Obstructive sleep apnea (OSA), characterized by the reduction of airflow during sleep, is a common disease, affecting approximately 2-7% of adults in the general population [
Serotonin is involved in the control of respiration at multiple sites in the central (CNS) and peripheral nervous system (PNS) [
As OSA is a prevalent condition associated with significant mortality and morbidity, in which a substantial proportion of individuals remain untreated due to intolerance to PAP, investigating alternate therapies would benefit not only individuals with OSA but also the population at large, in terms of healthcare-related costs on potentially preventable medical consequences associated with untreated OSA [
However, while some evidence exists for the utility of SRIs in OSA in the general population, this has not been specifically studied in PWE. Thus, the objectives of this study are to determine (1) whether the use of SRIs is associated with OSA severity in a population consisting of both PWO and PWE and (2) whether OSA severity, as a function of SRI status, differs in PWE compared to PWO.
This study was approved by the institution IRB. Subject consent was waived due to the retrospective nature of the research, as, for this type of study, formal consent is not required. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
A retrospective study of people with (PWE) and without (PWO) epilepsy was conducted. Inclusion criteria consisted of adults ≥ 18 years of age with depression who underwent diagnostic polysomnography for suspected sleep apnea at an academic sleep center between January 1, 2011, and January 1, 2016. Subjects with depression were included in order to increase the likelihood of concomitant SRI prescription for the purposes of this study. Potential subjects were identified via electronic search for the ICD-10/ICD-9 and CPT codes for sleep apnea, PSG, depression, and epilepsy. Search terms for sleep apnea included the ICD-10 code G47.3, and the ICD-9 codes for obstructive sleep apnea (327.23), sleep related nonobstructive alveolar hypoventilation (327.27), obesity hypoventilation syndrome (278.03), sleep related hypoventilation/hypoxemia (327.26), primary central sleep apnea (327.21), Cheyne Stokes breathing pattern (786.04), central sleep apnea/complex sleep apnea (327.27), other sleep apnea (327.29), apnea not elsewhere specified (786.03), and unspecified sleep apnea (327.20). Although only subjects with OSA were selected for the study, broader search terms encompassing any form of sleep apnea were utilized in order to capture potential subjects who may have been miscoded. Polysomnography search terms included ICD-10-PCS 4A1ZXQZ, ICD-9-CM 89.17, and CPT code 95807 (sleep study, simultaneous recording of ventilation, respiratory effort, ECG or heart rate, and oxygen saturation, attended by a technologist). Depression search terms included the ICD-10 codes F32 and F33, ICD-9 codes 311, 296.2, and 296.3, and epilepsy codes consisting of ICD-10 G40 and ICD-9-CM 345.
Charts were subsequently reviewed to confirm whether diagnostic PSG had been completed and whether a depression code was present, during the designated dates. Extended EEG was not performed with PSG. Charts were individually reviewed to verify the diagnoses of epilepsy (based on the 2014 International League Against Epilepsy operational clinical definition of epilepsy [
All subjects were divided into two groups by exposure: those taking (+SRI) and those not taking (-SRI) an SRI during PSG. Within these exposure groups, subjects were subdivided into PWE and PWO. Baseline characteristics were collected for age at the time of diagnostic PSG, gender, body mass index (BMI), hypertension (HTN), diabetes (DM), congestive heart failure (CHF), chronic obstructive pulmonary disease/asthma (COPD), epilepsy diagnosis, epilepsy syndrome (focal, generalized, or undetermined), tobacco use, alcohol abuse, illicit substance abuse, and a record of opioid, benzodiazepine, nonbenzodiazepine, and antiepileptic drug (AED) use at the time of baseline PSG.
The AHI was stratified into three categories of severity: mild OSA (5<AHI<15), moderate OSA (15≤AHI<30), and severe OSA (AHI≥30). Based on data from the Wisconsin Sleep Cohort study, which demonstrated that a significant risk of hypertension occurs at AHI values of approximately 30 or greater [
Four distinct analyses were conducted from the study sample. The relationship between OSA severity and SRIs was assessed for (1) the entire study sample (consisting of PWO and PWE), (2) PWO compared to PWE, (3) PWO only, and (4) PWE only.
Baseline characteristics were analyzed using Pearson’s
After screening, the first ninety PWE who potentially met inclusion criteria were selected and compared via convenience sampling to the first 90 PWO screened who also potentially met inclusion criteria, for a potential study population of 180 subjects. Of these individuals, 55 were not eligible (diagnostic PSG was not done or did not meet PSG scoring criteria for OSA), resulting in a total study sample of 125 subjects: 57 PWE and 68 PWO.
Across the entire cohort (PWE and PWO), 45 were +SRI and 80 were –SRI. Baseline characteristics comparing +SRI and –SRI exposure groups are listed in Table
Baseline characteristics.
-SRI (N=80) | +SRI (N=45) | p | ||
---|---|---|---|---|
Gender (male) | 44 (55) | 26 (58) | 0.090 | 0.764 |
Hypertension | 21 (26) | 18 (40) | 2.537 | 0.111 |
Diabetes | 15 (18.75) | 11 (24) | 0.567 | 0.451 |
Congestive Heart Failure | 7 (8.75) | 3 (6.67) | 0.170 | 0.680 |
Stroke/TIA | 15 (18.75) | 8 (17.78) | 0.018 | 0.893 |
COPD/asthma | 13 (16.25) | 13 (28.9) | 2.793 | 0.095 |
Epilepsy | 34 (42.5) | 23 (51) | 0.861 | 0.353 |
Focal epilepsy | 31 (38.75) | 18 (40) | 0.019 | 0.891 |
Generalized epilepsy | 2 (2.5) | 2 (4.44) | 0.352 | 0.553 |
Undetermined epilepsy | 1 (1.25) | 3 (6.67) | 2.728 | 0.099 |
Tobacco | 4 (5) | 0 (0) | 2.324 | 0.127 |
Alcohol | 0 (0) | 0 (0) | ------ | ------ |
Drug Abuse | 3 (3.75) | 1 (2) | 0.217 | 0.641 |
Opioids | 3 (3.75) | 1 (2) | 0.217 | 0.641 |
Benzodiazepines | 17 (21.25) | 13 (28.9) | 0.921 | 0.337 |
Non-benzodiazepines | 9 (11.25) | 4 (9) | 0.172 | 0.678 |
AED | 41 (51.25) | 32 (71.11) | 7.898 | 0.048 |
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Mean ± SD | Mean ± SD | CI | P | |
| ||||
Age (years) | 57.73±14.43 | 62.51±10.36 | -9.21- -0.366 | 0.034 |
Body Mass Index | 30.86±6.13 | 30.95±5.91 | -2.30-2.14 | 0.942 |
SRI: serotonin reuptake inhibitor, TIA: transient ischemic attack, COPD: chronic obstructive pulmonary disease, and AED: antiepileptic drug;
PWO and PWE: significantly different baseline characteristics.
PWO (N=68) | PWE (N=57) | p | ||
---|---|---|---|---|
Gender (male) | 37 (54) | 33 (58) | 0.153 | 0.696 |
Hypertension | 26 (38) | 13 (23) | 3.438 | 0.064 |
Diabetes | 19 (28) | 7 (12) | 4.616 | 0.032 |
Congestive Heart Failure | 8 (12) | 2 (3.51) | 2.872 | 0.090 |
Stroke/TIA | 15 (22) | 8 (14) | 1.330 | 0.249 |
COPD/asthma | 20 (29) | 6 (10.5) | 6.713 | 0.010 |
Tobacco | 4 (5.88) | 0 (0) | 3.464 | 0.063 |
Alcohol | 0 (0) | 0 (0) | ------ | ------ |
Drug Abuse | 2 (2.94) | 2 (3.51) | 0.032 | 0.857 |
Opioids | 4 (5.88) | 0 (0) | 3.464 | 0.063 |
Benzodiazepines | 18 (26.47) | 12 (21) | 0.499 | 0.480 |
Non-benzodiazepines | 9 (13.24) | 4 (7.02) | 1.286 | 0.257 |
AED | 18 (26.47) | 55 (96.49) | 65.712 | 0.001 |
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Mean ± SD | Mean ± SD | CI | P | |
| ||||
Age (years) | 63.21±12.67 | 54.97±12.65 | 3.74-12.74 | 0.001 |
Body Mass Index | 31.54±6.48 | 30.12±5.39 | -0.68-3.52 | 0.301 |
SRI: serotonin reuptake inhibitor, TIA: transient ischemic attack, COPD: chronic obstructive pulmonary disease, and AED: antiepileptic drug;
Four separate analyses were conducted, each examining the relationship between OSA severity and SRIs in different populations within the study sample: (1) PWO and PWE, (2) PWO compared to PWE, (3) PWO only, and (4) PWE. The mean AHI of each OSA severity category is listed by subpopulation (SRI and epilepsy status) in Table
Mean AHIs of OSA severity by SRI and epilepsy status.
OSA Severity | AHI: Mean±SD | |||
---|---|---|---|---|
PWO+PWE (N) | PWO (N) | PWE (N) | ||
Mild | -SRI | 10.04±2.74 (31) | 10.55±2.69 (14) | 9.62±2.79 (17) |
+SRI | 8.9±2.64 (17) | 8.07±1.80 (6) | 9.35±2.98 (11) | |
Total | 9.55±2.74 (48) | 9.81±2.68 (20) | 9.51±2.82 (28) | |
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Moderate | -SRI | 22.07±4.83 (18) | 21.51±5.72 (11) | 22.96±3.18 (7) |
+SRI | 20.65±5.24 (18) | 22.11±5.63 (9) | 19.19±4.66 (9) | |
Total | 21.36±5.02 (36) | 21.78±5.54 (20) | 20.84±4.40 (16) | |
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Severe | -SRI | 54.57±18.75 (31) | 56.61±16.55 (21) | 50.29±23.10 (10) |
+SRI | 68.62±16.40 (10) | 71.73±18.34 (7) | 61.37±9.40 (3) | |
Total | 58.00±19.02 (41) | 60.39±17.95 (28) | 52.85±20.94 (13) |
AHI: apnea-hypopnea index, OSA: obstructive sleep apnea,
SRI: serotonin reuptake inhibitor, PWO: people without epilepsy,
PWE: people with epilepsy, and SD: standard deviation.
Unadjusted and adjusted analysis, controlling for the significant covariates of age and AEDs, was performed.
Outcomes for total cohort: +SRI compared to -SRI.
Outcome | Covariate | p | OR | CI | |
---|---|---|---|---|---|
Severe OSA compared to Moderate OSA | Unadjusted | ------ | 0.022 | 0.323 | 0.123-0.848 |
Univariate | Age | 0.021 | 0.317 | 0.120-0.838 | |
Univariate | AED | 0.027 | 0.333 | 0.126-0.884 | |
Multivariate | Age, AED | 0.025 | 0.325 | 0.121-0.870 | |
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Severe OSA compared to Mild OSA | Unadjusted | ------ | 0.262 | 0.588 | 0.233-1.485 |
Univariate | Age | 0.146 | 0.489 | 0.187-1.282 | |
Univariate | AED | 0.556 | 1.339 | 0.507-3.537 | |
Multivariate | Age, AED | 0.346 | 1.625 | 0.592-4.458 |
SRI: serotonin reuptake inhibitor, AED: antiepileptic drug, AHI: apnea-hypopnea index, PWO: people without epilepsy, PWE: people with epilepsy, and COPD: chronic obstructive pulmonary disease;
Covariate: the listed characteristic(s) designates the variable(s) adjusted for in logistic regression analysis.
+SRI was less likely to have severe OSA than -SRI compared to moderate OSA in univariate and multivariate analysis. There was no association with SRI exposure in comparing the outcome of severe versus mild OSA.
Oxygen saturation nadir was not associated with SRI exposure, in unadjusted and adjusted analysis (data not shown).
Subgroup analysis was performed to determine whether PWE and PWO demonstrated similar or different associations with SRI exposure to outcome. Univariate and multivariate analysis adjusted for covariates which were significantly different at baseline between PWE and PWO: age, DM, COPD/asthma, and AED use.
Outcomes for PWE versus PWO: +SRI compared to -SRI
Outcome | Covariate | p | OR | CI | |
---|---|---|---|---|---|
Severe OSA compared to Moderate OSA | Unadjusted | ------ | 0.079 | 0.233 | 0.046-1.185 |
Univariate | Age | 0.106 | 0.238 | 0.042-1.355 | |
Univariate | DM | 0.083 | 0.469 | 0.026-5.395 | |
Univariate | COPD/asthma | 0.052 | 0.127 | 0.016-1.018 | |
Univariate | AED | 0.024 | 0.319 | 0.118-0.858 | |
Multivariate | Age, DM, COPD/asthma, AED | 0.015 | 0.264 | 0.091-0.770 | |
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Severe OSA compared to Mild OSA | Unadjusted | ------ | 0.314 | 0.464 | 0.104-2.071 |
Univariate | Age | 0.203 | 0.361 | 0.075-1.731 | |
Univariate | DM | 0.272 | 0.417 | 0.087-1.990 | |
Univariate | COPD/asthma | 0.266 | 0.412 | 0.087-1.964 | |
Univariate | AED | 0.447 | 1.471 | 0.545-3.970 | |
Multivariate | Age, DM, COPD/asthma, AED | 0.234 | 1.922 | 0.656-5.631 |
SRI: serotonin reuptake inhibitor, AED: antiepileptic drug, AHI: apnea-hypopnea index, PWO: people without epilepsy, PWE: people with epilepsy, COPD: chronic obstructive pulmonary disease, and DM: diabetes;
Outcomes for PWO: +SRI compared to -SRI
Outcome | Covariate | p | OR | CI | |
---|---|---|---|---|---|
Severe OSA compared to moderate OSA | Unadjusted | ------ | 0.152 | 0.407 | 0.119-1.391 |
Univariate | COPD/asthma | 0.085 | 0.302 | 0.077-1.180 | |
| |||||
Severe OSA compared to mild OSA | Unadjusted | ------ | 0.701 | 0.778 | 0.216-2.806 |
Univariate | COPD/asthma | 0.579 | 0.687 | 0.182-2.591 |
SRI: serotonin reuptake inhibitor, PWO: people without epilepsy, and COPD: chronic obstructive pulmonary disease.
The +SRI group with epilepsy was less likely to have severe OSA compared to moderate OSA, after multivariate adjustment. Severe compared to moderate OSA was also less likely when AED use was accounted for.
The outcomes of severe compared to mild OSA and O2 nadir (data not shown) again did not demonstrate any associations.
At baseline, +SRI was more likely to have COPD/asthma (
For PWO, there was no association between the outcome measures of OSA severity and O2 nadir (data not shown) and SRI exposure, without and with adjustment.
At baseline, +SRI was more likely to be older (60.70±8.64 versus 51.09±13.55, p=0.002, CI -15.50- -3.71), which was controlled for in logistic regression analysis.
Outcomes for PWE: +SRI compared to -SRI.
Outcome | Covariate | p | OR | CI | |
---|---|---|---|---|---|
Severe OSA compared to moderate OSA | Unadjusted | ------ | 0.079 | 0.233 | 0.046-1.185 |
Univariate | Age | 0.042 | 0.140 | 0.021-1.116 | |
| |||||
Severe OSA compared to mild OSA | Unadjusted | ------ | 0.314 | 0.464 | 0.104-2.071 |
Univariate | Age | 0.203 | 0.361 | 0.075-1.730 |
SRI: serotonin reuptake inhibitor and PWE: people with epilepsy;
For PWE, +SRI was less likely to have severe compared to moderate OSA after adjustment for age. There was no association between SRI exposure and O2 nadir (data not shown).
The main findings of this study are that, in people with depression, (1) SRI use is associated with reduced OSA severity and, (2) in PWE but not PWO, SRI use is associated with reduced OSA severity. This suggests that the association between SRIs and measures of OSA severity is more robust in PWE compared to PWO, as this outcome difference was also present when directly comparing PWE to PWO who used SRIs.
The first finding is in line with a large body of evidence, in which several human trials have shown that SRIs ameliorate measures of OSA. Treatment of OSA was compared in a randomized, crossover trial using either fluoxetine or protriptyline for 4 weeks. Baseline AHI decreased nearly 40% with both drugs, driven by improvement of the non-REM (NREM) AHI. There was no change in oxygen saturation. However, individual outcomes were widely variable, with only half of patients demonstrating a good response and not necessarily to both drugs [
In a double-blind, randomized, placebo-controlled crossover study, response to paroxetine administered for 6 weeks was studied in 20 men with OSA. Paroxetine reduced the NREM apnea index by 35%, but no significant effect was found for the hypopnea index or during REM sleep. Oxygenation was not reported [
Mirtazapine, a mixed 5-HT2/5-HT3 and alpha-2A antagonist, initially demonstrated promising results in a randomized, double-blind, placebo-controlled, 3-way crossover study of 12 adults with OSA, where patients were administered placebo, mirtazapine 4.5 mg, or mirtazapine 15 mg daily for 7 days. Mirtazapine at either dose significantly reduced NREM and REM AHI, as well as oxygen desaturation index [
It is well-established that serotonin plays an integral role in respiratory control [
Peripherally, however, serotonin appears to play a large inhibitory role in the control of respiration, where inhibitory effects at 5-HT2A and/or 5-HT2C and 5-HT3 dominate at the nodose ganglion [
Differential effects are also influenced by duration of exposure. In rat models, SRI administration for 14 or 23 days was associated with higher serotonin levels [
The selectivity of each SRI for 5-HT versus norepinephrine reuptake may also result in variability. In the present study, subjects were exposed to four SRIs: escitalopram (N=15), fluoxetine (N=13), sertraline (N=12), and paroxetine (N=2). Of these, 5-HT selectivity is the greatest with escitalopram, followed by sertraline, paroxetine, and fluoxetine [
Thus, serotonergic effects on respiration are complex and likely depend on multiple factors, including the degree of activity and selectivity at different receptor subtypes, anatomical location of response, and duration of exposure. While the literature generally suggests that SRIs have a positive modulating effect on OSA, the interaction between these variables likely accounts for the somewhat mixed results that SRIs have demonstrated in human studies of OSA.
Overall, human trials suggest that SRIs ameliorate measures of OSA, in accordance with the results of this study. Of interest, this association was present when those with moderate OSA were compared to the severe groups, but not when the mild severity group was compared to those with severe OSA. This suggests that SRIs may only modulate OSA after it reaches a certain degree of severity.
The other main finding of this study was that the association between SRIs and OSA severity is stronger in PWE compared to PWO. This is notable in that, to the author’s knowledge, no data exists evaluating the effect of SRIs on OSA in PWE, with the exception of one small case series in which protriptyline, a norepinephrine and serotonin reuptake inhibitor, was used [
The stronger association between OSA severity and SRIs in PWE is not a given, as there is evidence that PWE demonstrate serotonergic deficiency at baseline. In PWE, PET studies have shown decreased 5-HT1A receptor binding [
In this present study, PWE demonstrated a stronger association between OSA severity and SRIs compared to PWO, both in direct comparison and when analyzed separately as a group. In support of this, when examined as separate cohorts, PWO did not demonstrate a significant effect between SRI use and OSA severity, regardless of adjustment, whereas PWE did, after univariate adjustment for age. The reason(s) for this difference is unclear. However, one potential mechanism may be that, due to lower serotonergic function and/or concentration, PWE possess a lower threshold for serotonergic effects compared to PWO.
Significant baseline covariates which were identified and adjusted for in this study included those commonly associated with OSA in larger cohorts, including diabetes, older age, and pulmonary disease [
There are several limitations to this research. Although diagnostic accuracy was controlled for by confirmation of OSA and epilepsy diagnoses via individual chart review and significantly different baseline comorbidities were adjusted for, the limitations of retrospective research remain. ICD 10/9 and CPT codes for diagnoses other than OSA and epilepsy were not verified and may have been inaccurate. Adjustment for multiple potential confounders was not performed due to small sample size and incomplete data. This included seizure frequency, type(s) of AEDs used, SRI duration of use, SRI dose, type of SRI used, and medication adherence. Only associations could be established. As a single site study with a limited number of subjects, all of whom suffered from depression, the results may not be generalizable, and sampling error may have skewed results. Nonetheless, the findings of this study merit further investigation. As evidence exists for the role of serotonin in seizure control, additional benefits may also apply in PWE [
In summary, reduced OSA severity is associated with SRI use in populations consisting of people with and without epilepsy. For individuals with epilepsy, the relationship between reduced OSA severity and SRI use may be even more robust. SRIs, a drug class already well-established for use in conditions such as depression, may represent a potential and readily available treatment option for OSA in people with and without epilepsy and warrant further investigation.
The data used to support the findings of this study were provided by the site institution and so cannot be made freely available. Access to these data will be considered by the author upon request, with permission of the NYU School of Medicine Institutional Review Board.
Ethical Committee Permission was granted by the site institution. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
This research involves retrospective analysis of data from human participants. A waiver of consent was granted by the site institution due to the retrospective nature of the study.
Part of this research was previously presented in abstract form:
The author declares that there are no conflicts of interest regarding the publication of this paper.