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. Author manuscript; available in PMC: 2022 Aug 3.
Published before final editing as: West J Nurs Res. 2021 Feb 3:193945921989656. doi: 10.1177/0193945921989656

Depressive Symptoms in Comorbid Obstructive Sleep Apnea and Insomnia: An Integrative Review

Bomin Jeon 1, Faith S Luyster 1, Judith A Callan 1, Eileen R Chasens 1
PMCID: PMC8329133  NIHMSID: NIHMS1665630  PMID: 33533324

Abstract

The purpose of this integrative review was to synthesize evidence concerning the relationship between comorbid obstructive sleep apnea and insomnia (OSA+I), and depressive symptoms. OSA and insomnia are common sleep disorders, recently comorbid OSA+I has been recognized as prevalent in adults. Although each sleep disorder increases the risk and severity of depressive symptoms, the effect of comorbid OSA+I on depressive symptoms remains unclear. A systematic search of PubMed, CINAHL, and PsycINFO identified fifteen data-based studies. All the studies were observational with either a cross-sectional (n = 14) or a case-control design (n = 1). Study quality was assessed. Most of the studies (n = 14) indicated that comorbid OSA+I had an additive role on depressive symptoms. Insomnia appeared to have a more important role than OSA in increasing the severity of depressive symptoms in persons with comorbid OSA+I.

Keywords: Insomnia, obstructive sleep apnea, comorbid obstructive sleep apnea and insomnia, comorbidity, depressive symptoms

This integrative review examines studies that assessed the risk and severity of depressive symptoms in adults with comorbid obstructive sleep apnea and insomnia (OSA+I). Insomnia refers to sleep-specific complaints that include difficulty initiating sleep, difficulty maintaining sleep, and early morning awakenings with an inability to return to sleep (American Psychiatric Association [APA], 2013). Insomnia has an estimated prevalence in the general population that ranges from 6% to 43% depending on whether persons meet the diagnostic criteria (6% to 22%) or are classified by insomnia symptoms (35% to 43%; Ohayon, 2002; Ohayon & Reynolds, 2009; Roth et al., 2011; Walsh et al., 2011). Insomnia has been found to increase the risk of other medical conditions. The most common concurrent medical conditions associated with insomnia are mental disorders, including depression and anxiety, and cardiovascular diseases including hypertension, coronary heart disease, and heart failure (Bathgate & Fernandez-Mendoza, 2018; Javaheri & Redline, 2017; Laugsand et al., 2011).

Characteristics of OSA are repetitive upper airway obstructions that result in apneas, cessation of breathing, and hypopneas, decrease in airflow by at least 50% accompanied by a 4% reduction in oxygen saturation (Berry et al., 2012). The average hourly number of apneas and hypopneas, the apnea-hypopnea index (AHI), determines the severity of OSA. A respiratory disturbance index (RDI), the average number of apneas, hypopneas, and respiratory effort-related arousals per hour, is an alternative method to determine the severity of OSA (Berry et al., 2012; Malhotra et al., 2018). There is a high prevalence of OSA in the general population: an estimated 38% of adults have at least mild OSA (AHI ≥ 5) and 17% of adults have moderate to severe OSA (AHI ≥ 15; Senaratna et al., 2017). OSA has been found to be a risk factor for cardiovascular (e.g., hypertension, coronary heart disease, heart failure), cerebrovascular (e.g., stroke), metabolic diseases (e.g., type 2 diabetes; Dong et al., 2013; Gaines et al., 2018), and mental disorders (e.g., depression, anxiety; Garbarino et al., 2020).

Although OSA and insomnia are exclusive sleep disorders regarding diagnostic criteria, there is increasing evidence that OSA and insomnia frequently coexist. A recent systematic review and meta-analysis examined the prevalence of comorbid OSA+I (Zhang et al., 2019). This study found the overall prevalence of insomnia among persons with OSA was 38%; likewise, 35% of insomnia patients had OSA and 29% of insomnia patients had moderate to severe OSA. These findings suggest that not only are OSA and insomnia are widespread but that they frequently coexist. The negative impact of each sleep disorder on chronic medical conditions highlights the importance of examining their comorbid presentation.

Sleep disturbances are a common symptom associated with depression. As many as 88% of persons with depression describe that they have difficulty falling asleep, maintaining sleep, or poor sleep quality (Murphy & Peterson, 2017). Sleep disturbances are symptoms of depression and also risk factors for depression. Multiple studies found an increased prevalence of depressive symptoms and depressive disorders in persons with insomnia or OSA (Garbarino et al., 2020; Ohayon, 2003; Sharafkhaneh et al., 2005; Vandeputte & de Weerd, 2003; Wahner-Roedler et al., 2007). Data from previous longitudinal studies found that both insomnia and OSA were factors for an increased risk of developing depression and an increased severity of depressive symptoms (Baglioni et al., 2011; Chen et al., 2013; Hein et al., 2017; Li et al., 2016; Peppard et al., 2006).

Statement of the Problem

In a recent narrative review, persons with comorbid OSA+I experience greater emotional impairments relative to persons with either insomnia or OSA alone (Sweetman et al, 2019). However, the effect of comorbid OSA+I on depressive symptoms has not been systematically reviewed and this relationship remains unclear.

Purpose

The purpose of this integrative review was to explore and synthesize current evidence to clarify the relationship between comorbid OSA+I and depressive symptoms.

Method

The Whittemore and Knafl’s methodology (2005) was used to conduct the literature search for this integrative review. This method of conducting an integrative review enables synthesis of evidence from studies utilizing various research methodologies, thereby providing a comprehensive overview of the literature on a given topic.

Search Strategies

This integrative review was based on a systematic search of the existing literature that followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (Moher et al., 2009) and used three biomedical electronic databases: PubMed, CINAHL, and PsycINFO. Articles published from January 1, 1973 to May 31, 2020 were included as 1973 was the first year that comorbid OSA+I appeared in the literature. The following key words and combinations were used: (“sleep initiation and maintenance disorders” OR “insomnia”) AND (“sleep apnea, obstructive” OR “sleep apnea” OR “sleep apnoea” OR “sleep disordered breathing”). The total 2,350 articles were found in the first search. In order to identify relevant articles missed by the previous search, additional records were identified by repeating the literature search using the previous search terms with additional combinations of keywords: (“depressive disorder” OR “depression” OR “ depressive disorder, major” OR “depressed mood” OR “depressive symptoms”). The additional search found 294 articles. Reference lists of selected articles and a recent published review paper (Sweetman et al., 2019) about comorbid OSA+I were manually reviewed and identified an additional three articles. Initial screening was conducted by the first author (BJ) through reading titles and abstracts. Articles retrieved for initial screening were screened through the full text according to the purpose of the study and eligibility criteria. The two authors (BJ and ERC) read the full texts of articles and discussed any concerns or discrepancies in the inclusion of articles. The entire study selection process and the rationales for exclusion are shown in Figure 1.

Figure 1. PRISMA Flow Diagram for the Integrative Review.

Figure 1

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Eligibility Criteria

Studies were included if they (a) focused on comorbid OSA +I, (b) contained an assessment of depressive symptoms, and (c) written in English. Articles excluded from the integrative review were those that (a) focused on sleep disorders other than OSA + I, and (b) were not data-based articles (e.g., review paper, commentary).

Operational Definition for Insomnia, OSA, and Depression

Insomnia can be classified by the diagnostic criteria, the presence of insomnia symptoms or by objective measures of sleep. The diagnostic criteria for insomnia disorder by the Diagnostic and Statistical Manual of Mental Disorders (5th edition; DSM-5; APA, 2013) and the International Classification of Sleep Disorders, 3rd edition (ICSD-3; Sateia, 2014) are nocturnal symptoms of difficulty initiating or maintaining sleep or early morning awakenings with an inability to return to sleep. Symptoms occur at least 3 nights per week for at least 3 months, despite adequate opportunity and circumstances to sleep, and are accompanied by significant distress or impairment in social, occupational, or other important areas of functioning. Insomnia is also classified by self-reported questionnaires that measured the severity and impact of insomnia symptoms and the objective measures of nocturnal insomnia symptoms such as difficulty initiating and maintaining sleep, i.e., taking more than 30 minutes to fall asleep (sleep latency), extended time (≥ 30 minutes) awake after sleep onset (WASO), or sleep duration of less than 6.5 hours (Buysse, 2013; Morin et al., 2015). In this review of studies, insomnia was defined by various measures including insomnia disorder according to the diagnostic criteria, insomnia symptoms (difficulty initiating sleep, difficulty maintaining sleep, and early morning awakenings) measured by self-reported questionnaires, and objective measures (sleep latency, WASO, total sleep duration), medical records for insomnia diagnosis, or self-report by participants of a doctor telling them the diagnosis.

The presence and level of severity to define OSA varied in the reviewed studies. Diagnosis of OSA requires an overnight polysomnography sleep study done in-laboratory or at home with the measures of AHI or RDI (Berry et al., 2012). Severity of OSA is defined by the American Academy of Sleep Medicine as “mild” (AHI or RDI 5 to 14 per hour), “moderate” (AHI or RDI 15 to 29 per hour) or “severe” (AHI or RDI 30 or more) (Berry et al., 2012; Kapur et al., 2017). Symptoms of OSA include snoring, snorting/stopping breathing, and feeling overly sleepy during the day. In this review of studies, OSA was defined by the different criteria of AHI or RDI via polysomnography, OSA symptoms, medical records for OSA diagnosis, or self-report by participants of a doctor telling them the diagnosis.

Depression is mainly classified by depressive symptoms and depressive disorder. According to the diagnostic criteria for depressive disorder by DSM-5 (APA, 2013), depressive symptoms include depressed mood, anhedonia, feelings of worthlessness or guilt, recurrent suicidal ideation, fatigue or loss of energy, sleep disturbances, alteration of appetite or change in weight, diminished ability to think or concentrate, psychomotor retardation or agitation. The definition of clinical depression as a disorder is that the individual experiences five or more depressive symptoms nearly every day during a two-week period, and depressed mood or anhedonia must be present (APA, 2013). Self-reported depression questionnaires are commonly used to detect and assess the severity of depressive symptoms (Malhi & Mann, 2018). In this review of studies, depression was defined by self-reported questionnaires, depressive disorder which met diagnostic criteria, or medical records for depression diagnosis.

Data Extraction and Synthesis

Identified publications were analyzed by two independent authors (BJ, ERC). Articles were examined by first reading the title and abstract and those that met the inclusion criteria proceeded to full text review (Table 1). Data from the selected articles from the full text review were extracted and organized under the following headings: authors, year, and country; study design and sample source; sample details (sample size, sex, age, OSA severity); measures; and study findings. Extracted data were presented in tabular format and arranged sequentially by the year of publication and then by alphabet. The findings were iteratively compared for identification of relationships between articles. Articles with similar results were clustered based on the patient population evaluated: (a) the effect of comorbid insomnia on depressive symptoms among patients with OSA, (b) the effect of comorbid OSA+I on depressive symptoms in sleep clinic patients, and (c) the effect of comorbid OSA on depressive symptoms among patients with insomnia.

Table 1.

Characteristics and Findings of the Included Studies (n = 15)

Authors, Year, Country Study design & Sample Source Sample Details [n, %, mean (SD)] Measures Findings
Sample Size (n) Male (%) Age (yrs. or age bracket) AHI/RDI (/h)
Lichstein et al., 1999, United States - Descriptive cross-sectional study
- Community-dwelling persons who self-identified having insomnia		 Total: 80
- Insomnia: 57
- Comorbid OSA+I: 23		 40.0 69.4 (7.2) Insomnia:
3.4 (3.6)
Comorbid OSA+I:
29.0 (13.7)		 Insomnia: Structured interview based on ICSD criteria and sleep diary (SL and/or WASO > 30 min at least 3 times per week)
OSA: AHI > 15/h by laboratory-based PSG (moderate to severe OSA)
Depression: GDS		 ● Older adults with insomnia had worse depressive symptoms than those with comorbid OSA+I (p < .01).
Smith et al., 2004, Australia - Descriptive cross-sectional study
- Patients from sleep clinic		 Total: 105
- OSA: 64
- Comorbid OSA+I: 41		 69.5 53.9 (13.7) Not specified Insomnia: ISI ≥ 15 + SL and/or WASO > 30 min in PSG with at least one negative daytime consequence for 6 months
OSA: Physician’s diagnosis based on RDI by laboratory-based PSG
Depression: DASS-21 depression subscale 		● OSA patients with insomnia had worse depressive symptoms than OSA patients without insomnia (p < .001).
Ong et al., 2009, United States - Descriptive cross-sectional study; secondary analysis
- Patients from primary or mental health clinics		 Total: 51
- MDD patients with insomnia: 31
- MDD patients with comorbid OSA+I: 20		 43.0 48.3 (12.3) 14.9 (16.5) Insomnia: Structured interview based on DSM-IV-TR criteria for insomnia + SL and/or WASO > 30 min and TST ≤ 6.5 hours at least 3 times per week in sleep diary
OSA: AHI ≥ 15 by ambulatory PSG (moderate to severe OSA)
Depression: Presence: DSM-IV-TR criteria for MDD; Severity: HRSD-17, BDI-II		 ● No relationship in depressive symptoms between depressed patients with insomnia and those with comorbid OSA+I (HRSD-17; p = 0.099, BDI-II; p = .069).
Yang et al., 2011, Taiwan - Descriptive cross-sectional study
- Patients from sleep clinic		 Total: 88
- OSA: 33
- Comorbid OSA+I: 29
- Insomnia: 26		 100.0 OSA: 43.1 (8.5)
Comorbid OSA+I:
43.1 (11.2)
Insomnia:
37.5 (11.0)		 OSA: 17.2 (7.8)
Comorbid OSA+I:
16.4 (6.9)
Insomnia:
1.5 (1.5)		 Insomnia: Structured interview based on DSM-IV-TR criteria for insomnia
OSA: RDI ≥ 5/h by laboratory-based PSG (minimum criteria for OSA)
Depression: BDI-II		 ● Depressive symptoms were worse in persons with comorbid OSA+I (p < .001) and those with insomnia (p < .001) than those with OSA alone.
Kinugawa et al., 2012, France - Descriptive cross-sectional study
- Patients from sleep clinic		 Total: 64
- Insomnia: 20
- Comorbid OSA+I: 44		 37.5 Insomnia: 70.1 (7.8)
Comorbid OSA+I:
72.9 (8.9)		 33.6 (13.9) Insomnia: Structured interview based on ICSD-II criteria for insomnia
OSA: AHI ≥ 15/h by laboratory-based PSG
(moderate to severe OSA)
Depression: GDS		 ● No relationship in depressive symptoms between elderly adults with insomnia and those with comorbid OSA+I (p = .20).
Vozoris, 2012a; 2012b, United States - Retrospective, descriptive cross-sectional study
- NHANES data 2005–2008		 Total: 546
- OSA: 310
- Comorbid OSA+I: 236		 62.6 OSA:
40–59y; 59.2%
Comorbid OSA+I:
40–59y; 50.4%		 Not applicable Insomnia: Questions asking frequency of insomnia symptoms (difficulty falling asleep, prolonged nocturnal awakenings, undesired morning awakening) over the month; Experiencing at least one of insomnia symptoms ‘often’ or ‘almost always’
OSA: Participant reported physician- diagnosis of sleep apnea; the type of sleep apnea not specified.
Depression: Questions asking frequency of experiencing depressed mood and/or anhedonia over the previous two weeks; Experiencing depressive symptoms ≥ ½ day over 2 weeks		 ● The presence of depressed mood and/or anhedonia was higher for persons with comorbid OSA+I (26.5%) than those with OSA alone (7.6%).
● Among persons with OSA alone, depressed mood and/or anhedonia increase likelihood of having comorbid insomnia (OR = 3.53 [95% CI 1.49–8.35], p = .004)
Lichstein et al., 2013, United States - Retrospective, descriptive cross-sectional study
- Electronic medical records data of sleep clinic patients		 Total: 299
- OSA: 94
- Insomnia: 87
- Comorbid OSA+I: 108		 41.5 OSA: 49.5 (14.3)
Insomnia:
41.6 (14.3)
Comorbid OSA+I:
51.7 (14.1)		 OSA: 15.3 (1.5)
Insomnia:
3.3 (1.6)
Comorbid OSA+I:
17.8 (1.4)		 Insomnia: Structured interview based on ICSD-II criteria for insomnia
OSA: AHI ≥ 5/h by laboratory-based PSG (minimum criteria for OSA)
Depression: BDI-II		 ● Patients with comorbid OSA+I, and those with insomnia reported higher level of depressive symptoms than patients with OSA, although depressive symptoms were only significantly different between persons with insomnia and those with OSA (p < .01).
Mysliwiec et al., 2013, United States - Descriptive cross-sectional study
- U.S. military personnel		 Total: 110
- OSA: 27
- Insomnia: 28
- Comorbid OSA+I: 42
- Neither: 13		 97.3 33.6 (8.0) 13.4 (17.3) Insomnia: Structured interview based on ICSD-II criteria for insomnia
OSA: AHI > 5/h by laboratory-based PSG (minimum criteria for OSA)
Depression: Presence: QIDS ≥ 11; Severity: QIDS		 ● Depressive symptoms were worse in comorbid OSA+I and insomnia groups than OSA (p < .001) or control groups (p < .001).
● The presence of clinically significant depressive symptoms was higher for military personnel with comorbid OSA+I and with insomnia than those with OSA (p < .001) and control group (p = .001).
Bjorvatn et al., 2014, Norway - Descriptive cross-sectional study
- Random sample from national population registry of Norway		 Total: 93
- OSA: 39
- Comorbid OSA+I: 54		 78.5 40–69y; 75.2% Not applicable Insomnia: BIS; Experiencing 3 or higher days per week at least one of insomnia symptoms and daytime impairment or dissatisfaction of sleep
OSA: Questions asking frequency of OSA symptoms (snoring, breathing cessation during sleep, being tired or sleepy at work or during spare time); Experiencing all three symptoms ‘sometimes’ or ‘often’ or ‘always’
Depression: Self-reported depression (‘Do you have or have you previously been diagnosed with depression?’)		 ● Depression was higher in persons with comorbid OSA+I than those with OSA (p < .05).
Gupta & Knapp, 2014, Canada - Retrospective, case-control study
- U.S. representative epidemiologic data (NAMCS and NHAMCS) 1995– 2010		 Total: 62,253,910 ± 5,274,747 (weighted) / 7234 (unweighted)
- OSA: 58,259,806 ± 4,849,800 (weighted) / 6,576 (unweighted)
- Comorbid OSA+I: 3,994,104 ± 791,386 (weighted) / 658 (unweighted)		 60.5 ± 1.3 (weighted) 50.8 (0.6) Not applicable Insomnia: ICD9-CM code + ‘Reasons for visit’ coded as ‘Insomnia’
OSA: ICD9-CM code + ‘Reasons for visit’ coded as ‘Sleep Apnea’
Depression: ICD9-CM code		 ● The frequency of ‘Depressive disorders’ was not higher in patients with comorbid OSA+I than those with OSA (p = .720).
Lee et al., 2014, Korea - Descriptive cross-sectional study
- Patients from sleep clinic		 Total: 655
- OSA: 422
- Comorbid OSA+I: 233		 86.9 Men:
48.6 (11.8)
Women:
55.7 (9.2)		 28.5 (20.1) Insomnia: Questions asking insomnia symptoms (difficulty falling asleep, difficulty maintaining sleep, early morning awakening); Experiencing at least one of insomnia symptoms over one month at least one time per week
OSA: AHI ≥ 5/h by laboratory-based PSG (minimum criteria for OSA)
Depression: BDI		 ● Women with comorbid OSA+I had higher level of depressive symptoms than those with OSA (p < .05).
● Among men with OSA, insomnia symptoms were associated with higher level of depressive symptoms (p < .001).
Mysliwiec et al., 2014, United State - Retrospective, descriptive cross-sectional study
- Electronic health records data from U.S. military personnel		 Total: 206
- OSA: 39
- Comorbid OSA+I: 167		 96.6 36.5 (8.1) 8.44 (2.9) Insomnia: Structured interview based on ICSD-II criteria for insomnia
OSA: AHI ≥ 5 and < 15/h by laboratory-based PSG (mild OSA)
Depression: Service-related diagnosis of depression		 ● Service-related depression was more frequent in military personnel with comorbid OSA+I than those with OSA (p = .027; OR = 4.23, [95% CI .96 – 18.6]).
Hayley et al., 2015, United State - Retrospective, descriptive cross-sectional study
- NHANES data 2005–2008		 Total: 11,329
- OSA: 664
- Insomnia: 835
- Comorbid OSA+I: 1363
- Neither: 8467		 OSA: 60.4
Insomnia:
34.0
Comorbid OSA+I:
45.6		 OSA:
45–64y; 43.0%
Insomnia:
45–64y; 28.4%
Comorbid OSA+I:
45–64y; 41.4%		 Not applicable Insomnia: Self-reported physician-diagnosed insomnia + Experiencing all insomnia symptoms (trouble falling asleep, waking during the night, waking too early, feeling unrested during the day) ‘often’ or ‘almost always’
OSA: Self-reported physician-diagnosed OSA + Experiencing all OSA symptoms (snoring, snorting/stopping breathing, feeling overly sleepy during the day) ‘occasionally’ or ‘frequently and ‘often’ or ‘always’
Depression: Presence: PHQ-9 > 9; Severity: PHQ-9		 ● The presence of insomnia (OR = 6.57, [95% CI 3.89 – 11.11]), and OSA (OR = 5.14, [95% CI 3.14 – 8.41]), and OSA+I (OR = 6.67, [95% CI 4.44 – 10.00]) were associated with increased likelihood of experiencing depressive symptoms (all p < .001).
Lang et al., 2017, Australia - Retrospective, descriptive cross-sectional study
- MAILES data 2007–2012		 Total: 700
- OSA: 323
- Insomnia: 37
- Comorbid OSA+I: 47
- Neither: 293		 100.0 58.5 (11.0) AHI ≥ 10
OSA:
87.3%
Insomnia:
0%
Comorbid OSA+I:
12.7%		 Insomnia: Experiencing falling or maintaining sleep three or more times a week + fatigue (SF-36 vitality scale)
OSA: AHI ≥ 10/h by home PSG
(the part of mild OSA + moderate to severe OSA)
Depression: Presence: BDI-IA ≥10 or CES-D ≥16; Severity: CES-D, BDI-1A, PHQ-9		 ● The prevalence of clinically significant depressive symptoms was the highest in persons with comorbid OSA+I relative to those with OSA (p < .05) or insomnia (p < .05).
● Persons with comorbid OSA+I (all p < .05) or those with insomnia (all p < .05) were associated with higher level of depressive symptoms than those with OSA regardless of different depressive symptoms measurements.
Cho et al., 2018, Korea - Retrospective, descriptive cross-sectional study
- Patients from sleep clinic		 Total: 476
- OSA: 337
- Comorbid OSA+I: 139		 75.8 50.91 (13.7) OSA:
33.9 (24.6)
Comorbid OSA+I:
33.2 (25.1)		 Insomnia: ISI ≥ 15
OSA: AHI ≥ 5/h by laboratory-based PSG
(minimum criteria for OSA)
Depression: BDI-II		 ● Depression symptoms were worse in persons with comorbid OSA+I than those with OSA only (p < .001).
● Among persons with OSA alone, depressive symptoms increase likelihood of having comorbid insomnia (OR = 4.14, [95% CI 2.54 – 6.72], p < .001).
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Note. AHI = apnea/hypopnea index; BDI, BDI-1A, BDI-II = Beck Depression Inventory, 1A, II; BIS = Bergen Insomnia Scale; CES-D = Centre for Epidemiological Studies Depression Scale; CI = confidence interval; DASS-21 = Depression Anxiety Stress Scales – 21 Items; DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision; GDS = Geriatric Depression Scale; HRSD-17 = Hamilton Rating Scale for Depression-17; ICD9-CM = International Classification of Diseases, 9th edition; ICSD, ICSD-II = International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edition; ISI = Insomnia Severity Index; MAILES = Men Androgen Inflammation Lifestyle Environment Study; MDD = major depressive disorder; NAMCS = National Ambulatory Medical Care Survey; NHAMCS = National Hospital Ambulatory Medical Care Survey; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; OSA = obstructive sleep apnea; OSA+I = obstructive sleep apnea and insomnia; PHQ-9 = Patient Health Questionnaire-9; PSG = polysomnography; QIDS = Quick Inventory of Depressive Symptoms; RDI = respiratory disturbance index; SF-36 = 36-Item Short Form Health Survey Questionnaire; SL = sleep latency; TST = total sleep time; WASO = wake after sleep onset

Study Quality Assessment

The NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies (National Heart, Lung, and Blood Institute, n.d.) was used to evaluate the quality of each study. The quality of the study was evaluated by 14 questions asking research questions, study population, participation rate, inclusion criteria for recruitment, sample size justification, timeframe related with exposure and outcome measures, levels of exposure, the reliability of exposure and outcome measures, and the statistical analysis. The summary score of each study was calculated by the number of questions that met criteria. The questions not applicable to each study were not counted for calculation. Higher scores indicate higher quality. Scores are converted as percentages: poor (0 −25%), fair (25–50%), good (50–75%), or excellent (75–100%; Maass et al., 2015).

Results

Search Results

A total of 2,644 articles were identified through database searching (the first search = 2,350, the second search = 294), with three more found as additional records identified through reference lists review. Duplicates and those that did not meet the inclusion criteria were eliminated, resulting in 153 articles. Among the 153 articles that underwent a full- text review for eligibility, 15 articles were selected for critical analysis and synthesis of the findings (Figure 1). Of these articles, 14 were cross-sectional studies and one was a case-control study.

Study Quality

The selected articles had cross-sectional and case-control study design. As these study design measures exposure and outcomes at the same time, two questions in the NIH quality assessment tool regarding multiple exposure assessment and follow-up rates were not applicable to the selected articles. In a cross-sectional study and a case-control study, the participants are just selected based on the inclusion and exclusion criteria. The selected articles only reported the number of enrolled participants who met the eligibility criteria. Information regarding the participation rate was found in one article. The one article conducted a telephone survey among randomly selected eligible participants and the participants rate was reported as 72% (Bjorvatn et al., 2014). In addition, the question regarding levels of exposure was not applicable to the selected articles because the exposure was a dichotomous variable (i.e., having comorbid OSA+I or not). As a result, the quality of the selected articles were assessed by 10 or 11 questions of the NIH quality assessment tool for observational cohort and cross-sectional studies.

The mean score on the NIH quality assessment tool was 53%, which indicates good quality: 13 studies had good quality and 2 studies had fair quality (Figure 2). However, none of these observational studies did power calulation for sample size and eight studies did not account for potential confounding factors.

Figure 2. Quality Assessment Summary Based on the ‘Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies’ from National Health, Lung, and Blood Institute (n.d.).

Figure 2

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Note. The quality rating is categorized by poor (0–25%), fair (25–50%), good (50–75%), or excellent (75–100%) on items appropriate for observational studies.

Study Characteristics

Studies were conducted primarily in the United States, but also in other countries including Australia, Taiwan, France, Norway, Canada, and Korea (Table 1). Participants in the six studies were recruited from outpatient clinics including sleep clinics (Cho et al., 2018; Kinugawa et al., 2012; Lee et al., 2014; Smith et al., 2004; Yang et al., 2011) or primary care and mental health clinics (Ong et al., 2009). Four studies examined data from population-level databases (Gupta & Knapp, 2014; Hayley et al., 2015; Lichstein et al., 2013; Vozoris, 2012a, 2012b). Two studies selected samples from the community level population (Lang et al., 2017; Lichstein et al., 1999) and one study (Bjorvatn et al., 2014) randomly selected a sample from a general population registry. The remaining two studies were selected samples from U.S. military personnel (Mysliwiec et al., 2013, 2014).

All the studies included participants with comorbid OSA+I, but the approach to establishing the sample varied. Seven studies (Bjorvatn et al., 2014; Cho et al., 2018; Gupta & Knapp, 2014; Lee et al., 2014; Mysliwiec et al., 2014; Smith et al., 2004; Vozoris, 2012a, 2012b) assessed insomnia among persons with OSA, whereas three studies (Kinugawa et al., 2012; Lichstein et al., 1999; Ong et al., 2009) assessed OSA among persons with insomnia. The remaining of five studies classified participants into one of three or four groups of patients: insomnia only, OSA only, and comorbid OSA+I, or control group (Hayley et al., 2015; Lang et al., 2017; Lichstein et al., 2013; Mysliwiec et al., 2013; Yang et al., 2011). Within individual studies, the sample size ranged from 51 to 11,329. Structured interviews and self -reported insomnia questionnaires were used to assess insomnia (n = 10) along with data from sleep diaries and polysomnography. Most studies used laboratory and in-home polysomnography to assess OSA (n = 11). Depressive symptoms were evaluated by well-established questionnaires like the Beck Depression Inventory (Beck et al.,1988; n = 11; Table 1).

Participant Characteristics

Two studies only included males (Lang et al., 2017; Yang et al., 2011); the remaining studies included both males and females although the majority of the samples (n = 7) were predominantly male (Bjorvatn et al., 2014; Cho et al., 2018; Lee et al., 2014; Mysliwiec et al., 2013, 2014; Smith et al., 2004; Vozoris, 2012a, 2012b).

Most of the studies (Bjorvatn et al., 2014; Cho et al., 2018; Kinugawa et al., 2012; Lang et al., 2017; Lee et al., 2014; Lichstein et al., 2013; Mysliwiec et al., 2013, 2014; Smith et al., 2004; Yang et al., 2011) did not disclose information about race and ethnicity. Of the five studies that did report race and/or ethnicity, the majority (54.2% – 86.0%) of the participants identified as White or non-Hispanic White (Gupta & Knapp, 2014; Hayley et al., 2015; Lichstein et al., 1999; Ong et al., 2009; Vozoris, 2012a, 2012b).

In three studies (Bjorvatn et al., 2014; Hayley et al., 2015; Vozoris, 2012a, 2012b), participants were stratified by age group; the middle-age range was the most common, and the mean age in remaining articles ranged from 33.6 to 72.0 years old. Among these articles, participants in two studies (Bjorvatn et al., 2014; Lang et al., 2017) were limited to adults of a specific age range (40 – 70 years old or over 40 years old) and two studies limited participants to older adults (60 or more years old) (Kinugawa et al., 2012; Lichstein et al., 1999).

The estimated prevalence of comorbid OSA+I in the studies varied widely depending on the population characteristics and the diverse definition of OSA+I. In clinical populations, the estimated prevalence of comorbid OSA+I ranges from 29.0% to 85.6% (Bjorvatn et al., 2014; Cho et al., 2018; Kinugawa et al., 2012; Lee et al., 2014; Lichstein et al., 2013; Lichstein et al., 1999; Mysliwiec et al., 2013, 2014; Ong et al., 2009; Smith et al., 2004; Vozoris, 2012a, 2012b; Yang et al., 2011), and an estimated prevalence of 6.7% to 12.0% was found in the general population or community-based samples (Gupta & Knapp, 2014; Hayley et al., 2015; Lang et al., 2017).

Relationship between Comorbid OSA+I and Depressive Symptoms

Effect of Comorbid Insomnia on Depressive Symptoms among Patients with OSA

Six studies compared depressive symptoms between OSA patients with insomnia and OSA patients. In these studies, OSA patients with comorbid insomnia experienced higher levels of depressive symptoms or experienced higher rates of depressive symptoms compared to OSA patients (Bjorvatn et al., 2014; Cho et al., 2018; Lee et al., 2014; Mysliwiec et al., 2014; Smith et al., 2004; Vozoris, 2012a; 2012b).

Mysliwiec et al. (2014) reported that military personnel with mild OSA and insomnia more frequently experienced service-related depression than those with mild OSA alone (OR = 4.23, p = .027; Mysliwiec et al., 2014). A study by Lee et al. (2014), which investigated gender differences in the effect of insomnia among OSA patients, found that women with comorbid OSA+I had worse depressive symptoms than those with OSA alone (p < .05). The presence of insomnia significantly increased the severity of depressive symptoms in men with OSA (p < .001; Lee et al., 2014).

One study (Gupta & Knapp, 2014) differed from previous studies in that comorbid insomnia was not associated with higher rates of depression among OSA patients. The frequency of the diagnosis of depressive disorder was not significantly different when comparing patients with comorbid OSA+I to OSA patients (Gupta & Knapp, 2014). Insomnia, OSA and depressive disorders in this study were diagnosed and coded by physician using International Classification of Diseases, 9th edition, Clinical Modification (ICD9-CM) as the reason for the visit. The study’s authors hypothesized that their finding no significant association between comorbid OSA+I and depression compared to OSA alone may have been related to defining depression as cases identified by the ICD9-CM criteria. The authors concluded that the use of the clinical definition of depression may have underestimated the prevalence of depressive symptoms.

Effect of Comorbid Insomnia and OSA on Depressive Symptoms among Sleep Clinic Patients

Five studies from sleep clinic patients (Hayley et al., 2015; Lang et al., 2017; Lichstein et al., 2013; Mysliwiec et al., 2013; Yang et al., 2011) compared depressive symptoms among patients with insomnia only, OSA only, and comorbid OSA+I. Patients with comorbid OSA+I and those with insomnia alone had higher levels of depressive symptoms or experienced higher rates of depressive symptoms than those with OSA alone (Hayley et al., 2015; Lang et al., 2017; Lichstein et al., 2013; Mysliwiec et al., 2013; Yang et al., 2011). In theses studies, persons with comorbid OSA+I did not report worse depressive symptoms than those with insomnia alone when measured by either the Beck Depression Inventory Inventory (BDI-II, BDI-1A), Center for Epidemiological Studies Depression Scale (CES-D), Patient Health Questionnaire-9 (PHQ-9), or Quick Inventory of Depressive Symptoms (QIDS; Lang et al., 2017; Lichstein et al., 2013; Mysliwiec et al., 2013; Yang et al., 2011).

Effect of Comorbid OSA on Depressive Symptoms among Patients with Insomnia

Three studies examined the effect of comorbid OSA among insomnia patients. Compared with insomnia patients, comorbid OSA did not increase the severity of depressive symptoms in insomnia patients with comorbid OSA (Kinugawa et al., 2012; Lichstein et al., 1999; Ong et al., 2009). There was no significant difference in the severity of depressive symptoms between insomnia patients and insomnia patients with comorbid OSA in older adults (Kinugawa et al., 2012) or between major depressive disorder patients with insomnia and those with comorbid OSA+I (Ong et al., 2009). In contrast, another study found that older adults with insomnia had worse depressive symptoms (mean Geriatric Depression Scale; GDS = 4.9 ± 4.5) compared to older adults with comorbid OSA+I (mean GDS = 2.7 ± 2.3) (p < .01; Lichstein et al., 1999).

Discussion

This integrative review systematically examined fifteen studies to address the relationship between comorbid OSA+I, and depressive symptoms. Our findings suggest that comorbid insomnia in persons with OSA contributed to higher severity and prevalence of depressive symptoms compared to persons with OSA alone (Cho et al., 2018; Lee et al., 2014; Smith et al., 2004; Bjorvatn et al., 2014; Mysliwiec et al., 2014; Vozoris, 2012a, 2012b). Comorbid OSA among persons with insomnia was not associated with increasing the severity of depressive symptoms (Kinugawa et al., 2012; Lichstein et al., 1999; Ong et al., 2009). In addition, persons with comorbid OSA+I, and those with insomnia alone, experienced more severe depressive symptoms than those with OSA alone; however, there was no significant difference in depressive symptoms between persons with comorbid OSA+I, and those with insomnia alone (Hayley et al., 2015; Lang et al., 2017; Lichstein et al., 2013; Mysliwiec et al., 2013; Yang et al., 2011). These findings indicate that comorbid OSA+I have a significant additive role on depressive symptoms and insomnia may account for a more important role than OSA in increasing the severity of depressive symptoms in persons with comorbid OSA+I.

Our findings add new information to the existing evidence about the close relationship between insomnia, OSA and depressive symptoms, by revealing that when insomnia coexists with OSA, depressive symptoms worsen. However, the mechanism underlying the additive role of insomnia in depressive symptoms in persons with OSA remains unclear. There are several plausible mechanisms that may explain how comorbid insomnia adds to the severity of depressive symptoms among OSA patients. One possible mechanism is associated with hyperarousal, a key factor of the underlying physiological mechanism of insomnia. Hyperarousal is associated with a decrease in respiratory arousal threshold, which is an index of arousal induced by respiratory stimuli. A low respiratory arousal threshold contributes to continuous unnecessary arousals and unstable breathing (Bonnet & Arand, 2010; Osman et al., 2018) and may lead to higher levels of AHI. Therefore, when insomnia is accompanied by OSA, the changed respiratory arousal threshold by hyperarousal may exacerbate the severity of OSA and consequently worsen depressive symptoms.

Another plausible mechanism is associated with the similar neuropathological activities in the brain of persons with insomnia, OSA, and depression. Recent neuroimaging studies have found similar abnormal neurological changes in the limbic system of persons with major depressive disorder, insomnia, and OSA (Bagherzadeh-Azbari et al., 2019; Gray et al., 2020; Huang et al., 2019; Khazaie et al., 2017; Wu et al., 2020). The limbic system is a brain area which governs emotional regulation, cognition, learning process, and memory. Insomnia has a connection with major depressive disorder in the amygdala, which processes emotional response in the limbic system. The hyperactivity of amygdala and its dysfunction in response to emotional regulation were found in both insomnia and major depressive disorder (Bagherzadeh-Azbari et al., 2019; Khazaie et al., 2017). In contrast, OSA is predominantly associated with major depressive disorder in response to the regulation of consciousness and memory (Khazaie et al., 2017). Taken together, insomnia is more likely to impair emotional processes in major depression disorder than OSA, which supports the findings from this review.

This integrative review represents the first comprehensive evaluation of the relationship between comorbid OSA+I, and depressive symptoms. However, this review has several limitations. One limitation is that variances in insomnia and OSA measurements included in this review could affect the inconsistent findings regarding the relationship between comorbid OSA+I, and depressive symptoms, which prevented the use of meta-analysis. In addition, these cross-sectional studies cannot be used to propose a causal relationship between insomnia and depressive symptoms in persons with OSA. In terms of measures of OSA, not all studies define OSA based on AHI or RDI. The effect of severity of OSA on the relationship between comorbid OSA+I, and depressive symptoms is unknown. Lastly, patients from sleep clinics were self-selected from the population for having a higher risk for sleep disorders compared to those from community or population-based data. However, it was not possible to compare the severity of sleep disorders due to the variances in insomnia and OSA measurements.

The integrative review synthesized the available evidence on the relationship between comorbid OSA+I and depressive symptoms. Overall, the studies reviewed found a significant additive role of insomnia in increasing depressive symptoms in persons with comorbid OSA+I. Our findings suggest that insomnia symptoms in OSA patients may be an important hidden variable which can impact the development and severity of depressive symptoms. In addition, the presence and severity of OSA in persons complaining of insomnia, and the presence and severity of insomnia in persons with OSA should be considered by health care researchers and clinicians because of the high prevalence of comorbidity. Likewise, the presence and severity of mood disturbances should be evaluated in persons with insomnia, OSA, and comorbid OSA+I. Future studies are needed to determine whether specific insomnia symptoms are associated with depressive symptoms among persons with OSA. In addition, research designed to test the causal relationship between comorbid OSA+I and depressive symptoms would contribute to building robust evidence in this area. An intervention study designed to test the effect of treatment of insomnia and/or OSA on depression in persons with OSA+I could potentially improve patient outcomes.

Funding

This research was supported by the National Institute of Nursing Research (NINR): K24 NR016685 (Chasens).

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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