The Influence of the Tricyclic Antidepressant Amitriptyline on Periodic Limb Movements during Sleep

• Abstract
• Introduction
• Subjects and Methods
• Subjects
• Experimental design and procedure
• Polysomnographic recordings and scoring of periodic leg movements
• Statistical analysis
• Results
• Discussion
• References

Abstract

Introduction:

Many antidepressants are associated with periodic limb movements (PLM) during sleep. Although some tricyclic antidepressants, such as amitriptyline, promote sleep and are thus often prescribed as a treatment for sleep disturbances that can accompany depression, it remains unclear whether amitriptyline is associated with PLM.

Methods:

32 healthy males (18–39 years) spent 2 consecutive nights in the sleep lab for polysomnographic recording. During the second night, they received either 75 mg amitriptyline or placebo in a randomized, double-blind, placebo-controlled manner.

Results:

In subjects receiving amitriptyline but not in subjects receiving placebo, the number of periodic leg movements per h was significantly increased from baseline to intervention night. However, objective polysomnographic sleep parameters (such as the number of awakenings, wake after sleep onset, and sleep efficiency) and subjective sleep perception were not significantly associated with any PLM indices.

Discussion:

Our findings indicate that amitriptyline can induce or even increase the number of PLM during sleep in healthy subjects. When treating sleep disturbances with amitriptyline, PLM should be considered as a possible cause of insufficient improvement.

Introduction

Periodic limb movements (PLM) during sleep can result from medication and are a frequent problem in patient care. A number of psychotropic medications used to treat psychiatric disorders, particularly depression, are associated with this side effect [1] [2]. Among the various antidepressants, a broad range of selective serotonin reuptake inhibitors (SSRIs), venlafaxine [3] [4] [5], and tricyclic antidepressants, such as imipramine, trimipramine, and clomipramine [6] [7] [8] are thought to cause PLM. To the best of our knowledge, however, no data are available on the possible association between amitriptyline and PLM. According to a report published by one of the largest German health insurers, 46% of all antidepressants prescribed in Germany in 2008 and 2009 were SSRIs and 26% were tricyclic antidepressants, including amitriptyline, which was the fourth most commonly prescribed antidepressant during this period [9]. Because it promotes sleep, amitriptyline is frequently used to treat insomnia or the sleep disturbances that can accompany depression. An association between amitriptyline and PLM might be indicative of altered sleep quality and could cast doubt on the effectiveness of this form of treatment. PLM are characterized by episodes of repetitive and highly stereotyped limb movements – usually in the legs – that occur during sleep. The movements are often associated with a partial arousal or awakening [10], which are thought to be at least partially responsible for the sleep disturbances reported by patients treated with antidepressants [4] [11]. PLM, or the sleep changes induced by them, appear to be associated with decreased physical or psychological fitness after awakening in insomnia patients [12] and with dissatisfaction with sleep in randomly selected elderly people [13]. Patients suffering from periodic limb movement disorder (PLMD) – which is defined as PLM, poor sleep, and subsequent daytime somnolence – are more likely to experience clinically significant psychological difficulties than patients with other sleep disorders [14]. Along these lines, a large epidemiological study with 18 900 subjects showed a strong association between having PLMD and a mental disorder [15]. Furthermore, the prevalence of PLM may increase with age. Although Ohayon and Roth [15] were unable to find evidence of this, Ancoli-Israel et al. [13] reported PLM in 45% of a randomly selected elderly population aged 65 years and older, compared to between 5% and 6% among a younger adult population [16].

We conducted a double-blind, placebo-controlled, randomized parallel study in a sample at low risk for PLM – i. e., healthy young men – to determine (a) whether PLM is induced by the sleep-promoting tricyclic antidepressant amitriptyline and, if so, (b) whether amitriptyline has an effect on objective polysomnographic sleep-continuity parameters, subjective physical and mental state in the morning, and the restorative value of sleep.

Subjects and Methods

Subjects

A total of 32 healthy male subjects aged 18 through 39 years (mean age: 27.3 years) was included in the study. The study protocol was approved by the local ethics committee and the German Federal Institute for Drugs and Medical Devices (EudraCT 2007-003546-14). Prior to the study, all subjects provided written informed consent and underwent physical and mental health examinations. Inclusion criteria were (a) male gender, (b) age 18 through 40 years, and (c) ability to communicate effectively in German. Exclusion criteria were (a) shift-work within the past 24 months, (b) any sleep disorder as measured by the Pittsburgh sleep quality index [17], (c) irregular sleep/wake patterns or extreme chronotype as measured by the morningness-eveningness questionnaire [18] [19], (d) history of any neurological or psychiatric disorders, (e) regular medication intake within the past 4 weeks, (f) contraindications for amitriptyline, or (g) an abnormal electrocardiogram.

Experimental design and procedure

The present investigation was part of a larger study exploring the effect of pharmacological REM sleep suppression on sleep dependent memory consolidation. Subjects spent 2 consecutive nights in the sleep lab. The first night served as the polysomnographic baseline measure. For the second night, subjects were randomized in a double-blind manner to an amitriptyline group or a placebo group, receiving amitriptyline 25 mg at 9:30 pm and 50 mg at 1:30 am or placebo. As mentioned above, the aim of the main study was to successfully suppress REM sleep. The atypical medication regimen was used, since a single dose of amitriptyline in the evening would not have suppressed REM sleep in the later part of the night. Between 9:30 and 11:00 pm subjects were prepared for polysomnography. They went to bed at 11:00 pm and remained in bed until 7:00 am for polysomnographic recording. At 1:30 am they were woken up for the second medication administration. The next morning, subjects were required to fill out a morning protocol [20] by answering questions about their current physical and mental state (i. e., on a 6-point scale ranging from “dull/weak” to “fresh”) and about the restorative value of their sleep (i. e., on a 5-point scale ranging from “very restorative” to “not restorative at all”).

Polysomnographic recordings and scoring of periodic leg movements

Sleep was polygraphically recorded with the Sagura Polysomnograph 2000 (Dr. Sagura RMS AG) using standard filter settings and including 6 electroencephalogram (EEG) channels (F3-A2, F4-A1, C3-A2, C4-A1, O1-A2, O2-A1), 2 electrooculogram (EOG) channels, a mental electromyograph (EMG) channel, an EMG channel for the tibialis anterior muscle of each leg, and electrocardiography (ECG). In addition, nasal air flow, thoracic and abdominal excursion, peripheral oxygen saturation, and rectal (core body) temperature were measured. Sleep was scored according to the standardized criteria of Rechtschaffen and Kales in 30-s epochs by 2 experienced scorers who were blind to the treatment [21]. For the time in bed (TIB; i. e., time from lights off to lights on), every epoch was scored as (a) wake, (b) non-REM sleep stage 1, 2, 3, or 4, or (c) REM sleep. Time spent in non-REM stages 3 and 4 was defined as slow-wave sleep (SWS). “Sleep onset” was defined as the first epoch of stage 2 sleep; “end of sleep” as the first epoch of wake without a subsequent epoch of sleep; “sleep latency” as the time from lights off to sleep onset; “REM latency” as the time from sleep onset to the first epoch of REM sleep; “sleep period time” (SPT) as the time from sleep onset to the end of sleep; “total sleep time” (TST) as SPT minus time spent awake during SPT; “percentage of a sleep stage” as the percentage of SPT; “sleep efficiency” as the ratio of TST to TIB; “wake after sleep onset” as time spent awake during SPT; “number of awakenings” as the sum of periods with at least 1 epoch awake during SPT.

PLM were scored according to the ICSD-2 criteria [22]. Here, a movement was defined as EMG activity with a minimum of 25% of the toe dorsiflexion during biocalibration amplitude level and a duration of 0.5–5 s. It was irrespective of whether a movement was to be seen in one or in both legs. Only periodic movements occurring in a series of at least 4 with an interval between 5 and 90 s (onset to onset) were included in the analysis. We further calculated the number of periodic movements (a) per h of total sleep time (PLMS index), and (b) with an EEG-arousal per h of total sleep time (PLMA index).

Statistical analysis

Data from 1 subject were excluded from analysis because of an abnormal electroencephalogram (epileptic potentials). Due to technical difficulties with polysomnography, datasets from 28 subjects were available for the intervention night (13 amitriptyline, 15 placebo). Due to artifacts in the tibial EMG, which did not allow scoring of the PLM according to the biocalibration amplitude, PLM scoring for both the baseline and intervention night was only available from 22 subjects (11 amitriptyline, 11 placebo). Data were analyzed using PASW Statistics 18 (SPSS Inc.). Experimental variables were tested for normal distribution with the Shapiro-Wilk test. Because the indices were not normally distributed for either the baseline or intervention night, we employed non-parametric procedures, including the exact Wilcoxon signed-rank test (within groups) and Mann-Whitney test (between groups) for comparative analysis and Kendall’s Τ for correlative analysis. A 2-tailed p value <0.05 was considered significant. According to ICSD-2 [22] a PLMS index of ≥15/h for adults is regarded as pathological. Thus, we categorized subjects into 2 groups depending on whether their PLMS index was ≥15 or <15. Chi-square tests were performed to evaluate the relationship between treatment and periodic leg movements.

Results

In the amitriptyline group, the PLMS and PLMA indices were significantly higher for the intervention night than for the baseline night [PLMS index: T=3, p=0.01, 95% CI  − 16.88 ( − 27.98,  − 5.77); PLMA index: T=6, p=0.03, 95% CI  − 6.59 ( − 11.69,  − 1.50); see [Fig. 1] and for individual changes, see [Fig. 2]. As expected, there was no difference between the baseline and intervention nights in the placebo group for any of the indices [PLMS index: T=25, p=0.82, 95% CI  − 1.24 ( − 6.11, 3.62); PLMA index: T=23, p=1.00, 95% CI  − 0.12 ( − 1.39, 1.14)]. In addition, there was a significant association between the type of treatment and a PLMS index≥15 [χ ²(1)=4.92, p=0.03]. Subjects receiving amitriptyline were 7.88 times more likely than those receiving placebo to have a PLMS index ≥15. Subjects receiving amitriptyline did not differ from those receiving placebo in their baseline PLMS or PLMA indices [PLMS index amitriptyline group: 5.23±7.09, PLMS index placebo group: 4.54±7.41, U=60, p=1.00, 95% CI 0.69 ( − 5.76, 7.14); PLMA index amitriptyline group: 2.46±4.17, PLMA index placebo group: 2.63±6.05, U=50, p=0.57, 95% CI  − 0.17 ( − 4.79, 4.45)].

In the morning protocol, subjects in the amitriptyline group on average rated their physical and mental state after being woken up as “rather dull/weak” and the placebo group as “rather fresh”, although this difference did not reach statistical significance (U=64, p=0.12). In terms of restorative value, the amitriptyline group on average reported their sleep as having been “moderately restorative,” whereas the placebo group reported their sleep as having been “quite restorative”; here, too, the difference did not reach statistical significance (U=74, p=0.25; see [Table 1] for details).

Whereas there was a trend under amitriptyline towards fewer awakenings (U=59, p=0.08), the time spent awake after sleep onset was significantly lower and sleep efficiency was significantly greater than under placebo (time spent awake after sleep onset: U=46, p=0.02; sleep efficiency: U=52, p=0.04). Furthermore, amitriptyline increased REM sleep latency (U=27, p=0.001) and markedly reduced the amount of time spent in REM sleep (U=6, p=0.000) but also increased the amount of time spent in stage 2 sleep (U=26, p=0.001). No group differences were observed for the time spent in stage 1 sleep and SWS (stage 1 sleep: U=74, p=0.29; SWS: U=79, p=0.41, see [Table 1] for details). After being woken up for the second medication administration, subjects receiving amitriptyline needed significantly less time to fall asleep again than subjects receiving placebo [amitriptyline group: 4.00±1.38 min; placebo group: 11.77±9.69 min; U=36, p=0.003, 95% CI  − 7.77 ( − 13.17,  − 2.36)].

No significant correlations were observed between objective polysomnographic sleep-continuity parameters such as the number of awakenings, wake after sleep onset (WASO), sleep efficiency, or any of the PLM indices (all p-values >0.25; data not shown in detail). There were also no significant correlations between any of the PLM indices and subjective sleep variables (all p-values>0.66; data not shown in detail).

Discussion

To the best of our knowledge, the present study is the first to show an increase in period leg movements (a) per h of total sleep time (PLMS index) and (b) per h of total sleep time accompanied by EEG arousals (PLMA index) in subjects under the tricyclic antidepressant amitriptyline. This is an important finding considering that amitriptyline is often prescribed for insomnia or for the sleep disturbances that can accompany depression. Comparable results have been reported for patients with insomnia during the early phase of treatment with ≥100 mg of either imipramine or trimipramine [6]. Although administering a low dose of doxepin (25 or 50 mg) to patients with primary insomnia has not been associated with an increase in PLMS or PLMA indices, drug withdrawal after a 4-week treatment phase has been shown to be followed by a decrease in the PLMA index, indicating a possible relationship between doxepin and PLM [23]. Interestingly, 2 case reports suggest that amitriptyline may have a differential or even contradictory effect on a closely related disorder restless legs syndrome (RLS), which may be induced [24] or ameliorated [25] by this agent. The effects of other tricyclic antidepressants on movements during sleep appear to depend on their interaction with various transmitter systems. For example, clomipramine, which has a potent serotonergic effect, increases PLM [8], whereas nortriptyline, which is a noradrenergic agent, does not [26]. Similarly, selective serotonin reuptake inhibitors and venlafaxine, an antidepressant of the serotonin-norepinephrine reuptake inhibitor class, increase the risk of PLM [3]. In contrast, the dopamine reuptake inhibitor bupropion may actually decrease PLM [27]. These observations precipitated the hypothesis tested in the present study that an interaction between the serotonergic and dopaminergic neurotransmitter systems may cause a decrease in dopaminergic neurotransmission and thereby provoke PLM [1] – a potential mechanism by which amitriptyline can generate PLM.

Although significantly more subjects receiving amitriptyline demonstrated a clinically relevant PLMS index ≥15, none of the polysomnographic sleep continuity parameters were significantly affected. It is conceivable that the arousing effects of PLM caused by amitriptyline were outweighed by the sleep-inducing properties of this agent, leading to an overall increase in sleep efficiency. Considering, however, that sleep and well-being disturbing effects of amitriptyline on RLS have been described in a patient suffering from Parkinson’s disease and a depressed patient [24] [25], the effect of this agent may depend on the population being treated. Further studies investigating the effects of antidepressants on PLM and their sleep-disturbing properties should focus on different patient groups, such as those suffering from pain or depression. Our focus on only one population is an important limitation of the present study. Furthermore, subjective measures of morning well-being were not significantly affected in subjects receiving amitriptyline. This corresponds to the finding that PLM appear to have no relevant influence on the perceived sleep quality of patients diagnosed with RLS, primary insomnia, or insomnia associated with a psychiatric disorder [28]. Moreover, in patients suffering from PLMD, subjective sleep and awakening quality was not affected compared to controls [29] [30] and scores on the Pittsburgh sleep quality index of PLMD patients was similar to those from controls [31].

As mentioned above, dopaminergic transmission may play a role in the pathogenesis of PLM. A rate-limiting cofactor in the synthesis of dopamine is iron. Therefore, an association between iron and PLM has been hypothesized. A limitation of our study is that no serum ferritin levels or any other markers of iron metabolism were examined. However, whether there is an association between ferritin levels and PLM remains unclear. In children with PLM or patients suffering from obstructive sleep apnea no significant association between ferritin levels and PLM has been found [32] [33], while in RLS patients a significant association between ferritin levels and PLMA index was demonstrated [34]. Even though it is unlikely that changes in serum ferritin levels from baseline to intervention night account for the increase in PLM indices under amitriptyline during the intervention night, it cannot be ruled out that lower ferritin levels might have influenced the degree of the response to amitriptyline.

A further potential limitation is that we only measured the effect of amitriptyline on PLM in a single night after administration. The effect on PLM may vary depending on the duration of intake. Finally, the medication regimen administered may have influenced objective and subjective sleep quality. However, since the subjects receiving amitriptyline needed less time to fall asleep again after being woken up for the second medication administration, the sleep-disturbing effect of being woken up might have been outweighed by the sleep-inducing properties of amitriptyline. Furthermore, subjects receiving amitriptyline had a higher total sleep time than subjects receiving placebo, which, in part, can be attributed to falling asleep faster after being woken up at night. However, because the PLMS or PLMA indices are defined as number of PLM per h of total sleep time, it should have no influence on these indices and, therefore, on the results described above.

In summary, our data support the notion that amitriptyline – like many other antidepressants – can induce or intensify PLM in sleep. Although we did not find a correlation between PLMA index and sleep-continuity parameters in this sample as a whole, within the framework of clinical care on an individual basis PLM should be considered as a possible cause for insufficient relief from or the new occurrence of sleep disturbances while being treated with an antidepressant such as amitriptyline.

Conflict of Interest

Yes: DK received speakers bureau honoraria from AIT, Astra Zeneca, BMS, Knauf, Lundbeck, the Medical Tribune, PBV, Schwarz, Servier, Sanofi-Synthelabo, Trilux, Zumtobel, advisory panel payments from Astra Zeneca, BMS, the European Space Agency, the European Commission, Lundbeck, Philips Respironics, Pfizer, and research grants from Actelion, DIN, Knauf, MSD, Osram, and Uwe Braun. SC received lecture fees from Astra Zeneca, Servier, GSK, Sanofi-Aventis, and Lundbeck. AR and MG declare no conflicts of interest.

Acknowledgements

We would like to thank Matthew Gaskins for editing this manuscript.

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Correspondence

• References

• 1 Cohrs S, Rodenbeck A, Hornyak M et al. Restless-legs-Syndrom, periodische Gliedmassenbewegungen im Schlaf und Psychopharmakologie. Nervenarzt 2008; 79: 1263-1264, 1266-1272
  CrossrefPubMedSearch in Google Scholar
• 2 Hoque R, Chesson Jr AL. Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis. J Clin Sleep Med 2010; 6: 79-83
  PubMedSearch in Google Scholar
• 3 Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of sleep. Biol Psychiatry 2005; 58: 510-514
  CrossrefPubMedSearch in Google Scholar
• 4 Dorsey CM, Lukas SE, Cunningham SL. Fluoxetine-induced sleep disturbance in depressed patients. Neuropsychopharmacology 1996; 14: 437-442
  CrossrefPubMedSearch in Google Scholar
• 5 Salin-Pascual RJ, Galicia-Polo L, Drucker-Colin R. Sleep changes after 4 consecutive days of venlafaxine administration in normal volunteers. J Clin Psychiatry 1997; 58: 348-350
  CrossrefPubMedSearch in Google Scholar
• 6 Ware JC, Brown FW, Moorad PJ et al. Nocturnal myoclonus and tricyclic antidepressants. Sleep Res 1984; 13: 72
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• 7 Guilleminault C, Raynal D, Takahashi S et al. Evaluation of short-term and long-term treatment of the narcolepsy syndrome with clomipramine hydrochloride. Acta Neurol Scand 1976; 54: 71-87
  CrossrefPubMedSearch in Google Scholar
• 8 Casas M, Garcia-Ribera C, Alvarez E et al. Myoclonic movements as a side-effect of treatment with therapeutic doses of clomipramine. Int Clin Psychopharmacol 1987; 2: 333-336
  CrossrefPubMedSearch in Google Scholar
• 9 Glaeske G, Schicktanz C, Barmer GEK. Arzneimittel-Report 2010. St. Augustin: Asgard; 2010
  Search in Google Scholar
• 10 American Academy of Sleep Medicine . International classification of sleep disorders, revised: Diagnostic and coding manual. Chicago, Illinois: American Academy of Sleep Medicine; 2001
  Search in Google Scholar
• 11 Mendelson WB. Are periodic leg movements associated with clinical sleep disturbance?. Sleep 1996; 19: 219-223
  PubMedSearch in Google Scholar
• 12 Haba-Rubio J, Staner L, Krieger J et al. What is the clinical significance of periodic limb movements during sleep?. Neurophysiol Clin 2004; 34: 293-300
  CrossrefPubMedSearch in Google Scholar
• 13 Ancoli-Israel S, Kripke DF, Klauber MR et al. Periodic limb movements in sleep in community-dwelling elderly. Sleep 1991; 14: 496-500
  PubMedSearch in Google Scholar
• 14 Aikens JE, Vanable PA, Tadimeti L et al. Differential rates of psychopathology symptoms in periodic limb movement disorder, obstructive sleep apnea, psychophysiological insomnia, and insomnia with psychiatric disorder. Sleep 1999; 22: 775-780
  PubMedSearch in Google Scholar
• 15 Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 2002; 53: 547-554
  CrossrefPubMedSearch in Google Scholar
• 16 Bixler EO, Kales A, Vela-Bueno A et al. Nocturnal myoclonus and nocturnal myoclonic activity in the normal population. Res Commun Chem Pathol Pharmacol 1982; 36: 129-140
  PubMedSearch in Google Scholar
• 17 Buysse DJ, Reynolds 3rd CF, Monk TH et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989; 28: 193-213
  Search in Google Scholar
• 18 Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol 1976; 4: 97-110
  PubMedSearch in Google Scholar
• 19 Griefahn B, Künemund C, Brode P et al. Zur Validität der deutschen Übersetzung des Morningness-Eveningness-Questionnaires von Horne und Östberg. Somnologie 2001; 5: 71-80
  CrossrefPubMedSearch in Google Scholar
• 20 Hoffmann RM, Müller T, Hajak G et al. Abend-Morgenprotokolle in Schlafforschung und Schlafmedizin – Ein Standardinstrument für den deutschsprachigen Raum. Somnologie 1997; 1: 103-109
  Search in Google Scholar
• 21 Rechtschaffen A, Kales A. A manual of standarized terminology, techniques and scoring system for sleep stages in human subjects. Washington: US Government Printing Office; 1968
  Search in Google Scholar
• 22 American Academy of Sleep Medicine . International classification of sleep disorders, 2^nd edition: Diagnostic & coding manual (ICSD-2). Westchester, Ill: American Academy of Sleep Medicine; 2005
  Search in Google Scholar
• 23 Hornyak M, Kopasz M, Rodenbeck A et al. Influence of low-dose doxepin on periodic leg movements in primary insomnia patients. Somnologie 2006; 9: 111-115
  PubMedSearch in Google Scholar
• 24 Sandyk R, Gillman MA. The restless legs syndrome associated with amitriptyline. Br Med J 1984; 289: 162
  CrossrefPubMedSearch in Google Scholar
• 25 Sandyk R, Iacono RP, Bamford CR. Spinal cord mechanisms in amitriptyline responsive restless legs syndrome in Parkinson’s disease. Int J Neurosci 1988; 38: 121-124
  CrossrefPubMedSearch in Google Scholar
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