update on sleep and psychiatric disorders

8/13/2019 Update on Sleep and Psychiatric Disorders

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DOI 10.1378/chest.08-1834 2009;135;1370-1379Chest

Michael J. Sateia Update on Sleep and Psychiatric Disorders

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as mood disorders and anxiety disorders are associ-ated with high rates of insomnia. Likewise, for many of the patients presenting to sleep clinics with in-somnia, psychiatric disorders are likely to play animportant role in genesis and maintenance of theinsomnia. Ohayon et al1 reported a prevalence forinsomnia complaints (1 month duration and daytimeconsequences) of 12.7% in the general population.The prevalence of sleep disorders, mostly insomniadue to mental disorder, was 5.6%; primary psychiat-ric disorder diagnoses were applied to 8.4%. Al-though evidence of adverse effects of chronic insom-nia on both physiologic and psychological functioncontinues to accrue, the condition remains a seri-ously underdiagnosed and undertreated problem.

The relationship between sleep disorders andpsychiatric illness is not limited to insomnia, how-ever. In fact, it is difficult to identify a single majordiagnostic category within the International Classi-

fication of Sleep Disorders, 2nd edition (ICSD-2),2 in which mental illness, its treatment, or its complica-tions do not have relevance. This update approachesthe discussion of psychiatric disorders in sleep med-icine from the ICSD-2 categorical structure andfocuses on the bidirectional relationship betweensleep and mental disorders within each section. Theliterature is drawn from the past 3 years and wasidentified by means of Medline searches for majorICSD-2 categories (eg, “insomnia,” “sleep apnea,”and “hypersomnolence”) as well as “sleep” and majorpsychiatric disorders (eg, “depression” or “PTSD”).

Certain references outside the specified 3-year rangeare included for background purposes.

Insomnia

The studies of the last 3 years pertaining to sleepdisturbance and psychiatric disorders can be catego-rized into the following major areas: (1) subjectiveand objective changes in sleep associated with vari-ous major psychiatric conditions; (2) insomnia as arisk 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 alter-ations of sleep in patients with a variety of psychiatricillnesses. The issues raised by these studies areseveral-fold. Do sleep disorders contribute to thedevelopment of psychiatric disorders? Do changes insleep provide us with information that illuminatespotential pathophysiology of these disorders? Dosleep-related factors demonstrate significant correla-tions with other clinical symptoms or physiologicfactors? Do specific changes in sleep suggest specific

treatment strategies, and can alterations of sleepparameters in response to intervention predict treat-ment outcome?

Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) has been thefocus of many investigations. Difficulty initiating and

maintaining sleep have been recognized for centu-ries as common responses to trauma. Current studiesare aimed at further defining the nature of theseresponses and their implications with respect topathophysiology and management. Calhoun and oth-ers3 studied the sleep of 30 PTSD patients and 22control subjects with home actigraphy and sleep logsover 3 nights. They found significant differencesbetween patients and control subjects, with theformer demonstrating reduced sleep efficiency, in-creased latency to sleep onset, and more restlesssleep on actigraphy measures. Not unexpectedly,

sleep logs (in both groups) suggested worse sleepthan the actigraphy-derived data; results of the Pitts-burgh Sleep Quality Index (PSQI) showed no signif-icant correlation with objective data. In the PTSDpopulation, 37% had significant nightmare problems.Another investigation4 of sleep in 10 young adultpatients with PTSD compared with an equal numberof matched control subjects revealed modest butsignificant differences on polysomnography findings(decreased sleep efficiency, increased wake timeafter sleep onset and arousals, and decreased stage3/4 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 interrup-tion as well as wake time after sleep onset.

A metaanalysis5 of sleep findings in PTSD ad-dresses the long-standing issue of conflicting dataregarding sleep-related changes in this population.Kobayashi and colleagues5 report that a consistentpattern of increased stage 1, decreased stage 3/4, andincreased REM density is seen. Studies with pre-dominantly male populations showed greater de-grees of abnormalities; those with higher rates of

depression within the study group found less severedisturbances.

PTSD is frequently comorbid with other psychiat-ric disorders, especially substance abuse problems. Itis challenging to tease apart the relative contributionof each of these factors to sleep disturbance. A study 6

comparing sleep parameters in groups with PTSDalone, PTSD comorbid with alcohol dependence,alcohol dependence alone, and a control populationhas attempted to clarify this issue. Using subjectivereports, the investigation revealed, not surprisingly,that PTSD was associated with poorer sleep quality,

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longer latency, increased awakening, and early awak-ening. Severity of sleep disturbance correlated withPTSD severity. Significant effects were also seen foralcohol with increased latency and a trend towardlower quality. Of note, however, is that the investi-gators did not find a main effect for alcohol withrespect to frequency of awakening or early awaken-ing. Severity of alcohol abuse did not correlate withseverity of sleep disturbances. The authors suggestthat this may reflect tolerance to the effects of alcohol on sleep as the addiction progresses. Comor-bid PTSD/alcohol abuse did not significantly worsensleep compared with PTSD alone.

This literature provides further confirmation of the long-standing observations regarding sleep dis-turbance in this population of patients but under-scores the need for further study of the specificcharacteristics of these disturbances and the com-plexities introduced by related symptoms and comor-bid factors such as nightmares, mood disorder, andsubstance abuse. Critical questions are the extent to which sleep disturbance in this group is a fundamen-tal component of the pathophysiology of PTSD and whether independent treatment focused on the sleepdisturbance will improve overall outcome for thesepatients.

Insomnia as a Risk Factor for Mental Disorders

The topic of insomnia as a risk factor for mentalillness has been investigated in numerous epidemi-ologic studies over the past two decades.7,8 Several

more recent investigations extend the results already published. Perlis et al9 reported on a retrospectiveanalysis of 147 elderly patients who had no priorhistory of psychiatric illness. Of the 81 patients withan insomnia problem, 47 (58%) had indeterminateinsomnia and 34 (42%) had persistent insomnia. Tenof the 12 patients in whom depression developedover the subsequent 1-year follow-up fell into theinsomnia group (4 indeterminate, 6 persistent), sug-gesting significantly increased risk for major depres-sion in the insomnia group. Morphy et al10 sampled 2,000 UK residents at baseline and 12-month

follow-up. Measures of insomnia, depression, andanxiety demonstrated that baseline insomnia was asignificant risk factor for incident depression andanxiety at follow-up (adjusted risk ratios of 2.71 and2.28, respectively). In addition, an analysis of datafrom the Zurich longitudinal epidemiologic study 11

revealed that a new onset of depression developed in17 to 50% of patients with persistent, pure insomniaof 2 weeks duration at a later interview, withpredictive odds ratios of 1.6 to 1.9. Also of note isthat pure insomnia or insomnia comorbid with de-pression was a more reliable predictor of either

diagnosis in future interviews than was pure depres-sion. These data strongly support the concept of persistent insomnia as a risk factor for depressionand also suggest, as the authors point out, thatinsomnia and depression are highly related butdistinguishable disorders.

Not all large epidemiologic investigations, however,have identified persistent sleep disturbance as a risk

factor for incident depression. The Nord-TrondelagHealth Study (HUNT)-1 and HUNT-2 are county- wide Norwegian health surveys conducted about adecade apart in 85,000 adults. Neckelmann andcolleagues12 analyzed a sample of participants whohad no evidence of significant anxiety or mooddisorder at the time of initial (HUNT-1) assessmentto determine the relationship between the presenceof insomnia at either assessment point ( ie, atHUNT-1 or HUNT-2), or at both, with developmentof new-onset anxiety or depression as determined atHUNT-2 assessment. Their results appear to con-

firm previous data that suggest chronic insomnia is arisk factor for anxiety disorder. Onset of anxiety disorders was significantly greater in participants who had insomnia at HUNT-1 alone, HUNT-2alone, or at both points. In contrast to results fromnumerous other epidemiologic surveys, however,development of major depression (as determined atHUNT-2) was associated only with presence of insomnia at HUNT-2. As stated by the authors, theseresults suggest that, although chronic insomnia ap-pears to represent a trait marker for increased risk of developing an anxiety disorder, the relationship be-

tween 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 insom-nia cases identified at the first assessment repre-sented a prodromal symptom of a depression that was identified at the second assessment. The authorsalso noted that correcting for comorbidity betweenanxiety and depression reduces the potential con-found that associations between insomnia and de-pression are, in fact, a function of comorbid anxiety.

In addition to the evidence identifying persistentinsomnia as a risk factor for new psychiatric disor-

ders, findings from Pigeon et al13 have suggested thatchronic insomnia problems may also contribute topersistence of depression. This issue is of particularimportance in light of the significant rate of residualsleep disturbance in persons who have been other- wise successfully treated for depression. Drawing ondata from a large interventional study of enhancedcare for depressed elderly persons, the investigatorsfound that persistent insomnia was associated with a1.8 to 3.5 times greater likelihood of remainingdepressed, compared with the population withoutcontinued sleep disturbance. This effect was consid-

1372 Postgraduate Education Corner






erably more apparent in the usual care arm (pro- vided by subject’s primary care physician) than in theenhanced care group. Carney and colleagues14 as-sessed whether type of therapy for depression af-fected the frequency of residual insomnia in de-pressed patients. They found residual rates of 17 to26% for residual sleep onset and maintenance com-plaints following treatment, with no significant dif-

ference in frequency of these complaints in thepharmacotherapy vs the cognitive-behavioral therapy for depression group.

An important theoretical and clinical question thatemerges from this debate concerns impact of insom-nia treatment on reduction of risk for future depres-sion and improvement of current depression. Al-though the former issue has not been effectively addressed to date, several more recent studies shedsome light on the latter. An uncontrolled study 15 of cognitive behavioral treatment for insomnia alone in10 subjects with mild to moderate depression (based

on Structured Clinical Interview for Diagnostic andStatistical Manual of Mental Disorders, fourth edi-tion, criteria and Beck Depression scores) revealedthat seven of eight treatment completers no longermet criteria for depression and had normal Beckscores following six treatment sessions. Depressionscores were significantly lower than baseline scoresat 3-month follow-up. The authors understandably caution that these were patients with mild degrees of depression and further investigation with a largersample 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 information-only intervention. They found significant improve-ment in mood and anxiety symptoms in the activeintervention group, paralleling the improvements insleep. However, this study was not specifically de-signed to assess the impact of an insomnia interven-tion on major depression. The population includedindividuals with mild depressive symptoms, butpatients with active, more severe depression werescreened out. It is also unclear whether changescores for depression and anxiety ratings adjusted for

effects of improved sleep.Mounting clinical evidence suggests that com-

bined therapies for both depression and insomnia aresuperior to antidepressant (AD) medication alone inpatients 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 sleepdisturbance (eszopiclone), coadministered with an AD(fluoxetine), on sleep and mood. In the initial study, theinvestigators found that significantly greater improve-ments in mood, especially on investigator-rated instru-ments, in the combined hypnotic/AD group com-

pared with AD alone. These results held, by andlarge, when sleep-related items were removed fromdepression assessment scales. The follow-up study 18

revealed that the superior improvement in sleep andmood ratings for the combined therapy group con-tinued during the two week period following discon-tinuation of the eszopiclone.

Another study 19 combining AD medication withspecific insomnia treatment (in this case, cognitive-behavioral therapy for insomnia) demonstrated thatthe combined treatment was superior to AD aloneboth in terms of depression outcome (61.5% vs33.3% remission, respectively) and insomnia out-come (50% vs 7.7% remission, respectively).

Although these results are preliminary, they strongly suggest that a combined therapy approachfor patients with major depression with associatedinsomnia, including either hypnotic therapy or be-havioral treatment for insomnia with conventionalAD therapy, may be superior to AD alone. Clearly,this has far-reaching implications for all cliniciansinvolved in the management of patients with depres-sive disorders.

Psychotropic Medications and BehavioralTherapies

Several pharmacotherapy studies of potential in-terest to sleep medicine clinicians and researchershave 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 past2 or 3 years. A recent report20 documented wide-spread off-label administration to psychiatric pa-tients, most frequently those with mood disorders,substance abuse, and psychotic disorders. Eveninglow-dose administration is common, but efficacy datafor these uses are lacking. A brief report21 of open-label, low-dose (mean, 100 mg) quetiapine adminis-tered at bedtime for sleep disturbance in patients with PTSD suggests a clinically meaningful responseover the 6-week trial. Measures of quality, latency,and duration from the PSQI all demonstrated signif-

icant improvement. However, further randomizedcontrolled trials are necessary to confirm these pre-liminary results. Others22–24 have demonstrated sig-nificant improvement in sleep with quetiapine ad-ministered to patients with mood disorders. The only study to date of quetiapine in primary insomnia wasrecently 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. Al-though sleep latency (only 22 min at baseline) didnot improve subjectively or objectively, significant







improvement in subjective sleep quality and bothsubjective and objective total sleep time and effi-ciency were found. Clearly, further work is neededto explore the indications and efficacy of atypicalantipsychotic (AP) medications, but agents such asthis may prove to be useful sleep aids in certainpopulations of patients.

Sedating AD medications have become widely

used for insomnia, in spite of the limited empiricalevidence supporting efficacy. An uncontrolled inves-tigation26 of the effects of mirtazapine, 30 mg, onsleep in patients with a major depressive disorder(MDD) found polysomnographic evidence of in-creased slow-wave sleep in the first cycle, increasedREM latency, and decreased wake after sleep onset.Depression ratings (Hamilton Depression and BeckDepression) showed early and continued improve-ment in mood disorder over the 2-week study periodin these patients, who were using no other psycho-active or hypnotic medications.

Trazodone is an AD medication widely used in thetreatment of insomnia. The explanation for its pop-ularity is not entirely clear, but, in all likelihood, isattributable to the notion that it is in some ways saferthan standard benzodiazepine receptor agonist med-ication, particularly in longer term applications. Un-fortunately, there is a paucity of data supporting theefficacy of trazodone in the treatment of insomnia.Studies published to data have been largely con-ducted on depressed patients with sleep disturbance.Assessment measures have primarily been subjec-tive, and appropriate control subjects have been

lacking in many of these investigations. That said,studies27–29 have shown some improvement in sleepin these populations. Recently published guide-lines30 for the evaluation and management of insom-nia indicate that benzodiazepine receptor agonisthypnotic agents are considered the first-choiceagents in the pharmacotherapy of chronic insomnia,although the authors acknowledged the potentialusefulness of sedating ADs such as trazodone assecond-line agents, especially in comorbid insomnia.

Finally, Suresh Kumar and colleagues30 evaluatedthe effects of variable melatonin dosing vs placebo

for sleep-onset problems in chronic schizophrenicpatients. The results demonstrated reduced awaken-ings and increased total sleep time in the melatoningroup, although results for the primary target, sleep-onset latency, were mixed. Daytime mood and func-tioning also showed improvement.

Guidelines31 on the management of insomniafrom the American Academy of Sleep Medicinerecommend that treatment of insomnia in patients with comorbid psychiatric disorders follow the gen-eral guidelines of psychological and behavioral ther-apies, possibly coupled with a benzodiazepine recep-

tor agonist, but they also note the potentialusefulness of sedating ADs or atypical AP medica-tions in certain populations.

Sleep-Related Breathing Disorders

The relationship between sleep-related breathing

disorders, most notably obstructive sleep apnea(OSA), and psychiatric disorders, especially depres-sion, has been studied for decades. Earlier stud-ies32,33 demonstrated high rates of depressive symp-toms in OSA, as well as improvement of thesesymptoms with treatment of OSA.34 Limited evi-dence35 has also shown elevated rates of OSA inpatients with identified MDD. This latter finding was extended by Deldin and colleagues36 who reportsignificant increases of major flow limitations andevents with desaturations in a pilot group of 19depressed patients (vs nondepressed control sub-

jects) selected without regard to OSA symptoms.The nature of this association is unclear, but theauthors suggested that “respiratory-related sleepfragmentation of hypoxia-induced prefrontal dys-function” may predispose to mood disorder. Simi-larly, high rates of OSA have been reported inchronic schizophrenic patients.37 In this study,37

clear associations existed among use of atypicalneuroleptics, obesity, and the presence of OSA.

More recent evidence has confirmed previousfindings suggestive of important connections be-tween OSA and psychiatric disorders and furthers

our understanding of these linkages. Psychiatric co-morbidity in OSA patients was examined in a largeretrospective chart review 38 of 100,000 VeteransAffairs Hospital OSA patients. A significantly higherprevalence of numerous psychiatric disorders wasfound in this group, as compared with a non-OSApopulation. High comorbidity was found for majordepression (21.8%), anxiety disorders (16.7%), andPTSD (11.9%). Others39 have noted the frequency of depression symptoms in OSA as well. Analysis of Beck Depression Inventory (BDI) scores in 92 maleand 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 symptomsthan men, although apnea severity did not differbetween the groups. Depressive symptoms did notcorrelate with RDI, sleepiness, or desaturation fre-quency. However, in women, desaturation nadir didcorrelate significantly with BDI scores.

A number of investigations have assessed theresponse of mood symptoms to treatment for OSA.Schwartz and Karatinos40 found reductions of de-pression scores (seven-item BDI) in OSA patients







treated with continuous positive airway pressure(CPAP). Most of the sample fell into a minimal tomild depression range, and these groups demon-strated significant reductions in BDI scores at initialfollow-up and long-term follow-up. The magnitude of reduction was greatest for those in the moderate-to-severe range, although the differences did not reachstatistical significance, presumably due to the small

number of patients within this group. Modest reduc-tion in Zung depression scores following administra-tion of nasal CPAP to patients with severe OSA hasalso been reported.41 These reductions were paral-leled by and correlated with improvement in quality-of-life scores. One of the few placebo-controlledstudies42 of improvement in psychological symptomsfollowing CPAP demonstrated that psychologicalsymptoms improved with both CPAP and with oxy-gen vs sham CPAP. However, specific depressionsymptoms improved only with oxygen. The authorssuggest that this may underscore the role of hypox-

emia vs sleep disruption in the pathogenesis of depression symptoms in OSA. However, the findingdoes not account for the concurrent improvement inoxygen saturations associated with CPAP usage.

Identification and treatment of depression clearly plays an important role in fostering positive outcomein patients with OSA. A comparison of the impact of apnea severity and psychological symptoms on fa-tigue complaints in OSA patients43 found that agreater portion of fatigue in OSA patients is ex-plained by depression than by OSA variables them-selves. In this investigation,43 depression explained

about 25% of the variance for fatigue, whereas OSAseverity explained only 13%.

The interaction of psychological symptoms andCPAP adherence may be of considerable importancein determining long-term treatment outcome forOSA. A postal survey 44 of CPAP users found associ-ations between low CPAP compliance and anxiety, as well as between low compliance and depression andsleepiness. These findings may reflect a bidirectionalrelationship between OSA and psychological symp-toms. Although the depression and anxiety observedmay well be a function of poorly controlled OSA due

to low treatment compliance, it seems equally prob-able that low compliance may be the result of poorly controlled psychological distress. Wells and col-leagues45 explored this question and found no cor-relation between baseline depression symptoms andsubsequent CPAP compliance. Improvement inOSA symptoms did significantly predict improve-ment in depression following treatment.

In summary, these findings reinforce the complex-ity of the relationship between OSA and psycholog-ical symptoms. Evidence that treatment of OSAimproves depression has continued to emerge, al-

though not all studies have agreed. Depression may account for significant residual symptoms in thispopulation. Existing psychological distress may neg-atively impact adherence to treatment, althoughfurther assessment of this issue is required. Never-theless, there is sufficient data to suggest clearly thatclinicians must be vigilant for the presence of psy-chiatric comorbidity in their patients with OSA and

that adequate psychological assessment and treat-ment of identified psychiatric disorders is likely toimprove outcome in OSA patients.

Hypersomnolence Disorders

Previous epidemiologic studies8,46 have identifiedhigh rates of sleepiness in psychiatric populations.These findings have important implications withrespect to management of the primary psychiatriccondition, as well as treatment of underlying sleep

disorders that may give rise to hypersomnolenceproblems. Prior studies have suggested an associa-tion between depression and sleepiness, althoughthey have not, in general, demonstrated much objec-tive 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 toidentify associations between subjective reports of sleepiness and other factors, including psychiatricdisorders. In the study,47 12% of men and 6% of women reported excessive sleepiness (Epworth

sleepiness scale score

10). MDD was not associ-ated with sleepiness. The only association of exces-sive daytime sleepiness with mental illness was withbipolar disorder. This leads the authors to speculateon the possibility that a more unique relationshipexists between the pathophysiology of bipolar disor-der and excessive sleepiness. They also suggest thatprior associations between depression and sleepinessmay be a function of the underdiagnosis of bipolardisorder within the study populations.

In those patients with depression who do complainof sleepiness, medication choice may have an impor-

tant impact on clinical outcome, as shown by Papa-kostas et al,48 who studied a group of patients withmajor depression who were treated with either anselective serotonin reuptake inhibitor (SSRI), bupro-pion, or placebo. They found substantially less resid-ual hypersomnolence and fatigue in the bupropion-treated group vs the other groups.

Movement Disorders

Restless legs syndrome (RLS) and periodic limbmovement (PLM) disorder have been linked to







various psychiatric disorders and especially theirtreatments. For decades, there have been data, mostly derived from case series, linking movement disordersto 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 disordersamong those with daily RLS. Odds ratio for depres-

sion (Zung score 50 or AD medication use) inthose with daily RLS was 2.17 and 1.80 in those with“frequent” RLS (one to six times per week). Foranxiety disorders, odds ratios were 3.41 and 2.42 forthe two RLS groups, respectively. The authors50

acknowledged the limitations of the assessment pro-tocols and complexities of interpreting the associa-tions 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 thelimitations of the study by Winkelman.50 Lee and

colleagues51 administered a modified seven-itemRLS questionnaire to participants in the Epidemio-logic Catchment Area study, a long-standing mentalhealth epidemiologic investigation. The lifetimeprevalence of any psychiatric disorder was muchhigher among RLS subjects (36.8% vs 14.6% in those without RLS). The adjusted odds ratio for 12-monthprevalence of MDD was 4.7. For panic disorder,the adjusted odds ratios for lifetime and 12-monthprevalence were even higher than those for MDDin patients with RLS. Of note, no association wasfound between AD use and RLS in this study.

Certainly, one of the confounding factors in assess-ing psychiatric disorders, especially depression, inRLS patients is the overlap of symptoms/diagnosticcriteria that exists for these conditions. The possibil-ity that elevated depression scores are largely afunction of symptoms common to both depressionand RLS remains, although the studies just notedacknowledge and, to the extent possible, address thisconsideration. Hornyak et al52 explored this con-found by retrospective assessment of RLS severity and BDI scores in untreated RLS patients. In sum-mary, they found that it was the BDI items related to

poor sleep and complications thereof that were mostcommonly endorsed in patients with RLS. Thoseitems that pertained primarily to psychological symp-toms of depression did not correlate with RLSseverity. As the investigators suggested, these datasupport the assertion that the apparent associationmay be a function of symptom overlap and that thesymptoms observed in RLS patients do not consti-tute a true MDD. Further exploration of this ques-tion is necessary. To the extent that such an associ-ation might suggest common pathophysiologic linksbetween MDD and RLS, such an investigation may

advance our understanding of the pathogenesis of both disorders. A useful review of the literatureregarding linkage between RLS and depression waspublished by Picchietti and Winkelman.49

A limited number of studies have focused on therole of dopamine in psychiatric disorders and RLS.Inasmuch as schizophrenia is the mental disordermost closely associated with dopaminergic dysfunc-

tion, study of RLS in this population would be of particular interest. The data concerning RLS inschizophrenia are understandably focused on theissue of RLS/PLM in patients treated with APmedication. 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 thosetaking first-generation APs vs those who were AP-free for 2 weeks or more. Case series and reports54

have described development or exacerbation of RLSsymptoms in patients taking second-generation APs.Against the background of this relatively sparse

information, Kang and colleagues55 assessed RLSsymptoms in 182 treated schizophrenic patients andcompared them with 108 healthy control subjects.They found a substantial increase in the percentageof schizophrenic patients meeting RLS criteria(21.4%) compared with control subjects (9.3%).However, somewhat surprisingly, no relationship wasobserved between the number or dosage of APmedications and RLS. An association between RLSand insomnia was identified.

The medications most closely associated with exac-erbation of RLS/PLM are ADs. The reports to date

that link ADs to onset or worsening of sleep-relatedmovement disorders are largely case series. A retro-spective analysis56 of 200 patients who had presented toa sleep clinic for problems initiating sleep revealed nocorrelation between AD use and RLS. Of note is that45% of these patients met the criteria for RLS, and38% were receiving AD medication.

A current medication assessment57 found in-creased use of various medications among patients with RLS. Although AD use was higher in the RLSpopulation, GI and asthma medications were alsoused more frequently. Yang and colleagues58 looked

at the frequency of PLMs in patients receivingtherapy with various types of ADs and comparedthese to PLMs in patients not receiving AD medica-tions. They found significantly higher PLM indexesin patients taking any type of SSRI or venlafaxine vscontrol subjects or the bupropion group. Evaluationof PLM-related arousal indexes continues to demon-strate a statistically significant increase in the SSRI/ venlafaxine groups; the differences in indexes areonly 2 to 3 per hour, and all are below an absolutelevel of 5 per hour, raising some questions regardingthe clinical significance of these differences. The







data also suggest that bupropion, presumably by virtue of its inhibitory effect on dopamine reuptake,is not associated with the development or exacerba-tion of movement disorder and may conceivably beprotective This latter observation has been furthersupported in a case series59 describing improvementof RLS in three patients administered bupropion inopen fashion.

A review 49 described the existing literature con-cerning AD medications as an etiologic factor inRLS as “limited and conflicting.” Although epide-miologic data identify use of SSRIs as a risk factorfor RLS, data on specific ADs are variable andinconclusive.

Parasomnias

Of the common parasomnias, it is likely thatnightmare disorder has been most extensively stud-

ied with respect to psychiatric disorders, in particu-lar, PTSD. Some investigations have focused primar-ily on treatment trials. Prazosin has emerged as apromising pharmacotherapy for PTSD-related night-mares. Dierks et al60 conducted a comprehensivereview of the existing literature and found that, onthe whole, prazosin is associated with significantreductions in recurrent distressing dream scores and,in some cases, improvement in sleep quality. Themajor limitation of these data, however, is that all buttwo of the studies reported on were open-labelstudies. One of the two controlled investigations was

conducted by Raskind et al,61 who randomized 40combat veterans to prazosin or placebo over an8-week trial. They found that distressing dreamscores were reduced in 50% and were significantly lower than the placebo group, with large effect sizes.PSQI scores were significantly improved vs controlsubjects as were Clinical global impression (CGI)of change scores. A more recent report62 from thisgroup evaluated prazosin in a controlled, cross-overdesign involving civilian trauma patients. Night-mare-related scores showed significant reductionspost-prazosin. Moreover, total sleep time and REM

time were increased, PTSD symptoms reduced, andthe CGI improved. In an apparent extension of thisstudy, the effect of additional daytime administrationof prazosin on residual daytime symptoms of civiliantrauma victims has also been assessed.63 Emotionaldistress (Profile of Mood States subscale) in responseto trauma-related words was evaluated and signifi-cantly reduced in comparison to a placebo group.Reduction in the CGI of severity was observed at the2-week follow-up, and it was correlated with theimprovement in the Profile of Mood States subscaleduring the active study phase.

Nonpharmacologic therapies for PTSD-relatednightmares have also been the subject of consider-able investigation in more recent years. Imagery rehearsal therapy (IRT) has received considerableattention as a promising treatment for trauma-related nightmares. Krakow and Zadra64 have pro- vided a review of this topic, which includes generaldiscussion of posttraumatic nightmares as well as a

session-by-session description of treatment delivery.The modified approach described includes four ses-sions of 2 h each. The first two sessions focusprimarily on the conditioned insomnia elements thatare so frequently encountered as a component of thisproblem. The remaining sessions more directly ad-dress the nightmare imagery, including identificationand rehearsal of alternative dream content.

Davis and Wright65 have reported on a random-ized controlled trial of a therapeutic approach de-rived from IRT (exposure, relaxation, and rescriptingtherapy). The investigators delivered three 2-h ses-

sions of treatment to persons who had experiencedchronic traumatic nightmares and compared out-come to a wait-list control group. The therapy incorporates many of the exposure, rescripting, andrehearsal characteristics of IRT, as well as sleephygiene, stimulus control instructions, and progres-sive muscle relaxation training. They found a signif-icant reduction in the percentage of treated subjects with nightmares, from 100% at baseline to 50% at1 week posttreatment and 16% at the 6-monthfollow-up. In addition, reductions of PTSD symp-toms and depression were also observed, suggesting

some spillover effect of the therapy for relatedsymptoms. Wait-list control subjects showed littlechange, in any, in these symptoms.

A single 90-min intervention that incorporatedelements of IRT/exposure, relaxation, and rescript-ing therapy was found to improve sleep quality andreduce nightmare frequency and PTSD symptoms ina small group of violent crime victims.66 The smallnumber of subjects and absence of a control popu-lation requires that some caution be exercised in theinterpretation of these results until a more extensiveinvestigation of the approach has occurred.

In another brief preliminary report, Moore andKrakow 67 have described the application of IRT to asmall number of Iraqi combat soldiers (11 soldiers) with acute nightmare disorder following traumaexposure. In this uncontrolled application, 7 of the11 soldiers had marked reduction of nightmares as well as improvement in PTSD symptoms. Furtherassessment of this potentially preventive early intervention is warranted.

In summary, substantial progress is under way inthe development and evaluation of therapies forPTSD-related nightmares, a condition that has long







been recognized as refractory to many standardPTSD therapies. Both pharmacotherapy (prazosin)and behaviorally based treatment (IRT/exposure,relaxation, and rescripting therapy) produce signifi-cant improvements not only in nightmares but also insleep quality and daytime symptoms. Further assess-ment of brief interventions and the application of these modalities in the more acute trauma setting

hold promise.

Conclusion

Psychiatric disorders are encountered at high fre-quencies in clinical populations, and sleep medicineis no exception. Important bidirectional relationshipsexist between sleep disorders and psychiatric disor-ders. Investigation of the psychological and psychi-atric dimensions of sleep disorders may provideimportant information regarding pathophysiology

and clinical management of both the psychiatricand sleep disorders. Mental illness comorbid withsleep disorders contributes to disease burden andadversely affects the outcome of patients with theseconditions. Effective evaluation and management of patients with sleep disorders require careful psycho-logical assessment, evaluation for specific psychiatricdisorders, and, when necessary, independent phar-macologic and psychological treatment of psychopa-thology.

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DOI 10.1378/chest.08-1834 2009;135; 1370-1379Chest

Michael J. SateiaUpdate on Sleep and Psychiatric Disorders

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