A Review of REM Sleep Deprivation
Gerald W. Vogel, MD
Studies on the behavioral consequences of rapid eye movement
(REM) sleep deprivation in animals and humans are critically re-
viewed. In animals, converging evidence\p=m-\somereasonably well con-
trolled\p=m-\indicatesthat REM sleep deprivation probably heightens
central neural excitability and increases motivational behavior, but
has unclear or inconclusive effects on learning. In humans, evidence
indicates that REM sleep deprivation is not dream deprivation and is
not harmful to schizophrenic, depressed, or healthy subjects. Con-
troversy continues about whether or not (some) schizophrenic pa-
tients respond abnormally to REM sleep deprivation by having no
REM rebound. Controlled but unconfirmed work indicates that en-
dogenous, but not reactive, depressive patients are improved by
REM sleep deprivation, a finding consistent with the animal behav-
ioral consequences of the procedure and with the unique REM-de-
priving properties of efficacious antidepressant drugs.
focus will be the behavioral consequences of
Myrapid eye movement
on
(REM) sleep deprivation. Stud¬
ies using surgical and biochemical deprivation techniques
have been eliminated from the review because such tech¬
niques introduce too many confounding variables that
might affect behavior. (In this review, the term signifi¬
cant refers to a statistical significance of < .05.) I will
begin with animal studies and then turn to human studies.
A basic issue is the validity of nonsurgical, nonchemical
procedures for REM sleep deprivation of animals. Two
questions are relevant here. To what extent do the proce¬
dures and their controls deprive animals of REM sleep?
And, do the experimental procedures introduce confound¬
ing variables that can be controlled in order that the
dependent variables can be unequivocally related to REM
sleep deprivation?
The ideal technique for REM sleep deprivation, because
it does REM sleep-deprive and because it is least difficult
to control for confounds, is the replication of Dement's
original technique used in humans.1 Experimental animals
are aroused by external stimulation at the onset of each
REM period and control animals are aroused an equiva¬
lent number of times from non-REM (NREM) sleep, with
each kind of arousal indicated by polygraphic criteria.
Surprisingly, in the studies of animals listed in the sleep
deprivation section of the Brain Information Service Bib¬
liography to the present time, I could not find one that
used this technique exclusively. I then learned the reason
for this. In animals, the number of arousals becomes so
inordinately large in a short period of time that the proce¬
dure is practically impossible to perform. For example,
Morden et al reported that when rats were aroused from
REM sleep 8 hr/day and put on small flower pots for the
remaining 16 hr/day—where they were presumably REM-
Accepted for publication Feb 21, 1975.
From the Georgia Mental Health Institute and the Department of Psy-
chiatry, Emory University, Atlanta.
Read in part before the Association for the Psychophysiological Study of
Sleep, Jackson Hole, Wyo, June 6, 1974.
Reprint requests to the Sleep Lab, Georgia Mental Health Institute, 1256
Briarcliff Rd NE, Atlanta, GA 30306 (Dr. Vogel).
deprived—the number of arousals during the eight hours
increased from 134 on the first day to 350 on the third
day.2
Other ingenious techniques have been devised to over¬
come this practical difficulty. By far the most frequently
used technique for REM sleep deprivation in animals is
the so-called flower pot procedure, also called the platform,
pedestal, or water tank procedure.21 During this proce¬
dure, the animal (cat, rat, or mouse) resides on a little
platform, usually an inverted flower pot whose top just
protrudes above the surface of surrounding water. Experi¬
mental animals reside on smaller platforms than control
animals. Theoretically, the experimental platform permits
wakefulness and NREM sleep but not REM sleep because
the platform is so small that with the loss of postural
muscle tone at the onset of each REM period, the animal is
awakened as it begins to fall toward the water. And, theo¬
retically, the control platform is large enough to permit
REM sleep as well as NREM sleep and wakefulness. The
procedure has enormous practical advantages over the
ideal arousal technique. Since the platform procedure
theoretically deprives the animal of REM sleep without
polygraphic recording, and without the requirement that
the experimenters monitor the polygraph of each animal
24 hr/day, large numbers of animals can be REM sleep-de¬
prived simultaneously for several days.
However, the platform procedure also has practical dif¬
ficulties. First, it has been claimed that control animals
are REM sleep-deprived almost as much as experimental
animals,5 and, if that were so, then experimental and con¬
trol differences in dependent variables could not be due to
REM sleep deprivation. Second, it has been claimed that
the platform existence, particularly the small platform ex¬
istence, introduces several confounding variables,2 in par¬
ticular, stress, confinement, dampness, loss of total sleep
time (TST), arousals, and weight loss.
It is important to consider in detail the evidence about
these difficulties of the platform technique because most
animal REM sleep deprivation experiments use it. Hence,
if the technique is invalid, then the conclusions of most
animal experiments on REM sleep deprivation are also
invalid.
First, considerations about REM sleep. In order to ver¬
ify that different sized platforms differentially affect
REM sleep, it is necessary to obtain polygraphic record¬
ings of the animals while they are on the platforms. Four
studies report platform polygraphic recordings in rats,
two in cats, and one in mice. The studies using cats re¬
ported that the small platform eliminated REM sleep but
gave no report about REM sleep on larger control plat¬
forms.3·4 In the study with mice,6 since only three animals
were recorded on the small platform and an unspecified
number were recorded on the large platform, and since
the exact number of days on the platform was not uni¬
form across animals and was not specified—a variable that
we shall see is important—it is difficult to draw firm con¬
clusions about the differential effects of small and large
platforms on REM sleep.
There is, however, more information about rats on plat¬
forms in the four studies that recorded and compared rats
on small and large platforms for REM sleep712 (W. Men-
delson, MD, unpublished data). All four studies report that
rats on small platforms for several days have less mean
REM sleep than rats on large platforms. But the question
is, do they have significantly less? Stern5 has emphasized
that the frequently cited data by Duncan et al910 (viz, in
rats the five-day mean REM percent on small platforms
was 20% of base line and on large platforms was 50% of
base line values) imply that the differences in REM per¬
cent are too small to produce easily demonstrable physio¬
logical effects. But the monitoring of REM sleep on salient
days rather than the mean for a total of five days produces
a different interpretation. Mendelson et al11·12 recorded the
REM sleep in rats about 24 hr/day for four days. During
the first 24 hours, there was no significant REM sleep dif¬
ference between rats on small and large platforms; but
during the fourth 24 hours, the rats on the small platform
had significantly less REM sleep than both the rats on the
large platform and the base line rat. In the rats on the
large platforms during the fourth 24 hours, percent REM
sleep, in fact, was slightly though insignificantly, higher
than the base line value. Thus, the rats on the large plat¬
form adapt and return to base line levels during 96 hours
on the platform. On the first day off the platforms-after
96 hours-the small platform rats had significantly more
REM sleep than both large platform rats and base line
rats and the large platform rats did not have a REM
rebound. In short, at 96 hours the small platform rats are
REM-deprived and the large platform rats are not.
In summary, in studies of rats, using the platform tech¬
nique for 24 hours or less, dependent variable differences
between experimental and control groups cannot be due
to REM sleep differences. But in studies of rats using this
technique for about four days, dependent variable differ¬
ences between experimental and control groups could be
due to REM sleep deprivation, assuming that confounds
are controlled.
In on cats and mice, since there is little
experiments
or no information about REM sleep differences between
small and large platform groups, we should be much less
confident that dependent variable differences between an¬
imals on small and large platforms are the result of REM
sleep deprivation.
Let us now consider the more obvious confounds intro¬
duced by the platform method: stress, TST, number of
arousals, confinement and restriction, and wetness.
In rats, five separate studies have found no significant
stress differences, measured in a variety of ways, between
animals on small and large platforms, but both groups are
more stressed than nonplatform controls. The investiga¬
tions included adrenal weights,7·1114 plasma steroid lev¬
els,7·15 and thymus atrophy.15
Total sleep time is related to REM sleep; this measure
requires polygraphic recordings of animals on pedestals,
so again, our knowledge is limited to the studies on rats.
In the study by Mark et al,7 TST on small platforms was
49% of TST on large platforms. In the study by Duncan et
al,9·10 TST on the small platform was about 80% of TST on
the large platform. The only clear difference in the proce¬
dures was time and duration of recording (from 10 am to 4
PM in the Mark et al study and for 24 hr/day in the study
by Duncan et al). Possibly, rats on small platforms lose
disproportionately more sleep during the daylight hours—
their usual sleep time—and disproportionately less during
nocturnal hours. But I know of no data on this and thus
find no verified explanation for the discrepancy between
the two studies. Mendelson et al,12 recording for about 24
hr/day, found that during the fourth platform day, TST
on the small platform was 88% of TST on the large, a sta¬
tistically insignificant difference. Thus, most of the avail¬
able evidence suggests that there are no significant TST
differences between large and small platform animals.
However, all the studies in rats indicate that those on
small platforms have much less TST than caged rats.
Thus like stress, TST is a confound of REM sleep depriva¬
tion when the animals on small platforms are compared
with base line or with caged controls, but not with the ani¬
mals on large platforms.
With regard to dampness and falls in the water, three
studies (Albert et al,16 Steiner and Ellman,17 and Miller et
al18) report without systematic data that dampness and
falls in the water were not different in rats on small and
large platforms.
Number of arousals is another possible confound of
REM sleep deprivation but no published data on this vari¬
able were found. Rats on large and small platforms fall
into the water about equally often; this is consistent with
the notion that the number of arousals on the two plat¬
forms are not significantly different, but empirical data
are needed to resolve this issue.
Weight loss is a possible confound of REM sleep depri¬
vation because studies report that rats on small platforms
lose about 10% of their body weight.19·20 But Stern reports
no significant weight difference between small and large
platform rats after five days of treatment.12
In summary, rats on small platforms are REM-deprived
significantly more than those on large platforms after the
first 24 hours. Much evidence indicates that stress is not
a confound of REM sleep deprivation when comparing an¬
imals on large and small platforms. Some insufficient evi¬
dence indicates that TST, chronic dampness, falls into the
water, number of arousals, and weight loss are not signifi¬
cantly different in animals on small and large platforms.
Put more hopefully, there is no substantial evidence that
any of these variables is a confound of REM sleep depriva¬
tion in evaluating dependent variable differences between
rats on large and small platforms. Although there are res¬
ervations about the technique, on the whole, a comparison
of rats on large and small platforms, after 24 hours, seems
a valid method for assessing the effects of REM sleep dep¬
rivation. There is insufficient evidence for the same confi¬
dence about studies of cats and mice.
The combination of the treadmill and hand arousals
from REM sleep is another technique for REM sleep dep¬
rivation.20·21 In the typical experiment, for 16 to 22 hr/day,
both experimental and control animals are kept on a mov¬
ing treadmill, which theoretically prevents all sleep. The
remaining two to eight hr/day are spent in cages from
which polygraphic recordings permit REM or NREM arous¬
als. In practice though, many brief intervals of NREM
sleep are possible on the treadmill because the animal
rushes to the beginning of the treadmill and "sleeps" or
rests for 15 to 20 seconds until the end of the run. Fergu¬
son and Dement recorded cats on the treadmill and found
"slowing of the EEG suggestive of sleep even though the
cats were usually in a sitting position," and calculated if
all possible time were utilized for sleep, the cat would have
been sleeping as much as 40% of the time on the treadmill.
Though the exact amount of sleep was not systematically
determined, preliminary data suggested that this max¬
imum was unrealized.21
Thus, in treadmill-arousal studies, the experimental and
control animals do differ in REM sleep, but strictly speak¬
ing, because a treadmill deprives animals of so large a
proportion of total sleep, a treadmill-arousal study as¬
sesses the difference between substantial sleep depriva¬
tion and the interaction of substantial sleep deprivation
with REM sleep deprivation. The theoretical possibility
that the interaction produces confounds of REM sleep
deprivation, eg, stress, weight loss, and fatigue, which are
not present in the control group, has not been reported.
Generally, studies using this technique probably do assess
the effects of REM sleep deprivation, but future empirical
work would determine if confounds of the interaction are
not the decisive independent variable.
EFFECTS OF REM SLEEP DEPRIVATION ON ANIMALS
A number of studies indicate that REM sleep depriva¬
tion increases indicators of waking central excitability,
particularly cortical excitability. Five separate studies
found that REM sleep deprivation decreases electrical
threshold for waking seizures.19·2225 In a well-controlled
study, Cohen and Dement22 found that rats on small plat¬
forms for six days had significant decreases in seizure
threshold, while those on large platforms had a slight but
insignificant increase. Owen and Bliss, using different but
thorough controls, reported similar results.19 In a related
study, Cohen and Dement found that, compared with rats
on large platforms, rats on small platforms had a signifi¬
cantly longer tonic phase of electrically induced convul¬
sions. Less well-controlled studies in mice24 and cats25 also
reported that REM sleep deprivation decreased seizure
thresholds.
In a well-controlled study, Dewson et al, using the
combination treadmill-hand arousal technique, found that
REM sleep deprivation facilitates recovery of cortical po¬
tentials evoked by external auditory stimuli.26 The ob¬
served facilitation could not have been due to sleep loss
because polygraphic records showed no significant differ¬
ences between experimental and control groups in TST,
and there was no change in cortical recovery function
when cats were totally sleep-deprived.
In a related study, Satinoff et al found that, dur¬
ing seven days on small platforms, cats had an increase
in paleocortical excitability as measured by evoked re¬
sponses.27 Unfortunately, as the authors point out, there
were no large platform controls for variables such as sleep
loss, stress, and arousals. In view of the controls in the
Dewson study, the combined evidence suggests that REM
sleep deprivation does increase waking cortical excitabil¬
ity.
Satinoff et al found that during seven days on the small
platforms, cats had a decrease in excitability of the pri¬
mary sensory afferent pathways, as measured by evoked
potentials in hindbrain sensory areas to stimulation of
hindbrain sensory nuclei. They reconciled their finding of
decreased hindbrain sensory excitability with the para¬
doxical finding by Dewson of increased neocortical sen¬
sory excitability with the interpretation that REM sleep
deprivation increases cortical amplification of external
stimuli while it produces a filtering or inhibition of periph¬
eral sensory stimuli. In looser terms, these findings raise
the speculation that REM sleep deprivation intensifies—or
sharpens the focus on—external sensory stimuli by hind¬
brain inhibition of internally generated signals and simul¬
taneous cortical amplication of external signals.
Effects on Motor Activity and Waking
Drive-Oriented Behavior
Although it is a part of folklore that REM sleep depriva¬
tion increases motorie activity, only one study on rats ap¬
pears to report this effect. After three days on flower pots,
REM-deprived rats were found significantly more active
as measured by cage crossing than the control rats on
large platforms.16
The number of studies on waking motivated behavior is
another story. Morden et al examined the effects of REM
sleep deprivation on shock-induced fighting in rats who
were in dry cages and on small and large pedestals.2* Af¬
ter one day of treatment there was no effect. But at three,
five, and seven days of the treatment, rats on small plat¬
forms had a progressive and significant increase in the
number of fighting responses while rats on large plat¬
forms and rats in cages remained at base line levels. The
absence of an experimental-control difference in fighting
at 24 hours and its presence at 72 hours is consistent with
data11·12 that REM sleep is the same in rats on large and
small platforms at 24 hours and significantly different at
96 hours. Interestingly, 16 days after termination of the
platform treatment, rats that were on small platforms
still fought significantly more frequently than the con¬
trols.
In a related controlled experiment,29 when ampheta¬
mines were administered to rats after four days of the
platform condition, rats on small platforms showed signif¬
icantly more aggressive posturing and sexual mounting
than those on large platforms and those that were non-
platform controls. Since neither the amphetamine nor the
platform condition alone elicited this, it was concluded
that REM sleep deprivation and amphetamines together
enhanced or released stereotyped sexual and aggressive
behavior. The authors note this is similar to the enhancing
effect of REM deprivation in releasing aggressive behav¬
ior in electrically shocked rats. An abstract reports that
after two and five days of deprivation, male rats on small
platforms who were low base line copulators had a signifi¬
cant increase in copulation rate but rats on large plat¬
forms did not change.30 In cats, REM sleep deprivation, by
an uncontrolled treadmill-arousal technique, has been re-
ported to increase sexual behavior, motivation to obtain
food, and grooming behavior.31 Caution in such conclusions
seems additionally justified by the report that two cats did
not show an increase on a cat emotional behavior scale (of
unknown validity and reliability) during three to ten days
of REM sleep deprivation.32
The effect of REM sleep deprivation on intracranial self-
stimulation is another indicator of motivational behavior.
Compared with both yoked and nonyoked rats on large
platforms for four days, rats on small platforms showed
significantly lower thresholds of intracranial self-stimula¬
tion and significantly higher response rates.17·33 Indeed, no
control animal "demonstrated either a lowering of thresh¬
old or an increase in self-stimulation." The increase in re¬
sponse rate in the experimental animals was not a result
of a nonspecific increase in general activity because the
response rate in the experimental animals did not in¬
crease at zero intensity of stimulation.
Therefore, in rats, REM sleep deprivation reliably low¬
ers threshold for and increases the response rate of in¬
tracranial self-stimulation, and REM sleep deprivation
probably increases stimulus-evoked aggressive and sexual
behavior. In cats, uncontrolled studies indicate that REM
sleep deprivation increases sexual, eating, and grooming
behavior, but does not change an undefined, possibly unre¬
liable measure of "emotional behavior." Though the case
for these motivational effects is not incontrovertibly
proven, it seems that the sum of the behavioral evidence
with the evidence on heightened neural excitability dur¬
ing wakefulness makes it probable that REM sleep depri¬
vation does increase the animal's motivational behavior.
The Effects of REM Deprivation on Learning
It has been claimed that REM sleep deprivation inter¬
feres with learning in at least two different ways. It is
said to impair memory for tasks learned prior to REM
sleep deprivation and it is said to impair the acquisition of
new learning.5
In this regard, there are three methodological issues
useful to consider.
1. Studies show that both small and large platforms are
stressful.71115 Other studies show that stress in rats pro¬
duces learning deficits.'4 3li Hence, stress controls are par¬
ticularly important in these studies.
2. Since Mendelson et al have shown that at 24 hours
the animals on small and large platforms are equally REM
deprived,12 any small-large platform differences in learn¬
ing that appear in the first 24 hours of the platform exis¬
tence cannot be due to REM sleep deprivation.
3. This methodological point was suggested to me by
Charles Ksir, PhD, and Allan Rechtschaffen, PhD (oral
communication, March 1974). Let us assume that the large
platform were a perfect control for the small platform and
that the only variable by which rats on large and small
platforms differed was REM sleep deprivation. Assume
also that rats are trained to a task; then immediately
placed on large and small platforms for four days and
that, afterwards on retention tests, the rats that were on
small platforms performed significantly less well than the
large platform rats. We would still not be able to conclude
that REM sleep deprivation impaired memory for that
task, because REM sleep deprivation may have impaired
performance of the task without impairing memory. In or¬
der to conclude that REM sleep deprivation did not impair
performance, we need another control—one in which rats
were trained, then placed on platforms for three or four
days, then tested immediately after removal from the
platforms, and again tested a few days later. If a per¬
formance deficit appeared immediately after REM sleep
deprivation but was absent in the later testing, then one
would have to conclude that REM sleep deprivation im¬
paired performance but not memory of the task. Now the
punch line is that, with the exception of Fishbein's
work,37·38 so far as I can determine, no study of the effect
of REM sleep deprivation on retention of a task learned
before the deprivation has used such a control for per¬
formance deficit.
On that pessimistic note, let us turn first to the specific
studies of the effects of REM sleep deprivation on mem¬
ory, or retention, and lean heavily on Stern's clarifying re¬
view.5 Pearlman and Greenberg,39 Stern,40 and Fishbein37
concluded that REM sleep deprivation impaired memory
for a passive avoidance task learned prior to the depriva¬
tion. However, "all these studies lacked NREM sleep loss
controls, the mice experiments lacked adequate stress con¬
trols,"5 the Pearlman and Greenberg study found small
and large platform differences at 24 hours, a time when
small and large platform animals have equal losses of
REM sleep, and, with the exception of Fishbein's work,
none of the studies contained the necessary performance
deficit control suggested by Rechtschaffen and Ksir. As
Stern points out: "a non-memory impairment perform¬
ance decrement might result from sickness, activity level
change, change in motivation."5 Stern also writes, "it is
also possible to interpret the results as a REM depriva¬
...
tion state dependent phenomenon because the perform¬
ance impairments of the preceding studies occurred when
training was given in the normal state and retention test¬
ing was given in the REM deprived state."5 Indeed, either
performance impairment or state dependency seem likely
explanations of the finding, because in Fishbein's studies
of a passive avoidance task learned prior to REM sleep
deprivation, a retention deficit existed one half hour and
three hours after REM sleep deprivation, but no perform¬
ance decrement occurred if 24-hour recovery to the normal
state was permitted.37·38 With regard to active avoidance
tasks, two independent studies on rats, by Albert et al16
and Joy and Prinz,41 have failed to show that REM sleep
deprivation impairs retention of such a task.
More recently, Pearlman and his colleagues42'45 have
concluded that REM sleep deprivation in the rat, rather
than affecting simple avoidance tasks, impairs retention
of complex tasks, such as latent extinction, shuttle box
learning, and discrimination learning. But their studies,
which induced REM sleep deprivation by small platforms,
lacked animals on large platforms—or their equivalents—
to control for confounds such as persistent stress and wet¬
ness, sleep loss, weight loss, arousals, and performance
deficits.
In a series of reports about learning in mice, Fishbein
concluded that REM sleep deprivation impaired the con¬
version of short-term memory to long-term memory for
various tasks learned both prior to and after the depriva-
tion."·38·46 However, in part because there were no controls
on large platforms, these studies lacked any systematic
controls for wetness, stress, and restriction.
Stern provides perhaps the most persuasive evidence
that REM sleep deprivation impairs subsequent new
learning.40 Specifically, he found that prior REM sleep
deprivation impaired learning of an active avoidance task,
a passive avoidance task, and an alternation discrimina¬
tion task.
Acquisition of these tasks was significantly poorer in the REM
deprivation condition when compared to normal rats, cold water
stress controls, and NREM sleep loss controls—the latter control
was not conducted for the alternation discrimination. These ap¬
parent REM deprivation-induced learning deficits were probably
not due to (1) dissociation—both training and testing were con¬
ducted in the REM deprivation state; (2) altered activity levels—
both active and passive avoidance were impaired; (3) lowered
shock reactivity—REM deprivation produces an increased reactiv¬
ity to electric shock; and (4) a generalized nonspecific performance
impairment—performance of active avoidance trained prior to
REM deprivation was not disrupted. So [Stern concluded], since
the learning impairments occurred in three different tasks, it is
also unlikely that these effects were due to some unique property
of the behavioral testing situation.5
Though these elegant experiments are very compelling
arguments for the conclusion that REM sleep deprivation
impairs new learning, there are some qualifying consid¬
erations.
First, though Stern concluded that acquisition of pas¬
sive avoidance learning was impaired after REM sleep
deprivation, this was based on a comparison between
small platform and cold water stress controls. He found no
performance difference between rats on small platforms
and those on large platforms,40 a negative finding repli¬
cated by Miller et al.18
Second, though Stern found that acquisition of an active
avoidance task was impaired after experience on the small
pot compared with that on the large pot, three indepen¬
dent studies were unable to confirm this finding, (Albert
et al,16 Joy and Prinz,41 and Miller et al.18
And, third, though Stern concluded that acquisition of
an alternation discrimination task was impaired by REM
sleep deprivation, this conclusion was based on a compari¬
son of animals on small pots with cold water, one-hour day
controls. Other possible confounds of the platform proce¬
dure (ie, number of arousals, persistent rather than inter¬
mittent stress, and restriction) were not controlled.
In conclusion, the weight of evidence indicates that be¬
cause of many confounding variables, the effects of REM
sleep deprivation on retention and on new learning re¬
main unclear.
REM SLEEP DEPRIVATION IN HUMANS
Fifteen years ago, before the studies of Foulkes and his
colleagues demonstrated that dreaming occurred outside
of REM sleep,4748 REM sleep deprivation was called
"dream deprivation" and was considered to be dream
elimination, because it was thought that REM sleep was
the exclusive physiological correlate of dreaming. So the
initial studies of REM sleep deprivation reported that
"dream deprivation" produced anxiety, irritability, and
difficulty in concentrating, all of which disappeared after
a single night of uninterrupted sleep that contained the
REM rebound and none of which appeared during a period
of control NREM awakenings.1 As a result of these find¬
ings, it was speculated that prolonged "dream depriva¬
tion" would produce a serious disruption of the waking
personality and that a certain nightly quota of dreaming
or dreaming sleep was necessary for the integrity of the
waking personality. The first interpretation of the psycho¬
logical results of the "dream deprivation" experiment was
that regular, abundant, nightly dreaming served as a
safety valve to discharge the accumulated psychological
tensions of the day, and that, if discharge of that valve
was blocked by experimental intervention49 or by disease,
particularly schizophrenia50 and depression,51 serious psy¬
chological symptoms would occur during wakefulness. The
following discussion will critically review studies about
this issue of the behavioral or psychological effects of
REM sleep deprivation on healthy human subjects, schizo¬
phrenic patients, and depressive patients, and finally will
draw some conclusions about the implications of this
procedure.
Let us first dispose of the original—and mistakenly per¬
sistent—notion that REM deprivation is dream elimina¬
tion.
First, mental activity that is often visual and hallucina¬
tory is frequently reported from NREM sleep.47 And
although NREM reports and REM reports are 90%
discriminable,52 this distinction is often based on
characteristics other than visual hallucinations47·52·53; and
the discrimination between NREM and REM reports is
less in light sleepers when stage 2 reports are compared
with REM reports.54
Second, four separate studies have shown that frequent
dreaming occurs at sleep onset in the absence of REM
sleep.48·5557 Indeed, Foulkes and I reported that during
sleep onset, dreams, defined as hallucinated, dramatic epi¬
sodes—not just single isolated images—constituted 31% of
alpha REM reports, 43% of alpha slow eye movement re¬
ports, 76% of descending stage 1 reports, and 72% of de¬
scending stage 2 reports.48 Foulkes and his colleagues
showed that alpha slow eye movement and stage 1 sleep
onset reports were indistinguishable from REM reports in
terms of mean length, sexual content, aggressive content,
hedonic content, and dreamlike fantasy.55 In a discrimina¬
tion task based on the assumption that REM reports are
more dreamlike than sleep onset reports, I and my col¬
leagues found that 50% of REM reports were called sleep
onset and 25% of sleep onset reports were called REM.56
Thus, among experimental manipulations of sleep, only
total sleep deprivation—not REM sleep deprivation-
would produce dream elimination. And very recent and
dramatic findings by Foulkes imply that even total sleep
deprivation would not be dream elimination. Foulkes has
reported that during relaxed wakefulness without drugs
and without prior sleep deprivation and in the presence of
an awake non-alpha EEG, subjects frequently report hal¬
lucinated experiences that are similar to dreams.58·59 In
short, dreaming, similar to and often indistinguishable
from REM reports, occurs in all the other conventional
natural states of consciousness that sleep researchers rec¬
ognize, viz, wakefulness, sleep onset, and NREM sleep.
Thus, REM sleep deprivation cannot be dream elimina¬
tion.
To return to REM sleep deprivation, Dement and Fisher
reported initial studies of 21 subjects who were REM
sleep-deprived for two to seven consecutive nights60 and
Sampson described six subjects who were REM sleep-de¬
prived for three consecutive nights.61 Both reported dele¬
terious psychological effects of the procedure. But, as pre¬
viously reviewed62 (to 1968), other studies of similar
durations of REM sleep deprivation failed to confirm
these findings: Kales et al described two patients who
were REM sleep-deprived for six nights and two patients
REM sleep-deprived for ten nights63; Dement and Fisher,
one patient REM sleep-deprived for 12 nights60; Snyder,
two patients REM sleep-deprived for an unspecified num¬
ber of nights64; and Foulkes et al, eight subjects REM
sleep-deprived for one night.65 Also, my colleagues and I
found no harmful effects of REM sleep deprivation in
mentally ill subjects who were presumably highly vulner¬
able to psychological disruption, ie, five schizophrenic sub¬
jects REM-deprived for seven consecutive nights,66 and
nine seriously depressed subjects REM sleep-deprived for
7 to 14 consecutive nights.67·68
Resolution of these contradictory findings about the
harmful effects of REM sleep deprivation was suggested
by Dement who wrote, "It seems likely that the psycholog¬
ical changes observed in the earlier studies were an arti¬
fact of the experimental procedures and the expectations
of the experimenters."69<p5991 More specifically, analysis of
the early Dement and Fisher60 and Sampson61 studies
shows that one or more of several confounds could have
accounted for the results: (1) control NREM awakenings
often were not used; (2) whether or not control awak¬
enings were used, subjects were apparently aware of ex¬
perimental and control conditions; (3) the testers of psy¬
chological change were not blind about control and
experimental identity; and (4) either reliable measures of
psychological change were not used, or if used, they
showed no harm resulting from the procedure.
Thus, by the mid 1960s, the evidence refuted the hypoth¬
esis that REM sleep deprivation to about ten days was
harmful. Nevertheless, about this time Dement and col¬
leagues, through the use of a combination of ampheta¬
mine treatment and hand awakenings, REM sleep-de¬
prived two subjects for the longest ever attempted to that
time—15 and 16 consecutive nights—and reported dra¬
matic personality changes70 that another author called
psychotic symptomatology.71 Since these two cases of pro¬
longed REM sleep deprivation constitute, so far as I know,
the only cases in which experimental REM sleep depriva¬
tion has been claimed to produce serious symptomatology,
and since sleep researchers still cite them as examples of
the harmful effects of REM sleep deprivation, it is impor¬
tant to examine these results in some detail.
First, NREM control awakenings were not used and
amphetamines were used, so the effects of REM sleep dep¬
rivation are confounded by the effects of multiple awak¬
enings on each night for more than two weeks, by the ef¬
fects of chronic partial sleep loss, and by the effects of
amphetamines. Second, no controls for observer bias were
used. And third, in my opinion, the observed psychological
changes were not by any stretch of the imagination psy¬
chotic. One subject—a taciturn, inhibited, puritanical per¬
son—became after 14 nights of REM sleep depriving
awakenings voluable and annoyed, and wanted to go to a
burlesque show and to a tavern and cheat a waitress. Such
changes are clearly not psychotic! The second subject, a
schizoid and suspicious person became after 13 nights of
awakenings for REM sleep deprivation more suspicious in
that it occurred to him that his friends were belittling him
and he developed unspecified paranoid and autistic idea¬
tion. In the absence of controls for REM sleep deprivation
and of any specific data that this subject developed delu¬
sions, hallucinations, confusion, or loose associations, I
cannot conclude that the REM sleep deprivation produced
psychotic changes. A simpler explanation is that a natu¬
rally suspicious and withdrawn individual, having been ir¬
ritated by multiple awakenings for 14 to 16 consecutive
nights became more talkative about his suspicions. In
other words, for both subjects there were confounds of in¬
dependent and dependent variables and the dramatic in¬
terpretation that REM sleep deprivation produced psy¬
chotic changes seems unjustified.
Later, in 1969, Dement candidly disclaimed this inter-
pretation.72<p247) Yet, the notion of harm from REM sleep
deprivation continues to exist with implacable persistence
in the face of all the empirical evidence and disclaimers to
the contrary. Let me, therefore, add two more observa¬
tions to those already given. (1) Recently in our labora¬
tory, we REM-deprived a depressed woman for 25 con¬
secutive nights, so far as I know the longest ever achieved
in humans. She improved during this period. Also, (2) in
our study of the effects of REM sleep deprivation on de¬
pression, each of 50 hospitalized, depressed patients have
been REM-deprived for several weeks with an occasional
intermittent single recovery night to keep the number of
awakenings from becoming inordinately great. No pa¬
tient has become significantly worse or become schizo¬
phrenic, and most have improved. I conclude, as I did in
my 1968 review,62 REM sleep deprivation does not produce
psychological harm.
REM Sleep Deprivation and Schizophrenia
Though it is clear that REM deprivation does not pro¬
duce psychological disruption and though, even more per¬
tinently, Traub and I68 found that REM sleep deprivation
does not exacerbate schizophrenic symptoms, a finding
confirmed in three other studies (Azumi et al,73 de Barros-
Ferreira et al,74 and Gillin et al75), there is another possible
relationship between REM deprivation and schizophrenia
besides the causal one. The REM-deprived state may be a
correlate of schizophrenia—a physiological part of the syn¬
drome. According to this notion, the cause—or a cause—of
some, if not all, schizophrenia produces a number of ef¬
fects including the clinical symptoms and the REM-de¬
prived state. If verified, this finding would be of impor¬
tance because of the following: (1) it would be a reliable
physiological indicator of at least a subgroup of schizo¬
phrenia and, therefore, would be the first unequivocal
demonstration of a physiological abnormality in schizo-
phrenia; (2) it would have diagnostic and possibly thera¬
peutic and prognostic value; and (3) it would provide phys¬
iological and biochemical clues about a cause of some, if
not all, schizophrenia.
The evidence for a correlation between schizophrenia
and the REM-deprived state has recently been reviewed
by Wyatt et al.76 The following summarizes that review
and adds more recent work.
There have been several studies of REM sleep in schizo¬
phrenics. With few exceptions, these studies have not
found that REM sleep amounts in schizophrenic patients
are remarkably different from those in nonschizophren-
ics,66·7780 or more particularly, that REM sleep in halluci¬
nating schizophrenics is remarkably different from that in
nonhallucinating schizophrenics or nonschizophrenic
trols.77·79 Hence, most studies have not found evidence (eg,
low REM sleep amounts) to support the hypothesis that
schizophrenics are REM-deprived and have not found evi¬
dence (eg, high REM sleep amounts) to support the hy¬
pothesis that schizophrenics have increased REM pres¬
sure. Nevertheless, the review points out that three
studies reported schizophrenic subgroups to have less
REM time than controls. In one, acute schizophrenic pa¬
tients had less REM sleep than chronic schizophrenic sub¬
jects77; in another, chronic, actively ill schizophrenics had
less than normal subjects81; and in the third, schizophren¬
ics in the waxing, early phase of their illness had de¬
creased TST and disproportionately decreased REM time
that in the same patients normalized during the later,
waning phase of illness.82 The reviewers found "the ab¬
sence of subsequent REM rebound .
[during the waning
..
phase of the illness] surprising, particularly since psychot-
ically depressed patients with similar REM deficits evi¬
denced very large REM rebounds upon recovery."76 In ad¬
dition, studies by Zarcone et al83 and by Azumi et al73
found that active schizophrenic patients did not show nor¬
mal REM rebound following experimental REM depriva¬
tion. More recent work by Gillin et al,75 published after the
review, supported this finding. The review discounted
our66 finding of normal REM rebounds in schizophrenics
on the grounds that the REM deprivation was accom¬
plished by amphetamines whose withdrawal is known to
produce a REM rebound; and that the schizophrenics were
without florid symptomatology, and, hence, similar to re¬
mitted schizophrenic patients who were reported not to
have REM rebounds. Thus, taking the naturalistic and ex¬
perimental studies together, the review tended to support
the conclusion that absence of REM rebound may be an
important, perhaps pathognomonic, feature of schizophre¬
nia. Nevertheless, the review carefully qualified this sup¬
port by stating that "none of these theories has been con¬
sistently supported by experimental evidence."
As I understand it, the hypothesis that lack of REM
rebound is a (? distinctive) feature of schizophrenia is
based on three poorly supported propositions, viz, de¬
creased REM time in acute and actively symptomatic
chronic schizophrenics; large REM rebounds during the
waning phase of depression; and abnormally low REM
rebound in schizophrenic patients following experimental
REM deprivation.
With regard to the first proposition, the assertion that
the waxing phase of schizophrenia is characterized by a
decrease in REM sleep that is disproportionately greater
than the decrease in NREM sleep is based on the errone¬
ous assumption that the relation between REM sleep du¬
ration and NREM sleep duration is linear. It is well-estab¬
lished that the proportion of REM sleep increases as the
night progresses. Using Verdone's normative data on
amount of REM sleep for each hour of NREM sleep,84 I
calculated the amount of REM sleep that normal subjects
have in that duration of NREM that the schizophrenic pa¬
tients had during the waxing phase of their illness and I
found no physiologically important REM sleep differences
between schizophrenics and normals, ie, normal subjects
show the same difference without any striking correspon¬
con¬ dence with behavior. The reviewers cited another report
that showed that short-term schizophrenic patients had
significantly less REM sleep than long-term schizophren¬
ics, but the same report found no significant REM sleep
differences between short-term schizophrenics and non-
schizophrenic controls.77 Thus, the claim that ". acute
. .
and actively symptomatic chronic schizophrenic patients
reportedly evidence lower than normal amount of REM
sleep"76 appears to have little substantiation.
With regard to the second proposition, there is an infer¬
ence that lack of REM rebound may be specific to schizo¬
phrenia. This notion arises from a loose citation of Sny-
der's work85 that large REM rebounds occur in the waning
phase of depression. But Snyder does not generalize and
gives data on REM sleep rebounds for only one of nine pa¬
tients studied longitudinally. Nor can I find substantial
verification in other relevant writings by Snyder of the
claim that, on recovery, depressive subjects have large
rebounds.86-88 On the contrary, two independent studies,
one by Hartmann89 and the other by Bunney et al90 found
that, at least for manic depressive patients, as depression
lifts, REM time decreases.
With regard to the third proposition, the evidence that
schizophrenics do not have a REM rebound following ex¬
perimental REM deprivation is based on studies by Zar-
cone et al,83 by Azumi et al,73 and by Gillin et al.75 In the
first two studies, statistical comparisons of experimental
vs control differences were not presented in the original
report, possibly because of the small number of subjects
used in each study. My statistical testing of their data by
use of the Mann-Whitney U test discloses no significant
differences between schizophrenic and control groups in
various measures of REM rebound. In the Zarcone study,
there were no significant differences between schizo¬
phrenic and control patients for total REM time on first
recovery night (P>.3) and for average nightly REM per¬
cent of the five recovery nights (P=.2). In the Azumi
study, the experimental-control differences in the first
night's recovery REM percent and in three nights' recov¬
ery REM percent have probability of occurrence under the
null hypothesis of P= .350. Thus, although the small sam¬
ples of these studies make interpretation difficult, the Zar¬
cone and Azumi data actually contradict the theory that
schizophrenic and normal subjects have significantly dif¬
ferent REM rebound following experimental REM depri¬
vation. However, in the work of Gillin et al, compared
with nonschizophrenic controls, schizophrenic patients did
have astatistically significant smaller REM rebound, al¬
though some individual schizophrenic subjects had higher
REM rebounds than some nonschizophrenic controls. The
overlap suggests either that the schizophrenic subjects
constitute a biologically heterogenous group in which
some have low REM rebound and some do not; or that
schizophrenia is imperfectly correlated with more funda¬
mental (ubiquitous) variables that really determine REM
rebound (and that are not limited to schizophrenia). In¬
deed, in the Gillin study, at least two more fundamental
variables were confounds of schizophrenia as an explana¬
tion of the REM rebound phenomena. In the pooled group
of schizophrenics and controls, TST correlated with REM
rebound and, as suggested by Cartwright and others,91
field independence correlated with REM rebound.
While an explanation for the relation between field in¬
dependence and REM rebound is not clear, I think there is
a persuasive explanation for the relation between TST
and REM rebound. The subjects with reduced TST, par¬
ticularly the schizophrenic subjects, may have had
disturbed sleep that occasionally awakened them from
REM sleep and thereby reduced REM rebound. Indeed,
Monroe's92 classic study of good and poor sleepers demon¬
strated just this phenomenon, ie, the subjects with less
TST had significantly less REM percent as a result of
more awakenings from REM sleep. Thus, although Gillin
et al show that schizophrenic REM rebound is signifi¬
cantly less than nonschizophrenic REM rebound, the ef¬
fect of confounding variables obscures the relationship of
REM rebound to schizophrenia. In opposition to this, two
studies (Traub and I66 and de Barros-Ferreira et al74—the
latter published after the review) found normal REM
rebounds in schizophrenics. However, our finding is con¬
founded by the fact that REM deprivation was accom¬
plished by awakenings plus use of dextroamphetamine, a
REM-depriving drug whose discontinuation is associated
with a REM rebound. Hence, our finding of normal REM
rebound in schizophrenia might be a response to the drug
rather than to the awakenings. This argument is some¬
what weakened by Dement's report that the effects of ex¬
perimental awakenings and of dextroamphetamine on
REM rebound are additive.70 If that is the case, then our
finding of normal REM rebounds in schizophrenics REM-
deprived by awakenings plus use of dextroamphetamine
treatment cannot be explained as the sole result of normal
response to the drug.
Nevertheless, the question of REM rebound in schizo¬
phrenia is still unanswered. In all but one of the studies of
schizophrenic patients, experimental REM deprivation,
whether by awakenings or by awakenings plus ampheta¬
mines, produced no significant REM rebound differences
between schizophrenic and normal subjects. But the one
exception (Gillin et al) occurs in the most well-controlled
study and, hence, the issue remains unresolved and re¬
mains to be decided by future experimental work.
REM
Sleep Deprivation and Depression
Another report presented in greater detail the most re¬
cent findings by myself and others in an experimental test
of the hypothesis
that REM sleep deprivation, which in¬
creases REM pressure, alleviates depression (see 765).
(Increased REM pressure is a particular response to REM
sleep deprivation present during and immediately after
administration of an agent that decreases REM sleep,
such that following the withdrawal of the REM-decreas-
ing agent, there is more REM sleep than before its admin¬
istration.)
In brief, the findings were as follows: Thirty-four
endogenous and 18 reactive depressive patients—hospi¬
talized, moderately to severely ill, and without schizophre¬
nia, organic brain disease, and drug abuse—were treated
in a double-blind, crossover study of the hypothesis
that increased REM pressure, produced by REM-reducing
awakenings, will relieve depression. A total of 4,620 sub¬
ject nights were recorded by polygraph, coded, and scored
for wakefulness, and NREM and REM sleep. On nights of
experimental awakenings from REM sleep, REM percent
was significantly less than on base line nights and control
awakening nights. On nights of control awakenings from
NREM sleep, REM percent was not significantly less than
on the base line nights. Thus, experimental patients were
REM-deprived and control patients were not. In endoge¬
nous depressive patients, compared with pre-crossover
controls, experimental patients improved significantly
more and became significantly less depressed. Control pa¬
tients did not improve significantly before crossover but
did after crossover, though the pre- vs post-crossover im¬
provements were not significantly different. In reactive
depressives, experimental patients did not improve more
than the control patients. Eleven endogenous patients,
unimproved by REM deprivation were treated with imi¬
pramine hydrochloride and ten failed to improve. The re¬
sults supported the hypothesis that REM deprivation with
increased REM pressure relieves endogenous but not reac¬
tive depression and that antidepressants work, at least
partly, by decreasing REM sleep and increasing REM
pressure.
A number of objections have been made to this hypothe¬
sis in the six or seven years since its first publication. The
early ones, based in part on the limited nature of the pre¬
liminary data, are answered by our recent, more extensive
data. There have also been two persistent objections based
on sleep laboratory drug studies. These are as follows: (1)
If REM sleep deprivation that increases REM pressure al¬
leviates depression, then antidepressant drugs ought to
decrease REM sleep more than non-antidepressant drugs
and they do not. And (2) the antidepressant drugs ought
to increase REM pressure and they do not. I will now try
to show that these objections represent misconceptions of
the drug findings that do support the hypothesis.
With regard to the first objection, a review of the lit¬
erature on drugs in humans shows that there are signifi¬
cant differences in the REM-reducing potency of anti¬
depressants and non-antidepressants. More precisely, the
review shows that compared with non-antidepressants,
the antidepressants reduce REM sleep much more, for
longer periods, and with the development of noticeably
less tolerance to the REM-reducing effect. These differ¬
ences are important for the REM pressure hypothesis be¬
cause, on the basis of studies of monoamine oxidase
(MAO) inhibitors, current evidence suggests that the ther¬
apeutic effects of antidepressant drugs occur only after
REM sleep had been reduced and maintained to a certain
minimum level, which is probably at or lower than 10% of
TST.93"95 The "threshold effect" may explain why other
REM-reducing drugs do not have antidepressant effects.
They do not reduce REM sleep below that threshold or
cannot maintain it below that threshold because tolerance
quickly develops to the REM-reducing properties of the
drug.
Several studies report that in clinically effective doses,
MAO inhibitors suppress REM sleep to less than 10% of
TST and most often to less than 5% of TST. This includes
four studies using phenelzine sulfate,9396 two studies with
nialamide,97·98 and one study with isocarboxazid, pargyline
hydrochloride, phenelzine, and mebanazine.99 The MAO in¬
hibitor reduction of REM sleep is also of relatively long
duration because REM rebound following MAO inhibitor
withdrawal usually occurs only after several days without
the drug.93 94·99 Prolonged administration of MAO inhib¬
itors (eg, to 52 days) has not been associated with toler¬
ance to its REM-reducing properties.93·94·99 Also, three re¬
cent studies, originating with Akindele et al, Wyatt et al,
and Dunleavy and Oswald, have shown that "sustained
mood improvement" during treatment of depression with
MAO inhibitors begins at the time of maximum suppres¬
sion of REM sleep, often at a level of 5% of TST or
lower.93"95
Clinically effective tricyclic antidepressants also pro¬
duce substantial and sustained reductions of REM sleep.
Three studies of imipramine1"0102 and two studies of ami¬
triptyline hydrochloride100103 show that both these drugs,
which are effective antidepressants,104108 reduce REM
sleep 5% to 10% of TST, and though tolerance to the REM
suppressant effect of imipramine hydrochloride has been
shown to develop in a month of daily administration of
subclinical doses of 75 mg/day, even at the end of the
month, REM percent was at about the level of 10% of
TST.102 Desipramine, which one study has shown to be
more effective than placebo but less effective than imipra¬
mine in treating hospitalized depressives,105 reduces REM
sleep to less than 10% (but more than imipramine) and tol¬
erance to its REM suppressant effects is slightly more
than it is to imipramine.102 Three other tricyclics—doxepin,
iprindole, and trimipramine—have been claimed to be an¬
tidepressants and these do not have significant REM sup¬
pressant effects.102 Yet in my view, these drugs have not
been shown to be effective in treating serious endogenous
depressive patients. A search of Medlars II, NLM/
Medline, and Index Medicus to 1964 and the recent Mor¬
ris-Beck review of tricyclics108 did not disclose (with two
exceptions explained below) a double-blind study that tested
doxepin,108"127 iprindole,108·128144 or trimipramine108145151
against placebo in treating hospitalized endogenous de¬
pressives. The use of placebo is emphasized because
double-blind studies that find drug X to be no different in
treating depression than an efficacious antidepressant
(imipramine or amitriptyline) may mistakenly conclude
that drug X is an efficacious antidepressant. But such
studies do not prove the efficacy of drug X because they do
not disprove that placebo would also have done as well as
imipramine in the tested population. The two studies that
did test the drug against placebo were the following: (1)
Hunter et al found trimipramine no better than placebo'44;
and (2) Burrows et al found doxepin more effective than
placebo in treating hospitalized depressives.111 In the lat¬
ter study, since the patients, undiagnosed by kind of de¬
pression (eg, endogenous or reactive), had a mean age just
less than 40 years; and since factor analytic studies dis¬
close endogenous depression to be a disease of patients 40
and older,152154 there probably was not a test of the effi¬
cacy of doxepin in treating endogenous depression. In any
case, although the bibliographic search did not show stud¬
ies proving doxepin, iprindole, and trimipramine to be ef¬
fective against endogenous depression, it did show that
imipramine104·105108 and amitriptyline106108 were signifi¬
cantly more efficacious than placebo. Hence, the relation¬
ship between efficacy of tricyclics in treating endogenous
depression and their REM suppressant effects is not con¬
tradicted by current empirical data.
In contrast to the antidepressants, REM-reducing drugs
without antidepressant effects produce only mild to mod¬
erate initial reductions of REM sleep in humans—well
above 10% of TST—with rapid development of substantial
tolerance to the REM-reducing effects.
Clinical doses of barbiturates have been reported to re¬
duce REM sleep to 15% to 20% of TST155"157 and tolerance
quickly develops to the REM-reduction effect, so that by
the end of one week or less of nightly barbiturate admin¬
istration, REM percent has returned to predrug base line
levels (over 20%).156157
In clinical doses, seven nonbarbiturate hypnotics, which
have been called REM deprivers, produce no or minimal
initial decreases in REM sleep (typically levels of 18% to
21% of TST), and tolerance to them is rapid, so that by the
third consecutive night of drug administration, REM per¬
cent reaches essentially predrug levels.156·158
Meprobamate, which is also called a REM depriver, re¬
duced REM sleep from 24% to 20.5%.159 Alcohol reduced
REM percent to about 15% of TST and REM percent re¬
turned to base line levels within less than a week after its
continuous administration.160161
Though in cats diphenylhydantoin sodium has been re¬
ported to reduce REM percent by one half,"12 in humans
diphenylhydantoin does not suppress REM sleep.163·164
As for biogenic amines and related compounds, my
reading of human studies of L-tryptophan,1651"7 5-hy-
droxytryptophan,168 parachlorophenylalanine,169 and levo¬
dopa170 is that these drugs produce little or no suppression
of REM sleep, certainly nothing near 10% of TST.
The narcotics, morphine and heroin, substantially de¬
crease REM sleep to about 10% of TST or lower-depend¬
ing on the dose.171·172 However, the narcotics differ from
antidepressants in their effect on REM sleep because with
continued administration of narcotics, REM percentages
quickly increase, ie, tolerance develops, eg, by the third
night REM percent is greater than 15%.'7' ,7) ,71
Amphetamine and related compounds (which may have
mild antidepressant effects) suppress REM sleep moder¬
ately but not as extensively as the MAO inhibitors and tri¬
cyclics.175 Again, tolerance to dextroamphetamine's
REM-reducing properties rapidly develops, with REM per¬
cent at predrug levels on the third night of administra¬
tion.175·176
 In summary, other than morphine, heroin, and dex¬
troamphetamine, all of which have euphorigenic proper¬
ties, the drugs reviewed do not reduce REM sleep to near
10% of TST, and 10% is probably higher than that pro¬
duced by therapeutic doses of antidepressants. In contrast
to antidepressants, with continued administration of nar¬
cotics, dextroamphetamines, and other milder REM sup¬
pressants, tolerance develops almost immediately so that
REM sleep increases to about predrug levels within a
week or less. Thus, the evidence does not support the view
that drugs other than the major antidepressants (MAO in¬
hibitors and the tricyclics) produce a drastic and sustained
reduction of REM sleep.
With regard to the second objection, evidence is now ac¬
cumulating that antidepressant drugs produce a rebound
following their withdrawal. Probably this was not previ¬
ously reported because of the long delay in the REM
rebound following tricyclic or MAO inhibitor withdrawal.
Thus, three studies of MAO inhibitors94'96" and three
studies of tricyclic antidepressants100·102177 reported that,
on discontinuation of the drugs, a substantial REM
rebound occurred, though it was often delayed or it
peaked several days after discontinuation. In other words,
antidepressant drugs do not reduce the need for REM
sleep by substituting for REM sleep because the REM
rebound following their withdrawal indicates that a need
for REM sleep accumulated during their administration.
Rather, the antidepressant drugs reduce REM sleep and
increase the need or pressure for REM sleep.
In conclusion, the sleep laboratory drug studies are con¬
sistent with the hypothesis that REM sleep deprivation
that increases REM pressure improves depression. In ad¬
dition, since the results of the direct experimental test of
the REM deprivation hypothesis suggested that such dep¬
rivation causes recovery from depression, and since causal
experimental tests of the amine hypotheses of drug recov¬
ery from depression (ie, loading with either catachola-
mine177"181 or indole amine179·182·183 precursors) have not
clearly improved depression, the REM pressure hypothesis
is, at present, the only one about the mechanism of drug
recovery from depression that has both causal and corre¬
lational support.
The hypothesis that REM sleep deprivation improves
depression in humans is also consistent with evidence on
the effects of REM deprivation in animals. In the latter,
the evidence is that REM sleep deprivation increases cor¬
tical excitability, may sharpen and intensify sensory per¬
ception (see Kopell et al for similar findings in humans),184
increases motorie activity, and increases motivated behav-
ior-particularly what is presumably pleasurable behavior.
These are changes with analogues that usually occur dur¬
ing recovery from endogenous depression whose hall¬
marks are psychomotor retardation, loss of interest in the
external world, inhibited aggression, and a lack of desire
for the elemental bodily pleasures.
And yet, in spite of the direct evidence in humans and
the extensive indirect human and animal evidence for the
hypothesis that REM sleep deprivation relieves depres¬
sion, of course the hypothesis has not been proved. Veri¬
fication requires that our direct results be replicated in an¬
other laboratory, preferably one skeptical about the
hypothesis.
Nevertheless, for the sake of discussion, let us assume
for the moment that the hypothesis will be verified so that
we can speculate about where that might lead.
I believe we get a clue from Shakespeare. In his first so¬
liloquy Hamlet says, "How weary, stale, flat, and unprofi¬
table seem to me all the uses of this world." He is de¬
pressed and he tells us what might be the essence of
depression—a loss of interest in everything and a sense of
futility about everything. In less poetic and more psy¬
chiatric terms, the affective charge that the undepressed
person attaches to mental content is missing in the de¬
pressive. The evidence that REM sleep deprivation ele¬
vates mood in depressed subjects61·66·67·92 but not in nonde-
pressed subjects161 resembles the recent finding of
Cartwright and Ratzel that REM sleep deprivation inten¬
sifies fantasy in fantasy-impoverished subjects but not in
subjects without fantasy impoverishment.185 These paral¬
lel findings suggest that REM sleep deprivation, or more
accurately, increased REM pressure, may increase only an
already diminished affective charge. In line with the as¬
sumption that mental phenomena are paralleled by physio¬
logical phenomena, it is not implausible that there is a
physiological correlate of change in affective charge. Per¬
haps in the REM sleep deprivation experiments, both hu¬
man and animal, we begin to have a clue about the physio¬
logical system, which, generally speaking, is involved in
the change or maintenance of affective charge and that in
the narrower psychiatric sphere, appears to be involved in
the recovery from a major mental illness.
I close with still another effort to describe my vague
term "affective charge." Exactly 80 years ago, an obscure
dream researcher wrote:
I refer to the concept that in mental functions something is
to be
distinguished—a quota of affect or sum of excitation—which pos¬
sesses all the characteristics of a quantity [though we have no
means of measuring it], which is capable of increase, diminution,
displacement, and discharge, and which is spread over the mem¬
ory—traces of ideas somewhat as an electric charge is spread over
the surface of a body.186
It is my guess that a clue about a physiological correlate of
that quota of affect is the upshot of Dement's seminal ex¬
periment on REM sleep deprivation.
This investigation was supported in part by state funds from the Georgia
Mental Health Institute, Atlanta, and by grant MH-18391-04 from the Na¬
tional Institute of Mental Health.
Nonproprietary Names and Trademarks of Drugs
Amitriptyline hydrochloride-.EÏCMA
Iprindole—Tertran.
Phenelzine sulfate-Nardil.
References
1. Dement WC: The effect of dream deprivation. Science
131:1705-1707, 1960.
2. Morden B, Mitchell G, Dement W: Selective REM sleep depri-
vation and compensation phenomena in the rat. Brain Res 5:339\x=req-\
349, 1967.
3. Jouvet D, Vimont P, Delorme F, et al: \l=E'\tudede la privation
selective de la phase paradoxale de sommeil chez le chat. CR Soc
Biol 158:756-759, 1964.
4. Vimont-Vicary P, Jouvet D, Delorme F: \l=E'\ffets EEG et com-
portementaux des privations de sommeil paradoxal chez le chat.
Electroencephalogr Clin Neurophysiol 20:439-449, 1966.
 5. Stern WC: The relationship between REM sleep and learn-
ing: Animal studies, in Hartmann E (ed): Sleep and Dreaming.
Boston, Little, Brown & Co, 1970, pp 249-257.
6. Fishbein W: Interference with conversion of memory from
short term to long term storage by partial sleep deprivation. Com-
mun Behav Biol 5:171-176, 1970.
7. Mark J, Heiner L, Mandel P, et al: Norepinephrine turnover
in brain and stress reactions in rats during paradoxical sleep dep-
rivation. Life Sci 8:1085-1093, 1969.
8. Mouret J, Pujol JF, Kiyono S: Paradoxical sleep rebound in
rat: Effects of physical procedures involved in intracisternal injec-
tion. Brain Res 15:501-506, 1969.
9. Duncan R II, Henry P, Karadzic V, et al: Manipulation of the
sleep-wakefulness cycle in the rat: A longitudinal study. Psy-
chophysiol 4:379, 1968.
10. Duncan R, Harvey P, Karadzic V, et al: Baseline sleep and
REM deprivation in the rat. Read before the Association for the
Psychophysiological Study of Sleep, Santa Monica, Calif, 1967.
11. Mendelson W, Guthrie R, Frederich G, et al: Should flower
pots be used for flowers, pot, or rats? Sleep Res 2:169, 1973.
12. Mendelson WB, Guthrie RD, Frederich G, et al: The "flower
pot" technique of rapid eye movement (REM) sleep deprivation.
Pharmacol Biochem Behav, to be published.
13. Stern WC: Stress effects of REM sleep deprivation in rats:
Adrenal gland hypertrophy. Read before the Association for the
Psychophysiological Study of Sleep, Boston, 1969.
14. Ling GM, Usher DR: Effect of REM and total sleep depriva-
tion on the synthesis and release of ACTH. Read before the Asso-
ciation for the Psychophysiological Study of Sleep, Boston, 1969.
15. Dement W, Levine S, Morden B, et al: Steroid responses to
stress of rats deprived of REM sleep by the water tank method.
Read before the Association for the Psychophysiological Study of
Sleep, Santa Monica, Calif, 1967.
16. Albert I, Cicala GA, Siegel J: The behavioral effects of REM
sleep deprivation in rats. Psychophysiol 6:552-560, 1970.
17. Steiner SS, Ellman SJ: Relation between REM sleep and in-
tracranial self stimulation. Science 177:1122-1124, 1972.
18. Miller L, Drew WG, Schwartz I: Effect of REM sleep depri-
vation on retention of a one trial passive avoidance response. Per-
cept Mot Skills 33:118, 1971.
19. Owen M, Bliss EL: Sleep loss and cortical excitability. Am J
Physiol 218:171-173, 1970.
20. Dement W, Henry P, Cohen H, et al: Studies on the effect of
REM deprivation in humans and animals, in Kety S, Evarts E,
Williams H (eds): Sleep and Altered States of Consciousness. New
York, Grune & Stratton Inc, 1967, pp 456-468.
21. Ferguson J, Dement W: The effect of variations in total
sleep time on the occurrence of rapid eye movement sleep in cats.
EEG Clin Neurophysiol 22:2-10, 1967.
22. Cohen HB, Dement WC: Sleep: Changes in threshold to
electroconvulsive shock in rats after deprivation of "paradoxical"
phase. Science 150:1318-1319, 1965.
23. Cohen HB, Dement W: Electrically induced convulsions in
REM deprived mice: Prolongation of the tonic phase, abstracted.
Psychophysiol 4:381, 1968.
24. Hartmann E, Marcus J, Leinoff A: The sleep-dream cycle
and convulsive threshold. Psychon Sci 13:141-142, 1968.
25. Cohen H, Thomas J, Dement WC: Sleep styles, REM depri-
vation, and electroconvulsive threshold in the cat. Brain Res
19:317-321, 1970.
26. Dewson JH III, Dement WC, Wagener TE, et al: Rapid eye
movement sleep deprivation: A central neural change during
wakefulness. Science 156:403-406, 1967.
27. Satinoff E, Drucker-Cohn RR, Hernandez PR: Paleocortical
excitability and sensory filtering during REM sleep deprivation.
Physiol Behav 7:103-106, 1971.
28. Morden B, Conner R, Mitchell G, et al: Effects of rapid eye
movement (REM) sleep deprivation on shock induced fighting.
Physiol Behav 3:425-432, 1968.
29. Ferguson J, Dement W: The behavioral effects of ampheta-
mines on REM deprived rats. J Psychiatr Res 7:111-118, 1969.
30. Morden B, Mullins R, Levine S, et al: Effect of REMS depri-
vation on the mating behavior of male rats, abstracted. Psy-
chophysiol 5:241-242, 1968.
31. Dement W: Recent studies on the biological role of REM
sleep. Am J Psychiatry 122:404-408, 1965.
32. Siegel J, Gordon TP: Paradoxical sleep: Deprivation in the
cat. Science 148:978-980, 1965.
33. Cohen H, Edelman A, Bowen R, et al: Sleep and self-stimu-
lation in the rat. Sleep Res 1:158, 1972.
34. Riccio DC, Hodges LA: Retrograde amnesia produced by
hypothermia in rats. J Comp Physiol Psychol 66:618-622, 1968.
35. Booth DA: Neurochemical changes correlated with learning
and memory, in Ungar G (ed): Molecular Mechanisms in Memory
and Learning. New York, Plenum Press, 1970, pp 1-58.
36. Glassman E: The biochemistry of learning: An evaluation of
the role of RNA and protein. Ann Rev Biochem 38:605-616,1969.
37. Fishbein W: The effects of paradoxical sleep deprivation
during the retention interval on long term memory. Read before
the Association for the Psychophysiological Study of Sleep, Bos-
ton, 1969.
38. Fishbein W: Disruptive effects of rapid eye movement sleep
deprivation on long term memory. Physiol Behav 6:279-282,1971.
39. Pearlman C, Greenberg R: Effect of REM deprivation on re-
tention of avoidance learning in rats. Read before the Association
for the Psychophysiological Study of Sleep, Denver, 1968.
40. Stern WC: Effects of REM sleep deprivation upon the acbe--
sition and maintainence of learned behavior in the rat. Read be¬
fore the Association for the Psychophysiological Study of Sleep,
Boston, 1969.
41. Joy RM, Prinz PN: The effect of sleep altering environ-
ments upon the acquisition and retention of a conditioned avoid-
ance response in the rat. Physiol Behav 4:809-814, 1969.
42. Pearlman CA, Greenberg R: Brief REM deprivation impairs
retention of complex learning in rats. Sleep Res 1:164, 1972.
43. Pearlman CA, Becher MF: Brief post-trial REM sleep depri-
vation impairs discrimination learning in rats. Sleep Res 2:170,
1973.
44. Pearlman C: REM sleep deprivation impairs latent extinc-
tion in rats. Physiol Behav 11:233-237, 1973.
45. Pearlman CA: Latent learning impaired by REM sleep dep-
rivation. Psychon Sci 25:135-136, 1971.
46. Fishbein W, McGaugh JL, Swarz JR: Retrograde amnesia:
Electroconvulsive shock effects after termination of rapid eye
movement sleep deprivation. Science 172:80-82, 1971.
47. Foulkes D: Dream reports from different stages of sleep.
J Abnorm Soc Psychol 65:14-25, 1962.
48. Foulkes D, Vogel G: Mental activity at sleep onset. J Ab-
norm Psychol 70:231-243, 1965.
49. Dement WC, Fisher C: Experimental interference with the
sleep cycle. Can Psychiatr Assoc J 8:400-405, 1963.
50. Fisher C, Dement W: Dreams and psychosis. Read before
the Western New England Psychoanalytic Society, New Haven,
Conn, 1962.
51. Snyder F, Scott J, Karacan I, et al: Presumptive evidence of
REMS deprivation in depressive illness. Psychophysiol 4:382,1968.
52. Monroe LJ, Rechtschaffen A, Foulkes D, et al: Dis-
criminability of REM and NREM reports. J Pers Soc Psychol
2:456-460, 1965.
53. Rechtschaffen A, Verdone P, Wheaton J: Reports of mental
activity during sleep. Can Psychiatr Assoc J 8:404-414, 1963.
54. Zimmerman W: Sleep mentation and auditory awakening
thresholds. Psychophysiol 6:540-549, 1970.
55. Foulkes D, Spear PS, Symonds JD: Individual differences in
mental activity at sleep onset. J Abnorm Psychol 71:280-286,1966.
56. Vogel GW, Barrowclough B, Giesler D: Limited dis-
criminability of REM and sleep onset reports and its psychiatric
implications. Arch Gen Psychiatry 26:449-455, 1972.
57. Pope RA: Psychological Correlates of Theta Burst Activity
in Sleep Onset, thesis. University of Wyoming, 1973.
58. Foulkes D, Scott E: An above zero waking baseline for the
incidence of momentarily hallucinatory mentation. Sleep Res
2:108, 1973.
59. Foulkes D: Male and Female Sexual Development: A review.
Read before the European Society for Sleep Research, Rome, 1974.
60. Dement WC, Fisher C: Experimental interference with the
sleep cycle. Can Psychiatr Assoc J 8:400-405, 1963.
61. Sampson H: Deprivation of dreaming sleep by two methods:
I. Compensatory REM time. Arch Gen Psychiatry 13:79-86,1965.
62. Vogel GW: REM deprivation: III. Dreaming and psychosis.
Arch Gen Psychiatry 18:312-329, 1968.
63. Kales A, Hoedemaker FS, Jacobson A, et al: Dream depriva-
tion: An experimental reappraisal. Nature 204:1337-1338, 1964.
64. Snyder F: The new biology of dreaming. Arch Gen Psychia-
try 8:381-391, 1963.
65. Foulkes D, Pivik T, Aherns JB, et al: Effects of dream depri-
vation on dream content: An attempted cross night replication.
Psychophysiol 4:386-387, 1968.
66. Vogel GW, Traub AC: REM deprivation: I. The effect on
schizophrenic patients. Arch Gen Psychiatry 18:287-300, 1968.
67. Vogel GW, Traub AC, Ben-Horin P, et al: REM deprivation:
II. The effects on depressed patients. Arch Gen Psychiatry 18:301\x=req-\
311, 1968.
68. Vogel GW, Traub AC: Further studies on REM deprivation
of depressed patients. Psychophysiol 5:239, 1968.
69. Dement WC: Studies on the function of rapid eye movement
(paradoxical) sleep in human subjects, in Aspects Anatomo\x=req-\
Fonctionnels de la Physiologie du Sommeil. Lyon, France, Centre
Nationel de la Recherche Scientifique, 1965.
70. Dement WC: Experimental dream studies, in Academy of
Psychoanalysis: Science and Psychoanalysis. New York, Grune &
Stratton inc, 1964, vol 7, pp 129-184.
71. Fisher C: Psychoanalytic implications of recent research on
sleep and dreams. J Am Psychoanal Assoc 13:197-303, 1965.
72. Dement WC: The biological role of REM sleep (circa 1968),
in Kales A (ed): Sleep Physiology and Pathology. Philadelphia, JB
Lippincott Co, 1969, pp 245-265.
73. Azumi K, Takahashi S, Takahashi K, et al: The effects of
dream deprivation on chronic schizophrenics and normal adults: A
comparative study. Folia Psychiatr Neurol Jap 21:205-225, 1967.
74. de Barros-Ferreira M, Goldsteinas L, Lairy GC: REM sleep
deprivation in chronic schizophrenics: Effects on the dynamics of
fast sleep. Electroencephalogr Clin Neurophysiol 34:561-569,1973.
75. Gillin JC, Buchsbaum MS, Jacobs LS, et al: Partial REM
sleep deprivation, schizophrenia, and field articulation. Arch Gen
Psychiatry 30:653-662, 1974.
76. Wyatt R, Termini BA, Davis J: A review of the literature\p=m-\
1960-1970: II. Sleep studies. Schizophrenia Bull 4:45-66, 1971.
77. Feinberg I, Koresko RL, Gottlick F, et al: Sleep electroen-
cephalographic and eye movement patterns in schizophrenic pa-
tients. Compr Psychiatry 5:44-53, 1964.
78. Onheiber P, White PT, DeMyer MK, et al: Sleep and dream
patterns of child schizophrenics. Arch Gen Psychiatry 12:568-571,
1965.
79. Koresko RL, Snyder F, Feinberg I: Dream time: In halluci-
nating and nonhallucinating schizophrenic patients. Nature
199:1118-1119, 1963.
80. Feinberg I, Koresko RL, Gottlick F: Further observations
on electrophysiological sleep patterns in schizophrenia. Compr
Psychiatry 6:21-24, 1965.
81. Azumi K: A polygraphic study of sleep in schizophrenics.
Seishin Shinke Igaku Zasshi 68:1222-1241, 1966.
82. Kupfer DJ, Wyatt RJ, Scott J, et al: Sleep disturbance in
acute schizophrenic patients. Am J Psychiatry 126:1213-1223,
1970.
83. Zarcone V, Gulevich G, Pivik T, et al: Partial REM phase
deprivation and schizophrenia. Arch Gen Psychiatry 18:194-202,
1968.
84. Verdone P: Sleep satiation: Extended sleep in normal sub-
jects. Electroencephalogr Clin Neurophysiol 24:417-423, 1968.
85. Snyder F: Disturbance of the EEG sleep patterns in relation
to acute psychosis, in Siva Sankar DV (ed): Schizophrenia: Cur-
rent Concepts and Research. PJD Publications, Hicksville, NY,
1969, pp 751-774.
86. Snyder F: Electrographic studies of sleep in depression, in
Kline NS, Laska E (eds): Computers on Electronic Devise in Psy-
chiatry. 1968, pp 272-303.
87. Snyder F: NIH studies of EEG sleep in affective illness, in
Williams TA, Kato MM, Shields JA Jr (eds): Recent Advances in
the Psychobiology of Depressive Illness. Department of Health,
Education, and Welfare, 1972, pp 171-192.
88. Snyder F: Sleep disturbances in relation to acute psychosis,
in Kales A (ed): Sleep: Physiology and Pathology. Philadelphia, JB
Lippincott Co, 1969, pp 170-182.
89. Hartmann E: Longitudinal studies of sleep and dream pat-
terns in manic-depressive patients. Arch Gen Psychiatry 19:312\x=req-\
329, 1968.
90. Bunney WE Jr, Goodwin FK, Murphy DL, et al: The "switch
process" in manic-depressive illness: II. Relation to cate-
cholamines, REM sleep, and drugs. Arch Gen Psychiatry 27:304\x=req-\
309, 1968.
91. Cartwright RD, Monroe LJ, Palmer C: Individual differ-
ences in response to REM deprivation. Arch Gen Psychiatry
16:297-303, 1967.
92. Monroe LJ: Psychological and physiological differences be-
tween good and poor sleepers. J Abnorm Psychol 72:255-264,1967.
93. Akindele MO, Evans JI, Oswald I: Mono-amine oxidase in-
hibitors, sleep and mood. Electroencephalogr Clin Neurophysiol
29:47-56, 1970.
94. Wyatt RJ, Fram DH, Kupfer DJ, et al: Total prolonged
drug-induced REM sleep suppression in anxious-depressed pa-
tients. Arch Gen Psychiatry 24:145-155, 1971.
95. Dunleavy DLF, Oswald I: Phenelzine, mood response, and
sleep. Arch Gen Psychiatry 28:353-356, 1973.
96. Le Gassicke J, Ashcroft GW, Eccleston D, et al: The clinical
state, sleep and amine metabolism of a tranylcypromine (parnate)
addict. Br J Psychiatry 3:357-364, 1965.
97. Cramer H, Kuhlo W: Effects des inhibiteurs de la mono-ami-
nexydase sur le sommeil et l'\l=e'\lectroenc\l=e'\phalogrammechez
l'homme. Acta Neurol Belg 67:658-669, 1967.
98. Toyoda J: The effects of chlorpromazine and imipramine on
the human nocturnal sleep electroencephalogram. Folia Psychiatr
Neurol Japon 18:198-221, 1964.
99. Wyatt RJ, Kupfer DJ, Scott J, et al: Longitudinal studies of
the effect of monoamine oxidase inhibitors on sleep in man.
Psychopharmacologia 15:236-244, 1969.
100. Hartmann E: Amitriptyline and imipramine: Effects on hu-
man sleep. Psychophysiol 5:207, 1968.
101. Hartmann E: The effect of four drugs on sleep patterns in
man. Psychopharmacologia 12:346-353, 1968.
102. Dunleavy DLF, Brezinova V, Oswald I, et al: Changes dur-
ing weeks in effects of tricyclic drugs on human sleeping brain. Br
J Psychiatry 120:663-672, 1972.
103. Hartmann E, Cravens J, Auchincloss S, et al: Placebo,
reserpine, amitriptyline, chlorpromazine, chloral hydrate, and
chlordiazepoxide: Long term effects on human sleep, in Chase MH,
Stern WC, Walter PL (eds): Sleep Research. Los Angeles, Brain
Information Service, University of California, 1972, vol 1, p 52.
104. Raskin A, Schulterbrandt JG, Reatig N, et al: Differential
response to chlorpromazine, imipramine, and placebo. Arch Gen
Psychiatry 23:164-173, 1970.
105. Heller A, Zahourek R, Whittington HG: Effectiveness of
antidepressant drugs: A triple-blind study comparing imipramine,
desipramine, and placebo. Am J Psychiatry 127:1092-1095, 1971.
106. Skarbek A, Smedberg D: Amitriptyline: A controlled trial
in chronic depressive states. J Ment Sci 108:859-861, 1962.
107. Garry JW, Leonard JJ: Trial of amitriptyline in chronic de-
pression. Br J Psychiatry 109:54-55, 1963.
108. Morris JB, Beck AT: The efficacy of antidepressant drugs.
Arch Gen Psychiatry 30:667-674, 1974.
109. Beaubien J, Ban TA, Lehman HE, et al: Doxepin in the
treatment of psychoneurotic patients. Curr Ther Res 12:192-194,
1970.
110. Bianchi GN, Barr RF, Kiloh LG: A comparative trial of
doxepin and amitriptyline in depressive illness. Med J Aust 1:843\x=req-\
846, 1971.
111. Burrows GD, Mowbray RM, Davies B: Sequential compari-
son of doxepin and placebo in depressed patients. Med J Aust
1:367-389, 1972.
112. Butterworth AT, Watts RD: Treatment of hospitalized al-
coholics with doxepin and diazepam: A controlled study. QJ Stud
Alcohol 32:78-81, 1971.
113. Evaluation of doxepin hydrochloride (sinequan), editorial.
JAMA 215:1967-1968, 1971.
114. Gillmer RE: Treatment of the depressive reaction: A clini-
cal evaluation of a new psychotherapeutic drug, doxepin (sine-
quan). S Afr Med J 44:1386-1388, 1970.
115. Goldberg HL, Finnery RJ: The use of doxepin in the treat-
ment of symptoms of anxiety neurosis and accompanying depres-
sion: A collaborative controlled study. Am J Psychiatry 129:74-77,
1972.
116. Gomez-Martinez I: Preliminary double-blind clinical trial
with a new antidepressive doxepin. Curr Ther Res 10:116-118,
1968.
117. Grof P, Saxena B, Cantor R, et al: Doxepin versus ami-
triptyline in depression: A sequential double-blind study. Curr
Ther Res 16:470-476, 1974.
118. Hackett E, Bold RL, Kline NS, et al: Controlled eval-
uation of psychotropic drug in private practice (doxepin vs ami-
triptyline). Psychosomatics 8:162-165, 1967.
119. Hackett E, Kline NS: Antidepressant activity of doxepin
and amitriptyline: A double-blind evaluation. Psychosomatics
10:21-24, 1969.
120. Hasan KZ, Akhtar MI: Double-blind clinical study compar-
ing doxepin and imipramine in depression. Curr Ther Res 13:327\x=req-\
336, 1971.
121. Koknel O, Eper O: A study with sinequan (doxepin). Dis
Nerv Syst 32:405-408, 1971.
122. Lang WR: Trial of a new psychotropic drug doxepin. NZ
Med J 71:184-188, 1970.
123. Pitts NE: Clinical evaluation of doxepin a new psychother-
apeutic agent. Psychosomatics 10:164-191, 1969.
124. Sanger MD: The treatment of anxiety and depression in
the allergic patient. Ann AllerDoxepin6-510, 1969.
125. Satter FJ, Pearson RE: Doxepin hcl (sinequan) current in-
formation. Mich Med 69:771-772, 1970.
126. Solis H, Molina G, Pi\l=n~\eyroA: Clinical evaluation of doxe-
pin and amitriptyline in depressed patients. Curr Ther Res
12:524-527, 1970.
127. Sterlin C, Ban TA, Lehmann HE, et al: A comparative
evaluation of doxepin and chlordiazepoxide in the treatment of
psychoneurotic outpatients. Curr Ther Res 12:190-200, 1970.
128. Ayd FJ: Clinical evaluation of a new tricyclic anti-
depressant iprindole. Dis Nerv Syst 30:818-824, 1969.
129. Baxter BL, Gluckman MI: Iprindole: An antidepressant
which does not block REM sleep. Nature 223:750-752, 1969.
 130. Clein LJ: Allergy to iprindole (prondole) with hepatotoxic-
ity. Br Med J 4:494, 1970.
131. Clift AD: Allergy to iprindole (prondole) with hepatotoxic-
ity. Br Med J 2:712-719, 1971.
132. Clift AD: Treatment of depression in general practice: A
study of iprindole. Practitioner 205:89-93, 1970.
133. Daneman EA: Treatment of depressed patients with iprin-
dole. Psychosomatics 8:217-221, 1967.
134. El-Deiry NK, Forrest AD, Littmann SK: Clinical trial of a
new antidepressant (wy 3263). Br J Psychiatry 113:999-1004,1967.
135. Gluckman MI, Baum T: The pharmacology of iprindole, a
new antidepressant. Psychopharmacologia 15:169-185, 1969.
136. Harrison DF, Stanley IM: Allergy to iprindole (prondole)
with hepatotoxicity. Br Med J 4:368-369, 1970.
137. Hicks JT: Iprindole, a new antidepressant for use in gen-
eral office practice: A double blind, placebo-controlled study. Ill
Med J 128:622-626, 1965.
138. Narayanan HS, Reddy GN, Rao BS: A comparative double
blind evaluation of iprindole and imipramine in the treatment of
depressive states. Indian J Med Sci 27:1-7, 1973.
139. Rickels K, Gordon PE, Meckelnberg R, et al: Iprindole in
neurotic depressed general practice patients: A controlled study.
Psychosomatics 9:208-214, 1968.
140. Rickels K, Chung HR, Csanalosi I, et al: Iprindole and
imipramine in nonpsychotic depressed outpatients. Br J Psychia-
try 123:329-339, 1973.
141. Rickels K, Perloff M, Stepansky W, et al: Doxepin and
diazepam in general practice and hospital clinic neurotic patients:
A collaborative controlled study. Psychopharmacologia 15:265-279,
1969.
142. Sutherland SS, Philip AE, Sutherland MS: The response to
treatment of individual patients in a drug trial. Br J Psychiatry
115:1383-1385, 1969.
143. Young PJ: Allergy to iprindole (prondol) with hepatotoxic-
ity. Br Med J 1:367, 1970.
144. Hunter JW, Owen S, Eksi A, et al: A control crossover
study of trimipramine and amytobarbitone. Br J Psychiatry
113:667-670, 1967.
145. Burke BV, Sainsbury MJ, Mezo BA: A comparative trial of
amitriptyline and trimipramine in the treatment of depression.
Med J Aust 1:1216-1218, 1967.
146. Burns BH: Preliminary evaluation of a new anti-
depressant, trimipramine by a sequential method. Br J Psychia-
try 111:1155-1157, 1965.
147. Legg NJ, Swash M: Clinical note: Seizures and EEG activa-
tion after trimipramine. Epilepsia 15:131-135, 1974.
148. Marshal B: The treatment of depression in general practice
by a single dose schedule. Practitioner 206:806-810, 1971.
149. Rickels K, Gordon PE, Weise CC, et al: Amitriptyline and
trimipramine in neurotic depressed outpatients: A collaborative
study. Am J Psychiatry 127:208-218, 1970.
150. Salzmann MM: A controlled trial with trimipramine, a new
antidepressant drug. Br J Psychiatry 111:1105-1106, 1965.
151. Simpson GM, Blair JH, labal J, et al: A preliminary study
of trimipramine in chronic schizophrenia. Curr Ther Res 8:225\x=req-\
231, 1966.
152. Kiloh LG, Garside RF: The independence of neurotic de-
pression and endogenous depression. Br J Psychiatry 109:451-463,
1963.
153. Rosenthal SH, Klerman GL: Content and consistency in
the endogenous depressive pattern. Br J Psychiatry 122:471-484,
1966.
154. Mendels J, Cochrane C: The nosology of depression: The
endogenous-reactive concept. Am J Psychiatry 122(suppl):471-484,
1966.
155. Oswald I, Berger RJ, Maramille RA, et al: Melancholia and
barbiturates: A controlled EEG, body and eye movement study of
sleep. Br J Psychiatry 109:66-78, 1963.
156. Kales A, Preston TA, Tan TL, et al: Hypnotics and altered
sleep-dream patterns. Arch Gen Psychiatry 23:211-218, 1970.
157. Oswald I, Priest RG: Five weeks to escape the sleeping pill
habit. Br Med J 2:1093-1099, 1965.
158. Kales A, Kales J, Scharf MB, et al: Hypnotics and altered
sleep-dream patterns: II. All-night EEG studies of chloral hy-
drate, flurazepam, and methaqualone. Arch Gen Psychiatry
23:219-226, 1970.
159. Freemon FR, Agnew HW, Williams RL: An electroenceph-
alographic study of the effects of meprobamate on human sleep.
Clin Pharmacol Ther 6:172-176, 1965.
160. Gresham SC, Webb WB, Williams R: Alcohol and caffeine:
Effect on inferred visual dreaming. Science 140:1226-1227, 1963.
161. Yules RB, Freedman DX, Chandler KA: The effect of ethyl
alcohol on man's electroencephalographic sleep cycle. Electroen-
cephalogr Clin Neurophysiol 20:109-111, 1966.
162. Cohen HB, Duncan RF, Dement WC: The effect of diphen-
ylhydantoin on sleep in the cat. Electroencephalogr Clin Neu-
rophysiol 24:401-408, 1968.
163. Kales A, Adams G, Hanley J, et al: Sleep patterns during
withdrawal of tuinal: Effect of dilantin administration. Psy-
chophysiol 6:262, 1969.
164. Hartmann E: The effect of diphenylhydantoin (Dilantin) on
sleep in man. Psychophysiol 7:316, 1970.
165. Wyatt RJ, Engelman K, Kupfer DJ, et al: Effect of L\x=req-\
tryptophan (a natural sedative) on human sleep. Lancet 2:842-846,
1970.
166. Hartmann E: L-Tryptophan and 50H tryptophan: Effects
on human sleep. Psychophysiol 7:320, 1970.
167. Hartmann E: The effect of L-tryptophan on the sleep-
dream cycle in man. Psychon Sci 8:479-480, 1967.
168. Wyatt RJ, Zarcone V, Engelman K, et al: Effects of 5-hy-
droxytryptophan on the sleep of normal human subjects. Electro-
encephalogr Clin Neurophysiol 30:505-509, 1971.
169. Wyatt RJ, Engelman K, Kupfer DJ, et al: Effects of para-
chlorophenylalanine on sleep in man. Electroencephalogr Clin
Neurophysiol 27:529-532, 1969.
170. Wyatt RJ,Chase TN, Scott J, et al: Effect of L-dopa on the
sleep of man. Nature 228:999-1000, 1970.
171. Lewis SA, Oswald I, Evans J, et al: Heroin and human
sleep. Electroencephalogr Clin Neurophysiol 28:374-381, 1970.
172.Kay DC, Eisenstein RB, Jasinski DR: Morphine effects on
human REM state, waking state, and NREM sleep. Psychophar-
macologia 14:404-416, 1969.
173. Kay DC, Kelly OA: Some changes in human sleep during
chronic intoxication with morphine. Psychophysiol 7:346, 1970.
174. Kay DC: Human sleep during chronic intoxication with
morphine. Read before the Federation of American Societies for
Experimental Biology, Atlantic City, NJ, 1970.
175. Rechtschaffen A, Maron L: The effect of amphetamines on
the sleep cycle. Electroencephalogr Clin Neurophysiol 16:438-445,
1964.
176. Oswald I, Thacore VR: Amphetamine and phenmetrazine
addiction. Br Med J 2:427-431, 1963.
177. Lewis SA, Oswald I: Overdose of tricyclic antidepressants
and REM sleep rebound. Psychophysiol 6:258-259, 1969.
178. Klerman GL, Schildkraut JJ, Hasenbush LL, et al: Clinical
experience with dihydroxyphenylalanine (dopa) in depression. J
Psychiatr Res 1:289-297, 1963.
179. Bunney WE Jr, Brodie RH, Murphy DL, et al: Studies of
alpha-methyl-para-tyrosine, L-dopa, and L-tryptophan in depres-
sion and mania. Am J Psychiatry 127:872-880, 1971.
180. Turner W, Merlis S: A clinical trial of pargyline and dopa
in psychotic subjects. Dis Nerv Syst 25:538-541, 1964.
181. Goodwin FK, Murphy DL, Brodie HH, et al: L-Dopa, cat-
acholamines, and behavior: A clinical and biochemical study in de-
pressed patients. Biol Psychiatry 2:341-366, 1970.
182. Carroll BJ, Mowbray RM, Davis B: Sequential comparison
of L-tryptophan with ECT in severe depression. Lancet 1:967-969,
1970.
183. Dunner DL, Goodwin FK: Effect of L-tryptophan on brain
serotonin metabolism in depressed patients. Arch Gen Psychiatry
26:364-366, 1972.
184. Kopell BS, Zarcone V, de la Pena A, et al: Changes in selec-
tive attention as measured by the visual averaged evoked poten-
tial following REM deprivation in man. Electroencephalogr Clin
Neurophysiol 32:322-325, 1972.
185. Cartwright RD, Ratzel RW: Effects of dream loss on wak-
ing behaviors. Arch Gen Psychiatry 27:277-280, 1972.
186. Freud S: The neuro-psychoses of defense (1894), in Stra-
chey J (ed): The Standard Edition. London, Hogarth Press, 1962,
vol 3, pp 45-61.