<p>Obstructive sleep apnea (OSA) is a common sleep disorder in adults and is associated with multiple brain, mental, and cardiometabolic adverse health outcomes. Although standard treatments are available for OSA, the world does not have equal access to the best management approaches for OSA, which could be due to limited financial resources or a limited trained workforce. Pharmacological agents, if selected wisely based on the endophenotypes of OSA, may offer an appropriate approach for selective cases of OSA who refuse standard treatments or do not have access to the standard care. This review describes different OSA comorbidities, phenotypes, and endotypes of OSA and the role of trazodone and atomoxetine in the management of them. Finally, we will summarize the endophenotypes responsive to trazodone and atomoxetine and highlight the role of these agents in the management of OSA and its consequences, especially in underserved areas.</p>