given the high prevalence of MDD-PTSD co-morbidity, we will collaborate with the FACES team providing services to Kisumu County Hospital (KCH) primary care outpatient clinic ( 10,000 patients/month) to conduct a randomized trial of IPT versus fluoxetine for MDD and/or PTSD. 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. SMART participants will be randomized to: (1) first line treatment with IPT or fluoxetine; (2) second line treatment for non-remitters- treatment switch (e.g., IPT to fluoxetine) or treatment combination (e.g., addition of IPT to fluoxetine). Research with mental health specialists in high income countries suggests that antidepressants and psychotherapy have equivalent short-term efficacy and that psychotherapy yields superior long-term relapse prevention. We will test the role of previously identified mechanisms in mediating remission and key moderators of treatment effect. Results of moderator and Q learning analyses will produce first and second-line non-specialist treatment algorithms.

Official Title
-----------------
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

Conditions
-----------------
Depression, Unipolar, Posttraumatic Stress Disorder, Trauma

Intervention / Treatment
-----------------
* Drug: Fluoxetine
* Behavioral: Interpersonal Psychotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Kisumu County Hospital (KCH) adult primary care outpatient clinic attendees who screen positive for depression and/or PTSD Ability to attend weekly IPT sessions/fluoxetine monitoring; (3) 18 years or older Exclusion Criteria: Cognitive dysfunction compromising ability to participate in IPT or accurately take fluoxetine (lack of orientation to person, place, time and situation) acute suicidality requiring higher level of care drug/alcohol use disorders requiring substance use treatment (AUDIT score of 8 or higher, DAST score of 3 or higher) history of mania or requiring treatment for hypomania Outside mental health treatment during the study treatment phases (any mental health treatment is allowed during follow-up phases and is recorded by study team).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: fluoxetine versus interpersonal psychotherapy (IPT) for treatment of Major Depressive Disorder (MDD) and/or Posttraumatic Stress Disorder (PTSD)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Interpersonal psychotherapy<br>IPT was developed in the 1980s by Gerald Klerman and Myrna Weissman to address interpersonal issues in depression. IPT is now considered evidence-based, first-line treatment for depression. IPT improves symptoms by addressing problems in social relationships. IPT is traditionally delivered as weekly one-hour sessions over 12 weeks, focused on one interpersonal problem area. | Behavioral: Interpersonal Psychotherapy<br>* IPT was developed in the 1980s by Gerald Klerman and Myrna Weissman to address interpersonal issues in depression. IPT is now considered evidence-based, first-line treatment for depression. IPT improves symptoms by addressing problems in social relationships. IPT is traditionally delivered as weekly one-hour sessions over 12 weeks, focused on one interpersonal problem area.<br>* Other names: IPT;|
| Active Comparator: fluoxetine<br>Fluoxetine is a selective serotonin reuptake inhibitor that is FDA approved for the treatment of depression. Compared to placebo, fluoxetine is more likely to produce symptom response for MDD. Despite the interim development of many other antidepressants since the development of fluoxetine, it remains a first line treatment for depression. | Drug: Fluoxetine<br>* Fluoxetine is a selective serotonin reuptake inhibitor that is FDA approved for the treatment of depression. Compared to placebo, fluoxetine is more likely to produce symptom response for MDD. Despite the interim development of many other antidepressants since the development of fluoxetine, it remains a first line treatment for depression.<br>|
| Active Comparator: Fluoxetine after IPT<br>participants who do not remit from MDD and PTSD after treatment with IPT may be randomized to fluoxetine. | Drug: Fluoxetine<br>* Fluoxetine is a selective serotonin reuptake inhibitor that is FDA approved for the treatment of depression. Compared to placebo, fluoxetine is more likely to produce symptom response for MDD. Despite the interim development of many other antidepressants since the development of fluoxetine, it remains a first line treatment for depression.<br>|
| Active Comparator: IPT after fluoxetine<br>participants who do not remit from MDD and PTSD after treatment with fluoxetine may be randomized to IPT. | Behavioral: Interpersonal Psychotherapy<br>* IPT was developed in the 1980s by Gerald Klerman and Myrna Weissman to address interpersonal issues in depression. IPT is now considered evidence-based, first-line treatment for depression. IPT improves symptoms by addressing problems in social relationships. IPT is traditionally delivered as weekly one-hour sessions over 12 weeks, focused on one interpersonal problem area.<br>* Other names: IPT;|
| Active Comparator: IPT + fluoxetine<br>participants who do not remit from MDD and PTSD after treatment with fluoxetine may be randomized to IPT + fluoxetine. | Drug: Fluoxetine<br>* Fluoxetine is a selective serotonin reuptake inhibitor that is FDA approved for the treatment of depression. Compared to placebo, fluoxetine is more likely to produce symptom response for MDD. Despite the interim development of many other antidepressants since the development of fluoxetine, it remains a first line treatment for depression.<br>Behavioral: Interpersonal Psychotherapy<br>* IPT was developed in the 1980s by Gerald Klerman and Myrna Weissman to address interpersonal issues in depression. IPT is now considered evidence-based, first-line treatment for depression. IPT improves symptoms by addressing problems in social relationships. IPT is traditionally delivered as weekly one-hour sessions over 12 weeks, focused on one interpersonal problem area.<br>* Other names: IPT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depression | Change in threshold criteria for DSM V major depressive disorder | Baseline, End of study (an average of 30 months) | 
| PTSD | Change in threshold criteria for DSM V PTSD | Baseline, End of study (an average of 30 months) |