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Introduction Antidepressant medications are widely used by patients requiring spinal surgery. In spite of a generally favorable safety profile of newer antidepressants, several prior studies have suggested an association between use of serotonergic antidepressants and excessive bleeding. This study was designed to determine if there was any association between antidepressant use and the risk of excessive intraoperative blood loss during spinal surgery, and whether particular types of antidepressants were specifically associated with this increased blood loss. Materials and methods A retrospective case control study was conducted utilizing a population of 1,539 patients who underwent elective spinal fusion by a single surgeon at one medical center. Of the included patients, 213 used antidepressant medication and 1,326 patients did not use any type of antidepressant medication. Of patients taking antidepressants, 37 patients were excluded based on exclusion criteria, leaving 176 patients suitable for inclusion. The study group (176 patients) consisted of all patients who used an antidepressant medication for at least a 2-week period prior to spinal surgery. A control group of 352 patients were assembled from a random sample of 1,326 patients operated on by the same surgeon during the same time period in a two-to-one ratio with study group. Intraoperative blood loss was the primary outcome variable and was compared between the study and control group and between individuals in the study group taking serotonergic (SSRIs or SNRIs) or non-serotonergic antidepressants. Other variables, including length of hospital stay and surgical category, were also collected and analyzed separately. Results Overall, the mean blood loss (BL) for the antidepressant group was 298 cc, 23% more than the 241 cc lost by the procedure-and level-matched control group (p = 0.01). Patients taking serotonergic antidepressants also had statistically significant higher blood loss than the matched control group as a whole (334 vs. 241 cc, p = 0.015). This difference was also found in subgroups of patients who underwent anterior cervical discectomy and fusion, lumbar instrumented fusion, or anterior/posterior lumbar fusion. Blood loss was also higher in the subgroup of patients taking bupropion (708 cc, p = 0.023) compared with the control group. The mean length of hospital stay