S C I E N T I F I C I N V E S T I G AT I O N S

pii: jc-00354-14
http://dx.doi.org/10.5664/jcsm.5020

Depressive Symptoms before and after Treatment of

Obstructive Sleep Apnea in Men and Women
Cass Edwards, BSc1,2,3; Sutapa Mukherjee, MB, PhD2; Laila Simpson, PhD2,4,5; Lyle J. Palmer, PhD6; Osvaldo P. Almeida, MD7;
David R. Hillman, MB1,2,3,5
School of Surgery, University of Western Australia, Crawley, Australia; 2West Australian Sleep Disorders Research Institute,
1

Queen Elizabeth II Medical Centre, Nedlands, Australia; 3Department of Pulmonary Physiology and Sleep Medicine, Sir Charles
Gairdner Hospital, Nedlands, Australia; 4Centre for Genetic Origins of Health and Disease, University of Western Australia,
Crawley, Australia; 5Centre for Sleep Science, School of Anatomy, Physiology and Human Biology, University of Western
Australia, Crawley, Australia; 6The Joanna Briggs Institute and School of Translational Health Science, University of Adelaide,
Adelaide, Australia; 7WA Centre for Health & Ageing and School of Psychiatry & Clinical Neurosciences, University of Western
Australia, Crawley, Australia; Department of Psychiatry, Royal Perth Hospital, Perth, Australia

Study Objectives: To determine prevalence of depressive BMI (p < 0.001). In those without OSA, PHQ-9 ≥ 10 was more
symptoms in obstructive sleep apnea (OSA) and the impact common in women, but no gender difference was evident
of OSA treatment on depression scores. with OSA. Of 293 patients offered CPAP, 228 were compliant
Methods: Consecutive new patients referred for investigation (mean nightly use > 5 h) over 3 months of therapy. In them, with
of suspected OSA were approached. Consenting patients therapy, AHI decreased from 46.7 ± 27.4 to 6.5 ± 1.6 events/h,
completed a patient health questionnaire (PHQ-9) for PHQ-9 from 11.3 ± 6.1 to 3.7 ± 2.9 and PHQ-9 ≥ 10 from
depressive symptoms when attending for laboratory 74.6% to 3.9% (p < 0.001 in each case). Magnitude of change
polysomnography. Those with moderate/severe (apnea- in PHQ-9 was similar in men and women. Antidepressant use
hypopnea index [AHI] ≥ 15 events/h) and/or symptomatic mild was constant throughout.
OSA (AHI 5–14.99 events/h) were offered continuous positive Conclusions: Depressive symptoms are common in OSA
airway pressure (CPAP) therapy. PHQ-9 was repeated after and related to its severity. They improve markedly with CPAP,
3 months of CPAP with compliance recorded. Of a maximum implying a relationship to untreated OSA.
PHQ-9 score of 27, a cut point ≥ 10 (PHQ-9 ≥ 10) was Keywords: patient health questionnaire, depression,
used to indicate presence of clinically signifi cant depressive depressive symptoms, obstructive sleep apnea, continuous
symptoms. positive airway pressure.
Results: A total of 426 participants (243 males) were recruited. Citation: Edwards C, Mukherjee S, Simpson L, Palmer LJ,
Mean ± standard deviation body mass index (BMI) was Almeida OP, Hillman DR. Depressive symptoms before and
32.1 ± 7.1 kg/m2 and AHI 33.6 ± 28.9 events/h. PHQ-9 was after treatment of obstructive sleep apnea in men and women.
10.5 ± 6.1 and independently related to AHI (p < 0.001) and J Clin Sleep Med 2015;11(9):1029–1038.

P ersistent sleep loss causes symptoms that are similar to

those of depression, in part because frontal lobe centers re-
sponsible for emotional modulation are sensitive to disturbed
BRIEF SUMMARY
Current Knowledge/Study Rationale: Depressive symptoms are
common in patients with obstructive sleep apnea.
sleep.1 Consistent with this observation, obstructive sleep ap- Study Impact: This paper examines the nature of this relationship and
nea (OSA), a condition characterized by fragmented sleep, is the infl uence on it of gender and of effective treatment of obstructive
commonly associated with depressive symptoms.2 Conversely, sleep apnea in a large cohort of such patients.
depression is often associated with disturbed sleep. Further,
depression and OSA are prevalent in the community and, Previous studies of the relationship between OSA and de-
hence, could be expected to coexist in a significant proportion pression have demonstrated this shared symptomatology, al-
of patients. The multidirectional relationships between depres- though the extent to which depressive symptoms are present
sion, disturbed sleep, and OSA are a source of potential di- in OSA is still unclear.3,5,6 Many previous studies have been
agnostic confusion, which may explain why OSA, a generally of low power or have used a variety of instruments of varying
under-recognized condition, is particularly under-diagnosed quality to assess depressive symptoms.6 Lack of direct con-
among people with depression.3 Failure to recognize and treat tact with patients and retrospective assessment of depressive
OSA in depressed patients may lead to inappropriate prescrip- symptoms rather than assessment prior to diagnosis of OSA
tion of antidepressant therapy and/or persistence of depressive have been limitations of some of them.7 Others have failed to
symptoms despite such therapy. Equally the presence of de- specify the method used to identify OSA or have used limited
pressive symptoms in patients with untreated OSA could lead methods to characterize it rather than gold standard laboratory
to misdiagnosis of depression.4 based polysomnography (PSG).6
1029 Journal of Clinical Sleep Medicine, Vol. 11, No. 9, 2015
C Edwards, S Mukherjee, L Simpson et al.

MATERIALS AND METHODS

Figure 1—Public health questionnaire (PHQ-9).

Over last 2 weeks how often have you experienced? Subjects

1. Little interest or pleasure in doing things? The study was approved by the Sir Charles Gairdner Re-
2. Feeling down, depressed or hopeless? search Ethics Committee. Participants were required to speak
3. Trouble falling or staying asleep or sleeping too much? English and not to have been previously diagnosed with OSA.
4. Feeling tired or having little energy?
5. Poor appetite or overeating?
All participants were new patients reviewed at a sleep clinic at
6. Feeling bad about yourself—a failure, let yourself or family Sir Charles Gairdner Hospital. They were assessed by a board-
down? certified sleep specialist and found to meet standard indications
7. Trouble concentrating—reading, TV? for PSG evaluation for the suspected diagnosis of OSA. All de-
8. Moving, speaking slowly (so others noticed) or excessively cisions regarding patient diagnosis and treatment were made
restless?
9. Thoughts that you would be better dead or of self-harm? by their sleep specialist: the investigators had no part in these
decisions. Participants were excluded from this study if unable
Scoring to complete health questionnaires meaningfully. Participants
• Four possible responses for each: not at all (0 points); completed the Western Australian Sleep Health Study ques-
several days (1 point); more than half the days (2 points); tionnaire given to all new patients attending the sleep clinic
nearly every day (3 points).
• Minimum score = 0; maximum score = 27. to gather information relevant to sleep disorders and general
• Score ≥ 10 = moderate severity depression. health and age, gender, use of antidepressants, and body mass
index (BMI) were recorded.10

Protocol
An additional limitation in examining the relationship
between OSA and depression has been that the instruments Assessment at Baseline: Relationship between OSA and
to identify depression have been validated for the general Depressive Symptoms
population but not in OSA patients. Given the potential for Each eligible patient attending the sleep clinic over a
overlap in symptoms between the two conditions, it cannot 5-month period was approached and asked to participate.
be assumed that the presence of depressive symptoms in Those who provided informed consent completed the patient
OSA patients indicates the presence of depression indepen- health questionnaire (PHQ-9) to screen for depressive symp-
dent of OSA. While this may be so in some patients, it is toms prior to undergoing laboratory PSG.11
also possible that such symptoms are attributable to OSA
rather than depression or to a depressive illness caused by Effect of Treatment of OSA on Depressive Symptoms
untreated OSA. Defining the role of OSA in the genesis of Those participants found to have moderate or severe OSA
such symptoms could be achieved by elimination of the (apnea-hypopnea index [AHI] ≥ 15 events/h) or symptomatic
condition followed by reassessment.8 Continuous positive mild OSA (AHI 5–14.99 events/h) were referred for a physician
airway pressure (CPAP), the first-line therapy for moderate supervised trial of CPAP over a 3- to 6-week period, accord-
to severe OSA, provides an opportunity to do so, as it is ing to the standard practice of the sleep clinic. Where efficacy,
highly efficacious and compliance with it can be accurately compliance, and acceptance of therapy were satisfactory, the
monitored.9 trial was extended for an additional 6–9 weeks (12 weeks in
The present study has been designed to address these is- total). All CPAP compliant participants (mean use from device
sues. Its purpose was to determine: (a) the occurrence of de- download ≥ 5 h/night) were reassessed for depressive symp-
pressive symptoms among patients presenting with OSA, and toms with the PHQ-9 3 months after the date of commence-
(b) the extent to which depressive symptoms improved with ment of this trial.12 CPAP compliance was also assessed at that
CPAP treatment. We hypothesized that OSA would be com- time and was summarized as the mean daily usage from device
monly associated with depressive symptoms and that these download for the previous 8 to 12 weeks. Device download
would decrease in severity with OSA treatment. In addition, data was also used to determine AHI on CPAP therapy.
we postulated that there may be a subset of depressive symp-
toms in patients with OSA that persists despite treatment, PHQ-9 Depression Scale (Figure 1)
and that these may more reliably identify OSA-independent The PHQ-9 is a questionnaire-based depression scale that is
depression in this population. We also wished to determine used to assist primary care practitioners in diagnosing depres-
whether there were gender differences in symptomatology sion and monitoring treatment.11,13 It asks 9 questions which
and response to treatment, given the different prevalences of relate to feelings of sadness, tiredness and sleepiness or sleep-
both depression and OSA in men and women. In developing ing too much, little interest in doing things, thoughts of per-
the study we were careful to observe the distinction between sonal failures, troubles in concentration, perceived decreases
depressive symptoms and depression itself, as we recognized in self-confidence, slow/fast speech and suicidal ideation. Each
that symptoms can be shared between OSA and depression question is answered on a scale of 0 to 3, giving a range of pos-
and be a source of diagnostic confusion between them. In- sible scores from the sum of responses from 0 to 27. It has been
deed it is the potential for such confusion that provided a ma- suggested that a score of 0 to 4 indicates nil or minimal depres-
jor rationale for the study. sion; 5 to 9 mild depression; 10 to 14 moderate depression; 15

Journal of Clinical Sleep Medicine, Vol. 11, No. 9, 2015 1030

 Depressive Symptoms and OSA

Table 1—Clinical characteristics at baseline of all participants and of the subgroup assigned to CPAP therapy.
CPAP Therapy Subgroup (n = 293)
All Participants (n = 426) All (n = 293) Compliant with CPAP (n = 228) Non-Compliant (n = 65)
n % n % n % n %
Age ≥ 65 years 110 25.8 85 29.0 71 31.1 14 21.5
Male gender 243 57.0 181 61.7 144 63.1 37 56.9
BMI category (kg/m2)
< 25 59 13.8 27 9.2 18 7.9 9 13.8
25–29.99 117 27.4 79 26.9 57 25 22 33.8
≥ 30 250 58.6 187 63.8 153 67.1 34 52.3
AHI category (events/h)
<5 37 8.6 0 0 0 0 0 0
5–14.99 96 22.5 28 9.5 1 0.4 27 41.5
15–29.99 109 25.5 92 31.3 74 32.4 18 27.7
≥ 30 184 43.2 173 59.0 153 67.1 20 30.7
%TST < 90 category
0 107 52.1 45 15.3 26 11.4 19 290.2
0.01–1.99 294 69.0 226 77.1 185 81.1 41 63.0
2–4.99 21 4.9 18 6.1 14 6.1 4 6.1
≥5 4 0.9 4 1.3 3 1.3 1 1.5
PHQ-9 ≥ 10 279 65.4 213 72.6 170 74.5 43 66.2

BMI, body mass index; AHI, apnea-hypopnea index; %TST < 90, % total sleep time spent at an arterial oxygen saturation < 90%; PHQ-9, patient health
questionnaire.

to 19 moderately severe depression; and 20 to 27 severe de- Pearson χ2 tests were used to examine the relationships be-
pression. PHQ-9 validation studies suggest a cutoff value < 10 tween presence of clinically significant depressive symptoms
indicates a low likelihood of major depression in the general (PHQ-9 ≥ 10) and OSA severity and BMI categories. Multiple
population.11 logistic regression analysis was used to determine the inde-
pendent odds of presence of clinically significant depressive
Polysomnography symptoms with increasing OSA, BMI, and %TST < 90 (as cat-
Standard polysomnography was performed and AHI de- egorical variables) and age (in years).
rived using the American Academy of Sleep Medicine “Chi- Paired t-tests were used to compare PHQ-9 scores before
cago” scoring criteria, with hypopneas requiring either > 50% and after CPAP treatment in those who completed 3 months of
airflow reduction or a lesser airflow reduction with associ- treatment. The proportions of those with clinically significant
ated > 3% oxygen desaturation or arousal.14 The degree of hy- depressive symptoms before and after CPAP treatment were
poxemia during sleep was determined from the percentage of compared using the McNemar test. The relationship between
total sleep time spent below an arterial oxygen saturation of magnitude of change in PHQ-9 and hours of CPAP use was ex-
90% (%TST < 90). amined by linear regression analysis. These assessments were
repeated in a subgroup composed of all those patients taking
Analysis antidepressant medications. The sign test was used to com-
The data were analyzed using the Statistical Package for pare responses to the component questions in the PHQ-9 score
Social Sciences (SPSS version 19.0). The relationship be- before and after CPAP therapy to determine those symptoms
tween PHQ-9 scores at baseline and age, gender, BMI, AHI, most responsive to control of OSA.
and %TST < 90 were examined by simple linear regression Numerical data were expressed as mean ± standard devia-
analysis, treating each parameter as a continuous variable. The tion (SD). A p value < 0.05 was considered significant.
data were then entered into a multiple linear regression model
using backwards elimination of insignificant terms consider- RESULTS
ing interactions with gender for each parameter to determine
significant predictors of depressive symptoms. Of the 607 patients approached over the 5-month study
Analysis of variance was used to examine the relationships period, 181 were excluded because they had been exposed
between PHQ-9 scores and: (a) OSA severity (categorized by to CPAP therapy in the past, suffered from cognitive deficits
AHI as follows: < 5 events/h = nil; 5–14.99 events/h = mild; precluding meaningful completion of the PHQ-9 question-
15–29.99 events/h = moderate; and > 30 events/h = severe); naire, or could not speak English. The remaining 426 patients
(b) BMI (categorized according to World Health Organization (243 men, 183 women; age 52 ± 15 years; BMI 32.1 ± 7.1
guidelines as follows: < 25 kg/m2 = underweight to normal; kg/m 2) provided informed consent and were recruited into
25–29.99 kg/m2 = overweight; and ≥ 30 kg/m2 = obese). the study. Of these, 293 were subsequently assigned CPAP
1031 Journal of Clinical Sleep Medicine, Vol. 11, No. 9, 2015
C Edwards, S Mukherjee, L Simpson et al.

Table 2—Relationships at baseline of categorical severity of OSA to PHQ-9 score and to proportion of patients with a PHQ-9
score ≥ 10 (indicative of clinically significant depressive symptoms).
PHQ-9 ≥ 10
AHI Category n PHQ-9 Score p value n % p value
All Subjects < 0.001 < 0.001
<5 37 6.1 ± 6.1 9 24.3
5–14.99 96 9.2 ± 5.1 52 54.1
15–29.99 109 10.1 ± 5.9 75 68.8
≥ 30 184 12.3 ± 6.1 143 77.7
Men < 0.001 < 0.001
<5 13 4.9 ± 5.4 2 15.3
5–14.99 48 9.5 ± 5.0 29 60.4
15–29.99 61 10.2 ± 5.6 43 70.4
≥ 30 121 12.7 ± 6.2 96 79.3
Women 0.005 < 0.001
<5 24 6.8 ± 6.5 7 29.1
5–14.99 48 9.0 ± 5.2 23 47.9
15–29.99 48 9.9 ± 6.2 32 66.6
≥ 30 63 11.6 ± 6.0 47 74.6

n = 426. AHI, apnea-hypopnea index; PHQ-9, patient health questionnaire.

therapy. Table 1 shows the clinical characteristics (age, gen- When examined by BMI category (< 25 kg/m2, 25–29.99
der, BMI category, AHI category, %TST < 90 category, and kg/m2, ≥ 30 kg/m 2) increasing obesity was also associated with
proportion with depressive symptoms (PHQ-9 ≥ 10) of the increased PHQ-9 scores and proportion of patients with clini-
426 recruits at baseline, the 293 patients assigned CPAP cally significant depressive symptoms in both men and women
therapy and, of those assigned CPAP, the compliant vs. non- (p < 0.001 in each circumstance).
compliant patients. Univariate analysis of baseline data demonstrated that in-
creases in categorical AHI, BMI, and %TST < 90 were each
Determinants of PHQ-9 at Baseline associated with an increase in clinically significant depres-
PHQ-9 for the 426 patients at baseline was 10.5 ± 6.1 and sive symptoms. However multivariate logistic regression
AHI was 33.6 ± 28.9 events/h. Linear regression showed signif- analysis showed that while AHI and BMI were independent
icant associations between PHQ-9 score and BMI (p < 0.0001), determinants of clinically significant depressive symptoms,
AHI (p < 0.0001), and %TST < 90 (p < 0.017). The relation- %TST < 90 was not (Table 3). The analysis showed a greater
ship between subject characteristics and baseline PHQ-9 effect of AHI category in men than women: relative to the
score differed when stratified by gender. In men, AHI and AHI < 5 events/h reference category, men had higher odds of
%TST < 90 significantly predicted baseline PHQ-9 score. In depressive symptoms with all severities of OSA, while women
women, BMI and AHI significantly predicted baseline PHQ-9 only had greater odds of depressive symptoms where AHI was
score. However, when these variables were analyzed by mul- in the moderate to severe range (AHI ≥ 15 events/h). While
tiple linear regression analysis only AHI (β = 0.058, standard both overweight (BMI 25–30 kg/m 2) and obese (BMI > 30
error [SE] = 0.010, p < 0.001), and BMI (β = 0.118, SE = 0.04; kg/m 2) categories increase odds of clinically significant de-
p < 0.005) proved to be independent predictors of PHQ-9 pressive symptoms in men, only obesity increased the odds in
scores. Gender as a main effect or as an interaction term with women. In neither men nor women did age or %TST < 90 have
AHI or BMI, did not have any statistical relationship with base- an impact on the odds of depressive symptoms once the model
line PHQ-9 in a multivariate model. Similarly, %TST < 90 did was adjusted for AHI and BMI.
not appear to explain baseline PHQ-9 score once AHI and BMI
were accounted for. Effect of Treatment of Moderate/Severe OSA on
When the PHQ-9 data were examined by AHI category Depressive Symptoms
(Table 2), increased severity of OSA was found to be associ- Two hundred ninety-three participants with OSA (AHI ≥ 5
ated with increased PHQ-9 scores, and the proportion of sub- events/h) were prescribed CPAP therapy following PSG, of
jects with PHQ-9 score ≥ 10 (indicative of clinically significant whom 228 (144 males and 84 females) complied with 3 months
depressive symptoms) in both men and women (p < 0.001 in of treatment. The remaining 65 participants were non-compli-
each circumstance). The PHQ scores and proportions appeared ant (mean nightly use < 5 h) or were unable to complete the
to increase progressively with increasing OSA severity cat- study assessments. Compliance increased with increasing AHI
egory. It was notable that where OSA was absent (AHI < 5 category, with 153 of the 173 patients with an AHI ≥ 30 events/h
events/h), the PHQ-9 score was greater in women than men; compliant at 3 months (Table 1). All the 228 CPAP compliant
this was not the case where OSA was present. patients completed a repeat PHQ-9 assessment 3 months after

Journal of Clinical Sleep Medicine, Vol. 11, No. 9, 2015 1032

 Depressive Symptoms and OSA

Table 3—Relationships at baseline of categorical AHI, BMI, and TST < 90 to a PHQ-9 score ≥ 10 (indicative of clinically
significant depressive symptoms).
All Men Women
OR (95% CI) p value OR (95% CI) p value OR (95% CI) p value
AHI, events/h
<5 1 – 1 – 1 –
5–14.99 3.4 (1.4–8.3) 0.006 11.1 (2.0–60.6) 0.005 2.3 (0.7–7.6) 0.144
15–29.99 6.3 (2.5–15.9) < 0.001 14.9 (2.7–79.6) 0.002 6.1 (1.7–21.6) 0.005
≥ 30 7.4 (2.9–18.4) < 0.001 16.6 (3.1–87.1) 0.001 6.5 (1.8–22.7) 0.003
BMI, kg/m2
< 25 1 – 1 – 1 –
25–29.99 2.5 (1.2–5.1) 0.008 3.0 (1.1–8.1) 0.027 2.2 (0.7–6.4) 0.147
≥ 30 2.8 (1.4–5.6) 0.003 3.5 (1.2–10.3) 0.022 2.6 (1.0–6.8) 0.040
%TST < 90
0 1 – 1 – 1 –
> 0–1.99 1.1 (0.6–2.1) 0.604 2.3 (0.9–5.4) 0.050 0.6 (0.2–1.7) 0.415
2–4.99 1.6 (0.6–4.0) 0.293 1.8 (0.5–6.8) 0.351 1.6 (0.4–6.3) 0.468
≥5 1.4 (0.6–3.1) 0.320 1.6 (0.5–4.7) 0.332 1.6 (0.4–5.5) 0.417

n = 426. AHI, apnea-hypopnea index; BMI, body mass index; %TST < 90, % total sleep time spent at an arterial oxygen saturation < 90%; PHQ-9, patient
health questionnaire.

Table 4—AHI, PHQ-9 score, and PHQ-9 category at baseline and after 3 months of therapy in patients compliant with CPAP.
After 3 Months of
Baseline CPAP Therapy p value
All Subjects (n = 228)
AHI, events/h, mean ± SD 46.7 ± 27.4 6.5 ± 1.6 < 0.001
PHQ-9 score, mean ± SD 11.3 ± 6.1 3.7 ± 2.9 < 0.001
PHQ-9 ≥ 10, n (%) 170 (74.6) 9 (3.9) < 0.001
Men (n = 144)
AHI, events/h, mean ± SD 49.8 ± 29.4 6.7 ± 1.6 < 0.001
PHQ-9 score, mean ± SD 11.8 ± 6.1 3.9 ± 2.9 < 0.001
PHQ-9 ≥ 10, n (%) 112 (77.8) 5 (3.5) < 0.001
Women (n = 84)
AHI, events/h, mean ± SD 41.5 ± 21.9 6 ± 1.6 < 0.001
PHQ-9 score, mean ± SD 10.4 ± 5.9 3.4 ± 2.8 < 0.001
PHQ-9 ≥ 10, n (%) 58 (69.0) 4 (4.8) < 0.001

AHI, apnea-hypopnea index; PHQ-9, patient health questionnaire.

initiating CPAP therapy (mean nightly use 6.9 ± 0.82 h, range Effect of Treatment of Moderate/Severe OSA on PHQ-9
5–8 h). After 3 months of treatment, there was a substantial by Individual Questions
decrease in the mean AHI, PHQ-9 score and the proportion Table 5 demonstrates that scores for individual questions
of individuals with clinically significant depressive symptoms (Figure 1) significantly decreased in all except question
(Table 4). Clinically significant depressive symptoms failed to 7, which related to difficulty with concentration. Of the re-
remit in 9 individuals (5 men and 4 women). Total PHQ-9 score mainder, question 5, relating to appetite, showed least change.
remained unchanged in 18 individuals, and one individual re- Before CPAP, 18.3% of patients had positive responses to ques-
ported a PHQ-9 score post-CPAP therapy that was one point tion 9 (thoughts of being better off dead or of self-harm), while
higher than at baseline; however, these patients generally had none did after treatment. Of the 170 patients with a PHQ-9
low scores (mean PHQ-9 score = 1.2, range 0–10). score ≥ 10 at baseline who were compliant with CPAP at 3
Of the 228 CPAP compliant patients, 51.8% were previ- months, 161 had a reduction in PHQ-9 to < 10. Comparison
ously prescribed and used antidepressant drug therapy, and of them to the 9 patients whose PHQ-9 remained ≥ 10 did not
antidepressant use remained unchanged over the course of suggest differences with respect to age, BMI, AHI, or PHQ-9
the study. Analysis of these 118 patients demonstrated a simi- at baseline. Examination of differences in individual depres-
lar decline in PHQ-9 scores with therapy (from 12.0 ± 6.1 to sive symptoms between these groups was not possible due to
3.7 ± 2.8) compared with the complete patient group shown the small number of patients in the persistently high PHQ-9
in Table 4. score group.
1033 Journal of Clinical Sleep Medicine, Vol. 11, No. 9, 2015
C Edwards, S Mukherjee, L Simpson et al.

Table 5—Effect of CPAP treatment of OSA on overall PHQ-9 score and component questions in all subjects completing 3
months of CPAP use.
PHQ-9 Question Before CPAP After CPAP p value
1 1.43 ± 1.19 0.14 ± 0.38 < 0.001
2 1.36 ± 1.14 0.08 ± 0.32 < 0.001
3 1.65 ± 1.19 0.22 ± 0.6 < 0.001
4 2.16 ± 1.01 0.32 ± 0.66 < 0.001
5 1.49 ± 1.24 1.22 ± 1.17 0.003
6 1.16 ± 1.14 0.28 ± 0.7 < 0.001
7 1.09 ± 1.12 1.02 ± 1.16 0.41
8 0.64 ± 0.95 0.37 ± 0.84 < 0.001
9 0.28 ± 0.58 0 < 0.001
Overall 11.27 ± 6.09 3.71 ± 2.86 < 0.001

n = 228, sign test.

DISCUSSION antidepressant therapy making it imperative to identify and

rectify, where possible, factors contributing to this debilitat-
The major findings of the study were that: (a) depressive ing condition.15 It may be that the overlap between depressive
symptoms are common among patients referred for investiga- symptoms and OSA is due to chance, as both conditions are
tion of OSA; (b) in patients without OSA (AHI < 5 events/h) common in the community. Both depression and OSA are fre-
the proportion of women with clinically significant depressive quently associated with disturbed sleep, fatigue, and irritabil-
symptoms is higher than that of men but this difference is not ity. However, the relatively uniform impact of untreated OSA
evident when OSA is present; (c) depressive symptoms are di- across the range of depressive symptoms represented in the
rectly correlated with the severity of OSA; (d) symptoms of PHQ-9 questionnaire, does raise the possibility that disturbed
depression, including suicidal ideation, are relieved by effec- sleep from OSA could play a pathogenetic role in the occurrence
tive treatment of OSA with CPAP therapy; and (e) these ben- of depression. Frontal lobe centers responsible for emotional
eficial effects of CPAP are seen to a similar degree in men and modulation are sensitive to disturbed sleep and it is possible
women and are independent of the use of antidepressants. It that OSA-related sleep fragmentation and/or hypoxemia could
is important, and fundamental to the study, to note the dis- disturb cerebral neurochemical/neurophysiological function re-
tinction between depressive symptoms and depression itself. sulting in depression.16 While the relatively prompt response to
As our findings suggest, the shared symptomatology of OSA CPAP treatment might suggest relief of shared symptoms rather
and depression create the potential for diagnostic confusion than of OSA-induced depression, the possibility of a pathoge-
between these conditions. Where such symptoms are pres- netic role of OSA in depression remains. Sleep fragmentation
ent consideration of the differential diagnosis suggested by appears a more likely mechanism underpinning the associa-
them is required with further investigation before diagnosis tion between OSA and depressive symptoms than does upper
is finalized. airway obstruction-related hypoxemia, as our analysis demon-
strates that when AHI, an index of fragmentation, is taken into
Depressive Symptoms are Common among People account %TST < 90, an index of hypoxemia, ceases to be an
with OSA independent predictor of PHQ-9 score in the untreated state.
Previous investigations have suggested an association be- Regardless of mechanisms, the shared symptomatology be-
tween OSA and depression based on shared symptoms.5,7 This tween these common conditions is such that diagnostic confu-
study provides further evidence for this association, suggest- sion is likely to arise. Approximately 8.7% of Australians and
ing substantial potential for diagnostic confusion between the a similar proportion of Americans use antidepressant medica-
entities. It improves on previous studies by: investigating a tions.17,18 It was notable that a far higher proportion (51.8%) of
relatively large number of participants; characterizing OSA our patients were on antidepressant therapy at baseline, consis-
presence and severity using gold standard laboratory polysom- tent with their elevated PHQ-9 scores. It was also notable that
nography; assessing depressive symptoms prospectively using with CPAP treatment the proportion of patients with symptoms
a well validated screening tool; accounting for potential age of clinically significant depression decreased to below these
and obesity confounding; assessing the influence of gender proportions of people in the general community on antidepres-
on this relationship; and by determining the efficacy of CPAP sant therapy.
treatment on depressive symptomatology using an objective As with depression, OSA is a highly prevalent condition,
method (device recorded hours of use) to assess compliance. affecting approximately 7% of adults to a moderate or severe
Depression is highly prevalent worldwide and a leading degree.19 At present, the possibility of OSA is not widely consid-
cause of disability and loss of quality of life. A large propor- ered in depression management. Indeed, OSA remains a gener-
tion of depression sufferers fail to respond fully to standard ally under-diagnosed and under-recognized condition, possibly

Journal of Clinical Sleep Medicine, Vol. 11, No. 9, 2015 1034

 Depressive Symptoms and OSA

at least partly because symptoms are wrongly attributed to de- This may be particularly so in the context of OSA, given the
pression. Consistent with this notion, OSA seems to be partic- potential symptomatic overlap between the conditions. Re-
ularly under-diagnosed in people with depression.20 Failure to gardless, our findings suggest that where depressive symptoms
recognize and treat OSA may lead to persistence of depressive are present the possibility of OSA, a widely prevalent disorder,
symptoms and/or to unnecessary use of antidepressant therapy. should be considered.
While this study examines depressive symptoms among
OSA sufferers, the findings that these symptoms occur com- Depressive Symptoms are Equally Prevalent among
monly in association with OSA and are so responsive to CPAP Women and Men where OSA is Present
therapy suggest there is a case for systematic screening of de- Comparing the results between genders, where there is
pressed populations for OSA. The need for OSA screening may no OSA (AHI < 5 events/h) mean PHQ-9 scores were lower
be even greater among people with depression who fail to re- among men than women, a finding that is consistent with a
spond standard antidepressant treatment. greater female prevalence of depression in the general popula-
tion.32 However, when OSA was present, this gender imbalance
Depressive Symptomatology and Depression was no longer evident. Indeed, multivariate analysis shows
This study used the PHQ-9 to assess depressive symptom- that the effect of AHI category is greater in men than women.
atology. It is a tool developed to help diagnose depression in Women only have greater odds of clinically significant depres-
primary care. Its diagnostic validity has been established in sive symptoms when AHI is in the moderate range; however,
studies involving large numbers of patients and has been used men with OSA have high odds of such symptoms regardless
successfully in specialized clinics.21,22 The scale is brief, easy the AHI category. Only obesity (BMI ≥ 30 kg/m2) increases
to administer and its nine questions are directly based on the odds of clinically significant depressive symptoms in women,
DSM-IV criteria for a depressive episode. As Kroenke and col- whereas in men both overweight and obesity increase the odds.
leagues point out, the quantitative nature of the score allows In both men and women neither age nor %TST < 90 have an
it to be used to both establish the diagnosis of depression and impact on odds of clinically significant depressive symptoms
grade depressive symptom severity.11 Care was taken to mini- once the model is adjusted for AHI and BMI. This overriding
mize reporting bias by using word “well-being” rather than effect of OSA on the gender differences in depressive symp-
“depression” when first introducing the questionnaire and en- toms that are present without OSA underlines the apparently
suring it was answered before any discussion of OSA with the powerful effect it has on occurrence of these symptoms that
sleep physician. Tellingly, one of the 9 questions in the PHQ-9 our other findings also suggest.
questionnaire asks about suicidal ideation, and this elicited a
positive response prior to treatment in 41 of 228 patients who Depressive Symptoms are Independently Related to
went on to successfully use CPAP therapy and in none of them the Severity of OSA
at the 3-month follow up. The relationship between PHQ-9 and AHI was independent
While the PHQ-9 has not been formally validated as a tool of BMI. As our findings show, obesity is also independently as-
to diagnose depression in sleep clinic populations, it has been sociated with depressive symptoms. The association between
used in a substantial number of OSA-related studies.20,23–30 obesity and OSA is well known hence it is essential that it is
In the present paper we have been careful to refer to depres- taken into account in determining the relationship between
sive symptoms, not depression, recognizing that it may be the OSA and depression.33
symptoms that are confused between the conditions. The scor- It was also evident that while there was a univariate relation-
ing system used (PHQ-9) is a widely validated method of di- ship between %TST < 90 and PHQ-9 scores, this association
agnosing depression, seeking out as it does the key depressive was no longer apparent on multivariate analysis when AHI was
symptoms, being based directly on the nine diagnostic criteria taken into account. Again, this suggests that the sleep disrup-
for major depressive disorder in the DSM-IV (Diagnostic and tion and fragmentation that AHI represents is of greater im-
Statistical Manual of Mental Disorders, Fourth Edition).31 The portance in the generation of depressive symptoms than the
exclusive focus of PHQ-9 on these symptoms appears to be an hypoxemia that can accompany these obstructive events.
advantage in terms of its utility in detecting depression.11 Our Logistic regression analysis (Table 3) demonstrates that the
findings demonstrate that these widely accepted depressive odds of having clinically significant depressive symptoms in-
symptoms are highly prevalent in OSA, providing the poten- creases progressively with increasing categorical severity of
tial for OSA to be misdiagnosed in any setting, including the OSA, relative to those with without OSA (AHI < 5 events/h).
primary care setting for which the PHQ-9 was originally de-
vised and in which setting this simple tool has been validated Depressive Symptoms in OSA Patients are Relieved by
to diagnose depression. Both depression and OSA are common CPAP Therapy
problems in primary care. The high proportion of patients on The symptomatic response to effective treatment of OSA is
antidepressants at enrolment in the present study (51.8% [vs an important in helping determine the role of untreated OSA in
8.7% in the general community]) suggests that depression was symptom genesis. A recent meta-analysis of the effect of treat-
diagnosed before the possibility of OSA was considered. ment of OSA on depressive symptoms in 19 randomized con-
We used a PHQ-9 cut point of ≥ 10 to indicate clinically trolled trails demonstrates an overall improvement, although
significant depressive symptoms, as scores of < 10 are seldom there was significant heterogeneity between the trials in their de-
associated with major depression.11 It is important to note that signs and outcomes.34 Many of them involved low numbers of pa-
depressive symptoms do not necessarily equate to depression. tients, short follow-up periods, poor CPAP compliance, or failure
1035 Journal of Clinical Sleep Medicine, Vol. 11, No. 9, 2015
C Edwards, S Mukherjee, L Simpson et al.

to include patients with severe OSA. None of them involved the limitations in generalizing findings to the community at large,
present study’s combination of large numbers of patients, lengthy it ensured that the study population was enriched with sleep
follow-up periods, optimization of CPAP compliance, and inclu- apnea cases. As a result, a wide spectrum of sleep apnea se-
sion of severe OSA. While future studies addressing these issues verities was present among the subjects of the study, allowing
are called for, it is difficult to envisage ethical approval for ran- concentrated study of the influence of sleep apnea on depres-
domized controlled trials which require withholding effective sive symptomatology.
therapy for severe OSA for lengthy periods.35,36 By choosing an OSA-rich sample, this study demonstrated
PHQ-9 has previously been demonstrated to be a respon- that CPAP therapy ameliorated reports of depressive symp-
sive and reliable measure of depression treatment outcomes.37 toms in patients with OSA, such that only 9 patients had per-
Our study demonstrates a substantial effect on this metric of sistently high scores after 3 months of treatment. However, this
depressive symptoms in this large patient group, where OSA design limited examination of differences in symptom report
of all severities was studied with CPAP compliance optimized between those where OSA treatment did and did not affect de-
and sustained over a lengthy (3-month) period. This effect was pressive symptomatology. Our results indicated that there were
seen in both men and women regardless of whether antidepres- no differences between these groups with respect to report of
sants were prescribed or not. Only those achieving a minimum depressive symptoms before treatment, severity of OSA, adi-
mean nightly use of 5 hours of CPAP therapy at 3 months were posity, or age, which would suggest that these factors played
reevaluated for depressive symptoms. a minimal role in those with persistent depression after treat-
Such efficacy emphasizes the importance of screening peo- ment for OSA.
ple with depressive symptoms for OSA so that, if present, it The study used one instrument to assess depressive symp-
can be identified and effectively treated. At a minimum, such tomatology. However the PHQ-9 has been widely validated and
patients should be asked about common OSA symptoms in- is capable of question-by-question breakdown of responses, as
cluding habitual snoring, witnessed apneas, disrupted sleep, was performed here, to examine DSM-IV depressive symp-
and excessive daytime sleepiness. toms criterion-by-criterion, as each of the nine questions is
Examining the response to therapy by individual questions directly based one of the 9 DSM-IV depression criteria. Sig-
from the PHQ-9 score demonstrated a significant decrease in nificant changes were observed with OSA treatment across a
scores for each question, apart from Question 7, (“do you have broad spectrum of these questions suggesting that the findings
trouble concentrating?”). It seems unlikely that this symptom were not attributable to any one or two sleep-oriented depres-
is an indicator of depression that is independent of OSA, as sive symptoms. Furthermore previous experience with tools
neurocognitive deficits are often associated with OSA and for detecting depression suggests that scores are highly cor-
appear to improve with CPAP therapy.38 The narrow range of related and therefore that no one instrument is more effective
scores for the individual questions provide limited room for than another.40,41 The strength of the relationship between OSA
improvement and so may be subject to floor effects. treatment and resolution of depressive symptomology demon-
While 41 of 228 patients who complied with CPAP therapy strated in the present study was of sufficient degree to suggest
had positive responses to question 9 (“do you think you would that the PHQ-9 and other depression scales may be inadequate
be better dead or of self-harm?”) before treatment, none did at 3 for differentiating a priori between OSA related depressive
month follow-up. However, approximately 5% of those treated symptoms and depression independent of OSA.
with CPAP had persistent clinically significant depressive An additional limitation was the observational design of
symptoms despite therapy. Persistent depression independent the study. However, a randomized controlled design would
of OSA treatment in some individuals is to be expected given present significant difficulties for a study involving all severi-
its widespread occurrence in the general community. Indeed ties of sleep apnea, large numbers of patients, and follow-up
the proportion observed in our CPAP-treated patients was less of those started on treatment over a lengthy (3-month) period.
than population prevalences of depressive symptoms.39 Apart This length of follow-up is desirable, as the first 3 months of
from elimination of OSA (the presence of which may influence therapy is the period over which its use stabilizes and long-
such population prevalences) other potential influences causing term compliance becomes predictable.42 Withholding effective
this low prevalence of persisting depressive symptoms include therapy for this period in patients with severe OSA presents
the nonspecific effects of the care and attention that accompany ethical dilemmas.35,36 Nonetheless the present study would
the diagnostic and treatment process and a selection bias for have been enhanced by systematic follow-up of those who did
patients with a positive outlook among those able and willing not comply with CPAP at 3 months, to facilitate partitioning
to comply with CPAP therapy. The changes were not based of CPAP treatment effects from other influences on symptom-
on changes in antidepressant prescription, which remained atology. Notwithstanding these issues, the dose-effect relation-
constant throughout the study. Of the complete patient group ship between AHI and depressive symptoms at baseline and
52% were using antidepressants regularly prior to attending the the remission of these symptoms with OSA treatment strongly
sleep clinic. Of those who successfully undertook CPAP ther- suggests OSA was responsible for them.
apy, 51.8% were using antidepressants prior to commencement
and this remained unchanged after 3 months of therapy. CONCLUSIONS
Limitations We have shown that, in this sleep clinic population, a high
This study involved sleep clinic patients rather than patients percentage of patients diagnosed with moderate to severe OSA
drawn from the general population. While this may introduce also have symptoms of moderate to severe depression, and

Journal of Clinical Sleep Medicine, Vol. 11, No. 9, 2015 1036

 Depressive Symptoms and OSA

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C Edwards, S Mukherjee, L Simpson et al.

SUBMISSION & CORRESPONDENCE INFORMATION DISCLOSURE STATEMENT

Submitted for publication September, 2014 This was not an industry supported study. The study was supported in part by
Submitted in final revised form February, 2015 grant 1031575 from the National Health and Medical Research Council (NHMRC)
Accepted for publication March, 2015 of Australia. No other external funding was involved. Dr. Hillman was supported by
Address correspondence to: David R. Hillman, Department of Pulmonary Physiology NHMRC grant 1031575. Dr. Hillman has received research support from ResMed
and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; and has participated in speaking engagements for ResMed and Philips Healthcare.
Tel: +61 8 93462888; Fax: +61 8 93462034; Email: [email protected] The other authors have indicated no financial conflicts of interest.

Journal of Clinical Sleep Medicine, Vol. 11, No. 9, 2015 1038