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

Ronald B Postuma, Jean-Francois Gagnon, Maria Tuineaig, Josie-Anne Bertrand, Veronique Latreille, Catherine Desjardins, Jacques Y Montplaisir, Ronald B Postuma, Jean-Francois Gagnon, Maria Tuineaig, Josie-Anne Bertrand, Veronique Latreille, Catherine Desjardins, Jacques Y Montplaisir

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.

Figures

Figure 1
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
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.

References

    1. Schenck CH, Mahowald MW. REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in sleep. Sleep. 2002;25:120–38.
    1. Ohayon MM, Caulet M, Priest RG. Violent behavior during sleep. J Clin Psychiatry. 1997;58:369–76.
    1. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology. 1996;46:388–93.
    1. Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol. 2006;5:572–7.
    1. Postuma RB, Gagnon JF, Vendette M, Fantini ML, Massicotte-Marquez J, Montplaisir J. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology. 2009;72:1296–300.
    1. Schenck CH, Boeve B, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in 81% of older males initially diagnosed with idiopathic REM sleep behavior disorder (RBD): 16 year update on a previously reported series. Sleep Med. 2013;14:744–8.
    1. Postuma RB, Gagnon JF, Montplaisir J. Clinical prediction of Parkinson's disease - planning for the age of neuroprotection. J Neurol Neurosurg Psychiatry. 2010;81:1008–13.
    1. Teman PT, Tippmann-Peikert M, Silber MH, Slocumb NL, Auger RR. Idiopathic rapid-eye-movement sleep disorder: associations with antidepressants, psychiatric diagnoses, and other factors, in relation to age of onset. Sleep Med. 2009;10:60–5.
    1. Lam SP, Fong SY, Ho CK, Yu MW, Wing YK. Parasomnia among psychiatric outpatients: a clinical, epidemiologic, cross-sectional study. J Clin Psychiatry. 2008;69:1374–82.
    1. Ju YE, Larson-Prior L, Duntley S. Changing demographics in REM sleep behavior disorder: possible effect of autoimmunity and antidepressants. Sleep Med. 2011;12:278–83.
    1. Winkelman JW, James L. Serotonergic antidepressants are associated with REM sleep without atonia. Sleep. 2004;27:317–21.
    1. Gagnon JF, Postuma RB, Montplaisir J. Update on the pharmacology of REM sleep behavior disorder. Neurology. 2006;67:742–7.
    1. Schenck CH, Mahowald MW, Kim SW, O'Connor KA, Hurwitz TD. Prominent eye movements during NREM sleep and REM sleep behavior disorder associated with fluoxetine treatment of depression and obsessive-compulsive disorder. Sleep. 1992;15:226–35.
    1. Lam SP, Zhang J, Tsoh J, et al. REM sleep behavior disorder in psychiatric populations. J Clin Psychiatry. 2010;71:1101–3.
    1. Frauscher B, Gschliesser V, Brandauer E, et al. REM sleep behavior disorder in 703 sleep-disorder patients: the importance of eliciting a comprehensive sleep history. Sleep Med. 2010;11:167–71.
    1. Lam SP, Li SX, Chan JW, et al. Does REM sleep behavior disorder exist in psychiatric populations? A clinical and polysomnographic case-control study. Sleep Med. 2013;14:788–94.
    1. Schenck CH, Hurwitz TD, Mahowald MW. REM sleep behavior disorder. Am J Psychiatry. 1988;145:652.
    1. Alonso A, Rodriguez LA, Logroscino G, Hernan MA. Use of antidepressants and the risk of Parkinson's disease: a prospective study. J Neurol Neurosurg Psychiatry. 2009;80:671–4.
    1. Weisskopf MG, Chen H, Schwarzschild MA, Kawachi I, Ascherio A. Prospective study of phobic anxiety and risk of Parkinson's disease. Mov Disord. 2003;18:646–51.
    1. Byers AL, Yaffe K. Depression and risk of developing dementia. Nat Rev Neurol. 2011;7:323–31.
    1. Postuma RB, Lang AE, Massicotte-Marquez J, Montplaisir J. Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder. Neurology. 2006;66:845–51.
    1. Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir J. Olfaction and color vision identify impending neurodegeneration in REM behavior disorder. Ann Neurol. 2011;69:811–8.
    1. Postuma RB, Lang AE, Gagnon JF, Pelletier A, Montplaisir JY. How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain. 2012;135:1860–70.
    1. American Academy of Sleep Medicine. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2007. The international classification of sleep disorders: diagnostic and coding manual.
    1. Montplaisir J, Gagnon JF, Fantini ML, et al. Polysomnographic diagnosis of idiopathic REM sleep behavior disorder. Mov Disord. 2010;25:2044–51.
    1. Postuma RB, Gagnon JF, Vendette M, Montplaisir J. Markers of neurodegeneration in idiopathic REM sleep behavior disorder and Parkinson disease. Brain. 2009;132:2298–307.
    1. Gagnon JF, Vendette M, Postuma RB, et al. Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson's disease. Ann Neurol. 2009;66:39–47.
    1. Fahn S, Elton R, members of the UDC . The Unified Parkinson's Disease Rating Scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, editors. Recent developments in Parkinson's disease. Florham Park, NJ: MacMillan HealthCare Information; 1987. pp. 153–63.
    1. Nutt JG, Lea ES, Van HL, Schuff RA, Sexton GJ. Determinants of tapping speed in normal control subjects and subjects with Parkinson's disease: differing effects of brief and continued practice. Mov Disord. 2000;15:843–9.
    1. Desrosiers J, Hebert R, Bravo G, Dutil E. The Purdue Pegboard Test: normative data for people aged 60 and over. Disabil Rehabil. 1995;17:217–24.
    1. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39:142–8.
    1. Doty RL, Marcus A, Lee WW. Development of the 12-item Cross-Cultural Smell Identification Test (CC-SIT) Laryngoscope. 1996;106:353–6.
    1. Farnsworth D. The Farnsworth 100-hue test and dichotomous tests for color vision. J Optom Soc Am. 1943;33:568–78.
    1. Kinnear PR, Sahraie A. New Farnsworth-Munsell 100 hue test norms of normal observers for each year of age 5-22 and for age decades 30-70. Br J Ophthalmol. 2002;86:1408–11.
    1. Tison F, Seppi K, Sampaio C, et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS) Mov Disord. 2004;19:1391–402.
    1. Massicotte-Marquez J, Decary A, Postuma RB, et al. Executive dysfunction and memory impairment in idiopathic REM sleep behavior disorder. Neurology. 2008;70:1250–7.
    1. Postuma RB, Lang AE, Gagnon JF, Pelletier A, Montplaisir JY. How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain. 2012;135:1860–70.
    1. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007;22:2314–24.
    1. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65:1863–72.
    1. Postuma RB, Aarsland D, Barone P, et al. Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease. Mov Disord. 2012;27:617–26.
    1. Ross W, Petrovitch H, abbott RD, et al. Association of olfactory dysfunction with risk of future Parkinson's disease. Mov Disord. 2005;20(Supplement 10):S129–S30.
    1. Berendse HW, Booij J, Francot CM, et al. Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell. Ann Neurol. 2001;50:34–41.
    1. Siderowf A, Jennings D, Connolly J, Doty RL, Marek K, Stern MB. Risk factors for Parkinson's disease and impaired olfaction in relatives of patients with Parkinson's disease. Mov Disord. 2007;22:2249–55.
    1. Bertrand JA, Bedetti C, Postuma RB, et al. Color discrimination deficits in Parkinson's disease are related to cognitive impairment and white-matter alterations. Mov Disord. 2012;27:1781–8.
    1. Savica R, Carlin JM, Grossardt BR, et al. Medical records documentation of constipation preceding Parkinson disease: A case-control study. Neurology. 2009;73:1752–8.
    1. Abbott RD, Ross GW, Petrovitch H, et al. Bowel movement frequency in late-life and incidental Lewy bodies. Mov Disord. 2007;22:1581–6.
    1. Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel movements and the future risk of Parkinson's disease. Neurology. 2001;57:456–62.
    1. Postuma RB, Gagnon JF, Vendette M, Montplaisir JY. Idiopathic REM sleep behavior disorder in the transition to degenerative disease. Mov Disord. 2009;24:2225–32.
    1. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson's disease. N Engl J Med. 2004;351:2498–508.
    1. Lam SP, Li SX, Mok V, Wing YK. Young-onset REM sleep behavior disorder: Beyond the antidepressant effect. Sleep Med. 2012;13:211.
    1. Wing YK, Li SX, Mok V, et al. Prospective outcome of rapid eye movement sleep behaviour disorder: psychiatric disorders as a potential early marker of Parkinson's disease. J Neurol Neurosurg Psychiatry. 2012;83:470–2.
    1. Boot BP, Boeve BF, Roberts RO, et al. Probable rapid eye movement sleep behavior disorder increases risk for mild cognitive impairment and Parkinson disease: a population-based study. Ann Neurol. 2012;71:49–56.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere