Depression and Sleep Disorders: Clinical Relevance, Economic Burden and Pharmacological Treatment

Biological PsychiatryMain Editor: J. Mendlewicz (Brussels)

Original Paper

Neuropsychobiology 2000;42:107–119

Depression and Sleep Disorders:Clinical Relevance, Economic Burdenand Pharmacological Treatment

Nicoletta Brunelloa, b Roseanne Armitaged Irwin Feinberge Edith Holsboer-Trachsler i

Damien Légerj Paul Linkowskik Wallace B. Mendelsonf Giorgio Racagnib, c Bernd Saletul

Ann L. Sharpleym Fred Turekg Eve Van Cauterh Julien Mendlewiczk

aDepartment of Pharmaceutical Sciences, University of Modena and Reggio Emilia, bCentre of Neuropharmacology,Institute of Pharmacological Sciences, University of Milan, and cIRCCS, Centro San Giovanni di Dio-Fatebenefratelli,Brescia, Italy; dUniverstiy of Texas Southwestern Medical Center at Dallas, Tex., eVA/UCD Sleep Laboratory,Department of Psychiatry, University of California, Davis, Calif., fDepartment of Neurology, Cleveland ClinicFoundation, Cleveland, Ohio, gDepartment of Neurobiology and Physiology, Northwestern University, Evanston, Ill.and hUniversity of Chicago, Ill., USA; iPsychiatrische Universitätsklinik Basel, Switzerland; jHôtel-Dieu Sleep Center,Paris, France; kDepartment of Psychiatry, Erasme Hospital, University of Brussels, Belgium; lDepartment ofPsychiatry, School of Medicine, University of Vienna, Austria; mPsychopharmacology Research Unit, OxfordUniversity Department of Psychiatry, Oxford, UK

Prof. Nicoletta BrunelloCentre of Neuropharmacology, Institute of Pharmacological SciencesUniversity of Milan, Via Balzaretti, 9I–20133 Milan (Italy)Tel. +39 02 20488331, Fax +39 02 29403673, E-Mail brunello@mailserver.unimi.it

ABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com

© 2000 S. Karger AG, Basel0302–282X/00/0423–0107$17.50/0

Accessible online at:www.karger.com/journals/nps

Key WordsDepression W Sleep W Direct and indirect costs W

Treatment W Antidepressants W Tricyclic antidepressants W

Selective serotonin reuptake inhibitors W Nefazodone

AbstractA wide range of studies have been published over thepast two decades that involve the intersection of sleepEEG, insomnia, psychiatric illness (especially depressivedisorders) and psychopharmacology. Much of value hasbeen discovered, but there have also been false startsand contradictory results. There is in fact strong evi-dence that insomnia is associated with medical and psy-chiatric illness and that the sleepiness associated withinsomnia is the cause of many accidents. Thus, the direct(visits to doctors, cost of sleeping medication, complica-tions from use of these medications) and indirect (acci-

dents, quality of life) costs of insomnia are enormousand constitute a major public health problem in theindustrialized countries. Believing that it is now timely toassess the state of this important research area, a con-sensus conference was convened on June 26–28, 1998,in Porto Cervo (Italy) to attempt to clarify the importantissues and findings on the clinical effect of the differentclasses of antidepressant drugs on sleep quality in de-pression. The participants’ consensus on some of themain topics is presented with the hope that this discus-sion and analysis will contribute to productive researchin this important field.

Copyright © 2000 S. Karger AG, Basel

108 Neuropsychobiology 2000;42:107–119 Brunello et al.

Introduction

Human sleep is under the dual control of circadianrhythmicity and of a homoeostatic process relating thedepth of sleep to the duration of prior wakefulness [1].This homoeostatic process involves one or several puta-tive neural sleep factor(s) which rise(s) during waking anddecay(s) exponentially during sleep. Circadian rhythmici-ty, an endogenous nearly 24-hour periodic signal gener-ated by a pacemaker system located in the hypothalamicsuprachiasmatic nucleus, plays an important role in thecontrol of the timing of sleep onset, the timing of sleepoffset, the distribution of REM (rapid eye movement)sleep and sleep spindle activity [2]. In contrast, non-REMsleep, and in particular the deeper stages of sleep (i.e.slow-wave sleep), appears to be primarily controlled bythe homoeostatic process.

Insomnia, a more or less chronic sleep disturbance, is asubjective complaint describing the perception of dis-turbed or inadequate sleep, i.e. sleep that is difficult toinitiate or maintain, or that is non-refreshing or non-res-torative, and is usually associated with changes in day-time functioning and well-being. Causes include medicaldiseases, psychiatric disorders, drugs both prescribed andnon-prescribed (including alcohol), behavioural factors,circadian dysrhythmias and primary sleep disorders.Sleep disturbances can cause significant deterioration inthe quality of life including difficulties with concentra-tion, memory, ability to accomplish daily tasks and enjoy-ment of interpersonal relationships. The ability to copewith minor irritations is also significantly impaired [3].

Somnipathies are among the most frequent complaintsa general practitioner must deal with. According to epide-miological studies, 19–46% of the population reportssleeping problems [4–6] of which 13% suffer from moder-ate or severe disturbances. In terms of the narrow defini-tion of diagnostic criteria, that is initial insomnia, inter-rupted sleep and disturbance of daily well-being, 1.3% ofthe population suffers from somnipathy [4].

Risk factors for somnipathies are shift work, child-birth, psychic stress or psychiatric illness. Volunteers suf-fering from stress, tension, solitude or depression re-ported a high prevalence of somnipathies. Severer sleeping difficulties were found to be clearly related to psy-chiatric illness such as depression and phobias, as well asaddiction [4, 7]. A recent World Health Organization(WHO) collaborative study in 15 different countriesfound that insomnia is more common in females andincreases with age [8]. Indeed it is thought that half of thepopulation over 65 years of age suffer from chronic sleep

disturbances [9]. The WHO study also found that 51% ofpeople with an insomnia complaint had a well-definedInternational Classification of Diseases 10 [10] mentaldisorder (e.g. depression, anxiety, alcohol problems).

Although many somnipathies develop intermittently,70–80% of the surveyed patients had been suffering fromsleeping problems for more than 1 year. An American sur-vey [11] has found problems related to chronic insomniain 9% of the general population, with disturbance of con-centration and memory, difficulties in getting on with dai-ly affairs and depressive mood changes. The pressureimposed by their ailment leads many patients to seek helpin alcohol and drugs.

Direct and Indirect Costs of Insomnia

Insomnia affects daytime alertness (ICSD [12], DSM-IV [13]; it also affects daytime behaviour, quality of life[14] and has costly economic consequences. This econom-ic impact of insomnia can be divided into direct and indi-rect costs of insomnia.

Direct costs of insomnia include out-patient visits,sleep recordings and medications directly devoted toinsomnia. There is very little knowledge about this kind ofcost. Direct costs of insomnia were estimated USD 10.9billion in 1990 (with USD 1.1 billion devoted to sub-stances used to promote sleep and USD 9.8 billion associ-ated with nursing home care for elderly individuals withsleep problems). The direct costs related to sleep disordersevaluated by general practitioners seem to be a small partof the total cost of insomnia. The Gallup study [11] foundthat only 5% of insomniacs had ever specially visited aphysician to discuss their sleeping problem. In a recentstudy on the impact of insomnia [15], it was found that53% of severe insomniacs versus 27% of subjects withoccasional sleep problems had ever visited a doctor spe-cifically for insomnia (p ! 0.001). During the past year,they were respectively 18% (16% a general practitioner,2% a specialist) versus 8% (7% a general practitioner, 1%a specialist; p ! 0.0001), with an average of 0.34 (B 1.56)visits by insomniacs and 0.1 (B 0.50) in the other group(p = 0.0020).

In the indirect costs of insomnia are included thepotential consequences of insomnia, such as health prob-lems, professional consequences and accidents. This is amore controversial part, as we do not know if sleep disor-ders are the cause or the consequence of various somaticor psychiatric diseases. Two groups [16, 17] had previous-ly observed that insomniacs reported more medical prob-

Depression and Sleep Neuropsychobiology 2000;42:107–119 109

lems than good sleepers did. Weyerer and Dilling [17]showed that insomniacs had twice as many doctors’ visitsyearly than good sleepers (12.9 vs. 5.2 visits and 10.6 forsubjects with a mild insomnia). In a study performed onsevere insomniacs compared to good sleepers [15], it wasfound that insomniacs were hospitalized twice as often asgood sleepers over the previous 12 months. This is similarto the results reported by Weyerer and Dilling [17] whofound that 21.9% of insomniacs versus 12.2% of controlshad been hospitalized in the past year. Lavie [18] alsofound a higher rate of hospitalizations for insomniacs andBixler et al. [19] found a yearly hospitalization rate of15.7% with no control group. The average duration ofeach hospitalization was not different in this study be-tween the groups (6.3 vs. 7.4 days, n.s.) and the admis-sions to specialized departments demonstrated that in-somniacs were more often hospitalized for gastro-intesti-nal problems (11 vs. 3%), but good sleepers were morenumerous in cardiology (5 vs. 2%) and in traumatology(12 vs. 0%).

Individuals with insomnia reported lower quality oflife scores and increased health care resource utilizationcompared with individuals with no insomnia [20]. Insom-niacs consumed more medication than good sleepers forvarious treatments; however, there was no difference foranalgesics despite the fact that 46% of insomniacs versus29% of good sleepers (p ! 0.0001) said they were particu-larly sensitive to pain [15].

These results confirm previous observations showingthat insomnia is statistically linked to a worse health sta-tus than that of individuals with good sleep. We cannotconclude whether insomnia is the cause or the result ofthis worse status. However, one could reasonably hypo-thesize that insomnia promotes fatigue that could in-crease the risk of some diseases or more simply decreasethe threshold of others that could more easily develop.This hypothesis has clearly been demonstrated by Fordand Kamerow [21], in a group of 705 people under 65 whohad been followed for 3 years. The individuals who suf-fered from insomnia at the beginning were more than3 times as likely as those without sleep problems to bedepressed 2 years later. A similar result was observed foralcoholism in the same study. These observations havebeen confirmed by another study by Livingston et al. [22]in a population of elderly subjects.

In a survey on 1,308 workers, Leigh [23] found thatinsomnia (inside 37 independent variables) was the mostpredictable factor of absenteeism at work. In his study hefound that insomniacs had an average monthly sickabsence rate 2.8 times that of the total group. It has been

shown that insomniacs had more diseases than goodsleepers. We then have to discriminate how much of theabsenteeism was linked to insomnia and how much waslinked to other diseases. Some of the absenteeism could berelated to insomnia. Glazner [24] has previously demon-strated that insomnia could be a main cause of absen-teeism at work.

Insomnia can result in difficulties in coping with dailywork, difficulties of concentration, work accidents anddifficulties in accomplishing work duties. Mendelson etal. [25] showed in a group of 691 non-treated insomniacs aclear loss of diurnal performances. Lavie [18] found aworse work satisfaction for insomniacs and a loss of prod-uctivity. Johnson and Spinweber [26], in navy men, dem-onstrated than insomniacs were slower at work and had apoorer career advancement than good sleepers. Based onthis last study, Stoller [27] estimated the loss of productiv-ity due to insomnia as 41.1 billions USD in the USA in1988.

A clear difference was found between accidents atwork which were more common in insomniacs (i.e. in-somniacs had 7 times more work accidents than goodsleepers did) and traffic accidents which did not seem sig-nificantly different between our groups. The risk of workaccidents was not observed in previous studies on insom-nia. The difference observed between the higher risk ofaccidents at work and the lower risk at the wheel could beexplained by the more monotonous conditions at work,which could promote inattention and accidents [28].

However the risk of motor vehicle accidents was usual-ly found to be higher in insomniacs than in controls inprevious studies [11, 29, 30]. In this last study, chronicinsomniacs are 2.5 times (5 vs. 2%) more frequent thannon-insomniacs to report vehicle accidents in which fa-tigue was a factor. It was estimated that the costs of sleep-related accidents (including not only insomnia but also allsleep disorders and disturbances) were USD 46–52 billionin 1988 [31].

Sleep Abnormalities in Depression

Sleep abnormalities in those with major depressive dis-orders, as assessed by laboratory studies, can be classifiedas difficulties initiating and maintaining sleep, abnormalsleep architecture and disruptions in the timing of REMsleep. Sleep initiation and maintenance difficulties in-clude prolonged sleep latency (sleep onset insomnia),intermittent wakefulness and sleep fragmentation duringthe night, early morning awakenings with an inability to

110 Neuropsychobiology 2000;42:107–119 Brunello et al.

return to sleep, reduced sleep efficiency and decreasedtotal sleep time. With regard to sleep architecture, abnor-malities have been reported in the amounts and distribu-tion of non-REM sleep stages across the night and includeincreased light, stage 1 sleep and reductions in the amountof deep, slow-wave (stages 3 + 4) sleep. REM sleep distur-bances in depression include a short latency (!65 min) tothe first REM sleep, a prolonged first REM sleep periodand an increased total REM sleep time, particularly in thefirst half of the night [32–34]. Thase [35] has also suggest-ed that approximately 30% of depressed patients havehypersomnia rather than insomnia as the dominant sleepabnormality.

Sleep disturbances are generally more prevalent indepressed in-patients, whereas only 40–60% of out-pa-tients show sleep abnormalities [36, 37]. Moreover, arecent meta-analysis indicated that no single sleep vari-able reliably distinguished depressed patients fromhealthy controls or from subjects with other psychiatricdisorders, prompting some researchers to conclude thatclusters or combinations of sleep variables better describethe nature of sleep disturbance in depression [38].

Clinical Relevance of Sleep to Depression

Although there is some disagreement as to which spe-cific sleep EEG variables best characterize depressedpatients, the importance of sleep to depression is clear.Persistent sleep disturbance is associated with a signifi-cant risk of both relapse and recurrence [21, 39] and anincreased risk of suicide [40]. Sleep variables such asREM latency have also been shown to predict treatmentresponse and clinical course of illness in at least somestudies [41–46]. It has also recently been suggested thatthe nature of the sleep disturbance at the initial clinicalpresentation may be relevant to the choice of antidepres-sant medications and the likelihhod of experiencing treat-ment-emergent side-effects [47].

The most sensitive parameter for discrimination ofpatients with major depression from patients with otherpsychiatric disorders and healthy subjects is the density ofrapid eye movement during REM sleep (REM densityindex) which is substantially elevated only in depressedpatients [36, 38, 48].

The persistence of a depression-like sleep pattern infully remitted depressed patients suggests that the patternis a trait characteristic of the sleep measurements. How-ever, in the past, subjects have undergone investigationsonly after the onset of the disorder, and therefore the

altered sleep pattern may merely represent a biologicalscar. The answer to the question ‘trait or scar’ lies in theinvestigation of potential patients before the onset of thedisorder. The EEG sleep patterns of subjects without apersonal history but with a strong family history of anaffective disorder differed from those of the controls with-out any personal history of psychiatric disorders showinga depression-like sleep pattern with deminished slow-wave sleep and increased REM density. The follow-upwill determine whether the sleep pattern indeed repre-sents a trait marker indicating vulnerability [49]. A pre-liminary evaluation of the follow-up data corroboratedthe stability of the depression-like sleep pattern over4 years and found that 4 of the ‘high-risk probands’ haddeveloped a depression [50].

In addition to the changes in sleep architecture, pa-tients with major depression have profoundly altered pat-terns of nocturnal hormone secretion, possibly throughmechanisms that link regulation of sleep with neuroendo-crine activity [51–53]. Specifically an increased secretionof cortisol, an elevated cortisol nadir and a reduced timedifference between sleep onset and the morning rise ofplasma cortisol were found [54, 55]. The nocturnal growthhormone surge at sleep onset, which represents the majorportion of daily growth hormone secretion, was reportedto be blunted in patients with depression [56, 57]. Al-though abnormally high values of cortisol secretory activi-ty normalize after recovery from depression, growth hor-mone release and several characteristic disturbances ofthe sleep EEG may remain unchanged [56]. Preclinicalinvestigations and studies in young and elderly normalcontrols and in patients with depression demonstrate thatneuropeptides play a key role in sleep regulation. As anexample growth-hormone-releasing hormone is a com-mon stimulus of slow-wave sleep and growth hormonerelease, whereas corticotropin-releasing hormone exertsopposite effects. It is suggested that an imbalance of bothpeptides in favour of corticotropin-releasing hormonecontributes to changes in sleep endocrine activity duringdepression [51–53, 58].

Sleep Disturbance and Relapse

The association between sleep disturbance and depres-sion is well established. However, determining whichcomes first is a more difficult question to answer andrequires epidemiological research.

A recent longitudinal epidemiological study of youngadults estimated the association between sleep distur-

Depression and Sleep Neuropsychobiology 2000;42:107–119 111

bance and psychiatric disorders, cross-sectionally andprospectively [59]. When the history of other prior de-pressive symptoms (e.g. psychomotor retardation or agi-tation, suicidal ideation) was controlled for, prior in-somnia remained a significant predictor of subsequentmajor depression. It was concluded that complaints of 2weeks or more of insomnia nearly every night might bea useful marker of the subsequent onset of major de-pression.

A multicentre US epidemiological study examined thestrength of relationships between forms of depressivesymptoms over a 1-year period and the onset of majordepression. The results indicated a strong positive asso-ciation between an onset episode and diminished sexualdrive, feeling of worthlessness or excessive guilt and trou-ble concentrating or thinking. Sleep disturbance amongwomen and fatigue among men were also significantlyassociated with experiencing an onset of major depression[60].

A longitudinal study in an inner London communitywas undertaken to examine the prevalence of sleep distur-bance among the elderly [22]. Subjective sleep distur-bance was found to be common (over 30%) and was asso-ciated with being a woman, being unmarried, living alone,disability and current and future depression. The best pre-dictor of future depression in elderly people who were notdepressed was current sleep disturbance. This study there-fore indicates that sleep disorder is associated with pa-thology.

Sleep Disturbance and Suicide

The link between sleep disturbance and suicide is diffi-cult to establish, and the number of studies that have beencarried out is limited.

The issue of suicide proneness in depressed patients isnaturally of great importance. Results from the Weis-senau Depression Treatment and Research Group foundthat a ‘suicidal depressive syndrome’ can best be de-scribed by feelings of worthlessness, anxiety and depres-sive delusions, but also by more sleep disorders and morepast suicidal behaviour [61].

Few controlled prospective investigations into the pre-vention of suicidal behaviour have been carried out. In agroup of 58 high-risk patients with multiple episodes ofsuicidal behaviour, it was found that at 4 weeks reducedsleep and reduced appetite were highly significant predic-tors of further suicidal acts [62].

An epidemiological study of suicidal thoughts amongadolescents suggests that suicidal ideation was linked todrug use, non-specific somatic complaints (especiallytiredness, sleep difficulties, depression and feeling tense),a lack of self-esteem and dissatisfaction with family rela-tionships [63]. A further study looking at adolescent sui-cide attempters found that patients admitted to paediatricunits compared to other in-patient settings were moreoften described as manifesting depression and sleep diffi-culties [64].

It is thought that older white men are at a particularlyhigh risk for suicide. In this group, chronic sleep problemsalong with pain, degenerative illness and clinical depres-sion may be experienced [65]. The authors conclude thatholistic nursing care, including pain alleviation, depres-sion assessment and simple comfort measures, is impor-tant in suicide prevention in the elderly.

The studies described above all point to the impor-tance of sleep disturbances in both depressive relapse andsuicidal ideation. Complaints of sleep disturbance shouldbe taken seriously and might be a useful marker of subse-quent pathology.

Antidepressant Effects on Sleep in Depression

The majority of antidepressant medications suppressREM sleep and it has been suggested that the improve-ment in the symptoms of depression is related to REMsleep deprivation [66]. However, not all antidepressantsreduce REM sleep [67–69]. Moreover, antidepressanteffects are not restricted to REM sleep and also includealterations in sleep consolidation and sleep architecturethat may be relevant to both clinical response and theneed for concomitant or augmentative treatment (ta-ble 1).

Tricyclics

With the exception of iprindole, amineptine and trimi-pramine, tricyclic antidepressants (TCAs) are potentREM sleep suppressors, prolonging REM latency anddecreasing the total amount of REM sleep time [66, 70–74]. Clomipramine and desipramine are two of the mostpotent REM-suppressing TCAs, followed by imipramineand nortriptyline [75–79]. Clomipramine, desipramineand amitriptyline also significantly increase stage 1 sleepand decrease sleep efficiency over baseline levels [79].Since clomipramine has stronger serotonergic reuptake-

Stage 1

112 Neuropsychobiology 2000;42:107–119 Brunello et al.

Table 1. Effect of SSRIs, nefazodone and two TCAs on objective sleep quality

Paroxetine Fluoxetine Citalopram Fluvoxamine Sertraline Nefazodone Amitriptyline Imipramine

+ + ++++++ + ––– - +++

Stage 2 + + + +++ ++ +++

Stage 3 – – - - ++ - -Stage 4 – – - - - -REM density – - -REM sleep latency + + ++ + ++++++ + ++ - - ++++ +++

REM sleep - - - - –– - -–––– - - - - - + +++ ––––– ––– -

REM periods - - - - -Sleep efficiency - - ––– +++Sleep latency + + + -Sleep periodTotal time asleep - - - - – +Wake/TSP + + -–––– +Number of awakenings + + ++ ++++ – +

Each symbol represents 1 publication. +, + = Significant increase in normals (+) and patients (+); –, - = significant decrease in normals (-)and patients (–).

inhibiting effects than other TCAs, it is not surprising thatit has the most alerting effects on sleep [80]. Thus, clomi-pramine is probably best described as a serotonergic anti-depressant rather than a traditional TCA [76].

Interestingly, the clinical response to amitriptyline andclomipramine appears to be related to the degree of REMsleep suppression [81–83] in support of Vogel et al. [66].As mentioned above, the response to trimipramine is notrelated to a decrease in the amount of REM sleep [71–73].

Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) have alsobeen shown to suppress REM sleep in depressed patients,even eliminating REM sleep in some patients [80]. How-ever, the effects are delayed relative to TCAs but are asso-ciated with a substantial REM rebound upon withdrawal[84, 85]. This class of antidepressants also appears toreduce total sleep time and may decrease sleep efficiency[85].

By contrast, reversible MAOIs such as moclobemidemay actually enhance REM sleep, decreasing both REMlatency and the total amount of REM time [86]. Moclo-bemide has also been shown to improve sleep efficiency indepressed patients [86]. A more recent study indicateddecreased total sleep time, increased sleep latency, in-

creased wakefulness and prolonged REM latency after4 weeks of treatment with 450 mg/day moclobemide.However, only the effects on REM latency were statisti-cally significant [87]. Thus, it remains equivocal whethermoclobemide enhances or suppresses REM sleep.

Selective Serotonin Reuptake Inhibitors

Unlike the TCAs and older MAOIs, whose antidepres-sant properties were discovered by serendipity, selectiveserotonin reuptake inhibitors (SSRIs) were specificallydeveloped as antidepressants based on existing data thatserotonergic neurotransmission was compromised inthose with depression [88]. The majority of publishedstudies on SSRI effects on sleep have focused on fluoxe-tine.

FluoxetineAlthough Vogel et al. [66] suggested that the REM-sup-

pressing effects of fluoxetine were quite large, sleep stud-ies in depressed patients have not supported this view.Fluoxetine does appear to significantly decrease totalREM sleep time, but it is generally only a 3–5% reduction.The effects on REM latency, however, are substantial, vir-tually doubling the latency compared to baseline [89–92].

Depression and Sleep Neuropsychobiology 2000;42:107–119 113

All four of these studies have also reported significant-ly increased stage 1 sleep on fluoxetine. Two of the studies[89, 92] have shown increased wakefulness on this SSRIeither in the total number of awakenings or decreasedsleep efficiency, in support of an earlier study [93]. Alarge-scale double-blind comparison between two antide-pressants indicated that the 57 patients treated with fluox-etine showed significantly decreased sleep efficiency, anincrease in the number and percentage of awakenings, adecreased slow-wave sleep (stages 3 + 4), an increase inREM latency from 87 to 153 min and a 3.5% decrease intotal REM time, relative to baseline [94]. Moreover, thesleep effects of fluoxetine were similar in both respondersand non-responders. There was no evidence to suggestthat clinical response was related to the degree of REMsleep suppression, in contrast to some studies on TCAs[81–83]. A preliminary study suggests that the alertingeffects of fluoxetine may also be evident in depressed chil-dren and adolescents, although REM sleep measures werelargely unaffected by treatment [95].

A more recent study of the longer-term effects of fluox-etine reported significantly reduced sleep efficiency, de-creased stage 2 sleep, increased stage 1 sleep, prolongedREM latency and a 3.4% reduction in REM time at 10weeks of treatment in 36 acute-phase responders. After 30weeks of treatment, REM latency remained longer andthe percentage of stage 1 sleep was still elevated in com-parison to baseline. Thus, although there is some adapta-tion to fluoxetine, the alerting effects on sleep are stillpresent after 30 weeks of treatment. Post-discontinuationwas associated with some REM rebound, although themajority of sleep variables did not differ from baseline[96].

Several studies have also shown that fluoxetine is asso-ciated with significant eye movement and motor abnor-malities during sleep, particularly during lighter non-REM sleep stages. Its effect is postulated to derive from apotentiation of serotonergic neurons that inhibit thebrainstem which, in turn, inhibits saccadic eye move-ment, resulting in disinhibited release of saccades. Fluox-etine-reduced oculomotor abnormalities occur in 30–80%of adult patients [97–99] and may also be evident indepressed children and adolescents [95]. Although TCAshave also been reported to exacerbate periodic limbmovements during sleep [100], the incidence may be sub-stantially greater with SSRIs. Two additional reports indi-cate that fluoxetine or paroxetine exacerbate bruxism[101, 102]. Note that in all studies from Armitage’s groupreported above, depressed patients were excluded fromthe study if periodic limb movements or bruxism were

noted at baseline. Thus, it appears that fluoxetine (andperhaps other SSRIs) exacerbate pre-existing conditionsas well as inducing oculomotor abnormalities in manypatients.

ParoxetineIn comparison with other SSRIs and TCAs (fluoxetine,

fluvoxamine, sertraline, clomipramine, imipramine, ami-triptyline and desipramine), paroxetine demonstrates themost potent inhibition of serotonin reuptake in vitro.There is only little affinity for the ·-adrenergic, dopamin-ergic, histaminergic and histamine receptors. Unlike themetabolites of fluoxetine and sertraline, the metabolitesof paroxetine are pharmacologically inactive in vivo. EEGrecordings also show that paroxetine does not inducesedation [103].

In a placebo-controlled trial, 11 healthy volunteersreceived 30 mg paroxetine/day compared to placebo andnefazodone. Paroxetine reduced REM sleep and in-creased REM latency. Additionally paroxetine increasedawakenings and reduced actual sleep time and sleep effi-ciency [104].

In 16 depressed patients treated with 20 mg paroxetinefor 4 weeks, the number of awakenings and the number ofsleep stage shifts (a measure of consolidation within sleep)increased significantly from baseline [105]. The amountof REM sleep decreased by about 9%, whereas REMlatency more than doubled on treatment. Moreover, dis-continuation of paroxetine was associated with a signifi-cant REM rebound, well above baseline levels. This studyalso noted that REM sleep effects were comparable inboth responders and non-responders, indicating that theREM sleep changes were not related to clinical response,as reported previously with fluoxetine [94].

In a comparative clinical study in depressed out-patients, 61 received 20 mg of paroxetine for 6 weeks.HAMD scores improved in both drug groups with nointergroup differences. In terms of sleep disturbance pa-roxetine was significantly more effective than fluoxetinein week 4 of treatment but not at the end point [106].

A recent literature search did not identify additionalpublished studies of the effects of paroxetine on objectivesleep in depressed patients.

SertralineAs with paroxetine, there are few published studies on

objective sleep effects and only one report was found indepressed patients. Earlier pharmaco-EEG studies with100, 200 and 400 mg in normals had classified the drug asan activating antidepressant in the low dosage range with

114 Neuropsychobiology 2000;42:107–119 Brunello et al.

sedative effects after 200 and 400 mg [107]. In a 6-weekplacebo-controlled trial, 23 depressed patients showedboth prolonged sleep latency and decreased total REMtime, accompanied by decreased total sleep time in re-sponse to paroxetine. No other significant effects werenoted [108]. Beyond this, no further published reports indepressed patients were found.

Unpublished data from the University of Texas South-western Medical Center indicated increased wakefulnessand stage 1 sleep, prolonged REM latency and an approxi-mate 6% reduction in REM time in 3 depressed patientsafter 12–24 weeks of treatment, consistent with publishedreports on other SSRIs.

FluvoxamineFluvoxamine also appears to be alerting to sleep in

depressed patients. Kupfer et al. [77] reported longer sleeplatency, more awake time, increased stage 1 sleep, 3 timeslonger REM latency and dramatically reduced REM sleeptime (110%) after 3 weeks of treatment with fluvoxaminein 17 depressed patients. The alerting and REM sleepeffects were also fast acting, evident after only 1 or 2 dayson the drug. This study confirmed an earlier report of theimmediate effects of fluvoxamine on sleep in depressedpatients [109].

CitalopramAs compared to normal controls, patients treated with

citalopram showed EEG mapping changes characterizedby reduced total power, absolute and relative ·1 power,increased relative ß power, a fastened · and ß centroidand fastened centroid of the total power (IPEG). Thesechanges identify citalopram as an activating antidepres-sant.

In a single-blind and uncontrolled study, 16 patientswith major depression received placebo in the first weekand citalopram 20 mg in week 2, 40 mg in weeks 3–6 andplacebo in week 7. Compared to placebo/baseline, citalo-pram showed a significant decrease in REM sleep and asignificant lengthening of REM latency. No changes insleep continuity were found, but sleep stage 2 was signifi-cantly increased [110]. Again, clinical response to treat-ment was not significantly related to the changes in REMsleep.

Other Serotonergic Antidepressants

Trazodone and nefazodone, both of which affect sero-tonergic neurotransmission, are pharmacologically dis-tinct from SSRIs (and from each other) [68, 80]. Theireffects on sleep also differ dramatically from SSRIs.

TrazodoneIn an early report, Mouret et al. [111] showed no evi-

dence of decreased REM sleep time in 10 depressedpatients treated for 5 weeks with trazodone. Sleep assess-ments were conducted at baseline and again at the end oftreatment. Trazodone was associated with increased totalsleep time, enhanced slow-wave sleep, a decrease in noc-turnal awakenings and prolongation of REM latency. Anadditional study of 6 depressed patients with insomniaconfirmed this report and found shorter sleep latency,increased total sleep time, enhanced slow-wave sleep,slightly prolonged REM latency, but no effect on totalREM time over the course of 5 weeks of treatment. Due tothe sample size, however, the statistical significance ofthese effects was not evaluated [112].

In striking contrast, van Bemmel et al. [113] reportedno change in slow-wave sleep and 5–9% REM sleep sup-pression in 8 depressed patients, also over the course of5 weeks of treatment. This study, however, used substan-tially lower doses of trazodone than Scharf and Sachais[112] and nearly half the dose of the studies of Mouret etal. [111]. Although no laboratory assessment of sleep wasincluded, Jacobsen [114] reported improved subjectivesleep with the co-administration of trazodone in 20/21depressed patients who had MAOI-associated insomniaand 26/27 patients with insomnia but who were treatedwith other psychotropic medications. Nevertheless, trazo-done augmentation has been shown to improve subjectiveinsomnia in other studies [115, 116] and is widely pre-scribed as an adjunct treatment. Discrepancies in theeffect of trazodone on objective sleep data remain to beresolved. With regard to clinical impression, trazodone isviewed as a sedating antidepressant [114].

NefazodoneNefazodone may also be unique in that it does not

appear to suppress REM sleep either in healthy controlsor in depressed patients [68, 80, 117].

In an open-label preliminary study of the effect of 400–600 mg of nefazodone on sleep in 10 depressed patients,Armitage et al. [68] reported decreased awake and move-ment time and short duration arousals, increased stage 2sleep but noted minimal effects on REM sleep. Trends

Depression and Sleep Neuropsychobiology 2000;42:107–119 115

toward decreased stage 1 sleep were also found. Allpatients were treatment responders suggesting that theclinical efficacy of nefazodone was not tied to REM sleepsuppression.

These effects were confirmed in two subsequent dou-ble-blind studies comparing nefazodone and fluoxetine[89, 90]. Moreover, these data were part of a multicentretrial and subsequently included in a pooled analysis [94].The latter report included baseline to end point (lastobservation carried forward or at 8 weeks of treatment)sleep comparisons in 59 patients in the nefazodone arm ofthe protocol. Significantly greater improvement in clini-cian- and patient-rated sleep disturbance was found withnefazodone compared with fluoxetine. Nefazodone wasassociated with better sleep quality. Nefazodone signifi-cantly decreased the number of nocturnal awakenings,improved sleep efficiency, enhanced stage 2 sleep, de-creased slow-wave sleep, shortened REM latency andresulted in a small (2%), but significant, increase in REMtime. Restricting analysis only to treatment respondersproduced very similar results. Thus, the clinical efficacyof nefazodone does not appear to be tied to REM sleepchange [94].

It is important to point out that the effects of nefazo-done on sleep differ both from SSRIs and from trazodone[118]. SSRIs inhibit 5-HT reuptake whereas trazodone isprimarily a 5-HT2 antagonist characterized by ·1-adre-noreceptor-blocking activity which accounts for a sedat-ing effect. By contrast, nefazodone possesses both 5-HT2antagonism and inhibits synaptic uptake of 5-HT. Sincenefazodone does not produce the alerting effects of SSRIson sleep or the slow-wave sleep enhancement of trazo-done, it is likely that the combination of serotonergicantagonism and reuptake inhibition produces its uniqueprofile on sleep in depression [80]. Interestingly, it is com-mon clinical practice in the USA to prescribe trazodone asan augmentative therapy, particularly with SSRIs. Thiscombination of 5-HT reuptake inhibition and 5-HT2antagonism is very similar to the pharmacological charac-teristics of nefazodone. It remains to be seen, however,whether the combination of trazodone and SSRIs pro-duces similar sleep effects to those observed with nefazo-done.

Azapirones

Azapirones are agonists of serotonergic neurotransmis-sion at the 5-HT1A receptor and include buspirone, gepi-rone and ipsapirone. In a placebo-controlled study of 10-

or 20-mg doses in 18 depressed patients, Gillin et al. [119]demonstrated prolonged REM latency and a 5–8% reduc-tion in total REM time in response to ipsapirone. Sleepeffects were generally more pronounced in the higher dosecondition and included prolonged sleep onset. Moreover,the effects in depressed patients did not differ from thoseobserved in healthy controls. These findings contradicttwo early unpublished studies indicating that both ipsapi-rone and buspirone shorten REM latency in healthy con-trol subjects. Thus, the effects of azapirones on sleep inany population remain controversial.

Other Antidepressants

Bupropion is typically viewed as a dopaminergic anti-depressant, although recent preclinical evidence suggeststhat its effects are more selective for norepinephrine[120]. One study in depressed patients also indicates thatthis antidepressant may not suppress REM sleep [121]. In7 patients treated with bupropion for 16.4 B 4.1 weeks,REM latency was significantly shorter and REM sleeptime was increased by about 8%, compared to baseline. Ifthis study is replicated, then bupropion joins iprindole,trimipramine, nefazodone and perhaps moclobemide, asantidepressants with mechanisms of action that are notrelated to REM sleep suppression.

Mianserin is a tetracyclic antidepressant that acts as anantagonist on a number of monoamine receptors, includ-ing 5-HT2 [80]. Its primary effect on sleep in depression isa significant increase in REM latency with no apparentreduction in total REM time. It does not appear toinfluence slow-wave sleep but does improve sleep con-tinuity [121]. Mianserin, like trazodone, may also be amore sedating antidepressant.

Clinical Relevance of Antidepressant Effectson Sleep

One important issue is the clinical relevance of antide-pressant effects on sleep. As noted above, the majority ofantidepressants, even those that are alerting, are associat-ed with significant improvement in subjective sleep. Itraises the issue whether patients notice the disturbance inobjective sleep measures and whether it impacts on treat-ment or clinical course. Increases in motor activation andperiodic limb movements associated with SSRIs are likelyto contribute to increased wakefulness and the alertingeffects of fluoxetine. In one study [97], it was noted that

116 Neuropsychobiology 2000;42:107–119 Brunello et al.

the majority of events were intrusive and associated withEEG arousal. Nevertheless, only 12% of men and 38% ofwomen reported reduced sleep quality on fluoxetine.When specifically queried with regard to the number andduration of subjective awakenings, however, the majorityof patients did report an increase on treatment, comparedto baseline [47]. Thus, it appears that there is a better cor-respondence between objective and subjective sleep datawhen specific, concrete questions are posed. Sleep qualityand depth may be less tangible concepts and have beenshown to be poor correlates of objective sleep data, evenin healthy non-depressed adults [122]. Nevertheless,many patients, particularly men, do not appear to be sen-sitive to the alerting effects of SSRIs.

Improvement in sleep may also be associated withboth increased compliance and reduced economic costs oftreatment [94]. Recent data from the Texas and Califor-nia Medicare and Medicaid studies indicate that the inci-dence of co-prescription of hypnotic or anxiolytic agentsis significantly higher with SSRIs than with less alertingantidepressants such as nefazodone [123]. It is temptingto speculate that improvement in sleep is related to adecreased need for augmentative therapies. From an eco-

nomic viewpoint, however, reducing the need for aug-mentative or concomitant therapies dramatically reducesthe cost of antidepressant treatment [123].

Concluding Remarks

Although it is known that persistent sleep disturbanceis associated with an increased risk for relapse, recurrenceand suicide [21, 39, 40], it remains to be seen whetherimprovement or worsening of objective sleep measures isdirectly associated with the clinical course.

Finally, the nature of the dominant sleep complaint atinitial presentation may be useful in determining treat-ment choices. In those patients best characterized ashypersomniac, alerting antidepressants may produce amore ‘normal’ sleep architecture. Depressed women withinsomnia may do better in the long run with a less alertingantidepressant, since they are more likely to experienceobjective sleep disturbance. These women may also bemore likely to require augmentative therapies when pre-scribed alerting antidepressants. This is speculative, how-ever, and awaits confirmation.

References

1 Borbely AA: Processes underlying sleep regula-tion. Horm Res 1998;49:114–117.

2 Dijk DJ, Czeisler CA: Contribution of the cir-cadian pacemaker and the sleep homeostat tosleep propensity, sleep structure, electroence-phalographic slow waves, and sleep spindle ac-tivity in humans. J Neurosci 1995;15:3526–3538.

3 Shapiro C, Macfarlane J, Hussain M: Conquer-ing Insomnia. Hamilton, Empowering Press,1994.

4 Hochstrasser B: Epidemiology of somnipa-thies. Ther Umsch 1993;50:679–683.

5 Kuppermann M, Lubeck DP, Mazonson PD,Patrick DL, Stewart AL, Buesching DP, FiferSK: Sleep problems and their correlates in aworking population. J Gen Intern Med 1995;10:25–32.

6 National Sleep Foundation/Gallup Organiza-tion: Sleep in America. Princeton, NationalSleep Foundation, 1995.

7 Hatoum HT, Kania CM, Kong SX, Wong JM,Mendelson WB: Prevalence of insomnia. A sur-vey of the enrollees at five managed care orga-nizations. Am J Man Care 1998;4:79–86.

8 Costa e Silva JA, Chase M, Sartorius N, RothT: Special report from a symposium held by theWorld Health Organization and the WorldFederation of Sleep Research Societies: Anoverview of insomnias and related disorders –Recognition, epidemiology, and rational man-agement. Sleep 1996;19:412–416.

9 Campbell S, Dawson D, Anderson M: Allevia-tion of sleep maintenance insomnia with timedexposure to bright light. J Am Geriatr Soc1993;41:829–836.

10 World Health Organization: The ICD-10 Clas-sification of Mental and Behavioural Disor-ders: Clinical Descriptions and DiagnosticGuidelines. Geveva, WHO, 1992.

11 Ancoli-Israel S, Roth T: Characteristics of in-somnia in the United States: Results of the1991 National Sleep Foundation Survey. I.Sleep 1999;22:S347–S353.

12 Diagnostic Classification Steering Committee,Thorpy MJ: International Classification ofSleep Disorders: Diagnostic and coding man-ual. Rochester, American Sleep Disorders As-sociation, 1990, pp 28–35.

13 American Psychiatric Association: DSM-IV:Diagnostic and Statistical Manual of MentalDisorders, ed 4. Washington, APA, 1994.

14 Chilcott LA, Shapiro CM: The socioeconomicimpact of insomnia – An overview. Pharma-coeconomics 1996;10:1–14.

15 Leger D, Paillard M: Sleep and accidents. Con-frontations Psychiatr 1997;38:283–306.

16 Kales JD, Kales A, Bixler EO, Soldatos CR,Cardieux RJ, Kashurba GJ, Vela-Bueno A:Biopsychobehavioral correlates of insomnia.V. Clinical characteristics and behavioral cor-relates. Am J Psychiatry 1984;141:1371–1376.

17 Weyerer S, Dilling H: Prevalence and treat-ment of insomnia in the community: Resultsfrom the Upper Bavarian Field Study. Sleep1991;14:392–398.

18 Lavie P: Sleep habits and sleep disturbances inindustrial workers in Israel: Main findings andsome characteristics of workers complaining ofexcessive daytime sleepiness. Sleep 1981;4:147–158.

19 Bixler ET, Kales A, Soldatos C, Kales JD, Hea-ley S: Prevalence of sleep disorders in the LosAngeles metropolitan area. Am J Psychiatry1979;136:1257–1262.

20 Hatoum HT, Kong SX, Kania CM, Wong JM,Mendelson WB: Insomnia, health-related qual-ity of life and health care resource consumption– A study of managed care organization enrol-lees. Pharmacoeconomics 1998;14:629–637.

21 Ford DE, Kamerow DB: Epidemiologic studyof sleep disturbances and psychiatric disorders:An opportunity for prevention? JAMA 1989;262:1479–1484.

Depression and Sleep Neuropsychobiology 2000;42:107–119 117

22 Livingston G, Blizard B, Mann A: Does sleepdisturbance predict depression in elderly peo-ple? A study in inner London. Br J Gen Pract1993;43:445–448.

23 Leigh JP: Employee and job attributes as pre-dictors of absenteeism in a national sample ofworkers: The importance of health and danger-ous working conditions. Soc Sci Med 1991;33:127–137.

24 Glazner LK: Shiftwork: Its effect on workers.AAOHN J 1991;39:416–421.

25 Mendelson WB, Garnett D, Linnoila M: Doinsomniacs have impaired daytime function-ing? Biol Psychiatry 1984;19:1261–1264.

26 Johnson LC, Spinweber CL: Good and poorsleepers differ in navy performance. Milit Med1983;148:727–731.

27 Stoller MK: Economic effects of insomnia. ClinTher 1994;16:873–897.

28 Leger D, Hibon A, Proteau J: Sleep apnoea andwork. Arch Mal Prof Méd Travail Séc Soc1992;53:27–29.

29 Gillberg M, Akerstedt T: Sleep loss and perfor-mance: No ‘safe’ duration of a monotonoustask. Physiol Behav 1998;64:599–604.

30 Aldrich MS: Automobile accidents in patientswith sleep disorders. Sleep 1989;12:487–494.

31 Balter MB, Uhlenhuth EH, Kupfer DJ, De-ment WC, Gelenberg AJ, Jonas JM, Nino-Mur-cia G, Mendelson WB: New epidemiologicfindings about insomnia and its treatment. JClin Psychiatry 1992;53:34–42.

32 Leger D: The cost of sleep-related accidents: Areport for the National Commission on SleepDisorders Research. Sleep 1994;17:84–93.

33 Armitage R: Microarchitectural findings insleep EEG in depression: Diagnostic implica-tions. Biol Psychiatry 1995;37:72–84.

34 Berger M, Riemann D: REM sleep in depres-sion – An overview. J Sleep Res 1993;2:211–223.

35 Thase ME: Is there a biological boundary topsychotherapy response in depression? Psy-chiatry Grand Rounds Presentation at the Uni-versity of Texas Southwestern Medical Center,Dallas, March, 1998.

36 Reynolds CF, Kupfer DJ: Sleep research inaffective illness: State of the art circa 1987.Sleep 1987;10:199–215.

37 Armitage R, Hoffmann R: Sleep electrophysio-logy of major depressive disorders. Curr RevMood Anxiety Disord 1997;1:139–151.

38 Benca RM, Obermeyer WH, Thisted RA, Gil-lin JC: Sleep and psychiatric disorders. A meta-analysis. Arch Gen Psychiatry 1992;49:651–668.

39 Fawcett J, Scheftner WA, Fogg L, Clark DC,Young MA, Hedeker D, Gibbons R: Time-related predictors of suicide in major affectivedisorder. Am J Psychiatry 1990;147:1189–1194.

40 Wingard DL, Berkman LF: Mortality risk asso-ciated with sleeping patterns among adults.Sleep 1983;6:102–107.

41 Rush AJ, Giles DE, Roffwarg HP, Parker CR:Sleep EEG and dexamethasone suppressiontest findings in outpatients with unipolar majordepressive disorders. Biol Psychiatry 1982;17:327–340.

42 Rush AJ, Erman MK, Giles DE, Schlesser MA,Carpenter G, Vasavada N, Roffwarg HP: Poly-somnographic findings in recently drug-freeand clinically remitted depressed patients.Arch Gen Psychiatry 1986;43:878–884.

43 Frank E, Kupfer DJ, Hamer T, GrochocinskiVJ, McEachran AB: Maintenance treatmentand psychobiologic correlates of endogenoussubtypes. J Affect Disord 1992;25:181–190.

44 Thase ME, Reynolds CF III, Frank E, JenningsJR, Nofzinger E, Fasiczka AL, Garamoni G,Kupfer DJ: Polysomnographic studies of un-medicated depressed men before and after cog-nitive behavioral therapy. Am J Psychiatry1994;151:1615–1622.

45 Kupfer DJ, Frank E, McEachran AB, Grocho-cinski VJ: Delta sleep ratio: A biological corre-late of early recurrence in unipolar affectivedisorder. Arch Gen Psychiatry 1990;47:1100–1105.

46 Buysse DJ, Kupfer DJ, Frank E, Monk TH,Ritenour A: Do electroencephalographic sleepstudies predict recurrence in depressed patientssuccessfully treated with psychotherapy? De-pression 1994;2:105–108.

47 Armitage R, Sussman N: Effects of fluoxetineon sleep architecture and quality of sleep indepressed patients. Primary Psychiatry 1997;4:34–37.

48 Lauer CJ, Riemann D, Wiegand M, Berger M:From early to late adulthood: Changes in EEGsleep for depressed patients and healthy volun-teers. Biol Psychiatry 1991;29:979.

49 Lauer CJ, Schreiber W, Holsboer F, Krieg JC:In quest of identifying vulnerability markersfor psychiatric disorders by all-night polysom-nography. Arch Gen Psychiatry 1995;52:145–153.

50 Lauer CJ, Schreiber W, Modell S, Huber J,Holsboer F, Krieg J-C: Sleep changes specificfor major depression are a vulnerability markerfor affective disorders. J Sleep Res 1996;5:120.

51 Ehlers CL, Kupfer DJ: Hypothalamic peptidemodulation of EEG sleep in depression: A fur-ther application of the 2-process hypothesis.Biol Psychiatry 1987;22:513–517.

52 Steiger A, Von Bardeleben U, Guldner J, LauerC, Rothe B, Holsboer F: The sleep EEG andnocturnal hormonal secretion – Studies onchanges during the course of depression and oneffects of CNS-active drugs. Prog Neuropsy-chopharmacol Biol Psychiatry 1993;17:125–137.

53 Seifritz E, Müller MJ, Trachsel L, Lauer CJ,Hemmeter U, Hatzinger M, Moore P, Hols-boer-Trachsler E: Revisiting the Ehlers andKupfer hypothesis: The growth hormone corti-sol secretion ratio during sleep is correlatedwith electroencephalographic slow wave activi-ty in normal volunteers. Biol Psychiatry 1996;39:139–142.

54 Jarrett DB, Coble PA, Kupfer DJ: Reducedcortisol latency in depressive illness. Arch GenPsychiatry 1983;40:506–511.

55 Linkowski P, Mendlewicz J, LeClercq R, Bras-seur M, Hubain P, Goldstein J, Copinschi G,van Cauter E: The twenty-four-hour profiles ofACTH and cortisol in major depressive illness.J Clin Endocrinol Metab 1985;61:429–438.

56 Steiger A, von Bardeleben U, Herth T, Hols-boer F: Sleep EEG and nocturnal secretion ofcortisol and growth hormone in male patientswith endogenous depression before treatmentand after recovery. J Affec Disord 1989;16:189–195.

57 Jarrett DB, Kupfer DJ, Miewald JM, Grocho-cinski VJ, Franz B: Sleep-related growth hor-mone secretion is persistently suppressed inwomen with recurrent depression: A prelimi-nary longitudinal analysis. J Psychiatr Res1994;28:211–223.

58 Steiger A, Holsboer F: Neuropeptides and hu-man sleep. Sleep 1997;20:1038–1052.

59 Breslau N, Roth T, Rosenthal L, Andreski P:Sleep disturbance and psychiatric disorders: Alongitudinal epidemiological study of youngadults. Biol Psychiatry 1996;39:411–418.

60 Dryman A, Eaton W: Affective symptoms asso-ciated with the onset of major depression in thecommunity: Findings from the US NationalInstitute of Mental Health EpidemiologicalCatchment Area Program. Acta PsychiatrScand 1991;84:1–5.

61 Wolfersdorf M, Steiner B, Keller F, HautzingerM, Hole G: Depression and suicide: Is there adifference between suicidal and non-suicidaldepressed in-patients? Eur J Psychiatry 1990;4:235–252.

62 Montgomery S, Roy D, Montgomery D: Theprevention of recurrent suicidal acts. Br J ClinPharmacol 1983;15:183–188.

63 Choquet M, Kovess V, Poutignat N: Suicidalthoughts among adolescents: An interculturalapproach. Adolescence 1993;28:649–659.

64 Gasquet I, Choquet M: Hospitalization in apediatric ward of adolescent suicide attemptersadmitted to general hospitals. J Adolesc Health1994;15:416–422.

65 Mellick E, Buckwalter K, Stolley J: Suicideamong elderly white men: Development of aprofile. J Psychosoc Nurs Ment Health Serv1992;30:29–34.

66 Vogel GW, Buffenstein A, Minter K, Hennes-sey A: Drug effects on REM sleep and onendogenous depression. Neurosci BiobehavRev 1990;14:49–63.

67 Armitage R: Effects of antidepressant treat-ment on sleep EEG in depression. J Psycho-pharmacol 1996;10:22–25.

68 Armitage R, Rush AJ, Rivedi M, Cain J, Roff-warg HP: The effects of nefazodone on sleeparchitecture in depression. Neuropsychophar-macology 1994;10:123–127.

69 Vogel G, Cohen J, Mullis D, Kensler T, KaplitaS: Nefazodone and REM sleep: How do antide-pressant drugs decrease REM sleep? Sleep1998;21:70–77.

118 Neuropsychobiology 2000;42:107–119 Brunello et al.

70 Feuillade P, Pringuey D, Belugou JL, Robert P,Darcourt G: Trimipramine: Acute and lastingeffects on sleep in healthy and major depressivesubjects. J Affect Disord 1992;24:135–145.

71 Sonntag A, Rothe B, Guldner J, Yassouridis A,Hoslboer F, Steiger A: Trimipramine and imi-pramine exert different effects on the sleepEEG and on nocturnal hormone secretion dur-ing treatment of major depression. Depression1996;4:1–13.

72 Ware JC, Brown FW, Moorad PJJ, Pittard JT,Cobert B: Effects on sleep: A double-blindstudy comparing trimipramine to imipraminein depressed insomniac patients. Sleep 1989;12:537–549.

73 Wiegand M, Berger M, Zulley J, von ZerssenD: The effect of trimipramine on sleep inpatients with major depressive disorder. Phar-macopsychiatry 1986;19:198–199.

74 Hartmann E, Cravens J: The effects of longterm administration of psychotropic drugs onhuman sleep. 3. The effects of amitriptyline.Psychopharmacologia 1973;33:185–202.

75 Dunleavy DL, Brezinova V, Oswald I, Mac-Lean AW, Tinker M: Changes during weeks ineffects of tricyclic drugs on the human sleepingbrain. Br J Psychiatry 1972;120:663–672.

76 Kupfer DJ, Ehlers CL, Pollock BG, Nathan S,Perel JM: Clomipramine and EEG sleep indepression. Psychiatry Res 1989;30:165–180.

77 Kupfer DJ, Perel JM, Pollock BG, Nathan RS,Grochocinski VJ, Wilson MJ, McEachran AB:Fluvoxamine versus desipramine: Compara-tive polysomnographic effects. Psychiatry1991;29:23–40.

78 Shipley JE, Kupfer DJ, Dealy RS, Griffin SJ,Coble PA, McEachran AB, Grochocinski VJ:Differential effects of amitriptyline and of zi-melidine on the sleep electroencephalogram ofdepressed patients. Clin Pharmacol Ther 1984;36:251–259.

79 Shipley JE, Kupfer DJ, Griffin SJ, Dealy RS,Coble PA, McEachran AB, Grochocinski VJ,Ulrich R, Perel JM: Comparison of effects ofdesipramine and amitriptyline on EEG sleep ofdepressed patients. Psychopharmacology 1985;85:14–22.

80 Sharpley AL, Cowen PJ: Effect of pharmaco-logic treatments on the sleep of depressed pa-tients. Biol Psychiatry 1995;37:85–98.

81 Kupfer DJ, Foster FG, Reich L, ThompsonKS, Weiss R: EEG sleep changes in REM sleepand clinical depression. Am J Psychiatry 1976;133:622–626.

82 Gillin JC, Wyatt RF, Fram D, Snyder F: Therelationship between changes in REM sleepand clinical improvement in depressed patientstreated with amitriptyline. Psychopharmacolo-gy 1978;59:267–272.

83 Hochli D, Riemann D, Zulley J, Berger M: Ini-tial REM sleep suppression by clomipramine:A prognostic tool for treatment response inpatients with a major depressive disorder. BiolPsychiatry 1986;21:1217–1220.

84 Dunleavy DLF, Oswald I: Phenelzine, moodresponse and sleep. Arch Gen Psychiatry 1973;28:353–356.

85 Kupfer DJ, Bowers MB: REM sleep and mono-amine oxidase inhibition. Psychopharmacolog-ia 1972;27:183–190.

86 Monti JM: Effect of a reversible monoamineoxidase-A inhibitor (moclobemide) on sleep ofdepressed patients. Br J Psychiatry 1989;155:61–65.

87 Minot R, Luthringer R, Macher JP: Effect ofmoclobemide on the psychophysiology ofsleep/wake cycles: A neuroelectrophysiologicalstudy of depressed patients administered withmoclobemide. Int Clin Psychopharmacol 1993;7:181–189.

88 Burke MJ, Preskorn SH: Short-term treatmentof mood disorders with standard antidepres-sants; in Bloom FE, Kupfer DJ (eds): Psycho-pharmacology: The Fourth Generation of Pro-gress. New York, Raven Press, 1995, pp 1053–1065.

89 Armitage R, Yonkers K, Cole D, Rush AJ: Amulticenter, double-blind comparison of the ef-fects of nefazodone and fluoxetine on sleeparchitecture and quality of sleep in depressedoutpatients. J Clin Psychopharmacol 1997;17:161–168.

90 Gillin JC, Rapaport M, Erman MK, WinokurA, Albala BJ: A comparison of nefazodone andfluoxetine on mood and on objective, subjec-tive, and clinician-rated measures of sleep indepressed patients: A double-blind, 8-weekclinical trial. J Clin Psychiatry 1997;58:185–192.

91 Hendrickse WA, Roffwarg HP, GrannemannBD, Orsulak PJ, Armitage R, Cain JW, Batta-glia J, Debus JR, Rush AJ: The effects of fluox-etine on the polysomnogram of depressed out-patients: A pilot study. Neuropsychopharma-cology 1994;10:85–91.

92 Keck PE Jr, Hudson JI, Dorsey CM, CampbellPI: Effect of fluoxetine on sleep. Biol Psychia-try 1991;29:618–619.

93 Kerkhofs M, Rielaert C, de Maertelaer V, Lin-kowski P, Czarka M, Mendlewicz J: Fluoxetinein major depression: Efficacy, safety and effectson sleep polygraphic variables. Int Clin Psycho-pharmacol 1990;5:253–260.

94 Rush AJ, Armitage R, Gillin JC, Yonkers KA,Winokur A, Moldofsky H, Vogel GW, KaplitaSB, Fleming JB, Montplaisir J, Erman MK,Albala BJ, McQuade RD: Comparative effectsof nefazodone and fluoxetine on sleep in outpa-tients with major depressive disorder. Biol Psy-chiatry 1998;44:3–14.

95 Armitage R, Emslie G, Rintelmann J: Theeffect of fluoxetine on sleep EEG in childhooddepression: A preliminary report. Neuropsy-chopharmacology 1997;17:241–245.

96 Trivedi MH, Rush AJ, Armitage R, GullionCM, Grannemann BD, Orsulak PJ, RoffwargHP: Effects of fluoxetine on the polysomno-gram in outpatients with major depression.Neuropsychopharmacology 1999;20:447–459.

97 Armitage R, Trivedi M, Rush AJ: Fluoxetineand oculomotor activity during sleep in de-pressed patients. Neuropsychopharmacology1995;12:159–165.

98 Dorsey CM, Lukas SE, Cunningham S:Fluoxetine-induced sleep disturbance in de-pressed patients. Neuropsychopharmacology1996;14:437–442.

99 Schenck CH, Mahowald MW, Kim SW,O’Connor KA, Hurwitz TD: Prominent eyemovements during NREM sleep and REMsleep behavior disorder associated with fluox-etine treatment of depression and obsessive-compulsive disorder. Sleep 1992;15:226–235.

100 Roth T: Diagnosis and treatment of sleep dis-orders in the depressed elderly (abstract). AmPsychiatr Assoc 150th Annu Meet Ind SuppSymp 23 – Depression in the Elderly, SanDiego, 1997.

101 Ellison JM, Stanziani P: SSRI-associated noc-turnal bruxism in four patients. J Clin Psy-chiatry 1993;54:432–434.

102 Romanelli F, Adler DA, Bungay KM: Possi-ble paroxetine-induced bruxism. Ann Phar-macother 1996;30:1246–1248.

103 Tulloch IF, Johnson AM: Pharmacologic pro-file of paroxetine, a new selective serotoninreuptake inhibitor. J Clin Psychiatry 1992;53:7–12.

104 Sharpley AL, Williamson DJ, AttenburrowMEJ, Pearson G, Sargent P, Cowen PJ: Theeffects of paroxetine and nefazodone on sleep:A placebo controlled trial. Psychopharma-cology 1996;126:50–54.

105 Staner L, Kerkhofs M, Detroux D, Leyman S,Linkowski P, Mendlewicz J: Acute, sub-chronic and withdrawal sleep EEG changesduring treatment with paroxetine and ami-triptyline: A double-blind randomized trial inmajor depression. Sleep 1995;18:470–477.

106 Ontiveros A, Garcia-Barriga C: A doubleblind comparative study of paroxetine andfluoxetine in out-patients with depression. BrJ Clin Res 1997;8:23–32.

107 Saletu B, Grünberger J, Linzmayer L, Ande-rer P: On central effects of serotonin reuptakeinhibitors: Quantitative EEG and psychomet-ric studies with sertraline and zimelidine. JNeural Transm 1986;67:241–266.

108 Winokur A, Sewitch DE, Bimaur IV, PhilipsJL: Effects of sertraline on sleep architecturein patients with major depression. Clin Neu-ropharmacol 1992;(suppl 1):84B.

109 Berger M, Emrich HM, Lund D, Riemann D,Lauer C: Sleep-EEG variables as course crite-ria and predictors of antidepressant therapywith fluvoxamine/oxaprotiline. Adv Pharma-cother 1986;2:110–120.

110 van Bemmel AL, van den Hoofdakker RH,Beersma DGM, Bouhuys AL: Changes insleep polygraphic variables and clinical statein depressed patients during treatment withcitalopram. Psychopharmacology 1993;113:225–230.

111 Mouret J, Lemoine P, Minuit MP, BenkelfatC, Renardet M: Effects of trazodone on thesleep of depressed subjects – A polysomno-graphic study. Psychopharmacology 1988;95:S37–S43.

Depression and Sleep Neuropsychobiology 2000;42:107–119 119

112 Scharf MB, Sachais BA: Sleep laboratoryevaluation of the effects and efficacy of trazo-done in depressed insomniac patients. J ClinPsychiatry 1990;51:13–17.

113 van Bemmel AL, Havermans RB, van DiestR: Effects of trazodone on EEG sleep andclinical state in major depression. Psycho-pharmacology 1992;107:569–574.

114 Jacobsen FM: Low-dose trazodone as a hyp-notic in patients treated with MAOIs and oth-er psychotropics: A pilot study. J Clin Psy-chiatry 1990;51:298–302.

115 Nierenberg AA, Keck PE Jr: Management ofmonoamine oxidase inhibitor-associated in-somnia with trazodone. J Clin Psychophar-macol 1989;9:42–45.

116 Zimmer B, Daly F, Benjamin L: More oncombination antidepressant therapy. ArchGen Psychiatry 1984;41:527–528.

117 Sharpley AL, Walsh AES, Cowen PJ: Nefazo-done – a novel antidepressant – may increaseREM sleep. Biol Psychiatry 1992;31:1070–1073.

118 Ware JC, Rose FV, McBrayer RH: The acuteeffects of nefazodone, trazodone and buspi-rone on sleep and sleep-related penile tumes-cence in normal subjects. Sleep 1994;17:544–550.

119 Gillin JC, Sohn J-W, Stahl SM, Lardon M,Kelsoe J, Rapaport M, Ruiz C, Golshan S:Ipsapirone, a 5-HT1A agonist, suppressesREM sleep equally in unmedicated depressedpatients and normal controls. Neuropsycho-pharmacology 1996;15:109–115.

120 Cooper BR, Wang CM, Cox RF, Norton R,Shea V, Ferris RM: Evidence that the acutebehavioral and electrophysiological effects ofbupropion (Wellbutrin) are mediated by anoradrenergic mechanism. Neuropsycho-pharmacology 1994;11:133–141.

121 Mendlewicz J, Dunbar GC, Hoffman G:Changes in sleep EEG architecture during thetreatment of depressed patients with mian-serin. Acta Psychiatr Scand 1985;72:26–29.

122 Armitage R, Trivedi M, Hoffmann R, RushAJ: Relationship between objective and sub-jective sleep measures in depressed patientsand healthy controls. Depression Anxiety1997;5:97–102.

123 Lian J: Nefazodone treatment of depressionrequires less use of concomitant anxiolyt-ic and sedative/hypnotic drugs. Annu MeetAm Psychiatr Assoc San Diego, 1997, APANew Research program and Abstracts (volNR397), p 175.