As humankind ventures further into the depths of space, planning is already underway for long-duration exploration missions that will test the bounds of human performance. Deep space travel will include added risk related to stressors from the isolated, confined, and extreme environment that lies outside the boundaries of low Earth orbit. Currently, selective serotonin reuptake inhibitors (SSRIs) are considered the standard of care for many mental health diagnoses, including anxiety and depression; however, SSRIs are also associated with several undesired side effects. The utility of nonpharmacological therapies for the management of behavioral health conditions has not yet been fully explored. A comprehensive literature search was performed using PubMed. Relevant articles pertaining to the psychological impacts of isolated, confined, and extreme environments, use of SSRIs in spaceflight, side effects associated with SSRIs, and nonpharmacological treatments for anxiety and depression were reviewed. Over 70 studies were reviewed in total. Reduced bone mineral density, impaired hemostatic function, significant individual variability resulting from gene polymorphisms, and drug-drug interactions are well described adverse effects of SSRIs that may complicate their operational use in the deep space environment. Four alternative therapies for the treatment of anxiety and depression may show promise for long duration missions. Although SSRIs have long been considered standard of care treatment for many behavioral health conditions, we cannot trivialize the risk that prolonged pharmacological therapy may pose. The need to mitigate these risks by exploring alternative therapies has never been more relevant.