Journal of Mental Health
ISSN: 0963-8237 (Print) 1360-0567 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmh20
Diagnosis and treatment of sleep apnoea in women with schizophrenia Mary V. Seeman To cite this article: Mary V. Seeman (2014) Diagnosis and treatment of sleep apnoea in women with schizophrenia, Journal of Mental Health, 23:4, 191-196 To link to this article: http://dx.doi.org/10.3109/09638237.2013.869572
Published online: 16 Jan 2014.
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Date: 07 November 2015, At: 01:33
http://informahealthcare.com/jmh ISSN: 0963-8237 (print), 1360-0567 (electronic) J Ment Health, 2014; 23(4): 191–196 ! 2014 Informa UK Ltd. DOI: 10.3109/09638237.2013.869572
REVIEW
Diagnosis and treatment of sleep apnoea in women with schizophrenia Mary V. Seeman
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Department of Psychiatry, University of Toronto, Ontario, Canada
Abstract
Keywords
Background: Obstructive sleep apnoea (OSA) is often overlooked in the context of schizophrenia because its hallmark, daytime sleepiness, is so easily attributable to antipsychotic drugs. This is a special problem for women. Aims: To underscore the importance of diagnosing and treating OSA in women with schizophrenia. Methods: A review of the recent literature (search terms: Obstructive Sleep Apnoea; Schizophrenia; Women (or Gender); Obesity; Antipsychotics; Continuous Positive Airway Pressure (CPAP)) as it applies to a composite case vignette taken from the files of a specialty clinic that treats women with psychosis. Results: The rate of OSA in women who are both obese and postmenopausal is very similar to that of men. Family history, smoking, and the use of tobacco, alcohol and of antipsychotic medication increase the risk. Despite reluctance, patients with schizophrenia generally agree to undergo sleep studies. Compliance with CPAP is difficult, but can be aided by the physician and is, on the whole, relatively high in women. CPAP improves sleep parameters and may also improve cardiometabolic and cognitive indices, although this still needs to be more fully researched. Conclusion: Schizophrenia and untreated OSA are both associated with high mortality rates in women as well as men.
Antipsychotics, continuous positive airway pressure, obesity, obstructive sleep apnoea, schizophrenia, women
Introduction Partly as a result of an obesity epidemic among psychiatric patients (Dickerson et al., 2006; Taylor et al., 2012), the rate of medical morbidity has become very high in this population and is believed to be especially high in patients with schizophrenia (Leucht et al., 2007; von Hausswolff-Juhlin et al., 2009). One comorbidity, obstructive sleep apnoea (OSA), can be inordinately difficult to ascertain in the context of schizophrenia (Kalucy et al., 2013), especially in women where it is less expected than it is in men. Even when successfully diagnosed, OSA can be difficult to treat in this population (Kalucy et al., 2013). The prevalence of OSA in the population at large is often underestimated (Gibson, 2004). In patients with schizophrenia, daytime sleepiness, an important early clinical clue to OSA, is so commonplace (Poulin et al., 2010) that it is easily overlooked or attributed to the effects of therapeutic drugs. Even when OSA is suspected, the patient, for reasons of apathy or lack of understanding of the potential medical consequences of OSA, or general suspiciousness, may refuse a sleep assessment. And even when the diagnosis is
Correspondence: Mary V. Seeman, Professor Emerita, Department of Psychiatry, University of Toronto, #605 260 Heath St. W., Toronto, Ontario M5P 3L6, Canada. Tel: 416 486 3456. E-mail: mary.seeman@ utoronto.ca
History Received 10 June 2013 Revised 10 July 2013 Accepted 23 September 2013 Published online 16 January 2014
made and treatment accepted, adherence with continuous positive airway pressure (CPAP) can be difficult (Lin & Winkelman, 2012). It is important to identify and treat OSA when comorbid with schizophrenia because the daytime sleepiness leads to accidents and, over time, the condition exacerbates two existing problems associated with schizophrenia and its treatment: the cardiometabolic harms (Baguet et al., 2012; Botros et al., 2009; Dragers et al., 2010, 2011; Jun & Polotsky, 2009; Redline et al., 2010) and the cognitive impairment (Grigg-Damberger & Ralls, 2012; Lal et al., 2012; Verstraeten, 2007). In the general population, women are less likely than men to suffer from a severe form of OSA. The result is that when OSA does occur in women, it may go unrecognized. The male-to-female ratio was once estimated to be anywhere from 60:1 to 10:1. It has now been demonstrated that OSA is not as rare in women as previously thought, and that the general population male-to-female prevalence ratios are only 3:1 to 2:1 (Ye et al., 2009). The mechanisms that contribute to the higher prevalence in men are unclear. They are mainly attributable to differences in the collapsibility of the upper airway and the distribution of body fat. Abdominal fat (the male distribution pattern) reduces lung volume when a person is horizontal, as during sleep, and increases soft tissue along the walls of the pharynx, thus serving to collapse them and block air entry (Li & Veasey, 2012). In males, the amount
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of visceral fat correlates with the likelihood of OSA (Kritikou et al., 2013). Androgens appear to exert adverse effects on breathing during sleep and predispose to OSA via their effect on the neural control of breathing and on upper airway mechanics (Liu et al., 2007). In contrast, female hormones, estrogen and progesterone, protect against OSA. They are thought to stimulate respiratory drive, to enhance the activity of muscles that dilate the pharynx and upper trachea and they reduce upper airway resistance (Driver et al., 2005). Low levels of both progesterone and estradiol have been associated with more apnoeic events in women (Netzer et al., 2003). Male/female ratios are especially high (8:1) in clinical populations, suggesting that more than 90% of women with OSA are never clinically diagnosed. Women may not present with the classical picture: snoring, witnessed apnoeas, excessive daytime sleepiness. When they do present, women generally have a milder form of OSA and a higher body mass index (BMI) than men with OSA. Their clinical picture may be one of lack of energy (often from concomitant hypothyroidism), depression, and insomnia (Shah et al., 2013; Ye et al., 2009). There is very little literature available on sex differences as they relate to clinical outcomes in OSA (Shah et al., 2013). Epidemiology of OSA The current population prevalence rates for moderate to severe sleep-disordered breathing is 10% among men aged 30–49 and 17% for men aged 50–70. It is 3% for 30- to 49-year-old women; and 9% for 50- to 70-year-old women. (Peppard et al., 2013). There is a higher male:female ratio for severe cases than for mild cases (O’Connor et al., 2000). Link between obesity and OSA Global obesity is considered to be the main (but not the only) risk factor for OSA in women (Anttalainen et al., 2007; Kapsimalis & Kryger, 2009; Kritikou et al., 2013). Fatty tissue around the pharynx narrows the upper airway and contributes to disordered breathing (Isono, 2012). Obesity-related inflammation in the same area may be a further factor leading to narrowing of the airway (Kirkness & Patil, 2013). This is important for women with schizophrenia who, more than men, suffer from secondary obesity (BMI 30) when treated with antipsychotic drugs (Gurpegui et al., 2012).
J Ment Health, 2014; 23(4): 191–196
Vignette B. L. is a postmenopausal 55-year-old divorced woman with a diagnosis of schizophrenia who complains to her psychiatrist of fatigue and daytime somnolence. She lives alone and supports herself through a disability pension. Her ex-husband and 25-year-old-son live in the same city but rarely visit. B. L.’s parents are no longer living; she has one sister with whom she is close, but the sister lives a considerable distance away. B. L. is being treated for psychotic symptoms with fluphenazine at a daily dose of 4 mg. She had been prescribed second-generation (atypical) antipsychotics in the past but she stopped them because of weight gain. B. L. is 50 400 tall and weighs 165 pounds; she has tried very hard to diet and to participate in fitness programs but, like many people, especially people with schizophrenia, finds this to be a struggle (Faulkner et al., 2003). Her blood pressure is 140/85 while taking metoprolol 25 mg BID. On fluphenazine, B. L. is generally free of psychotic symptoms, but when she tries to go without her medication she develops suspicions about her sister and her ex-husband, her speech begins to ramble, and she experiences ‘‘white visions’’ – shadowy presences in her apartment. These disappear when she resumes her medication. Her current complaint of fatigue and daytime sedation is not new; her psychiatrist has always attributed it to her medication. Although the daytime sleepiness complaint is not new for B. L., she has become more concerned about it recently because she has begun to babysit her neighbour’s 3 month-old infant. She is concerned that, should she fall asleep while babysitting, she may not hear the baby crying. Alerted by the potential safety issue posed by B. L.’s new responsibilities, her psychiatrist first screened for immediate dangers: He asked whether she smoked (in case her somnolence caused her to fall asleep while smoking and inadvertently start a fire). He asked whether she drank alcohol (which could aggravate sleepiness and impair judgment). B. L. does not smoke and denies drinking alcohol except for the occasional glass of wine (never when babysitting). She does not drive, which relieved her physician’s concern because of the strong association between daytime sedation and traffic accidents (Karimi et al., 2013), and she does not operate heavy machinery that requires special vigilance. B. L. does, however, worry about leaving cooking pots unattended and then falling asleep, so now always uses a timer with a ringtone whenever she is cooking. Daytime somnolence and menopause
Methods To underscore the importance of diagnosing and treating OSA in women with schizophrenia, a clinical review of the OSA literature was undertaken, with emphasis on schizophrenia and on women. Search terms entered in various combinations into PubMed were: Obstructive Sleep Apnoea; Schizophrenia; Women (or Gender); Obesity; Antipsychotics; CPAP. The case for intervention in schizophrenia is made through the use of a clinical vignette taken from composite files of the Women’s Clinic for Psychosis, Centre for Addiction and Mental Health, University of Toronto. The vignette includes details from several women treated in the clinic over a 10-year period.
Daytime sleepiness is a common complaint in patients treated with antipsychotics (Kane, 2008). In addition to the sedating effect of antipsychotic drugs, night sleep is relatively poorer in women with schizophrenia than in men (de Moura Campos et al., 2008), thus increasing daytime sedation. The female/male difference in soundness of nighttime sleep is especially marked during the menopausal transition (Kravitz et al., 2003), and menopause is a known independent risk factor for OSA (Anttalainen et al., 2006). Compared to premenopause, the odds ratio of developing an apnea– hypopnea index (AHI) of five or more events per hour on somnography increases to 1.66 in perimenopausal women and
Apnoea
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DOI: 10.3109/09638237.2013.869572
to 2.82 in postmenopausal women (Young et al., 2003). For moderately severe OSA, defined by an AHI score of 15 events/h, the pre and post menopause difference in prevalence is even more pronounced, rising from 0.6% of premenopausal women to 3.9% of postmenopausal women, a rate very similar to that of age-matched men (Bixler et al., 2001). Using the AHI criterion of 15 or more events per hour, the rate of OSA in postmenopausal women on hormone replacement therapy (HRT) did not differ significantly in this study from that of premenopausal women, while postmenopausal women not on HRT were more than four times as likely to have OSA (Bixler et al., 2001). Other studies have found similar results, but the magnitude of the difference has been smaller (Shahar et al., 2003). This speaks to the role of estrogens and progestins, referred to above, in protecting the upper airway from collapse. Relative to younger women, postmenopausal women have high androgen and low estrogen levels, with subsequently increased visceral adiposity. They also retain more fluid (Stachenfeld & Taylor, 2004), some of which may shift during sleep from the lower extremities to the upper body and airway and contribute to disordered breathing. Antipsychotic medication Antipsychotic drugs appear to vary in their effects on sleep parameters (Cohrs, 2008; Krystal et al., 2008), but the findings are not straightforward. It has been reported that the specific medication that a person takes may, in fact, account for a relatively small amount of the variance in sleep quality (Waters & Manoach, 2012). Nevertheless, with respect to OSA, where both excess weight and sedation constitute important risk factors, medications associated with weight gain (Vgontzas, 2008; Wirshing et al., 2002) or with sedation (Lu et al., 2005) are best avoided if possible (Rishi et al., 2010). Besides weight gain and sedation, many antipsychotic medications (such as the one that B. L. was taking) also induce extrapyramidal or parkinsonian symptoms. The extrapyramidal effects of antipsychotic drugs, in the form of muscle rigidity, may aggravate OSA. Atypical antipsychotics, most of which do not cause muscular rigidity, have, however, also been associated with OSA (Rishi et al., 2010). When adjusted for BMI, gender, and use of benzodiazepines and sleeping aids, the odds ratios of severe OSA in patients taking atypical antipsychotics were twice that in patients not taking these drugs. Shirani et al. (2011) however, found no independent effect of atypical antipsychotics. Sex, age, BMI, and neck circumference on their own predicted OSA in their study. A possible pathophysiological link between atypical antipsychotics and OSA is through changes in glucose metabolism. Many antipsychotics are linked to high rates of type II diabetes mellitus and some evidence suggests a role for impaired glucose tolerance in OSA, independent of weight gain (Choudhury & Taheri, 2011). Screening for sleep apnoea B. L.’s psychiatrist screened for OSA by administering the Berlin questionnaire (Netzer et al., 1999) and the STOP questionnaire (Chung et al., 2008). These commonly used
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screening instruments may be less useful in patients with schizophrenia relative to other patients because they rely, in part, on reports of snoring and gasping for breath at night as observed by a bed partner, whereas the majority of people with schizophrenia are unpartnered. The psychiatrist also measured blood pressure, BMI, and neck circumference, measures that are elevated in patients at risk for sleep apnoea. For B. L., the results were respectively 140/90, 28.32, 14 in. B. L. was also questioned about morning headaches, which occur in 18–27% of patients with sleep disordered breathing (SDB) compared to 5% of the general population (Goksan et al., 2009). Frequency of nighttime urination has also been associated with SDB. Twenty-eight percent of SDB patients report from four to seven urination trips per night due to increased secretion of atrial natriuretic peptide induced by intra-abdominal pressure (Oztura et al., 2006; Yoshimura et al., 2010). B. L. has no complaints of either headaches or nocturia. She has no history of polycystic ovarian syndrome and has had no episodes of atrial fibrillation, two condition independently associated with OSA (Mansukhani et al., 2013; Vgontzas et al., 2001). OSA is known to have a strong familial basis (Patel et al., 2012) and this can serve as a clue to diagnosis. B. L. did not know of any member of her family who had suffered from sleep problems. As stated earlier, she does not smoke nor drink alcohol to excess but does sleep on her back. It has been calculated that, in many patients with sleep apnoea, the sleeping position (supine versus non-supine) accounts for much of the apnoea index score (Joosten et al., 2014, Ravesloot et al., 2013; Sunnergren et al., 2013). Various techniques and devices (pillows, alarms, vests) have been recommended to prevent sleeping on one’s back. If patients can learn to avoid the supine position, a substantial number will have less trouble breathing at night (Ravesloot et al., 2013). B. L., in fact, found that her daytime sleepiness was relieved when she was able to spend the night on her side but she found it difficult to do so every night. Although a wide range of cognitive impairment has been identified in OSA patients (Jackson et al., 2011; Sforza & Roche, 2012), screening for attention, vigilance, memory or executive functions is not indicated because these deficits vary with age, premorbid IQ, and, in the context of schizophrenia, are already impaired. OSA accelerates agerelated decline in cognition in middle-aged patients (445 years) through chronic intermittent hypoxia (Ayalon et al., 2010). While cognitive testing is not useful for screening, pre-treatment scores can serve as a basis from which to evaluate the potential effects of treatment. Sleep studies Though many patients with schizophrenia are known to refuse to be physically examined (Iwata et al., 2011), B. L. agreed to undergo sleep studies i.e. polysomnography (PSG). Alam et al. (2012) report that almost three quarters of patients with severe mental illness accept referral for PSG. PSG monitors and records EEG, eye movement, muscle activity, pulse oximetry, and ECG during sleep (Rasmusson et al., 2012) and is considered the gold standard for diagnosis of OSA. It requires a full night’s stay at a sleep laboratory with a
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technician in attendance – a stressful and costly endeavour for many patients with schizophrenia. Portable somnography, which costs less, is increasingly available for testing in the home (Kirsch, 2013; Punjabi et al., 2013). In-home tests, however, have a higher failure rate (3–18% depending on the report, and on the device used) (Flemons et al., 2003). OSA is diagnosed by the occurrence of frequent episodes of disturbed breathing during sleep that are caused by a partial or complete occlusion of airflow through the upper airway. The AHI refers to the number of episodes of disturbed breathing per hour of sleep as shown on PSG. An AHI of 5–15 means mild OSA; an AHI of 15–30 means moderate OSA and an AHI greater than 30 means severe OSA. For reasons of upper airway anatomy, fatty tissue distribution, and possible hormonal effects on muscle tone, women tend to have fewer apnoeic events than men and, therefore, a relatively lower AHI. Treatment B. L.’s AHI was 30. She was presented with several options for treatment. An electronic decision board has been developed to help clinicians present patients with information on the relative benefits and side effects of CPAP and oral appliances (Pelletier-Fleury et al., 2012). CPAP is the first-line treatment but, because of discomfort and side-effects, compliance with CPAP is difficult for most people and has been reported to be especially so for patients with schizophrenia (Lin & Winkelman, 2012). Having no bed partner (Baron et al., 2012; Cartwright, 2008; Gagnadoux et al., 2011), unemployment (Gagnadoux et al., 2011) and poverty (Simon-Tuval et al., 2009) are all associated with poor adherence to CPAP, and these all apply to B.L., as they do to most individuals with schizophrenia. Overall, relative to men, women are considered to show relatively good compliance with CPAP, but this may not hold for older women on psychoactive medication (Campos-Rodriguez et al., 2013). B. L. had a hard time adjusting to her CPAP device. CPAP means wearing a mask at night that blows air into the nose so as to generate positive pressure that acts as a pneumatic splint and prevents the upper airway from collapsing during sleep (Rasmusson et al., 2012). This improves oxygenation and increases lung volume. The commonest side effects are mouth and nose dryness, nasal congestion and rhinorrhoea, and pressure sores from the mask. The CPAP device itself permits very accurate monitoring of compliance. The clinician needs to screen for side-effects and assess patients’ difficulties in using the equipment (adjusting the mask straps to prevent leaks and pressure sores, knowing how to connect and disconnect tubing). Referral to a patient support group is useful (Culpepper & Roth, 2009), but may not always be acceptable to people with schizophrenia (Haniffa et al., 2004). For those unwilling or unable to persist with CPAP, oral appliances can also provide good results, but only for those with the milder forms of OSA (Hoffstein, 2007; Li et al., 2013). Follow-up With constant encouragement from her psychiatrist, B. L. stayed with her CPAP device. Sleep fragmentation was
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reduced and depth of sleep improved; there were fewer microarousals. As a result, she has been able to function much better during the day and is no longer concerned about babysitting. Now fully awake during the day, B. L. is able to engage with her dietician and exercise therapist. As a consequence, she has lost weight and her blood pressure has decreased. The reduction in blood pressure is probably more a result of weight loss than of CPAP treatment (Kasiakogias et al., 2013; Parati et al., 2013). The evidence is not yet in about the effects of CPAP on metabolic and cognitive indices (Iftikhar et al., 2013). Nevertheless, attention, vigilance and, perhaps, memory appear to improve with continuous CPAP treatment (FeriniStrambi et al., 2013).
Discussion Current psychotropic medication induces weight gain and, in the schizophrenia population, this is exacerbated by life style factors such as sedentariness, poor diet choices, and excessive use of alcohol. Obesity subsequently exposes people with schizophrenia to medical complications, among which is OSA, a problem that, particularly in women, the clinician may not anticipate. Antipsychotics used to treat schizophrenia are associated with sedation and type II diabetes and extrapyramidal symptoms, all of which can further increase the risk for OSA. Because people with schizophrenia are more likely than not to live alone, sleep disturbances may go unrecognized for longer periods than would otherwise be the case. Daytime sleepiness is too easily attributed to antipsychotic medication and the diagnosis may be missed, the more so because patients may not be willing to spend a night in a sleep laboratory. OSA poses immediate safety concerns because of daytime sedation, and exposes the patient to future cardiovascular and metabolic risks, as well as to cognitive decline. Standard treatment for OSA is cumbersome for many patients and requires caregiver support and regular monitoring. For many patients with milder forms of OSA, and this may be the case for many women, oral appliances may be as effective as CPAP and better tolerated. Follow through with the treatment of choice is important if for no other reason than because both schizophrenia and OSA are associated with a high mortality rate (Marshall et al., 2008), aggravated by the fact that most patients with serious mental illness are never screened for cardiovascular risk (Hardy et al., 2013). Though the evidence is not all in, adequate CPAP treatment may reduce this rate, especially in women (Campos-Rodriguez et al., 2012).
Teaching points
Although more common in men, obstructive sleep apnoea (OSA) is not uncommon in women. OSA poses immediate safety risks because of daytime sedation and long-term safety risks because of cardiovascular and metabolic sequelae. OSA tends to be milder in women and is not as readily suspected as in men. Women most at risk are: postmenopausal, overweight, on sedating medication, smokers, alcohol users, women with polycystic ovaries, and those with atrial fibrillation.
DOI: 10.3109/09638237.2013.869572
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Women with schizophrenia may have many of the above risk factors. Their daytime sleepiness may be erroneously attributed to their drugs. Because they live alone, disordered breathing at night cannot be corroborated. Cognitive impairment, already present in schizophrenia, may be heightened. All daytime sleepiness calls for safety measures and fullscale investigation. Diet, exercise, and counseling abstinence from tobacco and alcohol are first-line interventions. Sedating and weight-inducing medications should be withdrawn if possible. Continuous positive airway pressure (CPAP) is the treatment of choice for OSA, but adherence is difficult and needs to be encouraged and supported. For milder OSA, oral appliances may be as effective as CPAP and better tolerated. Long-term effects of treatment on cardiometabolic and cognitive impairment are promising, but not yet fully determined.
Declaration of interest The author is a medical consultant to Clera Inc., a start-up pharmaceutical company. There is no potential conflict with the subject matter of this manuscript. The author had no writing assistance for this manuscript.
References Alam A, Chengappa KNR, Ghinassi F. (2012). Screening for obstructive sleep apnea among individuals with severe mental illness at a primary care clinic. Gen Hosp Psychiatr, 34, 660–4. Anttalainen U, Saaresranta T, Aittokallio J, et al. (2006). Impact of menopause on the manifestation and severity of sleep disordered breathing. Acta Obstet Gynecol Scand, 85, 1381–8. Anttalainen U, Saaresranta T, Kalleinen N, et al. (2007). Gender differences in age and BMI distributions in partial upper airway obstruction during sleep. Respir Physiol Neurobiol, 159, 219–26. Ayalon L, Ancoli-Israel S, Drummond SP. (2010). Obstructive sleep apnea and age: A double insult to brain function? Am J Respir Crit Care Med, 182, 413–19. Baguet JP, Barone-Rochette G, Tamisier R, et al. (2012). Mechanisms of cardiac dysfunction in obstructive sleep apnea. Nat Rev Cardiol, 9, 679–88. Baron KG, Gunn HE, Czajkowski LA, et al. (2012). Spousal involvement in CPAP: Does pressure help? J Clin Sleep Med, 8, 147–53. Bixler EO, Vgontzas AN, Lin HM, et al. (2001). Prevalence of sleepdisordered breathing in women: Effects of gender. Am J Respir Crit Care Med, 163, 608–13. Botros N, Concato J, Mohsenin V, et al. (2009). Obstructive sleep apnea as a risk factor for type 2 diabetes. Am J Med, 122, 1122–7. Campos-Rodriguez F, Martinez-Garcia MA, de la Cruz-Moron I, et al. (2012). Cardiovascular mortality in women with obstructive sleep apnea with or without continuous positive airway pressure treatment. A cohort study. Ann Internal Med, 156, 115–22. Campos-Rodriguez F, Martinez-Garcia MA, Reyes-Nun˜ez N, et al. (2013). Long-term CPAP compliance in females with obstructive sleep apnoea. Eur Respir J, 42, 1255–62. Cartwright R. (2008). Sleeping together: A pilot study of the effects of shared sleeping on adherence to CPAP treatment in obstructive sleep apnea. J Clin Sleep Med, 4, 123–7. Choudhury S, Taheri S. (2011). Obstructive sleep apnoea and type 2 diabetes: Whose disease is it anyway? Practic Diabet Int, 28, 183–6a. Chung F, Yegneswaran B, Liao P, et al. (2008). STOP questionnaire: A tool to screen patients for obstructive sleep apnea. Anesthesiology, 108, 812–21.
Apnoea
195
Cohrs S. (2008). Sleep disturbances in patients with schizophrenia: Impact and effect of antipsychotics. Cent Nerv Syst Drugs, 22, 939–62. Culpepper L, Roth T. (2009). Recognizing and managing obstructive sleep apnea in primary care. Prim Care Comp J Clin Psychiatr, 11, 330–8. de Moura Campos E, Moura˜o Melo C, Soares-Maia W, et al. (2008). Sleep disturbances and gender differences in schizophrenia. Sleep Sci, 1, 27–30. Dickerson FB, Brown CH, Kreyenbuhl JA, et al. (2006). Obesity among individuals with serious mental illness. Acta Psychiatr Scand, 113, 306–13. Dragers LF, Jun JC, Polotsky VY. (2010). Metabolic consequences of intermittent hypoxia: Relevance to obstructive sleep apnea. Best Pract Res Clin Endocrinol Metabol, 24, 843–51. Dragers LF, Polotsky VY, Lorenzo-Filho G. (2011). Obstructive sleep apnea: An emerging risk factor for atherosclerosis. Chest, 140, 534–42. Driver HS, McLean H, Kumar DV, et al. (2005). The influence of the menstrual cycle on upper airway resistance and breathing during sleep. Sleep, 28, 449–56. Faulkner G, Soundy AA, Lloyd K. (2003). Schizophrenia and weight management: A systematic review of interventions to control weight. Acta Psychiatr Scand, 108, 324–32. Ferini-Strambi L, Marelli S, Galbiati A, Castronovo C. (2013). Effects of continuous positive airway pressure on cognition and neuroimaging data in sleep apnea. Int J Psychophysiol, 89, 203–12. Flemons WW, Littner MR, Rowley JA, et al. (2003). Home diagnosis of sleep apnea: A systematic review of the literature. An evidence review cosponsored by the American Academy of Sleep Medicine, the American College of Chest Physicians, and the American Thoracic Society. Chest, 124, 1543–79. Gagnadoux F, Le Vaillant M, Goupil F, et al. (2011). Influence of marital status and employment status on long-term adherence with continuous positive airway pressure in sleep apnea patients. PLoS One, 6, e22503. Gibson GJ. (2004). Obstructive sleep apnoea syndrome: Underestimated and undertreated. Br Med Bull, 72, 49–65. Goksan B, Gunduz A, Karadeniz D, et al. (2009). Morning headache in sleep apnoea: Clinical and polysomnographic evaluation and response to nasal continuous positive airway pressure. Cephalalgia, 29, 635–41. Grigg-Damberger M, Ralls F. (2012). Cognitive dysfunction and obstructive sleep apnea: From cradle to tomb. Curr Opin Pulm Med, 18, 580–7. Gurpegui M, Martı´nez-Ortega JM, Gutie´rrez-Rojas L, et al. (2012). Overweight and obesity in patients with bipolar disorder or schizophrenia compared with a non-psychiatric sample. Progr Neuropsychopharmacol Biol Psychiatr, 37, 169–75. Haniffa M, Lasserson TJ, Smith I. (2004). Interventions to improve compliance with continuous positive airway pressure for obstructive sleep apnoea. Cochrane Database Syst Rev, CD003531. Hardy S, Hinks P, Gray R. (2013). Screening for cardiovascular risk in patients with severe mental illness in primary care: A comparison with patients with diabetes. J Mental Health, 22, 42–50. Hoffstein V. (2007). Review of oral appliances for treatment of sleepdisordered breathing. Sleep Breath, 11, 1–22. Iftikhar IH, Khan MF, Das A, Magalang UJ. (2013). Meta-analysis: Continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes. Ann Am Thorac Soc, 10, 115–20. Isono S. (2012). Obesity and obstructive sleep apnoea: Mechanisms for increased collapsibility of the passive pharyngeal airway. Respirology, 17, 32–42. Iwata K, Strydom A, Osborn D. (2011). Insight and other predictors of physical examination refusal in psychotic illness. J Mental Health, 20, 319–27. Jackson ML, Howard ME, Barnes M. (2011). Cognition and daytime functioning in sleep-related breathing disorders. Progr Brain Res, 190, 53–68. Joosten SA, O’Driscoll DM, Berger PJ, Hamilton GS. (2014). Supine position related obstructive sleep apnea in adults: Pathogenesis and treatment. Sleep Med Rev, 18, 7–17. Jun J, Polotsky VY. (2009). Metabolic consequences of sleep-disordered breathing. Inst Animal Lab Resour J, 50, 289–306.
Downloaded by [University of California, San Diego] at 01:33 07 November 2015
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Kalucy MJ, Grunstein R, Lambert T, Glozier N. (2013). Obstructive sleep apnoea and schizophrenia – A research agenda. Sleep Med Rev, 17, 357–65. Kane JM. (2008). Sedation as a side effect of the treatment of mental disorders. J Clin Psychiatr, 69, e20. Kapsimalis F, Kryger M. (2009). Sleep breathing disorders in the U.S. female population. J Womens Health (Larchmont), 18, 1211–19. Karimi M, Eder DN, Eskandari D, et al. (2013). Impaired vigilance and increased accident rate in public transport operators is associated with sleep disorders. Acc Anal Prev, 51, 208–14. Kasiakogias A, Tsioufis C, Thomopoulos C, et al. (2013). Effects of continuous positive airway pressure on blood pressure in hypertensive patients with obstructive sleep apnea: A 3-year follow-up. J Hypertens, 31, 352–60. Kirkness JP, Patil SP. (2013). Pathogenesis of obstructive sleep apnea in obesity. Respir Med, 19, 71–97. Kirsch DB. (2013). In-home testing for obstructive sleep apnea. Continuum (Minneapolis Minnesota), 19, 223–8. Kravitz HM, Ganz PA, Bromberger J, et al. (2003). Sleep difficulty in women at midlife: A community survey of sleep and the menopausal transition. Menopause, 10, 19–28. Kritikou I, Basta M, Tappouni R, et al. (2013). Sleep apnoea and visceral adiposity in middle-aged male and female subjects. Eur Respir J, 41, 601–9. Krystal AD, Goforth HW, Roth T. (2008). Effects of antipsychotic medications on sleep in schizophrenia. Int Clin Psychopharmacol, 23, 150–60. Lal C, Strange C, Bachman D. (2012). Neurocognitive impairment in obstructive sleep apnea. Chest, 141, 1601–10. Leucht S, Burkard T, Henderson J, et al. (2007). Physical illness and schizophrenia: A review of the literature. Acta Psychiatr Scand, 116, 317–33. Li Y, Veasey SC. (2012). Neurobiology and neuropathophysiology of obstructive sleep apnea. Neuromol Med, 14, 168–79. Li W, Xiao L, Hu J. (2013). The comparison of CPAP and OA in treatment of patients with OSA: A systematic review and metaanalysis. Respir Care, 58, 1184–95. Lin WC, Winkelman JW. (2012). Obstructive sleep apnea and severe mental illness: Evolution and consequences. Curr Psychiatr Rep, 14, 503–10. Liu PY, Yee BJ, Philips CL, Grunstein RR. (2007). Sleep apnea and neuroendocrine function. Sleep Med Clin, 2, 225–36. Lu B, Budhiraja R, Parthasarathy S. (2005). Sedating medications and undiagnosed obstructive sleep apnea: Physician determinants and patient consequences. J Clin Sleep Med, 1, 367–71. Mansukhani MP, Calvin AD, Kolla BP, et al. (2013). The association between atrial fibrillation and stroke in patients with obstructive sleep apnea: A population-based case-control study. Sleep Medicine, 14, 243–6. Marshall NS, Wong KK, Liu PY, et al. (2008). Sleep apnea as an independent risk factor for all-cause mortality: The Busselton Health Study. Sleep, 31, 1079–85. Netzer NC, Eliasson AH, Strohl KP. (2003). Women with sleep apnea have lower levels of sex hormones. Sleep Breath, 7, 25–9. Netzer NC, Stoohs RA, Netzer CM, et al. (1999). Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Internal Med, 131, 485–91. O’Connor C, Thornley KS, Hanly PJ. (2000). Gender differences in the polysomnographic features of obstructive sleep apnea. Am J Respir Crit Care Med, 161, 1465–72. Oztura I, Kaynak D, Kaynak HC. (2006). Nocturia in sleep-disordered breathing. Sleep Med, 7, 362–67. Parati G, Lombardi C, Hedner J, et al., on behalf of the EU COST Action B26 members. (2013). Recommendations for the management of patients with obstructive sleep apnoea and hypertension. Eur Respirol J, 41, 523–38. Patel SR, Goodloe R, De G, et al. (2012). Association of genetic loci with sleep apnea in European Americans and African-Americans: The candidate gene association resource (CARe). PLoS ONE, 7, e48836. Pelletier-Fleury N, Gafni A, Krucien N, Fleury B. (2012). The development and testing of a new communication tool to help
J Ment Health, 2014; 23(4): 191–196
clinicians inform patients with obstructive sleep apnoea syndrome about treatment options. J Sleep Res, 21, 577–83. Peppard PE, Young T, Barnet JH, et al. (2013). Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol, [Epub ahead of print]. doi: 10.1093/aje/kws342. Poulin J, Chouinard S, Pampoulova T, et al. (2010). Sleep habits in middle-aged, non-hospitalized men and women with schizophrenia: A comparison with healthy controls. Psychiatr Res, 179, 274–8. Punjabi NM, Aurora RN, Patil SP. (2013). Home sleep testing for obstructive sleep apnea: One night is enough! Chest, 143, 291–4. Rasmusson L, Bidarian A, Sennerby L, Scott G. (2012). Pathophysiology and treatment options in obstructive sleep apnoea: A review of the literature. Int J Clin Med, 3, 473–84. Ravesloot MJ, Van Maanen JP, Dun L, De Vries N. (2013). The undervalued potential of positional therapy in position-dependent snoring and obstructive sleep apnea – a review of the literature. Sleep Breath, 17, 39–49. Redline S, Yenokyan G, Gottlieb DJ, et al. (2010). Obstructive sleep apnea-hypopnea and incident stroke: The sleep heart health study. Am J Respir Crit Care Med, 182, 269–77. Rishi MA, Shetty M, Wolff A, et al. (2010). Atypical antipsychotic medications are independently associated with severe obstructive sleep apnea. Clin Neuropharmacol, 33, 109–13. Sforza E, Roche F. (2012). Sleep apnea syndrome and cognition. Front Neurol, 3, 87. Shah N, Yaggi H, Redline S. (2013). Sex-related differences in cardiometabolic outcomes associated with obstructive sleep apnea: A review. Clin Pulmon Med, 20, 149–54. Shahar E, Redline S, Young T, et al. (2003). Hormone replacement therapy and sleep-disordered breathing. Am J Respir Crit Care Med, 167, 1186–92. Shirani A, Paradiso S, Dyken ME. (2011). The impact of atypical antipsychotic use on obstructive sleep apnea: A pilot study and literature review. Sleep Med, 12, 591–7. Simon-Tuval T, Reuveni H, Greenberg-Dotan S, et al. (2009). Low socioeconomic status is a risk factor for CPAP acceptance among adult OSAS patients requiring treatment. Sleep, 32, 545–52. Stachenfeld NS, Taylor HS. (2004). Effects of estrogen and progesterone administration on extracellular fluid. J Appl Physiol, 96, 1011–18. Sunnergren O, Brostro¨m A, Svanborg E. (2013). Positional sensitivity as a confounder in diagnosis of severity of obstructive sleep apnea. Sleep Breath, 17, 173–9. Taylor VH, McIntyre RS, Remington G, et al. (2012). Beyond pharmacotherapy: Understanding the links between obesity and chronic mental illness. Can J Psychiatr, 57, 5–12. Verstraeten E. (2007). Neurocognitive effects of obstructive sleep apnea syndrome. Curr Neurol Neurosci Rep, 7, 161–6. Vgontzas AN. (2008). Does obesity play a major role in the pathogenesis of sleep apnoea and its associated manifestations via inflammation, visceral adiposity, and insulin resistance? Arch Physiol Biochem, 114, 211–23. Vgontzas AN, Legro RS, Bixler EO, et al. (2001). Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: Role of insulin resistance. J Clin Endocrinol Metab, 86, 517–20. von Hausswolff-Juhlin Y, Bjartveit M, Lindstro¨m E, Jones P. (2009). Schizophrenia and physical health problems. Acta Psychiatr Scand, 119, 15–21. Waters F, Manoach DS. (2012). Sleep dysfunctions in schizophrenia: A practical review. Open J Psychiatr, 2, 384–92. Wirshing DA, Pierre JM, Wirshing WC. (2002). Sleep apnea associated with antipsychotic-induced obesity. J Clin Psychiatr, 63, 369–70. Ye L, Pien GW, Weaver TE. (2009). Gender differences in the clinical manifestation of obstructive sleep apnea. Sleep Med, 10, 1075–84. Yoshimura K, Oka Y, Kamoto T, et al. (2010). Differences and associations between nocturnal voiding/nocturia and sleep disorders. BJU Int, 106, 232–7. Young T, Finn L, Austin D, Peterson A. (2003). Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med, 167, 1181–5.
ISSN: 0963-8237 (Print) 1360-0567 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmh20
Diagnosis and treatment of sleep apnoea in women with schizophrenia Mary V. Seeman To cite this article: Mary V. Seeman (2014) Diagnosis and treatment of sleep apnoea in women with schizophrenia, Journal of Mental Health, 23:4, 191-196 To link to this article: http://dx.doi.org/10.3109/09638237.2013.869572
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http://informahealthcare.com/jmh ISSN: 0963-8237 (print), 1360-0567 (electronic) J Ment Health, 2014; 23(4): 191–196 ! 2014 Informa UK Ltd. DOI: 10.3109/09638237.2013.869572
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Diagnosis and treatment of sleep apnoea in women with schizophrenia Mary V. Seeman
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Department of Psychiatry, University of Toronto, Ontario, Canada
Abstract
Keywords
Background: Obstructive sleep apnoea (OSA) is often overlooked in the context of schizophrenia because its hallmark, daytime sleepiness, is so easily attributable to antipsychotic drugs. This is a special problem for women. Aims: To underscore the importance of diagnosing and treating OSA in women with schizophrenia. Methods: A review of the recent literature (search terms: Obstructive Sleep Apnoea; Schizophrenia; Women (or Gender); Obesity; Antipsychotics; Continuous Positive Airway Pressure (CPAP)) as it applies to a composite case vignette taken from the files of a specialty clinic that treats women with psychosis. Results: The rate of OSA in women who are both obese and postmenopausal is very similar to that of men. Family history, smoking, and the use of tobacco, alcohol and of antipsychotic medication increase the risk. Despite reluctance, patients with schizophrenia generally agree to undergo sleep studies. Compliance with CPAP is difficult, but can be aided by the physician and is, on the whole, relatively high in women. CPAP improves sleep parameters and may also improve cardiometabolic and cognitive indices, although this still needs to be more fully researched. Conclusion: Schizophrenia and untreated OSA are both associated with high mortality rates in women as well as men.
Antipsychotics, continuous positive airway pressure, obesity, obstructive sleep apnoea, schizophrenia, women
Introduction Partly as a result of an obesity epidemic among psychiatric patients (Dickerson et al., 2006; Taylor et al., 2012), the rate of medical morbidity has become very high in this population and is believed to be especially high in patients with schizophrenia (Leucht et al., 2007; von Hausswolff-Juhlin et al., 2009). One comorbidity, obstructive sleep apnoea (OSA), can be inordinately difficult to ascertain in the context of schizophrenia (Kalucy et al., 2013), especially in women where it is less expected than it is in men. Even when successfully diagnosed, OSA can be difficult to treat in this population (Kalucy et al., 2013). The prevalence of OSA in the population at large is often underestimated (Gibson, 2004). In patients with schizophrenia, daytime sleepiness, an important early clinical clue to OSA, is so commonplace (Poulin et al., 2010) that it is easily overlooked or attributed to the effects of therapeutic drugs. Even when OSA is suspected, the patient, for reasons of apathy or lack of understanding of the potential medical consequences of OSA, or general suspiciousness, may refuse a sleep assessment. And even when the diagnosis is
Correspondence: Mary V. Seeman, Professor Emerita, Department of Psychiatry, University of Toronto, #605 260 Heath St. W., Toronto, Ontario M5P 3L6, Canada. Tel: 416 486 3456. E-mail: mary.seeman@ utoronto.ca
History Received 10 June 2013 Revised 10 July 2013 Accepted 23 September 2013 Published online 16 January 2014
made and treatment accepted, adherence with continuous positive airway pressure (CPAP) can be difficult (Lin & Winkelman, 2012). It is important to identify and treat OSA when comorbid with schizophrenia because the daytime sleepiness leads to accidents and, over time, the condition exacerbates two existing problems associated with schizophrenia and its treatment: the cardiometabolic harms (Baguet et al., 2012; Botros et al., 2009; Dragers et al., 2010, 2011; Jun & Polotsky, 2009; Redline et al., 2010) and the cognitive impairment (Grigg-Damberger & Ralls, 2012; Lal et al., 2012; Verstraeten, 2007). In the general population, women are less likely than men to suffer from a severe form of OSA. The result is that when OSA does occur in women, it may go unrecognized. The male-to-female ratio was once estimated to be anywhere from 60:1 to 10:1. It has now been demonstrated that OSA is not as rare in women as previously thought, and that the general population male-to-female prevalence ratios are only 3:1 to 2:1 (Ye et al., 2009). The mechanisms that contribute to the higher prevalence in men are unclear. They are mainly attributable to differences in the collapsibility of the upper airway and the distribution of body fat. Abdominal fat (the male distribution pattern) reduces lung volume when a person is horizontal, as during sleep, and increases soft tissue along the walls of the pharynx, thus serving to collapse them and block air entry (Li & Veasey, 2012). In males, the amount
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of visceral fat correlates with the likelihood of OSA (Kritikou et al., 2013). Androgens appear to exert adverse effects on breathing during sleep and predispose to OSA via their effect on the neural control of breathing and on upper airway mechanics (Liu et al., 2007). In contrast, female hormones, estrogen and progesterone, protect against OSA. They are thought to stimulate respiratory drive, to enhance the activity of muscles that dilate the pharynx and upper trachea and they reduce upper airway resistance (Driver et al., 2005). Low levels of both progesterone and estradiol have been associated with more apnoeic events in women (Netzer et al., 2003). Male/female ratios are especially high (8:1) in clinical populations, suggesting that more than 90% of women with OSA are never clinically diagnosed. Women may not present with the classical picture: snoring, witnessed apnoeas, excessive daytime sleepiness. When they do present, women generally have a milder form of OSA and a higher body mass index (BMI) than men with OSA. Their clinical picture may be one of lack of energy (often from concomitant hypothyroidism), depression, and insomnia (Shah et al., 2013; Ye et al., 2009). There is very little literature available on sex differences as they relate to clinical outcomes in OSA (Shah et al., 2013). Epidemiology of OSA The current population prevalence rates for moderate to severe sleep-disordered breathing is 10% among men aged 30–49 and 17% for men aged 50–70. It is 3% for 30- to 49-year-old women; and 9% for 50- to 70-year-old women. (Peppard et al., 2013). There is a higher male:female ratio for severe cases than for mild cases (O’Connor et al., 2000). Link between obesity and OSA Global obesity is considered to be the main (but not the only) risk factor for OSA in women (Anttalainen et al., 2007; Kapsimalis & Kryger, 2009; Kritikou et al., 2013). Fatty tissue around the pharynx narrows the upper airway and contributes to disordered breathing (Isono, 2012). Obesity-related inflammation in the same area may be a further factor leading to narrowing of the airway (Kirkness & Patil, 2013). This is important for women with schizophrenia who, more than men, suffer from secondary obesity (BMI 30) when treated with antipsychotic drugs (Gurpegui et al., 2012).
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Vignette B. L. is a postmenopausal 55-year-old divorced woman with a diagnosis of schizophrenia who complains to her psychiatrist of fatigue and daytime somnolence. She lives alone and supports herself through a disability pension. Her ex-husband and 25-year-old-son live in the same city but rarely visit. B. L.’s parents are no longer living; she has one sister with whom she is close, but the sister lives a considerable distance away. B. L. is being treated for psychotic symptoms with fluphenazine at a daily dose of 4 mg. She had been prescribed second-generation (atypical) antipsychotics in the past but she stopped them because of weight gain. B. L. is 50 400 tall and weighs 165 pounds; she has tried very hard to diet and to participate in fitness programs but, like many people, especially people with schizophrenia, finds this to be a struggle (Faulkner et al., 2003). Her blood pressure is 140/85 while taking metoprolol 25 mg BID. On fluphenazine, B. L. is generally free of psychotic symptoms, but when she tries to go without her medication she develops suspicions about her sister and her ex-husband, her speech begins to ramble, and she experiences ‘‘white visions’’ – shadowy presences in her apartment. These disappear when she resumes her medication. Her current complaint of fatigue and daytime sedation is not new; her psychiatrist has always attributed it to her medication. Although the daytime sleepiness complaint is not new for B. L., she has become more concerned about it recently because she has begun to babysit her neighbour’s 3 month-old infant. She is concerned that, should she fall asleep while babysitting, she may not hear the baby crying. Alerted by the potential safety issue posed by B. L.’s new responsibilities, her psychiatrist first screened for immediate dangers: He asked whether she smoked (in case her somnolence caused her to fall asleep while smoking and inadvertently start a fire). He asked whether she drank alcohol (which could aggravate sleepiness and impair judgment). B. L. does not smoke and denies drinking alcohol except for the occasional glass of wine (never when babysitting). She does not drive, which relieved her physician’s concern because of the strong association between daytime sedation and traffic accidents (Karimi et al., 2013), and she does not operate heavy machinery that requires special vigilance. B. L. does, however, worry about leaving cooking pots unattended and then falling asleep, so now always uses a timer with a ringtone whenever she is cooking. Daytime somnolence and menopause
Methods To underscore the importance of diagnosing and treating OSA in women with schizophrenia, a clinical review of the OSA literature was undertaken, with emphasis on schizophrenia and on women. Search terms entered in various combinations into PubMed were: Obstructive Sleep Apnoea; Schizophrenia; Women (or Gender); Obesity; Antipsychotics; CPAP. The case for intervention in schizophrenia is made through the use of a clinical vignette taken from composite files of the Women’s Clinic for Psychosis, Centre for Addiction and Mental Health, University of Toronto. The vignette includes details from several women treated in the clinic over a 10-year period.
Daytime sleepiness is a common complaint in patients treated with antipsychotics (Kane, 2008). In addition to the sedating effect of antipsychotic drugs, night sleep is relatively poorer in women with schizophrenia than in men (de Moura Campos et al., 2008), thus increasing daytime sedation. The female/male difference in soundness of nighttime sleep is especially marked during the menopausal transition (Kravitz et al., 2003), and menopause is a known independent risk factor for OSA (Anttalainen et al., 2006). Compared to premenopause, the odds ratio of developing an apnea– hypopnea index (AHI) of five or more events per hour on somnography increases to 1.66 in perimenopausal women and
Apnoea
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to 2.82 in postmenopausal women (Young et al., 2003). For moderately severe OSA, defined by an AHI score of 15 events/h, the pre and post menopause difference in prevalence is even more pronounced, rising from 0.6% of premenopausal women to 3.9% of postmenopausal women, a rate very similar to that of age-matched men (Bixler et al., 2001). Using the AHI criterion of 15 or more events per hour, the rate of OSA in postmenopausal women on hormone replacement therapy (HRT) did not differ significantly in this study from that of premenopausal women, while postmenopausal women not on HRT were more than four times as likely to have OSA (Bixler et al., 2001). Other studies have found similar results, but the magnitude of the difference has been smaller (Shahar et al., 2003). This speaks to the role of estrogens and progestins, referred to above, in protecting the upper airway from collapse. Relative to younger women, postmenopausal women have high androgen and low estrogen levels, with subsequently increased visceral adiposity. They also retain more fluid (Stachenfeld & Taylor, 2004), some of which may shift during sleep from the lower extremities to the upper body and airway and contribute to disordered breathing. Antipsychotic medication Antipsychotic drugs appear to vary in their effects on sleep parameters (Cohrs, 2008; Krystal et al., 2008), but the findings are not straightforward. It has been reported that the specific medication that a person takes may, in fact, account for a relatively small amount of the variance in sleep quality (Waters & Manoach, 2012). Nevertheless, with respect to OSA, where both excess weight and sedation constitute important risk factors, medications associated with weight gain (Vgontzas, 2008; Wirshing et al., 2002) or with sedation (Lu et al., 2005) are best avoided if possible (Rishi et al., 2010). Besides weight gain and sedation, many antipsychotic medications (such as the one that B. L. was taking) also induce extrapyramidal or parkinsonian symptoms. The extrapyramidal effects of antipsychotic drugs, in the form of muscle rigidity, may aggravate OSA. Atypical antipsychotics, most of which do not cause muscular rigidity, have, however, also been associated with OSA (Rishi et al., 2010). When adjusted for BMI, gender, and use of benzodiazepines and sleeping aids, the odds ratios of severe OSA in patients taking atypical antipsychotics were twice that in patients not taking these drugs. Shirani et al. (2011) however, found no independent effect of atypical antipsychotics. Sex, age, BMI, and neck circumference on their own predicted OSA in their study. A possible pathophysiological link between atypical antipsychotics and OSA is through changes in glucose metabolism. Many antipsychotics are linked to high rates of type II diabetes mellitus and some evidence suggests a role for impaired glucose tolerance in OSA, independent of weight gain (Choudhury & Taheri, 2011). Screening for sleep apnoea B. L.’s psychiatrist screened for OSA by administering the Berlin questionnaire (Netzer et al., 1999) and the STOP questionnaire (Chung et al., 2008). These commonly used
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screening instruments may be less useful in patients with schizophrenia relative to other patients because they rely, in part, on reports of snoring and gasping for breath at night as observed by a bed partner, whereas the majority of people with schizophrenia are unpartnered. The psychiatrist also measured blood pressure, BMI, and neck circumference, measures that are elevated in patients at risk for sleep apnoea. For B. L., the results were respectively 140/90, 28.32, 14 in. B. L. was also questioned about morning headaches, which occur in 18–27% of patients with sleep disordered breathing (SDB) compared to 5% of the general population (Goksan et al., 2009). Frequency of nighttime urination has also been associated with SDB. Twenty-eight percent of SDB patients report from four to seven urination trips per night due to increased secretion of atrial natriuretic peptide induced by intra-abdominal pressure (Oztura et al., 2006; Yoshimura et al., 2010). B. L. has no complaints of either headaches or nocturia. She has no history of polycystic ovarian syndrome and has had no episodes of atrial fibrillation, two condition independently associated with OSA (Mansukhani et al., 2013; Vgontzas et al., 2001). OSA is known to have a strong familial basis (Patel et al., 2012) and this can serve as a clue to diagnosis. B. L. did not know of any member of her family who had suffered from sleep problems. As stated earlier, she does not smoke nor drink alcohol to excess but does sleep on her back. It has been calculated that, in many patients with sleep apnoea, the sleeping position (supine versus non-supine) accounts for much of the apnoea index score (Joosten et al., 2014, Ravesloot et al., 2013; Sunnergren et al., 2013). Various techniques and devices (pillows, alarms, vests) have been recommended to prevent sleeping on one’s back. If patients can learn to avoid the supine position, a substantial number will have less trouble breathing at night (Ravesloot et al., 2013). B. L., in fact, found that her daytime sleepiness was relieved when she was able to spend the night on her side but she found it difficult to do so every night. Although a wide range of cognitive impairment has been identified in OSA patients (Jackson et al., 2011; Sforza & Roche, 2012), screening for attention, vigilance, memory or executive functions is not indicated because these deficits vary with age, premorbid IQ, and, in the context of schizophrenia, are already impaired. OSA accelerates agerelated decline in cognition in middle-aged patients (445 years) through chronic intermittent hypoxia (Ayalon et al., 2010). While cognitive testing is not useful for screening, pre-treatment scores can serve as a basis from which to evaluate the potential effects of treatment. Sleep studies Though many patients with schizophrenia are known to refuse to be physically examined (Iwata et al., 2011), B. L. agreed to undergo sleep studies i.e. polysomnography (PSG). Alam et al. (2012) report that almost three quarters of patients with severe mental illness accept referral for PSG. PSG monitors and records EEG, eye movement, muscle activity, pulse oximetry, and ECG during sleep (Rasmusson et al., 2012) and is considered the gold standard for diagnosis of OSA. It requires a full night’s stay at a sleep laboratory with a
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technician in attendance – a stressful and costly endeavour for many patients with schizophrenia. Portable somnography, which costs less, is increasingly available for testing in the home (Kirsch, 2013; Punjabi et al., 2013). In-home tests, however, have a higher failure rate (3–18% depending on the report, and on the device used) (Flemons et al., 2003). OSA is diagnosed by the occurrence of frequent episodes of disturbed breathing during sleep that are caused by a partial or complete occlusion of airflow through the upper airway. The AHI refers to the number of episodes of disturbed breathing per hour of sleep as shown on PSG. An AHI of 5–15 means mild OSA; an AHI of 15–30 means moderate OSA and an AHI greater than 30 means severe OSA. For reasons of upper airway anatomy, fatty tissue distribution, and possible hormonal effects on muscle tone, women tend to have fewer apnoeic events than men and, therefore, a relatively lower AHI. Treatment B. L.’s AHI was 30. She was presented with several options for treatment. An electronic decision board has been developed to help clinicians present patients with information on the relative benefits and side effects of CPAP and oral appliances (Pelletier-Fleury et al., 2012). CPAP is the first-line treatment but, because of discomfort and side-effects, compliance with CPAP is difficult for most people and has been reported to be especially so for patients with schizophrenia (Lin & Winkelman, 2012). Having no bed partner (Baron et al., 2012; Cartwright, 2008; Gagnadoux et al., 2011), unemployment (Gagnadoux et al., 2011) and poverty (Simon-Tuval et al., 2009) are all associated with poor adherence to CPAP, and these all apply to B.L., as they do to most individuals with schizophrenia. Overall, relative to men, women are considered to show relatively good compliance with CPAP, but this may not hold for older women on psychoactive medication (Campos-Rodriguez et al., 2013). B. L. had a hard time adjusting to her CPAP device. CPAP means wearing a mask at night that blows air into the nose so as to generate positive pressure that acts as a pneumatic splint and prevents the upper airway from collapsing during sleep (Rasmusson et al., 2012). This improves oxygenation and increases lung volume. The commonest side effects are mouth and nose dryness, nasal congestion and rhinorrhoea, and pressure sores from the mask. The CPAP device itself permits very accurate monitoring of compliance. The clinician needs to screen for side-effects and assess patients’ difficulties in using the equipment (adjusting the mask straps to prevent leaks and pressure sores, knowing how to connect and disconnect tubing). Referral to a patient support group is useful (Culpepper & Roth, 2009), but may not always be acceptable to people with schizophrenia (Haniffa et al., 2004). For those unwilling or unable to persist with CPAP, oral appliances can also provide good results, but only for those with the milder forms of OSA (Hoffstein, 2007; Li et al., 2013). Follow-up With constant encouragement from her psychiatrist, B. L. stayed with her CPAP device. Sleep fragmentation was
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reduced and depth of sleep improved; there were fewer microarousals. As a result, she has been able to function much better during the day and is no longer concerned about babysitting. Now fully awake during the day, B. L. is able to engage with her dietician and exercise therapist. As a consequence, she has lost weight and her blood pressure has decreased. The reduction in blood pressure is probably more a result of weight loss than of CPAP treatment (Kasiakogias et al., 2013; Parati et al., 2013). The evidence is not yet in about the effects of CPAP on metabolic and cognitive indices (Iftikhar et al., 2013). Nevertheless, attention, vigilance and, perhaps, memory appear to improve with continuous CPAP treatment (FeriniStrambi et al., 2013).
Discussion Current psychotropic medication induces weight gain and, in the schizophrenia population, this is exacerbated by life style factors such as sedentariness, poor diet choices, and excessive use of alcohol. Obesity subsequently exposes people with schizophrenia to medical complications, among which is OSA, a problem that, particularly in women, the clinician may not anticipate. Antipsychotics used to treat schizophrenia are associated with sedation and type II diabetes and extrapyramidal symptoms, all of which can further increase the risk for OSA. Because people with schizophrenia are more likely than not to live alone, sleep disturbances may go unrecognized for longer periods than would otherwise be the case. Daytime sleepiness is too easily attributed to antipsychotic medication and the diagnosis may be missed, the more so because patients may not be willing to spend a night in a sleep laboratory. OSA poses immediate safety concerns because of daytime sedation, and exposes the patient to future cardiovascular and metabolic risks, as well as to cognitive decline. Standard treatment for OSA is cumbersome for many patients and requires caregiver support and regular monitoring. For many patients with milder forms of OSA, and this may be the case for many women, oral appliances may be as effective as CPAP and better tolerated. Follow through with the treatment of choice is important if for no other reason than because both schizophrenia and OSA are associated with a high mortality rate (Marshall et al., 2008), aggravated by the fact that most patients with serious mental illness are never screened for cardiovascular risk (Hardy et al., 2013). Though the evidence is not all in, adequate CPAP treatment may reduce this rate, especially in women (Campos-Rodriguez et al., 2012).
Teaching points
Although more common in men, obstructive sleep apnoea (OSA) is not uncommon in women. OSA poses immediate safety risks because of daytime sedation and long-term safety risks because of cardiovascular and metabolic sequelae. OSA tends to be milder in women and is not as readily suspected as in men. Women most at risk are: postmenopausal, overweight, on sedating medication, smokers, alcohol users, women with polycystic ovaries, and those with atrial fibrillation.
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Women with schizophrenia may have many of the above risk factors. Their daytime sleepiness may be erroneously attributed to their drugs. Because they live alone, disordered breathing at night cannot be corroborated. Cognitive impairment, already present in schizophrenia, may be heightened. All daytime sleepiness calls for safety measures and fullscale investigation. Diet, exercise, and counseling abstinence from tobacco and alcohol are first-line interventions. Sedating and weight-inducing medications should be withdrawn if possible. Continuous positive airway pressure (CPAP) is the treatment of choice for OSA, but adherence is difficult and needs to be encouraged and supported. For milder OSA, oral appliances may be as effective as CPAP and better tolerated. Long-term effects of treatment on cardiometabolic and cognitive impairment are promising, but not yet fully determined.
Declaration of interest The author is a medical consultant to Clera Inc., a start-up pharmaceutical company. There is no potential conflict with the subject matter of this manuscript. The author had no writing assistance for this manuscript.
References Alam A, Chengappa KNR, Ghinassi F. (2012). Screening for obstructive sleep apnea among individuals with severe mental illness at a primary care clinic. Gen Hosp Psychiatr, 34, 660–4. Anttalainen U, Saaresranta T, Aittokallio J, et al. (2006). Impact of menopause on the manifestation and severity of sleep disordered breathing. Acta Obstet Gynecol Scand, 85, 1381–8. Anttalainen U, Saaresranta T, Kalleinen N, et al. (2007). Gender differences in age and BMI distributions in partial upper airway obstruction during sleep. Respir Physiol Neurobiol, 159, 219–26. Ayalon L, Ancoli-Israel S, Drummond SP. (2010). Obstructive sleep apnea and age: A double insult to brain function? Am J Respir Crit Care Med, 182, 413–19. Baguet JP, Barone-Rochette G, Tamisier R, et al. (2012). Mechanisms of cardiac dysfunction in obstructive sleep apnea. Nat Rev Cardiol, 9, 679–88. Baron KG, Gunn HE, Czajkowski LA, et al. (2012). Spousal involvement in CPAP: Does pressure help? J Clin Sleep Med, 8, 147–53. Bixler EO, Vgontzas AN, Lin HM, et al. (2001). Prevalence of sleepdisordered breathing in women: Effects of gender. Am J Respir Crit Care Med, 163, 608–13. Botros N, Concato J, Mohsenin V, et al. (2009). Obstructive sleep apnea as a risk factor for type 2 diabetes. Am J Med, 122, 1122–7. Campos-Rodriguez F, Martinez-Garcia MA, de la Cruz-Moron I, et al. (2012). Cardiovascular mortality in women with obstructive sleep apnea with or without continuous positive airway pressure treatment. A cohort study. Ann Internal Med, 156, 115–22. Campos-Rodriguez F, Martinez-Garcia MA, Reyes-Nun˜ez N, et al. (2013). Long-term CPAP compliance in females with obstructive sleep apnoea. Eur Respir J, 42, 1255–62. Cartwright R. (2008). Sleeping together: A pilot study of the effects of shared sleeping on adherence to CPAP treatment in obstructive sleep apnea. J Clin Sleep Med, 4, 123–7. Choudhury S, Taheri S. (2011). Obstructive sleep apnoea and type 2 diabetes: Whose disease is it anyway? Practic Diabet Int, 28, 183–6a. Chung F, Yegneswaran B, Liao P, et al. (2008). STOP questionnaire: A tool to screen patients for obstructive sleep apnea. Anesthesiology, 108, 812–21.
Apnoea
195
Cohrs S. (2008). Sleep disturbances in patients with schizophrenia: Impact and effect of antipsychotics. Cent Nerv Syst Drugs, 22, 939–62. Culpepper L, Roth T. (2009). Recognizing and managing obstructive sleep apnea in primary care. Prim Care Comp J Clin Psychiatr, 11, 330–8. de Moura Campos E, Moura˜o Melo C, Soares-Maia W, et al. (2008). Sleep disturbances and gender differences in schizophrenia. Sleep Sci, 1, 27–30. Dickerson FB, Brown CH, Kreyenbuhl JA, et al. (2006). Obesity among individuals with serious mental illness. Acta Psychiatr Scand, 113, 306–13. Dragers LF, Jun JC, Polotsky VY. (2010). Metabolic consequences of intermittent hypoxia: Relevance to obstructive sleep apnea. Best Pract Res Clin Endocrinol Metabol, 24, 843–51. Dragers LF, Polotsky VY, Lorenzo-Filho G. (2011). Obstructive sleep apnea: An emerging risk factor for atherosclerosis. Chest, 140, 534–42. Driver HS, McLean H, Kumar DV, et al. (2005). The influence of the menstrual cycle on upper airway resistance and breathing during sleep. Sleep, 28, 449–56. Faulkner G, Soundy AA, Lloyd K. (2003). Schizophrenia and weight management: A systematic review of interventions to control weight. Acta Psychiatr Scand, 108, 324–32. Ferini-Strambi L, Marelli S, Galbiati A, Castronovo C. (2013). Effects of continuous positive airway pressure on cognition and neuroimaging data in sleep apnea. Int J Psychophysiol, 89, 203–12. Flemons WW, Littner MR, Rowley JA, et al. (2003). Home diagnosis of sleep apnea: A systematic review of the literature. An evidence review cosponsored by the American Academy of Sleep Medicine, the American College of Chest Physicians, and the American Thoracic Society. Chest, 124, 1543–79. Gagnadoux F, Le Vaillant M, Goupil F, et al. (2011). Influence of marital status and employment status on long-term adherence with continuous positive airway pressure in sleep apnea patients. PLoS One, 6, e22503. Gibson GJ. (2004). Obstructive sleep apnoea syndrome: Underestimated and undertreated. Br Med Bull, 72, 49–65. Goksan B, Gunduz A, Karadeniz D, et al. (2009). Morning headache in sleep apnoea: Clinical and polysomnographic evaluation and response to nasal continuous positive airway pressure. Cephalalgia, 29, 635–41. Grigg-Damberger M, Ralls F. (2012). Cognitive dysfunction and obstructive sleep apnea: From cradle to tomb. Curr Opin Pulm Med, 18, 580–7. Gurpegui M, Martı´nez-Ortega JM, Gutie´rrez-Rojas L, et al. (2012). Overweight and obesity in patients with bipolar disorder or schizophrenia compared with a non-psychiatric sample. Progr Neuropsychopharmacol Biol Psychiatr, 37, 169–75. Haniffa M, Lasserson TJ, Smith I. (2004). Interventions to improve compliance with continuous positive airway pressure for obstructive sleep apnoea. Cochrane Database Syst Rev, CD003531. Hardy S, Hinks P, Gray R. (2013). Screening for cardiovascular risk in patients with severe mental illness in primary care: A comparison with patients with diabetes. J Mental Health, 22, 42–50. Hoffstein V. (2007). Review of oral appliances for treatment of sleepdisordered breathing. Sleep Breath, 11, 1–22. Iftikhar IH, Khan MF, Das A, Magalang UJ. (2013). Meta-analysis: Continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes. Ann Am Thorac Soc, 10, 115–20. Isono S. (2012). Obesity and obstructive sleep apnoea: Mechanisms for increased collapsibility of the passive pharyngeal airway. Respirology, 17, 32–42. Iwata K, Strydom A, Osborn D. (2011). Insight and other predictors of physical examination refusal in psychotic illness. J Mental Health, 20, 319–27. Jackson ML, Howard ME, Barnes M. (2011). Cognition and daytime functioning in sleep-related breathing disorders. Progr Brain Res, 190, 53–68. Joosten SA, O’Driscoll DM, Berger PJ, Hamilton GS. (2014). Supine position related obstructive sleep apnea in adults: Pathogenesis and treatment. Sleep Med Rev, 18, 7–17. Jun J, Polotsky VY. (2009). Metabolic consequences of sleep-disordered breathing. Inst Animal Lab Resour J, 50, 289–306.
Downloaded by [University of California, San Diego] at 01:33 07 November 2015
196
M. V. Seeman
Kalucy MJ, Grunstein R, Lambert T, Glozier N. (2013). Obstructive sleep apnoea and schizophrenia – A research agenda. Sleep Med Rev, 17, 357–65. Kane JM. (2008). Sedation as a side effect of the treatment of mental disorders. J Clin Psychiatr, 69, e20. Kapsimalis F, Kryger M. (2009). Sleep breathing disorders in the U.S. female population. J Womens Health (Larchmont), 18, 1211–19. Karimi M, Eder DN, Eskandari D, et al. (2013). Impaired vigilance and increased accident rate in public transport operators is associated with sleep disorders. Acc Anal Prev, 51, 208–14. Kasiakogias A, Tsioufis C, Thomopoulos C, et al. (2013). Effects of continuous positive airway pressure on blood pressure in hypertensive patients with obstructive sleep apnea: A 3-year follow-up. J Hypertens, 31, 352–60. Kirkness JP, Patil SP. (2013). Pathogenesis of obstructive sleep apnea in obesity. Respir Med, 19, 71–97. Kirsch DB. (2013). In-home testing for obstructive sleep apnea. Continuum (Minneapolis Minnesota), 19, 223–8. Kravitz HM, Ganz PA, Bromberger J, et al. (2003). Sleep difficulty in women at midlife: A community survey of sleep and the menopausal transition. Menopause, 10, 19–28. Kritikou I, Basta M, Tappouni R, et al. (2013). Sleep apnoea and visceral adiposity in middle-aged male and female subjects. Eur Respir J, 41, 601–9. Krystal AD, Goforth HW, Roth T. (2008). Effects of antipsychotic medications on sleep in schizophrenia. Int Clin Psychopharmacol, 23, 150–60. Lal C, Strange C, Bachman D. (2012). Neurocognitive impairment in obstructive sleep apnea. Chest, 141, 1601–10. Leucht S, Burkard T, Henderson J, et al. (2007). Physical illness and schizophrenia: A review of the literature. Acta Psychiatr Scand, 116, 317–33. Li Y, Veasey SC. (2012). Neurobiology and neuropathophysiology of obstructive sleep apnea. Neuromol Med, 14, 168–79. Li W, Xiao L, Hu J. (2013). The comparison of CPAP and OA in treatment of patients with OSA: A systematic review and metaanalysis. Respir Care, 58, 1184–95. Lin WC, Winkelman JW. (2012). Obstructive sleep apnea and severe mental illness: Evolution and consequences. Curr Psychiatr Rep, 14, 503–10. Liu PY, Yee BJ, Philips CL, Grunstein RR. (2007). Sleep apnea and neuroendocrine function. Sleep Med Clin, 2, 225–36. Lu B, Budhiraja R, Parthasarathy S. (2005). Sedating medications and undiagnosed obstructive sleep apnea: Physician determinants and patient consequences. J Clin Sleep Med, 1, 367–71. Mansukhani MP, Calvin AD, Kolla BP, et al. (2013). The association between atrial fibrillation and stroke in patients with obstructive sleep apnea: A population-based case-control study. Sleep Medicine, 14, 243–6. Marshall NS, Wong KK, Liu PY, et al. (2008). Sleep apnea as an independent risk factor for all-cause mortality: The Busselton Health Study. Sleep, 31, 1079–85. Netzer NC, Eliasson AH, Strohl KP. (2003). Women with sleep apnea have lower levels of sex hormones. Sleep Breath, 7, 25–9. Netzer NC, Stoohs RA, Netzer CM, et al. (1999). Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Internal Med, 131, 485–91. O’Connor C, Thornley KS, Hanly PJ. (2000). Gender differences in the polysomnographic features of obstructive sleep apnea. Am J Respir Crit Care Med, 161, 1465–72. Oztura I, Kaynak D, Kaynak HC. (2006). Nocturia in sleep-disordered breathing. Sleep Med, 7, 362–67. Parati G, Lombardi C, Hedner J, et al., on behalf of the EU COST Action B26 members. (2013). Recommendations for the management of patients with obstructive sleep apnoea and hypertension. Eur Respirol J, 41, 523–38. Patel SR, Goodloe R, De G, et al. (2012). Association of genetic loci with sleep apnea in European Americans and African-Americans: The candidate gene association resource (CARe). PLoS ONE, 7, e48836. Pelletier-Fleury N, Gafni A, Krucien N, Fleury B. (2012). The development and testing of a new communication tool to help
J Ment Health, 2014; 23(4): 191–196
clinicians inform patients with obstructive sleep apnoea syndrome about treatment options. J Sleep Res, 21, 577–83. Peppard PE, Young T, Barnet JH, et al. (2013). Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol, [Epub ahead of print]. doi: 10.1093/aje/kws342. Poulin J, Chouinard S, Pampoulova T, et al. (2010). Sleep habits in middle-aged, non-hospitalized men and women with schizophrenia: A comparison with healthy controls. Psychiatr Res, 179, 274–8. Punjabi NM, Aurora RN, Patil SP. (2013). Home sleep testing for obstructive sleep apnea: One night is enough! Chest, 143, 291–4. Rasmusson L, Bidarian A, Sennerby L, Scott G. (2012). Pathophysiology and treatment options in obstructive sleep apnoea: A review of the literature. Int J Clin Med, 3, 473–84. Ravesloot MJ, Van Maanen JP, Dun L, De Vries N. (2013). The undervalued potential of positional therapy in position-dependent snoring and obstructive sleep apnea – a review of the literature. Sleep Breath, 17, 39–49. Redline S, Yenokyan G, Gottlieb DJ, et al. (2010). Obstructive sleep apnea-hypopnea and incident stroke: The sleep heart health study. Am J Respir Crit Care Med, 182, 269–77. Rishi MA, Shetty M, Wolff A, et al. (2010). Atypical antipsychotic medications are independently associated with severe obstructive sleep apnea. Clin Neuropharmacol, 33, 109–13. Sforza E, Roche F. (2012). Sleep apnea syndrome and cognition. Front Neurol, 3, 87. Shah N, Yaggi H, Redline S. (2013). Sex-related differences in cardiometabolic outcomes associated with obstructive sleep apnea: A review. Clin Pulmon Med, 20, 149–54. Shahar E, Redline S, Young T, et al. (2003). Hormone replacement therapy and sleep-disordered breathing. Am J Respir Crit Care Med, 167, 1186–92. Shirani A, Paradiso S, Dyken ME. (2011). The impact of atypical antipsychotic use on obstructive sleep apnea: A pilot study and literature review. Sleep Med, 12, 591–7. Simon-Tuval T, Reuveni H, Greenberg-Dotan S, et al. (2009). Low socioeconomic status is a risk factor for CPAP acceptance among adult OSAS patients requiring treatment. Sleep, 32, 545–52. Stachenfeld NS, Taylor HS. (2004). Effects of estrogen and progesterone administration on extracellular fluid. J Appl Physiol, 96, 1011–18. Sunnergren O, Brostro¨m A, Svanborg E. (2013). Positional sensitivity as a confounder in diagnosis of severity of obstructive sleep apnea. Sleep Breath, 17, 173–9. Taylor VH, McIntyre RS, Remington G, et al. (2012). Beyond pharmacotherapy: Understanding the links between obesity and chronic mental illness. Can J Psychiatr, 57, 5–12. Verstraeten E. (2007). Neurocognitive effects of obstructive sleep apnea syndrome. Curr Neurol Neurosci Rep, 7, 161–6. Vgontzas AN. (2008). Does obesity play a major role in the pathogenesis of sleep apnoea and its associated manifestations via inflammation, visceral adiposity, and insulin resistance? Arch Physiol Biochem, 114, 211–23. Vgontzas AN, Legro RS, Bixler EO, et al. (2001). Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: Role of insulin resistance. J Clin Endocrinol Metab, 86, 517–20. von Hausswolff-Juhlin Y, Bjartveit M, Lindstro¨m E, Jones P. (2009). Schizophrenia and physical health problems. Acta Psychiatr Scand, 119, 15–21. Waters F, Manoach DS. (2012). Sleep dysfunctions in schizophrenia: A practical review. Open J Psychiatr, 2, 384–92. Wirshing DA, Pierre JM, Wirshing WC. (2002). Sleep apnea associated with antipsychotic-induced obesity. J Clin Psychiatr, 63, 369–70. Ye L, Pien GW, Weaver TE. (2009). Gender differences in the clinical manifestation of obstructive sleep apnea. Sleep Med, 10, 1075–84. Yoshimura K, Oka Y, Kamoto T, et al. (2010). Differences and associations between nocturnal voiding/nocturia and sleep disorders. BJU Int, 106, 232–7. Young T, Finn L, Austin D, Peterson A. (2003). Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med, 167, 1181–5.
