Post-ICU Syndromes (PICS) remain a devastating problem for intensive care unit (ICU) survivors. It is currently unknown if de novo initiation of an antidepressant medication during ICU stay decreases the prevalence of post-ICU depression. We performed a retrospective, pilot study evaluating patients who had not previously been on an antidepressant medication and who were started on an antidepressant while in the trauma surgical, cardiothoracic, or medical intensive care unit (ICU). The PHQ-2 depression scale was used to ascertain the presence of depression after ICU discharge and compared this to historical controls. Of 2,988 patients admitted to the ICU, 69 patients had de novo initiation of an antidepressant medication and 27 patients were alive and available for study inclusion. We found the prevalence of depression in these patients to be 26%, which is not statistically different than the prevalence of post-ICU depression in historical controls [95% CI (27.6%, 51.6%)]. De novo initiation of an antidepressant medication did not substantially decrease the prevalence of post-ICU depression in this retrospective, pilot study.