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Efficacy of Antidepressants in the Treatment of Obstructive Sleep Apnea Compared to Placebo. A Systematic Review with Meta-Analyses.

  • Magda R. AbdelFattah
  • Song W. Jung
  • Melvin A. Greenspan
  • Mariela Padilla
  • Reyes EncisoEmail author
Sleep Breathing Physiology and Disorders • Review

Abstract

Purpose

To establish the efficacy of oral antidepressants compared to placebo in improving obstructive sleep apnea (OSA) as measured on a polysomnography study. Secondary outcomes included self-reported sleepiness.

Methods

Authors identified prospective randomized placebo-controlled studies from MEDLINE through PubMed, Web of Science, the Cochrane Library and EMBASE up to February 2019 in English language. Antidepressants included tricyclic antidepressants (TCA), tetracyclic antidepressants (TeCA), selective serotonin reuptake inhibitors (SSRI), and serotonin receptor modulators (SRM). Studies were assessed for inclusion and exclusion criteria, as well as risk of bias based on the Cochrane handbook.

Results

The initial search yielded 254 unduplicated references ultimately reduced to 8 relevant studies, in which 198 OSA participants were included. Patients with an average baseline AHI of 26.7 events/hour taking 15-45mg mirtazapine had a statistically significant reduction in apnea-hypopnea index compared to placebo by -10.5 events/hour (p<0.001), apnea index by -3.6 events/hour (p=0.001) and hypopnea index by -5.9 events/hour (p=0.037). In one study, patients taking 100mg trazodone 1 night improved significantly in AHI compared to placebo group (p<0.001). Arousal index, sleepiness, and sleep efficiency were not statistically significantly reduced with any antidepressant medication compared to placebo (p>0.05).

Conclusions

Of the five antidepressant medications studied, only mirtazapine and trazadone showed a statistically significant reduction in AHI in the treated groups but not in sleepiness scale nor an increase in sleep efficiency. In this review, the total sample sizes were small, adverse side effects of some of the antidepressant medications were clinically significant, overall risk of bias of the studies was high or unclear, and overall quality of the evidence was low. Based on the evidence available at this time, we cannot recommend the antidepressants studied in the treatment of OSA.

Keywords

Obstructive sleep apnea Antidepressants Mirtazapine Trazodone Polysomnography Apnea Hypopnea Index apnea index sleepiness 

Abbreviations

CPAP

continuous positive airway pressure;

MAD

mandibular advancement device;

OSA

obstructive sleep apnea;

RCT

randomized controlled trial;

M.R.A

Dr. Magda R AbdelFattah;

S.W.J

Dr. Song Woo Jung;

M.A.G

Dr. Melvin A Greenspan;

R.E

Dr. Reyes Enciso;

AASM

American Academy of Sleep Medicine;

AHI

Apnea–hypopnea index;

CI

confidence interval;

PSG

polysomnography;

TCAs

Tricyclic antidepressants

TeCAs

Tetracyclic antidepressants

SSRIs

Selective serotonin reuptake inhibitors

SRMs

Serotonin receptor modulators

SNRIs

Selective serotonin-norepinephrine reuptake inhibitors

MAOs

Monoamine oxidase inhibitors

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-analyses

PICO

Patient, intervention, comparison and outcome

REM

Rapid eye movement

NREM

Non-rapid eye movement

SD

Standard deviation

SEM

Standard error of the mean

IQR

Interquartile range

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

For this type of study (systematic review), formal consent is not applicable.

Ethical approval

For this type of study (systematic review), ethical approval is not applicable.

Supplementary material

11325_2019_1954_MOESM1_ESM.docx (659 kb)
ESM 1 (DOCX 659 kb)

References

  1. 1.
    Bratton DJ, Gaisl T, Schlatzer C, Kohler M (2015) Comparison of the effects of continuous positive airway pressure and mandibular advancement devices on sleepiness in patients with obstructive sleep apnoea: A network meta-analysis. Lancet Respir Med 3:869–878.  https://doi.org/10.1016/S2213-2600(15)00416-6 CrossRefPubMedGoogle Scholar
  2. 2.
    Wolkove N, Elkholy O, Baltzan M, et al (2007) Sleep and aging: 2. Management of sleep disorders in older people.CMAJ 176:1449–1454.  https://doi.org/10.1503/cmaj.070335 CrossRefGoogle Scholar
  3. 3.
    Weaver TE, Grunstein RR (2008) Adherence to Continuous Positive Airway Pressure Therapy: The Challenge to Effective Treatment. Proc Am Thorac Soc 5:173–178.  https://doi.org/10.1513/pats.200708-119mg CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Douglas NJ, Engleman HM (1998) CPAP therapy: outcomes and patient use. Thorax 53(Suppl 3):S47–S48PubMedPubMedCentralGoogle Scholar
  5. 5.
    Carley DW, Olopade C, Ruigt GS, Radulovacki M (2007) Efficacy of mirtazapine in obstructive sleep apnea syndrome. Sleep 30:35–41CrossRefGoogle Scholar
  6. 6.
    Stahl SM (1998) Not so selective serotonin reuptake inhibitors. J Clin Psychiatry 59:343–344.  https://doi.org/10.1016/S0165-0327(98)00221-3 CrossRefPubMedGoogle Scholar
  7. 7.
    D’Agostino A, English CD, Rey JA (2015) Vortioxetine (brintellix): a new serotonergic antidepressant. P T 40:36–40.  https://doi.org/10.4088/JCP.14027ah1 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ritter J, Lewis L, Mant T, Ferro A (2008) A textbook of clinical pharmacology and therapeutics, 5th edn. CRC Press, London (England)CrossRefGoogle Scholar
  9. 9.
    Davis R, Wilde M (1996) Mirtazapine A Review of its Pharmacology and Therapeutic Potential in the Management of Major Depression. CNS Drugs 5:389–402CrossRefGoogle Scholar
  10. 10.
    Wichniak A, Wierzbicka A, Walęcka M, Jernajczyk W (2017) Effects of Antidepressants on Sleep. Curr Psychiatry Rep 19:1–7.  https://doi.org/10.1007/s11920-017-0816-4 CrossRefGoogle Scholar
  11. 11.
    Douse MA, White DP (1996) Serotonergic effects on hypoglossal neural activity and reflex responses. Brain Res 726:213–222.  https://doi.org/10.1016/0006-8993(96)00335-6 CrossRefPubMedGoogle Scholar
  12. 12.
    Berger AJ, Bayliss DA, Viana F (1992) Modulation of neonatal rat hypoglossal motoneuron excitability by serotonin. Neurosci Lett 143:164–168.  https://doi.org/10.1016/0304-3940(92)90257-8 CrossRefPubMedGoogle Scholar
  13. 13.
    Veasey SC, Panckeri KA, Hoffman EA et al (1996) The Effects of Serotonin Antagonists in an Animal Model of Sleep-Disordered Breathing. Am J Respir Crit Care Med 153:776–786.  https://doi.org/10.1164/ajrccm.153.2.8564132 CrossRefPubMedGoogle Scholar
  14. 14.
    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097.  https://doi.org/10.1371/journal.pmed.1000097 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Higgins J, Green S (editors) (2011) Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011].Google Scholar
  16. 16.
    Marshall NS, Yee BJ, Desai AV et al (2008) Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea. Sleep 31:824–831CrossRefGoogle Scholar
  17. 17.
    Taranto-Montemurro L, Sands SA, Edwards BA et al (2016) Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation. Eur Respir J 48:1340–1350.  https://doi.org/10.1183/13993003.00823-2016 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Schwingshackl L, Knüppel S, Schwedhelm C, Hoffmann GMB, Stelmach-Mardas M, Dietrich S, Eichelmann F, Kontopantelis EIK, Aleksandrova K, Lorkowski S, Leitzmann MF, Kroke ABH (2017) Perspective: NutriGrade: A Scoring System to Assess and Judge the Meta-Evidence of Randomized Controlled Trials and Cohort Studies in Nutrition Research. Adv Nutr An Int Rev J 8:789–790.  https://doi.org/10.3945/an.117.016188 CrossRefGoogle Scholar
  19. 19.
    Kraiczi H, Hedner J, Dahlof P et al (1999) Effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnea. Sleep 22:61–67PubMedGoogle Scholar
  20. 20.
    Berry RB, Yamaura EM, Gill K, Reist C (1999) Acute effects of paroxetine on genioglossus activity in obstructive sleep apnea. Sleep 22:1087–1092CrossRefGoogle Scholar
  21. 21.
    Brownell LG, West P, Sweatman P et al (1982) Protriptyline in obstructive sleep apnea: a double-blind trial. N Engl J Med 307:1037–1042.  https://doi.org/10.1056/NEJM198210213071701 CrossRefPubMedGoogle Scholar
  22. 22.
    No authors. (1999) Sleep-related breathing disorders in adults: Recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 22:667–689Google Scholar
  23. 23.
    Iber C, Ancoli-Israel S, Chesson A, Quan S. (2007) The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, 1st Ed. Westchester, IllinoisGoogle Scholar
  24. 24.
    Smales ET, Edwards BA, Deyoung PN et al (2015) Trazodone effects on obstructive sleep apnea and non-REM arousal threshold. Ann Am Thorac Soc 12:758–764.  https://doi.org/10.1513/AnnalsATS.201408-399OC CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Stepanski EJ, Conway WA, Young DK et al (1988) A double-blind trial of protriptyline in the treatment of sleep apnea syndrome. Henry Ford Hosp Med J 36:5–8PubMedGoogle Scholar
  26. 26.
    Berry RB, Budhiraja R, Gottlieb DJ, et al. (2012) Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin sleep Med. 8(5):597-619.  https://doi.org/10.5664/jcsm.2172
  27. 27.
    Brownell LG, Perez-Padilla R, West P, Kryger MH (1983) The role of protriptyline in obstructive sleep apnea. Bull Eur Physiopathol Respir 19:621–624PubMedGoogle Scholar
  28. 28.
    Rosenberg R, Doghramji P (2009) Optimal treatment of obstructive sleep apnea and excessive sleepiness. Adv Ther 26:295–312.  https://doi.org/10.1007/s12325-009-0016-7 CrossRefPubMedGoogle Scholar
  29. 29.
    Lin CM, Huang YS, Guilleminault C (2012) Pharmacotherapy of obstructive sleep apnea. Expert Opin Pharmacother 13:841–857.  https://doi.org/10.1517/14656566.2012.666525 CrossRefPubMedGoogle Scholar
  30. 30.
    Jayaraman G, Sharafkhaneh H, Hirshkowitz M, Sharafkhaneh A (2008) Pharmacotherapy of obstructive sleep apnea. Ther Adv Respir Dis 2:375–386.  https://doi.org/10.1177/1753465808098225 CrossRefPubMedGoogle Scholar
  31. 31.
    Grunstein RR, Hedner J, Grote L (2001) Treatment options for sleep apnoea. Drugs 61:237–251.  https://doi.org/10.2165/00003495-200161020-00007 CrossRefPubMedGoogle Scholar
  32. 32.
    Levy P, Pepin JL, Mayer P et al (1996) Management of simple snoring, upper airway resistance syndrome, and moderate sleep apnea syndrome. Sleep 19:S101–S110CrossRefGoogle Scholar
  33. 33.
    Ballard RD (2008) Management of patients with obstructive sleep apnea. J Fam Pract 57:S24–S30PubMedGoogle Scholar
  34. 34.
    Smith I, Lasserson TJ, Wright J (2006) Drug therapy for obstructive sleep apnoea in adults. Cochrane Database Syst Rev:CD003002.  https://doi.org/10.1002/14651858.CD003002.pub2
  35. 35.
    Heck T, Zolezzi M (2015) Obstructive sleep apnea: Management considerations in psychiatric patients. Neuropsychiatr Dis Treat 11:2691–2698.  https://doi.org/10.2147/NDT.S90521 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Abad V, Guilleminault C (2006) Pharmacological management of sleep apnoea. Expert Opin Pharmacother 7:11–23CrossRefGoogle Scholar
  37. 37.
    Kohler M, Bloch KE, Stradling JR (2009) Pharmacological approaches to the treatment of obstructive sleep apnoea. Expert Opin Investig Drugs 18:647–656.  https://doi.org/10.1517/13543780902877674 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Master of Science Program in Orofacial Pain and Oral MedicineHerman Ostrow School of Dentistry of USCLos AngelesUSA
  2. 2.Department of Restorative Dentistry & ProsthodonticsUniversity of Texas Health Science Center at Houston School of DentistryHoustonUSA
  3. 3.Division of Periodontology, Diagnostic Sciences and Dental Hygiene, Herman Ostrow School of Dentistry of USCLos AngelesUSA
  4. 4.Division of Dental Public Health and Pediatric Dentistry, Herman Ostrow School of DentistryUniversity of Southern CaliforniaLos AngelesUSA

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