Improving Outcomes in Depression in Primary Care in a Low Resource Setting

Study Overview
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Brief Summary
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The OptimizeD study aims to improve outcomes in depression in primary care in India. This study will randomize 1500 patients with moderate to severe depression to either psychotherapy based on behavioral activation called the Healthy Activity Program (HAP) or antidepressant medication (fluoxetine). The study has two primary objectives: Use patient characteristics to generate a precision treatment rule for predicting what works best for whom (and which patients are unlikely to respond to either treatment and should be referred to specialist care). Conduct a cost-effectiveness analysis by comparing relative costs and effectiveness between those who were randomly allocated to their optimal treatment with those who were randomly allocated to a non-optimal treatment based on the precision treatment rule.

Detailed Description
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Depression is the leading mental health contributor to the Global Burden of Disease. The World Health Organization's mhGAP initiative advocates the use of brief psychological therapies such as behavioral activation or antidepressant medications as first-line options for the treatment of moderate to severe depression in primary care settings, but not all patients will fully remit on either treatment. It is likely that different patients will respond to different treatments, but the optimal treatment for each individual remains unknown (and which patients are unlikely to respond to either treatment and should be referred to specialist care). Enhancing our ability to determine the optimal intervention for a particular patient has the potential to enhance the overall effectiveness of mental health care delivery in a more cost-efficient manner. This is a critical gap in knowledge in the treatment of depression across clinical settings globally. The main objective of the OptimizeD study is to determine whether different patients respond differentially to brief psychological treatment or a widely used generic SSRI and, if so, whether one can optimize outcomes in a cost-effective fashion for primary care patients with moderate to severe depression. The study has two specific aims and two exploratory aims: Specific Aim 1 (Clinical and Functional Outcomes): To evaluate the effectiveness of optimization via generating a precision treatment rule (PTR) on patients with moderate to severe depression randomized to either psychotherapy based on behavioral activation called the Healthy Activity Program (HAP) or antidepressant medication (fluoxetine). The study will use machine learning to develop the PTR, using a wide range of clinical, socio-economic, and neuro-cognitive characteristics measured at baseline as predictors. The investigators hypothesize that patients randomized by chance to their optimal intervention will be more likely to remit and recover than patients who are not. Specific Aim 2 (Cost-effectiveness Outcomes): To assess the costs of optimal vs. non-optimal treatments and to conduct a cost-effectiveness analysis by comparing relative costs and effectiveness between those who were randomly allocated to their optimal treatment with those who were randomly allocated to a non-optimal treatment, based on the PTR developed in Aim 1. The investigators hypothesize that optimizing will be more cost-effective than not. Exploratory Aim 1 (Mediators): To explore whether one can use the PTR to make our tests of mediation more precise. Patients who respond differentially to different treatments adhere to different causal mechanisms, and inclusion of the PTR in interaction terms with the purported mediators should facilitate the detection of moderated mediation among patients who show specificity of response. The investigators will also consider whether treatment-related factors (e.g., adherence, quality) act as mediators of the effects of each treatment on remission and recovery. This exploratory aim will offer insights into mechanisms of action for each treatment. Exploratory Aim 2 (Genetic Predictors): To explore whether polygenic risk scores and other biomarkers can enhance the prediction of both general and differential response to either treatment.

Official Title
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Improving Outcomes in Depression in Primary Care in a Low Resource Setting

Conditions
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Depression, Depressive Disorder

Intervention / Treatment
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* Behavioral: Healthy Activity Program (HAP)
* Drug: Antidepressant medication (fluoxetine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants will be adults aged 18 or over of any gender attending one of eight Primary Health Care Centers with a diagnosis of moderate to severe depression based on scores of 10 or above on the Patient Health Questionnaire-9 (PHQ-9). Exclusion Criteria: Women who are pregnant or are breastfeeding or lactating Patients with a history of psychosis including schizophrenia spectrum disorders or bipolar disorder. Participants planning to move out of the study area during the follow-up period. Patients over 65 years of age with evidence of cognitive impairment - Patients who do not speak the study or local language (English or Hindi) Patients who are undergoing treatment for depression at the time of recruitment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Fluoxetine versus a contextually adapted version of behavioral activation called the Healthy Activity Program (HAP) delivered by non-specialists for treatment of depression
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Activity Program (HAP)<br>HAP is a brief psychological treatment adapted from behavioral activation therapy, an empirically supported psychological treatment recommended by WHO. | Behavioral: Healthy Activity Program (HAP)<br>* HAP, delivered over 6-8 sessions by non-specialist healthcare workers, has behavioural activation as the core psychological strategy along with other strategies such as problem-solving and activation of social networks.<br>|
| Experimental: Antidepressant medication (fluoxetine)<br>Fluoxetine is a selective serotonin reuptake inhibitors (SSRIs) and one of the safest medications used to treat depression. It is a routinely used medication and part of the Essential Drug List (EDL) in India. | Drug: Antidepressant medication (fluoxetine)<br>* Patients assigned to antidepressant medication will start on fluoxetine 20 mg/day and can be raised to 40 mg/day (the maximum mandated by treatment guidelines for primary care in India) at week 3 or 6 for patients who have yet to remit.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depression severity, as measured by the Patient Health Questionnaire-9 (PHQ-9) | The PHQ-9 is a 9-item self-report scale to screen for symptoms of depression. Items are rated on a 4-point Likert scale from 0 (not at all) to 3 (nearly every day), with total scores ranging from 0 to 27, where higher scores indicate more severe depressive symptoms. | 3 months post recruitment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cost-effectiveness of optimization | Cost-effectiveness analysis by comparing costs and effectiveness between those who were randomly allocated to their optimal treatment vs. those who were randomly allocated to a non-optimal treatment. Effectiveness will be measures by (1) likelihood of remission and (2) Quality Adjusted Life Years (QALYs). Costs will be measured using the Client Service Receipt Inventory (CSRI) and system-level costs (see sections below for a description of these measures). | 3-, 6-, 9-, 12-months post recruitment | 
| Depression remission | Remission is defined as PHQ-9 total score < 5. The PHQ-9 is a self-report measure of depressive symptoms in the prior 2 weeks. Items are rated on a 4-point Likert scale from 0 (not at all) to 3 (nearly every day), with total scores ranging from 0 to 27, where higher scores indicate more severe depressive symptoms. We will dichotomised the total score using the cut-off score of 5. | 3-, 6-, 9-, 12-months post recruitment | 
| Generalized Anxiety Disorder Assessment (GAD-7) | The GAD-7 is a 7-item self-report scale to screen for symptoms of generalized anxiety disorder. Items are rated on a 4-point Likert scale from 0 (not at all) to 3 (nearly every day), with total scores ranging from 0 to 21, where higher scores indicate more severe anxiety symptoms. | 3-, 6-, 9-, 12-months post recruitment | 
| WHO Disability Assessment Schedule II (WHODAS-II) | The WHODAS-II consists of 12-items that capture level of functioning across six life domains including cognition, mobility, self-care, getting along, life activities, and participation in society. Each item ranges from 1 (none) to 5 (extreme), with total scores from 12-60. Raw scores are then converted to a summary score ranging from 0 (no disability) to 100 (full disability). | 3-, 6-, 9-, 12-months post recruitment | 
| Minimal Clinically Important Difference (MCID) | We will use the anchor-based approach for estimating MCID that ties change in outcome on the PHQ-9 to the patient's subjective sense of improvement. We will follow Weobong (2017) methodology to compute this. | 3-, 6-, 9-, 12-months post recruitment | 
| World Health Organization Well-Being Index (WHO-5) | The WHO-5 consists of 5-items that measure current mental well-being. Each item is rated on 6-point Likert scale, ranging from 0 (at no the time) to 5 (all of the time). The total raw score, ranging from 0 to 25, is multiplied by 4 to give the final score, with 0 representing the worst imaginable well-being and 100 representing the best imaginable well-being. | 3-, 6-, 9-, 12-months post recruitment |