Knee osteoarthritis (KOA) is one of the most common causes of chronic pain, mobility problems, and disability among United States Veterans. Many Veterans with KOA also experience depressive symptoms, which can worsen pain, reduce motivation to exercise, and make recovery more difficult. This study will test whether a structured hybrid aerobic exercise program that combines supervised and home-based walking with the medication duloxetine can improve physical function, reduce pain, lessen depressive symptoms, and improve overall health-related outcomes in Veterans with KOA. The goal of this research is to develop a practical and scalable treatment strategy that could improve rehabilitation and quality of life for Veterans with chronic knee pain and depressive symptoms and potentially be adapted for other chronic musculoskeletal conditions treated within the VA healthcare system.

Knee osteoarthritis (KOA) and depressive symptoms are both common among older adults and Veterans and are major contributors to chronic pain, reduced mobility, declines in physical function, disability, and poorer overall health outcomes. Veterans with KOA frequently experience co-occurring depressive symptoms, which can worsen pain, interfere with rehabilitation, and reduce adherence to exercise and other self-management strategies. Existing VA care guidelines generally treat KOA and depressive symptoms separately, and there remains limited evidence supporting integrated interventions that target both conditions simultaneously while also improving physical function.

Current knowledge gaps include how to optimize adherence to aerobic exercise among individuals with pain and depressive symptoms and whether combining pharmacologic and rehabilitative approaches provides greater benefit than usual care alone. Aerobic exercise is a recommended first-line treatment for KOA and can improve both mood and physical function, but sustained participation is often difficult in individuals with chronic pain and depressive symptoms. Similarly, duloxetine has demonstrated benefits for both depressive symptoms and KOA-related pain, although interventions targeting only one condition have generally produced limited effects.

Preliminary work conducted by the study team demonstrated that combining duloxetine with a hybrid supervised aerobic exercise program that included both center-based and home-based walking components was feasible and acceptable among individuals with symptomatic KOA and depressive symptoms. Participants experienced clinically meaningful improvements in pain, activities of daily living, walking ability, endurance, psychological symptoms, self-efficacy, and willingness to engage in pain self-management strategies. These findings support the rationale for the proposed study and the evaluation of a complementary care model integrating pharmacologic and non-pharmacologic treatments for Veterans with KOA and depressive symptoms. This study is a Phase II, three-arm, randomized clinical trial designed to evaluate the efficacy of a hybrid supervised aerobic exercise program combined with duloxetine among Veterans with symptomatic knee osteoarthritis and depressive symptoms.

Inclusion Criteria:

• Veterans aged ≥40 years
• English-speaking
• symptomatic KOA based on American College of Rheumatology (ACR) criteria
• Patient Health Questionnaire-9 (PHQ-9) scores indicating mild to severe depressive symptoms
• no planned knee surgery within the next 6 months
• ability to participate in supervised aerobic exercise

Exclusion Criteria:

• current use of antidepressants, opioids, benzodiazepines, or antipsychotics
• engaging in structured aerobic or resistance exercise ≥3 times per week
• cognitive impairment defined as a Mini-Mental State Examination (MMSE) score <20
• diagnosis of bipolar disorder, psychosis, recent substance use disorder, or suicidal ideation per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
• medical conditions contraindicating exercise (e.g., recent myocardial infarction, unstable angina, peripheral arterial disease with ulcers, -uncontrolled hypertension >190/110, or New York Heart Association class ≥3 cardiac or pulmonary disease)
• pregnant or lactating individuals
• active cancer that is currently undergoing treatment (receiving chemotherapy and/or radiation therapy
• other conditions deemed by study team to endanger the health of the participant

Participants randomized to receive the exercise program will be blinded to duloxetine or placebo. Outcome assessors will be blinded to treatment allocation/group assignment.