This study evaluates the addition of duloxetine to aerobic exercise in the treatment of symptomatic knee osteoarthritis and depressive symptoms in adults. All participants will receive the receive the treatment protocol, which will first be evaluated in terms of feasibility and then pilot tested.

Symptomatic knee osteoarthritis (OA) affects 10% of men and 13% of women 60 years or older, and depressive symptoms are common, occurring in one-fifth of these patients. Depressive symptoms worsen knee OA disease severity and are a barrier to pain management and engagement in physical activity. Guidelines recommend depression treatment in older adults with knee OA but provide no direction on how to simultaneously manage the co-occurrence of physical and mental morbidity. Treatment recommendations advise exercise to manage pain and disability and improve psychosocial health in knee OA patients; however, compliance to exercise programs is low in persons with chronic pain and disability and is only made worse by comorbid depression. Adherence is critical to the efficacy of depression treatments using exercise training, and no such exercise program has ever been designed for and tested in OA patients with co-occurring depressive symptoms in a way to enhance compliance. Duloxetine is the only antidepressant medication indicated for pain management in knee OA patients that has demonstrated efficacy and tolerability when treating depression in older adults and is a viable pharmacological complement to exercise. There are no protocols that combine treatments using interventions that affect symptoms of both knee OA and depression, and the study goals are to evaluate the feasibility of and then pilot test a protocol comprised of aerobic exercise training plus duloxetine for the treatment of symptomatic knee OA and comorbid depression.

Inclusion Criteria:

1. English speaking
2. 40 years or older
3. Symptomatic knee osteoarthritis fulfilling 1986 American College of Rheumatology criteria
4. No plan for surgical knee osteoarthritis intervention within six months of enrollment
5. Major depressive disorder satisfying diagnostic criteria according to the DSM-V
6. Ability to participate in a supervised aerobic exercise program

Exclusion Criteria:

1. Already performing aerobic or resistive exercise 2x/week or more
2. Taking duloxetine, antipsychotics, benzodiazepines, or opioid analgesics
3. Other medications deemed by study team to endanger the health of the participant or unduly confound the results
4. Cognitive impairment (Mini-Mental State Examination score < 20)
5. Past or current bipolar disorder or psychotic symptoms according to the DSM-V
6. Substance abuse disorder or suicidal ideation within the previous year
7. Not able to participate in a supervised exercise program based on the presence of unstable angina, recent MI (within last 3 months), hemiparetic gait, inability to walk at least 1mph on treadmill safely, poorly controlled hypertension (resting blood pressure > 190/110), peripheral arterial disease with current foot or leg ulcers, or cardiac or pulmonary disease with exercise tolerance NYHA class 3 or higher.
8. Active cancer that is currently undergoing treatment (receiving chemotherapy and/or radiation therapy)
9. Pregnant or lactating women
10. Other conditions deemed by study team to endanger the health of the participant or unduly confound the results