Obstructive sleep apnea (OSA), the most common type of sleep-disordered breathing disorder, is highly prevalent and often undiagnosed.1 It is characterized by repeated cessation of breathing (apnea) or decreased airflow accompanied by reduction in oxygen saturation of 4% or more (hypopnea) during sleep.2 This occurs due to partial or complete obstruction of the upper airway during sleep when the muscles of the pharynx are more relaxed. Table 1 summarizes various definitions of sleep-disordered breathing.
Definition of Sleep-Related Breathing Disorders
The prevalence of OSA in the general population is approximately 20% for mild OSA, defined by an apnea-hypopnea index (AHI) of 5 to 15 events per hour.1 OSA is more commonly seen in obese patients. Patients with OSA are at increased risk of developing excessive daytime sleepiness (EDS), poor neurocognitive performance, and multi-organ dysfunction. This is thought to be caused by intermittent hypoxemia and sleep fragmentation from OSA. The severity and duration of OSA does not predict the severity of neurocognitive impairment or EDS. However, severe OSA increases the risk for cardiovascular mortality and morbidity.
A 40-year-old married man with a history of diabetes, obesity, and hypertension was seen in an outpatient psychiatric clinic for depression. He reported feeling depressed nearly every day for more than 1 month, with a decreased interest in previously enjoyable activities. The patient also complained of trouble maintaining sleep and daytime sleepiness. His wife described an episode when he fell asleep while driving and had an accident (fortunately, no one was injured). His Patient Healthcare Questionnaire (PHQ-9) score was 20 (normal is <10), indicating severe depression. On examination, his body mass index was 40 kg/m2 and his neck circumference was 20 inches. He was prescribed the selective serotonin reuptake inhibitor (SSRI) citalopram (20 mg/day) after an initial diagnosis of major depressive disorder (MDD) was made.
Three months later, the patient described some improvement in his mood but continued to complain of poor concentration and EDS. When asked about his sleep, his wife reported that he snored loudly and often stopped breathing then gasped for air.
Due to concern for OSA, an attended polysomnogram (PSG) was performed. It showed severe OSA with an AHI of 84 events per hour (normal is <5) and an arousal index of 50 per hour. Oxygen saturation nadir was 70%. A trial of continuous positive airway pressure (CPAP) was initiated during the PSG, and at pressure of 10 cm H2O most of the sleep-disordered breathing events were eliminated. Oxygen saturation was normalized. At the visit after CPAP initiation, the patient reported a remarkable improvement in his mood and a significant increase in his energy level. The patient requested to be tapered off his antidepressant medication and was able to maintain improvement in mood and alertness despite no longer taking citalopram.
Prevalence of Depression in Patients with OSA
The prevalence of depression in patients with OSA ranges from 5% to 63%.1,3 Depression reported is of variable severity. It is typically diagnosed via self-administered questionnaires or through clinician observations. Many of the depression questionnaires used have sleep-related items. Some studies have found no difference in prevalence of depression in OSA patients.4,5
In a retrospective review of Veteran's Health Administration data of more than 100,000 patients, depression was found to be more common in patients with OSA (21.8%) versus without OSA (9.43%).6 In the same study, patients with OSA also had an increased prevalence of other anxiety disorders. Millman et al.7 reported that among 55 patients with OSA, 45% had depressive symptoms on the Zung Depression Rating Scale. Moreover, those who had severe depression had higher AHI scores.
Many other studies have found higher rates of depression in patients with OSA. In a multinational European telephone survey of 18,980 people from five countries, approximately 18% of participants with a breathing-related disorder met Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)8 criteria for MDD.9 The prevalence of MDD without breathing-related disorder was 4.3%.
In the National Health and Nutrition Examination Survey, more than 9,000 patients were surveyed.10 Respondents were asked about snoring, snorting, gasping, or pauses in breathing while asleep, and also completed the PHQ-9 questionnaire. Snorting or stopping breathing for 5 or more nights per week was associated with probable MDD among men (odds ratio = 3.1; 95% confidence interval [CI], 1.8–5.2) and women (odds ratio = 3.0; 95% CI, 1.6–5.4).10
Is There a Relationship Between OSA and Depression?
Study results are mixed about whether OSA can cause depression. There may be several reasons for the mixed results. For example, severity of depression is not necessarily related to the number of symptoms, but to the severity of these symptoms. Similarly, magnitude of the AHI does not always translate into severity of EDS or neurocognitive dysfunction in patients with OSA. Comparing quantified and qualitative measures between the two diagnoses might demonstrate different relationships. Another source of variability is inconsistent diagnostic criteria and different questionnaires used in the studies.
Lastly, confounding factors such as cardiovascular disease, obesity, and diabetes may affect the relationship between OSA and depression. Both depression and OSA have been independently shown to be associated with metabolic syndrome and with cardiovascular disease.11–13
Most of the studies looking at the relationship between OSA and depression are either retrospective or cross-sectional in nature, with the exception of one study.1 Peppard et al.14 reported that significantly increased severity of sleep-disordered breathing was associated with double the risk of developing depression. Despite limitations, most of the studies show a higher rate of depression in patients with OSA, suggesting a relationship between OSA and depression. Causation remains to be demonstrated. Table 2 shows the diagnostic symptoms of OSA and MDD, as well as the overlapping symptoms between the two disorders.
Overlapping Symptoms of Obstructive Sleep Apnea and Depression
Sleep Fragmentation and Intermittent Hypoxemia
Studies suggest that OSA causes EDS, which is most likely mediated through intermittent hypoxemia and frequent arousals from sleep-disordered breathing.15,16 Recurrent intermittent hypoxemia, a common feature of OSA, has been studied in animal models and has been associated with dose-dependent cell loss in areas rich in dopaminergic and noradrenergic pathways. These pathways are involved in both sleep-wake regulation and depression.17,18 Imaging studies have demonstrated hippocampal and frontal cortex injury in OSA patients, and suggest that treatment of OSA might possibly reverse some of the changes.17,19
Role of Serotonin in Depression and Upper Airway Control in OSA
Decreased serotonin transmission has been implicated in the pathophysiology of depression, and SSRIs lead to improvement in depression.20 Serotonin has a stimulating effect on upper airway dilator motor neurons through the hypoglossal nucleus.21 Reduced transmission of serotonin in the central nervous system has been hypothesized to play a role in depression and reduced genioglossus activity in OSA.
OSA, depression, and cardiovascular disease are all associated with elevated levels of proinflammatory substances and cytokines.22 Interleukin-6 and tumor necrosis factor-alpha (TNF-alpha) are thought to contribute to EDS; administration of TNF antagonists has been shown to reduce EDS.23 TNF-alpha is also increased in patients with mood disorders.24 Proinflammatory substances could be a link among these illnesses.
In a study of 17 patients with treatment-resistant depression and comorbid OSA, Habukawa et al.25 showed improvement in Beck Depression Inventory (BDI), Hamilton Rating Scale for Depression (HRSD), and Epworth Sleepiness Score after use of CPAP for 2 months. BDI and HRSD scores decreased from 19.7 to 10.8 (P ˂ .01) and 16.7 to 8.0 (P ˂ .01), respectively. In another study, Means et al.26 reported improvement in BDI scores after 3 months of treatment with CPAP.
The effect of CPAP on psychological status was evaluated by McMahon et al.27 in a systematic literature review. Five of eight studies of a subset showed statistically significant improvement in depressive symptoms. The authors concluded that based on randomized, controlled studies, CPAP has a significant and positive impact on depressive symptoms. In another systematic review and meta-analysis, Povitz et al.28 showed that CPAP treatment resulted in improvement in depressive symptoms. Improvement was greater in trials where baseline scores of depression were high. These improvements are not confined to CPAP treatment; meta-analysis of five trials of mandibular advancement devices showed significant improvement in depressive symptoms versus controls.28 Hypoglossal nerve stimulation is another treatment for OSA, and it involves electrical stimulation of the genioglossal muscle causing tongue protrusion and stiffening of the anterior pharyngeal wall. In a study by Eastwood et al.,29 treatment of OSA by hypoglossal nerve stimulation also resulted in continuous improvement of BDI scores from baseline at the third and sixth months.
Adherence to CPAP treatment is an obstacle, and despite ongoing efforts to improve adherence, only 40% to 60% of patients continue CPAP use long-term or as prescribed.30 The Self-Efficacy Measure for Sleep Apnea was developed by Weaver et al.31 to assess adherence-related cognitions prior to initiation of CPAP. In their study, 213 patients with newly diagnosed OSA were surveyed, and approximately half were lacking knowledge of comorbidities associated with OSA (such as depression). Their research found that nonadherence is not only established early in treatment, but this early discontinuation may be in part due to a lack of pretreatment education. These patients were unable to draw a connection between being depressed and suffering from OSA.31
Clinicians should be careful treating depression or anxiety comorbid with insomnia with benzodiazepines in patients with OSA, because benzodiazepines may worsen OSA by decreasing pharyngeal muscle tone and can blunt the arousal response by increasing the arousal threshold.32,33
Depression and OSA are common comorbid conditions with serious health consequences. The prevalence of depression is higher in patients with OSA, both in clinical and community samples.
There is need for better identification of patients with comorbid depression and OSA. There is positive effect of treatment of OSA with CPAP and other modalities in patients with comorbid OSA and depression, but it is not conclusive because it is difficult to differentiate improvement of depressive symptoms per se from improvement in fatigue and EDS.
Further randomized, controlled studies using established diagnostic criteria for OSA and depression are needed. Clinicians are advised to screen for OSA in their patients presenting with depression and vice versa.
- Ejaz SM, Khawaja IS, Bhatia S, Hurwitz TD. Obstructive sleep apnea and depression: a review. Innov Clin Neurosci. 2011;8(8):17–25.
- Ballard RD. Management of patients with obstructive sleep apnea. J Fam Pract. 2008;57(8 Suppl):S24–30.
- BaHammam AS, Kendzerska T, Gupta R, et al. Comorbid depression in obstructive sleep apnea: an under-recognized association. Sleep Breath. 2015Jul9. [Epub ahead of print]. doi:10.1007/s11325-015-1223-x [CrossRef]
- Phillips BA, Berry DT, Lipke-Molby TC. Sleep-disordered breathing in healthy, aged persons. Fifth and final year follow-up. Chest. 1996;110(3):654–658. doi:10.1378/chest.110.3.654 [CrossRef]
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- Sharafkhaneh A, Giray N, Richardson P, Young T, Hirshkowitz M. Association of psychiatric disorders and sleep apnea in a large cohort. Sleep. 2005;28(11):1405–1411.
- Millman RP, Fogel BS, McNamara ME, Carlisle CC. Depression as a manifestation of obstructive sleep apnea: reversal with nasal continuous positive airway pressure. J Clin Psychiatry. 1989;50(9):348–351.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
- Ohayon MM. The effects of breathing-related sleep disorders on mood disturbances in the general population. J Clin Psychiatry. 2003;64(10):1195–1200. doi:10.4088/JCP.v64n1009 [CrossRef]
- Wheaton AG, Perry GS, Chapman DP, Croft JB. Sleep disordered breathing and depression among U.S. adults: National Health and Nutrition Examination Survey, 2005–2008. Sleep. 2012;35(4):461–467.
- Lett HS, Blumenthal JA, Babyak MA, et al. Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med. 2004;66(3):305–315.
- Khawaja IS, Westermeyer JJ, Gajwani P, Feinstein RE. Depression and coronary artery disease: the association, mechanisms, and therapeutic implications. Psychiatry (Edgmont). 2009;6(1):38–51.
- Ramasubbu R. Insulin resistance: a metabolic link between depressive disorder and atherosclerotic vascular diseases. Med Hypotheses. 2002;59(5):537–551. doi:10.1016/S0306-9877(02)00244-X [CrossRef]
- Peppard PE, Szklo-Coxe M, Hla KM, Young T. Longitudinal association of sleep-related breathing disorder and depression. Arch Intern Med. 2006;166(16):1709–1715. doi:10.1001/archinte.166.16.1709 [CrossRef]
- Cohen-Zion M, Stepnowsky C, Marler M, Shochat T, Kripke DF, Ancoli-Israel S. Changes in cognitive function associated with sleep disordered breathing in older people. J Am Geriatr Soc. 2001;49(12):1622–1627. doi:10.1111/j.1532-5415.2001.49270.x [CrossRef]
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- Cross RL, Kumar R, Macey PM, et al. Neural alterations and depressive symptoms in obstructive sleep apnea patients. Sleep. 2008;31(8):1103–1109.
- Gozal D, Daniel JM, Dohanich GP. Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat. J Neurosci. 2001;21(7):2442–2450.
- Zimmerman ME, Aloia MS. A review of neuroimaging in obstructive sleep apnea. J Clin Sleep Med. 2006;2(4):461–471.
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- McMahon JP, Foresman BH, Chisholm RC. The influence of CPAP on the neurobehavioral performance of patients with obstructive sleep apnea hypopnea syndrome: a systematic review. WMJ. 2003;102(1):36–43.
- Povitz M, Bolo CE, Heitman SJ, Tsai WH, Wang J, James MT. Effect of treatment of obstructive sleep apnea on depressive symptoms: systematic review and meta-analysis. PLoS Med. 2014;11(11):e1001762. doi:10.1371/journal.pmed.1001762 [CrossRef]
- Eastwood PR, Barnes M, Walsh JH, et al. Treating obstructive sleep apnea with hypoglossal nerve stimulation. Sleep. 2011;34(11):1479–1486.
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Definition of Sleep-Related Breathing Disorders
||Cessation of airflow for at least 10 seconds or more
||Reduction of airflow with resultant oxygen desaturation of ≥4%
||Average frequency of apnea and hypopnea events per hour of sleep
|Obstructive sleep apnea
||AHI of ≥15 or ≥5 associated symptoms such as excessive daytime sleepiness, impaired cognition, mood disorders, insomnia, hypertension, heart disease, or history of stroke
|Central sleep apnea
||AHI of ≥5 or ≥50% of the respiratory events occurring without any inspiratory effort—associated with symptoms of either excessive daytime sleepiness or disrupted sleep
Overlapping Symptoms of Obstructive Sleep Apnea and Depression
|Obstructive Sleep Apnea
Unrefreshing sleep despite sufficient opportunities to sleep