Update on Sleep and Psychiatric Disorders

Michael J. Sateia Chest 2009;135;1370-1379 DOI 10.1378/chest.08-1834 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/135/5/1370.full.html

Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2009by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

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CHEST
Michael J. Sateia, MD

Postgraduate Education Corner

CONTEMPORARY REVIEWS IN SLEEP MEDICINE

Update on Sleep and Psychiatric Disorders*

Current data demonstrate a high rate of comorbidity between sleep disorders and various psychiatric illnesses, especially mood and anxiety disorders. The disturbance of sleep quality and continuity that is associated with many sleep disorders predisposes to the development or exacerbation of psychological distress and mental illness. Likewise, the presence of psychiatric illness may complicate the diagnosis and treatment of sleep disorders. This focused review examines the literature concerning the interaction between major International Classification of Sleep Disorders, 2nd edition, diagnoses and psychiatric conditions with respect to sleep findings in various psychiatric conditions, psychiatric comorbidity in sleep disorders, and reciprocal interactions, including treatment effects. The data not only underscore the high frequency of psychopathology and psychological distress in sleep disorders, and vice versa, but also suggest that combined treatment of both the mental disorder and the sleep disorder should become the standard for effective therapy for all patients. (CHEST 2009; 135:1370 1379)
Key words: anxiety disorder; depression; hypersomnolence; insomnia; movement disorder; nightmare disorder; obstructive sleep apnea; parasomnia; posttraumatic stress disorder; restless legs syndrome Abbreviations: AD antidepressant; AP antipsychotic; BDI Beck Depression Inventory; CGI clinical global impression; CPAP continuous positive airway pressure; HUNT Nord-Trondelag Health Study; ICSD-2 International Classification of Sleep Disorders 2nd edition; IRT imagery rehearsal therapy; MDD major depressive disorder; OSA obstructive sleep apnea; PLM periodic limb movement; PSQI Pittsburgh Sleep Quality Index; PTSD posttraumatic stress disorder; REM rapid eye movement; RLS restless legs syndrome; SSRI selective serotonin reuptake inhibitor

among sleep, psychological processes, and psychiatric disorders. As the discipline has evolved and expanded into numerous other areas of inquiry and attention, the focus on psychiatric disorders in sleep medicine has comparatively declined. Yet evidence of key linkages, of both theoretical and clinical importance, continues to accrue.
*From the Section of Sleep Medicine, Dartmouth Medical School, Lebanon, NH. Dr. Sateia is a member of a Cephalon (armodafinil) medical advisory board. Manuscript received July 25, 2008; revision accepted November 6, 2008. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/site/misc/reprints.xhtml). Correspondence to: Michael J. Sateia, MD, Professor of Psychiatry (Sleep Medicine), Chief, Section of Sleep Medicine, Dartmouth Medical School, Section of Sleep Medicine, One Medical Center Dr, Lebanon, NH 03756; e-mail: msateia@dartmouth.edu DOI: 10.1378/chest.08-1834
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of the early explorations in the field of sleep M any medicine focused heavily on the relationships

This review addresses the practical clinical aspects of the complex relationships between psychiatric disorders and sleep. The discussion can be examined from two major perspectives: (1) psychiatric disorders and their treatments as factors contributing to sleep disorders, and (2) psychiatric disorders as a complication of sleep disorders. Effective management of sleep disorders requires recognition and effective treatment of mental disorders. The great majority of physicians practicing sleep medicine today do not come from a background of psychiatry and may understandably feel inexperienced, reluctant, and even avoidant when confronted by such issues in practice. However, an understanding of basic diagnostic and therapeutic principles in key areas will allow the clinician to manage or refer these patients effectively. Mental disorders are highly prevalent in the general population and even more so among individuals with sleep disorders.1 Many psychiatric illnesses such
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as mood disorders and anxiety disorders are associated with high rates of insomnia. Likewise, for many of the patients presenting to sleep clinics with insomnia, psychiatric disorders are likely to play an important role in genesis and maintenance of the insomnia. Ohayon et al1 reported a prevalence for insomnia complaints (1 month duration and daytime consequences) of 12.7% in the general population. The prevalence of sleep disorders, mostly insomnia due to mental disorder, was 5.6%; primary psychiatric disorder diagnoses were applied to 8.4%. Although evidence of adverse effects of chronic insomnia on both physiologic and psychological function continues to accrue, the condition remains a seriously underdiagnosed and undertreated problem. The relationship between sleep disorders and psychiatric illness is not limited to insomnia, however. In fact, it is difficult to identify a single major diagnostic category within the International Classification of Sleep Disorders, 2nd edition (ICSD-2),2 in which mental illness, its treatment, or its complications do not have relevance. This update approaches the discussion of psychiatric disorders in sleep medicine from the ICSD-2 categorical structure and focuses on the bidirectional relationship between sleep and mental disorders within each section. The literature is drawn from the past 3 years and was identified by means of Medline searches for major ICSD-2 categories (eg, insomnia, sleep apnea, and hypersomnolence) as well as sleep and major psychiatric disorders (eg, depression or PTSD). Certain references outside the specified 3-year range are included for background purposes.

treatment strategies, and can alterations of sleep parameters in response to intervention predict treatment outcome? Posttraumatic Stress Disorder Posttraumatic stress disorder (PTSD) has been the focus of many investigations. Difficulty initiating and maintaining sleep have been recognized for centuries as common responses to trauma. Current studies are aimed at further defining the nature of these responses and their implications with respect to pathophysiology and management. Calhoun and others3 studied the sleep of 30 PTSD patients and 22 control subjects with home actigraphy and sleep logs over 3 nights. They found significant differences between patients and control subjects, with the former demonstrating reduced sleep efficiency, increased latency to sleep onset, and more restless sleep on actigraphy measures. Not unexpectedly, sleep logs (in both groups) suggested worse sleep than the actigraphy-derived data; results of the Pittsburgh Sleep Quality Index (PSQI) showed no significant correlation with objective data. In the PTSD population, 37% had significant nightmare problems. Another investigation4 of sleep in 10 young adult patients with PTSD compared with an equal number of matched control subjects revealed modest but significant differences on polysomnography findings (decreased sleep efficiency, increased wake time after sleep onset and arousals, and decreased stage 3/4 sleep in PTSD subjects). Of note, a significantly greater amount of rapid eye movement (REM) interruption was found in the experimental group. Nightmare severity correlated with REM interruption as well as wake time after sleep onset. A metaanalysis5 of sleep findings in PTSD addresses the long-standing issue of conflicting data regarding sleep-related changes in this population. Kobayashi and colleagues5 report that a consistent pattern of increased stage 1, decreased stage 3/4, and increased REM density is seen. Studies with predominantly male populations showed greater degrees of abnormalities; those with higher rates of depression within the study group found less severe disturbances. PTSD is frequently comorbid with other psychiatric disorders, especially substance abuse problems. It is challenging to tease apart the relative contribution of each of these factors to sleep disturbance. A study6 comparing sleep parameters in groups with PTSD alone, PTSD comorbid with alcohol dependence, alcohol dependence alone, and a control population has attempted to clarify this issue. Using subjective reports, the investigation revealed, not surprisingly, that PTSD was associated with poorer sleep quality,
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Insomnia The studies of the last 3 years pertaining to sleep disturbance and psychiatric disorders can be categorized into the following major areas: (1) subjective and objective changes in sleep associated with various major psychiatric conditions; (2) insomnia as a risk factor for psychiatric illness; and (3) treatment of sleep disorders in patients with mental illness. Many investigations over the past 4 decades or more have described subjective and objective alterations of sleep in patients with a variety of psychiatric illnesses. The issues raised by these studies are several-fold. Do sleep disorders contribute to the development of psychiatric disorders? Do changes in sleep provide us with information that illuminates potential pathophysiology of these disorders? Do sleep-related factors demonstrate significant correlations with other clinical symptoms or physiologic factors? Do specific changes in sleep suggest specific
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longer latency, increased awakening, and early awakening. Severity of sleep disturbance correlated with PTSD severity. Significant effects were also seen for alcohol with increased latency and a trend toward lower quality. Of note, however, is that the investigators did not find a main effect for alcohol with respect to frequency of awakening or early awakening. Severity of alcohol abuse did not correlate with severity of sleep disturbances. The authors suggest that this may reflect tolerance to the effects of alcohol on sleep as the addiction progresses. Comorbid PTSD/alcohol abuse did not significantly worsen sleep compared with PTSD alone. This literature provides further confirmation of the long-standing observations regarding sleep disturbance in this population of patients but underscores the need for further study of the specific characteristics of these disturbances and the complexities introduced by related symptoms and comorbid factors such as nightmares, mood disorder, and substance abuse. Critical questions are the extent to which sleep disturbance in this group is a fundamental component of the pathophysiology of PTSD and whether independent treatment focused on the sleep disturbance will improve overall outcome for these patients. Insomnia as a Risk Factor for Mental Disorders The topic of insomnia as a risk factor for mental illness has been investigated in numerous epidemiologic studies over the past two decades.7,8 Several more recent investigations extend the results already published. Perlis et al9 reported on a retrospective analysis of 147 elderly patients who had no prior history of psychiatric illness. Of the 81 patients with an insomnia problem, 47 (58%) had indeterminate insomnia and 34 (42%) had persistent insomnia. Ten of the 12 patients in whom depression developed over the subsequent 1-year follow-up fell into the insomnia group (4 indeterminate, 6 persistent), suggesting significantly increased risk for major depression in the insomnia group. Morphy et al10 sampled 2,000 UK residents at baseline and 12-month follow-up. Measures of insomnia, depression, and anxiety demonstrated that baseline insomnia was a significant risk factor for incident depression and anxiety at follow-up (adjusted risk ratios of 2.71 and 2.28, respectively). In addition, an analysis of data from the Zurich longitudinal epidemiologic study11 revealed that a new onset of depression developed in 17 to 50% of patients with persistent, pure insomnia of 2 weeks duration at a later interview, with predictive odds ratios of 1.6 to 1.9. Also of note is that pure insomnia or insomnia comorbid with depression was a more reliable predictor of either
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diagnosis in future interviews than was pure depression. These data strongly support the concept of persistent insomnia as a risk factor for depression and also suggest, as the authors point out, that insomnia and depression are highly related but distinguishable disorders. Not all large epidemiologic investigations, however, have identified persistent sleep disturbance as a risk factor for incident depression. The Nord-Trondelag Health Study (HUNT)-1 and HUNT-2 are countywide Norwegian health surveys conducted about a decade apart in 85,000 adults. Neckelmann and colleagues12 analyzed a sample of participants who had no evidence of significant anxiety or mood disorder at the time of initial (HUNT-1) assessment to determine the relationship between the presence of insomnia at either assessment point (ie, at HUNT-1 or HUNT-2), or at both, with development of new-onset anxiety or depression as determined at HUNT-2 assessment. Their results appear to confirm previous data that suggest chronic insomnia is a risk factor for anxiety disorder. Onset of anxiety disorders was significantly greater in participants who had insomnia at HUNT-1 alone, HUNT-2 alone, or at both points. In contrast to results from numerous other epidemiologic surveys, however, development of major depression (as determined at HUNT-2) was associated only with presence of insomnia at HUNT-2. As stated by the authors, these results suggest that, although chronic insomnia appears to represent a trait marker for increased risk of developing an anxiety disorder, the relationship between insomnia and depression, in this study at least, is state dependent. The length of the follow-up (11 years) in this study reduces the chances that insomnia cases identified at the first assessment represented a prodromal symptom of a depression that was identified at the second assessment. The authors also noted that correcting for comorbidity between anxiety and depression reduces the potential confound that associations between insomnia and depression are, in fact, a function of comorbid anxiety. In addition to the evidence identifying persistent insomnia as a risk factor for new psychiatric disorders, findings from Pigeon et al13 have suggested that chronic insomnia problems may also contribute to persistence of depression. This issue is of particular importance in light of the significant rate of residual sleep disturbance in persons who have been otherwise successfully treated for depression. Drawing on data from a large interventional study of enhanced care for depressed elderly persons, the investigators found that persistent insomnia was associated with a 1.8 to 3.5 times greater likelihood of remaining depressed, compared with the population without continued sleep disturbance. This effect was considPostgraduate Education Corner

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erably more apparent in the usual care arm (provided by subjects primary care physician) than in the enhanced care group. Carney and colleagues14 assessed whether type of therapy for depression affected the frequency of residual insomnia in depressed patients. They found residual rates of 17 to 26% for residual sleep onset and maintenance complaints following treatment, with no significant difference in frequency of these complaints in the pharmacotherapy vs the cognitive-behavioral therapy for depression group. An important theoretical and clinical question that emerges from this debate concerns impact of insomnia treatment on reduction of risk for future depression and improvement of current depression. Although the former issue has not been effectively addressed to date, several more recent studies shed some light on the latter. An uncontrolled study15 of cognitive behavioral treatment for insomnia alone in 10 subjects with mild to moderate depression (based on Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria and Beck Depression scores) revealed that seven of eight treatment completers no longer met criteria for depression and had normal Beck scores following six treatment sessions. Depression scores were significantly lower than baseline scores at 3-month follow-up. The authors understandably caution that these were patients with mild degrees of depression and further investigation with a larger sample would be helpful. Germain and colleagues16 used a brief behavioral intervention for insomnia in older adults with variable degrees of depression/ anxiety and compared this to a control informationonly intervention. They found significant improvement in mood and anxiety symptoms in the active intervention group, paralleling the improvements in sleep. However, this study was not specifically designed to assess the impact of an insomnia intervention on major depression. The population included individuals with mild depressive symptoms, but patients with active, more severe depression were screened out. It is also unclear whether change scores for depression and anxiety ratings adjusted for effects of improved sleep. Mounting clinical evidence suggests that combined therapies for both depression and insomnia are superior to antidepressant (AD) medication alone in patients with major depression. An investigation by Fava et al,17 with a follow-up study by Krystal et al,18 addresses the effects of pharmacotherapy for sleep disturbance (eszopiclone), coadministered with an AD (fluoxetine), on sleep and mood. In the initial study, the investigators found that significantly greater improvements in mood, especially on investigator-rated instruments, in the combined hypnotic/AD group comwww.chestjournal.org

pared with AD alone. These results held, by and large, when sleep-related items were removed from depression assessment scales. The follow-up study18 revealed that the superior improvement in sleep and mood ratings for the combined therapy group continued during the two week period following discontinuation of the eszopiclone. Another study19 combining AD medication with specific insomnia treatment (in this case, cognitivebehavioral therapy for insomnia) demonstrated that the combined treatment was superior to AD alone both in terms of depression outcome (61.5% vs 33.3% remission, respectively) and insomnia outcome (50% vs 7.7% remission, respectively). Although these results are preliminary, they strongly suggest that a combined therapy approach for patients with major depression with associated insomnia, including either hypnotic therapy or behavioral treatment for insomnia with conventional AD therapy, may be superior to AD alone. Clearly, this has far-reaching implications for all clinicians involved in the management of patients with depressive disorders. Psychotropic Medications and Behavioral Therapies Several pharmacotherapy studies of potential interest to sleep medicine clinicians and researchers have been published in recent years. The use of quetiapine as a sleep aid has become widespread, primarily by psychiatrists, although virtually no data have been available regarding efficacy until the past 2 or 3 years. A recent report20 documented widespread off-label administration to psychiatric patients, most frequently those with mood disorders, substance abuse, and psychotic disorders. Evening low-dose administration is common, but efficacy data for these uses are lacking. A brief report21 of openlabel, low-dose (mean, 100 mg) quetiapine administered at bedtime for sleep disturbance in patients with PTSD suggests a clinically meaningful response over the 6-week trial. Measures of quality, latency, and duration from the PSQI all demonstrated significant improvement. However, further randomized controlled trials are necessary to confirm these preliminary results. Others2224 have demonstrated significant improvement in sleep with quetiapine administered to patients with mood disorders. The only study to date of quetiapine in primary insomnia was recently published in a brief report by Wiegand et al25 They evaluated the effects of doses of 25 to 75 mg of quetiapine in 18 outpatients with primary insomnia (undefined) by polysomnography and PSQI. Although sleep latency (only 22 min at baseline) did not improve subjectively or objectively, significant
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improvement in subjective sleep quality and both subjective and objective total sleep time and efficiency were found. Clearly, further work is needed to explore the indications and efficacy of atypical antipsychotic (AP) medications, but agents such as this may prove to be useful sleep aids in certain populations of patients. Sedating AD medications have become widely used for insomnia, in spite of the limited empirical evidence supporting efficacy. An uncontrolled investigation26 of the effects of mirtazapine, 30 mg, on sleep in patients with a major depressive disorder (MDD) found polysomnographic evidence of increased slow-wave sleep in the first cycle, increased REM latency, and decreased wake after sleep onset. Depression ratings (Hamilton Depression and Beck Depression) showed early and continued improvement in mood disorder over the 2-week study period in these patients, who were using no other psychoactive or hypnotic medications. Trazodone is an AD medication widely used in the treatment of insomnia. The explanation for its popularity is not entirely clear, but, in all likelihood, is attributable to the notion that it is in some ways safer than standard benzodiazepine receptor agonist medication, particularly in longer term applications. Unfortunately, there is a paucity of data supporting the efficacy of trazodone in the treatment of insomnia. Studies published to data have been largely conducted on depressed patients with sleep disturbance. Assessment measures have primarily been subjective, and appropriate control subjects have been lacking in many of these investigations. That said, studies2729 have shown some improvement in sleep in these populations. Recently published guidelines30 for the evaluation and management of insomnia indicate that benzodiazepine receptor agonist hypnotic agents are considered the first-choice agents in the pharmacotherapy of chronic insomnia, although the authors acknowledged the potential usefulness of sedating ADs such as trazodone as second-line agents, especially in comorbid insomnia. Finally, Suresh Kumar and colleagues30 evaluated the effects of variable melatonin dosing vs placebo for sleep-onset problems in chronic schizophrenic patients. The results demonstrated reduced awakenings and increased total sleep time in the melatonin group, although results for the primary target, sleeponset latency, were mixed. Daytime mood and functioning also showed improvement. Guidelines31 on the management of insomnia from the American Academy of Sleep Medicine recommend that treatment of insomnia in patients with comorbid psychiatric disorders follow the general guidelines of psychological and behavioral therapies, possibly coupled with a benzodiazepine recep1374

tor agonist, but they also note the potential usefulness of sedating ADs or atypical AP medications in certain populations.

Sleep-Related Breathing Disorders The relationship between sleep-related breathing disorders, most notably obstructive sleep apnea (OSA), and psychiatric disorders, especially depression, has been studied for decades. Earlier studies32,33 demonstrated high rates of depressive symptoms in OSA, as well as improvement of these symptoms with treatment of OSA.34 Limited evidence35 has also shown elevated rates of OSA in patients with identified MDD. This latter finding was extended by Deldin and colleagues36 who report significant increases of major flow limitations and events with desaturations in a pilot group of 19 depressed patients (vs nondepressed control subjects) selected without regard to OSA symptoms. The nature of this association is unclear, but the authors suggested that respiratory-related sleep fragmentation of hypoxia-induced prefrontal dysfunction may predispose to mood disorder. Similarly, high rates of OSA have been reported in chronic schizophrenic patients.37 In this study,37 clear associations existed among use of atypical neuroleptics, obesity, and the presence of OSA. More recent evidence has confirmed previous findings suggestive of important connections between OSA and psychiatric disorders and furthers our understanding of these linkages. Psychiatric comorbidity in OSA patients was examined in a large retrospective chart review38 of 100,000 Veterans Affairs Hospital OSA patients. A significantly higher prevalence of numerous psychiatric disorders was found in this group, as compared with a non-OSA population. High comorbidity was found for major depression (21.8%), anxiety disorders (16.7%), and PTSD (11.9%). Others39 have noted the frequency of depression symptoms in OSA as well. Analysis of Beck Depression Inventory (BDI) scores in 92 male and 29 female patients with moderate-to-severe OSA revealed at least mild depressive symptoms in 45%; nearly 12% manifested at least moderate depression. Women demonstrated more depressive symptoms than men, although apnea severity did not differ between the groups. Depressive symptoms did not correlate with RDI, sleepiness, or desaturation frequency. However, in women, desaturation nadir did correlate significantly with BDI scores. A number of investigations have assessed the response of mood symptoms to treatment for OSA. Schwartz and Karatinos40 found reductions of depression scores (seven-item BDI) in OSA patients
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treated with continuous positive airway pressure (CPAP). Most of the sample fell into a minimal to mild depression range, and these groups demonstrated significant reductions in BDI scores at initial follow-up and long-term follow-up. The magnitude of reduction was greatest for those in the moderate-tosevere range, although the differences did not reach statistical significance, presumably due to the small number of patients within this group. Modest reduction in Zung depression scores following administration of nasal CPAP to patients with severe OSA has also been reported.41 These reductions were paralleled by and correlated with improvement in qualityof-life scores. One of the few placebo-controlled studies42 of improvement in psychological symptoms following CPAP demonstrated that psychological symptoms improved with both CPAP and with oxygen vs sham CPAP. However, specific depression symptoms improved only with oxygen. The authors suggest that this may underscore the role of hypoxemia vs sleep disruption in the pathogenesis of depression symptoms in OSA. However, the finding does not account for the concurrent improvement in oxygen saturations associated with CPAP usage. Identification and treatment of depression clearly plays an important role in fostering positive outcome in patients with OSA. A comparison of the impact of apnea severity and psychological symptoms on fatigue complaints in OSA patients43 found that a greater portion of fatigue in OSA patients is explained by depression than by OSA variables themselves. In this investigation,43 depression explained about 25% of the variance for fatigue, whereas OSA severity explained only 13%. The interaction of psychological symptoms and CPAP adherence may be of considerable importance in determining long-term treatment outcome for OSA. A postal survey44 of CPAP users found associations between low CPAP compliance and anxiety, as well as between low compliance and depression and sleepiness. These findings may reflect a bidirectional relationship between OSA and psychological symptoms. Although the depression and anxiety observed may well be a function of poorly controlled OSA due to low treatment compliance, it seems equally probable that low compliance may be the result of poorly controlled psychological distress. Wells and colleagues45 explored this question and found no correlation between baseline depression symptoms and subsequent CPAP compliance. Improvement in OSA symptoms did significantly predict improvement in depression following treatment. In summary, these findings reinforce the complexity of the relationship between OSA and psychological symptoms. Evidence that treatment of OSA improves depression has continued to emerge, alwww.chestjournal.org

though not all studies have agreed. Depression may account for significant residual symptoms in this population. Existing psychological distress may negatively impact adherence to treatment, although further assessment of this issue is required. Nevertheless, there is sufficient data to suggest clearly that clinicians must be vigilant for the presence of psychiatric comorbidity in their patients with OSA and that adequate psychological assessment and treatment of identified psychiatric disorders is likely to improve outcome in OSA patients. Hypersomnolence Disorders Previous epidemiologic studies8,46 have identified high rates of sleepiness in psychiatric populations. These findings have important implications with respect to management of the primary psychiatric condition, as well as treatment of underlying sleep disorders that may give rise to hypersomnolence problems. Prior studies have suggested an association between depression and sleepiness, although they have not, in general, demonstrated much objective evidence of this, even in those groups (eg, bipolar depressed) who have historically been viewed as hypersomnolent. An investigation of community-dwelling French persons47 undertook to identify associations between subjective reports of sleepiness and other factors, including psychiatric disorders. In the study,47 12% of men and 6% of women reported excessive sleepiness (Epworth sleepiness scale score 10). MDD was not associated with sleepiness. The only association of excessive daytime sleepiness with mental illness was with bipolar disorder. This leads the authors to speculate on the possibility that a more unique relationship exists between the pathophysiology of bipolar disorder and excessive sleepiness. They also suggest that prior associations between depression and sleepiness may be a function of the underdiagnosis of bipolar disorder within the study populations. In those patients with depression who do complain of sleepiness, medication choice may have an important impact on clinical outcome, as shown by Papakostas et al,48 who studied a group of patients with major depression who were treated with either an selective serotonin reuptake inhibitor (SSRI), bupropion, or placebo. They found substantially less residual hypersomnolence and fatigue in the bupropiontreated group vs the other groups. Movement Disorders Restless legs syndrome (RLS) and periodic limb movement (PLM) disorder have been linked to
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various psychiatric disorders and especially their treatments. For decades, there have been data, mostly derived from case series, linking movement disorders to psychotropic medication, particularly ADs.49 Winkelman et al50 examined RLS symptoms in the Wisconsin sleep cohort. He found substantially higher rates of psychiatric symptoms and disorders among those with daily RLS. Odds ratio for depression (Zung score 50 or AD medication use) in those with daily RLS was 2.17 and 1.80 in those with frequent RLS (one to six times per week). For anxiety disorders, odds ratios were 3.41 and 2.42 for the two RLS groups, respectively. The authors50 acknowledged the limitations of the assessment protocols and complexities of interpreting the associations identified in this study, but, at the very least, the study underscores the potential comorbidity of psychiatric disorders in RLS patients. Another analysis of a large data set addresses some of the limitations of the study by Winkelman.50 Lee and colleagues51 administered a modified seven-item RLS questionnaire to participants in the Epidemiologic Catchment Area study, a long-standing mental health epidemiologic investigation. The lifetime prevalence of any psychiatric disorder was much higher among RLS subjects (36.8% vs 14.6% in those without RLS). The adjusted odds ratio for 12-month prevalence of MDD was 4.7. For panic disorder, the adjusted odds ratios for lifetime and 12-month prevalence were even higher than those for MDD in patients with RLS. Of note, no association was found between AD use and RLS in this study. Certainly, one of the confounding factors in assessing psychiatric disorders, especially depression, in RLS patients is the overlap of symptoms/diagnostic criteria that exists for these conditions. The possibility that elevated depression scores are largely a function of symptoms common to both depression and RLS remains, although the studies just noted acknowledge and, to the extent possible, address this consideration. Hornyak et al52 explored this confound by retrospective assessment of RLS severity and BDI scores in untreated RLS patients. In summary, they found that it was the BDI items related to poor sleep and complications thereof that were most commonly endorsed in patients with RLS. Those items that pertained primarily to psychological symptoms of depression did not correlate with RLS severity. As the investigators suggested, these data support the assertion that the apparent association may be a function of symptom overlap and that the symptoms observed in RLS patients do not constitute a true MDD. Further exploration of this question is necessary. To the extent that such an association might suggest common pathophysiologic links between MDD and RLS, such an investigation may
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advance our understanding of the pathogenesis of both disorders. A useful review of the literature regarding linkage between RLS and depression was published by Picchietti and Winkelman.49 A limited number of studies have focused on the role of dopamine in psychiatric disorders and RLS. Inasmuch as schizophrenia is the mental disorder most closely associated with dopaminergic dysfunction, study of RLS in this population would be of particular interest. The data concerning RLS in schizophrenia are understandably focused on the issue of RLS/PLM in patients treated with AP medication. This subject was addressed in a review.53 It has been noted that the percentage of patients with a PLM index score 5 was no higher in those taking first-generation APs vs those who were APfree for 2 weeks or more. Case series and reports54 have described development or exacerbation of RLS symptoms in patients taking second-generation APs. Against the background of this relatively sparse information, Kang and colleagues55 assessed RLS symptoms in 182 treated schizophrenic patients and compared them with 108 healthy control subjects. They found a substantial increase in the percentage of schizophrenic patients meeting RLS criteria (21.4%) compared with control subjects (9.3%). However, somewhat surprisingly, no relationship was observed between the number or dosage of AP medications and RLS. An association between RLS and insomnia was identified. The medications most closely associated with exacerbation of RLS/PLM are ADs. The reports to date that link ADs to onset or worsening of sleep-related movement disorders are largely case series. A retrospective analysis56 of 200 patients who had presented to a sleep clinic for problems initiating sleep revealed no correlation between AD use and RLS. Of note is that 45% of these patients met the criteria for RLS, and 38% were receiving AD medication. A current medication assessment57 found increased use of various medications among patients with RLS. Although AD use was higher in the RLS population, GI and asthma medications were also used more frequently. Yang and colleagues58 looked at the frequency of PLMs in patients receiving therapy with various types of ADs and compared these to PLMs in patients not receiving AD medications. They found significantly higher PLM indexes in patients taking any type of SSRI or venlafaxine vs control subjects or the bupropion group. Evaluation of PLM-related arousal indexes continues to demonstrate a statistically significant increase in the SSRI/ venlafaxine groups; the differences in indexes are only 2 to 3 per hour, and all are below an absolute level of 5 per hour, raising some questions regarding the clinical significance of these differences. The
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data also suggest that bupropion, presumably by virtue of its inhibitory effect on dopamine reuptake, is not associated with the development or exacerbation of movement disorder and may conceivably be protective This latter observation has been further supported in a case series59 describing improvement of RLS in three patients administered bupropion in open fashion. A review49 described the existing literature concerning AD medications as an etiologic factor in RLS as limited and conflicting. Although epidemiologic data identify use of SSRIs as a risk factor for RLS, data on specific ADs are variable and inconclusive.

Parasomnias Of the common parasomnias, it is likely that nightmare disorder has been most extensively studied with respect to psychiatric disorders, in particular, PTSD. Some investigations have focused primarily on treatment trials. Prazosin has emerged as a promising pharmacotherapy for PTSD-related nightmares. Dierks et al60 conducted a comprehensive review of the existing literature and found that, on the whole, prazosin is associated with significant reductions in recurrent distressing dream scores and, in some cases, improvement in sleep quality. The major limitation of these data, however, is that all but two of the studies reported on were open-label studies. One of the two controlled investigations was conducted by Raskind et al,61 who randomized 40 combat veterans to prazosin or placebo over an 8-week trial. They found that distressing dream scores were reduced in 50% and were significantly lower than the placebo group, with large effect sizes. PSQI scores were significantly improved vs control subjects as were Clinical global impression (CGI) of change scores. A more recent report62 from this group evaluated prazosin in a controlled, cross-over design involving civilian trauma patients. Nightmare-related scores showed significant reductions post-prazosin. Moreover, total sleep time and REM time were increased, PTSD symptoms reduced, and the CGI improved. In an apparent extension of this study, the effect of additional daytime administration of prazosin on residual daytime symptoms of civilian trauma victims has also been assessed.63 Emotional distress (Profile of Mood States subscale) in response to trauma-related words was evaluated and significantly reduced in comparison to a placebo group. Reduction in the CGI of severity was observed at the 2-week follow-up, and it was correlated with the improvement in the Profile of Mood States subscale during the active study phase.
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Nonpharmacologic therapies for PTSD-related nightmares have also been the subject of considerable investigation in more recent years. Imagery rehearsal therapy (IRT) has received considerable attention as a promising treatment for traumarelated nightmares. Krakow and Zadra64 have provided a review of this topic, which includes general discussion of posttraumatic nightmares as well as a session-by-session description of treatment delivery. The modified approach described includes four sessions of 2 h each. The first two sessions focus primarily on the conditioned insomnia elements that are so frequently encountered as a component of this problem. The remaining sessions more directly address the nightmare imagery, including identification and rehearsal of alternative dream content. Davis and Wright65 have reported on a randomized controlled trial of a therapeutic approach derived from IRT (exposure, relaxation, and rescripting therapy). The investigators delivered three 2-h sessions of treatment to persons who had experienced chronic traumatic nightmares and compared outcome to a wait-list control group. The therapy incorporates many of the exposure, rescripting, and rehearsal characteristics of IRT, as well as sleep hygiene, stimulus control instructions, and progressive muscle relaxation training. They found a significant reduction in the percentage of treated subjects with nightmares, from 100% at baseline to 50% at 1 week posttreatment and 16% at the 6-month follow-up. In addition, reductions of PTSD symptoms and depression were also observed, suggesting some spillover effect of the therapy for related symptoms. Wait-list control subjects showed little change, in any, in these symptoms. A single 90-min intervention that incorporated elements of IRT/exposure, relaxation, and rescripting therapy was found to improve sleep quality and reduce nightmare frequency and PTSD symptoms in a small group of violent crime victims.66 The small number of subjects and absence of a control population requires that some caution be exercised in the interpretation of these results until a more extensive investigation of the approach has occurred. In another brief preliminary report, Moore and Krakow67 have described the application of IRT to a small number of Iraqi combat soldiers (11 soldiers) with acute nightmare disorder following trauma exposure. In this uncontrolled application, 7 of the 11 soldiers had marked reduction of nightmares as well as improvement in PTSD symptoms. Further assessment of this potentially preventive early intervention is warranted. In summary, substantial progress is under way in the development and evaluation of therapies for PTSD-related nightmares, a condition that has long
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been recognized as refractory to many standard PTSD therapies. Both pharmacotherapy (prazosin) and behaviorally based treatment (IRT/exposure, relaxation, and rescripting therapy) produce significant improvements not only in nightmares but also in sleep quality and daytime symptoms. Further assessment of brief interventions and the application of these modalities in the more acute trauma setting hold promise. Conclusion Psychiatric disorders are encountered at high frequencies in clinical populations, and sleep medicine is no exception. Important bidirectional relationships exist between sleep disorders and psychiatric disorders. Investigation of the psychological and psychiatric dimensions of sleep disorders may provide important information regarding pathophysiology and clinical management of both the psychiatric and sleep disorders. Mental illness comorbid with sleep disorders contributes to disease burden and adversely affects the outcome of patients with these conditions. Effective evaluation and management of patients with sleep disorders require careful psychological assessment, evaluation for specific psychiatric disorders, and, when necessary, independent pharmacologic and psychological treatment of psychopathology. References
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Update on Sleep and Psychiatric Disorders Michael J. Sateia Chest 2009;135; 1370-1379 DOI 10.1378/chest.08-1834 This information is current as of May 1, 2012
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