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Mlyncekova, Z.; Hutka, P.; Visnovcova, Z.; Ferencova, N.; Kovacova, V.; Macejova, A.; Tonhajzerova, I.; Ondrejka, I. Vortioxetine´s Effects on Sleep of Adolescent Major Depression. Encyclopedia. Available online: https://encyclopedia.pub/entry/51713 (accessed on 14 May 2024).
Mlyncekova Z, Hutka P, Visnovcova Z, Ferencova N, Kovacova V, Macejova A, et al. Vortioxetine´s Effects on Sleep of Adolescent Major Depression. Encyclopedia. Available at: https://encyclopedia.pub/entry/51713. Accessed May 14, 2024.
Mlyncekova, Zuzana, Peter Hutka, Zuzana Visnovcova, Nikola Ferencova, Veronika Kovacova, Andrea Macejova, Ingrid Tonhajzerova, Igor Ondrejka. "Vortioxetine´s Effects on Sleep of Adolescent Major Depression" Encyclopedia, https://encyclopedia.pub/entry/51713 (accessed May 14, 2024).
Mlyncekova, Z., Hutka, P., Visnovcova, Z., Ferencova, N., Kovacova, V., Macejova, A., Tonhajzerova, I., & Ondrejka, I. (2023, November 16). Vortioxetine´s Effects on Sleep of Adolescent Major Depression. In Encyclopedia. https://encyclopedia.pub/entry/51713
Mlyncekova, Zuzana, et al. "Vortioxetine´s Effects on Sleep of Adolescent Major Depression." Encyclopedia. Web. 16 November, 2023.
Vortioxetine´s Effects on Sleep of Adolescent Major Depression
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This entry is adapted from the peer-reviewed paper 10.3390/clockssleep5040042

The relationship between depression and insomnia is bidirectional and both conditions need to be treated adequately, especially in a vulnerable neurodevelopmental stage of adolescence. Sleep disturbances in adolescents have been associated with a more severe clinical course of depression (i.e., suicidal behavior, worse psychosocial functioning, and risk of recurrence). Due to the rising incidence of both disorders, it is crucial to understand the underlying pathophysiology (e.g., disrupted neuroplasticity and neurotransmitter dysbalance), especially in the vulnerable adolescent age period characterized by developmental changes and sensitivity to endogenous and exogenous factors.

vortioxetine depression adolescent sleep architecture sleep abnormalities insomnia antidepressants

1. Depression and Insomnia in Adolescents

Major depressive disorder (MDD) and co-occurring insomnia represent a serious concern, particularly in the adolescent period. The prevalence of depression in children and adolescents is estimated to be 14.3% [1] and the prevalence of insomnia is estimated to be 51–74% in clinically depressed adolescents [2]. In this aspect, recent scientific research is focused on their bidirectional relationship [2][3]. More specifically, sleep disturbances in adolescents have been associated with a more severe clinical course of depression (i.e., suicidal behavior, worse psychosocial functioning, and risk of recurrence) [2]. Due to the rising incidence of both disorders, it is crucial to understand the underlying pathophysiology (e.g., disrupted neuroplasticity and neurotransmitter dysbalance), especially in the vulnerable adolescent age period characterized by developmental changes and sensitivity to endogenous and exogenous factors [3][4]. Sleep architecture reflects not only physiological neurodevelopmental changes but also the effect of antidepressant treatment. The major changes in sleep during adolescence manifest as a decrease in total sleep time, a decrease of the N3 stage (represented by slow wave sleep, SWS), an increase in daytime sleepiness, and a circadian shift towards later hours [2]. With respect to depression, there are several consistent sleep alternations observed in depressed adolescents but expressed to a lesser degree when compared to sleep studies on adults. It is predominantly rapid eye movement (REM) sleep disinhibition, which can be influenced by antidepressants, as discussed in the following paragraphs.

2. Sleep Abnormalities in Adolescent Depression

There are several sleep electroencephalogram (EEG) biomarkers registrable by a polysomnographic study that correlate with a predisposition to developing the affective disorder, with the severity of depression, and have predictive value of response to treatment [2][5][6]. The most prominent ones are REM sleep abnormalities, reduction of SWS, and impaired sleep continuity (presented by increased sleep latency, sleep fragmentation by increased arousals, and wakefulness after sleep onset) [7]. More specifically, the REM disinhibition and its instability characterized by short REM latency (REM-L), increased REM sleep duration (REM%), increased REM density (RD), and REM fragmentation (the index of the total number of arousals during REM sleep/REM sleep duration in hours) is considered not only epiphenomena but to be a crucial biomarker of endogenous depression [2][6][8]. Moreover, restless REM sleep is deeply involved in the alternation of synaptic plasticity in limbic circuits leading to emotional distress and subsequent vulnerability to developing mood disorder [9]. Similarly, based on the knowledge that REM sleep has an important role in memory consolidation, emotional memory processing, stress response, reward, and energy homeostasis, chronic REM sleep alternations contribute to the pathophysiology and manifestation of mood disorders [10]. Thus, REM sleep disturbances represent a relevant clinical hallmark of depression and can be modified by pharmacologic therapy [6]. Moreover, periodic limb movements during sleep (PLMS) characterized as involuntary repetitive and stereotypical limb movements [11] was reported to be associated with psychiatric disorders including depression [12] already at adolescent age [13].

3. The Effects of Antidepressants on Sleep Architecture

The principal therapeutic intervention to manage symptoms linked to depression and insomnia is psychopharmacotherapy. However, antidepressants (ADs) are reported to have distinct effects on sleep architecture [7][14][15]. Some can eventually lead to sleep disturbances and contribute to a vicious circle. In general, the enhanced serotoninergic tone caused by ADs via interaction with the serotonin (5-HT) receptors potentiates cortical activity, and arousal system during sleep and suppresses REM sleep. This effect on REM sleep is typical and consistent for selective serotonin reuptake inhibitors (SSRIs) (except for escitalopram), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (except for trimipramine) [6][7]. The resulting subjective sleep effect is variable since ADs (mostly SSRIs, the first-line treatment of depression in adolescence) might induce other sleep disturbances such as periodic limb movements, restless leg syndrome, or daytime somnolence [14]. Another hypothesis is that the REM-suppressing effect is distinct and not immediately connected to the antidepressant effect, as seen in acute administration of ADs, and may be related to dysfunction of brain structures (such as the limbic system) that are involved in both the REM sleep and mood regulation [6][7]. Furthermore, REM suppression was suggested to predict the treatment response [6]. In contrast, the effects of ADs on non-rapid eye movement (NREM) sleep and sleep continuity differ by interaction with specific receptors, as described in the article written by Hutka et al. [15]. Additionally, antidepressant treatment can trigger PLMS [16]; however, there is virtually no information on AD-induced PLMS at the adolescent age. Thus, this led to our interest in researching a novel AD such as VOR in association with sleep.

4. Vortioxetine—Pharmacokinetic/Molecular Mechanisms Related to Sleep

VOR, acting as multimodal serotoninergic AD, blocks serotonin transporter (SERT), 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, and 5-HT1A receptor agonist, and as a result, increases levels of dopamine, acetylcholine and noradrenaline in the frontal cortex and ventral hippocampus [17]. According to several clinical studies, VOR is characterized by antidepressant, anxiolytic, and procognitive effects due to changes in synaptic neuroplasticity, in an effective dose ranging from 5 to 20 mg (i.e., from 50 to 80% SERT occupancy) [18]. VOR shows linear and time-independent pharmacokinetics, with a mean Tmax of 7–8 h and a mean elimination half-life of 57 h upon oral administration [19][20], which reduces the risk of discontinuation syndrome. VOR has a moderate oral bioavailability of 75% and an extensive tissue distribution. VOR is primarily metabolized by cytochrome P450 enzymes, mostly to an inactive major metabolite, with no clinical relevance with respect to sex, age, race/ethnicity, body size, or hepatic or renal function [20]. Notably, the treatment of depression by VOR in the pediatric population is off-label, but a long-term, open-label, clinical trial [21] reported its safety and efficacy in children and adolescents. However, the effectiveness of VOR remains controversial, since another study by the same author found no significant difference between VOR and placebo [22]. In general, VOR has proved its efficacy and tolerability in different studies [23]. Since cognitive impairment is an important symptom of MDD and is linked to sleep quality, it merits more attention in the context of VOR treatment. Moreover, it is suggested that, mostly through antagonism on the 5-HT3 receptor, it has a significant procognitive effect via modulation of neurotransmission in the medial prefrontal cortex and via enhancement of neurogenesis and neurotrophic processes in the hippocampus, as found in animal models [24]. In the quantitative EEG analysis, VOR increases low and high frontal cortical frequency ranges, which is also associated with cognitive processing enhancement [25][26]. According to functional imaging measurements, VOR shows direct positive effects on neural activity in typically overactive regions during acute episodes of MDD (such as dorsolateral prefrontal cortex and hippocampus) related to the decrease of subjective cognitive functions [23]. Apart from its procognitive effect, VOR has been intensively studied for its potential analgesic and anti-inflammatory effects [23]. Focusing on its sleep effect, there are only a few studies that assess the clinical effects of VOR on subjective sleep quality in positive correlation with depressive symptoms [27][28]. Only abnormal dreams, but not treatment-emergent insomnia or somnolence have been previously associated with VOR treatment in clinical trials [29]. To our knowledge, there are only two polysomnographic studies (one experimental in rats and one in healthy humans) that demonstrated REM-suppressing effects of VOR [17][30]. By increasing the levels of serotonin, one of the key regulators of the sleep–wake cycle, paradoxically VOR seems to be less fragmenting sleep compared to activating SSRIs or SNRIs and has a less intense REM-suppressing effect, indicating its different pharmacological profile [17]. Although this effect is particularly attributed to 5-HT3 receptor antagonism [18][30], other mechanisms are also suggested. However, the current knowledge of VOR´s effects on sleep is limited (see Table 1).
Table 1. Vortioxetine and its effects on sleep.
Study n
(Number of Subjects)		 Study Design Treatment Duration
Dosing Regimen		 Results
Liguori et al., 2019 [27] 15 adults
with MDD and insomnia		 A retrospective analysis of questionnaires
(PSQI, ESS, BDI)		 6 months
VOR at 10 mg		 Improvements in subjective sleep complaints and reduction of depressive symptoms
Cao et al., 2019 [28] 92 adults with MDD and 54 healthy
controls		 A post-hoc analysis of the clinical trial of sleep questionnaires
(PSQI, ESS, ISI)		 8 weeks
VOR
at 10–20 mg		 Improvements in sleep (predictive of AD response) and linearly correlated to depressive symptoms
Leiser et al., 2015 [30] Animals (rats) Bipolar sleep EEG 1, 3, 7, 10 days
VOR at 0.6 mg/kg
(s.c. injection, drug-infused chow, or water)		 ↓ REM sleep %
(only acute effect)
Wilson et al., 2015 [17] 19 healthy men A randomized, double-blind, placebo-controlled
(compared to paroxetine and placebo)
PSG study		 2 days
VOR at 20–40 mg
paroxetine at 20 mg		 ~↑ REM-L,
~↓ REM sleep %
↑ N1 stage %
~↑ WASO
(at 40 mg dose)
AD—antidepressants, EEG—electroencephalography, PSG—polysomnographic, VOR—vortioxetine, PSQI—the Pittsburgh Sleep Quality Index, ISI—the Insomnia Severity Index, ESS—the Epworth Sleepiness Scale, BDI—the Beck Depression Inventory, REM—rapid eye movement sleep, REM-L—rapid eye movement sleep latency, MDD—major depressive disorder, WASO—wake after sleep onset. ↑—increased sleep variable, ↓—decreased sleep variable, ~ dose-dependent effect on the evaluated sleep variable.

References

  1. Barker, M.M.; Beresford, B.; Bland, M.; Fraser, L.K. Prevalence and Incidence of Anxiety and Depression Among Children, Adolescents, and Young Adults With Life-Limiting Conditions: A Systematic Review and Meta-analysis. JAMA Pediatr. 2019, 173, 835–844.
  2. Urrila, A.S.; Paunio, T.; Palomäki, E.; Marttunen, M. Sleep in adolescent depression: Physiological perspectives. Acta Physiol. 2015, 213, 758–777.
  3. Palagini, L.; Baglioni, C.; Ciapparelli, A.; Gemignani, A.; Riemann, D. REM sleep dysregulation in depression: State of the art. Sleep Med. Rev. 2013, 17, 377–390.
  4. Palagini, L.; Hertenstein, E.; Riemann, D.; Nissen, C. Sleep, insomnia and mental health. J. Sleep Res. 2022, 31, e13628.
  5. Palagini, L.; Bastien, C.H.; Marazziti, D.; Ellis, J.G.; Riemann, D. The key role of insomnia and sleep loss in the dysregulation of multiple systems involved in mood disorders: A proposed model. J. Sleep Res. 2019, 28, e12841.
  6. Wang, Y.-Q.; Li, R.; Zhang, M.-Q.; Zhang, Z.; Qu, W.-M.; Huang, Z.-L. The Neurobiological Mechanisms and Treatments of REM Sleep Disturbances in Depression. Curr. Neuropharmacol. 2015, 13, 543–553.
  7. Steiger, A.; Pawlowski, M. Depression and Sleep. Int. J. Mol. Sci. 2019, 20, 607.
  8. Augustinavicius, J.L.S.; Zanjani, A.; Zakzanis, K.K.; Shapiro, C.M. Polysomnographic features of early-onset depression: A meta-analysis. J. Affect. Disord. 2014, 158, 11–18.
  9. Van Someren, E.J.W. Brain mechanisms of insomnia: New perspectives on causes and consequences. Physiol. Rev. 2021, 101, 995–1046.
  10. Gazea, M.; Del Rio-Bermudez, C.; Nissen, C.; Adamantidis, A.R. Chapter 17—Functions and Circuits of REM Sleep. In Handbook of Sleep Research; Dringenberg, H.C., Ed.; Handbook of Behavioral Neuroscience; Elsevier: Amsterdam, The Netherlands, 2019; Volume 30, pp. 249–267.
  11. Drakatos, P.; Olaithe, M.; Verma, D.; Ilic, K.; Cash, D.; Fatima, Y.; Higgins, S.; Young, A.H.; Chaudhuri, K.R.; Steier, J.; et al. Periodic limb movements during sleep: A narrative review. J. Thorac. Dis. 2021, 13, 6476–6494.
  12. Figorilli, M.; Puligheddu, M.; Congiu, P.; Ferri, R. The Clinical Importance of Periodic Leg Movements in Sleep. Curr. Treat. Options Neurol. 2017, 19, 10.
  13. Boz, S.; Lanquart, J.P.; Mungo, A.; Delhaye, M.; Loas, G.; Hein, M. Risk of Excessive Daytime Sleepiness Associated to Major Depression in Adolescents. Psychiatr. Q. 2021, 92, 1473–1488.
  14. Wichniak, A.; Wierzbicka, A.; Walęcka, M.; Jernajczyk, W. Effects of Antidepressants on Sleep. Curr. Psychiatry Rep. 2017, 19, 63.
  15. Hutka, P.; Krivosova, M.; Muchova, Z.; Tonhajzerova, I.; Hamrakova, A.; Mlyncekova, Z.; Mokry, J.; Ondrejka, I. Association of Sleep Architecture and Physiology with Depressive Disorder and Antidepressants Treatment. Int. J. Mol. Sci. 2021, 22, 1333.
  16. Kolla, B.P.; Mansukhani, M.P.; Bostwick, J.M. The influence of antidepressants on restless legs syndrome and periodic limb movements: A systematic review. Sleep Med. Rev. 2018, 38, 131–140.
  17. Wilson, S.; Højer, A.-M.; Buchberg, J.; Areberg, J.; Nutt, D.J. Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 1, a pharmacokinetic/pharmacodynamic comparison with paroxetine in healthy men. J. Psychopharmacol. 2015, 29, 1085–1091.
  18. Sanchez, C.; Asin, K.E.; Artigas, F. Vortioxetine, a novel antidepressant with multimodal activity: Review of preclinical and clinical data. Pharmacol. Ther. 2015, 145, 43–57.
  19. Areberg, J.; Petersen, K.B.; Chen, G.; Naik, H. Population pharmacokinetic meta-analysis of vortioxetine in healthy individuals. Basic Clin. Pharmacol. Toxicol. 2014, 115, 552–559.
  20. Chen, G.; Højer, A.-M.; Areberg, J.; Nomikos, G. Vortioxetine: Clinical Pharmacokinetics and Drug Interactions. Clin. Pharmacokinet. 2018, 57, 673–686.
  21. Findling, R.L.; Robb, A.S.; DelBello, M.P.; Huss, M.; McNamara, N.K.; Sarkis, E.H.; Scheffer, R.E.; Poulsen, L.H.; Chen, G.; Lemming, O.M.; et al. A 6-Month Open-Label Extension Study of Vortioxetine in Pediatric Patients with Depressive or Anxiety Disorders. J. Child Adolesc. Psychopharmacol. 2018, 28, 47–54.
  22. Findling, R.L.; DelBello, M.P.; Zuddas, A.; Emslie, G.J.; Ettrup, A.; Petersen, M.L.; Schmidt, S.N.; Rosen, M. Vortioxetine for Major Depressive Disorder in Adolescents: 12-Week Randomized, Placebo-Controlled, Fluoxetine-Referenced, Fixed-Dose Study. J. Am. Acad. Child Adolesc. Psychiatry 2022, 61, 1106–1118.e2.
  23. De Diego-Adeliño, J.; Crespo, J.M.; Mora, F.; Neyra, A.; Iborra, P.; Gutiérrez-Rojas, L.; Salonia, S.F. Vortioxetine in major depressive disorder: From mechanisms of action to clinical studies. An updated review. Expert Opin. Drug Saf. 2022, 21, 673–690.
  24. Bennabi, D.; Haffen, E.; Van Waes, V. Vortioxetine for Cognitive Enhancement in Major Depression: From Animal Models to Clinical Research. Front. Psychiatry 2019, 10, 771.
  25. Leiser, S.C.; Pehrson, A.L.; Robichaud, P.J.; Sanchez, C. Multimodal antidepressant vortioxetine increases frontal cortical oscillations unlike escitalopram and duloxetine—A quantitative EEG study in rats. Br. J. Pharmacol. 2014, 171, 4255–4272.
  26. Nissen, T.D.; Laursen, B.; Viardot, G.; l’Hostis, P.; Danjou, P.; Sluth, L.B.; Gram, M.; Bastlund, J.F.; Christensen, S.R.; Drewes, A.M. Effects of Vortioxetine and Escitalopram on Electroencephalographic Recordings—A Randomized, Crossover Trial in Healthy Males. Neuroscience 2020, 424, 172–181.
  27. Liguori, C.; Ferini-Strambi, L.; Izzi, F.; Mari, L.; Manfredi, N.; D’Elia, A.; Mercuri, N.B.; Placidi, F. Preliminary evidence that vortioxetine may improve sleep quality in depressed patients with insomnia: A retrospective questionnaire analysis. Br. J. Clin. Pharmacol. 2019, 85, 240–244.
  28. Cao, B.; Park, C.; Rosenblat, J.D.; Chen, Y.; Iacobucci, M.; Subramaniapillai, M.; Mansur, R.B.; Zuckerman, H.; Lee, Y.; McIntyre, R.S. Changes in sleep predict changes in depressive symptoms in depressed subjects receiving vortioxetine: An open-label clinical trial. J. Psychopharmacol. 2019, 33, 1388–1394.
  29. Doghramji, K.; Jangro, W.C. Adverse Effects of Psychotropic Medications on Sleep. Sleep Med. Clin. 2016, 11, 503–514.
  30. Leiser, S.C.; Iglesias-Bregna, D.; Westrich, L.; Pehrson, A.L.; Sanchez, C. Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism. J. Psychopharmacol. 2015, 29, 1092–1105.
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Subjects: Pharmacology & Pharmacy
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Zuzana Mlyncekova
,
Peter Hutka
,
Zuzana Visnovcova
,
Nikola Ferencova
,
Veronika Kovacova
,
Andrea Macejova
,
Ingrid Tonhajzerova
,
Igor Ondrejka
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Update Date: 20 Nov 2023
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