Secondary Restless Legs Syndrome during Psychopharmacological Treatment: Real-World Evidence from a Multinational Pharmacovigilance Program

Secondary Restless Legs Syndrome (RLS) has repeatedly been associated with psychopharmacotherapy, especially antidepressants (ADs) and antipsychotics (APs). However, existing evidence is conflicting in terms of the magnitude of the association as well as the significance of substance classes or individual compounds. The objective of the present study was to evaluate secondary RLS linked to psychotropic medication in real-world, inpatient clinical routine treatment settings. For this purpose, a large dataset from a multinational pharmacovigilance program in German-speaking countries (AMSP) from January 2001 to December 2016 was retrospectively analyzed. In a total of 340 099 monitored inpatients, 67 cases of newly diagnosed and severe RLS related to psychotropic drug treatment were recorded equivalent to a relative frequency of 0.02%. Over 80% of the cases were attributable to two compounds: the AD mirtazapine and the AP quetiapine. Mirtazapine was found in 39 patients, while quetiapine was found in 16 patients with secondary RLS. For both substances drug dosages were generally low at onset of secondary RLS. Most cases exhibited an onset within 1 or 2 days after dosage start or change. Histamine neurotransmission may represent a crucial common denominator in terms of secondary RLS in association with psychopharmacotherapeutics, as both substances exhibit antihistamingeric effects at lower dosages.