Impact of Escitalopram on Nocturnal Sleep, Day

Original Paper

Impact of Escitalopram on Nocturnal Sleep, DayTime Sleepiness and Performance Compared to Amitriptyline: A Randomized, Double-Blind, PlaceboControlled Study in Healthy Male Subjects Authors

J. P. Doerr1, K. Spiegelhalder1, F. Petzold1, B. Feige1, V. Hirscher1, R. Kaufmann1, D. Riemann1, U. Voderholzer1,2

Affiliations

1 2

Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg, Germany Medical-Psychosomatic Clinic Roseneck, Prien, Germany

Abstract ▼ Introduction: Antidepressant drugs vary in their effects on sleep, day-time sedation and performance. Up to now, no data are available for either escitalopram (ESCIT) or amitriptyline (AMI), measuring these by an objective test, such as the multiple sleep latency test (MSLT). Subjects and Methods: We therefore investigated the impact of a single evening dose of 10 mg ESCIT on polysomnographically recorded nocturnal sleep, day-time sleepiness and performance in comparison to 75 mg AMI and placebo (PLAC) in healthy male subjects. Results: Both antidepressants significantly suppressed REM sleep (p < 0.001). Although polysomnographically measured sleep continu-

received revised accepted

26.08.2009 02.12.2009 17.12.2009

Bibliography DOI http://dx.doi.org/ 10.1055/s-0030-1249049 Published online ahead of print Pharmacopsychiatry © Georg Thieme Verlag KG Stuttgart · New York ISSN 0176-3679 Correspondence J. P. Doerr, MD Department of Psychiatry and Psychotherapy University Medical Center Freiburg Hauptstraße 5 79104 Freiburg Germany Tel.: + 49/761/270 6625 Fax: + 49/761/270 6528 john-peter.doerr@ uniklinik-freiburg.de

Introduction ▼ Escitalopram (ESCIT), the S-enantiomer of citalopram, is a highly selective serotonin reuptake inhibitor (SSRI). It has been shown to be an effective and well-tolerated treatment for depression and anxiety disorders in different placebo-controlled trials [6, 7, 29, 50]. In general, non-sedative antidepressants such as the SSRIs show inconsistent results concerning their effects on sleep quality. Insomnia has increasingly been reported as a side effect of SSRIs, e. g., paroxetine 14 %, sertraline 16.4 %, fluvoxamine 4.5 %, fluoxetine 15 % [15]. In contrast, Kiev and Feiger [23] reported sedative effects in up to 40 % of depressed patients after fluvoxamine and paroxetine intake. At least in the early stage of treatment, SSRIs lead to a prolongation of REM sleep latency, and to an increase in wake time and stage 1 sleep. The percentage of REM sleep, as well as the total sleep time (TST), is decreased [33]. However, not all studies showed these disturbances. After citalopram these were

Doerr JP et al. Impact of Escitalopram on Nocturnal Sleep … Pharmacopsychiatry

ity was impaired after ESCIT (p = 0.006), subjective estimates of sleep parameters did not differ. Periodic limb movements (PLMS) were increased after AMI (p < 0.001) but not after ESCIT. Processing speed and performance were enhanced after ESCIT compared with AMI (p = 0.011), but not with PLAC. Next-day alertness was significantly impaired by AMI (p = 0.012), but not by ESCIT. Mean day-time sleep onset latencies increased significantly after evening ESCIT (p < 0.001). In contrast, AMI led to a pronounced increase of day-time sleepiness (p = 0.007). Discussion: This study demonstrates that single evening doses of either AMI or ESCIT exhibit different effects on next-day vigilance and alertness in terms of a slightly stimulating effect of ESCIT and a significant reduction after AMI.

not affected during a five-week treatment study in depressed patients (medication intake at 6 p.m.). Additionally, there was no increase in nocturnal sleep latency comparable with paroxetine and fluvoxamine. Like most antidepressants, citalopram leads to a prolonged REM sleep latency [48]. Regarding the effect of ESCIT on sleep, a post-hoc analysis suggested that in patients suffering from major depressive disorder, it might have a significant beneficial effect compared with citalopram in reducing sleep disturbances [27]. Most sedating tricyclic antidepressants (TCA) such as amitriptyline (AMI) improve sleep initiation and maintenance and suppress REM sleep as well. Regarding REM sleep trimipramine is an exception [39]. TCAs often induce sleepiness or drowsiness during daytime [10, 18, 43, 46], and impair attentional ability and psychomotor performance [22]. Regarding daytime vigilance, decrements have been discussed for the SSRIs fluoxetine and paroxetine [35, 38]. However, sertraline and

Original Paper

citalopram have been reported to induce dose-dependent increases in cerebral arousal and psychomotor functioning and perceptual coding skills [26, 32]. Herberg [17] found that citalopram (20 and 40 mg daily) did not impair psychomotor performance in healthy subjects. Wingen et al. [53] demonstrated for ESCIT that driving performance and psychomotor functioning is unaffected after administration to healthy male subjects. Wilson et al. [51] found that 100 mg dothiepin induced significantly shorter day-time sleep latencies in healthy subjects than fluoxetine. A limitation of this study was that nocturnal sleep duration before day-time napping was different. Finally, to evaluate the impact of the SSRIs ESCIT and the TCA AMI on nocturnal sleep and especially day-time sleepiness a reliable objective test like the multiple sleep latency test (MSLT) is needed and nocturnal sleep duration should be the same. Regarding the influence of antidepressants on periodic limb movements during sleep (PLMS) and on − the sometimes associated − restless legs syndrome (RLS), previous studies have suggested that selective serotonergic or dual acting antidepressants, such as fluoxetine and venlafaxine, might induce PLMS [1, 9, 45]. PLMS can result in electroencephalographic (EEG) arousals or awakenings, which might contribute to difficulties in initiating and maintaining sleep, or in excessive day-time sleepiness (periodic limb movement disorder, PLMD). Other authors contend that the reason for the differential response to various antidepressants is unknown and might be mediated by individual characteristics [21]. However, recently it has been reported that SSRIs − including ESCIT − induced RLS symptoms in about 5–10 % of treated patients [42]. In fact, there is no placebo-controlled comparative data (SSRI vs. TCAs) on PLMS in depressive patients or in healthy subjects. Therefore the aim of this study was to determine the acute effects of ESCIT compared to placebo (PLAC) and amitriptyline (AMI) on subjective and objective sleep parameters, the PLMS, day-time sleepiness and performance (attention, concentration, working memory) measured by polysomnography, MSLT and a standardized test battery.

Subjects and Methods ▼ Subjects Fourteen healthy, male volunteers [age range: 20–32 years; mean (SD): 24. 6 ( ± 2.4 years)] were recruited by personal contact and included after the screening visit. Subjects showed normal findings in a general and neurological examination. A semi-structured interview performed by an experienced psychiatrist showed neither psychopathological symptoms nor a positive personal history for psychiatric disorders or substance abuse. Laboratory parameters for hematology, biochemistry and thyroid parameters as well as electrocardiography and EEG were within normal values. Urine drug and substance abuse tests were negative. All were non-smokers and were paid for their participation. Approval from the local ethics committee was obtained and subjects provided their written informed consent prior to screening. For all tasks a verbal explanation was given to ensure subjects’ understanding of test procedures, and subjects were excluded if they were unable to adequately understand or perform the relevant tasks. Exclusion criteria were: any clinically relevant medical or neurological disorder, shift working or unstable sleep habits – controlled by keeping a sleep diary during the study –, participation in any other clinical trial within

the last month, intake of any medication within 2 weeks before the start of the study and throughout the whole study. Additionally, to rule out any psychiatric or sleep disorders, different questionnaires had to be filled out at the screening visit [Beck depression inventory mean (SD): 1.00 ( ± 1.61); Pittsburgh sleep quality index mean (SD): 2.36 ( ± 1.3), Epworth sleepiness scale mean (SD): 2.82 ( ± 1.47)]. Subjects with sleep abnormalities – recorded at first adaptation nights − such as sleep apneas (apnea index > 5/h) or more than 5 periodic limb movements during sleep (PLMS) per hour with arousal were excluded. One subject was excluded after the first polysomnographic recordings because of an atrio-ventricular block, another subject because of technical problems and one subject because of protocol violation (shift working), which he recounted at his final visit.

Study design This was a double-blind, placebo-controlled, randomized, crossover study in which each subject received both drug treatments and placebo. All treatments were provided as matching white capsules by the pharmacy of the Johannes Gutenberg-University of Mainz. The subjects underwent 3 periods of 2 consecutive nights of polysomnography in the sleep laboratory separated by at least 7 days. After an adaptation night, either 10 mg ESCIT, 75 mg AMI or placebo (PLAC) were administered at 9 p.m. before the second night. After a fixed bedtime from 11 p.m. to 7 a.m., subjective sleep/sleepiness parameters and standardized neuropsychological test battery (d2 test, TAP, digit span) (see below) had to be completed by 8.30 a.m. Afterwards the MSLT was conducted. The MSLT is a measure of manifest sleep tendency at regular intervals consisting of 5 polygraphic recording sessions (e. g., at 09.30, 11.30, 13.30, 15.30, 17.30). The time taken to fall asleep (sleep latency) and sleep stages attained are recorded by polysomnography. Two or more episodes of REM sleep within 15 min of sleep onset (SOREMPs) are supportive of a diagnosis of narcolepsy. Also sleep latencies shorter than 8 min are needed to diagnose an idiopathic hypersomnia [25]. At the end of the study (7–14 days after finishing the third period), subjects underwent the laboratory tests again as well as a final physical assessment in order to ensure mental and physical health.

EEG recordings and analysis All sleep recordings were scored according to Rechtschaffen and Kales criteria by an experienced rater who was unaware of the experimental conditions of the recordings [37]. Recordings were analyzed by epoch (30 s length). An all-night spectral analysis was performed on the same 30 s epochs. Heart rate was obtained by ECG and pulse oximetry. Heart rates were averaged over each 5 s of an epoch, and mean values were calculated by a computerized algorithm. Polysomnography encompassed EEG (C3-A2, C4A1), horizontal and vertical eye movements, submental EMG as well as EMG of musculus anterior tibialis, and respiration recording (oral/nasal air flow and thoracic/abdominal respiratory effort and oxygen saturation). The following sleep parameters were determined: total sleep time (min), sleep efficiency (total sleep time: time in bed × 100 %), latency to stage 2 (sleep latency in min, i. e., time from lights out until the first occurrence of stage 2) and latency to stage REM (min, i. e., time from the first occurrence of stage 2 until the first occurrence of REM sleep), number of wake periods; wake, stage 1, stage 2, SWS (represents stages 3 and 4), REM expressed as %SPT (sleep period time = time between sleep onset and final Doerr JP et al. Impact of Escitalopram on Nocturnal Sleep … Pharmacopsychiatry

Original Paper

awakening) and REM density, as the percentage of 3 s miniepochs of REM sleep containing rapid eye movements from all 3 s mini-epochs of REM sleep. PLMS were scored according to the Atlas and scoring rules 1993 [2], and were scored only if they were part of a series of 4 or more consecutive movements lasting at least 0.5 s. PLMS indices were calculated as (1) the PLMS index indicating the number of PLMS per hour of total sleep time and (2) the PLMS arousal index (PLMS-A index) indicating only PLMS associated with arousal per hour of total sleep time. Afterwards, spectral power was calculated using the fast Fourier transform (FFT) algorithm from twenty-two 512-point windows overlapping by half, resulting in a spectral resolution of 0.39 Hz. Separately within each FFT window, the EEG was demeaned and detrended by subtracting the linear least-squares regression line before applying a Welch window and calculating the FFT. The 22 spectral power estimates were averaged. Logarithmic spectral band power was calculated after adding the spectral power values within the following frequency bands: delta 0.1–3.5 Hz, theta 3.5–8 Hz, alpha 8–12 Hz, sigma 12–16 Hz, beta1 16–24 Hz, beta2 24–32 Hz, and gamma 32–48 Hz. Epochs deviating from the surrounding 10 min in either gamma or total band power were excluded as described by Feige et al. [11].

Subjective sleep parameters and test battery To determine subjective sleep quality of the previous night a visual bipolar analogue scale (VAS; 0–100 mm) ranging from the feeling of fully refreshed to totally tired and the SF-A [14] were used every morning. For the SF-A the subscales ’sleep quality,’ ’feeling refreshed in the morning’, ’well-being in the evening’, ’exhaustedness in the evening before going to bed’, and ’psychosomatic symptoms during sleep’ were analyzed. These scales range from 1 to 5, with 1 denoting impaired quality etc., whereas a score of 5 represents positive estimates (the scale ’psychosomatic symptoms’ has inverse scaling). Adverse reactions and side effects were assessed according to the FSUCL scale (Fischer’s somatic symptom and undesired effect checklist [12]. The FSUCL scale comprises a total of 26 items for the assessment of CNS (psychological and neurological), autonomic, gastrointestinal and cardiovascular symptoms. The severity of each of these symptoms was rated on a 4-point scale (absent to very severe). The standardized test battery included a computerized test for attentional performance (TAP) to assess alertness [55], the d2 test as a measure of attentional processes and the digit span test for verbal short term and working memory. For TAP, subjects were instructed to press a button after a task presentation with a preceding acoustic stimulus (80 times). Reaction times were recorded and the mean value was calculated. The “d2 concentration test’’ provides information about the ability to discriminate between similar stimuli, measured by speed and accuracy of performance. It consists of 14 lines of 47 randomly mixed letters (either d or p). Subjects were instructed to mark, within 20 s for each line, only the letter d with two additional strokes (d”) [5]. A value for sustained attention speed and concentration was calculated, and the difference between medication nights was used for analysis. During the digit span test (forward and backward) a sequence of digits is read aloud by the examiner at a rate of 1/s [24]. The subject is required to repeat the entire sequence forward or backward, which is related to short-term memory and working memory, respectively. After two sequences of the same length, the number of digits is increased by one. In the forward Doerr JP et al. Impact of Escitalopram on Nocturnal Sleep … Pharmacopsychiatry

test, the number of digits is between three and eight and in the backward test between two and seven. The subject’s score is the total number of correctly repeated forward and backward sequences; the highest possible score is 24.

Statistical analysis Descriptive statistics include presentation of mean and standard deviation. To evaluate statistical differences, analysis of variance (ANOVA) for repeated measurements was performed, comparing sleep variables for placebo, AMI and ESCIT in each drug condition with Bonferroni alpha adjustment. Significance of p-values was accordingly adjusted for multiple endpoints for the subjective (p < 0.01) and objective night-time sleep variables (p < 0.00417), the periodic limb movements during sleep (p < 0.025), heart rate (p < 0.01) and the day-time sleep variables measured by MSLT (p < 0.005) as well as the performance tasks (p < 0.0166). In addition, to evaluate significant group differences t-tests for dependent variables were performed pairwise between the three conditions. Analyses for dependent samples were performed with a level of significance of p < 0.05.

Results ▼ Polysomnographic nocturnal sleep variables ▶ Table 1 the alpha-adjusted p-values (p < 0.00417) As shown in ● of ANOVA indicated significant effects for TST, sleep efficiency, WASO, stage Wake, NREM stage 2 as well as sleep stage REM and REM sleep latencies. No significant effects were demonstrated for sleep onset latency, the number of wake periods, NREM stage 1 and slow wave sleep as well as REM density. Whereas AMI had no impact on total sleep time and sleep efficiency compared to placebo, ESCIT significantly decreased both. AMI tended to increase TST and sleep efficiency, although not reaching the level of significance. Sleep latency was not significantly affected for AMI or for ESCIT. Compared to PLAC, AMI significantly decreased WASO, but not the number of wake periods. ESCIT also did not influence the number of wake periods, but significantly increased WASO and stage wake. Compared with ESCIT, TST and sleep efficiency were significantly higher and sleep onset latency was remarkably lower following AMI. AMI led to significantly lower percentages of stage Wake and WASO as well as higher NREM sleep parameters. The level of statistical significance was reached for stage 2. Regarding REM sleep, there were highly significant drug effects on the percentage of REM sleep and REM latency, but not on REM density. The percentage of REM sleep decreased significantly for both antidepressants compared to PLAC. REM latency was significantly prolonged after intake of ESCIT as well as AMI. Regarding the heart rate (HR), alpha-adjusted p-values (p < 0.01) showed significant effects during sleep stage 1 and SWS. While ESCIT had no impact on HR compared to PLAC, AMI, on the other hand, significantly increased HR during all NREM sleep stages, except of stage 2. HR was higher after the intake of AMI compared to ESCIT and significantly so during NREM sleep stage 1 and SWS. ANOVA (p < 0.01) for periodic limb movements during sleep (PLMS) showed a statistical significance concerning PLMS with and without arousal. AMI significantly increased the PLMS index with and without arousal compared to PLAC and ESCIT. The PLMSIndex of nearly all subjects was influenced by AMI, as shown ▶ Fig. 1. PLMS indices were unaffected after intake of ESCIT. in ●

Original Paper

Table 1 Objective and subjective sleep variables measured using conventional polysomnography. Placebo

2 Escitalopram

3 Amitripyline

mean ± SD

mean ± SD

mean ± SD

TST sleep efficiency % sleep latency min no. wake periods WASO stage wake % SPT stage 1 % SPT stage 2 %SPT stage SWS % SPT stage REM % SPT REM latency min REM density %

426.68 ± 34.21 88.30 ± 6.81 22.36 ± 21.54 25.36 ± 8.12 31.23 ± 13.58 6.93 ± 3.35 8.48 ± 2.62 53.18 ± 4.09 9.76 ± 5.27 21.40 ± 3.41 76.32 ± 28.10 26.34 ± 8.23

381.59 ± 39.63 79.25 ± 7.90 21.77 ± 11.73 31.27 ± 6.81 73.36 ± 39.26 16.11 ± 8.45 9.65 ± 3.31 50.58 ± 9.46 12.28 ± 6.48 11.02 ± 3.64 188.73 ± 104.90 21.57 ± 7.95

PLMS Index PLMS Index_Ar./h

3.28 ± 6.04 0.24 ± 0.50

3.19 ± 6.13 0.70 ± 1.55

HR wake % HR stage 1 % HR stage 2 % HR stage SWS % HR stage REM %

57.04 ± 8.48 51.51 ± 8.00 49.79 ± 7.89 50.47 ± 7.89 52.7 ± 8.23

54.97 ± 8.38 50.6 ± 6.75 49.69 ± 6.77 50.80 ± 7.40 52.08 ± 7.84

SFA – sleep quality SFA – feeling refreshed (morning) SFA – well-being (evening) SFA – exhaustedness (evening) SFA – psychosomatic symptoms VAS FSUCL

3.57 ± 0.64 3.62 ± 0.54 4.02 ± 0.41 2.51 ± 0.46 1.64 ± 0.56 39.00 ± 18.58 0.46 ± 0.52

3.21 ± 0.70 3.38 ± 0.68 3.96 ± 0.50 2.47 ± 0.49 1.73 ± 0.48 41.91 ± 21.77 0.46 ± 0.52

P (ANOVA)

2 vs. 1

Objective Sleep Variables 440.73 ± 19.60 < 0.001* 0.012* 92.11 ± 3.97 < 0.001* 0.013* 9.32 ± 5.87 0.064 0.929 23.64 ± 13.88 0.173 0.117 26.32 ± 18.82 < 0.001* 0.006* 5.63 ± 4.01 < 0.001* 0.006* 6.32 ± 3.46 0.005 0.205 64.27 ± 6.91 < 0.001* 0.364 14.28 ± 7.13 0.044 0.208 8.56 ± 4.66 < 0.001* < 0.001* 283.27 ± 106.46 < 0.001* 0.012* 26.14 ± 9.94 0.012 < 0.001 Periodic Limb Movements (PLMS) 16.29 ± 13.86 < 0.001* 0.974 3.56 ± 4.47 0.005* 0.368 Heart Rate (HR) 57.62 ± 7.01 0.045 0.026 54.81 ± 5.40 0.003* 0.430 52.68 ± 6.33 0.012 0.918 54.27 ± 6.97 0.003* 0.748 55.08 ± 6.91 0.056 0.632 Subjective Sleep Variables (SF-A) 3.93 ± 0.72 0.071 0.151 3.34 ± 0.64 0.369 0.300 4.11 ± 0.38 0.469 0.695 < 0.001* 0.850 3.24 ± 0.62 1.40 ± 0.46 0.097 0.572 42.18 ± 23.53 0.865 0.635 1.09 ± 0.70 0.022 1.00

3 vs. 1

2 vs. 3

0.232 0.111 0.076 0.638 0.045* 0.359 0.009 < 0.001* 0.007 < 0.001* < 0.001* 0.916

0.001* 0.001* 0.013 0.163 0.008* 0.006* 0.014 0.002* 0.280 0.147 0.095 0.034

0.001* 0.029*

0.004* 0.013*

0.609 0.025* 0.024 0.008* 0.108

0.046 0.002* 0.016 0.009* 0.009

0.230 0.195 0.360 0.002* 0.146 0.847 0.026

0.070 0.873 0.245 < 0.001* 0.036 0.969 0.041

TST = total sleep time; WASO = wake time after sleep onset; SFA = sleep questionnaire; SWS = slow-wave sleep; REM = rapid eye movement; HR = heart rate; PLMS = periodic limb movements during sleep Data are presented as mean ± SD. Significant p-values (subjective and objective night-time sleep variables (p < 0.01; p < 0.00417), PLMS (p < 0.025) and HR (p < 0.01) as well as significant group differences (p < 0.05) are marked with *

Fig. 1 Periodic limb movements during sleep (PLMS) Index and PLMS-arousal Index. The mean values for each medication are marked with a line.

40

30

20

10

0 PLAC

ESCIT PLMS-Index

AMI

PLAC

ESCIT

AMI

PLMS-Arousal-Index


Original Paper

Table 2 MSLT - sleep onset latencies and mean day-time wake efficiency measured by MSLT (multiple sleep latency test). MLST

1 Placebo

2 Escitalopram

3 Amitriptyline

mean ± SD

mean ± SD

mean ± SD

14.74 ± 3.85 15.05 ± 6.55 15.78 ± 5.16 13.27 ± 5.69 14.55 ± 5.72 15.05 ± 6.09

8.16 ± 4.49 4.73 ± 5.78 6.82 ± 6.4 6.95 ± 5.91 7.73 ± 5.24 14.55 ± 6.93

80.53 ± 15.98

48.65 ± 22.07

Daytime Sleep Onset Latency (min.) mean ± SD 12.42 ± 2.89 9.30 a.m. 7.36 ± 5.54 11.30 a.m. 12.78 ± 6.85 1.30 p.m. 11.09 ± 5.43 3.30 p.m. 12.73 ± 6.23 5.30 p.m. 18.14 ± 4.16 Wake Efficiency ( %) mean ± SD 71.55 ± 13.33

P (ANOVA)

2 vs. 1

3 vs. 1

2 vs. 3

(t-test)

(t-test)

(t-test)

< 0.001* < 0.001* 0.005* 0.021 0.005* 0.251

0.028* < 0.001* 0.309 0.375 0.409 0.174

0.007* 0.283 0.051 0.050 0.002* 0.125

< 0.001* < 0.001* < 0.001* 0.011 0.012* 0.845

< 0.001*

0.048*

0.002*

< 0.001*

Data are presented as mean ± SD Significant p-values and significant group differences (p < 0.05) are marked with*

Sleep Latency (SL) in min

20

cantly, especially compared to ESCIT. ESCIT instead led to a sig▶ Fig. 2 shows nificant decrease of sleepiness compared to PLAC. ● the changes of day-time sleep onset latency during the day. Until 5.30 p.m. AMI induced comparable changes with patients suffering from idiopathic hypersomnia as mean sleep latency and sleep efficiency was reduced to about 8 min and less than 50 %, respectively. A statistical significance vs. PLAC was reached at 3.30 p.m. Except for the time point 5.30 p.m. ESCIT always caused a higher day-time vigilance compared to PLAC, with a statistical significance at 9.30 a.m. Drug-drug comparison reached significance level at 9.30 and 11.30 a.m. by reducing AMI’s and slightly increasing ESCIT’s sleep latency and wake efficiency.

Escitalopram Amitriptyline Placebo

15

10

5

Daytime performance 0 9:30

11:30

13:30

15:30

17:30

Measurement Time Fig. 2 Day-time sleep latencies measured by MSLT (multiple sleep latency test) at five measurement time points (9.30 a.m.; 11.30 a.m.; 01.30 p.m.; 3.30 p.m., 5.30 p.m.).

Because a standard EEG is insufficient to exactly describe the changes in the EEG frequency bands, spectral analysis was performed and spectral power was calculated. This revealed that theta, alpha, sigma, beta and gamma frequencies were unaffected after the intake of ESCIT as well as AMI.

Subjective sleep variables ▶ Table 1 the intake of ESCIT did not impair As also shown in ● subjective sleep quality, the feeling of being refreshed in the morning, nor subjects’ well-being in the evening measured by the SFA. No significant differences surfaced regarding psychosomatic symptoms after medication nights. No significant effects were detectable using the visual analogue scale. ANOVA only indicated statistical significance in the item “exhaustedness” two hours after the intake of AMI. Also the FSUCL revealed a higher incidence of experienced fatigue with AMI in the morning, in comparison to PLAC and ESCIT.

Polysomnographic day-time sleep variables ▶ Table 2 indicates statistical significance (p < 0.005) for mean ● day-time sleep onset latency and mean sleep efficiency measured by MSLT. As a measure of sleepiness AMI increased it signifiDoerr JP et al. Impact of Escitalopram on Nocturnal Sleep … Pharmacopsychiatry

Regarding the test for attentional performance (TAP) and the d2 test ANOVA’s significance level (p < 0.017), was reached. After the intake of AMI, there were significantly longer reaction times in TAP and fewer correctly marked letters compared to PLAC and especially to ESCIT. ESCIT slightly improved performance tasks, which reached a level of significance compared to AMI, but not to PLAC. The results of the digit span test showed no significant ▶ Table 3). differences (●

Discussion ▼ To the best of our knowledge this is the first study investigating the impact of the SSRI ESCIT versus a TCA on objectively measured day- and night-time sleep. Our major findings are that the SSRI ESCIT significantly suppresses REM sleep and disturbs nocturnal sleep continuity. Despite these effects, day-time sleepiness is reduced and performance during day-time is slightly but significantly improved compared with a TCA. AMI increases sleep continuity, suppresses REM sleep as well but also increases daytime sleepiness on the next day. The polysomnographic findings for ESCIT are in agreement with earlier findings for other SSRIs in healthy subjects. Vasar et al. [49] demonstrated that fluoxetine decreases total sleeptime and increases wake time. With paroxetine (15–30 mg) a reduction of total sleeptime was shown [47]. Wilson [52] described that suppression of REM sleep and sleep continuity were both altered by 20 mg citalpram and 20 mg paroxetine. These typical sleep effects were stronger after paroxetine (intake for 3 days). The sleep disturbing effects of paroxetine were also demonstrated in depressed patients [34]. However, citalopram did not

Original Paper

Table 3 Performance of the standardized test battery. Test battery TAP (ms) D2 Test (No.) digit span test (No.)

1 placebo

2 Escitalopram

3 Amitriptyline

(mean ± SD)

(mean ± SD)

(mean ± SD)

202.84 ± 20.29 553.00 ± 84.19 20.45 ± 3.05

199.91 ± 25.04 557.27 ± 68.54 19.64 ± 3.75

214.65 ± 22.80 531.27 ± 86.12 19.72 ± 3.20

P (ANOVA)

2 vs. 1

3 vs. 1

2 vs. 3

0.006* 0.014* 0.459

0.511 0.470 0.300

0.012* 0.053 0.195

0.003* 0.011* 0.930

Mean values are the sum of all reaction times recorded by TAP (ms), the number (No.) of correctly marked d with two additional strokes (d”) measured by the d2 Concentration task and the number of recalled digits (dígit span test) (No.) Significant p-values ( < 0.017) as well as significant group differences (p < 0.05) are marked with *

impair total sleep time during 5 weeks of treatment in depressed patients [48].The reason for discrepancies between healthy and depressed patients might be that the depressed already have sleep disturbances to start with. On the other hand it could be that the magnitude of the arousing effects on sleep continuity is larger in healthy volunteers. As SSRIs have relatively long absorption times with maximum plasma concentrations not achieved until about 4 h after administration [8], van Bemmel’s results of unimpaired sleep latency were also surprising (medication intake at 6 p.m.). Similarly, ESCIT − in our study − did not either. However, it could be argued that plasma concentrations were probably not high enough. REM sleep suppression was comparable with other SSRIs. Finally, the authors want to emphasize that our data are demonstrating the acute effects and are not directly comparable to data of depressed patients. The observed effects of SSRIs on sleep are thought to be due to increased levels of serotonin on 5-HT-1A and 5-HT-2 receptors. The REM sleep suppression after SSRI administration may be mediated through the postsynaptic 5-HT-1A receptor. In fact, Monaca et al. [30] showed that in 5-HT-1A knock-out mice, the REM sleep-suppressing effect of citalopram was absent. Sleep fragmentation is more likely to be due to stimulation of 5-HT-2 receptors [28]. Regarding the polysomnographic effects of AMI, our study confirmed REM sleep suppression as well as the sleep-consolidating influence. These effects seem to be long-term because these were also demonstrated in depressed patients after a 6-week treatment [13, 47]. For REM sleep suppression the increased aminergic activity seems to be important [19, 20]. Regarding NREM sleep the postsynaptic 5-HT-2-, histamine 1- and cholinergic receptors antagonistic influence of AMI seems to explain the sedating effects [16]. The importance of the cholinergic system in sleep has been demonstrated in our study, which showed a significant increase of heart rate during NREM sleep stages but not in stage wake nor during REM sleep. One could conclude that the acute anticholinergic effects are one of the main reasons for the increase of NREM sleep in our study. In contrast, the SSRI ESCIT − as expected − had no influence on heart rate. Regarding the results of unchanged spectral analysis this is in line with the results for paroxetine during subchronic treatment in healthy subjects. However, treatment with citalopram resulted in suppression of spectral power in the 8–9 Hz range. In both studies no influence of SSRIs on delta power was observed [31, 40]. Because our study investigated the acute effects on EEG sleep, it cannot be excluded that chronic administration of ESCIT would result in significant changes. The discrepancy between the results of objective and unaffected subjective measurement of sleep (after the intake of ESCIT) corresponds with findings for fluoxetine. Subjective sleep quality

also remained unchanged [44]. Citalopram has even been shown to improve subjective sleep quality in depressed patients compared to imipramine [41]. As in our study both medications suppressed REM sleep similarly, we confirmed that the suppression of REM sleep does not influence declarative memory consolidation the following day. In fact, ESCIT compared to AMI, generally tended to improve test results for daytime processing speed and performance and led to higher wake efficiencies during the day. These stimulating effects of ESCIT and the sedating effects of AMI are in line with the findings by Wingen et al. [53], who demonstrated that driving performance as well as psychomotor functioning were not affected by ESCIT and seemed to be impaired after ingestion of sedating medications. For the authors the − AMI-induced − reduction of MSLT sleep onset latencies to less than 8 min is a remarkable impairment, because this is one of the main criteria for diagnosing idiopathic hypersomnia in patients [4]. In accordance, Ray et al. [36] described an increase in road accidents in patients taking tricyclic antidepressants. These findings may suggest that an improvement/impairment of daytime alertness can objectively be measured by the MSLT. However, larger sample sizes are needed. The finding of unchanged frequency of periodic limb movements during sleep (PLMS) after ESCIT − seems to be important, as there is a lack of data with placebo-controlled randomized studies in healthy volunteers. However, relevance is demonstrated by Yang and colleagues [54] as they described, that after the intake of the SSRIs citalopram, fluoxetine, paroxetine and sertraline, 23 % of the depressed patients had a PLMS-Index > 20 per hour. Previous studies discussed that especially serotonergic antidepressants might induce PLMS and consecutive sleep disturbances or a restless legs syndrome [1, 31]. However, latest research demonstrated that venlafaxine − an SSRI with additional NE receptor binding − as well as mirtazapine (NE and 5HT) caused significantly more PLMS [3, 43]. With respect to our data, more investigations are needed on whether SSRIs are really more likely to induce PLMD than other antidepressants with norepinephrinergic, cholinergic or histaminergic properties, or whether it is a side effect that could be improved by establishing enantiomers. Finally, it is necessary to emphasize that our observations were made in healthy subjects and not in depressed patients and higher doses might also induce PLMS. In conclusion, the acute intake of escitalopram, the S-enantiomer of citalopram, induce a disturbance of sleep continuity as has been reported for other SSRIs, but neither impaired subjective sleep quality nor caused PLMS. Additionally, it decreased daytime sleepiness and seemed to increase performance compared to amitriptyline. The acute intake of the latter led to a significant decrease in vigilance as measured by the MSLT.


Original Paper

Future studies should confirm these results in depressed patients and investigate the relationship between daytime vigilance and treatment outcome.

Acknowledgements ▼ The authors would like to thank Maria Rechenbach, Gerda Deeb, Patrick Anjard and Bernd Tritschler for their assistance. This study was supported by a grant from Lundbeck GmBH, Germany.

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