Selective serotonin reuptake inhibitors and the risk of restless legs syndrome: a symmetry analysis

Purpose Largely based on case series, several drugs have been implicated in drug-induced restless legs syndrome (RLS)
including selective serotonin reuptake inhibitors (SSRI). We aimed to assess the association between initiation of SSRIs and
RLS in a self-controlled design.
Methods We conducted a symmetry analysis, including Danish adults who filled in their first prescription of an SSRI in the
period of 1997–2017 and initiated an RLS drug (quinine, ropinirole, pramipexole or rotigotine) 1 year prior to or after this date. A
symmetrical distribution of prescriptions before and after SSRI initiation is expected if there is no association between SSRI and
RLS (a sequence ratio (SR) of 1.0). The symmetry analysis design is robust to confounders that are stable over time. Subgroup
analyses were conducted, restricting the population on sex, age, selected diagnoses and concurrent medication.
Results A total of 10,875 patients filled in their first-ever prescription of both an SSRI and an RLS drug within a 1-year interval;
5341 patients filled their prescription of SSRI prior to their prescription of an RLS drug, and 5534 patients redeemed their
prescriptions in the opposite order (SR 0.97, 95%CI 0.93–1.00). Restricting the outcome to dopamine agonist initiation revealed
a slightly increased sequence ratio (SR 1.34, 95% CI 1.24–1.46), which was reduced when adjusting for trends in prescription
(adjusted SR 1.21, 95% CI 1.12–1.32). Restricting the outcome to quinine initiation showed no association.
Conclusion We found no association between the initiation of an SSRI and the development of RLS assessed by the prescription
of an RLS drug.