A Phase 3 interventional study of Healthy Activity Program (HAP) and Antidepressant medication (fluoxetine) in Depression and Depressive Disorder, sponsored by Harvard Medical School (HMS and HSDM). Active, not recruiting at 1 site in India. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-05-22.
Sponsored by Harvard Medical School (HMS and HSDM) · Phase 3, Interventional, and Health services research
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:
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:
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.
All trial procedures used in the main trial were first evaluated in a pilot study (NCT06153004), which employed the same design and methods to assess feasibility across recruitment, randomization, retention, treatment adherence and fidelity, and data quality assurance.
8,057 studies on the registry are indexed under Depression; 1,641 are open to participants now.
This study's planned enrollment of 1,500 is above the median of 84 across 6,720 interventional studies indexed under Depression.
Browse Depression studies →Harvard Medical School (HMS and HSDM) is the lead sponsor of 53 studies on the registry; 12 are open to participants now.
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Exclusion Criteria:
HAP is a brief psychological treatment adapted from behavioral activation therapy, an empirically supported psychological treatment recommended by WHO.
Behavioral: Healthy Activity Program (HAP)
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)
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.
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).
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.
Time frame: 3 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 12-month post recruitment
Client Service Receipt Inventory (CSRI)
Out-of-pocket costs for receiving care and the related non-medical costs.
Time frame: 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.
Time frame: 3-, 6-, 9-, 12-months post recruitment
Plan to share: Yes — 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.
Supporting information: Study protocol, Sap
This study is active, not recruiting, as verified in May 2026. You cannot join it, but the record below documents what was studied.
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Harvard Medical School (HMS and HSDM)