Antidepressants and REM sleep behavior disorder: isolated side effect or neurodegenerative signal?

Abstract

Objectives: Antidepressants, among the most commonly prescribed medications, trigger symptoms of REM sleep behavior disorder (RBD) in up to 6% of users. Idiopathic RBD is a very strong prodromal marker of Parkinson disease and other synuclein-mediated neurodegenerative syndromes. It is therefore critically important to understand whether antidepressant-associated RBD is an independent pharmacologic syndrome or a sign of possible prodromal neurodegeneration.

Design: Prospective cohort study.

Setting: Tertiary sleep disorders center.

Participants: 100 patients with idiopathic RBD, all with diagnosis confirmed on polysomnography, stratified to baseline antidepressant use, with 45 matched controls.

Measurements/results: Of 100 patients, 27 were taking antidepressants. Compared to matched controls, RBD patients taking antidepressants demonstrated significant abnormalities of 12/14 neurodegenerative markers tested, including olfaction (P = 0.007), color vision (P = 0.004), Unified Parkinson Disease Rating Scale II and III (P < 0.001 and 0.007), timed up-and-go (P = 0.003), alternate tap test (P = 0.002), Purdue Pegboard (P = 0.007), systolic blood pressure drop (P = 0.029), erectile dysfunction (P = 0.002), constipation (P = 0.003), depression indices (P < 0.001), and prevalence of mild cognitive impairment (13% vs. 60%, P < 0.001). All these abnormalities were indistinguishable in severity from RBD patients not taking antidepressants. However, on prospective follow-up, RBD patients taking antidepressants had a lower risk of developing neurodegenerative disease than those without antidepressant use (5-year risk = 22% vs. 59%, RR = 0.22, 95%CI = 0.06, 0.74).

Conclusions: Although patients with antidepressant-associated RBD have a lower risk of neurodegeneration than patients with "purely-idiopathic" RBD, markers of prodromal neurodegeneration are still clearly present. Development of RBD with antidepressants can be an early signal of an underlying neurodegenerative disease.

Keywords: Parkinson disease; REM sleep behavior disorder; antidepressants.

Figure 1

Selected prodromal markers of synuclein-mediated neurodegeneration in controls and in idiopathic RBD patients according to antidepressant use. Olfaction (A), color vision (B), orthostatic blood pressure drop (C), motor speed (alternate tap test) (D). For figure legibility, individual results have been rounded to the nearest integer. *Significant difference compared to controls (there were no significant differences between RBD patients taking vs. not taking antidepressants).

Figure 2

Kaplan-Meier life table analysis of disease-free survival in patients with idiopathic RBD according to history of antidepressant use. Cox proportional hazards P = 0.016 for antidepressant vs. no antidepressant.