Major depressive disorder (MDD) is a substantial health burden worldwide and is characterized by single or recurrent major depressive episodes. Like other neuropsychiatric disorders, depression has a varied etiology, including genetic, epigenetic, and environmental factors. The most prevalent environmental factor is stress. MDD can be spontaneous, but it often follows a traumatic emotional experience, or it can be a symptom of other conditions, most often neurological (stroke, multiple sclerosis, or Parkinson’s disease) or endocrine. MDD has also been linked to cardiovascular disease, diabetes, asthma, obesity, and several adverse health behaviors.

MDD is associated with considerable morbidity and mortality. For many patients, an initial episode of depression evolves into a recurrent and debilitating chronic illness with significant and pervasive impairments in psychosocial functioning. According to the National Institute of Mental Health, an estimated 16.1 million adults aged 18 or older in the United States had at least one major depressive episode in 2015. This number represented 6.7% of all U.S. adults.

Despite a multitude of antidepressants available today, it is estimated that 50% of patients will not respond to their first therapy and 35% will not return to a normal level of functioning. There remains a significant unmet need for new antidepressants that can achieve a faster onset of action, better efficacy, less side effect, or effectiveness in subpopulations.