Sleep and Depression - Results From Psychobiological Studies: An Overview

Biological Psychology 57 (2001) 67 – 103
www.elsevier.com/locate/biopsycho
Sleep and depression — results from

psychobiological studies: an overview
Dieter Riemann *, Mathias Berger, Ulrich Voderholzer
Department of Psychiatry and Psychotherapy, Uni6ersity hospital of Freiburg, Hauptstrasse 5,
79104 Freiburg, Germany
Abstract
Disturbances of sleep are typical for most depressed patients and belong to the core
symptoms of the disorder. Polysomnographic sleep research has demonstrated that besides
disturbances of sleep continuity, in depression sleep is characterized by a reduction of slow
wave sleep and a disinhibition of REM sleep, with a shortening of REM latency, a
prolongation of the first REM period and increased REM density. These findings have
stimulated many sleep studies in depressive patients and patients with other psychiatric
disorders. In the meantime, several theoretical models, originating from basic research, have
been developed to explain sleep abnormalities of depression, like the two-process-model of
sleep and sleep regulation, the GRF/CRF imbalance model and the reciprocal interaction
model of non-REM and REM sleep regulation. Interestingly, most of the effective antide-
pressant agents suppress REM sleep. Furthermore, manipulations of the sleep– wake cycle,
like sleep deprivation or a phase advance of the sleep period, alleviate depressive symptoms.
These data indicate a strong bi-directional relationship between sleep, sleep alterations and
depression. © 2001 Elsevier Science B.V. All rights reserved.
Keywords: Antidepressants; Depression; REM sleep; Sleep; Sleep deprivation
1. Sleep disturbances and depression
The relationship between depression and insomniac symptoms is not a one-way

street as it was formerly assumed. Recent epidemiological studies strongly suggest
that not only is insomnia a typical symptom of depression but, vice versa, insomnia
* Corresponding author. Tel.: +49-761-2706919; fax: +49-761-2706619.

E-mail address: dieter – riemann@psyallg.ukl.uni-freiburg.de (D. Riemann).
0301-0511/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
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68 D. Riemann et al. / Biological Psychology 57 (2001) 67–103
may be an independent risk factor for depression in the long run. The relation
between insomnia and depression constitutes a situation with evidence supporting a
strong bi-directional linkage.
More than 90% of depressed patients complain about impairments of sleep
quality (e.g. Mendelson et al., 1977). Typically, patients suffer from difficulties in
falling asleep, frequent nocturnal awakenings, and early morning awakening.
Whereas sleep onset problems and frequent awakenings accompany almost any
kind of insomnia, early morning awakening was considered to be specific for
endogenous but not for neurotic depression (Kiloh and Garside, 1963). This
hypothesis was, however, not confirmed (Costello and Selby, 1965; Hinton 1963).
A complaint of hypersomnia is less typical for depression (Garvey et al., 1984;
Hawkins et al., 1985; Shimizu et al., 1979). In contrast to insomnia, the complaint
of hypersomnia was confirmed to be related specifically to certain subtypes of
depression, i.e. depressive episodes of bipolar patients (Detre et al., 1972; Michaelis
and Hofmann, 1973; Thase et al., 1989).
Depression, thus, is considered to be one of the most frequent and prominent
causes of insomnia. Vollrath et al. (1989) published data from a long-term
epidemiological study in Switzerland and reported that 25% of the patients com-
plaining of chronic insomnia suffered from depression. Our epidemiological data
from patients of general practitioners showed that the likelihood of having depres-
sion was increased fourfold in patients with severe insomnia (Hohagen et al., 1993a;
Schramm et al., 1995). Similar results were obtained by Breslau et al. (1996), who
reported a relative risk of 4.0 for new onset of major depression in persons with a
history of insomnia at baseline. Several other publications (Brabbins et al., 1993;
Chang et al., 1997; Foley et al., 1999; Ford and Kamerow, 1989; Livingston et al.,
1993; Pfaffenberger et al., 1994), all based on epidemiological investigations, point
out that insomnia in a given individual might be a prominent risk factor for the
subsequent development of depression.
These results can be interpreted in different ways. One the one hand, insomnia
may be considered a prodromal symptom or predictor of a depressive disorder
developing later. This view is supported by an investigation of Perlis et al. (1997),
who described self-reported sleep disturbance as a prodromal symptom in the 5
weeks prior to the recurrence of a depressive episode. Other studies (Brown et al.,
1996; Frank et al., 1997) stressed the importance of stable sleep–wake rhythms and
proper sleep hygiene to prevent relapses in remitted bipolar depressed patients. It is
also well known that sleep loss is an important risk factor for the development of
mania in patients with bipolar disorders (Barbini et al., 1996; Wehr, 1991). On the
other hand, chronic insomnia itself may become relevant as one factor that triggers
depression. Insomniac patients may experience helplessness and despair as a result
of fruitless efforts to combat their sleeplessness. The experience that all efforts to
initiate sleep are unsuccessful may lead to ‘learned helplessness’ which is considered
to be a valid model for the induction of depression. Ford and Kamerow (1989) and
others (Eaton et al., 1995; Weissman et al., 1997), therefore, suggested that
adequate early treatment of sleep disorders might constitute an opportunity for the
prevention of psychiatric disorders (see also Riemann and Berger, 1998).
D. Riemann et al. / Biological Psychology 57 (2001) 67–103 69
Gillin (1998) expanded this view and suggested that subjective insomnia might be
a risk factor not only for depression, but also for anxiety and addictive disorders.
He stressed that further epidemiological research is necessary to show that insomnia
is an independent predictor for later psychiatric disorders and not simply a
subclinical or subsyndromal prodrome of a psychiatric disorder, especially depres-
sion. Future epidemiological research is needed to clarify this issue. Longitudinal
designs, for example, might be used to evaluate the hypothesis that early and
adequate insomnia treatment lead to a reduced depression risk.
2. Polysomnographic studies in depression
Systematic sleep EEG investigations in unmedicated depressed patients using

formalized diagnostic criteria were initiated by the group of David Kupfer (Kupfer,
1976; Kupfer and Foster, 1972). Besides sleep continuity disturbances, sleep in
depression was characterized by a reduction of slow wave sleep (SWS) and by a
shortening of the interval between sleep onset and the occurrence of the first REM
period (i.e. REM latency). Further abnormal features included an increased amount
of REM sleep, a prolongation of the first REM period, and an increased number
of eye movements during REM periods (i.e. REM density; see Fig. 1). Initially,
reduced REM latency was postulated to be a biological marker for primary
depression (Kupfer, 1976). Further research on this issue did not confirm this
assumption; in the meantime disinhibition of REM sleep has also been observed in
non-melancholic and secondary depression and in other psychopathological condi-
tions (see Benca et al., 1992 for review and Section 2.1).
2.1. Subtypes of depression and sleep
Here we will review the pertinent literature with respect to the question of the
differential diagnostic value of sleep abnormalities for subtypes of depression. This
approach provided the initial conceptual impetus for the polysomnographic study
of sleep in depression.
2.1.1. Primary 6ersus secondary depression

The first studies (Kupfer, 1976; Kupfer and Foster, 1972) indicated that REM
sleep abnormalities might constitute a biological marker for the primary subgroup
of depressive disorders. In this context ‘primary’ refers to depressive disorders
unrelated to any other mental or organic disorder, whereas ‘secondary’ indicates a
subtype of depression being caused by another disease. A reanalysis of the original
data by the same group (Thase et al., 1984) did not confirm these assumptions.
After exactly age-matching primary and secondary depressives it was concluded
that the differences initially found had been an artifact of different age distributions
between both patient groups.
2.1.2. Endogenous/melancholic 6ersus non-endogenous depression

Later, it was postulated that REM sleep abnormalities are specific for the
endogenous/melancholic subtype of depression. The terms endogenous and melan-
cholic have a long history of association with the psychiatric taxonomy of affective
disorders. They denote a type of depression with more organic features, implying
also a biological substrate of the disorder (versus neurotic, i.e. due to a psycholog-
ical conflict).
Two studies showing decreased REM latencies in the endogenous subgroup
(Feinberg and Carroll, 1984; Feinberg et al., 1982) included non-endogenous
Fig. 1. Sleep profile of a medication-free depressed female patient and a healthy female control.
Compared to the healthy subject, the sleep profile of this patient shows many of the typical features of
sleep in depression — impaired sleep continuity, disinhibition of REM sleep and reduction of slow wave
sleep. W, Wake; REM, rapid eye movement sleep; S1 – 4, sleep stages 1 – 4; MT, Movement time; BM,
body movements; EM, rapid eye movements.
patients who were on average 10–15 years younger than the endogenous group.
Three of the studies comparing age-matched patients or using a statistical age-cor-
rection (Berger et al., 1982, 1983; Riemann et al., 1990a, 1994a) were unable to
detect significant differences with respect to REM sleep abnormalities between both
patient groups. However, the issue is still controversial because three other studies,
carefully matching for age confirmed shorter REM latencies in endogenous com-
pared to non-endogenous depressed patients (Giles et al., 1986, 1987a; Kerkhofs et
al., 1988; Rush et al., 1982).
The discrepant results may be explained by the impact of depression severity (see
Section 3.2.) on sleep in depression. Those studies confirming a differential-diagnos-
tic value of sleep abnormalities for endogenous depression (see above), compared
less severely depressed non-endogenous patients with more severely depressed
endogenous patients.
Table 1 summarizes the results of polysomnographic studies in primary/sec-
ondary and endogenous/non-endogenous subgroups of depression.
2.1.3. Psychotic 6ersus non-psychotic depression

Regarding depression with and without psychotic features (e.g. delusions), the
picture is not uniform. Three studies (Kupfer and Foster, 1972; Kupfer et al.,
1986a; Naylor et al., 1990) described more pronounced abnormalities of REM sleep
(such as sleep-onset REM periods) in psychotic depressed patients compared with
a non-psychotic group. This relationship was not evident in other studies (Kerkhofs
et al., 1988; Kupfer and Foster, 1978). As severity of depression is influenced by the
presence of psychotic features, this factor (see Section 3.2.) may underlie the
differences found in some of the studies.
2.1.4. Unipolar 6ersus bipolar depression

Assuming that unipolar and bipolar depression might represent different biolog-
ical subtypes of depressive disorders, it was hypothesized that these patient groups
differ with regard to polysomnographic features. Studies comparing unipolar
depressed and bipolar depressed patients, however, failed to detect any significant
differences in nocturnal sleep patterns (Berger et al., 1982; Duncan et al., 1979;
Feinberg and Carroll, 1984; Feinberg et al., 1982; Kerkhofs et al., 1988; Lauer et
al., 1992).
2.1.5. Mania
Several studies polysomnographically investigated sleep during manic episodes
(Hudson et al., 1988, 1992; Knowles et al., 1979). The same abnormalities of sleep,
also of REM sleep, were described in manic patients. Our own study of a patient
with rapid-cycling, displaying day to day changes of mood from depression to
hypomania, showed sleep-onset REM periods (SOREMPs, REM latency5 25 min)
after depressed days, whereas after hypomanic days REM latency was slightly
prolonged but still short (550 min, Gann et al., 1993).
Table 1
72
Sleep abnormalities in subtypes of depression: overview of the literaturef
Authors Primary depression Secondary depression Sleep continuity SWSd REM sleep
N= Age (years) N= Age (years) SOLa WASOb EMAc REM-latencye REM density
Akiskal et al., 1982 49 43.0 9 13.0 19 41.8 911.5 – – – – ¡ (51 vs. 75) –
Ansseau et al., 1984 8 47–61 4 28–53 – – – – ¡– –
D. Riemann et al. / Biological Psychology 57 (2001) 67–103

Berger et al., 1982 36 33.0 9 9.5 9 38.4 9 7.1 ¥ ¥ ¥ ¥ ¥ (58 vs. 50) –
Coble et al., 1976 15 37.1 93.2 25 29.1 9 1.7 – ¥ – ¥ ¡ (48 vs. 78)
Foster et al., 1976 12 41.4 95.0 12 41.7 93.6 ¥ ¥ ¥ ¥ ¡ (42 vs. 71)
Giles et al., 1987a 88 34.4 99.7 15 42.8 911.8 – – – – ¥ (69 vs. 67) ¥
Kerkhofs et al., 1988 124 ca. 45 29 ca. 45 – ¥ – ¥ ¥ (57 vs. 51) ¥
Kupfer, 1976 18 44.5 93.2 11 32.7 9 3.5 – ¥ – ¥ ¡ (39 vs. 71) –
Kupfer & Foster, 1978 47 45.7 9 1.9 48 ca. 35 ¥ – ¡ (38 vs. 72)
Rush et al., 1982 58 36.6 911.8 12 35.8 9 8.7 – – – ¥ (68 vs. 53) ¡
Thase et al., 1984 23 38.8 911.1 23 38.6 9 10.9 ¥ ¥ ¥ ¥– ¥
Endogenous Non-endogenous
depression depression
N= Age (years) N= Age (years)
Berger et al., 1982 20 34.7 9 9.7 19 35.4 97.6 ¥ ¥ ¥ ¥ ¥ (53 vs. 60) –
Berger et al., 1983 15 23–60 12 23-60 ¥ ¥ ¥ ¥ ¥ (58 vs. 54) ¥
Feinberg et al., 1982 33 48.8 916.8 28 34.6 9 12.0 ¥ ¡ ¡ (52 vs. 72)
Feinberg & Carroll, 1984 66 ca. 50 65 ca. 36 – – – – ¡–
Giles et al., 1986, 1987a 41 35.2 9 10.4 62 35.9 910.4 – – – – ¡ (56 vs. 77) –
Kerkhofs et al., 1988 127 ca. 45 26 ca. 45 – – ¡ ¡ (53 vs. 73) –
Riemann et al., 1994a 113 43.6 913.2 65 37.6 9 10.8 ¥ ¥ ¥ ¥ ¥ (52 vs. 57) ¥
Rush et al., 1982 32 33.9 912.1 38 38.6 9 10.3 – – – ¥ ¡ (56 vs. 73) ¥
a
SOL, sleep onset latency.
b
WASO, Wake time after sleep onset.
c
EMA, Early morning awakening.
d
SWS, Slow Wave Sleep.
e
For REM-latency means (minutes) of primary/endogenous versus secondary/non-endogenous patients are given in parentheses.
f
, statistically significant increased in primary/endogenous depressives; ¡, statistically significant shortened in primary/endogenous depressives; ¥, no
difference; –, no data given.
Table 2
Sleep abnormalities in depression and other psychopathological conditions (based on Benca et al.,
1992)
Disorder Sleep continuity SWS reduction REM sleep Hypersomnia

disturbances disinhibition
Affective disorders +++a ++b ++ +c

Anxiety disorders + ød ø ø
Alcohol dependence ++ +++ + ø
Borderline personality + ø + ø
disorders
Dementias +++ +++ ø +
Eating disorders + ø ø ø
Schizophrenias +++ ++ + +
a
+++, present in almost all of the patients.
b
++, present in ca. 50% of the patients.
c
+, present in ca. 10-20% of the patients.
d
ø, not reported up to now.
2.1.6. Depressi6e patients with hypersomnia

Polysomnographic studies in depressed patients with hypersomnia are few. Thase
et al. (1989) reported normal nocturnal sleep profiles in a sample of 26 bipolar
depressed patients suffering from hypersomnia. Nofzinger et al., (1991) performed
a multiple sleep latency test (MSLT) to evaluate hypersomnia. Mean sleep onset
latency was \10 min, i.e. not different from normals. One can conclude from these
data that hypersomnia in depression, unlike hypersomnia in narcolepsy or other
organic forms of hypersomnia, is more a subjective complaint than an objective
finding.
2.1.7. Seasonal affecti6e disorder (SAD)

Several polysomnographic studies have been performed in patients with SAD
(Anderson et al., 1994; Brunner et al., 1993, 1996; Partonen et al., 1993; Rosenthal
et al., 1989). In none of these investigations were the typical sleep patterns of major
depression found.
In summary, polysomnographically measured abnormalities of sleep are not
specific for subtypes of depression and therefore support the concept of Major
Depression. As already mentioned, a meta-analysis of sleep laboratory studies in
depressed patients and patients with other psychiatric disorders (Benca et al., 1992)
also demonstrated the occurrence of sleep disturbances and REM sleep disinhibiton
in other psychopathological conditions. A condensed version of this meta-analysis
is given in Table 2.
As can be seen, the combination of severe sleep continuity disturbances, SWS
reduction and REM sleep disinhibition is encountered most frequently, but is not
highly specific to affective disorders compared to all other psychopathological
conditions investigated. Thus, polysomnography is probably not useful as an
instrument to enhance diagnostic precision in everyday clinical practice. On the
other hand, polysomnography in depression has contributed greatly to the genera-

tion and evaluation of pathophysiological theories of the disorder and therefore
should be viewed primarily as a research tool in psychobiologically oriented
depression research.
3. Important confounding/intervening influences on sleep parameters
Prior to the discussion of pathophysiological models interrelating sleep abnor-

malities and depression, several important methodological issues have to be men-
tioned in order to outline limitations, constraints and problems of
polysomnographic research in psychiatry, especially in depression.
3.1. Age and gender
Age-related changes of sleep in healthy humans are well documented (Bliwise

1993; Miles and Dement, 1980; Williams et al., 1974). These include an increased
number of nocturnal awakenings and decrease of slow-wave sleep. The changes of
sleep in the senium are comparable to typical features of sleep in adult depressives.
Moreover, early morning awakening and a shortening of REM latency (in subjects
older than 70 years) also occur in some elderly healthy subjects.
In depression, sleep continuity and, with the exception of one study (Kupfer et
al., 1986a,b), SWS decrease with aging. Most studies in depressives showed a
negative correlation between REM latency and age, whereas REM density was
unrelated to age (Gillin et al., 1981; Lauer et al., 1991). Table 3 summarizes studies
reporting data on correlations between age and sleep parameters in depression.
In our own studies, SWS displayed a parallel decrease in both healthy controls
and patients with MDD (Riemann et al., 1994a). On the other hand, REM latency
showed age-dependent decreases in depression, and became increasingly shortened
with progressive age. In agreement with other studies, REM density was increased
in depressives regardless of age.
These data raise the question of whether abnormalities of sleep, especially REM
sleep, are already present in young depressed individuals. Table 4 summarizes
studies investigating sleep in depressed children and adolescents.
Approximately half of the studies reported some degree of disturbances of sleep
continuity, shortening of REM latency and increased REM density already at that
early age in depressed individuals. A reduction of SWS was not present in young
depressed individuals.
What might be the reason for the discrepant findings in Table 4 regarding REM
latency? Giles et al. (1992) suggested that family history for affective disorders may
play a decisive role, and that only depressed children and adolescents with an
affective family ‘loading’ display the typical features of sleep in depression. In our
own study (Riemann et al., 1995), five of the depressed adolescents had a parent
with a depressive disorder. These data suggest a role of genetic factors in the
development of sleep abnormalities in depression, at least in young patients.
Table 3

The influence of age on sleep in depression: an overview of the literaturee
Authors Depressed patients Sleep continuity SWSd REM sleep
N= Age (years) SOLa WASOb EMAc REM latency REM density
Akiskal et al., 1982 68 ca. 40 – – – – ¥ –

Cartwright, 1983 29 38.1 96.7 – – – – ¥ ¥
Gillin et al., 1981 69 ca. 45 ¥ ¡ ¡ ¥
Kerkhofs et al., 1988 153 46.5 912.6 – – ¡ ¥ –
Kumar et al., 1987 62 ca. 45 – – – – ¡ –
Kupfer et al., 1986a,b 67 ca. 45 ¥ ¥ ¡ ¥
Lauer et al., 1991 74 39.0 9 12.4 ¥ ¡ ¡ ¥
Riemann et al., 1994a 178 41.2 9 12.7 ¥ ¡ ¡ ¥
Thase et al., 1986 106 40.5 ¥ ¡ ¡
Ulrich et al., 1980 87 36.9 ¥ ¡ ¡ ¥
a
b
WASO, Wake time after sleep onset.
c
EMA, Early morning awakening.
d
SWS, Slow Wave Sleep.
e
, significant positive correlation with age; , significant negative correlation with age; ¥, no significant correlation; –, no data given.
75
76
Table 4
Sleep in depressed children and adolescents: overview of the literaturee
Authors Healthy controls Depressed patients Sleep continuity SWSd REM sleep

N= Age (years) N= Age (years) SOLa WASOb EMAc REM latency REM density
Appelboom-Fondu et 12 15.0 93.0 21 15.0 92.0 – – ¥ ¥ ¥

al., 1988
Cashman et al., 1986 15 ‘matched’ 15 13–18 – – – ¥ ¥
Dahl et al., 1996 21 15.3 9 1.6 16 16.1 9 1.6 ¥ – ¥ ¡ ¥
Emslie et al., 1987 27 12.5 17 12.3 91.5 ¥ ¥ ¥ ¡
Emslie et al., 1990 20 11.5 9 1.4 25 11.5 91.7 ¥ ¥ ¡ –
Goetz et al., 1987 40 15.6 9 1.5 49 15.0 9 2.0 – ¥ ¥ ¥
Kane et al., 1977 – – 1 11 ¥ ¡ ¥
Kutcher et al., 1992 23 ‘adolescents’ 23 ‘matched’ ¥ – ¥ ¡ –
Lahmeyer et al., 1983 13 ‘matched’ 13 11–19 ¥ ¥ ¥ ¥ ¡
McCracken et al., 13 15.6 9 0.6 20 16.0 9 0.3 ¥ ¥ – ¥ ¥
1997
Puig-Antich et al., 11 9.1 9 1.1 54 9.5 91.3 ¥ ¥ – ¥ ¥ –
1982
Riemann et al., 1995 10 16.6 9 1.9 10 16.5 91.7 ¥ ¥ – ¥ ¡ –
Young et al., 1982 12 ‘matched’ 12 10.3 ¥ ¥ – ¥ ¥ –
a
b
WASO, wake time after sleep onset.
c
EMA, early morning awakening.
d
SWS, Slow Wave Sleep,
e
, statistically significant increased in depressed patients compared to healthy controls; ¡, statistically significant shortened in depressed patients compared
to healthy controls; ¥, no difference; –, no data given.
Only a few studies explicitly commented on the impact of gender on sleep in

depression. Reynolds et al. (1990b) found reduced SWS in male compared to female
depressives. Similar findings have also been reported for healthy subjects (Williams
et al., 1974). More recently Armitage and coworkers (Armitage et al., 1995)
described significant sex differences of sleep EEG frequencies detected by period-
amplitude analysis. Depressed women had more fast frequencies (beta activity) than
males.
3.2. Se6erity of depression
There is evidence that with increasing severity of depression, as measured for

example by the Hamilton Depression Scale (HAMD) or the Beck Depression
Inventory (BDI) sleep continuity is increasingly impaired (Kerkhofs et al., 1988;
Spiker et al., 1978; Thase et al., 1986). For slow wave sleep, only one study showed
a negative correlation (Thase et al., 1986). Four studies found REM latency to be
inversely related to the severity of depression (Akiskal et al., 1982; Cartwright,
1983; Spiker et al., 1978; Thase et al., 1986), two other studies did not (Giles et al.,
1987a; Kerkhofs et al., 1988). REM density was found to increase with severity in
two studies (Cartwright, 1983; Thase et al., 1986), but not in two other studies
(Kerkhofs et al., 1988; Spiker et al., 1978).
3.3. Impact of pre-medication
The methodological issue of drug wash-out prior to polysomnography has to be

mentioned here, because most antidepressants suppress REM sleep and the with-
drawal from these drugs is accompanied by a REM sleep rebound (Dunleavy et al.,
1972; Oswald, 1973 and Section 5.1.). Therefore, the question of drug wash-out
periods before polysomnographic studies is crucial. Currently, most investigators
schedule a drug-free interval of 7–14 days prior to sleep studies in psychiatric
patients. Lauer and Pollmächer (1992) analyzing data from a sample of 61
depressed patients previously treated with antidepressants/benzodiazepines con-
cluded that longer (\ 14 days) and shorter (7–14 days) wash-out periods had no
different impact on sleep. It also has to be considered that probably many
depressed patients, especially those with psychotic features, receive treatment with
neuroleptics. Thaker et al. (1990) observed a reduction of REM sleep following
withdrawal from neuroleptics, whereas Tandon et al. (1992) described shorter REM
latencies in previously neuroleptic-treated patients compared with drug-naive pa-
tients. Given the unclear situation, a 2-week wash-out period prior to polysomnog-
raphy is recommended for all psychotropic drugs. Exceptions from this rule are the
antidepressant fluoxetine, irreversible MAO-inhibitors, depot neuroleptics and long
half-life benzodiazepines. Due to their slow elimination, these drugs require wash-
out periods of at least 4 weeks.
In summary, when conducting PSG studies in psychiatric populations, reference
or control groups need to be exactly matched for age and gender. If not, differences
found might be artifactual. Likewise, when comparing subgroups of depressed
patients, depression severity needs to be controlled. The question of drug wash-out

is the most important and the most difficult issue to approach. Given the situation
that in most western countries, outpatient psychiatric care is now widely available,
a majority of depressed patients have already received psychotropic pre-treatment
prior to participating in PSG research. With respect to drug wash-out periods
before sleep investigations, 14 days wash-out periods would be most desirable.
However, in many cases of severe depression, this will not be feasible from a clinical
and ethical point of view.
4. How stable are sleep abnormalities in depressed individuals over time?
An important research strategy in psychobiological research is based on the

question of whether a given abnormality that is present during the acute disease
phase normalizes with remission (‘state’-marker), can still be detected when the
disorder is no longer present (‘scar’), or was already present prior to the clinical
onset of the disorder and persists throughout the life-span (‘trait’- or ‘vulnerability’-
marker). Rush et al. (1986) found a persistence of REM sleep abnormalities in a
sample of 13 remitted patients with a previous MDD. This result was confirmed by
Steiger et al. (1989, 1993). Other authors (Buysse et al., 1997; Cartwright, 1983;
Hauri et al., 1974; Schulz and Trojan, 1979; Schulz et al., 1979) described a
tendency for REM sleep abnormalities to normalize with remission. Knowles et al.
(1986) even demonstrated a total normalization of sleep parameters in formerly
depressed patients compared to healthy controls. The latter findings are in line with
the assumption that REM sleep abnormalities are a state-dependent phenomenon
in depression.
A variety of other findings, however, do not support this view. Giles and
coworkers (Giles et al., 1987b, 1988, 1989) investigated relatives of depressed
patients with a lifetime history of depression, and described shortened REM
latencies even in healthy relatives of depressed probands.
Pursuing a different research strategy, Sitaram et al. (1980) and Nurnberger et al.
(1989) showed that cholinergic stimulation (see Section 6.3.) during sleep with
arecoline provoked faster REM sleep induction in remitted depressives than in
healthy subjects. Even euthymic subjects with a family history of affective illness
showed an augmented response of the REM sleep system (Sitaram et al., 1982). In
a pedigree study, Sitaram et al. (1987) demonstrated that affectively ill first-degree
relatives of probands with a primary affective illness and supersensitive arecoline
REM induction response showed faster cholinergic REM induction than affectively
well relatives. These results were interpreted as evidence of a cholinergic supersensi-
tivity as a trait- or vulnerability marker of affective illness.
Schreiber and coworkers (Schreiber et al., 1992) investigated high-risk subjects,
i.e. non-depressed healthy persons with a family history of depression who are at
high risk for depression in later life, but who were not clinically depressed at or
before the time of the investigation. These subjects more frequently displayed sleep
onset REM periods with the cholinergic REM induction test compared to healthy
controls. Similar findings were obtained by Lauer et al. (1995) who investigated 54
healthy subjects with one first-degree relative with major depression or bipolar
disorder and at least one further close relative with major depression, a bipolar or
schizophrenic disorder. The high risk subjects had a reduced amount of slow wave
sleep and increased REM density in the first sleep cycle compared to a control
group. Twenty percent of the healthy subjects with a high genetic load for
psychiatric disorders had sleep patterns similar to those of depressed patients.
Whether this depression-like sleep pattern indicates an increased risk for depression
or other psychiatric disorders can only be answered by the further longitudinal
investigation of these subjects that is now in progress (C. Lauer: personal commu-
nication, 1999).
These results emphasize the assumption that REM sleep abnormalities observed
under baseline or following cholinergic stimulation may indicate an increased
vulnerability for depression. This view is further supported by data from Buysse et
al. (1997) who reported a shorter mean REM latency and lower delta activity in
remitted depressed patients who relapsed into depression compared to those who
did not relapse. In another study, patients with recurrent depression had more
pronounced REM sleep abnormalities than depressed patients suffering from a
single episode (Thase et al., 1995). Analyzing the polysomnographic findings of 78
unmedicated depressed patients, the same group (Thase et al., 1998) demonstrated
that certain aspects of the sleep disturbances (reduced REM latency, decreased
delta sleep ratio and decreased slow wave sleep) were stable across time whereas
other disturbances (sleep efficiency, REM density) were reversible to some extent
with remission.
However, as the literature cited above shows, the empirical evidence is ambigu-
ous concerning the state/trait issue. Our work (Riemann and Berger, 1989) showed
that sleep, especially REM sleep regulation, tended to normalize in remitted
patients. These remitted patients were, however, free of drugs for a mean interval
of 3 years, and free of depressive symptomatology for an even longer time.
It is hypothesized that the selection procedure for remitted patients in this type
of study may have decisively influenced the results. One can assume, for example,
that patients with a low risk of relapse after a depressive episode may normalize
their sleep, whereas patients being more prone to relapse may continuously display
these abnormalities. Furthermore, perhaps a strict differentiation between state-,
trait- and vulnerability-markers is not an adequate view for REM sleep abnormal-
ities in depression. REM sleep abnormalities may persist for a certain time after an
overt depressive episode, and may only normalize after a longer time of absent
symptomatology. Up to now we do not know what the time constant is for REM
sleep deviations after a patient goes from the acute manifest disorder through
recovery and remission. Besides all the confounding/intervening influences discussed
earlier, the ‘affective family loading’ of a given depressed individual might exert a
certain influence on his/her sleep data. Thus, for methodological reasons, it is
strongly suggested that future research in this area adheres to the operationalized
criteria for recovery, remission, relapse and recurrence as defined by Frank et al.
(1991a).
5. The impact of antidepressive therapies on sleep in depression
The type of research described under this heading aims at correlating changes of
sleep seen during any kind of antidepressive therapy with concurrent or delayed
changes of psychopathology. Also relevant is the relationship between pre-therapy
sleep abnormality and therapeutic outcome.
5.1. Pharmacological treatment
A large body of evidence demonstrates a clear-cut and immediate REM sleep

suppressing effect of antidepressants (for reviews see Sandor and Shapiro, 1994; ).
This is true for the classical tricyclic antidepressants such as amitriptyline,
clomipramine, desipramine, or imipramine (Nicholson et al., 1989; Scherschlicht et
al., 1982), as well as for the tetracyclic substance mianserin (Maeda et al., 1990),
selective 5-HT reuptake inhibitors such as fluoxetine (Nicholson and Pascoe, 1988)
or other new antidepressants like venlafaxine (Salı́n-Pascual et al., 1997). A marked
REM sleep suppression has also been reported for the MAO-inhibitors phenelzine,
tranylcypromine, and brofaromine (Akindele et al., 1970; Hoff et al., 1986; Steiger
et al., 1987). REM sleep suppression is less pronounced with the selective and
reversible MAO-A inhibitor moclobemide (Steiger et al., 1994).
Exceptions to this rule are trimipramine (Dunleavy et al., 1972; Wiegand et al.,
1986) and trazodone (Ware and Pittard, 1990), where no REM sleep suppression
seems to occur. Nefazo-done and bupropion, two atypical antidepressants, even
seem to enhance REM sleep (Nofzinger et al., 1995; Sharpley et al., 1992).
It is not entirely clear how long REM sleep suppression persists under long-term
treatment with antidepressants. Some studies have demonstrated an attenuation of
REM sleep suppression within 3 to 5 weeks of treatment (Berger et al., 1986;
Riemann and Berger, 1990; Riemann et al., 1990b). Only few controlled long-term
observations have been published. Kupfer et al. (1994) found a persistent effect of
antidepressants on REM sleep that persisted over 3 years. In a double-blind
placebo-controlled study by Reynolds et al. (1997), maintenance nortriptyline
consistently suppressed REM sleep over a period of 1 year in elderly depressives
who did not relapse during that time period.
Based on the hypothesis that REM sleep suppression is a necessary prerequisite
for the antidepressant effect, it was presumed that the REM sleep suppression at
the outset of antidepressant treatment would predict therapy outcome. This hy-
pothesis was confirmed by several studies (Gillin et al., 1978; Kupfer et al., 1975,
1981; Reynolds et al., 1991). We were, however, unable to replicate this relationship
with clomipramine (Riemann and Berger, 1990). Other authors assumed that
shortened REM latency prior to treatment would predict response to pharmacolog-
ical treatment (Rush et al., 1989). Again, we were unable to confirm this assump-
tion (Berger et al., 1986; Riemann and Berger, 1990). However, an abnormal sleep
profile seems to have a predictive value for poor treatment outcome with interper-
sonal psychotherapy (IPT) alone (Thase et al., 1997). In the latter study 75% of the
patients who did not respond to IPT had remissions during subsequent pharmaco-
therapy.
Mood stabilizers do not exhibit the strong influences on REM sleep that one
sees from antidepressants. Lithium only slightly decreases REM sleep, but clearly
enhances SWS (Friston et al., 1989). Carbamazepine was found to increase SWS
as well, but had only a minor impact on REM sleep duration (Yang et al.,
1989). In our own study with carbamazepine, an effect on REM sleep was
observed only for the reduction of REM density (Gann et al., 1994; Riemann et
al., 1993b).
With respect to newer prophylactic drugs (e.g. valproate, lamotrigine or
gabapentin), few data are available. For sodium valproate, a decrease in rapid
eye movement activity and an increase in delta activity was observed (Harding et
al., 1985), and Lamotrigine and gabapentin both increased REM sleep in a study
in epileptic patients (Placidi et al., 2000).
5.2. Electrocon6ulsi6e therapy (ECT)
Zarcone et al. (1967) and Grunhaus and coworkers (Grunhaus et al., 1987)
reported a marked REM sleep suppression following ECT. In a recent study by
Grunhaus and coworkers (Grunhaus et al., 1997), ECT improved sleep continuity
parameters and prolonged REM latency in MDD patients. In this study, patients
with persisting sleep onset REM periods (SOREMPs) after ECT exhibited a
poorer response to ECT.
5.3. Sleep depri6ation therapy
Since the initial publications of Schulte and coworkers (Pflug and Tölle, 1971),
the therapeutic effect of total sleep deprivation (TSD) in depression was confi-
rmed in many experimental studies. Wu and Bunney (1990) published a meta-
analysis of sleep deprivation studies and concluded that approximately 50–60%
of all depressed patients show a transient improvement of mood after TSD.
Because about 80% of unmedicated TSD responders relapse into depressed mood
after the next night of sleep, the clinical usefulness of this therapy is limited.
However, from a research point of view, total sleep deprivation offers a unique
opportunity to relate rapidly occurring changes in mood to simultaneous changes
of biological variables (on the future perspectives of sleep deprivation research
see Wirz-Justice and van den Hoofdakker, 1999).
It was consistently shown that a positive diurnal variation of mood with a
spontaneous improvement towards the afternoon and evening hours predicts a
positive response to sleep deprivation (Reinink et al., 1990; see Van den Hoof-
dakker, 1997 for review). There is evidence that the ability of a patient to
produce diurnal variations of mood (i.e. ‘diurnality’), and not the actual diurnal
variation of mood prior to TSD, is the best predictor of a positive sleep depriva-
tion response. In our own study (Riemann et al., 1991) we showed that besides
diurnal mood variation a shortened REM latency predicted a positive response
to sleep deprivation. Furthermore, in agreement with other authors (Duncan et
al., 1980), we observed that TSD responders exhibited a prolongation of REM

latency after TSD (Riemann and Berger, 1990) that was absent in non-respon-
ders.
Positron emission tomography (PET) studies have revealed that sleep depriva-
tion responders have an elevated glucose metabolism in the cingulate gyrus at
baseline, which normalizes after TSD (Smith et al., 1999; Wu et al., 1992, 1994,
1999). Similar findings were reported by Ebert et al. (1991, 1994) and Volk et al.
(1992, 1997) performing single photon emission computed tomography (SPECT)
before and after sleep deprivation. It is interesting to note that the signal trans-
duction in the gyrus cinguli is dominated by cholinergic neurotransmission (Wu et
al., 1992), which is involved in REM sleep regulation (see Section 6.3.).
Besides chronobiological models to explain the therapeutic effect of sleep depri-
vation (see Section 5.5. and Section 6.1.), several neurochemical hypotheses have
been proposed as well. Ebert and Berger (1998) compared the rapid onset of
mood changes observed with sleep deprivation to the effects of psychostimulants
that primarily induce positive effects on mood via stimulation of the dopamine
system. Another model focuses on the role of the neuromodulator adenosine,
which is now widely accepted to be involved in sleep regulation. Van Calker and
Berger (1993) proposed that electroconvulsive therapy and sleep deprivation in
animals increased central A1-receptors. As adenosine per se has sedative, anxi-
olytic and sleep promoting behavioral effects, such an effect could also underlie
the antidepressive response to sleep deprivation.
5.4. Selecti6e depri6ation of REM sleep
Based on the observation of REM sleep suppression following almost all

antidepressants, one might ask whether this pharmacological effect is a ‘conditio
sine qua non’ or even the basic underlying mechanism of action of antidepressant
treatments. Vogel and colleagues (Vogel et al., 1980) addressed this question by
depriving REM sleep without pharmacological intervention with selective noctur-
nal awakenings over a period of 3 weeks in endogenously depressed patients. This
experimental therapy led to a 50% reduction of the percentage of REM sleep and
exhibited an antidepressive treatment response comparable to that of imipramine.
A control group of patients was deprived of non-REM sleep by selective awaken-
ings, and did not show any clinical improvement. Short-term REM sleep depriva-
tion over two nights did not exert antidepressant effects (Reynolds et al., 1990a).
Only one study (Grözinger, 2000) attempted to replicate the findings of Vogel
and colleagues with a methodologically improved design. Selective REM sleep
deprivation was compared to the same amout of well-balanced awakenings lead-
ing to non-REM sleep deprivation in depressed inpatients. In accordance with the
data of Vogel, REM deprivation induced an antidepressant effect. The non-REM
deprivation group, however, exhibited an even stronger antidepressant effect. In
this study it was found that both experimental conditions increased the duration
of Non-REM sleep cycles and it was therefore postulated that this might be the
underlying mechanism of action.
5.5. Other manipulations of the sleep–wake cycle
An important approach for studying the impact of sleep on depressed mood is

the ‘nap paradigm’ after successful sleep deprivation. Some anecdotal reports
showed that even very brief periods of sleep during the sleep deprivation periods
reverse the positive effects of the procedure (Knowles et al., 1979). In a pilot study
(Wiegand et al., 1987) we investigated the impact of naps on mood at 13:00 h.
Almost half of the patients relapsed into depressed mood after the nap and most of
these patients had REM sleep during their naps.
In several ensuing experiments we tried to confirm the initial coupling of REM
sleep with the depressiogenic effect of naps (Dressing et al., 1992; Riemann et al.,
1993a; Wiegand et al., 1993). The impact of naps on mood was investigated at
05:00, 09:00 and 15:00 h. Contrary to our expectation, none of these studies
confirmed the association between REM sleep and negative mood swings. However,
it was noted that naps in the morning were more detrimental to mood than naps in
the afternoon.
Based on the results of the nap studies and earlier findings showing that partial
sleep deprivation in the second but not in the first half of the night has antidepres-
sive effects (see Wehr, 1990 for overview), we postulated based on the ‘internal
coincidence model’ (Wehr and Wirz-Justice, 1981) that sleep exerts a depressiogenic
effect only within a critical time zone in the early morning hours. Based on the
assumption that the avoidance of sleep during the early morning hours is crucial for
the sleep deprivation effect we developed a combined sleep deprivation and sleep
phase advance protocol. Depressed patients who responded positively to one night
of sleep deprivation were kept on a phase advance schedule allowing them to sleep
from 17:00 until 24:00 h after the sleep deprivation night. The advanced sleep phase
was then shifted to the normal phase position within 1 week. It was shown in
several studies that this combined sleep deprivation and sleep phase advance
therapy was able to maintain the positive effect of sleep deprivation in about
60– 75% of the patients (Albert et al., 1998; Berger et al., 1997; Riemann et al.,
1996b, 1999; Vollmann and Berger, 1993), compared to a 40% response rate in a
control condition (‘phase delay’).
Polysomnographic data were gathered in one of these studies (Riemann et al.,
1999) and showed that improvements of psychopathology with this treatment were
not paralleled by sleep changes, neither of REM sleep nor of SWS.
5.6. Psychotherapy
Structured psychotherapy such as cognitive behavioral therapy (CBT) or inter-

personal psychotherapy (IPT) administered alone has been proven to be as effective
as pharmacotherapy in mild to moderate depression (e.g. Frank et al., 1991b).
Several polysomnographic studies failed to demonstrate decisive changes in sleep
EEG following short-term psychotherapy in depressives (Buysse et al., 1992a,b;
Frank and Kupfer, 1992; Jarret et al., 1990a). The interpretation of these initial
studies was limited since most of the patients showed fairly normal baseline sleep
patterns. One study in depressed patients with reduced REM latencies at baseline
(Jarret et al., 1990a) reported a favorable response to CBT as well. In recent studies
by Thase et al. (1996, 1997), a large group of drug-free depressed patients was
studied in the sleep laboratory and then initially treated by interpersonal psy-
chotherapy alone. The authors classified the patients into a group with normal
(N = 50) and abnormal (N = 41) sleep profiles on the basis of sleep efficiency, REM
density and REM latency. Treatment response to IPT was significantly poorer in
the group with abnormal sleep profiles. Thase et al. concluded from their studies
that an abnormal sleep profile reflects a more marked disturbance of the CNS
arousal that warrants pharmacotherapy.
In summary, the literature on the impact of antidepressant treatment on REM
sleep shows that the majority of the successful treatment modalities suppress REM
sleep. The evidence for a correlative or causal relationship between pretreatment
REM sleep abnormalities, initial REM sleep suppression, and therapeutic response
is ambiguous. Some successful treatments, either pharmacological or psychothera-
peutic strategies, do not suppress REM sleep. These data challenge the assumption
that REM sleep suppression is a necessary prerequisite for antidepressant properties
of an effective antidepressant treatment.
Reynolds (1998) stressed the importance of evaluating the antidepressant drug
effects on sleep suggesting that differential sleep effects may reflect differences in
receptor pharmacology and thereby signal different pathways to treatment re-
sponse. Whereas one pathway may primarily involve REM sleep suppression, an
alternative pathway may involve the augmentation of early slow-wave activity.
Both types of EEG sleep changes may reflect the correction of increased arousal in
depression. The arousal concept is supported by a recent PET-sleep study in
depressed patients (Nofzinger et al., 2000) demonstrating greater beta-power during
non-REM sleep in patients to be related to increased relative glucose metabolism in
the ventromedial prefrontal cortex.
Thus, despite many advances in the search for the biological substrate(s) of
depression, it is important to recognize that we are still ‘fishing in the dark’ with
respect to identifying the essentials of a successful antidepressive treatment. We still
do not know, for example, whether sleep changes associated with a given treatment
are just signs (i.e. epiphenomena) of a normalization of psychopathology or reflect
a real impact on relevant disease mechanisms. Combining sleep research with
neuroimaging might be a promising strategy to answer these questions.
6. The pathophysiology of sleep abnormalities in depression
6.1. Chronobiological models
The most influential model suggested to explain sleep abnormalities in depression

based on chronobiological assumptions is the two-process model of Borbély and
coworkers (Borbély, 1982; Borbély and Wirz-Justice, 1982). This model attempts to
explain the effects of sleep deprivation on depression, REM sleep disinhibition, and
reduced SWS. According to this model the so-called process ‘S’ is deficient in
depression, which is reflected by a diminution of delta-activity and SWS (see Fig.
2). Studies utilizing frequency analysis of sleep EEG confirmed the assumption that
delta sleep production is reduced in depression (Borbély et al., 1984; Kupfer et al.,
1984, 1985). As a consequence of reduced SWS, REM sleep occurs earlier. This
model accounts for the antidepressive effect of sleep deprivation by proposing that
due to prolonged wakefulness the deficient process ‘S’ is enhanced. Not all authors,
however, were able to show a reduction of delta power in the sleep EEG of
depressed patients (Mendelson et al., 1987; Van den Hoofdakker and Beersma,
1988). Similarly, not all studies revealed differences in visually scored SWS between
depressed patients and healthy controls (for a meta-analysis on the topic see
Knowles and MacLean, 1990). These data doubt the basic assumption of the
two-process model in terms of a reduced process ‘S’ in depression.
Kupfer et al. (1990) suggested that rather than SWS or delta power over the
whole night, the ‘delta sleep ratio’ (quotient of automatically measured delta sleep
Fig. 2. Two-Process model of sleep, sleep regulation and sleep deprivation effect in depression (Borbély,
1982; Borbély and Wirz-Justice, 1982): The upper part of the figure depicts the courses of processes S
and C under normal conditions and after sleep deprivation in healthy subjects. Process S is reflected in
delta-activity during sleep, which decreases exponentially. The tendency to fall asleep depends on the
difference between C and S. Awakening occurs when S and C fall together. In the depressed subjects
(lower part of the figure) it is postulated that S is decreased, leading to more superficial sleep and
reduced sleep duration. Sleep deprivation, by prolonging wakefulness increases process S and delta wave
activity and improves depressed mood.
of the first and the second non-REM period) might be reduced in depression. Healthy
subjects usually show a decrease of delta sleep from the first to the second Non-REM
period, whereas no such decline or even an increase was noted in depressive patients.
However, Armitage et al. (1992) were unable to confirm an abnormal delta-sleep
ratio in depressives.
To summarize, in accordance with many of the studies with visually scored SWS
who failed to detect differences between depressives and healthy controls, the data
base of studies using automated analysis does not give strong support for the inital
assumption of the two-process model of reduced SWS or delta-power in depression.
Research now focuses on the delta ratio, measured as the ratio of slow wave activity
in the first to the second non-REM cycle. As mentioned above, delta ratio is
decreased in depression compared to healthy subjects. Studies with pharmacotherapy
(Ehlers et al., 1996) and psychotherapy (Buysse et al., 1992a,b; Kupfer et al., 1990;
Thase et al., 1998) described a more favorable outcome with higher delta ratio
compared to patients with lower delta ratio.
Future directions of chronobiological research in the field of depression are
exemplified by a study of Boivin et al. (1997). Using a ‘forced desynchrony’ protocol
in healthy subjects that puts subjects on ‘scheduled days’ much longer than 24 h, it
was concluded that subjective mood is influenced by a complex and non-additive
interaction of circadian phase and duration of prior wakefulness. Moderate changes
in the timing of the sleep– wake cycle seemed to have profound effects on subsequent
mood. Studies in depressed patients with that paradigm are still lacking but will be
of great value to disentangle sleep–mood interrelationships in psychopathology.
6.2. Sleep-neuroendocrine interrelationships
Numerous studies have demonstrated abnormalities of neuroendocrine systems in

depression (for an overview see Holsboer, 1995). Increased hypothalamic–pituitary–
adrenocortical (HPA) activity, evidenced by increased cortisol secretion, is one of the
most consistent biological findings in depression. Some authors also report reduced
sleep-related growth hormone secretion in untreated depressives (Jarret et al., 1990b;
Steiger et al., 1989; Voderholzer et al., 1993), although Rubin et al. (1990) failed to
confirm this finding. It would be important to know whether the abnormal endocrine
findings and the sleep abnormalities in depression are related or even causally linked
to each other.
In healthy humans, the first hours of sleep are characterized by peaks of SWS and
growth hormone along with a nadir in cortisol output. These endocrine findings in
depression, with a lowered growth hormone secretion and an increased cortisol
secretion, correspond to the finding of reduced SWS in depression. Ehlers and Kupfer
(1987) were the first to postulate a disturbance in the interaction of two hypothalamic
peptides [growth hormone releasing factor (GRF) and cortisol releasing factor
(CRF)] in the pathophysiology of sleep in depression (see Table 5). They assumed
a deficient release of GRF and an increased output of CRF in accordance with the
assumption that an ‘overdrive’ of CRF plays a key role in depression (Holsboer,
1992).
Table 5
CRF/GRF and the two-process model of sleep in depression (Ehlers and Kupfer, 1987)
Process S Process C
A sleep-dependent process that A sleep-independent circadian
builds up during the day and is process
released at night
Sleep stage relationship Slow-wave sleep REM sleep

Neuroendocrine GRF and/or GRF/CRF ratio CRF-HPA axis
relationship
Alteration in depression Deficient Increased
Physiological consequences GH hyposecretion after sleep Cortisol hypersecretion over 24-h
in depression onset, decreased delta density, period, increased REM activity
delayed sleep onset, lighter overall and density
sleep pattern
Attempts were made to replicate the finding of sleep-endocrine abnormalities of

depression by pharmacological challenge studies in healthy subjects. Repetitive
nocturnal administration of corticotropin releasing factor (CRF) only partially
mimicked the sleep-endocrine abnormalities, such as reduction of SWS, an increase
of the ‘shallow’ sleep stages I and II, a decrease of growth hormone secretion, and
increased cortisol secretion (Holsboer et al., 1988). However, no signs of REM
sleep disinhibition were observed, since REM sleep was suppressed by acute
administration of CRF. Results of studies employing infusions of cortisol (Friess et
al., 1994) or ebiratide, an analogue of adrenocorticotropin (ACTH; Steiger et al.,
1993) yielded similar results regarding the EEG. This indicates that the effect of
CRF on sleep EEG is a direct effect on the CNS and is not mediated by stimulation
of ACTH or cortisol. Support for the hypothesis of Ehlers and Kupfer (1987) is
given by the findings of Seifritz et al. (1996) showing that EEG slow wave activity
correlated with the ratio of growth hormone and cortisol secretion during sleep.
Other findings do not fit with the assumption that a diminished somatotropic
activity causes the typical alterations of sleep in depression. The repetitive adminis-
tration of growth hormone releasing hormone failed to normalize abnormalities of
sleep in depressed patients (Steiger et al., 1994).
6.3. The reciprocal interaction model of non-REM and REM sleep regulation
A further explanation of the sleep abnormalities in depression is based on

Hobson and McCarley’s reciprocal interaction model (Hobson et al., 1975). As
shown in animal studies, aminergic neurons inhibit REM sleep (REM ‘off’ neu-
rons), whereas cholinergic neurons stimulate REM sleep (REM ‘on’ neurons). The
first version of this model posited that these neuronal groups are located in the
brain stem and that mainly noradrenergic neurons in the locus coeruleus and
serotonergic neurons (REM ‘off’ neurons) in the dorsal raphé inhibit REM sleep,
whereas cholinergic neurons (REM ‘on’ neurons) in the pontine tegmentum stimu-
late and maintain REM sleep. This model was later modified and now posits that
the cholinergic network involved in the generation and maintenance of REM sleep
is widely spread throughout the whole nervous system (Hobson and Steriade, 1986;
Hobson et al., 1986).
Work in healthy humans with the cholinesterase inhibitors physostigmine (Berger
et al., 1983; Sitaram et al., 1976), galanthamine (Riemann et al., 1994b), SDZ-ENA
713 (Holsboer-Trachsler et al., 1993; Riemann et al., unpublished data) and the
muscarinic agonists arecoline (Sitaram et al., 1978), pilocarpine (Berkowitz et al.,
1990), RS 86 (Riemann et al., 1988; Spiegel, 1984), SDZ 210-086 (Hohagen et al.,
1993b), and tacrine (Riemann et al., 1996a), demonstrated, with the exception of
SDZ-ENA 713, that all cholinomimetics shortened REM latency and all but
arecoline decreased SWS (see Fig. 3). A differential profile was noted for the
cholinesterase inhibitors compared to the muscarinic agonists; the former class of
drugs impaired sleep continuity and increased REM density. From these studies it
can be concluded that M1, M2 and nicotinic receptors are involved to a different
degree in the regulation of the complex phenomenon of REM sleep, including EEG
desynchronisation, muscle atonia, PGO (ponto–geniculo–occipital) spikes and eye
movements. As shown in animal experiments (Velazquez-Moctezuma et al., 1989),
EEG desynchronisation may be related to the M1 receptor, whereas muscle atonia
may be triggered by the M2 receptor, and nicotinic receptors may be involved in the
generation of PGO spikes. Therefore, the latter may play a role in the generation
of eye movements during REM sleep.
Several studies also tested the noradrenergic/serotonergic side of this imbalance
model. Alpha-methyl-para-tyrosine (AMPT), which inhibits catecholamine synthe-
sis also provoked REM sleep abnormalities in healthy humans (Gillin et al., 1984).
Investigations with the tryptophan depletion test (Bhatti et al., 1998; Voderholzer et
al., 1998) at least partially mimicked some of the REM sleep abnormalities of
depression.
To test the hypothesis of a cholinergic supersensitivity in depression, a variety of
pharmacological studies were conducted in depressed patients and other psychiatric
patients using cholinergic stimuli such as physostigmine, arecoline, RS 86 and
pilocarpine. After physostigmine, we did not find a shortening of REM latency in
depressed patients (Berger et al., 1983), but an increased rate of awakenings and
arousals occurred. With arecoline injected intravenously during the second non-
REM period, Gillin et al. (1982, 1991) demonstrated a significantly stronger
reduction of this interval in depressed patients compared to healthy subjects. These
results were not replicated with pilocarpine (Lauriello et al., 1993). In several of our
own studies, we investigated the impact of the muscarinic agonist RS 86 and
placebo on the sleep of healthy controls, depressed patients, and patients with
eating disorders, personality disorders, anxiety disorders and schizophrenia (Berger
et al., 1989; Gann et al., 1992; Lauer et al., 1990; Riemann and Berger, 1989, 1992;
Riemann et al., 1994c). The most pronounced impact of RS 86 on REM latency
occurred in depressed subjects (see Fig. 4), with more than 60% of the sample
displaying rapid sleep onset REM periods (REM latency B 25 min). A high
incidence of SOREMPs also occurred in schizophrenia. This does not support the
assumption that a cholinergic supersensitivity is specific for major depression.

However, none of the groups with other psychiatric diagnoses displayed the strong
REM sleep responses that were noted in the depressed group. Concerning REM
density (see Fig. 4), a distinct increase was present in depressives only, but not in
any of the other groups.
Fig. 3. Impact of cholinomimetics on sleep in healthy subjects (own studies — for references see text).
The figure shows the impact of different cholinomimetics on REM latency (min), total REM density (%)
and slow wave sleep expressed (% sleep period time). Asterisks mark statistical significance (*PB 0.05;
**PB 0.01; ***PB 0.001).
Fig. 4. Impact of RS 86 on REM sleep parameters (REM latency in minutes, REM density of the 1st
REM period in percent and Sleep Onset REM (SOREMP) latency in minutes) in healthy controls,
depressed patients and patients with other psychiatric disorders. Asterisks mark statistical significance
(× PB 0.05; × ×PB 0.01; × × × PB 0.001).
The relevance of the reciprocal interaction model for an etiological or pathophys-

iological theory of depression is based on studies demonstrating that the neuronal
centers involved in the regulation of REM sleep are linked to higher brain areas
(e.g. limbic system). The locus coeruleus and the dorsal raphé are the decisive parts
of the central nervous monoaminergic neuronal system. The REM sleep generating
cholinergic neurons are linked to cholinergic neuronal populations in higher brain
areas (Hobson and Steriade, 1986; Hobson et al., 1986). Thus, REM sleep
dysregulation may serve as a window to the neurochemical processes that are
involved in the regulation of affect.
The most attractive fact about the reciprocal interaction model is that it can be
easily linked with other psychobiological approaches to depression. Independent of
findings on sleep in depression, Janowsky and coauthors (Janowsky et al., 1972)
formulated their own cholinergic–aminergic imbalance model of affective disorders.
Their model postulates a central neurotransmitter disequilibrium with increased
cholinergic activity in depression. To be consistent with this model, all therapeutic
interventions suppressing REM sleep and thereby correcting the assumed underly-
ing neurotransmitter imbalance would be expected to have antidepressive effects.
An integrative view of the imbalance hypothesis of depression and the reciprocal
interaction model of REM sleep regulation was suggested by McCarley (1982). One
shortcoming of this model is, however, that it cannot account for the antidepressant
properties of total sleep deprivation, or the positive effects of a combined sleep
deprivation and sleep phase advance procedure in depressed patients. Based on
animal studies (Kafka et al., 1981), therefore, we suggest that besides an ultradian
rhythm of cholinergic/aminergic interaction (manifested as non-REM/REM cycle
during the night), the interaction of cholinergic/aminergic neurotransmission is
subject to circadian modulation as well.
We assume that in depression the balance between both neurotransmitter systems
is disturbed. During sleep this imbalance is manifested as an early onset of REM
sleep. Sleep deprivation may prevent the nocturnal dominance of cholinergic
neurotransmission and enhance noradrenergic activity in the morning hours. Morn-
ing naps may be more detrimental to mood than afternoon naps as sleep may be
accompanied by higher cholinergic activity. Avoiding this ‘critical time’ by shifting
sleep into the afternoon (see our sleep phase advance protocol) leads to an
amelioration of depression.
7. Conclusion
After reviewing all theories on the pathophysiology of sleep alterations in

depression, one has to conclude that there is still no entirely convincing model
capable of explaining all typical changes in the sleep EEG of depressives. The initial
hope that the investigation of sleep may be a valuable tool for differential-diagnosis
in psychiatry has not been fulfilled. Numerous studies in different psychiatric
populations have not conclusively demonstrated specificity in the relationship
between sleep changes, such as REM sleep abnormalities or reduced SWS and
disorders such as depression. However, research on sleep in depression has pro-
duced an immense database and fruitful theoretical considerations concerning the
etiology and pathophysiology of depression, as well as the vulnerability for develop-
ing depressive episodes.
For a future perspective it is suggested that research on REM sleep be more

closely connected with the work on non-REM sleep, especially SWS, to approach
a more adequate view of these two interdependent sleep states. Additional issues
that merit attention involve sleep–neuroendocrine interactions. At present, the
different approaches relating neurotransmission, neuroendocrinology and chronobi-
ological aspects of depression have very rarely have been studied simultaneously.
Furthermore, theories linking the different areas of research are sparse. Future
studies with animals are also necessary to generate and test multi-dimensional
theories of human depression from a biological point of view.
Additonally, the area of neuroimaging in combination with sleep research has
already provided interesting perspectives relevant to the understanding of depres-
sion and related sleep abnormalities. Finally, a deeper insight into depression– sleep
interrelationships may come from molecular biological research on so-called ‘clock
genes’. Bunney and Bunney (2000) reviewed the literature with respect to the
genetic basis of the circadian clock and rhythm research in depression and
concluded that 24-h-rhythm abnormalities in major depression may be related to
alterations of clock genes.
Acknowledgements
We thank Professor Dr Charles Reynolds for his comments and suggestions

concerning an earlier version of this manuscript.
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Biological Psychology 57 (2001) 67 – 103

Sleep and depression — results from

Keywords: Antidepressants; Depression; REM sleep; Sleep; Sleep deprivation

1. Sleep disturbances and depression

The relationship between depression and insomniac symptoms is not a one-way

* Corresponding author. Tel.: +49-761-2706919; fax: +49-761-2706619.

2. Polysomnographic studies in depression

Systematic sleep EEG investigations in unmedicated depressed patients using

2.1. Subtypes of depression and sleep

2.1.1. Primary 6ersus secondary depression

2.1.2. Endogenous/melancholic 6ersus non-endogenous depression

2.1.3. Psychotic 6ersus non-psychotic depression

2.1.4. Unipolar 6ersus bipolar depression

D. Riemann et al. / Biological Psychology 57 (2001) 67–103

Disorder Sleep continuity SWS reduction REM sleep Hypersomnia

Affective disorders +++a ++b ++ +c

2.1.6. Depressi6e patients with hypersomnia

2.1.7. Seasonal affecti6e disorder (SAD)

other hand, polysomnography in depression has contributed greatly to the genera-

3. Important confounding/intervening influences on sleep parameters

Prior to the discussion of pathophysiological models interrelating sleep abnor-

3.1. Age and gender

Age-related changes of sleep in healthy humans are well documented (Bliwise

D. Riemann et al. / Biological Psychology 57 (2001) 67–103

Authors Depressed patients Sleep continuity SWSd REM sleep

N= Age (years) SOLa WASOb EMAc REM latency REM density

Akiskal et al., 1982 68 ca. 40 – – – – ¥ –

D. Riemann et al. / Biological Psychology 57 (2001) 67–103

Appelboom-Fondu et 12 15.0 93.0 21 15.0 92.0 – – ¥ ¥ ¥

Only a few studies explicitly commented on the impact of gender on sleep in

3.2. Se6erity of depression

There is evidence that with increasing severity of depression, as measured for

3.3. Impact of pre-medication

The methodological issue of drug wash-out prior to polysomnography has to be

patients, depression severity needs to be controlled. The question of drug wash-out

4. How stable are sleep abnormalities in depressed individuals over time?

An important research strategy in psychobiological research is based on the

5. The impact of antidepressive therapies on sleep in depression

A large body of evidence demonstrates a clear-cut and immediate REM sleep

5.2. Electrocon6ulsi6e therapy (ECT)

5.3. Sleep depri6ation therapy

al., 1980), we observed that TSD responders exhibited a prolongation of REM

5.4. Selecti6e depri6ation of REM sleep

Based on the observation of REM sleep suppression following almost all

5.5. Other manipulations of the sleep–wake cycle

An important approach for studying the impact of sleep on depressed mood is

Structured psychotherapy such as cognitive behavioral therapy (CBT) or inter-

6. The pathophysiology of sleep abnormalities in depression

6.1. Chronobiological models

The most influential model suggested to explain sleep abnormalities in depression

6.2. Sleep-neuroendocrine interrelationships

Numerous studies have demonstrated abnormalities of neuroendocrine systems in

Sleep stage relationship Slow-wave sleep REM sleep

Attempts were made to replicate the finding of sleep-endocrine abnormalities of

A further explanation of the sleep abnormalities in depression is based on

assumption that a cholinergic supersensitivity is specific for major depression.

The relevance of the reciprocal interaction model for an etiological or pathophys-

After reviewing all theories on the pathophysiology of sleep alterations in