Sleep deprivation as a treatment for depression

Results of a MEDLINE Search by Ivan Goldberg, M.D.

1: World J Biol Psychiatry 2000 Oct;1(4):180-6

Sleep in depression and sleep deprivation: a brief conceptual review.

Holsboer-Trachsler E, Seifritz E.

Department of Psychiatry, University of Basel, Switzerland.

Risk factors for somnipathies are psychological stress or psychiatric illness.
More severe sleep difficulties have been found to be clearly related to
psychiatric illness such as depression and phobias, as well as to addiction.
Somnipathies can objectively be identified by means of polygraphy. Overall,
polysomnographic measures in patients with affective disorders differ most
frequently and significantly from those in normal control subjects. Persistent
sleep disturbances are associated with significant risk of both relapse and
recurrence in mood disorders and an increased risk of suicide. In addition to
changes in sleep architecture, patients with major depression show profoundly
altered patterns of nocturnal hormone secretion, possibly through mechanisms
that link regulation of sleep with neuroendocrine activity. Basic and clinical
approaches of sleep research established neurobiological models into the
underlying pathophysiology associated with psychiatric disorders.

PMID: 12607213 [PubMed – in process]


2: Sleep Med Rev 2002 Oct;6(5):361-77

Therapeutic use of sleep deprivation in depression.

Giedke H, Schwarzler F.

Department of Psychiatry, University of Tubingen, Osianderstr. 24, Germany.

Total sleep deprivation (TSD) for one whole night improves depressive symptoms
in 40-60% of treatments. The degree of clinical change spans a continuum from
complete remission to worsening (in 2-7%). Other side effects are sleepiness and
(hypo-) mania. Sleep deprivation (SD) response shows up in the SD night or on
the following day. Ten to 15% of patients respond after recovery sleep only.
After recovery sleep 50-80% of day 1 responders suffer a complete or partial
relapse; but improvement can last for weeks. Sleep seems to lead to relapse
although this is not necessarily the case. Treatment effects may be stabilised
by antidepressant drugs, lithium, shifting of sleep time or light therapy. The
best predictor of a therapeutic effect is a large variability of mood. Current
opinion is that partial sleep deprivation (PSD) in the second half of the night
is equally effective as TSD. There are, however, indications that TSD is
superior. Early PSD (i.e. sleeping between 3:00 and 6:00) has the same effect as
late PSD given equal sleep duration. New data cast doubt on the time-honoured
conviction that REM sleep deprivation is more effective than non-REM SD. Both
may work by reducing total sleep time. SD is an unspecific therapy. The main
indication is the depressive syndrome. Some studies show positive effects in
Parkinson’s disease. It is still unknown how sleep deprivation works.

Publication Types:
Review, Academic

PMID: 12531127 [PubMed – indexed for MEDLINE]


3: Depress Anxiety 2002;16(1):1-3

Bright light augments antidepressant effects of medication and wake therapy.

Loving RT, Kripke DF, Shuchter SR.

Department of Psychiatry, University of California, San Diego, La Jolla,
California 92093-0667, USA.

Inpatient studies have suggested that bright light therapy can be used to
sustain the antidepressant effects of wake therapy (sleep deprivation). In an
outpatient trial, a half night of home wake treatment was followed by 1 week of
light treatment. All subjects had Major Depressive Disorders according to DSM-IV
criteria and were receiving concomitant antidepressant medication. Subjects were
randomly assigned to receive either 10,000 lux bright white light for 30 min
between 6 and 9 AM or dim red (placebo) light at a comparable time. Seven
subjects completed treatment with bright white light and six completed treatment
with placebo. On the Hamilton Depression Rating Scale (HDRS17, SIGH-SAD-SR
version), the group receiving bright light improved 27% in 1 week (P=0.002). The
group receiving placebo did not improve, except for one outlier. The benefit of
bright light was significant compared to placebo with removal of the outlier
(P<0.025). Copyright Wiley-Liss, Inc.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 12203667 [PubMed – indexed for MEDLINE]


4: J Clin Psychiatry 2002 Jul;63(7):628-40

Alternative treatments for depression: empirical support and relevance to women.

Manber R, Allen JJ, Morris MM.

Department of Psychiatry and Behavioral Sciences, Stanford University, Calif.
94305, USA.

BACKGROUND: This article is a critical review of the efficacy of selected
alternative treatments for unipolar depression including exercise, stress
management techniques, acupuncture, St. John’s wort, bright light, and sleep
deprivation. Issues related to women across the life span, including pregnancy
and lactation, are highlighted. DATA SOURCES: Evidence of efficacy is based on
randomized controlled trials. A distinction is made between studies that address
depressive symptoms and studies that address depressive disorders. The review
emphasizes issues related to effectiveness, such as treatment availability,
acceptability, safety, and cost and issues relevant to women. DATA SYNTHESIS:
Exercise, stress reduction methods, bright light exposure, and sleep deprivation
hold greater promise as adjuncts to conventional treatment than as monotherapies
for major depression. The evidence to date is not sufficiently compelling to
suggest the use of St. John’s wort in favor of or as an alternative to existing
U.S. Food and Drug Administration-regulated compounds. Initial evidence suggests
that acupuncture might be an effective alternative monotherapy for major
depression, single episode. CONCLUSION: This review indicates that some
unconventional treatments hold promise as alternative or complementary
treatments for unipolar depression in women and have the potential to contribute
to its long-term management. Additional research is needed before further
recommendations can be made, and there is an urgent need to carefully document
and report the frequency of minor and major side effects.

Publication Types:
Review, Tutorial

PMID: 12143922 [PubMed – indexed for MEDLINE]


5: Life Sci 2002 Mar 1;70(15):1741-9

Sleep deprivation in depression stabilizing antidepressant effects by repetitive
transcranial magnetic stimulation.

Eichhammer P, Kharraz A, Wiegand R, Langguth B, Frick U, Aigner JM, Hajak G.

Department of Psychiatry and Psychotherapy, University of Regensburg, Germany.

Partial sleep deprivation (PSD) has a profound and rapid effect on depressed
mood. However, the transient antidepressant effect of PSD – most patients
relapse after one night of recovery sleep – is limiting the clinical use of this
method. Using a controlled, balanced parallel design we studied, whether
repetitive transcranial magnetic stimulation (rTMS) applied in the morning after
PSD is able to prevent this relapse. 20 PSD responders were randomly assigned to
receive either active or sham stimulation during the following 4 days after PSD.
Active stimulation prolonged significantly (p < 0.001) the antidepressant effect
of PSD up to 4 days. This finding indicates that rTMS is an efficacious method
to prevent relapse after PSD.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 12002519 [PubMed – indexed for MEDLINE]


6: Neuropsychobiology 2002;45 Suppl 1:7-12

Sleep and sleep-wake manipulations in bipolar depression.

Riemann D, Voderholzer U, Berger M.

Department of Psychiatry and Psychotherapy, University Hospital of Freiburg,

In the last 30 years, it has been convincingly demonstrated that sleep in major
depression is characterized by disturbances of sleep continuity, a reduction of
slow wave sleep, a disinhibition of REM sleep including a shortening of REM
latency (i.e. the time between sleep onset and the occurrence of the first REM
period) and an increase in REM density. Furthermore, manipulations of the
sleep-wake cycle like total or partial sleep deprivation or phase advance of the
sleep period have been proven to be effective therapeutic strategies for
patients with unipolar depression. The database concerning sleep and sleep-wake
manipulations in bipolar disorder in comparison is not yet as extensive. Studies
investigating sleep in bipolar depression suggest that during the depressed
phase sleep shows the same stigmata as in unipolar depression. During the
hypomanic or manic phase, sleep is even more curtailed, though subjectively not
experienced as disturbing by the patients. REM sleep disinhibition is present as
well. An important issue is the question, whether sleep-wake manipulations can
also be applied in patients with bipolar depression. Work by others and our own
studies indicate that sleep deprivation and a phase advance of the sleep period
can be used to treat bipolar patients during the depressed phase. The risk of a
switch into hypomania or mania does not seem to be more pronounced than the risk
with typical pharmacological antidepressant treatment. For patients with mania,
sleep deprivation is not an adequate treatment–in contrast, treatment
strategies aiming at stabilizing a regular sleep-wake schedule are indicated.
Copyright 2002 S. Karger AG, Basel

Publication Types:
Review, Tutorial

PMID: 11893871 [PubMed – indexed for MEDLINE]


7: J Psychiatr Res 2002 May-Jun;36(3):131-5

Relation between responses to repetitive transcranial magnetic stimulation and
partial sleep deprivation in major depression.

Padberg F, Schule C, Zwanzger P, Baghai T, Ella R, Mikhaiel P, Hampel H, Moller
HJ, Rupprecht R.

Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstr. 7, 80336
Munich, Germany.

Repetitive transcranial magnetic stimulation (rTMS) has been found to ameliorate
symptoms in major depression. However, its mechanism of action has to be further
elucidated and the relationship between responses to rTMS and other
antidepressant interventions except electroconvulsive therapy has not been
investigated to date. Here we studied in an open trial whether the response to
partial sleep deprivation may predict the clinical outcome of rTMS treatment.
Thirty-three drug-free patients suffering from a major depressive episode
underwent a partial sleep deprivation at least 5 days prior to rTMS and
subsequently received 10 sessions of 10 Hz rTMS of the left prefrontal cortex.
After rTMS a significant overall improvement of 32% on the Hamilton Rating Scale
for Depression was observed. Forty-two percent of patients showed an
antidepressant response after rTMS. Amelioration of depression after partial
sleep deprivation was inversely correlated with improvement after rTMS. There
was no clinically applicable predictive value of the response to partial sleep
deprivation for the outcome after rTMS. Apparently, different subgroups of
depressed patients respond to both interventions. Further studies are needed to
characterize the response to rTMS by means of clinical and biological

Publication Types:
Clinical Trial

PMID: 11886690 [PubMed – indexed for MEDLINE]


8: Psychiatry Res 2001 Nov 30;104(3):239-46

Dopaminergic augmentation of sleep deprivation effects in bipolar depression.

Benedetti F, Campori E, Barbini B, Fulgosi MC, Colombo C.

Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric
Sciences, Universita Vita-Salute San Raffaele, Via Stamira d’Ancona 20, 20127
Milan, Italy.

Total sleep deprivation (TSD) has been used in association with lithium salts
and with serotonergic and noradrenergic antidepressants, leading to sustained
improvements in patients affected by major depression. Current theories on the
neurobiological mechanism of action of TSD propose a major role for enhanced
dopamine activity. To test the clinical relevance of dopaminergic enhancement in
TSD, we treated a homogeneous sample of 28 bipolar depressed patients with three
cycles of TSD combined with placebo or with the dopaminergic antidepressant
amineptine. Changes in mood over time were rated with self-administered visual
analogue scales and with the Montgomery-Asberg Depression Rating Scale. Patients
showed improved mean daily-mood scores after TSD, an effect that was highest at
the first cycle and decreased with treatment repetition. Amineptine enhanced the
effects of TSD on perceived mood during the first two TSD cycles, but patients
in the placebo and amineptine groups showed comparable results at the end of the
treatment. Despite its theoretical importance, the clinical usefulness of
combining TSD with a dopaminergic agent must be questioned.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 11728613 [PubMed – indexed for MEDLINE]


9: J Psychiatr Res 2001 Nov-Dec;35(6):323-9

Sleep phase advance and lithium to sustain the antidepressant effect of total
sleep deprivation in bipolar depression: new findings supporting the internal
coincidence model?

Benedetti F, Barbini B, Campori E, Fulgosi MC, Pontiggia A, Colombo C.

Universita Vita-Salute San Raffaele, School of Medicine, Department of
Neuropsychiatric Sciences, Via Stamira d’Ancona 20 20127, Milano, Italy.

Recent European studies suggested that sleep phase advance (SPA) could sustain
the effects of total sleep deprivation (TSD) both with or without a combined
antidepressant drug treatment. Previous studies by our group showed that an
ongoing lithium treatment could enhance and sustain the effect of repeated TSD.
In the present study we studied the effect of a single TSD followed by 3 days
SPA (beginning with sleep allowed from 17:00 until 24:00, with daily shiftbacks
of 2 h) in consecutively admitted bipolar depressed inpatients who were taking a
chronic lithium salts treatment (n=16) or who were devoid of psychotropic
medications (n=14). Changes in mood during treatment were recorded with self
administered visual analogue scales and with Hamilton rating scale for
depression. Results showed that SPA could sustain the acute antidepressant
effect of TSD, and that lithium enhanced the effect of the chronobiological
treatment. According to the internal coincidence model, the better clinical
effects observed in lithium-treated patients could be due to the phase delaying
effect of lithium on biological rhythms, leading to a better synchronization of
biological rhythms with the sleep-wake cycle.

Publication Types:
Clinical Trial

PMID: 11684139 [PubMed – indexed for MEDLINE]


10: Neuropsychopharmacology 2001 Nov;25(5 Suppl):S79-84

Sleep deprivation, EEG, and functional MRI in depression: preliminary results.

Clark CP, Frank LR, Brown GG.

University of California, San Diego and San Diego Veterans Affairs Medical
Center, San Diego, CA, USA.

One night of total or partial sleep deprivation (SD) produces temporary
remissions in 40-60% of patients with major depression. Two unmedicated patients
with major depression and a matched control received quantitative perfusion MR
images at baseline and after one night of partial SD (PSD). A reduction > or
=30% in the 17-item Hamilton Depression Rating Scale (omitting sleep and weight
loss items) defined antidepressant response. Theory, techniques, strengths and
weaknesses of quantitative perfusion MRI are described in detail. At baseline,
the responder exhibited elevated perfusion covering ventral anterior
cingulate/medial frontal cortex; the control’s maximal perfusion area was
markedly smaller. The nonresponder’s perfusion was lowest of all, particularly
ventrally. PSD decreased perfusion over much of the responder’s hyperperfused
area but did not change the nonresponder’s scan. These preliminary findings are
consistent with previous SD studies using PET and SPECT.

Publication Types:
Clinical Trial

PMID: 11682279 [PubMed – indexed for MEDLINE]


11: J Psychiatr Res 2001 May-Jun;35(3):155-63

Delta sleep ratio as a predictor of sleep deprivation response in major

Nissen C, Feige B, Konig A, Voderholzer U, Berger M, Riemann D.

Department of Psychiatry and Psychotherapy of the University Hospital of
Freiburg, Hauptstrasse 5, D-79104 Freiburg, Germany.

The fast but short-lasting improvement of depressive symptoms by sleep
deprivation (SD) in about 60% of patients with a major depressive disorder is
well established, but the mechanisms of action are still not clear. Recent
studies suggest that changes in non rapid eye movement (NREM) sleep, especially
in slow wave activity (SWA), could be associated with the therapeutic outcome of
SD. In the current study, spectral analysis of NREM sleep EEG directly prior to
SD was performed to determine if automatically derived sleep parameters predict
SD response. Sixteen pair matched and drug free patients with a major depressive
disorder, 8 SD responders and 8 non-responders (response criterion: 50%
reduction on the 6-item HAMD score), were included. Average EEG spectral power
was calculated for the whole night before SD and for single NREM episodes. While
whole-night averages of spectral power did not differ significantly between
subgroups, SD responders showed a steady decrease of SWA across successive NREM
episodes, whereas in non-responders an increase from the first to the second
episode was observed. The different distribution of SWA was significantly
expressed in the delta sleep ratio (quotient of SWA in the first to the second
NREM episode). In conclusion, a high delta sleep ratio is a positive predictor
for SD response. Referred to psycho- and pharmacotherapeutic results it is
hypothesized that low and high values of the delta sleep ratio characterize
subgroups of depressed patients with different neurobiological alterations,
which could be relevant for further scientific and therapeutic approaches.

PMID: 11461711 [PubMed – indexed for MEDLINE]


12: Fortschr Neurol Psychiatr 2001 Apr;69(4):156-63

[Sleep deprivation as a predictor of response to light therapy in major
depression] [Article in German]

Heller R, Fritzsche M, Hill H, Kick H.

Psychiatrische Klinik, Universitat Heidelberg.

Light therapy (LT) is regarded as the treatment of choice for seasonal affective
disorder (SAD). In nonseasonal depression the results of light therapy are
nonconclusive. Sleep deprivation (SD), however, is effective in 50-60% of the
patients with major depression. The predictive value of Total Sleep Deprivation
(TSD) for the treatment outcome of antidepressiva has been already examined.
Purpose of the present study was to test whether light therapy is more
beneficial in TSD responders than in TSD nonresponders. 40 inpatients with major
depressive disorder completed one night of TSD. Twenty TSD responders and 20 TSD
nonresponders were randomly assigned to 14 days of bright light therapy (2500
lux, 7-9 a.m.) or 14 days of dim light therapy (red light 50 lux, 7-9 a.m.).
Manova with repeated measurements revealed a significant difference in the
course of depression over the time between TSD responders and nonresponders, but
no significant difference between bright and dim light. Questions of placebo
effect, of SAD and of personality variables as predictors of response to SD and
LT are being discussed.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 11386120 [PubMed – indexed for MEDLINE]


13: J Affect Disord 2001 May;64(2-3):257-60

Patterns of response to repeated total sleep deprivations in depression.

Wiegand MH, Lauer CJ, Schreiber W.

Department of Psychiatry and Psychotherapy, Technical University, Munich,

BACKGROUND: Patterns of response and nonresponse in repeated sleep deprivation
(SD) are of both clinical and scientific interest; as yet, studies have yielded
inconsistent results. METHODS: Eighteen inpatients suffering from a major
depression were subjected to a series of six scheduled total sleep deprivations
within 3 weeks; 12 of them completed the whole protocol. All were under a
constant antidepressant medication with amitriptyline. SD effects were measured
using observer and self rating scales. RESULTS: Each single SD led to a
significant improvement. Of the 12 patients who completed the protocol, seven
were classified as responders at endpoint (i.e., 1 week after the sixth TSD).
The majority of patients exhibited a pattern of responses and nonresponses
randomly distributed over time. There was no temporal trend. The initial effect
did not predict the average response to the following SDs. LIMITATIONS: One
third of patients dropped out before completing the protocol which limits the
scope of the study. CONCLUSIONS: Response to a single SD is not generalizable on
a series of following SDs in an individual. The mechanism of action of SD does
probably not involve mechanisms subjected to habituation or sensitization.

PMID: 11313092 [PubMed – indexed for MEDLINE]


14: J Affect Disord 2001 Feb;62(3):207-15

Sleep deprivation as a predictor of response to light therapy in major

Fritzsche M, Heller R, Hill H, Kick H.

Voss-Str. 2, Department of Psychiatry, University of Heidelberg, D-69115
Heidelberg, Germany.

BACKGROUND: While the majority of depressed patients benefit from total sleep
deprivation (TSD), light therapy is regarded as a first-line treatment only for
seasonal affective disorder (SAD). The results of light therapy in nonseasonal
major depressive disorder have been non-conclusive. We examined the correlation
of TSD response and light therapy response in major depressed patients. METHODS:
40 inpatients with major depressive disorder (seven with seasonal pattern, 33
without seasonal pattern) were deprived of a night’s sleep. The TSD responders,
as well as the TSD nonresponders, were randomly assigned to receive adjunct
light therapy either with bright white light (2500 lux) or dim red light (50
lux) during 2 weeks beginning on the third day after TSD. RESULTS: The 20 TSD
responders improved significantly better under the light therapy than the 20 TSD
nonresponders (according to the Hamilton Depression Rating Scale and the
self-rating depression scale Bf-S; v. Zerssen). LIMITATIONS: No significant
difference could be found between the two light intensities. Since the patients
were additionally treated with medication an interaction with the two adjunctive
therapies cannot be excluded. CONCLUSION: Our results indicate that a positive
TSD response in major depressed patients can be predicative of beneficial
outcome of subsequent light therapy.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 11223108 [PubMed – indexed for MEDLINE]


15: Psychiatry Res 2000 Dec 4;97(1):41-9

The clinical response to total sleep deprivation and recovery sleep in geriatric
depression: potential indicators of antidepressant treatment outcome.

Hernandez CR, Smith GS, Houck PR, Pollock BG, Mulsant B, Dew MA, Reynolds CF

Department of Psychiatry, Western Psychiatric Institute and Clinic, University
of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

The clinical response to antidepressant treatment in late-life depression is
often delayed and highly variable. Better indicators of antidepressant efficacy
are needed early in the course of treatment, so that augmentation strategies or
alternative treatments may be initiated. The goal of this study was to evaluate
whether the change in the Hamilton depression rating scale (HDRS) after 36 h of
total sleep deprivation (TSD) and recovery sleep predicted clinical outcome
after 12 weeks of antidepressant treatment, and whether greater predictive value
was observed in certain aspects of depressive symptomology. Fifteen elderly
patients diagnosed with major depression underwent combined treatment with an
initial 36 hours of TSD and a 12-week trial with the antidepressant paroxetine.
Six HDRS subscores were evaluated with respect to how the changes after TSD and
after one night of recovery sleep correlated with HDRS scores after 12 weeks of
treatment. A significant correlation was obtained between the change in the core
depressive symptomology subscale from baseline to recovery sleep and the HDRS
score at 12 weeks, but the correlation was not significant when evaluating the
change from baseline to TSD. These results indicate that the decrease in
symptoms after recovery sleep compared with baseline levels (indicating the
persistence of the antidepressant response), rather than the symptom reduction
after TSD, has greater predictive value with respect to treatment outcome.

PMID: 11104856 [PubMed – indexed for MEDLINE]


16: J Affect Disord 2000 Nov;60(3):201-12

Can critically timed sleep deprivation be useful in pregnancy and postpartum

Parry BL, Curran ML, Stuenkel CA, Yokimozo M, Tam L, Powell KA, Gillin JC.

Department of Psychiatry, University of California – San Diego, 9500 Gilman
Drive, La Jolla, CA 92093-0804, USA.

BACKGROUND: The aim of this study was to test the efficacy of critically timed
sleep deprivation in major mood disorders (MMD) occurring during pregnancy and
postpartum. METHODS: Nine women who met DSM-IV criteria for a MMD with onset
during pregnancy or within 1 year postpartum underwent a trial of either
early-night sleep deprivation (ESD), in which they were sleep deprived in the
early part of one night and slept from 03:00-07:00 h, or late-night sleep
deprivation (LSD), in which they were deprived of sleep in the latter part of
one night and slept from 21:00-01:00 h. Mood was assessed before the night of
sleep deprivation, after the night of sleep deprivation, and after a night of
recovery sleep (sleep 22:30-06:30 h) by trained clinicians, blind to treatment
condition, using standardized scales. RESULTS: More patients responded to LSD
(nine of 11 trials: 82%) compared with ESD (two of six trials: 33%) and they
responded more after a night of recovery sleep (nine of 11 nights: 82%) than
after a night of sleep deprivation (six of 11 nights: 55%). Pregnant women were
the only responders to ESD and the only nonresponders to LSD. LIMITATIONS: The
small and heterogeneous sample size prevents us from making more definitive
conclusions based on statistical analyses. CONCLUSIONS: Although the findings
are preliminary, the results suggest that with further study, critically timed
sleep deprivation interventions may benefit women with pregnancy or postpartum
major mood disorders and potentially provide a viable alternative treatment
modality for those women who are not candidates for pharmacologic or
psychotherapeutic interventions. Such interventions are needed to help prevent
the devastating effects of depression during pregnancy and the postpartum period
on the mother, infant, her family and society.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 11074109 [PubMed – indexed for MEDLINE]


17: Biol Psychiatry 2000 Aug 15;48(4):323-6

Thyroid function and response to 48-hour sleep deprivation in
treatment-resistant depressed patients.

David MM, Owen JA, Abraham G, Delva NJ, Southmayd SE, Wooltorton E, Lawson JS.

Department of Psychiatry, Queen’s University and Kingston Psychiatric Hospital,
and School of Medicine, Queen’s University (EW), Kingston, Canada.

BACKGROUND: Clinical depression is associated with abnormalities of the
hypothalamic-pituitary-thyroid axis. Changes in thyroid function during sleep
deprivation may be related to its antidepressant effects. METHODS: Levels of
thyroid-stimulating hormone, tri-iodothyronine, tri-iodothyronine uptake,
thyroxine, and free thyroxine were measured before, during, and after a 48-hour
sleep deprivation in nine treatment-resistant depressed patients. Clinical state
was assessed every 4 hours. A retrospective study of 26 similar patients was
added for cross-validation. RESULTS: Significant increases in
thyroid-stimulating hormone and tri-iodothyronine during sleep deprivation were
not correlated with clinical improvement. Sleep deprivation responders had lower
tri-iodothyronine uptake levels than nonresponders in both the prospective (p
<.02) and the retrospective (p <.03) samples. CONCLUSIONS: The lower
tri-iodothyronine uptake values in responders may identify a subgroup of
depressed patients who respond to sleep deprivation by virtue of some
abnormality of the hypothalamic-pituitary-thyroid axis that is temporarily
corrected by sleep deprivation.

PMID: 10960165 [PubMed – indexed for MEDLINE]


18: Psychiatry Res 2000 Jul 24;95(1):43-53

Total sleep deprivation combined with lithium and light therapy in the treatment
of bipolar depression: replication of main effects and interaction.

Colombo C, Lucca A, Benedetti F, Barbini B, Campori E, Smeraldi E.

Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric
Sciences, University of Milan, School of Medicine, Italy.

The clinical usefulness of total sleep deprivation (TSD) in the treatment of
bipolar depression is hampered by a high-rate short-term relapse. Previous
literature has suggested that both long-term lithium treatment and light therapy
could successfully prevent relapse. We randomized 115 bipolar depressed
inpatients to receive three cycles of TSD, alone or in combination with morning
light exposure, given at an intensity of 150 or 2500 lux. Forty-nine patients
were undergoing long-term treatment with lithium salts (at least 6 months),
while 66 patients were taking no psychotropic medication. Mood was self-rated by
the Visual Analogue Scale three times a day during treatment. The results showed
that both light therapy and ongoing lithium treatment significantly enhanced the
effects of TSD on the perceived mood, with no additional benefit when the two
treatments were combined. Subjective sleepiness during TSD, as rated by the
self-administered Stanford Sleepiness Scale, was significantly reduced by light
exposure, and was correlated with the outcome. This study confirms the
possibility of obtaining a sustained antidepressant response to TSD in bipolar

Publication Types:
Clinical Trial
Controlled Clinical Trial

PMID: 10904122 [PubMed – indexed for MEDLINE]


19: J Clin Psychiatry 2000;61 Suppl 9:57-67

The treatment of bipolar depression.

Compton MT, Nemeroff CB.

Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, Ga 30322, USA.

BACKGROUND: The treatment of bipolar depression represents a relatively
understudied area in clinical psychiatry. The depressive phases of bipolar
disorder can be very disabling, with significant associated comorbidity and
suicide risk, impairment in functioning, and infringement on quality of life. We
review the current evidence for the management of bipolar depression. METHOD:
References for this review were obtained through MEDLINE searches of the medical
literature on subjects pertaining to the treatment of bipolar depression. Search
terms included bipolar depression, antidepressants, and bipolar disorder. Only
publications in English are reviewed here. RESULTS: Lithium is currently the
gold standard and most appropriate initial treatment for the depressive phase of
bipolar disorder. Other mood stabilizers have demonstrated preliminary efficacy.
Of the antidepressants, bupropion and the selective serotonin reuptake
inhibitors may be associated with less risk of inducing hypomania, mania, and
rapid cycling compared with tricyclic antidepressants. Monoamine oxidase
inhibitors should be considered for patients with anergic bipolar depression.
Electroconvulsive therapy has been shown to be highly efficacious. Other
treatment modalities, including psychotherapy, sleep deprivation, phototherapy,
and newer medications, require further research. CONCLUSIONS: Although the
treatment of bipolar depression can be a complicated clinical task, the
treatment armamentarium is expanding. Further research, especially in the form
of randomized controlled trials, is warranted. Clinicians should be familiar
with general guidelines for the use of psychopharmacologic agents for treating
bipolar depression.

Publication Types:
Review, Tutorial

PMID: 10826663 [PubMed – indexed for MEDLINE]


20: J Affect Disord 2000 Jul;59(1):77-83

Preliminary evidence of an association between increased REM density and poor
antidepressant response to partial sleep deprivation.

Clark C, Dupont R, Golshan S, Gillin JC, Rapaport MH, Kelsoe JR.

Department of Psychiatry 9116A University of California at San Diego 92093, USA.

BACKGROUND: One night of total sleep deprivation or of late-night partial sleep
deprivation (PSD) produces a temporary remission in approximately 40-60% of
patients with major depressive disorder; however, little is known about
polysomnography (PSG) characteristics of responders to these types of sleep
deprivation (SD). METHODS: Twenty-three unmedicated unipolar patients (17-item
Hamilton Depression Rating Scale (HDRS17) >16) and 14 normal controls underwent
1 night of late-night PSD (awake after 3 a.m.) Subjects underwent baseline PSG
and received the HDRS17 at standard times before and after PSD. Clinical
response was defined as a reduction of >30% in the modified HDRS17 (omitting
sleep and weight loss items) following PSD. RESULTS: The 12 responders and 11
nonresponders did not differ from each other significantly on baseline HDRS17 or
PSG variables. The only PSG variable correlating with percent decrease in
modified HDRS17 was baseline REM density (Pearson’s r=-0.52, n=23, P=0.01.) In
other words, the lower the baseline REM density, the more robust the
antidepressant response was. Limitations: Subject numbers are relatively small.
CONCLUSIONS: Increased REM density, which reflects the number of rapid eye
movements per epoch of REM sleep, may be a physiological marker for severity or
poor prognosis in a variety of psychiatric disorders, including relapse in
recovering alcoholics, suicidality in schizophrenia, and poor response to PSD or
interpersonal psychotherapy in depression.

PMID: 10814775 [PubMed – indexed for MEDLINE]


21: Psychiatry Res 1994 Jun;55(2):101-9

Increased limbic blood flow and total sleep deprivation in major depression with

Ebert D, Feistel H, Barocka A, Kaschka W.

Department of Psychiatry, University of Erlangen, Germany.

Single photon emission computed tomography (SPECT) with
technetium-99m-d,l-hexamethyl-propylene amine oxime (99Tcm-HMPAO) was carried
out in 20 melancholic patients before and after total sleep deprivation.
Findings in 11 responders to total sleep deprivation (defined by > or = 40%
improvement on the Hamilton Rating Scale for Depression) were compared with
findings in nine nonresponders. On the basis of a semiquantitative evaluation of
SPECT findings, responders showed relative hyperperfusion before sleep
deprivation in the right anterior cingulate cortex and in the right and left
fronto-orbital cortex and basal cingulate gyrus. Responders who showed > or =
50% improvement also showed hippocampal overactivation before sleep deprivation.
It is possible that limbic overactivation may characterize depressed responders
to total sleep deprivation as a distinct subtype. Another possibility is that
the pattern of limbic hyperactivation reflects the increased number of bipolar
patients in the responder group, with response to total sleep deprivation being
only a covariate of this bipolar-unipolar distinction.

PMID: 10711798 [PubMed – indexed for MEDLINE]


22: Wien Med Wochenschr 1999;149(18):520-4

[Therapeutic sleep deprivation and phototherapy] [Article in German]

Praschak-Rieder N, Willeit M, Neumeister A, Hilger E, Kasper S.

Klinischen Abteilung fur Allgemeine Psychiatrie, Universitatsklinik fur
Psychiatrie, Wien.

Since ancient times the influence of chronobiological factors on the
pathogenesis, course, and treatment of depression has been well known. Amongst
antidepressive treatment strategies two are based on chronobiological knowledge:
therapeutic sleep deprivation, which exerts a rapid and dramatic, albeit usually
short-lasting, improvement of mood in the majority of patients with major
depressive disorder, and light therapy with full-spectrum bright light. About
sixty percent of all depressed patients improve after a single night of total or
partial sleep deprivation. It has been shown that a combination of
pharmacotherapy with antidepressants and sleep deprivation is superior to
pharmacotherapy alone. Moreover, sleep deprivation has proved to hasten the
onset of action of antidepressant medication and repeated sleep deprivation can
also be an efficient treatment strategy in drug refractory depression. Light
therapy with bright artificial light is especially beneficial in patients with a
fall/winter pattern of depressive symptomatology that has been termed seasonal
affective disorder. Similar to sleep deprivation, bright light therapy is
characterized by a fast onset of antidepressant action and by the exertion of
additive properties to antidepressive medication. Bright light therapy,
beginning in the morning after partial sleep deprivation, is able to prevent the
depressive relapse after the next night of sleep in sleep deprivation

Publication Types:
Review, Tutorial

PMID: 10637957 [PubMed – indexed for MEDLINE]


23: Eur Arch Psychiatry Clin Neurosci 1999;249(5):231-7

How to preserve the antidepressive effect of sleep deprivation: A comparison of
sleep phase advance and sleep phase delay.

Riemann D, Konig A, Hohagen F, Kiemen A, Voderholzer U, Backhaus J, Bunz J,
Wesiack B, Hermle L, Berger M.

Department of Psychiatry and Psychotherapy, University Hospital of Freiburg,
Hauptstr. 5, D-79104 Freiburg, Germany.

Total sleep deprivation (TSD) leads to an immediate amelioration of depressed
mood in approximately 70 % of patients with the melancholic subtype of
depression. The clinical utility of this procedure is limited, as the
improvement usually subsides after the next night of sleep. In the present
study, 40 depressed inpatients, being free of psychoactive medication for at
least 7 days and who had responded to a TSD were then distributed (according to
a matched-pair design) to a sleep phase advance (SPA = time in bed scheduled
from 1700-2400 hrs) or a sleep phase delay (SPD = time in bed from 0200-0700
hrs) with a succeeding shift back (for one hour in the SPA group per day)
respectively shift forward (for 30 minutes in the SPD group per day), until the
initial sleep phase (2300-0600 hrs) was reached after seven days again. Based on
previous observations it was hypothesized that a phase advance of the sleep
period should prevent responders to TSD from relapsing. Whereas 75% of the TSD
responders were stabilized by the phase advanced condition and did not relapse
over a period of seven days, only 40% of the patients in the phase delayed
condition did not relapse. Polysomnography during the course of the study gave
no evidence that the unusual sleep schedules caused prolonged sleep deprivation.
Abnormalities of REM sleep persisted both in the clinical responders and
non-responders after the sleep wake manipulation. It is concluded that the
clinical effectiveness of TSD can be significantly improved by combining TSD
with a following phase advance of the sleep period.

Publication Types:
Clinical Trial
Controlled Clinical Trial

PMID: 10591988 [PubMed – indexed for MEDLINE]


24: Psychiatr Clin North Am 1999 Sep;22(3):585-607

Rapid-cycling bipolar disorder. An overview of research and clinical experience.

Kilzieh N, Akiskal HS.

VA Puget Sound Health Care Services, Tacoma, Washington, USA.

Although many studies of RCBD have been reported over the last 2 decades,
knowledge remains limited. Higher incidence in women is the sole clearly
replicated finding in most studies. This finding might be mediated by
cyclothymia, a temperament that is of higher prevalence in women and that might
be considered as a normal variant of RC. Many questions remain unanswered.
Review of putative risk factors, such as hypothyroidism and treatment with
antidepressants, provides no conclusive answers. There is clinical evidence to
implicate both factors. In principle, the thyroid connection can be approached
rationally, yet there seems to be no relationship between thyroid status and
response to thyroid augmentation. For this reason and given the potential risks
of long-term thyroid use, this strategy should not be the first one to be tried
in RC. Cumulatively, naturalistic studies over the past 30 years have strongly
implicated antidepressants in switching and cycle acceleration, yet the
double-blind, controlled, prospective studies that are needed to provide
definitive answers are unlikely to be conducted for ethical reasons discussed in
this article. Bipolar family history of RC probands appears indistinguishable
from non-RC probands, indicating that most likely RCBD does not breed true.
Although RC seems to be more lithium resistant with less likelihood of being
symptom-free after 2 to 5 years of follow-up, many of these patients nonetheless
have resolution of the RC course. There is no marked difference in suicide
rates. An association of RC with bipolar type II, D-M-I pattern and those who
switch into mania or hypomania on antidepressants is a provocative possibility:
Antidepressants might introduce RC by first inducing a switch during a
depressive episode, creating a D-M-I pattern, a pattern that is poorly
responsive to lithium, which eventually degenerates into RC. Again, this
sequence might be mediated by the high prevalence of cyclothymia in bipolar II
patients. Thus, data from phenomenology, family history, and long-term outcome
do not support RC as a separate entity. RC appears to be a temporary complicated
phase in the illness, not a stable feature. This was noted by Kraepelin: I think
I am convinced that that kind of classification must of necessity wreck on the
irregularity of the disease. The kind and duration of the attacks and the
intervals by no means remain the same in the individual case but may frequently
change, so that the case must be reckoned always to new forms. Data by
Gottschalk et al testify to the chaotic mood swings of contemporary bipolar
disorder. Moreover RC is seen in other medical diseases, such as epilepsy, in
which patients have phases of increase in frequency of episodes (seizures) that
become refractory to treatment. Further longitudinal prospective studies are
required to understand the complexity of this intriguing phenomenon and to
provide better treatments. Algorithms deriving from tertiary research or
university-based clinical experience may not generalize to RC or otherwise
treatment-resistant bipolar patients seen in more routine practice. Illness
severity in RCBD generally precludes double-blind controlled investigations.
Meanwhile, clinicians may rely on discontinuing antidepressants, maintaining
patients on combined mood stabilizers–of which valproate is probably the most
useful–and making judicious use of atypical neuroleptics. Benzodiazepines and
alcohol (which produce withdrawal), caffeine, stimulants, exposure to bright
light, and sleep deprivation during excited phases should be avoided. Thyroid
and nimodipine augmentation can be considered in those with the most malignant
course. These are patients who need the maximal support that their psychiatrist
can provide them. Office visits must be arranged as the last appointment of the

Publication Types:
Review, Tutorial

PMID: 10550857 [PubMed – indexed for MEDLINE]


25: Psychiatry Res 1999 Jun 30;86(3):267-70

Rate of switch from depression into mania after therapeutic sleep deprivation in
bipolar depression.

Colombo C, Benedetti F, Barbini B, Campori E, Smeraldi E.

IRCCS Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric
Sciences, University of Milan, School of Medicine, Italy.

Sleep deprivation is a potentially useful non-pharmacological treatment for
depression. A relationship between sleep loss and the onset of mania has been
reported, so it is possible that a switch from depression into mania after sleep
deprivation might be expected in bipolar depressed patients who are treated with
sleep deprivation. In a sample of 206 bipolar depressed treated with three
cycles of sleep deprivation, alone or in combination with heterogeneous
medications, we observed a 4.85% switch rate into mania and a 5.83% switch rate
into hypomania. These percentages are comparable to those observed with
antidepressant drug treatments.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 10482346 [PubMed – indexed for MEDLINE]


26: J Clin Psychopharmacol 1999 Jun;19(3):240-5

Ongoing lithium treatment prevents relapse after total sleep deprivation.

Benedetti F, Colombo C, Barbini B, Campori E, Smeraldi E.

Department of Neuropsychiatric Sciences, Instituto Scientifico Ospedale San
Raffaele, University of Milan, School of Medicine, Milano, Italy.

Forty bipolar depressed inpatients underwent three consecutive cycles of total
sleep deprivation (TSD). At the beginning of the study, 20 patients were free of
psychotropic drugs and 20 had been receiving lithium medication for at least 6
months. Mood was rated on the Hamilton Rating Scale for Depression before and
after TSD; perceived mood changes during treatment were evaluated with
self-administered visual analog scales. Patients undergoing long-term lithium
treatment showed a significantly better response to TSD as rated on both scales:
13 of 20 patients (vs. 2 of 20 patients without lithium) showed a sustained
response during a follow-up period of 3 months. This preliminary evidence of a
positive interaction of TSD and long-term lithium treatment could be explained
by a synergistic effect of both treatments on brain serotonergic function,
possibly via a desensitization of 5-hydroxytryptamine-1A inhibitory

Publication Types:
Clinical Trial

PMID: 10350030 [PubMed – indexed for MEDLINE]


27: J Psychiatr Res 1999 Jan-Feb;33(1):69-72

Worsening of delusional depression after sleep deprivation: case reports.

Benedetti F, Zanardi R, Colombo C, Smeraldi E.

Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric
Sciences, University of Milan, School of Medicine, Italy.

Five patients (three bipolars and two unipolars) affected by a major depressive
episode with psychotic features were treated with total sleep deprivation (TSD)
without concurrent psychotropic medication. After TSD we observed a worsening in
psychotic as well as in depressive symptoms as rated on the Dimension of
Delusional Experience Rating Scale and on Hamilton Rating Scale for Depression,
respectively. TSD is known to markedly enhance the activity of brain
monoaminergic pathways. Given the interaction between brain serotonergic and
dopaminergic systems in delusional depression, it is possible that an
enhancement in dopaminergic activity may be responsible of the symptomatological
worsening in delusional depressives observed after TSD.

Publication Types:
Clinical Trial

PMID: 10094242 [PubMed – indexed for MEDLINE]


28: Neuropsychopharmacology 1999 Apr;20(4):380-5

Sustained antidepressant effect of sleep deprivation combined with pindolol in
bipolar depression. A placebo-controlled trial.

Smeraldi E, Benedetti F, Barbini B, Campori E, Colombo C.

Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric
Sciences, University of Milan, School of Medicine, Italy.

Total sleep deprivation (TSD) shows powerful but transient clinical effects in
patients affected by bipolar depression. Pindolol blocks the serotonergic 5-HT1A
autoreceptor, thus improving the antidepressant effect of selective serotonin
reuptake inhibitors. We evaluated the interaction of TSD and pindolol in the
treatment of acute episodes of bipolar depression. Forty bipolar depressed
inpatients were randomized to receive pindolol 7.5 mg/day or placebo for nine
days in combination with three consecutive TSD cycles. Pindolol significantly
improved the antidepressant effect of TSD, and prevented the short-term relapse
after treatment. The response rate (HDRS scores < 8) at the end of treatment was
15/20 for pindolol, and 3/20 for placebo. Coadministration of pindolol and TSD
resulted in a complete response, which could be sustained for six months with
lithium salts alone, in 65% of cases. This results suggest a major role for
serotonergic transmission in the mechanism of action of TSD, and makes TSD
treatment more effective in the treatment of bipolar depression.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 10088139 [PubMed – indexed for MEDLINE]


29: Psychiatry Res 1998 Jun 2;79(1):43-50

The unipolar-bipolar dichotomy and the response to sleep deprivation.

Barbini B, Colombo C, Benedetti F, Campori E, Bellodi L, Smeraldi E.

IRCCS Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric
Sciences, University of Milan, School of Medicine, Milano, Italy.

Fifty-one inpatients affected by a major depressive episode were divided into
four groups according to mood disorder diagnosis and previous clinical history
(bipolar disorder type I; bipolar disorder type II; major depressive disorder
with at least three previous depressive episodes; and single depressive episode
patients) and administered three consecutive total sleep deprivation (TSD)
cycles. Mood changes were rated with a reduced version of the Hamilton
Depression Rating Scale and with self-administered visual analogue scales. TSD
caused better clinical effects in bipolar and single-episode patients; in
particular, unipolar patients lacked effects in perceived mood after the first
TSD and showed worse Hamilton ratings in respect to the other groups after the
three TSD treatments. Discriminant function analysis could correctly classify
80% of bipolar patients, post hoc, based on TSD response. Further researches on
the clinical efficacy of TSD must take into account the heterogeneity of
depression and of its biological substrate.

Publication Types:
Clinical Trial

PMID: 9676825 [PubMed – indexed for MEDLINE]


30: Brain Res Mol Brain Res 1998 Jun 15;57(2):235-40

REM sleep deprivation increases the levels of tyrosine hydroxylase and
norepinephrine transporter mRNA in the locus coeruleus.

Basheer R, Magner M, McCarley RW, Shiromani PJ.

VA Medical Center and Harvard Medical School, Brockton, MA 02401, USA.

The present study was conducted to determine the effects of REM sleep
deprivation on the levels of tyrosine hydroxylase (TH) and norepinephrine
transporter (NET) mRNA in the locus coeruleus (LC) of rats. The animals were
deprived of REM sleep for 1, 3 or 5 days, then killed and changes in the mRNA
levels were determined using in situ hybridization. The levels of both TH and
NET mRNA increased in animals deprived of REM sleep for 3 days or longer whereas
no change in these messages were observed in the LC of control animals. REM
sleep deprivation has been used as a mode of treatment for major depression.
Others have shown that treatment with tricyclic antidepressants also results in
increased levels of TH and NET mRNA in LC. Our results suggest that the
antidepressant effect of REM sleep deprivation and tricyclic antidepressants may
share similar molecular changes in the norepinephrine system.

PMID: 9675421 [PubMed – indexed for MEDLINE]


31: Biol Psychiatry 1998 Jun 1;43(11):829-39

Microsleep during partial sleep deprivation in depression.

Hemmeter U, Bischof R, Hatzinger M, Seifritz E, Holsboer-Trachsler E.

Depression Research Unit, Psychiatric University Hospital, Basel, Switzerland.

BACKGROUND: Sleep deprivation (SD) exerts a beneficial effect on mood and sleep
in about 60% of depressed patients usually followed by a relapse into depression
after the recovery night. Short phases of sleepiness, especially naps in the
early morning, may be responsible for this phenomenon. METHODS: To evaluate the
effect of short, even ultrashort phases of sleep-microsleep (MS) during partial
sleep deprivation (PSD) on mood, cognitive psychomotor performance (CPP), and
sleep, an electroencephalograph (EEG) was continuously recorded over 60 hours in
12 patients with major depression. Subjective mood was assessed by a visual
analogue scale and CPP by a letter cancellation test. RESULTS: The results
illustrate that in depressed patients during PSD the amount of MS is increased,
predominantly in the early morning, which was subjectively unrecognized and not
observed by nursing staff. Patients with a low cumulative amount of MS during
PSD improved significantly in mood, CPP, and sleep pattern compared to the
patients with a high amount of MS who showed only slight changes. CONCLUSION:
Therefore, accumulated MS may influence the SD-induced positive effects in
depressed patients.

PMID: 9611673 [PubMed – indexed for MEDLINE]


32: Nervenarzt 1998 Jan;69(1):66-9

[Sleep deprivation and subsequent sleep phase advance stabilizes the positive
effect of sleep deprivation in depressive episodes] [Article in German]

Albert R, Merz A, Schubert J, Ebert D.

Psychiatrische Universitatsklinik mit Poliklinik, Erlangen.

Approximately 60% of patients with major depression disorder show a beneficial
response to total sleep deprivation (TSD), but the positive effect of TSD is
short, and naps or the following night’s sleep destroy it. Various methods have
been tried to stabilize the positive sleep-deprivation effect. A consecutive
1-week advance in the sleep phase stabilized mood in more than 50% of the
sleep-deprivation responders. We examined 40 male patients with major depression
who in addition to medical treatment took part in a phase advance study to prove
possible synergistic effects. About 60% of the patients showed positive mood
stabilization after 1-week of treatment when the patients were sleep-deprivation
responders. These results support data from other groups.

PMID: 9522335 [PubMed – indexed for MEDLINE]


33: J Affect Disord 1998 Feb;48(1):69-74

Sleep deprivation response in seasonal affective disorder during a 40-h constant

Graw P, Haug HJ, Leonhardt G, Wirz-Justice A.

Chronobiology and Sleep Laboratory, Psychiatric University Clinic, Basel,

BACKGROUND: There are no controlled studies investigating the response of
patients with seasonal affective disorder (SAD) to a total sleep deprivation
(SD). METHODS: The clinical response to SD of patients with SAD in winter was
investigated under the stringently controlled conditions of a 40-h constant
routine protocol. RESULTS: 52% of the SAD patients (N=11 women) improved, using
a mean of a multiple ratings. This is in the range of response found for
non-seasonal major depression. In contrast, controls (N=8 women) showed less
improvement of mood (29%). CONCLUSION: SAD patients respond to SD as do
non-seasonal major depressives. The best discrimination of response was obtained
in an observer rating (Clinical Global Impression: global severity improvement),
and the morning values of two different self ratings (v. Zerssen depression
scale, 100 mm VAS with the criterion of > or =10 mm improvement). LIMITATION: A
more reliable estimate of the SD response rate in SAD patients would require a
larger group. CLINICAL RELEVANCE: SAD patients do not differ from other
subgroups of major depression in their response to SD, and therefore this is an
additional treatment option to light therapy.

PMID: 9495604 [PubMed – indexed for MEDLINE]


34: Depress Anxiety 1997;6(3):113-8

Accelerating response in geriatric depression: a pilot study combining sleep
deprivation and paroxetine.

Bump GM, Reynolds CF 3rd, Smith G, Pollock BG, Dew MA, Mazumdar S, Geary M,
Houck PR, Kupfer DJ.

Mental Health Clinical Research Center for the Study of Late-Life Mood
Disorders, University of Pittsburgh, PA 15213, USA.

Elderly depressed patients often require an average of 12 weeks of
pharmacotherapy before attaining remission. The delay between treatment
initiation and remission may decrease compliance and prolongs suffering; hence,
interventions that decrease the time to onset of antidepressant activity are
needed. Our objective was to evaluate, in an open trial, the use of one night of
total sleep deprivation combined with paroxetine to accelerate antidepressant
response in elderly patients. Thirteen elderly patients with major depression
were sleep-deprived for one night and started paroxetine on the night of
recovery sleep. Patients were followed for twelve weeks, and clinical
improvement was rated using the 17-item Hamilton Depression Rating Scale and a
version of the Hamilton modified for sleep deprivation studies. 8/13 (62%)
patients experienced significant improvement of depressive symptoms by 2 weeks.
Within 12 weeks 11/13 (85%) patients responded to the combination of sleep
deprivation and paroxetine. Median response time was 2 weeks. Clinical response
at 12 weeks was correlated with changes in Sleep Deprivation Depression Rating
Scale Scores between baseline and recovery sleep. In an open trial, the combined
use of total sleep deprivation and paroxetine appears to be an effective method
for speeding the onset of clinical antidepressant activity in geriatric
depression and for improving early recognition of non-response.

Publication Types:
Clinical Trial

PMID: 9442985 [PubMed – indexed for MEDLINE]


35: Psychiatry Res 1997 Sep 29;75(2):67-74

Can response to partial sleep deprivation in depressed patients be predicted by
regional changes of cerebral blood flow?

Volk SA, Kaendler SH, Hertel A, Maul FD, Manoocheri R, Weber R, Georgi K, Pflug
B, Hor G.

Department of Clinical Psychiatry and Psychotherapy II, Johann Wolfgang
Goethe-University, Frankfurt am Main, Germany.

The possible predictive value of regional cerebral perfusion patterns with
respect to the response to partial sleep deprivation (PSD) was evaluated in 15
major depressive patients (mean age = 54.9 years, mean Hamilton depression score
= 21.6). Patients were studied with single photon emission computed tomography
with technetium-99 m-D,L-hexamethyl-propylene amine oxime. Scans were performed
on the morning before and after (at 08.00 h) PSD. Responders to PSD had
significantly higher perfusion in the right orbitofrontal cortex than did
non-responders before PSD. Multiple regression analysis indicated that right
orbitofrontal/basal cingulate perfusion (r = -0.77, P < 0.001) before PSD, and
left inferior temporal perfusion (r = 0.59, P = 0.01) after PSD, were fairly
accurate predictors of change in Hamilton depression scores. Thus, it appears
that the orbitofrontal cortex and the cingulate are involved in PSD and may
serve as predictors of therapeutic response.

PMID: 9351489 [PubMed – indexed for MEDLINE]


36: Am J Psychiatry 1997 Jun;154(6):870-2

Comment in:
Am J Psychiatry. 1998 Aug;155(8):1134-5.

Sleep deprivation combined with consecutive sleep phase advance as a fast-acting
therapy in depression: an open pilot trial in medicated and unmedicated

Berger M, Vollmann J, Hohagen F, Konig A, Lohner H, Voderholzer U, Riemann D.

Klinikum der Albert-Ludwigs-Universitat Freiburg, Germany.

OBJECTIVE: The authors’ goal was to test the hypothesis that the antidepressant
effect of total sleep deprivation can be maintained by initially avoiding sleep
during a supposedly “critical” time period in the early morning. METHOD: They
studied 33 inpatients with major depression, melancholic type, all of whom
responded positively to total sleep deprivation. Twelve of the patients were men
and 21 were women; their mean age was 46.7 years (SD = 13.7). After total sleep
deprivation, the patients started a sleep schedule from 5:00 p.m. to 12:00
midnight, which then was shifted back by 1 hour each day until a sleep time of
11:00 p.m. to 6:00 a.m. was reached. RESULTS: Twenty (61%) of the 33 patients
who responded to total sleep deprivation with an improved state of mood
maintained this improvement during sleep phase advance therapy. Drug-free and
medicated patients did not differ from each other. CONCLUSIONS: The rapid
amelioration of mood observed with total sleep deprivation can be preserved with
a succeeding phase shift of the sleep period.

Publication Types:
Clinical Trial

PMID: 9167521 [PubMed – indexed for MEDLINE]


37: J Affect Disord 1997 Feb;42(2-3):93-101

Can negative self-schemes in depressives be altered through sleep deprivation?

Baving L, Maes H, Bohus M, Lis S, Krieger S, Olbrich H, Berger M.

Psychiatric Hospital, Albert-Ludwig University, Freiburg, Germany.

This paper addresses the question whether negative cognitive style represents a
state or trait variable of depressive patients. For this reason, it studies the
influence of sleep deprivation on negative self-schemes of those patients. 10
patients suffering from DSM-III-R major depression were compared with 10 age-
and sex-matched controls on a task for rating the self-descriptiveness of
positive and negative adjectives as well as a subsequent word recognition task.
Three sessions were involved: an initial session (baseline), the second
following a night of sleep deprivation, and the third after a successive full
night’s sleep. During the baseline examination, depressives showed a relatively
negative cognitive bias; that is, the same number of positive and negative
self-scheme elements. In comparison to controls, they showed significantly more
negative and significantly less positive self-scheme elements. The same pattern
emerged in a word recognition task for the number of recognized self-scheme
elements. These variables indicated no change in the depressive group following
sleep deprivation. Depressive subjects’ reaction times on self-descriptiveness
rating were significantly longer for positive than for negative self-scheme
elements at the baseline session. The opposite was true for controls. Here, a
sleep deprivation effect was evident. There was no longer a difference in the
speed of information processing for positive as compared to negative self-scheme
elements. This applied to both depressive and control groups.

PMID: 9105950 [PubMed – indexed for MEDLINE]


38: Eur Arch Psychiatry Clin Neurosci 1997;247(2):100-3

Sleep deprivation hastens the antidepressant action of fluoxetine.

Benedetti F, Barbini B, Lucca A, Campori E, Colombo C, Smeraldi E.

Department of Neuropsychiatric Sciences, Istituto Scientifico Ospedale San
Raffaele, School of Medicine, University of Milan, Italy.

Among ten bipolar depressed patients admitted to our psychiatric ward, five
patients were treated with fluoxetine alone and five subjects were treated with
fluoxetine in association with total sleep deprivation (TSD) in order to
evaluate the effect of the interaction between the administration of the
serotonergic antidepressant compound fluoxetine and repeated cycles of TSD.
Patients treated with fluoxetine plus repeated TSD showed a faster amelioration
of depressive symptomatology compared with the other group. We discuss our
findings hypothesizing an enhancement in dopaminergic and possibly in
serotonergic transmission due to repeated TSD adding to the increase in
serotonergic transmission due to fluoxetine medication.

Publication Types:
Clinical Trial
Controlled Clinical Trial

PMID: 9177956 [PubMed – indexed for MEDLINE]


39: Psychiatry Res 1996 Dec 20;65(3):179-84

Dopamine agonist amineptine prevents the antidepressant effect of sleep

Benedetti F, Barbini B, Campori E, Colombo C, Smeraldi E.

Istituto Scientifico Ospedale San Raffaele, IRCCS Department of Neuropsychiatric
Sciences, University of Milan School of Medicine, Italy.

In a double-blind study, the effects of the interaction between the
administration of amineptine versus placebo and repeated cycles of total sleep
deprivation (TSD), which is thought to act through an enhancement in
dopaminergic transmission, were analyzed. Twenty-two consecutively admitted
patients with bipolar depression formed the study group. Repeated
administrations of TSD significantly enhanced perceived mood levels in
placebo-treated patients, while amineptine administration blocked the
antidepressant action of TSD. Hypothesized changes in brain dopaminergic
transmission attributable to amineptine pretreatment are discussed.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 9029666 [PubMed – indexed for MEDLINE]


40: Neuropsychopharmacology 1996 Oct;15(4):332-9

Eye-blink rates and depression. Is the antidepressant effect of sleep
deprivation mediated by the dopamine system?

Ebert D, Albert R, Hammon G, Strasser B, May A, Merz A.

Department of Psychiatry, University of Erlangen, Germany.

A series of studies demonstrated a possible correlation between eye-blink rate
and central dopamine activity. The hypothesis has been put forward that the
antidepressant effect of sleep deprivation (SD) is mediated by an enhanced
dopamine release resulting in an amphetaminelike action of SD. Therefore, the
blink rates of 12 drug-naive patients with major depression and 12 healthy
controls were compared before and after SD and before and after 2.5 mg
bromocriptine as a dopaminergic challenge. The main result of the study was that
the depressed patients had a significantly higher increase of blinking after SD
both with and without a dopaminergic challenge. Basal eye-blink rate was not
different in nonretarded major depression patients compared to controls. Sleep
deprivation increased blink rate in depression patients but not in controls, and
the increase was proportional to improvements in depressive state after sleep
deprivation. Bromocriptine did not increase blink rate 1 hour after application.
This result is consistent with the hypothesis that antidepressant SD acts
through dopamine release, although it is not conclusive, because other
neurotransmitters like acetylcholine may be involved in the regulation of

PMID: 8887987 [PubMed – indexed for MEDLINE]


41: J Affect Disord 1996 Apr 12;37(2-3):121-8

Advanced vs. normal sleep timing: effects on depressed mood after response to
sleep deprivation in patients with a major depressive disorder.

Riemann D, Hohagen F, Konig A, Schwarz B, Gomille J, Voderholzer U, Berger M.

Psychiatric Department, University of Freiburg, Germany.

Total sleep deprivation (TSD) exerts beneficial but only transient effects on
mood in patients with a major depressive disorder (MDD). Though approximately 50
to 70% of depressed patients improve after sleep deprivation, the majority
relapse after recovery sleep, some even after a short nap. One theoretical model
postulates a critical period in the early morning hours where sleep is likely to
induce a relapse, and nap studies indicate that sleep may be particularly
‘depressogenic’ at this time of day. A second model attributes the relapse to
the release of non-REM sleep. We therefore compared the impact of an advanced
sleep period (17:00-24:00 h) to a normal sleep period (23:00-06:00 h) on mood in
patients who had responded to sleep deprivation. Less relapses into depression
occurred after advanced sleep. Polysomnographic data showed that, as expected,
normal sleep was characterized by a more pronounced improvement of sleep
continuity and increased slow-wave sleep. The normal sleep group showed a
stronger decrease in REM sleep density than the advanced sleep group compared
with baseline. These data add to a growing body of evidence that the timing of
sleep following successful sleep deprivation may be crucial for a stabilization
of its antidepressant effect. Thus, avoidance of sleep during a “critical
period’ for more than a single night is necessary to provide a longer-lasting
treatment modality.

PMID: 8731074 [PubMed – indexed for MEDLINE]


42: J Affect Disord 1996 Feb 12;37(1):31-41

Amitriptyline in combination with repeated late sleep deprivation versus
amitriptyline alone in major depression. A randomised study.

Kuhs H, Farber D, Borgstadt S, Mrosek S, Tolle R.

Department of Psychiatry, University of Munster, Germany.

Only few systematic studies are available on the status of sleep deprivation
therapy in the overall treatment regimen of depressive patients. 51 patients
suffering from a major depressive episode (ICD-10) were randomly allocated to 4
weeks’ treatment with amitriptyline (150 mg/day) or to a combination of
amitriptyline with six partial-sleep-deprivation treatments late in the night
(at 4-5 day intervals). According to observer rating (Hamilton Rating Scale for
Depression, 21- and 10-item version), a highly significant amelioration was
recorded in both groups until the 14th day of treatment. A further improvement
occurred, however, only in those patients treated with both antidepressants and
sleep deprivation. Hence the response rate ( > or = 50% HAMD reduction) after 4
weeks’ treatment was distinctly more favourable in this group than in those
patients under pharmacotherapy alone. The superiority of the combined therapy
cannot be confirmed statistically by self-rating (Befindlichkeitsskala: von
Zerssen; Visual Analogue Mood Scale). The immediate antidepressive effect of
sleep deprivation diminished in the course of the sleep deprivation series. The
response to the first sleep deprivation was a predictor neither for the response
to further sleep deprivation treatments nor for the overall treatment outcome.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 8682976 [PubMed – indexed for MEDLINE]


43: Wien Med Wochenschr 1996;146(13-14):309-10

[Subjective diurnal fatigue and sleep deprivation response] [Article in German]

Volk S, von Nessen S, Brandt J, Georgi K, Pflug B.

Klinik fur Klinische Psychiatrie und Psychotherapie II,
Johann-Wolfgang-Goethe-Universitat, Frankfurt am Main, Deutschland.

29 major depressive patients, the majority suffering from a melancholic subtype
and typical diurnal variation of mood, rated subjective tiredness on a 100 mm
analogous scale before and after total sleep deprivation (TSD). In study A every
four hours during the day before and after TSD and every 2 hours during the
TSD-night ratings were performed, in study B at 8.00 a.m. before and after TSD.
The mean response rate was 55.2% in the 2 studies. In study A subsequent
responders were less tired during the afternoon before TSD. Responding patients
were more alert the morning after sleep deprivation than non-responders. A
higher inter-individually variability of tiredness ratings in responders before
and after sleep deprivation was found in study B, assuming an arousing property
and a greater variability in subjective arousal at least during the morning
hours. In summary the determination of the subjective arousal level may help to
predict response.

PMID: 9012163 [PubMed – indexed for MEDLINE]


44: Prog Neuropsychopharmacol Biol Psychiatry 1995 Jul;19(4):593-602

Serial partial sleep deprivation as adjuvant treatment of depressive insomnia.

Hemmeter U, Seifritz E, Hatzinger M, Muller MJ, Holsboer-Trachsler E.

Departement of Psychiatry, University of Basel, Switzerland.

1. Sleep disturbance is a prominent symptom of major depression. Despite
specific treatment with antidepressants, there is a substantial number of
patients who improve in depressed mood but remain sleep disturbed. 2.
Polysomnographic sleep (PSG) data and self reported sleep measures were assessed
at baseline and after one week in 18 patients (35-65 years) randomly assigned to
treatment with either trimipramine alone 200 mg/d (group 1) or trimipramine (200
mg/d) and additional serial partial sleep deprivation in the second half of the
night (3x/week) (group 2). 3. In group 1 no marked changes between baseline and
after treatment were found. 4. In group 2 the PSG data showed a significant
increase of slow wave sleep and a compensatory decrease in stage 1. Sleep
continuity improved in terms of numbers of awakenings, sleep onset latency and
total sleep time. These changes were in parallel with the subjective estimation
of sleep in group 2. 5. There was no significant difference in the Hamilton
rating scale scores neither at baseline nor after treatment. 6. These observed
effects on sleep following additional serial PSD therapy seem to occur
independent from the antidepressive effect.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 8588058 [PubMed – indexed for MEDLINE]


45: Biol Psychiatry 1995 Apr 1;37(7):457-61

The relationship between tiredness prior to sleep deprivation and the
antidepressant response to sleep deprivation in depression.

Bouhuys AL, van den Burg W, van den Hoofdakker RH.

Department of Biological Psychiatry, University Hospital, Groningen, The

Recently it was hypothesized that the antidepressant response to total sleep
deprivation (SD) results from a disinhibition process induced by the increase of
tiredness in the course of SD. In the present study, the role of tiredness in
the antidepressant response to SD is further investigated. Seventy-two depressed
patients scored subjective tiredness and depressed mood three times daily (in
the morning, afternoon, and evening) on the days preceding and following SD. It
was found that averaged tiredness on the day prior to SD was related to the SD
response, when the severity of depression prior to SD had been held
statistically constant. Also, when both severity of depression and diurnal
variation of mood prior to SD were partialed out, tiredness showed a positive
correlation with the SD response: patients who reported a relatively low degree
of tiredness on the day preceding SD improved by SD. This result suggests that
tiredness has an influence on SD effects, and that this influence is independent
from that of the severity of depression. The findings are in accordance with
current ideas on the role of tiredness as a mediating factor in the induction of
the therapeutic effects of SD.

PMID: 7786959 [PubMed – indexed for MEDLINE]


46: Biol Psychiatry 1994 May 15;35(10):794-7

Effects of sleep on the antidepressant response to sleep deprivation.

Reist C, Chen CC, Chhoeu A, Berry RB, Bunney WE Jr.

Psychiatry Service, Veterans Affairs Medical Center, Long Beach, CA 90822.

The effect of a 90-min nap period on mood was studied in 22 sleep-deprived
patients with a diagnosis of major depression. All patients remained awake from
7 AM until 12 noon the following day at which time they were permitted to nap
while being monitored by sleep encephalography. Fifteen subjects showed a
significant response to sleep deprivation as defined by a 35% improvement on the
Hamilton Rating Scale for Depression. After the nap a relapse of depressive
symptoms occurred which was significantly related to the amount of non-rapid eye
movement sleep time.

PMID: 8043709 [PubMed – indexed for MEDLINE]


47: Psychiatry Res 1994 Mar;51(3):283-95

Lithium sustains the acute antidepressant effects of sleep deprivation:
preliminary findings from a controlled study.

Szuba MP, Baxter LR Jr, Altshuler LL, Allen EM, Guze BH, Schwartz JM, Liston EH.

Department of Psychiatry, University of Pennsylvania, School of Medicine,
Philadelphia 19104-4283.

Early morning sleep deprivation (patient awake from 0200 to 2200 hours) produces
a same-day antidepressant effect in approximately one-half of patients with
major depression. Unfortunately, these antidepressant effects are short-lived
and patients usually relapse to baseline depression levels within 48 hours.
Recent work suggests, however, that the use of lithium with early morning sleep
deprivation sustains this rapid antidepressant effect and makes it clinically
useful. In a 30-day study, we compared the abilities of four different
treatments (lithium plus early morning sleep deprivation, lithium plus a control
sleep deprivation procedure, and desipramine with either of the two sleep
manipulations) to induce a rapid (next-day) and sustained antidepressant
response in 16 depressed patients. Lithium plus early morning sleep deprivation
produced a quicker response than lithium with the control sleep deprivation, and
the response was sustained for at least 30 days. In this design, however,
lithium/early morning sleep deprivation was no faster than either of the two
desipramine/sleep deprivation conditions in inducing remission. These results
support the results of previous studies and suggest further investigation of
this novel sleep/pharmacologic intervention is warranted.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 8208874 [PubMed – indexed for MEDLINE]


48: Br J Psychiatry 1993 Nov;163:679-80

Mania following sleep deprivation.

Wright JB.

St James’s University Hospital, Leeds.

A first episode of mania is described in a previously healthy man who was
partially sleep deprived for four nights. The sleep deprivation preceded the
psychosis. During the psychotic episode he believed that he was the Messiah.
This case is discussed in the light of reports exploring the relationship
between psychosis and sleep deprivation.

PMID: 8298841 [PubMed – indexed for MEDLINE]


49: Psychiatry Res 1993 Nov;49(2):109-20

Naps after total sleep deprivation in depressed patients: are they

Riemann D, Wiegand M, Lauer CJ, Berger M.

Sleep-EEG Laboratory, Psychiatric Clinic, Central Institute of Mental Health,
Mannheim, Germany.

Total sleep deprivation (TSD) exerts beneficial but transient effects on mood in
approximately 60% of patients with a major depressive disorder. The positive
effects of a night of total sleep deprivation are generally reversed after the
next night of sleep. Several anecdotal reports and a pilot study by our group
indicated that even short naps during the period of sleep deprivation are
capable of re-inducing depressive mood in responders to TSD. The present study
explored whether the structure of naps at 9 a.m. was crucial for the
“depressiogenic” impact of naps on mood. A negative effect on mood was
replicated, but this effect was not related to any of the nap sleep variables.
The effect of naps on mood was attenuated in the early afternoon. The results
support the assumption of a “depressiogenic” effect of naps in patients with
major depression after successful TSD.

PMID: 8153186 [PubMed – indexed for MEDLINE]


50: Biol Psychiatry 1993 Mar 15;33(6):467-76

Effect of morning and afternoon naps on mood after total sleep deprivation in
patients with major depression.

Wiegand M, Riemann D, Schreiber W, Lauer CJ, Berger M.

Max Planck Institute of Psychiatry, Munich, Germany.

In 30 depressed patients who had responded to total sleep deprivation therapy,
morning naps led more frequently to relapses into depression than did afternoon
naps. Longer naps were less detrimental than shorter ones, and there was no
significant relationship between the effect of a nap on mood and its content of
slow-wave-sleep. The amount of the rapid eye-movement sleep, too, was unrelated
to clinical nap effects. Thus, some of the current theories on the relationship
between sleep and depressive symptomatology are not supported by the data. Our
results demonstrate the importance of nap timing, suggesting a circadian
variation of propensity to relapse into depression.

PMID: 8490073 [PubMed – indexed for MEDLINE]


51: Psychiatry Res 1993 Mar;46(3):213-27

A clinical trial of sleep deprivation in combination with antidepressant

Leibenluft E, Moul DE, Schwartz PJ, Madden PA, Wehr TA.

Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, MD

The literature suggests that sleep deprivation can potentiate the effect of
antidepressant medication in depressed patients. However, the clinical efficacy
of sleep deprivation has not been demonstrated definitively, in part because it
is difficult to design an adequate control condition. We conducted a trial of
sleep deprivation in 26 depressed patients who remained symptomatic despite 3
months of treatment with antidepressant medication. Since the literature
indicates that early sleep deprivation (ESD), carried out in the first half of
the night, is a less effective antidepressant than late sleep deprivation (LSD),
carried out in the second half of the night, we designed a study that attempted
to use ESD as a control condition for LSD. Patients were randomly assigned to
ESD or LSD, received a total of 4 nights of sleep deprivation over 2 weeks, and
were followed in clinic for the 3 subsequent weeks. ESD proved to be as
effective an antidepressant as LSD, with the overall sample showing a mild, but
statistically significant, response. There was a significant correlation between
patients’ acute response at the time of the first course of sleep deprivation
treatments and their improvement over the course of the study. There were
significant changes in plasma levels of thyroid stimulating hormone, free
triiodothyronine, prolactin, and cortisol measured at 8 a.m. before and after
sleep deprivation, and in the followup period, but there were no significant
correlations between changes in hormonal levels and either acute or chronic
response to sleep deprivation.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 8493292 [PubMed – indexed for MEDLINE]


52: Acta Psychiatr Scand 1993 Feb;87(2):102-9

Antidepressant response to sleep deprivation as a function of time into
depressive episode in rapidly cycling bipolar patients.

Gill DS, Ketter TA, Post RM.

Biological Psychiatry Branch, US National Institutes of Mental Health, Bethesda,
Maryland 20892.

Three patients with treatment-resistant rapidly cycling bipolar disorder were
studied with multiple sleep deprivations (SD) during several depressive episodes
to assess the effect of phase or duration of a depressive episode on SD
response. There was little response to SD early in a depressive episode, but
responses were often robust late in an episode, sometimes triggering its
termination. In 2 subjects, the duration of antidepressant response to SD
increased linearly as time into episode increased. Neither the number of SD
given in an episode nor the medication status of the patients appeared to
account for the observed increases in antidepressant response. These results
suggest that the neurobiological substrates underlying depression may change
over the course of an episode, resulting in an increased responsivity to sleep
deprivation later compared with earlier in the course of an episode in rapidly
cycling patients. The generalizability of these findings to unipolar patients
remains to be explored.

PMID: 8447235 [PubMed – indexed for MEDLINE]


53: J Affect Disord 1993 Feb;27(2):107-16

Therapy and prevention of affective illness by total sleep deprivation.

Papadimitriou GN, Christodoulou GN, Katsouyanni K, Stefanis CN.

Department of Psychiatry, Athens University Medical School, Greece.

The therapeutic effect of total sleep deprivation (SD) given twice a week, for 4
weeks, was investigated in 16 drug-free patients with major affective disorders.
The response was excellent in five patients, satisfactory in three and minimal
in eight patients. Six of these patients were treated prophylactically once a
week, and four had an excellent response. Additionally, out of five normothymic
drug-free patients with affective illness treated prophylactically with SD,
without prior therapeutic SD treatment, three had an excellent response. The
majority of responders were rapid cycling patients. This method is worth
applying to patients resistant to classical treatment.

PMID: 8440806 [PubMed – indexed for MEDLINE]


54: Biol Psychiatry 1993 Jan 1;33(1):54-7

Sleep deprivation with consecutive sleep-phase advance therapy in patients with
major depression: a pilot study.

Vollmann J, Berger M.

Department of Psychiatry, University of Freiburg, Germany.

PMID: 8420597 [PubMed – indexed for MEDLINE]


55: Eur Neuropsychopharmacol 1992 Dec;2(4):463-5

Sleep deprivation in rapid-cycling bipolar affective disorder: case report.

Benjamin J, Zohar J.

Division of Psychiatry, Ben Gurion University of the Negev, Israel.

We describe a 4-month long hypomanic response to sleep deprivation in a patient
with consistent (20-day cycles) rapid cycling. He subsequently reverted to very
rapid cycling; however, sleep deprivation remained effective for each attack of
depression. Sleep deprivation treatment, its immediate but short-lived
beneficial effect, may have a role in the treatment of the ultra-short
depressions encountered in very rapid cycling.

PMID: 1490098 [PubMed – indexed for MEDLINE]


56: Acta Psychiatr Scand 1992 Dec;86(6):478-83

Evaluation of the effects of total sleep deprivation on cerebral blood flow
using single photon emission computerized tomography.

Volk S, Kaendler SH, Weber R, Georgi K, Maul F, Hertel A, Pflug B, Hor G.

Department of Psychiatry II, Johann Wolfgang Goethe University, Frankfurt am
Main, Germany.

HMPAO-single photon emission computerized tomography (SPECT) is a useful
technique in studying cerebral blood flow (CBF). This method is suitable to
evaluate the differences of CBF with reference to total sleep deprivation (TSD)
within 24 h because of the short half-life of the radiopharmaceutical compound.
In the present study, CBF before and after TSD was analysed in patients
suffering from major depression. The morning before and after TSD,
Tc-HMPAO-SPECT was performed in 20 patients. Hamilton Rating Scale for
Depression scores and subjective ratings were obtained daily. Eleven patients
responded to TSD; 9 were nonresponders. The main finding was a significant left
temporal and mainly right parietal increase of CBF, which was observed in the
responders only. CBF values and the severity of depression correlated inversely.

PMID: 1471542 [PubMed – indexed for MEDLINE]


57: Acta Psychiatr Scand 1992 Jul;86(1):84-5

Therapeutic sleep deprivation in a depressed patient: prolongation of response
with concurrent thyroxine.

Southmayd SE, Kasurak P, MacDonald B, Waldron J.

Department of Psychiatry, Queen’s University Ontario, Canada.

A 53-year-old woman with major depression was studied throughout 7 trials of
therapeutic sleep deprivation (SD). Under conditions where the patients was
either medication-free or receiving antidepressant therapy, improvement with SD
was followed by full relapse on returning to sleep. Four SD sessions conducted
while the patient was receiving thyroxine each resulted in remission, sustained
for several days. These results suggest that the beneficial effects of SD may be
mediated by thyroid hormones, or associated activity in the
hypothalamic-pituitary-adrenal axis.

PMID: 1414408 [PubMed – indexed for MEDLINE]


58: J Clin Psychiatry 1992 Jun;53(6):204-6

Response to sleep deprivation in three women with postpartum psychosis.

Strouse TB, Szuba MP, Baxter LR Jr.

Department of Psychiatry and Biobehavioral Sciences, University of California,
School of Medicine, Los Angeles.

BACKGROUND: Postpartum psychotic disorders are rare and poorly understood
phenomena occurring after approximately 1 in 2000 births. Increasing attention
has been given to the concept of postpartum psychosis as an affective spectrum
disorder. We sought to characterize the responses to sleep deprivation of three
women with postpartum psychotic and mood symptoms. METHOD: Three hospitalized
postpartum women with no prior history of psychotic disorder were treated
according to a partial sleep deprivation protocol. Each patient was awakened at
2:00 a.m. and kept awake until 9:00 p.m. the following night. A full and an
abbreviated Hamilton Rating Scale for Depression (HAM-D) were completed for each
patient before and after partial sleep deprivation. RESULTS: Two of the three
patients became transiently manic and the third became hypomanic after sleep
deprivation. HAM-D scores decreased drastically for each patient. After recovery
sleep, each patient de-escalated but required further treatment with
mood-stabilizing agents. CONCLUSION: These findings suggest that postpartum
psychosis in our patients may represent a variant of bipolar affective disorder.

PMID: 1607349 [PubMed – indexed for MEDLINE]


59: Am J Psychiatry 1992 Apr;149(4):538-43

Effect of sleep deprivation on brain metabolism of depressed patients.

Wu JC, Gillin JC, Buchsbaum MS, Hershey T, Johnson JC, Bunney WE Jr.

Department of Psychiatry and Human Behavior, College of Medicine, University of
California, Irvine 92717.

OBJECTIVE: Sleep deprivation is a rapid, nonpharmacologic antidepressant
intervention that is effective for a subset of depressed patients. The objective
of this study was to identify which brain structures’ activity differentiates
responders from nonresponders and to study how metabolism in these brain regions
changes with mood. METHOD: Regional cerebral glucose metabolism was assessed by
positron emission tomography (PET) with [18F]deoxyglucose (FDG) before and after
total sleep deprivation in 15 unmedicated awake patients with unipolar major
depression and 15 normal control subjects, who did the continuous performance
test during FDG uptake. RESULTS: After sleep deprivation, four patients showed a
40% or more improvement on the Hamilton Rating Scale for Depression. Before
sleep deprivation the depressed responders had a significantly higher cingulate
cortex metabolic rate than the depressed nonresponders, and this normalized
after sleep deprivation. The normal control subjects and nonresponding depressed
patients showed no change in cingulate metabolic rate after sleep deprivation.
CONCLUSIONS: Overactivation of the limbic system as assessed by PET scans may
characterize a subset of depressed patients. Normalization of activity with
sleep deprivation is associated with a decrease in depression.

PMID: 1554042 [PubMed – indexed for MEDLINE]


60: J Affect Disord 1992 Feb;24(2):101-8

Can non-REM sleep be depressogenic?

Beersma DG, van den Hoofdakker RH.

Department of Biological Psychiatry, University Hospital, Groningen,

Sleep and mood are clearly interrelated in major depression, as shown by the
antidepressive effects of various experiments, such as total sleep deprivation,
partial sleep deprivation, REM sleep deprivation, and temporal shifts of the
sleep period. The prevailing hypotheses explaining these effects concern the
antidepressant potency of the suppression of either REM sleep or non-REM sleep.
This issue is discussed in the light of present knowledge of the kinetics of
non-REM sleep intensity, REM sleep production, and their interaction. Recent
findings have led us to suggest that the suppression of non-REM sleep intensity
is the common pathway in the set of experimental data on the antidepressant
effects of sleep manipulations.

PMID: 1541764 [PubMed – indexed for MEDLINE]


61: Encephale 1992 Jan;18 Spec No 1:45-50

The role of sleep and wakefulness in the genesis of depression and mania.

Kasper S, Wehr TA.

Psychiatric Department, University of Bonn, FRG.

Disturbances of the sleep-wake cycle are frequently seen in affective illness
and are exhibited in other psychiatric illness as well. In addition to being a
useful research probe, manipulations of the sleep-wake cycle such as sleep
deprivation (SD) and phase advance can cause depression to remit and thus can be
used as alternative or as adjunctive to pharmacologic treatment. The
antidepressant response to SD occurs whether antidepressant drugs are
administered or not. However, there is some evidence that the concomitant use of
antidepressants may prevent the relapses that occur after recovery sleep. Data
from clinical investigations also indicate that disrupted sleep can trigger and
intensify mania. Rapid cycling bipolar patients may be especially vulnerable to
mania/hypomania after disrupted sleep or SD. Characteristic changes in body
temperature have been recorded in sleep deprivation as well as in other
antidepressant treatment modalities. Thermoregulatory physiology may therefore
provide a framework for understanding the effects of sleep-wake manipulations in
affective illness.

Publication Types:
Review, Tutorial

PMID: 1600904 [PubMed – indexed for MEDLINE]


62: Acta Med Austriaca 1992;19 Suppl 1:98-102

Thyroid hormones and depressive illness: implications for clinical and basic

Baumgartner A, Campos-Barros A, Meinhold H.

Psychiatrische Klinik und Poliklinik, Universitatsklinikum Rudolf-Virchow
(Charlottenburg), Germany.

It has been well-known for at least 100 years that both hypo- and
hyperthyroidism may cause almost any psychiatric symptom, depending on the
severity of the illness. No thyroid disorder, however, induces symptoms that are
specific for a psychiatric disorder. Laboratory tests show depressed patients to
be euthyroid. Any abnormalities that have been found, such as slightly elevated
T4 levels or decreased T3 or TSH concentrations, have frequently failed to be
replicated and do not fit any endocrinological diagnosis. They could reflect
either “intervening factors” such as stress, methodological problems or a
disturbance of central thyroid hormone metabolism. All antidepressant therapies
(antidepressant drugs, carbamazepine, lithium, electroconvulsive therapy and
sleep deprivation) have a marked influence on peripheral thyroid hormone levels.
In particular, decreases in serum T4 and rT3 levels are often correlated to
antidepressant response, suggesting that an effect on central thyroid hormone
metabolism is involved in the as yet unknown mechanism of action of these
therapies. Indeed, animal studies have shown that antidepressants do affect
deiodinase activities and T3 and T4 concentrations in rat brain. However, the
effects are highly area specific and dependent on the drug administered and the
time of day at which the investigation was conducted. Although the mechanism of
thyroid hormone action on CSF signal transduction is as yet unknown, effects on
“general CNS functions” such as second messengers, G-proteins or calcium
homeostasis seem more likely than specific effects on the different receptor

PMID: 1519467 [PubMed – indexed for MEDLINE]


63: Biol Psychiatry 1991 Oct 15;30(8):817-29

Effects of partial sleep deprivation on the diurnal variation of mood and motor
activity in major depression.

Szuba MP, Baxter LR Jr, Fairbanks LA, Guze BH, Schwartz JM.

Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine.

Partial sleep deprivation (PSD), keeping a subject awake from 2 AM to 9 PM
produces an acute mood improvement in 60% of patients with major depression. We
sought to characterize the timing, subcomponent mood, and motor activity changes
of this response. Thirty-seven subjects with major depression were rated with
the 6-item Hamilton Depression Scale (HAM-6) at 1 PM and completed the Profile
of Mood States (POMS) every 2 hr on the day before and day of PSD. Locomotor
activity was monitored continuously during the trial with an automated device.
Bipolar I patients responded more frequently than other groups. Positive mood
responders had greater improvement than nonresponders in POMS subscales of
depression, tension, confusion, and anger. The mood improvement increased
steadily during the day, peaked in late afternoon, and declined thereafter.
Responders showed significantly higher levels of locomotor activity on the
baseline pre-PSD day than did nonresponders. All subjects increased motor
activity following sleep deprivation, however.

PMID: 1751624 [PubMed – indexed for MEDLINE]


64: Eur Neuropsychopharmacol 1991 May;1(2):107-11

Therapeutic sleep deprivation and antidepressant medication in patients with
major depression.

Kasper S, Kick H, Voll G, Vieira A.

Psychiatric Department, University of Bonn, Germany.

Although there is a body of literature on the therapeutic efficacy of sleep
deprivation (SD) there are only a few investigations in which the relevance of
antidepressive medication for the clinical efficacy of SD has been studied.
Based on the literature and on our own investigations with major depressed
patients it seems that for the day-1 response it does not matter if and what
type of antidepressive medication the patient receives. Furthermore, the results
of our double blind study reveal that the day-1 response to total sleep
deprivation (TSD) is not associated with a clear relationship to the outcome
after 4 weeks treatment with either fluvoxamine or maprotiline. On the other
hand, our data indicate that the day-2 response to TSD is significantly
correlated with a beneficial outcome after subchronic treatment with

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 1821699 [PubMed – indexed for MEDLINE]


65: Biol Psychiatry 1991 Apr 1;29(7):707-10

Are there predictors for sleep deprivation response in depressed patients?

Riemann D, Wiegand M, Berger M.

Sleep-EEG Laboratory, Central Institute of Mental Health, Mannheim, FRG.

PMID: 2054442 [PubMed – indexed for MEDLINE]


66: Biol Psychiatry 1991 Mar 15;29(6):600-12

Towards a model of mood responses to sleep deprivation in depressed patients.

Bouhuys AL.

Department of Biological Psychiatry, University Psychiatric Clinic, Groningen,
The Netherlands.

It is hypothesized that in depressed patients diurnal variation in mood (DV) is
a daily recurring phenomenon, which fails to achieve expression on all days
(showing a random distribution of DVs). From this perspective a meta-analysis
was performed on the raw data of earlier presented studies. The effect of total
sleep deprivation (TSD) on mood was examined in 14 so-called prototypical
patients, showing on three successive days either positive DVs (feeling better
in the evening) or inverse DVs. It was hypothesized that under baseline
conditions mood follows a monotonous course with switching points at 7 AM and 11
PM and that during the TSD night the 7-AM switch took place earlier. The
position of this switch was calculated, assuming that (1) before the switch the
curve ran parallel to the nightly baseline curves, and (2) after the switch the
curve showed a monotonous change parallel to the daily baseline curves. The best
fit between predicted and measured depression after TSD was found for a switch
at 3 AM, varying the switching point during the TSD night with hourly intervals.
The characteristics based on prototypical patients contributed significantly to
the prediction of the morning and the afternoon depression levels after TSD in a
group of 53 patients (prototypical and nonprototypical).

Publication Types:

PMID: 1829009 [PubMed – indexed for MEDLINE]


67: Biol Psychiatry 1990 Dec 1;28(11):979-88

Sleep deprivation in depression: pattern of relapse and characteristics of
preceding sleep.

Southmayd SE, David MM, Cairns J, Delva NJ, Letemendia FJ, Waldron JJ.

Department of Psychiatry, Queen’s University, Kingston, Ontario, Canada.

The pattern of relapse following therapeutic response to 40-hr sleep deprivation
(SD) was examined in nine depressed patients. On the night ending SD patients
were awakened from polygraphically recorded sleep on one or more occasions, in
order to assess the clinical state. All subjects were found to demonstrate a
precipitous and full relapse over this night, the timing of the relapse varying
considerably between individuals. No association was found between deterioration
in the clinical state and characteristics of preceding sleep. These results are
consistent with the notion that, in predisposed individuals, some process
associated with sleep has a depressogenic effect. However, they necessitate
revision of theories of SD and depression that emphasize the infrastructure of

Publication Types:
Clinical Trial

PMID: 2275955 [PubMed – indexed for MEDLINE]


68: Psychiatry Res 1990 Nov;34(2):149-62

Effects of total sleep deprivation on urinary cortisol, self-rated arousal, and
mood in depressed patients.

Bouhuys AL, Flentge F, Van den Hoofdakker RH.

Department of Biological Psychiatry, Academic Hospital, University of Groningen,
The Netherlands.

The possibility that the clinical response to total sleep deprivation (TSD) is
mediated by dimensions of arousal was investigated in a group of 16 depressed
patients. Self-reports of activation, stress, and mood were assessed 3 days
before, during, and 2 days after TSD. Urinary cortisol excretion and responses
to the dexamethasone suppression test (DST) were also measured. TSD increased
cortisol excretion in depressed patients and advanced the time of the maximal
excretion of cortisol. No such changes have been reported for normal subjects.
Neither the increased excretion nor the time shift was related to the mood
response to TSD. The DST results were also unrelated to this response.
Indications that the mood response to TSD may be mediated by dimensions of
arousal are the significant relationships between this response and the
responses of subjective stress and activation to TSD. The TSD-induced cortisol
increase was not related to the subjective arousal response to TSD. The
increased cortisol excretion itself could be predicted by the averaged baseline
levels of subjective stress: the lower the stress levels before TSD, the larger
the cortisol response to TSD.

PMID: 2287648 [PubMed – indexed for MEDLINE]


69: J Affect Disord 1990 Oct;20(2):93-9

The influence of physical activity and posture on the antidepressant effect of
sleep deprivation in depressed patients.

Baumgartner A, Sucher N.

Psychiatrische Klinik und Poliklinik of the Klinikum Rudolf-Virchow
(Charlottenburg), Freie Universitat Berlin, Germany.

A possible role of the factors ‘physical activity’ and ‘posture’ in the
antidepressant effect of a total night’s sleep deprivation (TSD) was
investigated in 30 patients with major depressive disorder. Fifteen patients
underwent TSD under ‘conventional’ conditions, while the other 15 were kept in
bed during TSD but were not permitted to sleep. There was no significant
difference between the antidepressant effects of TSD in the two groups. This
result suggests that it is wakefulness itself rather than changes in physical
activity or posture that is involved in the mechanism of the antidepressant
action of TSD.

Publication Types:
Clinical Trial
Controlled Clinical Trial

PMID: 2148333 [PubMed – indexed for MEDLINE]


70: J Affect Disord 1990 Aug;19(4):249-58

Relations between depressed mood and vocal parameters before, during and after
sleep deprivation: a circadian rhythm study.

Bouhuys AL, Schutte HK, Beersma DG, Nieboer GL.

Department of Biological Psychiatry, University Hospital Groningen, The

The mechanism underlying improvement after total sleep deprivation (TSD) was
studied in 14 major depressed patients. The suggestions that (1) circadian
processes and/or (2) dimensions of arousal may play a role in the response to
TSD were investigated. Diurnal variation of depressed mood and of mood- and
arousal-related vocal parameters was studied in relation to the effect of TSD on
depressed mood and vocal parameters. During 3 baseline days, during TSD and 2
days after TSD vocal parameters and depressed mood were assessed 6 and 3 times
daily respectively. The mean fundamental frequency (frequency of vocal fold
vibration, F0) (presumably reflecting aspects of arousal) as well as the range
of the F0 (proposed to reflect sadness) showed a clear circadian pattern with a
peak at about 4.00 p.m. TSD affected the circadian organization of the mean F0
and advanced the peak of the curve. After one night of subsequent sleep this
effect disappeared. In addition, improvement after TSD coincided with an
increase of the mean F0. The diurnal variation of mood before TSD predicted the
mood response to TSD, whereas diurnal variation of vocal parameters did not.
Moreover, circadian changes in vocal parameters were not related to changes in
depressed mood. These findings suggest that the diurnal variations in mood and
vocal parameters are regulated by different mechanisms. Data support the
presumption that circadian as well as arousal processes are involved in the mood
response to TSD. Circadian changes in vocal parameters due to TSD are not likely
to reflect changes in the biological clock.

PMID: 2146301 [PubMed – indexed for MEDLINE]


71: Pharmacopsychiatry 1990 May;23(3):135-42

Response to total sleep deprivation before and during treatment with fluvoxamine
or maprotiline in patients with major depression–results of a double-blind

Kasper S, Voll G, Vieira A, Kick H.

Psychiatric Department of the University of Bonn, FRG.

To test the hypothesis that the antidepressant effects of total sleep
deprivation (TSD) are linked to the serotonergic and/or noradrenergic system the
authors carried out a double-blind study (fluvoxamine versus maprotiline) in 42
inpatients with endogenous depression (ICD). Patients were randomized to a
four-week treatment with either fluvoxamine (100-300 mg/day) or maprotiline
(100-300 mg/day). In addition, patients underwent a TSD procedure before and
after one week of antidepressant medication. There was a statistically
significant reduction of depression ratings (HDRS) in both the fluvoxamine and
maprotiline group. The day-1 response to TSD before antidepressive medication
was not associated with a clear relationship to the outcome after four weeks of
treatment with either fluvoxamine or maprotiline. On the other hand, the day-2
response to TSD was significantly correlated with a good outcome to subchronic
treatment with maprotiline. Furthermore, the results of the authors’ data
suggest that a favorable short-term outcome of TSD may be connected to
antidepressants enhancing the serotonergic neurotransmission. The global
comparison between fluvoxamine and maprotiline revealed that the group of
patients treated with fluvoxamine had a significantly higher efficiency index
(CGI) than the maprotiline group; fluvoxamine was rated to be tolerated
excellently in 70% of the patients whereas this percentage was only 43% in the
maprotiline group. There was also significantly more vertigo and dry mouth in
the maprotiline group whereas the fluvoxamine group was rated to have
significantly more sleep disturbances during the trial.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 2115680 [PubMed – indexed for MEDLINE]


72: Clin Neuropharmacol 1990;13 Suppl 1:S54-65

Manipulations of sleep and phototherapy: nonpharmacological alternatives in the
treatment of depression.

Wehr TA.

Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, MD

Manipulations of sleep and light (for winter depression) rapidly improve mood in
60% of depressed patients. These two unconventional treatments for depression
may prove useful in patients who do not respond to drug treatments, in patients
who prefer nonpharmacological treatments, or as adjuncts to drug treatments.
This article reviews research on the parameters of effective sleep and light
treatments and their biological mechanisms. The results of recent experiments
suggest that the depressant effect of sleep may depend on thermoregulatory
adjustments that occur after sleep begins.

Publication Types:
Review, Tutorial

PMID: 2199036 [PubMed – indexed for MEDLINE]


73: Eur Arch Psychiatry Clin Neurosci 1990;240(1):60-1

Maintenance of antidepressant effect of sleep deprivation with the help of

Grube M, Hartwich P.

Department of Psychiatry, Stadtisches Krankenhaus Frankfurt am Main, Federal
Republic of Germany.

The antidepressant effect of sleep deprivation is often not longer than 1 or 2
days. Therefore we investigated systematically the combination of lithium and
sleep deprivation on 26 depressive patients (ICD/DSM 296). We measured the
depression scores with the Hamilton Depression Scale and the Brief Depression
Rating Scale on 4 days. A comparison between sleep deprivation with and without
lithium showed a highly significant difference on the 2nd and 3rd days after
sleep deprivation. The positive antidepressant effect remained with those who
received lithium.

PMID: 2147906 [PubMed – indexed for MEDLINE]


74: J Psychiatr Res 1990;24(4):281-92

Thyrotropin (TSH) and thyroid hormone concentrations during partial sleep
deprivation in patients with major depressive disorder.

Baumgartner A, Graf KJ, Kurten I, Meinhold H.

Psychiatrische Klinik und Poliklinik, Klinikum Rudolf-Virchow Charlottenburg,
Berlin, Federal Republic of Germany.

Thyrotropin (TSH), thyroxine (T4), free T4, triiodothyronine (T3), and free T3
(fT3) concentrations were measured in 25 patients with major depressive disorder
at 8 a.m. both before and after partial sleep deprivation (PSD) during the
second half of the night. Significant increases in TSH and T3 levels and a
corresponding trend in fT3 levels were seen. No convincing correlations occurred
between changes in the secretion of any of the hormones and the antidepressant
effect of PSD. However, this does not rule out the possibility that the two
phenomena, which occur in depression at different anatomical levels with
presumably different degrees of disturbance in the respective receptor systems,
have common underlying neurochemical mechanisms. Comparison of the effect of the
PSD on changes in hormone secretion and mood with the corresponding effects in a
sample of depressed patients who underwent total sleep deprivation showed no
significant differences between the effects of these two forms of sleep
deprivation on either variable.

PMID: 2090827 [PubMed – indexed for MEDLINE]


75: Int Clin Psychopharmacol 1989 Jul;4(3):217-28

Treatment of resistant depression. Review on the efficacy of various biological
treatments, specifically in major depression resistant to cyclic

Nolen WA, Haffmans J.

Department of Biological Psychiatry, Psychiatric Centre Bloemendaal, Hague, The

The biological treatment of depression includes administration of psychoactive
drugs (cyclic antidepressants, MAO-inhibitors, neuroleptics and lithium), use of
certain substances which in small amounts are normally present in food such as,
L-tryptophan (L-TP) and L-5-hydroxytryptophan (L-5HTP), electroconvulsive
therapy (ECT) and various manipulations of the sleep-wake rhythms. This paper
reviews the literature on the efficacy of these treatments in patients resistant
to earlier adequate treatment(s) with cyclic antidepressants. Subsequently the
following strategy for the biological treatment of (non-psychotic) major
depression is suggested: (1) administration of a cyclic antidepressant; (2) if
after a period of 4 to 6 weeks a patient has not responded to an adequate dose,
another cyclic antidepressant should be tried, adding lithium if the patient
still does not respond; (3) MAO-inhibitors and (4) ECT. In psychotic depression
the suggestions for the first, third and fourth steps are the same. In the
second step, the cyclic antidepressant should be combined with a neuroleptic.

Publication Types:
Review, Tutorial

PMID: 2571635 [PubMed – indexed for MEDLINE]


76: Psychiatry Res 1989 Mar;27(3):253-65

Effects of brief naps on mood and sleep in sleep-deprived depressed patients.

Gillin JC, Kripke DF, Janowsky DS, Risch SC.

Department of Psychiatry, San Diego Veterans Administration Medical Center, CA.

To determine the effects of brief naps on mood and electroencephalographic (EEG)
sleep in sleep-deprived depressed patients, data from 19 hospitalized patients
with depression were analyzed; all were kept awake from 0700h until the
following day, when they were allowed 10-min naps at either 0830h or 1500h. Six
of the patients showed a clinically significant improvement (greater than 40%
change) on the Hamilton Rating Scale for Depression (HRSD) before the nap after
all-night sleep deprivation, and the group as a whole showed a significant
improvement on the HRSD, the Profile of Mood States, and the Brief Psychiatric
Rating Scale subscale for depression. Naps did not alter mood in the responders,
but did improve measured depression on the HRSD in the non-responders. Morning
and afternoon naps did not differ significantly in their effects on mood or nap
sleep. On the recovery sleep, patients who were classified as responders after
the nap showed a significantly greater increase in delta (Stage 3 + 4) sleep
compared with baseline than nonresponders.

PMID: 2710868 [PubMed – indexed for MEDLINE]


77: Biol Psychiatry 1988 Oct;24(6):631-41

Nocturnal TSH and prolactin secretion during sleep deprivation and prediction of
antidepressant response in patients with major depression.

Kasper S, Sack DA, Wehr TA, Kick H, Voll G, Vieira A.

Clinical Psychobiology Branch, NIMH, Bethesda, MD 20892.

In order to test the hypothesis that changes in the hypothalamic-pituitary axis
during sleep deprivation are related to the antidepressant effects of this
procedure, we measured thyroid-stimulating hormone (TSH) and prolactin levels in
32 depressed patients at 2:00 AM during a night before, during, and after total
sleep deprivation (TSD). TSH levels increased significantly (p less than 0.05)
during TSD, and prolactin levels decreased significantly (p less than 0.0001).
When we divided the patients into responder and nonresponder groups based on a
30% reduction in the Hamilton Rating Scale, there was no difference between the
two groups in their hormone levels on the baseline, TSD, or recovery nights.
Changes in prolactin or TSH were not correlated with clinical improvement when
the two groups were considered together or in the responder/nonresponder groups
separately. Baseline values of both hormones were significantly (p less than
0.01) correlated with their respective levels during TSD and recovery sleep.
These findings indicate that the relative levels of nocturnal TSH and prolactin
are stable even within acutely depressed individuals and that changes in their
levels are not related to the clinical response to sleep deprivation.

PMID: 3167147 [PubMed – indexed for MEDLINE]


78: Acta Psychiatr Scand 1988 Feb;77(2):219-24

The timing and duration of sleep in partial sleep deprivation therapy of

Sack DA, Duncan W, Rosenthal NE, Mendelson WE, Wehr TA.

Clinical Psychobiology Branch, National Institute of Mental Health, Maryland.

The antidepressant response to partial sleep deprivation early in the night
(PSD-E) was compared with the response to partial sleep deprivation late in the
night (PSD-L) in 16 drug-free depressed inpatients using a balanced order
crossover design. PSD-L had a significantly greater antidepressant effect that
PSD-E. The response to PSD-L was sustained and enhanced by a second night of
treatment. Patients had significantly shorter sleep durations and reduced REM
sleep on PSD-L that did not occur in the PSD-E situation. There was a
significant negative correlation between response to PSD and sleep duration, and
in particular, REM sleep duration, in the late sleep deprivation situation.
Thus, the amount and timing of sleep appear to be factors in the response to
PSD, but additional studies are needed to evaluate the relative importance of
these parameters.

PMID: 3364206 [PubMed – indexed for MEDLINE]


79: J Clin Psychopharmacol 1987 Dec;7(6 Suppl):24S-35S

Modifications of the serotonin system by antidepressant treatments: implications
for the therapeutic response in major depression.

Blier P, de Montigny C, Chaput Y.

Neuroscience Research Center, Montreal, Quebec, Canada.

Results of electrophysiological single-cell recording studies suggest that most,
if not all, types of antidepressant treatments increase 5-hydroxytryptamine
(5-HT) neurotransmission. Tricyclic antidepressants, electroconvulsive shock
treatment, mianserin, adinazolam, and possibly sleep deprivation may exert their
therapeutic effect through sensitization of postsynaptic neurons to 5-HT.
Serotonin reuptake blockers may relieve depression through an increased efficacy
of the presynaptic element resulting from a desensitization of somatodendritic
and terminal 5-HT autoreceptors. Similarly, monoamine oxidase inhibitors may act
by increasing the efficacy of 5-HT neurons. Intensification of 5-HT function
appears to be a common denominator to antidepressant treatments; however,
evidence suggests that this modification may only be a link in a chain of events
leading to an antidepressant response.

Publication Types:
Review, Tutorial

PMID: 3323264 [PubMed – indexed for MEDLINE]


80: Acta Psychiatr Scand 1987 Jun;75(6):614-8

Effect of interrupted sleep patterns and partial sleep deprivation on DST and
mood in psychiatric house officers.

Altshuler LL, Kagan BL, Baxter LR Jr, Smith G, Wilkins JN.

To gain further insight into clinical associations seen in depression, the
authors investigated the effect of interrupted night-time sleep on the HPA axis
and mood in 20 psychiatric house officers taking overnight call. Specific
interest was in whether multiple awakenings could induce a positive DST. No
statistically significant association emerged between number of nocturnal
awakenings, number of hours of sleep deprivation or temporal occurrence of sleep
deprivation and cortisol, DST or mood. The results suggest that cortisol and DST
changes are not likely to be causally linked to, or epiphenomenon of disrupted
sleep. The implications of these findings for major depression are discussed.

PMID: 3618284 [PubMed – indexed for MEDLINE]


81: Am J Psychiatry 1987 Feb;144(2):201-4

Erratum in:
Am J Psychiatry 1987 Apr;144(4):542

Sleep reduction as a final common pathway in the genesis of mania.

Wehr TA, Sack DA, Rosenthal NE.

Diverse psychological, interpersonal, environmental, and pharmacological factors
that appear to trigger the onset of mania could act via their capacity to cause
sleep deprivation, a mechanism that has been shown in experiments with bipolar
patients to induce transient or sustained switches into mania. Since mania in
turn causes insomnia, the development of mania is potentially self-reinforcing
and could become autonomous after being initiated by precipitating factors. The
sleep reduction model is based on experimental evidence and is a parsimonious
explanation for the precipitation of manic episodes by a wide variety of
factors. Furthermore, this model has clear implications for the prevention and
treatment of mania and provides a conceptual focus and an experimental paradigm
for psychological investigations of the causes of mania.

PMID: 3812788 [PubMed – indexed for MEDLINE]


82: J Psychiatr Res 1987;21(2):151-61

Response to total sleep deprivation and clomipramine in endogenous depression.

Elsenga S, Van den Hoofdakker RH.

In 44 endogenously depressed patients, response to total sleep deprivation (TSD)
was investigated as a function of several biographical and clinical variables.
All patients were subjected to a schedule of sleep-TSD-sleep-TSD. Antidepressant
drug treatment (clomipramine) was started on the day before the first TSD. Sex,
age, educational status, number of previous hospitalizations and duration of the
current depressive episode were not related to the response to either the first
or the second TSD. Likewise, no significant differences were found in the
responses of unipolar and bipolar patients. In contrast, diurnal variation
appeared to be positively correlated with response to TSD. Depressives with
psychotic features reacted more favourably than non-psychotic depressives.

PMID: 3585805 [PubMed – indexed for MEDLINE]


83: Fortschr Neurol Psychiatr 1986 Nov;54(11):341-55

[Sleep deprivation (wakefulness therapy) as an antidepressant] [Article in German]

Kuhs H, Tolle R.

In this complete survey of publications concerning therapeutic sleep deprivation
(including reports of a conference held in 1985) first the practical management
and especially the advantages of sleep deprivation of the second half of the
night are explained. After discussing the psychological conditions and methods
of therapeutic evaluation the treatment results in endogenous depression
(melancholia), the effectiveness of repetition and of combination with
antidepressive pharmacotherapy, the comparison with electroconvulsive therapy
and the predictors are described. Sleep deprivation is indicated in nearly every
therapeutic situation, including drug-resistant melancholia, furthermore in
severe neurotic depression and in depressive states of schizophrenic patients.
Side effects are unimportant, and complications are almost absent. In addition
psychophysiological, neuroendocrinological and biochemical investigations are
reported, as far as they concern either the mechanism of action of sleep
deprivation or chronobiological hypotheses of depression.

PMID: 3804162 [PubMed – indexed for MEDLINE]


84: Psychiatry Res 1986 Sep;19(1):17-23

Prolongation of the antidepressant response to partial sleep deprivation by

Baxter LR Jr, Liston EH, Schwartz JM, Altshuler LL, Wilkins JN, Richeimer S,
Guze BH.

Depressed patients given a loading dose of lithium on the first of 2 successive
days of partial sleep deprivation (PSD), and kept at maintenance levels
thereafter, showed significantly greater prolongation of the antidepressant
effects of PSD than patients treated with PSD and placebo, even though the acute
elevation in mood derived from PSD was as great on placebo as on lithium.
Depression was assessed 3 days after PSD with an augmented version of the
Hamilton Rating Scale for Depression. Patients on lithium alone, without PSD,
did not have the acute elevation in mood seen in the two PSD groups and had
significantly less improvement in depression than those who received PSD with

Publication Types:
Clinical Trial
Controlled Clinical Trial

PMID: 3097691 [PubMed – indexed for MEDLINE]


85: Acta Psychiatr Scand 1986 Aug;74(2):190-2

Is there a relationship between response to total sleep deprivation and efficacy
of clomipramine treatment in depressed patients?

Hochli D, Riemann D, Zulley J, Berger M.

Total sleep deprivation (TSD) and tricyclic medication are successful treatment
modalities for patients with a major depressive disorder. Recent studies have
suggested a positive relationship between TSD response and succeeding tricyclic
treatment, even on a very specific level, thus supporting the assumption of two
distinct biochemical subtypes of depression. The present study tested this
hypothesis by treating 10 inpatients with a major depressive disorder first with
TSD and succeedingly with clomipramine. Contrary to expectation, a negative
relationship between clinical response to the two treatment modalities was

PMID: 3776665 [PubMed – indexed for MEDLINE]


86: Acta Psychiatr Scand 1985 Aug;72(2):161-5

Antidepressant effects of sleep deprivation in bright and dim light.

Wehr TA, Rosenthal NE, Sack DA, Gillin JC.

In order to test whether exposure to bright artificial light at night is a
necessary condition for the antidepressant response to sleep deprivation
therapy, five patients were totally sleep-deprived on two separate nights, once
in very bright light and once in nearly total darkness. During the day after the
sleep-deprivation night patients were found to have responded equally well to
sleep deprivation in both conditions. During the sleep-deprivation night,
however, antidepressant responses may have been greater in the bright light
condition. Thus, light at night is not necessary for the antidepressant response
to sleep deprivation, but we cannot rule out the possibility that the effects of
light exposure and sleep deprivation are additive or that exposure to light at
some time after sleep deprivation begins (including during the following day) is
necessary for the response.

PMID: 4050508 [PubMed – indexed for MEDLINE]


87: Am J Psychiatry 1985 May;142(5):606-8

Potentiation of antidepressant medications by phase advance of the sleep-wake

Sack DA, Nurnberger J, Rosenthal NE, Ashburn E, Wehr TA.

Four patients with major depression who were unresponsive to antidepressant
medications rapidly improved and remained euthymic after an advance of the
sleep-wake cycle. Phase advance of the sleep-wake cycle and antidepressant
treatment may have complementary effects on the circadian system. The authors
suggest that the combination may be useful in treating drug nonresponders and in
hastening response to antidepressant drugs.

PMID: 3985199 [PubMed – indexed for MEDLINE]


88: Zh Nevropatol Psikhiatr Im S S Korsakova 1985;85(4):565-70

[Treatment of endogenous depressions by sleep deprivation] [Article in Russian]

Nosachev GN.

Eighty-six patients with endogenous depression (cyclothymia, manic-depressive
psychosis and schizophrenia) were treated by sleep deprivation. The efficacy of
this treatment with regard to the structure of the depressive syndrome, the
course of the attack and nosological nature is discussed. The author also
considers the frequency, sequence and effectiveness of sessions of sleep
deprivation in both hospital and outpatient settings. Series of total sleep
deprivation were shown to be highly effective in cyclothymia and
manic-depressive psychosis with melancholic and anesthetic depression, including
cases with a protracted course.

PMID: 4002948 [PubMed – indexed for MEDLINE]


89: South Med J 1984 Nov;77(11):1435-42

The internship year: a study of sleep, mood states, and psychophysiologic

Ford CV, Wentz DK.

Previous reports have suggested that first-year graduate physicians have a high
incidence of psychologic distress and may show cognitive impairment as a result
of sleep deprivation. We periodically evaluated 27 interns during their training
year to determine amount of sleep, mood states, reaction time, critical flicker
fusion, and symptoms of depression. We found the incidence of major depression
in our subjects (four of 27) to be lower than previously reported but higher
than expected for that age group in the general population. Risk factors for
depression during the internship year were history of major depression, female
sex, and unmarried status. The only significant change in average mood state was
that anger progressively increased during the year. Subjects slept an average of
5.95 hours per 24-hour day during the year. Correlational analysis indicated
that, contrary to predictions, performance on reaction time and critical flicker
fusion improved with less sleep. At the end of the year, subjects regarded the
year as stressful but not more so than had been anticipated.

PMID: 6494967 [PubMed – indexed for MEDLINE]


90: Can J Psychiatry 1984 Oct;29(6):530-6

Clinical and biological correlates of sleep deprivation in depression.

Joffe RT, Brown P.

Sleep deprivation is reported to have therapeutic effectiveness in depressive
illness. Furthermore, the response to sleep deprivation has important research
implications. Recent conceptual advances, resulting in increased understanding
of the role of abnormal biological rhythms and neurotransmitter function of the
pathophysiology of affective disorder, highlight the future role of sleep
deprivation in the research and treatment of these disorders.

Publication Types:

PMID: 6149013 [PubMed – indexed for MEDLINE]


91: Biol Psychiatry 1984 Mar;19(3):347-52

Neuroendocrine predictors of the antidepressant effect of partial sleep

Joffe R, Brown P, Bienenstock A, Mitton J.

Twenty-one patients with major depressive disorder were studied to establish the
relationship between selective neuroendocrine responses and the antidepressant
response to partial sleep deprivation. Dexamethasone suppression and normal
thyrotropin response to TRH were associated with a positive mood response.

PMID: 6426532 [PubMed – indexed for MEDLINE]


92: Psychiatr Clin (Basel) 1983;16(1):17-25

Dexamethasone suppression test combined with total sleep deprivation in
depressed patients.

Kasper S, Moises HW, Beckmann H.

The effect of one night’s total sleep deprivation (SD) on the dexamethasone
suppression test (DST) was studied in groups of endogenously and nonendogenously
depressed patients who were diagnosed according to different research
classification systems. The DST was normal (less than 5 micrograms/dl) before
and after SD in the group of nonendogenously depressed patients. Deterioration,
no change or only slight clinical response in single items occurred. In the
group of endogenous depressives 8 out of 11 were baseline nonsuppressors
(greater than 5 micrograms/dl). After SD a large variability of cortisol
nonsuppression was found in this group. Clinical response occurred in the
majority of these patients but was more favorable in those who had a trend for
normalization of DST. Clinical diagnosis as well as DST seem to have a
therapy-predictive value for one night’s total SD in patients with affective

PMID: 6844658 [PubMed – indexed for MEDLINE]


93: Psychiatry Res 1982 Aug;7(1):93-9

The dexamethasone suppression test as a predictor of sleep deprivation
antidepressant effect.

King D, Dowdy S, Jack R, Gardner R, Edwards P.

An abnormal dexamethasone suppression test (DST) result, a sensitive and
specific marker for endogenous depression, was found to be associated with an
antidepressant response to sleep deprivation in patients who met DSM-III
criteria for Major Depressive Episode regardless of whether they met criteria
for melancholia or psychotic subtypes of this disorder. These findings support
previous reports of an association between an abnormal DST result and
antidepressant effects of sleep deprivation in depressed patients. Our results
extend the positive association between an abnormal DST result and the
antidepressant response to sleep deprivation to include depressed patients who
are clinically nonmelancholic during their current episode but who have an
abnormal DST result.

PMID: 6957903 [PubMed – indexed for MEDLINE]


94: Bibl Psychiatr 1981;(160):56-61

Sleep deprivation psychoprophylaxis in recurrent affective disorders.

Papadimitriou GN, Christodoulou GN, Trikkas GM, Malliaras DE, Lykouras EP,
Stefanis CN.

Administration of prophylactic 36 h total sleep deprivation to 9
manic-depressive patients (5 bipolar and 4 unipolar depressives) reduced the
frequency of relapses and increased the duration of normothymia in 5 patients,
left the course of illness unchanged in 3 patients whilst in 1 patient the
effect could not be evaluated. Sleep deprivation appeared to be more effective
in women, ‘rapid cyclers’, patients with a positive family history of mental
illness and patients with recurrent depression. These observations confirm
previous impressions and suggest a possible prophylactic effect of sleep

PMID: 7458886 [PubMed – indexed for MEDLINE]


95: Chronobiologia 1980 Oct-Dec;7(4):505-11

Repeated sleep deprivation as a therapeutic Zeitgeber for circular type manic
depressive disturbance.

Lovett Doust JW, Christie H.

A post-menopausal woman suffering from a circular type manic depressive
psychosis who had been treated by drugs was followed for 8 months on a
self-reporting mood rating scale. The drug regimen was continued over a further
8 months but with the addition of 5 nights of sleep deprivation at the depth of
her recurrent depressed moods. Time series analyses of the subject’s
longitudinal mood scores revealed a persistent cycle of 32 days. After 5 sleep
deprivation treatments this cycle shortened to 28 days which endured at least
for the ensuing 8 months. After sleep deprivation and decrease of the amplitude,
an improvement of mood was obtained. It is suggested that the increased LD ratio
obtained in sleep deprivation may be as therapeutic as the actual loss of sleep

PMID: 7449580 [PubMed – indexed for MEDLINE]


96: Dis Nerv Syst 1977 Nov;38(11):873-9

Pathological and therapeutic consequences of sleep loss: a review.

King D.

Until recently sleep deprivation has been studied from the point of view of
determining whether or not it produces deleterious effects. Evidence, however,
has begun to accumulate indicating that both REM deprivation and single night
sleep deprivation may have antidepressant effects. Although beneficial effects
are found primarily in endogenously depressed patients, variable results have
been obtained in both “endogenous” and “reactive” depressions, suggesting that
these diagnostic categories include biologically heterogeneous populations.

Publication Types:

PMID: 199403 [PubMed – indexed for MEDLINE]


97: Acta Psychiatr Scand 1976 Sep;54(3):184-92

Sleep deprivation therapy in depression.

Svendsen K.

A study of sleep deprivation therapy was made in 62 females and 15 males, aged
20-72, with monopolar (60 patients) and bipolar (17 patients) types of
manic-depressive psychosis. Of these patients, 30 had suffered only the current
depression, 29 a maximum of five depressions, and 18 more than five depressions
before the sleep deprivation therapy. Twenty-five patients had been treated with
antidepressant drugs for less than 10 days, 12 patients for 10-24 days, and 36
patients for more than 24 days. Twenty-four patients were treated with one sleep
deprivation, 29 patients with one sleep deprivations per week (average 1.59),
and 24 patients with two sleep deprivations per week (average 2.5). The effect
of the sleep deprivation therapy was evaluated clinically and by means of
Cronholm-Ottosson’s rating scale. The effect was found good and lasting in 29%,
good but temporary in 38%, and poor in 32% of the cases. The best results were
achieved with twice-weekly treatments, the poorest results with once-weekly
treatment. The results were equal in monopolar and bipolar cases and were
independent of the number of previous depressions as well as antidepressant drug
treatment. No side effects have been observed, in particular no conversion to
mania. The results of the present investigation indicate that depression and
sleep disturbances are symptoms produced by a common factor which, however, it
as yet unknown. Sleep deprivation therapy is seen to have at least some effect
on all cases of endogenous depression. Sleep deprivation therapy has no side
effects and is more quick-acting than any other treatment procedure hitherto
known. It should therefore be considered the first treatment offer to all
endogenously depressed patients in whom immediate ECT is not necessitated.

PMID: 970195 [PubMed – indexed for MEDLINE]


98: Acta Psychiatr Scand 1976 Sep;54(3):167-73

Sleep deprivation as treatment for endogenous depression.

Larsen JK, Lindberg ML, Skovgaard B.

Twenty-six depressed patients, 19 of whom suffered from an endogenous
depression, were sleep-deprived for one night, and eight of these were
additionally sleep-deprived for three to nine nights with two sleep deprivations
per week. While the sleep deprivation was being carried through, none of the
patients were treated with tricyclic antidepressants. The patients were rated
before and after the sleep deprivation(s). Sleep deprivation appeared to be
effective for both unipolar and bipolar depressions. According to the rating
scale an improvement was registered especially when the clinical picture was
characterized by depressed mood, psycho-motor retardation and anxiety. As sleep
deprivation cured 25% of the patients and further incidentally improved another
20% of the patients, it can be concluded that sleep deprivation seems to be a
valuable treatment, especially in retarded endogenous depressions.

PMID: 970193 [PubMed – indexed for MEDLINE]


99: Acta Psychiatr Scand 1976 Feb;53(2):148-58

The effect of sleep deprivation on depressed patients.

Pflug B.

In this paper an account is given of the effect of single-night sleep
deprivation (SD) therapy in 124 depressive patients of different diagnostic
groups. Phasic depressives showed a marked improvement after treatment by sleep
deprivation. Because these improvements were often of short duration, we
repeated the treatments and combined them with thymoleptic drugs. In the group
of neurotic depressives the therapeutic effect of sleep deprivation varied; on
the whole, however, the improvement was less marked. It is pointed out that the
vital symptoms and “critical time” are of importance. Sleep deprivation can be
explained as a resynchronization of disturbed circadian rhythms brought about by
interrupting these rhythms.

PMID: 1251760 [PubMed – indexed for MEDLINE]


100: Br J Psychiatry 1975 Sep;127:222-6

The treatment of psychotic depression by sleep deprivation: a replication study.

Bhanji S, Roy GA.

A replication study of the effects of single-night sleep deprivation therapy was
carried out as a preliminary to a controlled comparison with orthodox
antidepressent measures. The results show that sleep deprivation therapy was
acceptable to a majority of the patients studied, and was followed by an
improvement in over half those who completed treatment. Adverse effects were
minimal. The authors feel that further clinical and physiological study is

PMID: 1182378 [PubMed – indexed for MEDLINE]


101: Arch Gen Psychiatry 1975 Sep;32(9):1121-5

Total sleep deprivation on endogenous depression.

van den Burg W, van den Hoofdakker RH.

Ten endogenous depressive patients were deprived of sleep for two whole nights
according to the following schedule: sleep/sleep deprivation/sleep/sleep
deprivation/sleep. No drugs were administered. Experimental conditions were as
neutral as possible. Blind and nonblind ratings were taken. The patients were
generally rated as improved after sleep deprivation, but a substantial effect,
though temporary with rapid relapse, occurred in only two cases. After
subsequent sleep, relapse followed as a rule. The net antidepressive effect of
the total procedure was slightly more than nil.

Publication Types:
Clinical Trial

PMID: 1101846 [PubMed – indexed for MEDLINE]