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

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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

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

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

    Article  PubMed  Google 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

  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

    Article  PubMed  Google Scholar 

  4. 4.

    Douglas NJ, Engleman HM (1998) CPAP therapy: outcomes and patient use. Thorax 53(Suppl 3):S47–S48

    PubMed  Google Scholar 

  5. 5.

    Carley DW, Olopade C, Ruigt GS, Radulovacki M (2007) Efficacy of mirtazapine in obstructive sleep apnea syndrome. Sleep 30:35–41

    Article  Google 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

    CAS  Article  PubMed  Google 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

    Article  PubMed  Google 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)

    Google 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 5:389–402

    CAS  Article  Google 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

    Article  Google 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

    CAS  Article  PubMed  Google 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

    CAS  Article  PubMed  Google 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

    CAS  Article  PubMed  Google 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

    Article  PubMed  Google Scholar 

  15. 15.

    Higgins J, Green S (editors) (2011) Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011].

  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 31:824–831

    Article  Google 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

    CAS  Article  PubMed  Google 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

    Article  Google 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 22:61–67

    CAS  PubMed  Google Scholar 

  20. 20.

    Berry RB, Yamaura EM, Gill K, Reist C (1999) Acute effects of paroxetine on genioglossus activity in obstructive sleep apnea. Sleep 22:1087–1092

    CAS  Article  Google 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

    CAS  Article  PubMed  Google 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 22:667–689

  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, Illinois

  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

    Article  PubMed  Google 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 36:5–8

    CAS  PubMed  Google 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 19:621–624

    CAS  PubMed  Google 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

    Article  PubMed  Google 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

    CAS  Article  PubMed  Google 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

    Article  PubMed  Google 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

    CAS  Article  PubMed  Google 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–S110

    CAS  Article  Google Scholar 

  33. 33.

    Ballard RD (2008) Management of patients with obstructive sleep apnea. J Fam Pract 57:S24–S30

    PubMed  Google 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

    Article  PubMed  Google Scholar 

  36. 36.

    Abad V, Guilleminault C (2006) Pharmacological management of sleep apnoea. Expert Opin Pharmacother 7:11–23

    CAS  Article  Google 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

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Reyes Enciso.

Ethics declarations

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 659 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

AbdelFattah, M.R., Jung, S.W., Greenspan, M.A. et al. Efficacy of Antidepressants in the Treatment of Obstructive Sleep Apnea Compared to Placebo. A Systematic Review with Meta-Analyses.. Sleep Breath 24, 443–453 (2020). https://doi.org/10.1007/s11325-019-01954-9

Download citation

Keywords

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