Use mood disorder history, antidepressant exposure, and iron status to avoid worsening restless legs syndrome with the wrong medication choice. Document the dominant clinical clue and the next bedside decision.

Bupropion is often preferred when depression and restless legs syndrome coexist; Mirtazapine and duloxetine can worsen restless legs syndrome; Restless legs syndrome is strongly heritable; Central iron deficiency is a leading pathophysiologic hypothesis; Medication review is the first step when restless legs symptoms appear