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U C U U h l 8 M T T Z H G o U o l o 0% Z l 0 C C U C C C C C U C C C G C C C C o C C C C C C C C C > :# : Sertraline and rapid eye movement sleep without atonia: an 8-week, open-label study in depressed patients
Bin Zhang 1 *, MD, PhD; Yanli Hao 2 *, MD, PhD; Fujun Jia 1, MD, PhD; Yi Tang 1 ,, MD, PhD; Xueli Li 1, Mphil; Wuhan Liu 1, Mr; Isabelle Arnulf a *, MD, PhD 3
* These authors equally contributed to this work
1 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Mental Health Centre, Guangzhou 510120, China.
2 Department of Human Anatomy, Guang Zhou Medical University, Guangzhou 510182, China
3 Sleep Disorder Unit, Piti-Salptrire Hospital, Centre de Recherche de l'Institut du Cerveau et de la Molle pinire - Pierre and Marie Curie University; Inserm UMR_S 975; CNRS UMR 7225, Paris, France
Word Count: 4480 words (main body) with 2 figures and 4 tables
Article submitted to: Prog Neuropsychopharmacol Biol Psychiatry
Version: 1
Corresponding author: Bin Zhang, MD, PhD, Guang Dong General Hospital, Guang Dong Academy of Medical Science, Guang Dong Mental Health Center, No 123, Hui Fu Xi Road, 510120, Guang Zhou, China.
Tel: +86-20-81888553, Fax: +86-20-81862664, E-mail: HYPERLINK "mailto:zhang73bin@hotmail.com" zhang73bin@hotmail.com
Abstract
Previous studies have reported that selective serotonin reuptake inhibitors (SSRIs) may induce or exacerbate rapid eye movement (REM) sleep without atonia (RSWA) and increase the risk of developing REM sleep behavior disorder (RBD). However, most of them were retrospective and cross-sectional studies with small sample size on a mixture of SSRIswith small sample sizes and included data on a mixture of SSRIs. As different SSRIs have different pharmacological profiles, the specific effects of a singleof individual SSRIs on RSWA should be studied. In an 8-week, open-label trial of sertraline in depressed patients (n=31), depressed patients were administered 50 mg sertraline at 8 am on the 1st day, ; this dose and was subsequently titrated up to a maximum of 200 mg/day. All patients had underwent repeated video-polysomnography (vPSG) (baseline, 1st day, 14th day, 28th day, and 56th day). Both tonic (submental) and phasic (submental and anterior tibialis) RSWA were visually counted. The tTonic RSWA increased from 3.21.8% at baseline to 5.12.3% on the 1st day on sertraline and 10.42.7% on the 14th day; from then on,, with stable measures until were taken until the 56th day. A similar profile was observed for phasic RSWA, as well as and for the proportion of patients with abnormal phasic anterior tibialis. No RBD was observed. The increase of in tonic muscle tone during REM sleep over time correlated with reduced REM sleep Latency latency (r=0.56, p=0.004), PLMI (r =0.39, p=0.047), and improvement improved in depression (HRSD score, r =-0.43, p=0.03). The increases of in phasic submental RSWA (r =-0.51, p=0.02) and anterior tibialis (r=0.41, p=0.04) RSWA was were correlated with decreased REM sleep Llatency, and it were was not correlated with patient s demographics and or clinical characteristics. Sertraline could induced or exacerbated RSWA, but did not induce RBD. Compared with idiopathic RBD, the sertraline-related RSWA had some specific characteristics of being correlated with REM latency and no predominance of male sex and elder older age, so suggesting they that RSWA might have involve different mechanisms with than idiopathic RBD.
Key-wordsKey words: rapid eye movement (REM) sleep without atonia (RSWA); REM sleep behavior disorder (RBD); Sertraline; depressed patient
Clinical Trial Registry: An 8-week, open-label study to evaluate the effect of sertraline on the polysomnogramy of depressive depressed patients with insomnia, HYPERLINK "https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0002AZS&selectaction=View&uid=U0000LL9&ts=2&cx=-tnkowi" http://clinicaltrials.gov/ct2/show/NCT01032434 . Registry identifier: NCT01032434
Abbreviations: 5-HT: serotonin; AASM-2007: American Academy of Sleep Medicine 2007 version; AHI: apnea-hypopnea index; AI: arousal index; ANOVA: one-way analysis of variance; BMI: body mass index; CT: Computed computed tTomography; DA: dopaminergic; DSM-IV: diagnostic and statistical manual of mental disorders fourth edition; ECG: Electrocardiographelectrocardiograph; EMG: electromyogram; EOG: electrooculography; ESS: Epworth sleepiness scale; HRSD: Hamilton rating scale for depression; MSLT: multiple sleep latency test; OSA: obstructive sleep apnea; OCD: obsessive-compulsive disorder; PD: parkinsonsParkinsons disorder; PLMI: periodic limb movement index; PLMS: periodic limb movement during sleep; PSG: Polysomnogrampolysomnogramy; PSQI: Pittsburgh sleep quality index; REM: rapid eye movement; RSWA: REM sleep without atonia; RLS: restless legs syndrome; SCID-2: the second version of the Structured Clinical Interview for DSM-IV Axis I Disorders; SE: Sleep sleep Efficiencyefficiency; SL: Sleep sleep Latencylatency; SSRI: selective serotonin reuptake inhibitors; TESS-S: treatment emergent symptom scale-severity; TESS-T: treatment emergent symptom scale-treatment; TRT: total recording time; TST: total sleep time; vPSG: video-ploysomnographypolysomnography; WASO: wake after sleep onset.
1. INTRODUCTION
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of normal atonia during REM sleep and dream- enacting behavior ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_30" \o "Schenck, 2002 #108" Schenck and Mahowald, 2002, HYPERLINK \l "_ENREF_1" \o "AASM, 2005 #105" AASM, 2005). Idiopathic RBD is a male-predominant disorder that usually emerges after 50 years the of age of 50 years ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_30" \o "Schenck, 2002 #108" Schenck and Mahowald, 2002, HYPERLINK \l "_ENREF_1" \o "AASM, 2005 #105" AASM, 2005), and it is frequently described before the onset and during the course of synucleinopathies, that include ing Parkinsons disorder (PD), multiple system atrophy, and dementia with Lewy bodies ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_16" \o "Iranzo, 2009 #109" Iranzo et al., 2009). RBD is strongly associated with an abnormal increase of in phasic and tonic muscle tone during REM sleep, a condition named REM sleep without atonia (RSWA). However, it is not known whetherWhether RSWA is a sufficient and necessary condition for the emergence of RBD remains unknown, ; however, although some cases of RSWA have been documented with RSWA andto later become full-blown RBD ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_9" \o "Gagnon, 2006 #114" Gagnon et al., 2006, HYPERLINK \l "_ENREF_3" \o "Arnulf, 2012 #159" Arnulf, 2012, HYPERLINK \l "_ENREF_1" \o "AASM, 2005 #105" AASM, 2005). According to the international International classification Classification of sleep Sleep disorders Disorders, Ssecond edition Edition (ICSD-2), the criteria of for RBD include the appearance of elevated submental electromyogram (EMG) tone and/or excessive phasic submental or anterior tibialis EMG activity during REM, combined with sleep sleep-related injurious, potentially injurious, or abnormal REM sleep behaviors documented during polysomnographic (PSG) monitoring; . while Alternatively, the criteria of for subclinical RBD only include the REM sleep PSG abnormalities and but withoutdo not a include a clinical history of RBD ADDIN EN.CITE AASM2005105(AASM, 2005)1051056AASMInternational Classification of Sleep Disorders: Diagnostic and Coding Manual2nd2005Westchester, IllinoisAmerican Academy of Sleep Medicine( HYPERLINK \l "_ENREF_1" \o "AASM, 2005 #105" AASM, 2005). The abnormal amount of RSWA (as a percentage of REM sleep) has been determined by different methods, based on measures in normal subjects and in patients with idiopathic RBD. When using theUsing the American Academy of Sleep Medicine 2007 version (AASM-2007) criteria for measuring tonic and phasic muscle activity ADDIN EN.CITE Iber C200742(Iber C, 2007)42426Iber C, Ancoli-Israel S, Cheeson A, and Quan SF for the academy of Sleep MedicineThe AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications1st2007Westchester, IllinoisAmerican Academy of Sleep Medicine( HYPERLINK \l "_ENREF_14" \o "Iber C, 2007 #42" Iber C, 2007), 18% of REM sleep time with in which any 3-second lasting tonic or phasic muscle activity lasted 3 seconds on in an epoch was specific characterized of as RBD in a series of 15 patients with idiopathic RBD, 15 with RBD associated with Pparkinsons disease and 30 matched controls ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_8" \o "Frauscher, 2012 #165" Frauscher et al., 2012). Gagnon argued that a similar cutoff (greater than 20% )%) of the tonic submental muscle activity during REM sleep was a reasonable threshold for defining muscle activity as excessive or potentially pathological ADDIN EN.CITE Gagnon2006114(Gagnon et al., 2006)11411417Gagnon, J. F.Postuma, R. B.Montplaisir, J.Centre d'Etude du Sommeil et des Rythmes Biologiques, Hopital du Sacre-Coeur de Montreal, Institut Universitaire de Geriatrie de Montreal, Montreal, Quebec, Canada.Update on the pharmacology of REM sleep behavior disorderNeurologyNeurologyNeurologyNeurologyNeurologyNeurology742-76752006/09/13Anticonvulsants/adverse effects/*therapeutic useClonazepam/*therapeutic useHumansMonoamine Oxidase Inhibitors/administration & dosage/adverse effectsREM Sleep Behavior Disorder/diagnosis/*drug therapy/epidemiology/physiopathology2006Sep 121526-632X (Electronic)
0028-3878 (Linking)16966533Research Support, Non-U.S. Gov'thttp://www.ncbi.nlm.nih.gov/pubmed/1696653310.1212/01.wnl.0000233926.47469.73eng( HYPERLINK \l "_ENREF_9" \o "Gagnon, 2006 #114" Gagnon et al., 2006). In another study being consisted ofcomprising 80 patients with idiopathic RBD, tonic submental muscle activity greater than 30% of the total REM sleep time, and a phasic submental muscle activity greater than 15% were considered optimal cut-offs to for the diagnose diagnosis of idiopathic RBD from in normal controls ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_23" \o "Montplaisir, 2010 #156" Montplaisir et al., 2010).
In view of the clinical lore and a small number of published studies, antidepressants may induce or exacerbate RSWA and increase the risk of developing RBD or subclinical RBD ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_10" \o "Guilleminault, 1976 #131" Guilleminault et al., 1976, HYPERLINK \l "_ENREF_4" \o "Bental, 1979 #140" Bental et al., 1979, HYPERLINK \l "_ENREF_31" \o "Schenck, 1992 #130" Schenck et al., 1992, HYPERLINK \l "_ENREF_26" \o "Onofrj, 2003 #129" Onofrj et al., 2003, HYPERLINK \l "_ENREF_33" \o "Winkelman, 2004 #115" Winkelman and James, 2004, HYPERLINK \l "_ENREF_34" \o "Zhang, 2010 #47" Zhang et al., 2010, HYPERLINK \l "_ENREF_13" \o "Hoque, 2010 #134" Hoque and Chesson, 2010). A recent clinical epidemiological study on parasomnia in psychiatric out-patients find outrevealed that the lifetime and 1-year prevalences of RBD and/or subclinical RBD among psychiatric out-patients are 5.8% and 3.8% respectively%, respectively. It These prevalences are is ten times more commonhigher than the prevalencethe prevalence of RBD in the general population. Further, compared with RBD patients in the general population, these patients are were of younger in age, were predominantly female predominance, being were associated withmore likely to be using antidepressants usage, and no had less concurrent neurodegenerative diseases compared to the RBD patients in the general population ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_19" \o "Lam, 2008 #106" Lam et al., 2008). In recent decades, The sselective serotonin (5-HT) reuptake inhibitors (SSRIs) are have become the first-line antidepressants; in recent decades, and their potential effects on RSWA can beare suspected from based on basic knowledge on of muscle atonia during REM sleep. The normal loss of muscle tone during REM sleep results from two mechanisms, one passive and one active. Serotonergic neurons descending to the nuclei of the cranial nerves and to the lower motor neurons reduce their firing, leading to the disfacilitation ofing the neurons during non non-REM sleep, and the cease ceasing of firing during REM sleep ADDIN EN.CITE Siegel2006158(Siegel, 2006)15815817Siegel, J. M.The stuff dreams are made of: anatomical substrates of REM sleepNat NeurosciNature neuroscienceNat NeurosciNature neuroscienceNat NeurosciNature neuroscience721-2962006/05/30AnimalsBrain Stem/anatomy & histology/*physiologyHumansHypothalamus/anatomy & histology/physiologyModels, NeurologicalNeural Pathways/anatomy & histology/*physiologyNeurotransmitter Agents/physiologyReticular Formation/anatomy & histology/*physiologySleep Disorders/physiopathologySleep, REM/*physiologySynaptic Transmission/physiology2006Jun1097-6256 (Print)
1097-6256 (Linking)16732200Newshttp://www.ncbi.nlm.nih.gov/pubmed/1673220010.1038/nn0606-721eng( HYPERLINK \l "_ENREF_32" \o "Siegel, 2006 #158" Siegel, 2006). As a consequence, muscle tone is reduced from light to deep non-REM sleep, as well as and then during REM sleep, leading to hypotonia (postural muscle tone is reduced but still present). In addition to this passive mechanism, an active paralysis of postural muscle tone (termed atonia) (named atonia) occurs specifically during REM sleep, and uses a the cholinergic-glutaminergic-glycinergic pathway to eventually block the postsysnapticpostsynaptic lower motor neurons. In humans, drugs that stimulate the serotonin system (e.g., fluoxetine, paroxetine, and venlafaxine) and those that block acetylcholine transmission (tricyclics such as clomipramine) can induce RSWA and/or RBD, possibly because due to their they prevention of the normal sleep-related hypotonia (serotoninergic drugs) or the normal REM sleep-related atonia (anticholinergics) ADDIN EN.CITE Arnulf2012159(Arnulf, 2012)15915917Arnulf, I.Sleep disorders unit, Pitie-Salpetriere Hospital, Pierre and Marie Curie University, Inserm U975, CRICM, Paris, France. isabelle.arnulf@psl.aphp.frREM sleep behavior disorder: motor manifestations and pathophysiologyMov DisordMovement disorders : official journal of the Movement Disorder SocietyMov DisordMovement disorders : official journal of the Movement Disorder SocietyMov DisordMovement disorders : official journal of the Movement Disorder Society677-892762012/03/27Cognition Disorders/complications/*physiopathologyDementia/complications/*physiopathologyHumansParkinson Disease/complications/*physiopathologyREM Sleep Behavior Disorder/complications/*physiopathologySleep, REM/*physiology2012May1531-8257 (Electronic)
0885-3185 (Linking)22447623Reviewhttp://www.ncbi.nlm.nih.gov/pubmed/2244762310.1002/mds.24957eng( HYPERLINK \l "_ENREF_3" \o "Arnulf, 2012 #159" Arnulf, 2012). Previous studies suggested that compared with controls, SSRIs could intensify dreaming ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_27" \o "Pace-Schott, 2001 #144" Pace-Schott et al., 2001), and produce increasemore RSWA than did controls, and might possibly increase the risk of developing RBD ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_31" \o "Schenck, 1992 #130" Schenck et al., 1992, HYPERLINK \l "_ENREF_33" \o "Winkelman, 2004 #115" Winkelman and James, 2004, HYPERLINK \l "_ENREF_9" \o "Gagnon, 2006 #114" Gagnon et al., 2006, HYPERLINK \l "_ENREF_34" \o "Zhang, 2010 #47" Zhang et al., 2010, HYPERLINK \l "_ENREF_13" \o "Hoque, 2010 #134" Hoque and Chesson, 2010). However, most of these researches studies are were retrospective, and cross-sectional studies with small sample size on a mixture of SSRIswith small sample sizes that received a mixture of SSRIs. It is well known that not all SSRIs do not have the same pharmacological profiles, ; so thus, different SSRIs might have different ial tendencyies to induce RSWA. The specific effects of a singleindividual SSRIs on RSWA should be studied. The main purpose of this study is was to characterize the effect of sertraline on RSWA in depressed patients in an 8-week clinical trial with using repeated video-ploysomnographypolysomnography (vPSG) assessment.
2. METHODS
2.1. Patients and Study Design
The protocol of this study was approved by the Independent Ethics Committee (IEC) of Guangdong Provincial Mental Health Centre. Written informed consents were was signed obtained from each patient prior to participation.
All patients were enrolled from the inpatient population of Guangdong Provincial Mental Health Center. If a patient was diagnosed with a single or recurrent type of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) upon admission, the patients diagnosis of the patient would was be ascertained by one of the authors (BZ) using the second version of the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-2) ADDIN EN.CITE First MB199641(First MB, 1996)41416First MB, Spitzer RL, Williams JBW, Gibbon M, Williams JWBUser's Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders: SCID-II Clinician Version1996American Psychiatric Association( HYPERLINK \l "_ENREF_7" \o "First MB, 1996 #41" First MB, 1996). None of the patients included in the study fulfilled any other current or lifetime diagnostic criteria of for DSM-IV Axis I disorders. Patients were male and female, aged 18 to 65 years, with h a d a H a m i l t o n R a t i n g S c a l e f o r D e p r e s s i o n ( H R S D ) s c o r e s e" 1 8 a n d a s l e e p d i s t u r b a n c e f a c t o r s c o r e s i n H R S D e" 3 i n t h e H R S D H Y P E R L I N K \ l " _ E N R E F _ 2 1 " \ o " H a m i l t o n , 1 9 6 0 # 1 7 " A D D I N E N . C I T E <