Retrospective Analysis of Risk Factors for Periodic Limb Movements in a Large Cohort of Insomnia and Chronic Fatigue Patients

Abstract

Introduction Although the pathophysiology of periodic limb movements in sleep (PLMS) is not well understood, there is increasing belief that management of PLMS can modulate humans’ general health. The aim of this study is to investigate the associations between risk factors including the use of antidepressants, hypnotics, and antihistamines as well as of caffeine, alcohol, and nicotine and the occurrence of PLMS and periodic limb movement disorder (PLMD). Methods Patients with either chronic fatigue or insomnia who underwent polysomnography as standardized clinical assessment were included in a retrospective study. Associations were calculated between substance use and sleep variables. Results Tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitor (SNRI) are significantly associated with higher rates of PLMS. Additionally, SNRI is significantly positive associated with PLMD, as also seen for selective serotonin reuptake inhibitors (SSRI). The most frequently used SSRI escitalopram was significantly positively associated with PLMS and PLMD. A significantly negative association was found between paroxetine and PLMS. Benzodiazepines are negatively associated with PLMS and PLMD. Sedative antidepressants, antihistamines, and substance use are not associated with PLMS nor PLMD in this study. Discussion This retrospective study adds supportive evidence to the association of drug classes with PLMS and PLMD. These findings may impact on clinical management of patients with a combined anxiety or mood disorder in need for these drug classes on the one hand and a significant sleep architecture disturbance through PLMS, potentially contributing to daytime symptoms, on the other hand.

Periodic limb movements during sleep: a narrative review

“…Several psychotropic medications have been linked to PLMI above 15 events per hour (78). For example, whilst dopamine-receptor antagonists, anticonvulsants, and lithium can potentially precipitate PLMS symptoms, it is typically the antidepressants, including selective-serotonin reuptake inhibitors (SSRIs; including sertraline), tricyclic anti-depressants (TCA; e.g., amitriptyline), and serotonin and norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine and mirtazapine) which have been linked to pharmacologically induced PLMs (77). However, several antidepressants have been identified that do not appear to precipitate PLMs and are hence clinically recommended in affected or vulnerable patients, namely trazodone, bupropion (134), nefazodone and doxepin (10,135).…”

Association of Periodic Limb Movements With Medication Classes

“…This finding is in keeping with a previous cohort study that demonstrated a decrease in PLMS and PLMD with benzodiazepines in a cohort of patients with insomnia and chronic fatigue. 11 Furthermore, 2 previous studies that compared clonazepam and a placebo also found a reduction in PLMS in the clonazepam group. 37,38 Another cohort study, however, did not find a significant association between benzodiazepine use and a PLMI greater than 15.…”

“…Previous studies have also demonstrated an increased PLMI in association with SSRI and SNRI use. 9,11,27 The mechanism underlying this association has not been fully elucidated; however, previous studies have speculated that SSRIs and SNRIs may increase PLMS through a serotoninergic mediated increase in dopamine transporters ultimately leading to a subsequent decline in dopaminergic activity. [27][28][29] In addition, because SNRIs increase both norepinephrine and serotonin levels, prior research suggests that they may also increase PLMS through a norepinephrine-mediated increase in sympathetic nervous system activity.…”

“…37,38 Another cohort study, however, did not find a significant association between benzodiazepine use and a PLMI greater than 15. 5 Benzodiazepine use has been shown to be associated with a decreased global arousal index during sleep 11 and thus previous literature has speculated that this increase in uninterrupted sleep may be the mechanism responsible for the association with decreased PLMS. 11 Given the minimal literature and conflicting findings, future studies are needed to further investigate the association between benzodiazepines and PLMS and potential therapeutic applications.…”

“…Researchers have examined associations between PLMS and medication classes such as β-blockers, neuroleptics, antihistamines, hypnotics, benzodiazepines, and antidepressants, with inconsistent results for some medications. 5,6,[9][10][11] Some studies were limited by small sample sizes for some medications or only looked at a limited number of medication classes. Therefore, a larger study investigating a wider spectrum of medication classes is required.…”