International Journal of Psychiatry in Clinical Practice, 2006; 10(2): 117 123
ORIGINAL ARTICLE
Excessive daytime sleepiness in psychiatry: a relevant focus for clinical attention and treatment?
CHRIS J. HAWLEY1,2 Department of Psychiatry, QEII Hospital, Welwyn Garden City, UK, and 2Faculty of Health and Human Science, University of Hertfordshire, Hatfield, UK Int J Psych Clin Pract Downloaded from informahealthcare.com by CDL-UC Santa Cruz on 10/26/14 For personal use only.
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Abstract Excessive daytime sleepiness is a feature of many general medical disorders and is associated with significant impairment in function and well-being. It has, however, received little attention in psychiatry although it may be a common and clinically important problem. The opinions of two expert groups, and a survey of the literature, were used to form views about the prevalence and clinical significance of excessive sleepiness in psychiatric populations. Issues relating to pharmacological treatment were also considered. Despite a scant evidence base, the conclusions are that excessive sleepiness may be a common and significant problem, and potentially amenable to treatment. However, clinician awareness is probably limited and there are opportunities for further research.
Key Words: Excessive daytime sleepiness, excessive sleepiness, hypersomnia, somnolence, psychiatry, modafinil
Introduction It is well known that excessive daytime sleepiness (hereafter excessive sleepiness: ES) accompanies many general medical disorders such as obstructive sleep apnoea-hypopnoea syndrome (OSAHS), Parkinson’s disease, multiple sclerosis, myotonic dystrophy and narcolepsy [1 5]. The behavioural and functional consequences of ES are well reported and include impairment of work-performance and social roles, reduced subjective well-being, cognitiveslowing and increased risk for accidents [69]. In neurology and respiratory medicine it is well accepted that ES deserves to be identified, managed and treated. Moreover, the efficacy of treatments for ES in these areas is established [10 15]. Although ES is an important symptom, and potentially amenable to treatment, it appears to have received little consideration in psychiatry. For example, standard post-graduate texts make, at best, passing reference to ES as a clinical problem. Insomnia, by comparison, receives substantial attention. One can reasonably propose that ES should be a prevalent symptom in psychiatric populations; not least because many psychiatric disorders affect sleep and somnolence is a common unwanted effect of pharmacotherapy used in psychiatric conditions. It could be argued, for example, that there would be
value in screening of psychiatric populations for ES using a quick and inexpensive tool, such as the Epworth Sleepiness Scale (ESS [16]). Cases with ES might thereby be identified and assisted. But the argument for ‘‘raising the game’’ regarding ES in psychiatry depends on at least two things. Firstly; that the problem is a prevalent one; and, secondly, that when present it is of clinical relevance and not merely a trivial issue amidst other more profound problems. That ES is both prevalent and relevant in psychiatric populations is far from selfevident: Indeed, some have suggested that ES is ‘‘rarely, if ever, due to a psychological or psychiatric condition’’ [17]. Thus, the purpose of this paper is to gain an understanding of the extent of ES in general psychiatry and whether greater clinical and research enquiry is justified. Method Initially an attempt was made to systematically review the literature on ES in psychiatric populations. This attempt failed. All permutations of relevant search terms (e.g. hypersomnolenece, hypersomnia, excessive sleepiness, depression, schizophrenia, sedation, psychiatric, mental health) failed to yield a literature that could be evaluated systematically and
Correspondence: Professor C.J. Hawley, Department of Psychiatry, QEII Hospital, Howlands, Welwyn Garden City, Herts AL7 4HQ, UK. Tel: +44 1707 365073. Fax: +44 1707 365169. E-mail [email protected]
(Received 19 April 2005; accepted 15 December 2005) ISSN 1365-1501 print/ISSN 1471-1788 online # 2006 Taylor & Francis DOI: 10.1080/13651500600578904
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quantitatively, with the exception of papers relating to clinical trials of modafinil in psychiatric disorders. Thus it was decided to proceed on the basis of surveying the literature as extensively as possible and to supplement this survey by drawing on the experience and opinions of clinicians via round-table discussions. It is hoped that this approach at least describes the scope of the current literature and clinical understanding and that formal reviews may be possible when more data have accumulated. Two discussion groups were held under the direction of the author. The first group consisted of eight psychiatrists chosen for their ability to represent the experiences of day-to-day clinical practice. The second group comprised six academic psychiatrists chosen to represent a more theoretical position. The groups were asked to contribute clinical understanding and expert opinion and not merely comment critically on the available literature. The agenda for both groups was the same, to consider: 1. whether ES is a prevalent problem in psychiatric populations; 2. whether ES deserves clinical attention; 3. what treatment options might be applied to ES in psychiatric populations. This article presents a synthesis of discussions, along with a summary of the literature, which highlighted the following key areas of consideration: 1. difficulties arising from definitions and terminology; 2. prevalence and clinical relevance of excessive sleepiness in psychiatry; 3. options for treatment; 4. screening for excessive sleepiness in psychiatric populations. Problems in terminology and definition The meaning of the term ‘‘excessive sleepiness’’ was considered by the discussion groups to be problematic in itself. In relation to psychiatry at least, terms such as hypersomnia, hypersomnolence, sleepiness, somnolence, sedation, drowsiness, tiredness and fatigue may be used more-or-less interchangeably or, at the very least, describe overlapping concepts relating to the same symptoms or experiences. Undoubtedly, fatigue and tiredness can be confused with sleepiness, yet even if clearly experienced as separate entities, may be caused by the same underlying condition. The groups were of the opinion that definition of such terms would be useful. But the literature is not forthcoming. For example: the DSM-IV [18], while including hypersomnia as a criterion symptom for some disorders, does not provide a definition of the term. Similarly, the National Library of Medicine
Dictionary of Terms [19] lists various terms such as drowsiness, somnolence and hypersomnia as synonyms. The matter of definition is further complicated depending on what approach one uses to determine that ES is present in a patient. In essence there are two methods: 1. Objective, behavioural tests such as the Multiple Sleep Latency Test (MSLT) [20] or the Maintenance of Wakefulness Test (MWT) [21]. 2. Introspective, subjective, reporting by the patient, for example through paper-and-pencil tests such as the ESS [16,22] or Stanford Sleepiness Scale [23,24] or for that matter through ordinary clinical reporting of symptoms. Objective measures of sleepiness (i.e. MWT, MSLT) may, however, correlate rather poorly with subjective measures [25]. Chervin et al. [26] found a correlation of only 0.37 between the ESS and the MSLT in a population of patients with sleep disordered breathing or narcolepsy. Thus, at least with the currently available techniques, subjective reporting of sleepiness corresponds only partially to objectively measured propensity to sleep. This in itself is problematic for defining what constitutes ‘‘excessive sleepiness’’. Although the psychiatric literature is scant, a study by Nofzinger et al [27] adds further support to this view. Nofzinger et al. compared hypersomniac bipolar depressed patients with narcoleptics and found a weaker correspondence between the complaint of excessive sleepiness and objective sleep tendency (measured by MSLT) in the former. Thus in medical disorders generally, and psychiatric disorders particularly, a correlation between subjective sleepiness and objective propensity to sleep should not be too readily assumed. In conclusion on this point, the groups felt that the problem of definition of terms could not be resolved without further research in psychiatric populations. Until then we must accept that the language is imprecise and operate within that limitation. A satisfactory provisional description of ES might be ‘‘difficulty in maintaining wakefulness and an increased likelihood of falling asleep in inappropriate situations’’: a description broad enough not to exclude patients with shift work-related sleep disorder in whom the excessive sleepiness occurs at night, not during the day. Prevalence of excessive sleepiness as a clinical problem The discussion groups were invited to discuss psychiatric scenarios in which excessive sleepiness may present as a clinically evident problem. Two diagnostic groups attracted the greatest attention: depression and schizophrenia.
Excessive daytime sleepiness in psychiatry Regarding depression, two main areas became our focus: firstly those patients with syndromal major depression (unipolar or bipolar) in whom excessive sleepiness, rather than insomnia, was a chief clinical complaint; and secondly, those patients where excessive sleepiness, or somnolence, was the unwanted effect of pharmacotherapy for a mood disorder. Regarding schizophrenia, the chronic inert/apathetic patient with extensive daytime sleeping, or time spent in bed, was seen as a prototypical and common problem. The propensity of anti-psychotic drugs to cause somnolence was also regarded as a major clinical issue.
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Excessive sleepiness in relation to depression Reflecting on clinical experience, the groups were of the opinion that excessive sleepiness in major depression was a common feature, with maybe a quarter or a fifth of patients being so affected. But there was not a clear consensus about the clinical importance of excessive sleepiness when present. However, the groups did agree that they might be lacking in awareness, and undervaluing what could be an important, or impairing, symptom for the patient. The limited education for psychiatrists regarding normal and abnormal sleep was highlighted. An additional opinion arising from the groups’ discussions was as follows: that any debate about the importance of excessive sleepiness in depression is not simply a debate about the validity of the atypical specifier. Some hold that atypical specified depression is a discreet nosological entity while others argue otherwise [28]. However, our groups thought that this did not matter: if excessive sleepiness deserves greater clinical attention then it does so on its own merits, and irrespective of typology of depression. What then is the prevalence of ES in depressed populations? To the best of our knowledge there have been no substantial prevalence studies addressing this directly. But there are at least two general lines of attack on the question. Firstly, if we assume that ES is no less prevalent in clinical depressed populations than in epidemiological populations then the estimate in the latter should provide the minimum estimate in the former. Secondly, if it is assumed that excessive sleepiness is sine qua non for atypical depression then the proportion of all Major Depressed cases that are atypical-specified should act as a proxy estimate for the prevalence of ES in depressive populations as a whole. The prevalence of ES in normal (epidemiological) populations is known to some extent. A Finnish population questionnaire study found that 9% reported ES ‘‘every or nearly every day’’ [29]. Additionally, this study found a particularly strong association between ES and depression: about a
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quarter of minor depressed cases (BDI score 14 24 inc.) reported ES and a little more than a half of major depressed cases (BDI /24) did too. Hara et al [30] reported in a Brazilian population that the prevalence of excessive sleepiness occurring ‘‘three or more times week’’ was 16.8% and other reports produce convergent results [31]. A report by Horwath et al [32] is informative about the proportion of all major depressed cases that are atypical-specified. In a community study of 662 major depressed cases, 104 (15.7%) were found to be atypical (hypersomnia was set as a necessary criterion for atypicality in this study). In addition, of the 558 non-atypical cases 23% were reported as sleeping too much. Thus, for the major depressive sample as a whole, about 35% reported hypersomnia during depressed episodes. Matza et al. [33] found 36.4% of all major depressed cases (n /836) to be atypical specified and, as in Horwath et al. [32], hypersomnia was a necessary criterion for atypicality. There has been one brief report of a study specifically intended to determine the prevalence of ES in a psychiatric population [34]. Of 161 Major Depressed outpatients, 45% scored ]/10 on the ESS. Consistent with the Finnish population questionnaire study an association was found between severity of depression (BDI scores) and the prevalence of caseness on the ESS. However, one is reminded that caseness on a screening tool does not necessarily equate to a clinical diagnosis or a clinically significant disorder, and the sensitivity and specificity of the ESS in psychiatric populations is not known. Overall, the clinical impression of the expert groups that a ‘‘quarter or a fifth’’ of depressed cases exhibit excessive sleepiness is given credence by the literature. While it does not necessarily follow that just because a symptom is present it thereby must be the focus of clinical attention, the substantial prevalence of ES suggests that clinical awareness is important. Excessive sleepiness in relation to schizophrenia The discussion groups readily called to mind example cases of schizophrenia in which excessive sleeping appeared to be a predominant clinical problem. A typical scenario being the chronically ill patient with no regular sleep wake cycle, apathetic, prone to stay in bed all day and engaging in little meaningful activity. In depression it can be readily established that excessive sleepiness is often an inherent part of the patient’s condition. But the same cannot be said for schizophrenia. Despite the clinical impression of the discussion groups there appears to be no reports in the literature to validate the notion that excessive sleepiness is inherent to the schizophrenic condition. Polysomnographic studies in schizophrenia point to sleep onset and mainte-
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nance insomnia as the most common features [35]. It could be that excessive sleepiness is an inherent feature in schizophrenia, but if so, it has yet to be demonstrated.
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Iatrogenic somnolence In depression, iatrogenic somnolence ought, on the face of it, to be a problem of some clinical significance. The most widely used antidepressants are the selective serotonin re-uptake inhibitors (SSRIs) and in acute treatment studies in major depression, somnolence with SSRIs is reported in approximately 820% of cases, typically a two- to three-fold excess over placebo [3639]. Some have commented on the clinical importance of this antidepressant-related sedation [40,41]. But our groups were unimpressed on this point and did not see it as a pressing clinical issue despite awareness of the high apparent prevalence. Why so? A plausible answer is as follows: firstly, although SSRI-related somnolence is common, its severity is such that it only leads to discontinuation of treatment in a minority of cases [42]. Secondly, continuation studies with SSRIs show very low rates of persisting somnolence once the peak of events associated with initiation has passed [43]. In short, SSRI somnolence is common but generally mild and time limited. Other antidepressants are more sedative than the SSRIs (e.g. mirtazapine, trazodone, some tricyclics) and for these the considerations may be different. But as regards the most commonly used antidepressants, the SSRIs, iatrogenic sedation, of a problematic degree, appears to be uncommon. Regarding schizophrenia, the discussion groups thought that drug-induced somnolence was a problem of substantial clinical significance. However, quantifying this is surprisingly difficult. In acute studies of schizophrenia the reported incidence of somnolence ranges from as little as 2% to as much as 50% [4449]. Detailed data on severity of adverse events is rather seldom presented in trial reports. However, surveys of patients on chronic antipsychotic therapy may provide some insight. Although such naturalistic data lacks rigorous control it does suggest persisting somnolence in a substantial proportion of cases: Levoyer [50] found persisting somnolence in 22% of clozapine-treated cases. In patients receiving long-term treatment with a variety of antipsychotics, Hofer et al. [51] found that 42% complained of sedation. In a controlled trial of antipsychotic therapy (quetiapine versus risperidone), Mullen et al. [49] found in about a quarter of cases that somnolence did not resolve with continued treatment up to 12 weeks. If these figures are broadly representative then it appears that persisting excessive sleepiness is a common iatrogenic problem in schizophrenia and deserving of clinical attention not least because
anti-psychotic pharmacotherapy is often life-long. The difference between antidepressants and antipsychotics is that somnolence with the former is typically self-limiting but often persistent with the latter. Overall, we are drawn to the conclusion that excessive sleepiness does have a substantial prevalence in psychiatric populations. As far as can be ascertained ES will be most commonly observed by the clinician as an inherent symptom in depression and as an iatrogenic feature in schizophrenia. In addition the discussion groups provided a reminder that psychiatric populations are no less prone to general medical disorders than the general population; the psychiatrist’s differential diagnosis of ES should include general medical disorders although clinical skills in this respect may not be uniformly high. Treatment options for excessive sleepiness The discussion groups were asked to consider possible treatments for ES in psychiatric populations. The options to consider were limited. Classic psychostimulants On the face of it classic psychostimulants (e.g. dexamfetamine, methylphenidate) could be effective treatments for excessive sleepiness arising from a variety of causes. They are undoubtedly wakefulness-promoting and enhance cognitive performance [52,53]. But the groups’ opinion was that the potential for abuse and dependence is so high in psychiatric populations that their use could not be countenanced in anything other than exceptional circumstances. Furthermore, there is no literature to support the use of classic psychostimulants for ES in psychiatric populations, other than inferences that can be drawn from occasional case reports [54]. Modafinil Systematic data regarding effectiveness, safety and tolerability of modafinil in schizophrenia-related ES is limited to one study of 11 cases [55]: Adjunctive modafinil was described as ‘‘generally well tolerated’’. Hallucinations occurred in two subjects but no direct relation to modafinil is stated. Other than single case reports there are no other data. There is one placebo-controlled study of modafinil as a treatment for ES in major depression [56]. Modafinil add-on to pre-existing SRRI therapy improved ESS scores more than did placebo addon (n /311), but statistical significance was not seen at all time points. Modafinil add-on to SSRI was effective in reducing ESS scores in an open label study (n /20) by Schwartz et al. [57]. Space does not permit a detailed analysis of adverse events here
Excessive daytime sleepiness in psychiatry but the tolerability of modafinil, in combination with antidepressants appears similar to that of modafinil when administered as a sole therapy [5763]. The data on modafinil appears to be of interest but falls short of allowing any unequivocal treatment recommendations.
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Screening in psychiatric populations The discussion groups considered whether there would be value in screening psychiatric populations for excessive sleepiness. Doing so might have the general effect of improving clinician awareness regarding excessive sleepiness and, in particular, help to identify hitherto undetected cases. A suitable brief questionnaire, that demands no clinician input, would be the eight-item Epworth Sleepiness Scale (ESS). The reliability and validity of the ESS has been adequately studied [16,25,64]. The ESS is a non-copyright instrument, free to be used and copied. A score greater than 10 is generally taken to indicate caseness, then warranting further clinical questioning. The groups thought there was a balance of considerations. On the one hand the scale is so quick and easy to administer and interpret that there is little to deter the psychiatrist from using the scale liberally: administering it, for example, to patients in waiting areas. On the other hand, it was noted that the operating characteristics for the scale as a screening tool in psychiatric populations specifically have yet to be studied. Although the scale has desirable properties when used in neurology or respiratory populations it cannot necessarily be inferred that the scale will operate as well in psychiatric populations. On balance, the groups’ opinion was that the use of the ESS by psychiatrists is to be actively encouraged but with the proviso that test results should be interpreted cautiously. And, of course that treatment decisions should rest on the clinical evaluation that follows from screening and not on the test result per se .
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application of modafinil tolerates consideration; however, it is not licensed for the treatment of drug-induced somnolence. Throughout the groups’ discussions, and in the survey of the literature, it was apparent how little is known about ES in psychiatry: little is known about prevalence, the lexicon is poorly defined, the operating properties of screening tools (e.g. ESS) are not known and to date only one drug has been studied systematically. These areas present ample opportunity for future research. Key points . Excessive daytime sleepiness is a feature of many general medical disorders and is associated with significant impairment in function and well-being. . It has, however, received little attention in the psychiatric literature although it may be a common and clinically important problem. . Excessive sleepiness is occurs with a number of conditions and treatments including: syndromal major depression (unipolar or bipolar) and somnolence as an unwanted effect of antidepressants or antipsychotics. . The prevalence of excessive sleepiness in psychiatric populations is unknown but was estimated to be as high as 25% by an expert panel. . This review suggests that further research on the prevalence and treatment of excessive sleepiness in psychiatry is warranted. Acknowledgements I am grateful to the following people for their contributions to the discussion groups: Dr Sanjay Rao, Dr Simon Groves, Professor Reinhard Heun, Professor Naomi Fineberg, Dr Ian Smith, Dr Deepa Deo, Dr Richard O’Flynn, Dr Avi Dhariwal, Dr Digby Quested, Dr Paul Reading. Thanks also to two anonymous reviewers for their comments on an earlier draft of this paper. Statement of interest
Conclusion In this paper we have attempted to synthesise the opinions of expert groups with a survey of the literature to determine whether excessive sleepiness is a prevalent problem in psychiatric populations and whether it is amenable to identification and treatment. Although research data is limited we conclude that ES is a prevalent problem in psychiatric populations manifesting most obviously in hypersomniac depressives and in medicated schizophrenics. The Epworth Sleepiness Scale may be of assistance to the clinician in the identification of ES and its use is to be encouraged. Treatment options are limited but the
The author has no conflict of interest with any commercial or other associations in connection with the submitted article.
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Excessive daytime sleepiness in psychiatry [45] Tollefson GD, Birkett MA, Kiesler GM, Wood AJ; Lilly Resistant Schizophrenia Study Group. Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol Psychiatry 2001;49:52 63. [46] Bitter I, Dossenbach MRK, Brook S, Feldman PD, Metcalfe S, et al. Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 2004;28:173 80. [47] Azorin JM, Spiegel R, Remington G, Vanelle JM, Pere JJ, Giguere M, et al. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry 2001;158:1305 13. [48] Marder SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, et al. Aripiprazole in the treatment of schizophrenia: Safety and tolerability in short-term, placebo-controlled trials. Schizophrenia Res 2003;61:123 36. [49] Mullen J, Jibson MD, Sweitzer D. A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: The quetiapine experience with safety and tolerability (QUEST) study. Clin Ther 2001;23(11): 1839 54. [50] Levoyer D, Martinet JP, Badiche A, Millet B. Ten years of clinical experience with clozapine about 170 patients. Encephale 2004;30(3):285 95. [51] Hofer A, Kemmler G, Eder U, Honeder M, Hummer M, Fleischhacker WW. Attitudes toward antipsychotics among outpatient clinic attendees with schizophrenia. J Clin Psychiatry 2002;63(1):49 53. [52] Hartmann E, Orzack MH, Branconnier R. Sleep deprivation deficits and their reversal by d- and l- amphetamine. Psychopharmacology 1977;53(2):185 9. [53] Koelega HS. Stimulant drugs and vigilance performance: A review. Psychopharmacology 1993;111(1):1 16. [54] Burke M, Sebastian CS. Treatment of clozapine sedation (letter). Am J Psychiatry 1993;150:1900 1. [55] Rosenthal MH, Bryant SL. Benefits of adjunct modafinil in a open-label, pilot study in patients with schizophrenia. Clin Neuropharmacol 2004;27(1):38 43. /
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[56] Fava M, Thase ME, DeBattista C. A multi-center, placebocontrolled study of Modafinil augmentation in SSRI partial responders with persistent fatigue and sleepiness. J Clin Psychiatry 2005;66(1):85 93. [57] Schwartz TL, Azhar N, Cole K, Hopkins G, Nihalani N, Simionescu M, et al. An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy. J Clin Psychiatry 2004;65(9): 1223 7. [58] Schwartz TL, Azhar N, Cole K, Hopkins G, Nihalani N, Simionescu M, et al. An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy. J Clin Psychiatry 2004;65(9): 1223 7. [59] De Battista C, Lembke A, Solvason HB, Poirier J. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacology 2004;24(1): 87 90. [60] Ninan PT, Hassman HA, Glass SJ, McManus FC. Adjunctive modafinil at initiation of treatment with a selective serotonin reuptake inhibitor enhances the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue. J Clin Psychiatry 2004;65(3): 414 20. [61] DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR. Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: A preliminary double-blind, placebo-controlled study. J Clin Psychiatry 2003;64(9):1057 64. [62] Markovitz PJ. An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol 2003;23(2):207 9. [63] Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000;61(5):378 81. [64] Miletin MS, Hanly PJ. Measurement properties of the Epworth sleepiness scale. Sleep Med 2003;4:195 9. /
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ORIGINAL ARTICLE
Excessive daytime sleepiness in psychiatry: a relevant focus for clinical attention and treatment?
CHRIS J. HAWLEY1,2 Department of Psychiatry, QEII Hospital, Welwyn Garden City, UK, and 2Faculty of Health and Human Science, University of Hertfordshire, Hatfield, UK Int J Psych Clin Pract Downloaded from informahealthcare.com by CDL-UC Santa Cruz on 10/26/14 For personal use only.
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Abstract Excessive daytime sleepiness is a feature of many general medical disorders and is associated with significant impairment in function and well-being. It has, however, received little attention in psychiatry although it may be a common and clinically important problem. The opinions of two expert groups, and a survey of the literature, were used to form views about the prevalence and clinical significance of excessive sleepiness in psychiatric populations. Issues relating to pharmacological treatment were also considered. Despite a scant evidence base, the conclusions are that excessive sleepiness may be a common and significant problem, and potentially amenable to treatment. However, clinician awareness is probably limited and there are opportunities for further research.
Key Words: Excessive daytime sleepiness, excessive sleepiness, hypersomnia, somnolence, psychiatry, modafinil
Introduction It is well known that excessive daytime sleepiness (hereafter excessive sleepiness: ES) accompanies many general medical disorders such as obstructive sleep apnoea-hypopnoea syndrome (OSAHS), Parkinson’s disease, multiple sclerosis, myotonic dystrophy and narcolepsy [1 5]. The behavioural and functional consequences of ES are well reported and include impairment of work-performance and social roles, reduced subjective well-being, cognitiveslowing and increased risk for accidents [69]. In neurology and respiratory medicine it is well accepted that ES deserves to be identified, managed and treated. Moreover, the efficacy of treatments for ES in these areas is established [10 15]. Although ES is an important symptom, and potentially amenable to treatment, it appears to have received little consideration in psychiatry. For example, standard post-graduate texts make, at best, passing reference to ES as a clinical problem. Insomnia, by comparison, receives substantial attention. One can reasonably propose that ES should be a prevalent symptom in psychiatric populations; not least because many psychiatric disorders affect sleep and somnolence is a common unwanted effect of pharmacotherapy used in psychiatric conditions. It could be argued, for example, that there would be
value in screening of psychiatric populations for ES using a quick and inexpensive tool, such as the Epworth Sleepiness Scale (ESS [16]). Cases with ES might thereby be identified and assisted. But the argument for ‘‘raising the game’’ regarding ES in psychiatry depends on at least two things. Firstly; that the problem is a prevalent one; and, secondly, that when present it is of clinical relevance and not merely a trivial issue amidst other more profound problems. That ES is both prevalent and relevant in psychiatric populations is far from selfevident: Indeed, some have suggested that ES is ‘‘rarely, if ever, due to a psychological or psychiatric condition’’ [17]. Thus, the purpose of this paper is to gain an understanding of the extent of ES in general psychiatry and whether greater clinical and research enquiry is justified. Method Initially an attempt was made to systematically review the literature on ES in psychiatric populations. This attempt failed. All permutations of relevant search terms (e.g. hypersomnolenece, hypersomnia, excessive sleepiness, depression, schizophrenia, sedation, psychiatric, mental health) failed to yield a literature that could be evaluated systematically and
Correspondence: Professor C.J. Hawley, Department of Psychiatry, QEII Hospital, Howlands, Welwyn Garden City, Herts AL7 4HQ, UK. Tel: +44 1707 365073. Fax: +44 1707 365169. E-mail [email protected]
(Received 19 April 2005; accepted 15 December 2005) ISSN 1365-1501 print/ISSN 1471-1788 online # 2006 Taylor & Francis DOI: 10.1080/13651500600578904
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quantitatively, with the exception of papers relating to clinical trials of modafinil in psychiatric disorders. Thus it was decided to proceed on the basis of surveying the literature as extensively as possible and to supplement this survey by drawing on the experience and opinions of clinicians via round-table discussions. It is hoped that this approach at least describes the scope of the current literature and clinical understanding and that formal reviews may be possible when more data have accumulated. Two discussion groups were held under the direction of the author. The first group consisted of eight psychiatrists chosen for their ability to represent the experiences of day-to-day clinical practice. The second group comprised six academic psychiatrists chosen to represent a more theoretical position. The groups were asked to contribute clinical understanding and expert opinion and not merely comment critically on the available literature. The agenda for both groups was the same, to consider: 1. whether ES is a prevalent problem in psychiatric populations; 2. whether ES deserves clinical attention; 3. what treatment options might be applied to ES in psychiatric populations. This article presents a synthesis of discussions, along with a summary of the literature, which highlighted the following key areas of consideration: 1. difficulties arising from definitions and terminology; 2. prevalence and clinical relevance of excessive sleepiness in psychiatry; 3. options for treatment; 4. screening for excessive sleepiness in psychiatric populations. Problems in terminology and definition The meaning of the term ‘‘excessive sleepiness’’ was considered by the discussion groups to be problematic in itself. In relation to psychiatry at least, terms such as hypersomnia, hypersomnolence, sleepiness, somnolence, sedation, drowsiness, tiredness and fatigue may be used more-or-less interchangeably or, at the very least, describe overlapping concepts relating to the same symptoms or experiences. Undoubtedly, fatigue and tiredness can be confused with sleepiness, yet even if clearly experienced as separate entities, may be caused by the same underlying condition. The groups were of the opinion that definition of such terms would be useful. But the literature is not forthcoming. For example: the DSM-IV [18], while including hypersomnia as a criterion symptom for some disorders, does not provide a definition of the term. Similarly, the National Library of Medicine
Dictionary of Terms [19] lists various terms such as drowsiness, somnolence and hypersomnia as synonyms. The matter of definition is further complicated depending on what approach one uses to determine that ES is present in a patient. In essence there are two methods: 1. Objective, behavioural tests such as the Multiple Sleep Latency Test (MSLT) [20] or the Maintenance of Wakefulness Test (MWT) [21]. 2. Introspective, subjective, reporting by the patient, for example through paper-and-pencil tests such as the ESS [16,22] or Stanford Sleepiness Scale [23,24] or for that matter through ordinary clinical reporting of symptoms. Objective measures of sleepiness (i.e. MWT, MSLT) may, however, correlate rather poorly with subjective measures [25]. Chervin et al. [26] found a correlation of only 0.37 between the ESS and the MSLT in a population of patients with sleep disordered breathing or narcolepsy. Thus, at least with the currently available techniques, subjective reporting of sleepiness corresponds only partially to objectively measured propensity to sleep. This in itself is problematic for defining what constitutes ‘‘excessive sleepiness’’. Although the psychiatric literature is scant, a study by Nofzinger et al [27] adds further support to this view. Nofzinger et al. compared hypersomniac bipolar depressed patients with narcoleptics and found a weaker correspondence between the complaint of excessive sleepiness and objective sleep tendency (measured by MSLT) in the former. Thus in medical disorders generally, and psychiatric disorders particularly, a correlation between subjective sleepiness and objective propensity to sleep should not be too readily assumed. In conclusion on this point, the groups felt that the problem of definition of terms could not be resolved without further research in psychiatric populations. Until then we must accept that the language is imprecise and operate within that limitation. A satisfactory provisional description of ES might be ‘‘difficulty in maintaining wakefulness and an increased likelihood of falling asleep in inappropriate situations’’: a description broad enough not to exclude patients with shift work-related sleep disorder in whom the excessive sleepiness occurs at night, not during the day. Prevalence of excessive sleepiness as a clinical problem The discussion groups were invited to discuss psychiatric scenarios in which excessive sleepiness may present as a clinically evident problem. Two diagnostic groups attracted the greatest attention: depression and schizophrenia.
Excessive daytime sleepiness in psychiatry Regarding depression, two main areas became our focus: firstly those patients with syndromal major depression (unipolar or bipolar) in whom excessive sleepiness, rather than insomnia, was a chief clinical complaint; and secondly, those patients where excessive sleepiness, or somnolence, was the unwanted effect of pharmacotherapy for a mood disorder. Regarding schizophrenia, the chronic inert/apathetic patient with extensive daytime sleeping, or time spent in bed, was seen as a prototypical and common problem. The propensity of anti-psychotic drugs to cause somnolence was also regarded as a major clinical issue.
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Excessive sleepiness in relation to depression Reflecting on clinical experience, the groups were of the opinion that excessive sleepiness in major depression was a common feature, with maybe a quarter or a fifth of patients being so affected. But there was not a clear consensus about the clinical importance of excessive sleepiness when present. However, the groups did agree that they might be lacking in awareness, and undervaluing what could be an important, or impairing, symptom for the patient. The limited education for psychiatrists regarding normal and abnormal sleep was highlighted. An additional opinion arising from the groups’ discussions was as follows: that any debate about the importance of excessive sleepiness in depression is not simply a debate about the validity of the atypical specifier. Some hold that atypical specified depression is a discreet nosological entity while others argue otherwise [28]. However, our groups thought that this did not matter: if excessive sleepiness deserves greater clinical attention then it does so on its own merits, and irrespective of typology of depression. What then is the prevalence of ES in depressed populations? To the best of our knowledge there have been no substantial prevalence studies addressing this directly. But there are at least two general lines of attack on the question. Firstly, if we assume that ES is no less prevalent in clinical depressed populations than in epidemiological populations then the estimate in the latter should provide the minimum estimate in the former. Secondly, if it is assumed that excessive sleepiness is sine qua non for atypical depression then the proportion of all Major Depressed cases that are atypical-specified should act as a proxy estimate for the prevalence of ES in depressive populations as a whole. The prevalence of ES in normal (epidemiological) populations is known to some extent. A Finnish population questionnaire study found that 9% reported ES ‘‘every or nearly every day’’ [29]. Additionally, this study found a particularly strong association between ES and depression: about a
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quarter of minor depressed cases (BDI score 14 24 inc.) reported ES and a little more than a half of major depressed cases (BDI /24) did too. Hara et al [30] reported in a Brazilian population that the prevalence of excessive sleepiness occurring ‘‘three or more times week’’ was 16.8% and other reports produce convergent results [31]. A report by Horwath et al [32] is informative about the proportion of all major depressed cases that are atypical-specified. In a community study of 662 major depressed cases, 104 (15.7%) were found to be atypical (hypersomnia was set as a necessary criterion for atypicality in this study). In addition, of the 558 non-atypical cases 23% were reported as sleeping too much. Thus, for the major depressive sample as a whole, about 35% reported hypersomnia during depressed episodes. Matza et al. [33] found 36.4% of all major depressed cases (n /836) to be atypical specified and, as in Horwath et al. [32], hypersomnia was a necessary criterion for atypicality. There has been one brief report of a study specifically intended to determine the prevalence of ES in a psychiatric population [34]. Of 161 Major Depressed outpatients, 45% scored ]/10 on the ESS. Consistent with the Finnish population questionnaire study an association was found between severity of depression (BDI scores) and the prevalence of caseness on the ESS. However, one is reminded that caseness on a screening tool does not necessarily equate to a clinical diagnosis or a clinically significant disorder, and the sensitivity and specificity of the ESS in psychiatric populations is not known. Overall, the clinical impression of the expert groups that a ‘‘quarter or a fifth’’ of depressed cases exhibit excessive sleepiness is given credence by the literature. While it does not necessarily follow that just because a symptom is present it thereby must be the focus of clinical attention, the substantial prevalence of ES suggests that clinical awareness is important. Excessive sleepiness in relation to schizophrenia The discussion groups readily called to mind example cases of schizophrenia in which excessive sleeping appeared to be a predominant clinical problem. A typical scenario being the chronically ill patient with no regular sleep wake cycle, apathetic, prone to stay in bed all day and engaging in little meaningful activity. In depression it can be readily established that excessive sleepiness is often an inherent part of the patient’s condition. But the same cannot be said for schizophrenia. Despite the clinical impression of the discussion groups there appears to be no reports in the literature to validate the notion that excessive sleepiness is inherent to the schizophrenic condition. Polysomnographic studies in schizophrenia point to sleep onset and mainte-
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nance insomnia as the most common features [35]. It could be that excessive sleepiness is an inherent feature in schizophrenia, but if so, it has yet to be demonstrated.
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Iatrogenic somnolence In depression, iatrogenic somnolence ought, on the face of it, to be a problem of some clinical significance. The most widely used antidepressants are the selective serotonin re-uptake inhibitors (SSRIs) and in acute treatment studies in major depression, somnolence with SSRIs is reported in approximately 820% of cases, typically a two- to three-fold excess over placebo [3639]. Some have commented on the clinical importance of this antidepressant-related sedation [40,41]. But our groups were unimpressed on this point and did not see it as a pressing clinical issue despite awareness of the high apparent prevalence. Why so? A plausible answer is as follows: firstly, although SSRI-related somnolence is common, its severity is such that it only leads to discontinuation of treatment in a minority of cases [42]. Secondly, continuation studies with SSRIs show very low rates of persisting somnolence once the peak of events associated with initiation has passed [43]. In short, SSRI somnolence is common but generally mild and time limited. Other antidepressants are more sedative than the SSRIs (e.g. mirtazapine, trazodone, some tricyclics) and for these the considerations may be different. But as regards the most commonly used antidepressants, the SSRIs, iatrogenic sedation, of a problematic degree, appears to be uncommon. Regarding schizophrenia, the discussion groups thought that drug-induced somnolence was a problem of substantial clinical significance. However, quantifying this is surprisingly difficult. In acute studies of schizophrenia the reported incidence of somnolence ranges from as little as 2% to as much as 50% [4449]. Detailed data on severity of adverse events is rather seldom presented in trial reports. However, surveys of patients on chronic antipsychotic therapy may provide some insight. Although such naturalistic data lacks rigorous control it does suggest persisting somnolence in a substantial proportion of cases: Levoyer [50] found persisting somnolence in 22% of clozapine-treated cases. In patients receiving long-term treatment with a variety of antipsychotics, Hofer et al. [51] found that 42% complained of sedation. In a controlled trial of antipsychotic therapy (quetiapine versus risperidone), Mullen et al. [49] found in about a quarter of cases that somnolence did not resolve with continued treatment up to 12 weeks. If these figures are broadly representative then it appears that persisting excessive sleepiness is a common iatrogenic problem in schizophrenia and deserving of clinical attention not least because
anti-psychotic pharmacotherapy is often life-long. The difference between antidepressants and antipsychotics is that somnolence with the former is typically self-limiting but often persistent with the latter. Overall, we are drawn to the conclusion that excessive sleepiness does have a substantial prevalence in psychiatric populations. As far as can be ascertained ES will be most commonly observed by the clinician as an inherent symptom in depression and as an iatrogenic feature in schizophrenia. In addition the discussion groups provided a reminder that psychiatric populations are no less prone to general medical disorders than the general population; the psychiatrist’s differential diagnosis of ES should include general medical disorders although clinical skills in this respect may not be uniformly high. Treatment options for excessive sleepiness The discussion groups were asked to consider possible treatments for ES in psychiatric populations. The options to consider were limited. Classic psychostimulants On the face of it classic psychostimulants (e.g. dexamfetamine, methylphenidate) could be effective treatments for excessive sleepiness arising from a variety of causes. They are undoubtedly wakefulness-promoting and enhance cognitive performance [52,53]. But the groups’ opinion was that the potential for abuse and dependence is so high in psychiatric populations that their use could not be countenanced in anything other than exceptional circumstances. Furthermore, there is no literature to support the use of classic psychostimulants for ES in psychiatric populations, other than inferences that can be drawn from occasional case reports [54]. Modafinil Systematic data regarding effectiveness, safety and tolerability of modafinil in schizophrenia-related ES is limited to one study of 11 cases [55]: Adjunctive modafinil was described as ‘‘generally well tolerated’’. Hallucinations occurred in two subjects but no direct relation to modafinil is stated. Other than single case reports there are no other data. There is one placebo-controlled study of modafinil as a treatment for ES in major depression [56]. Modafinil add-on to pre-existing SRRI therapy improved ESS scores more than did placebo addon (n /311), but statistical significance was not seen at all time points. Modafinil add-on to SSRI was effective in reducing ESS scores in an open label study (n /20) by Schwartz et al. [57]. Space does not permit a detailed analysis of adverse events here
Excessive daytime sleepiness in psychiatry but the tolerability of modafinil, in combination with antidepressants appears similar to that of modafinil when administered as a sole therapy [5763]. The data on modafinil appears to be of interest but falls short of allowing any unequivocal treatment recommendations.
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Screening in psychiatric populations The discussion groups considered whether there would be value in screening psychiatric populations for excessive sleepiness. Doing so might have the general effect of improving clinician awareness regarding excessive sleepiness and, in particular, help to identify hitherto undetected cases. A suitable brief questionnaire, that demands no clinician input, would be the eight-item Epworth Sleepiness Scale (ESS). The reliability and validity of the ESS has been adequately studied [16,25,64]. The ESS is a non-copyright instrument, free to be used and copied. A score greater than 10 is generally taken to indicate caseness, then warranting further clinical questioning. The groups thought there was a balance of considerations. On the one hand the scale is so quick and easy to administer and interpret that there is little to deter the psychiatrist from using the scale liberally: administering it, for example, to patients in waiting areas. On the other hand, it was noted that the operating characteristics for the scale as a screening tool in psychiatric populations specifically have yet to be studied. Although the scale has desirable properties when used in neurology or respiratory populations it cannot necessarily be inferred that the scale will operate as well in psychiatric populations. On balance, the groups’ opinion was that the use of the ESS by psychiatrists is to be actively encouraged but with the proviso that test results should be interpreted cautiously. And, of course that treatment decisions should rest on the clinical evaluation that follows from screening and not on the test result per se .
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application of modafinil tolerates consideration; however, it is not licensed for the treatment of drug-induced somnolence. Throughout the groups’ discussions, and in the survey of the literature, it was apparent how little is known about ES in psychiatry: little is known about prevalence, the lexicon is poorly defined, the operating properties of screening tools (e.g. ESS) are not known and to date only one drug has been studied systematically. These areas present ample opportunity for future research. Key points . Excessive daytime sleepiness is a feature of many general medical disorders and is associated with significant impairment in function and well-being. . It has, however, received little attention in the psychiatric literature although it may be a common and clinically important problem. . Excessive sleepiness is occurs with a number of conditions and treatments including: syndromal major depression (unipolar or bipolar) and somnolence as an unwanted effect of antidepressants or antipsychotics. . The prevalence of excessive sleepiness in psychiatric populations is unknown but was estimated to be as high as 25% by an expert panel. . This review suggests that further research on the prevalence and treatment of excessive sleepiness in psychiatry is warranted. Acknowledgements I am grateful to the following people for their contributions to the discussion groups: Dr Sanjay Rao, Dr Simon Groves, Professor Reinhard Heun, Professor Naomi Fineberg, Dr Ian Smith, Dr Deepa Deo, Dr Richard O’Flynn, Dr Avi Dhariwal, Dr Digby Quested, Dr Paul Reading. Thanks also to two anonymous reviewers for their comments on an earlier draft of this paper. Statement of interest
Conclusion In this paper we have attempted to synthesise the opinions of expert groups with a survey of the literature to determine whether excessive sleepiness is a prevalent problem in psychiatric populations and whether it is amenable to identification and treatment. Although research data is limited we conclude that ES is a prevalent problem in psychiatric populations manifesting most obviously in hypersomniac depressives and in medicated schizophrenics. The Epworth Sleepiness Scale may be of assistance to the clinician in the identification of ES and its use is to be encouraged. Treatment options are limited but the
The author has no conflict of interest with any commercial or other associations in connection with the submitted article.
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