There exists a clear link between depression and pain and use of anti-depressants has resulted in an understanding of the pain-relieving effects of these medications. Further, non-pharmacologic psychological interventions remain a mainstay in treating psychological conditions in the pain patient. Consisting of drugs from multiple categories including serotonin-selective reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) among others, anti-depressants have variable amount of relief from pain that must be balanced with adverse effects with these medications and various drug-drug interactions. Knowledge of this area is key not only for the board exam but for clinical practice. Questions regarding medications will be present throughout the text, not limited to this chapter alone which focuses more on non-pharmacologic treatments.