Improving Outcomes in Depression in Primary Care in a Low Resource Setting (OptimizeD)

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:

1. Use patient characteristics to generate a precision treatment rule based on baseline information for predicting in advance what works best for whom (and which patients are unlikely to respond to either treatment and should be referred to specialist care).
2. 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.

Study Overview

• Status: Recruiting
• Conditions: Depressive Disorder; Depression
• Intervention / Treatment: Behavioral: Healthy Activity Program (HAP); Drug: Antidepressant medication (fluoxetine)

Detailed Description

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.

As a secondary objective, the study will evaluate the effectiveness of optimization in the long-term. The investigators hypothesize that patients allocated to their optimized treatment will be more likely to recover than patients who are allocated to their non-optimal treatment.

• Study Type: Interventional
• Enrollment (Estimated): 1500
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Julia R Pozuelo, PhD; Phone Number: 617-432-1707; Email: julia_ruizpozuelo@hms.harvard.edu

Study Locations

• India
  • Madhya Pradesh
    • Bhopal, Madhya Pradesh, India, 462016
      • Recruiting
      • Sangath
      • Contact: Deepak Tugnawat, MSW; Phone Number: 91-8523843957; Email: deepak.tugnawat@sangath.in
      • Principal Investigator: Anant Bhan, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants will be adults aged 18 or over of any gender attending one of the selected 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy Activity Program (HAP); HAP is a brief psychological treatment adapted from behavioral activation therapy, an empirically supported psychological treatment recommended by WHO.	Behavioral: Healthy Activity Program (HAP); 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.
Experimental: Antidepressant medication (fluoxetine); 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); 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. Participants who do not tolerate fluoxetine can be switched to escitalopram at week 6 (10mg which can be titrated up to 20 mg).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 months post recruitment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 of treatments include three components: system-level costs incurred at the health facility level, individual costs incurred by HAP counselors and Medical Officers in delivering each treatment, and costs incurred by patients for participating in the treatment. See section below for a description of these measures.	3-, 6-, 9-, 12-months post recruitment
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-, 6-, 9-, 12-months post recruitment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Client Service Receipt Inventory (CSRI)	Out-of-pocket costs for receiving care and the related non-medical costs.	3-, 6-, 9-, 12-months post recruitment
Quality Adjusted Life Years (QALYs) as measured by WHODAS II	WHODAS II is a 12-item scale that captures the level of functioning across six life domains, including cognition, mobility, self-care, getting along, life activities, and participation in society (Saltychev et al., 2021). Each item ranges from 1 (none) to 5 (extreme), with total simple scores from 12-60. Standardized summary scores will be converted to a preference-weighted utility index, which will then be used to compute the additional number of QALYs generated by the interventions. The answers to two questions in WHODAS can be used to estimate the number of days in the previous month that someone was completely unable to work or able to work only part time because of a health condition.	3-, 6-, 9-, 12-months post recruitment
Recovery from depression as measured by the PHQ-9	Recovery from depression symptoms is defined as going nine months without relapse (PHQ-9 ≥5) following remission.	12-month post recruitment

Collaborators and Investigators

• Sponsor: Harvard Medical School (HMS and HSDM)
• Collaborators: Sangath; National Institute of Mental Health (NIMH); Massachusetts General Hospital; Centre for Addiction and Mental Health; Brigham and Women's Hospital; Vanderbilt University; Harvard School of Public Health (HSPH); All India Institute of Medical Sciences, Bhopal
• Investigators: Principal Investigator: Vikram Patel, MD, Vikram_Patel@hms.harvard.edu

Publications and helpful links

General Publications

• Weobong B, Weiss HA, McDaid D, Singla DR, Hollon SD, Nadkarni A, Park AL, Bhat B, Katti B, Anand A, Dimidjian S, Araya R, King M, Vijayakumar L, Wilson GT, Velleman R, Kirkwood BR, Fairburn CG, Patel V. Sustained effectiveness and cost-effectiveness of the Healthy Activity Programme, a brief psychological treatment for depression delivered by lay counsellors in primary care: 12-month follow-up of a randomised controlled trial. PLoS Med. 2017 Sep 12;14(9):e1002385. doi: 10.1371/journal.pmed.1002385. eCollection 2017 Sep.

Helpful Links

• Study overview

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2024
• Primary Completion (Estimated): August 30, 2025
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: June 2, 2023
• First Submitted That Met QC Criteria: July 2, 2023
• First Posted (Actual): July 13, 2023

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Selective Serotonin Reuptake Inhibitors; Fluoxetine; Antidepressive Agents
• Other Study ID Numbers: IRB20-2144; 1R01MH121632-01A1 (U.S. NIH Grant/Contract); CTRI/2024/01/061932 (Other Identifier: Clinical Trials Registry - India (ICMR-NIMS))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data will be shared through the NIMH Data Archive. To ensure participant privacy and data security, all shared data will be de-identified according to established protocols and guidelines. The data sharing plan will be periodically reviewed and updated, as necessary, to align with evolving best practices, policies, and guidelines for data sharing.
• IPD Sharing Time Frame: Data will be available indefinitely or for as long as the NIMH repositories support it.
• IPD Sharing Access Criteria: Researchers and interested parties who wish to access the data can submit a formal data access request to the NIMH Data Archive. Researchers who gain access to the data will be required to comply with the data usage policies and guidelines set forth by the NIMH Data Archive.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No