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This study examined quantitative measures of sleep electroencephalogram (EEG) and phasic rapid eye movements (REM) as correlates of remission and recovery in depressed patients. To address correlates of remission, pre-treatment EEG sleep studies were examined in 130 women outpatients with major depressive disorder treated with interpersonal psychotherapy (IPT). To address correlates of recovery, baseline and post-treatment EEG sleep studies were examined in 23 women who recovered with IPT alone and 23 women who recovered with IPT+fluoxetine. Outcomes included EEG power spectra during non-rapid eye movement (NREM) sleep and REM sleep and quantitative REMs. IPT non-remitters had increased phasic REM compared with remitters, but no significant differences in EEG power spectra. IPT+fluoxetine recoverers, but not IPT recoverers, showed increases in phasic REM and REM percentage from baseline to recovery. In NREM sleep, the IPT+fluoxetine group showed a decrease in alpha power from baseline to recovery, while the IPT group showed a slight increase. The number of REMs was a more robust correlate of remission and recovery than modeled quantitative EEG spectra during NREM or REM sleep. Quantitative REMs may provide a more direct measure of brainstem function and dysfunction during REM sleep than quantitative sleep EEG measures.

This study sought to clarify the neurobiological basis of variations in one aspect of central nervous system 'arousal' in depression by characterizing the functional neuroanatomic correlates of beta electroencephalographic (EEG) power density during non-rapid eye movement (NREM) sleep. First, nine healthy (n=9) subjects underwent concurrent EEG sleep studies and [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) scans during their first NREM period of sleep in order to generate hypotheses about specific brain structures that show a relationship between increased beta power and increased relative glucose metabolism. Second, brain structures identified in the healthy subjects were then used as a priori regions of interest in similar analyses from identical studies in 12 depressed subjects. Statistical parametric mapping was used to identify the relationship between beta power and relative regional cerebral glucose metabolism (rCMRglu) during NREM sleep. Regions that demonstrated significant correlations between beta power and relative cerebral glucose metabolism in both the healthy and depressed subjects included the ventromedial prefrontal cortex and the right lateral inferior occipital cortex. During a baseline night of sleep, depressed patients demonstrated a trend toward greater beta power in relation to a separate age- and gender-matched healthy control group. In both healthy and depressed subjects, beta power negatively correlated with subjective sleep quality. Finally, in the depressed group, there was a trend for beta power to correlate with an indirect measure of absolute whole brain metabolism during NREM sleep. This study demonstrates a similar relationship between electrophysiological arousal and glucose metabolism in the ventromedial prefrontal cortex in depressed and healthy subjects. Given the increased electrophysiological arousal in some depressed patients and the known anatomical relations between the ventromedial prefrontal cortex and brain activating structures, this study raises the possibility that the ventromedial prefrontal cortex plays a significant role in mediating one aspect of dysfunctional arousal found in more severely aroused depressed patients.

Based on recent functional brain imaging studies of healthy human REM sleep, we hypothesized that alterations in REM sleep in mood disorder patients reflect a functional dysregulation within limbic and paralimbic forebrain structures during that sleep state. Six unipolar depressed subjects and eight healthy subjects underwent separate [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) PET scans during waking and during their first REM period of sleep. Statistical parametric mapping contrasts were performed to detect changes in relative regional cerebral glucose metabolism (rCMRglu) from waking to REM sleep in each group as well as interactions in patterns of change between groups. Clinical and EEG sleep comparisons from an undisturbed night of sleep were also performed. In contrast to healthy control subjects, depressed patients did not show increases in rCMRglu in anterior paralimbic structures in REM sleep compared to waking. Depressed subjects showed greater increases from waking to REM sleep in rCMRglu in the tectal area and a series of left hemispheric areas including sensorimotor cortex, inferior temporal cortex, uncal gyrus-amygdala, and subicular complex than did the control subjects. These observations indicate that changes in limbic and paralimbic function from waking to REM sleep differ significantly from normal in depressed patients.

Background: We compared pretreatment subjective and electroencephalographic sleep measures among depressed patients who remitted with psychotherapy alone and those who did not remit., Methods: Patients were 111 midlife women with recurrent major depressive disorder. Baseline psychiatric ratings and sleep studies were conducted prior to treatment with weekly interpersonal psychotherapy. Remission was defined as a score of < or = 7 for 3 consecutive weeks on the Hamilton Depression Rating Scale. Clinical and sleep measures were compared between remitters (n = 62) and nonremitters (n = 49) using t tests and random regression. Linear discriminant function analyses were used to categorize remitters and nonremitters on the basis of sleep measures., Results: Treatment nonremitters had significantly worse subjective sleep quality and significantly elevated phasic REM sleep as measured by multivariate and univariate analyses. The linear accumulation of REM activity during sleep occurred at a significantly higher rate in nonremitters than in remitters. Linear discriminant function analyses based on subjective sleep quality and REM activity correctly identified 68.3% of nonremitters and 68.5% of remitters., Conclusions: These findings highlight the role of subjective and REM sleep measures as correlates of short-term psychotherapy treatment response in major depressive disorder. Disturbed sleep may be a physiological indicator of increased limbic and brain stem arousal.

Although sleep is characterized by relative behavioral inactivity, cortical activity is known to cycle in well-defined periods across this state. Cognitive function during sleep has been difficult to define, although disturbances in sleep are known to result from, and to cause, various human pathologies, including neuropsychiatric disorders. Assessment of brain function in humans (related to cognitive operations) during sleep has been limited, until recently, to surface electrophysiologic recordings that limit analysis of regional function, particularly in deep structures. The current report describes one method of assessing human forebrain activation during sleep using the [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) method and positron emission tomography (PET) measures of regional cerebral glucose utilization. In comparison with other functional brain imaging techniques (e.g., assessment of blood flow or functional magnetic resonance imaging), this method offers the advantage of a more naturalistic study of sleep since subjects do not have to sleep in a scanning device. This leads to a higher rate of successful completion of studies. The primary disadvantage of this method is the decreased temporal resolution necessitating assessments of global sleep states (e.g., REM or NREM) as opposed to assessing events within a sleep state (e.g., sleep spindles or rapid eye movements)., (Copyright 1998 Elsevier Science B.V.)

Objective: This study presents polysomnographic data and psychiatric history for parents and siblings of probands with unipolar depression and short REM latency, probands with unipolar depression and normal REM latency, and normal comparison probands., Method: Parents and adult siblings (N = 252) of probands (N = 64) were evaluated for lifetime history of psychiatric disorders and were studied in the sleep laboratory for 3 nights., Results: REM latency predicted lifetime history of major depression. Short REM latency was also associated with slow wave sleep deficits. Rate of short REM latency in relatives of depressed probands with short REM latency quadrupled the rate in relatives of both depressed probands with normal REM latency and normal probands. Lifetime risk of depression was almost twice as high in relatives of depressed probands with short REM latency as in relatives of depressed probands with normal REM latency., Conclusions: Short REM latency and slow wave sleep deficits are familial. Short REM latency is associated with increased risk of major depression beyond the familial risk associated with a depressed proband. Polysomnographic abnormalities also occurred in unaffected relatives. Although the data can be considered only suggestive, these findings indicate that polysomnographic abnormalities may precede the clinical expression of depression and may be useful in identifying those at highest risk for the illness.

This study was designed to evaluate the effect of race, specifically African-American, on electroencephalographic (EEG) sleep and clinical symptom profile in unipolar major depression. A clinical research database was used to identify appropriate subjects and a double-matched historical case-control design was implemented. African-American depression patients were double matched within protocol to Euro-American depressed patients. Age, sex, and protocol of origin were matching variables. African-American depressed patients had less total sleep, less slow wave sleep, more stage 2 sleep, longer rapid eye movement (REM) sleep latency, less REM sleep, and lower REM density than Euro-American depressed patients. African-American depressed patients did not differ from Euro-American patients in symptom severity, age of onset, number of episodes, socio-economic status, and, as planned, did not differ in age and sex distribution. Depressive symptom constellation also did not distinguish the two groups. African-American depressed patients demonstrated differences in EEG sleep profile, with less total sleep, overall lighter nonREM sleep, and relatively preserved REM sleep, despite a clinical symptom profile that did not differ from Euro-American depressed patients. The sleep profile appeared to be consonant with the sleep findings in chronic insomnia. The pathological implications of these differences remained to be explored in careful prospective studies of African-American depressed patients and in well-characterized, racially matched normal control comparisons.

The following four issues were assessed in a group of 110 adults between the age of 20 and 59y: (1) the effect of age (regarded as a continuous variable) on polysomnographic sleep characteristics, habitual sleep-diary patterns, and subjective sleep quality; (2) the effects of age on morningness-eveningness; (3) the effects of morningness-eveningness on sleep, after controlling for the effects of age; and (4) the role of morningness-eveningness as a mediator of the age and sleep relationship. Increasing age was related to earlier habitual waketime, earlier bedtime, less time in bed and better mood and alertness at waketime. In the laboratory, increasing age was associated with less time asleep, increased number of awakenings, decreased sleep efficiency, lower percentages of slow-wave sleep (SWS) and rapid eye movement (REM) sleep, higher percentages of Stage 1 and 2, shorter REM latency and reduced REM activity and density. Increasing age was also associated with higher morningness scores. After controlling for the effects of age, morningness was associated with earlier waketime, earlier bedtime, less time in bed, better alertness at waketime, less time spent asleep, more wake in the last 2 h of sleep, decreased REM activity, less stage REM (min and percentage), more Stage 1 (min and percentage) and fewer minutes of Stage 2. For one set of variables (night time in bed, waketime, total sleep time, wake in the last 2 h of sleep and minutes of REM and REM activity), morningness-eveningness accounted for about half of the relationship between age and sleep. For another set of variables (bedtime, alertness at waketime, percentages of REM and Stage 1), morningness-eveningness accounted for the entire relationship between age and sleep. In conclusion, age and morningness were both important predictors of the habitual sleep patterns and polysomnographic sleep characteristics of people in the middle years of life (20-59 y).

Sleep complaints and electroencephalographic (EEG) sleep abnormalities are associated with risk for new onset depression, illness severity, treatment outcome, and vulnerability for recurrence of depression. The aim of this study was to evaluate the strength of association between EEG sleep measures and depression symptoms, and to identify the variables that account for the majority of the association. Depression ratings from the Hamilton Rating Scale for Depression and the Beck Depression Inventory and polysomnographic measures were examined in 361 adult outpatients with major depressive disorder. Canonical correlation and serial multiple regression analyses were used to determine the associations between depressive symptoms and sleep measures. Canonical correlation showed a unidimensional relationship between depressive symptoms and sleep measures (R = .55, p < .05). Fifteen depression items and nine sleep measures accounted for 95% of the correlation. Depression variables encompassed a core set of mood, neurovegetative, and cognitive symptoms. Sleep variables were primarily related to delta EEG activity, and this may be reflective of impaired sleep "drive" or heightened arousal during sleep.

Rapid eye movement (REM) sleep is a behavioral state characterized by cerebral cortical activation with dreaming as an associated behavior. The brainstem mechanisms involved in the generation of REM sleep are well-known, but the forebrain mechanisms that might distinguish it from waking are not well understood. We report here a positron emission tomography (PET) study of regional cerebral glucose utilization in the human forebrain during REM sleep in comparison to waking in six healthy adult females using the 18F-deoxyglucose method. In REM sleep, there is relative activation, shown by increased glucose utilization, in phylogenetically old limbic and paralimbic regions which include the lateral hypothalamic area, amygdaloid complex, septal-ventral striatal areas, and infralimbic, prelimbic, orbitofrontal, cingulate, entorhinal and insular cortices. The largest area of activation is a bilateral, confluent paramedian zone which extends from the septal area into ventral striatum, infralimbic, prelimbic, orbitofrontal and anterior cingulate cortex. There are only small and scattered areas of apparent deactivation. These data suggest that an important function of REM sleep is the integration of neocortical function with basal forebrain-hypothalamic motivational and reward mechanisms. This is in accordance with views that alterations in REM sleep in psychiatric disorders, such as depression, may reflect dysregulation in limbic and paralimbic structures.

As part of a larger bedrest study involving various life science experiments, a study was conducted on the effects of 17 days of continuous bedrest and elimination of daylight on circadian rectal temperature rhythms, mood, alertness, and sleep (objective and diary) in eight healthy middle-aged men. Sleep was timed from 2300 to 0700 hours throughout. Three 72-hour measurement blocks were compared: ambulatory prebedrest, early bedrest (days 5-7), and late bedrest (days 15-17). Temperature rhythms showed reduced amplitude and later phases resulting from the bedrest conditions. This was associated with longer nocturnal sleep onset latencies and poorer subjectively rated sleep but with no reliable changes in any of the other sleep parameters. Daily changes in posture and/or exposure to daylight appear to be important determinants of a properly entrained circadian system.

The study of electroencephalogram (EEG) sleep in depressed patients before and after treatment with psychotherapy can distinguish episode-related and persistent biological features. With longitudinal follow-up, we can also assess whether EEG sleep measures are associated with recurrence of depression. In the current study, we examined EEG sleep during the depressed state and during symptomatic remission after treatment with interpersonal psychotherapy in 42 outpatients with major depression. Analyses included both visually-scored and computer-analyzed measures. Patients showed significant increases in sleep latency (p = .01) and rapid eye movement (REM) latency (p = .04) from baseline to remission, as well as a decrease in REM sleep percent (p = .03). Total delta EEG counts decreased from baseline to remission (p = .03), specifically in the second nonrapid eye movement (NREM) period (p = .03); as a result, the relative distribution of delta activity shifted toward sleep onset (i.e., increased delta sleep ratio; p = .03). Automated REM counts also decreased from depression to remission (p = .006). Compared to patients who remained well through one year of follow-up, those who suffered a recurrence of depression had less delta EEG activity at baseline and remission (p = .01), particularly in the lowest delta frequency band of 0.5-1.0 Hz. Specific components of sleep (total delta activity, delta ratio, REM activity) constitute episode-related biological features. Other components (slowest delta activity) may represent vulnerability factors for recurrence.

Owing to the use of scalp electrodes in human sleep recordings, cortical EEG signals are inevitably intermingled with the electrical activity of the muscle tissue on the skull. Muscle artifacts are characterized by surges in high frequency activity and are readily identified because of their outlying high values relative to the local background activity. To detect bursts of myogenic activity a simple algorithm is introduced that compares high frequency activity (26.25-32.0 Hz) in each 4-s epoch with the activity level in a local 3-min window. A 4-s value was considered artifactual if it exceeded the local background activity by a certain factor. Sensitivity and specificity of the artifact detection algorithm were empirically adjusted by applying different factors as artifact thresholds. In an analysis of sleep EEG signals recorded from 25 healthy young adults 2.3% (SEM: 0.16) of all 4-s epochs during sleep were identified as artifacts when a threshold factor of four was applied. Contamination of the EEG by muscle activity was more frequent towards the end of non-REM sleep episodes when EEG slow wave activity declined. Within and across REM sleep episodes muscle artifacts were evenly distributed. When the EEG signal was cleared of muscle artifacts, the all-night EEG power spectrum showed significant reductions in power density for all frequencies from 0.25-32.0 Hz. Between 15 and 32 Hz, muscle artifacts made up a substantial part (20-70%) of all-night EEG power density. It is concluded that elimination of short-lasting muscle artifacts reduces the confound between cortical and myogenic activity and is important in interpreting quantitative EEG data. Quantitative approaches in defining and detecting transient events in the EEG signal may help to determine which EEG phenomena constitute clinically significant arousals.

The aim of this experiment was to study the effects on sleep and temperature rhythms of a 6-hour (h) phase advance of the sleep/wake cycle in healthy elderly subjects. Twenty-five subjects (77-91 y.o.) lived in a time-isolation apartment on an experimenter-controlled routine for 15 days. The experiment started with five baseline days. The wake time on the 6th night was phase advanced by 6-h and the routine for the remaining nine days was held constant to the new phase position. After the phase shift, temperature circadian rhythms showed rapid phase adjustment leading to a small (1.1 h) phase angle disturbance. Sleep efficiency decreased and showed little evidence of recovery back to baseline following the phase shift. The amount of wakefulness in the first two hours of sleep increased after the phase shift while no effect was found for the amount of wakefulness in the last two hours of sleep. The 6-h phase shift did not change the percentages of REM and SWS. Early night sleep propensity appeared to be very sensitive to a small phase angle disturbance of the circadian oscillator in this healthy elderly sample. The phase angle disturbance induced in this study did not seem to be large enough to have a systematic effect on sleep propensity at the end of the night or on REM sleep parameters, suggesting that these variables are less sensitive to an altered phase relationship with the circadian oscillator than early night sleep propensity. These results indicate that there might be a variable phase tolerance for different sleep parameters in older subjects.

Objective: The authors compared the effects of bupropion, fluoxetine, and cognitive behavior therapy on EEG sleep in depressed subjects., Method: All-night sleep EEG studies were performed before treatment and after partial or full remission on 18 men with depression diagnosed according to Research Diagnostic Criteria and randomly assigned to treatment with either bupropion (N = 7) or fluoxetine (N = 11). Response to these drugs was measured by changes in Hamilton Depression Rating Scale scores. Pre- and posttreatment EEG sleep study results before and after treatment with cognitive behavior therapy were also available for 18 men matched in age and severity of Hamilton depression scale score, and one-time EEG sleep measures were available for 36 men who were not depressed., Results: REM latency was reduced and REM sleep percent and REM time increased after treatment in the depressed men given bupropion. These effects contrasted with the effects of fluoxetine and cognitive behavior therapy., Conclusions: This study represents the first report of an antidepressant medication that shortens REM latency and increases REM sleep. If confirmed, this finding may require a revision of our current understanding of the relation among depression, REM sleep, and anti-depressant mechanisms.

Two different initial dosing regimens with clomipramine (CMI) were used to compare early response indicators and dose strategies. Thirty-two inpatients with major depressive disorder were randomized in a double-blind protocol. The pulse-loading group received 150 and 200 mg of CMI on 2 consecutive evenings and then received a placebo for 8 days. The traditional dosing group began at 50 mg of CMI followed by gradual increases every second day until 200 mg was reached. After 10 days, both groups were placed on an adjustable dosing schedule of CMI, initially set at 200 mg, for an additional 2 weeks. Significant drug effects were noted on several sleep parameters demonstrating suppression of rapid eye movement (REM) sleep. In the pulse-loading group, drug responders were found to have a significantly faster and more robust rebound in REM sleep than nonresponders. Both measures of REM activity and REM sleep time showed a significant difference between the groups. In addition, a significant correlation was found between falling levels of the desmethylclomipramine metabolite of CMI and REM sleep activity during the rebound phase. The clinical and theoretical implications of these findings are discussed.

This article explored the relationship between daytime affect and REM sleep in 45 depressed men before and after treatment with cognitive-behavioral therapy and in a control group of 43 healthy subjects. The intensity of daytime affect (as measured by the sum of positive and negative affects) in depressed men correlated significantly and positively with phasic REM sleep measures at both pre- and posttreatment. This relationship was not found in healthy control subjects. In depressed men, both affect intensity and phasic REM sleep measures decreased over the course of treatment. The results suggest a relationship between phasic REM sleep and intensity of affect reported by depressed men. On the basis of this preliminary observation, it was hypothesized that abnormalities in phasic REM sleep in depressed patients are related, in part, to fundamental alterations in the intensity of their affective experience.

Rapid eye movement (REM) sleep measures distinguish elderly patients with depression from those with dementia. The authors used a 2-night REM sleep deprivation (RSD) protocol to characterize patients with mixed symptoms of depression and dementia in comparison with patients with "pure" depression or dementia and healthy controls. Mixed-symptom patients resembled dementia patients in baseline sleep measures, but their large change in phasic REM activity following RSD suggests neurobiological similarities to depression. Mixed-symptom patients with stable cognitive impairment had greater REM sleep rebound than those with a more progressive dementing course. These results are consistent with previous neuropathological and neurochemical data.

Sixteen male outpatients with major depression and 20 age-equated healthy controls were awakened from rapid eye movement (REM) sleep between 1:30 and 3:30 AM, and the rapidity of return to REM sleep was determined. The time it took to return to REM sleep was reduced in depressives compared with controls: 61.6 (17.9 SD) min versus 80.6 (24.9 SD) min, respectively (p = 0.01). The time elapsed until the return to REM sleep was significantly correlated with baseline REM latency in controls (but not depressives). In contrast, return to REM time was significantly correlated with depression severity scores in depressives (but not controls). There was no evidence to support the hypothesis that the more rapid return to REM sleep in depression was caused by a slow wave sleep deficit. The mechanism underlying the rapid return of REM sleep in depression thus may be related to a severity-linked disturbance, such as a proposed increase in REM "pressure."

The effects of a 2-night rapid eye movement (REM) sleep deprivation (RSD) procedure on electroencephalographic sleep and mood were examined in 15 healthy elderly control subjects, 14 elderly patients with endogenous depression, and 15 patients with primary degenerative dementia. Compared with control subjects, both patient groups maintained a higher amount of REM sleep time and REM activity during RSD. Unexpectedly, depressed patients showed little rebound in visually scored or automated REM sleep measures following RSD, and they showed stability of REM activity temporal distribution from baseline to recovery conditions. This contrasted with the rebound in REM sleep activity seen in control subjects, and the more modest increase in demented patients. The RSD was fairly specific, with some impact on delta sleep during the procedure but not during recovery sleep. Mood ratings were unaffected by RSD. These findings demonstrated a greater plasticity of REM sleep regulation in the healthy elderly control subjects and suggested a higher REM "pressure" with a "ceiling effect" in depressed patients. Patients with dementia appeared to have an impaired capacity to respond to the challenge of RSD.

Sleep changes described in depressed patients may represent alterations in the timing of rapid-eye-movement (REM) sleep or sleep onset. We examined these variables in groups of healthy control subjects (n = 47), depressed outpatients (n = 98), and depressed inpatients (n = 41). Outpatient depressives had greater severity of clinical symptoms than inpatients using the Hamilton Rating Scale for Depression. The depressed inpatient group had a later mean sleep onset time than the other groups, and the depressed outpatient group had a wider range of good night times than control subjects. REM timing in each group was examined as a relative frequency distribution of REM sleep (FDRS) for each minute across the night. The FDRSs for the three groups were statistically compared using the parameters from a two-component model, which includes a deterministic sinusoidal function and a time series process for errors. The slope of the linear trend in the FDRS rhythm was smaller (less positive) for both depressed groups than for controls. The ultradian FDRS rhythm occurred at an earlier phase, relative to sleep onset, in the inpatient depressed group compared to the control group. The ultradian FDRS rhythm had a longer period in the outpatient group compared to the control and inpatient groups. When referenced to 24-hr clock time in an exploratory analysis, the depressed groups appeared to have less robust FDRS ultradian rhythms than controls, but they did not appear to have a systematic phase alteration compared to controls. Abnormalities of REM sleep timing in groups of depressed patients may reflect a disturbance of sleep initiation and generation, or difficulty in entrainment of REM, rather than a systematic phase alteration in REM sleep propensity.

Within the last decade, the application of neurophysiological and neuroendocrine techniques has led directly to the identification of specific psychobiological correlates of depression. More recent efforts have attempted to establish linkages between mechanisms of action by antidepressants and such psychobiological factors. EEG sleep investigations, conducted with various antidepressants, have focused on the "specificity" of REM suppression or slow-wave sleep alterations. To date, results point to a greater commonality of action for REM suppression, lack of sedative effect as a necessary condition for clinical improvement, and the need for greater emphasis on slow-wave sleep research in relation to clinical recovery. The need for integrated theories of neurophysiological and neuroendocrine factors in depression is stressed.

The phase of the REM sleep rhythm was studied in 10 normal subjects each of whom was sleep studied for 4 consecutive nights. For analysis, each night of sleep was aligned according to clock time and each minute was scored as REM or non-REM. With these data, REM probability was found as a function of clock time. Fractional harmonic analysis indicates a 90 min periodicity. The REM probability curve shows peaks occurring at 1:30 a.m., 3:15 a.m., 4:30 a.m., 5:45 a.m. and 7:00 a.m. Statistical measures comparing the time of REM sleep across subjects suggests that subjects tend to have REM sleep at the same time of the night as each other. The influence of elapsed time after sleep onset on REM sleep is also reestablished. Results indicate that the time of REM sleep is determined by both clock time and time of sleep onset, suggesting two clocks, one sleep dependent and the other related to the basic rest activity cycle (BRAC), which are responsible for driving REM sleep. Furthermore, the similarity of REM times across subjects indicates the possible existence of an extra-personae REM driving force linked to clock time and possibly the BRAC.

In a sample of 92 inpatients with major depression, REM latency showed a unimodal, rather than bimodal, distribution, with peak frequency between 50-59 min (on each of 4 consecutive nights). A total of 20 patients (21.6%) exhibited a sleep onset REM period (SOREMP-10) i.e., REM latency less than or equal to 10 min, during at least 1 of the 4 nights; an additional 11 patients (12%) showed REM latencies of 11-20 min on at least one night. SOREMP-10 positive patients were older both at the time of study (p less than 0.01) and at the age of onset of depressive illness (p less than .01) than the rest of the sample. They also showed greater sleep continuity disturbances, while patients with at least one SOREMP-20, i.e., REM latency less than or equal to 20 min, exhibited higher REM percentage (p less than or equal to 0.05) and a higher first-period density (p less than 0.05) than the remaining patients. No other clinical or polysomnographic correlates of SOREMP positivity were noted with regard to gender, RDC subtypes, severity of illness, or clinical response to tricyclic antidepressants. The unimodal distribution of REM latency, as well as the absence of a relationship between SOREMP positivity and severity of depression or therapeutic outcome, may result from the low representation of psychotic depressives in this sample (n = 6), who might constitute a qualitatively different subgroup.

The electroencephalographic sleep patterns of 12 patients with a final diagnosis of primary depression and those of 12 patients admitted to the Clinical Research Unit with this diagnosis, but subsequently also found to be suffering from severe medical disease, were compared. Patients with depression concurrent with severe medical disease have significantly less phasic conjugate rapid eye movement (REM) activity during REM sleep than subjects with the diagnosis of a primary depression. These findings suggest that quantification of REM density may be used clinically to distinguish between medical-depressive syndromes and primary affective disorders.

Among 92 inpatients with major depressive disorders, variability in REM latency (RL) during the first two recording nights was assessed by means of an "adaptation coefficient" (AC = night 1 RL--night 2 RL X 100 divided by mean RL for nights 1 and 2). Although mean RL was very similar for both nights (48.1 and 50.7 min), individual ACs showed a gaussian distribution [range: -176.5-171.4; mean: -1.2 (67.3); median: -4.4]. Forty-two patients (45.7%) exhibited shortening of RL on night 2 compared with night 1 (positive AC, corresponding to an "expected" evolution), 48 patients (52.2%) displayed the opposite pattern (negative AC, corresponding to a "paradoxical" evolution), and two patients had identical values on both nights. Extent of increase in RL from first to second night (i.e., extent of "paradoxical" evolution) correlated significantly with increasing duration of current episode, earlier age of onset, and poorer clinical response to tricyclic antidepressants. A cutoff AC of -7 correctly classified 62% of patients according to treatment response. The research diagnostic criteria-based retarded subtype of depression was associated with a more negative AC (i.e., a more "paradoxical" evolution), and the situational subtype was associated with a more positive AC (i.e., a more "expected" evolution) than the remainder of the sample. The subgroup with the most negative ACs (i.e., largest increases in RL from first to second night) also had longer sleep latencies, whereas the subgroup with the most positive ACs (i.e., largest decreases in RL) had higher REM activity and REM density as compared with the remainder of the sample. These results suggest that RL in major depression is not a static parameter and that the study of its within-subject variability can be helpful for diagnostic confirmation and prediction of treatment response.

Sleep EEG (7 h) were obtained from 11 rats given 5, 10, and 20 mg/kg zimelidine, and a control dose of saline. Zimelidine significantly suppressed REM sleep, lengthened REM latency, and reduced total sleep time (TST) in a dose-dependent manner. Sleep latency was not affected except at the highest dose of zimelidine. Slow-wave sleep (SWS) was not affected at any dose. The results are discussed in terms of their implication for the use of zimelidine in the clinical treatment of depression.

In the last decade all night EEG sleep research has attempted to delineate the sleep features most characteristics of depressive states occurring in adult life. We have reported that EEG sleep variables could be used to verify a diagnostic classification for affective syndromes. This EEG sleep generated schema significantly dichotimized each major clinical category using only two or three EEG sleep measures. REM latency and REM density were sufficient to separate out primary from secondary depressed patients. Sleep efficiency, REM sleep percent, and delta sleep percent discriminated between the psychotic and nonpsychotic subgroups in the primary depressive group. Furthermore, EEG sleep variables separated secondary depression with concurrent medical disease from secondary depression without medical disease using REM activity and intermittent nocturnal awakening as the requisite variables of discrimination. Other ongoing investigations have established that the REM intensity of the first REM period is increased in primary depression. The search for EEG sleep correlates of clinical response in depressed patients receiving tricyclic antidepressants has suggested that, the more rapid the suppression of REM sleep, the more likely that the patient will respond to tricyclic antidepressants. Finally, clinical response appears to be associated with a period of sustained elevation of REM latency.

Continued interest in rapid eye movement (REM) sleep abnormalities in depression stimulated comparative studies on daytime naps versus nighttime sleep. In a group of 15 depressed patients, REM latencies in morning and afternoon naps were similar to the shortened REM onset at night. Although REM latency did not vary across the three times, the propensity for REM sleep appeared to be greater in the morning nap than in the afternoon nap and the early portion of nocturnal sleep. Finally, the data suggest that responders to tricyclic treatment tend to be poor sleepers during daytime naps.

REM sleep in 35 inpatients with primary depression was automatically analyzed for 7 consecutive nights during placebo administration. For the total night of sleep, as well as each individual REM period, the number of REMs, their total voltage integral over time, the sum of their durations and the average REM size were automatically calculated. Validity of these automated REM measures was established by significant correlations with manually scored REM measures. Changes in REM sleep across the night were also investigated. Similar to findings in normal subjects, REM time did not change from REM period to REM period. Average REM size increased significantly from REM period 2-3 and 3-4. Contrary to what is seen in normal subjects, REM frequency was high during the first REM period, significantly decreased from the first to second REM period and then remained constant. Finally, a significant inverse correlation between REM frequency for the first REM period and REM latency was noted. This pattern of REM sleep is interpreted as indicating a high pressure for phasic REM at the beginning of the night which is dissipated by the first REM period.

Among the various disturbances in sleep architecture among major depressive patients, the shortening of REM latency seems the most specific feature. Therefore, several groups have tested the usefulness of this parameter as a "biological marker" of major depression. The divergent results of those studies probably result from the marked differences in the methodology used. In this context, we compared the diagnostic sensitivity of various methodologies for selection of REM latency data among 92 major depressive inpatients recorded for 4 consecutive nights. The selection of individual night values or of mean values yielded very similar diagnostic sensitivity. However, the selection of the shortest REM latency from consecutive nights was associated with a higher diagnostic sensitivity, especially if at least 3 nights were included. After controlling for age, 87% of patients were identified by this methodology (sum of REM latency and age less than 90). Therefore we propose to standardize the methodology for use of REM latency: recording of 3 consecutive nights and selection of the shortest REM latency. If the sum of this value and of patient'age equals 90 or less, the diagnosis of major depression is supported.

A comparison of electroencephalographic sleep measures between young and middle-aged groups of depressed inpatients was conducted with specific interest in the application of automated measures of REM and delta wave sleep. Aside from the expected differences in sleep continuity, increased Stage 1 percent, decreased Stage 2 percent, and decreased REM latency in the middle-aged depressives as compared to the younger depressives, distinct findings from automated analyses were noted in the distribution of REM and delta sleep throughout the night. Although the younger depressed patients showed increased numbers of delta waves, the middle-aged depressives showed greater average REM count. Such changes were more pronounced in the first third of the night. Finally, in the middle-aged depressives, little statistical relationship between manual measures of slow-wave sleep and automated measures of delta sleep was found.

Studies of severely depressed hospitalized patients suggest a shortened rapid eye movement (REM) latency as a specific biological marker for primary affective disease. To assess the validity of these findings, 40 outpatients referred to our Electroencephalographic Sleep Center for evaluation of depressive symptoms were studied. Concurrent with the all night EEG sleep studies, all patients received a brief clinical interview and a battery of self-rating scales. The entire sample was then subdivided into primary and secondary depressives on the basis of follow-up diagnoses. While there were no significant differences between groups on self-ratings of depressive symptoms, the group of primary depressives had significantly shorter REM latencies and higher measures of phasic REM than the secondary depressives. Furthermore, in this patient group, the delineation of primary vs secondary depression was greater than 80% on the basis of only two nights of EEG sleep. Such objective biological measures, if replicated, could provide a method for increasing the accuracy of differential diagnosis among depressed populations in clinical research.

An understanding of the effects of antidepressants on sleep can be aided by determinations of tricyclic plasma levels in relationship to sleep. Previous studies have been established that steady state plasma levels of amitriptyline relate to certain aspects of rapid eye movement (REM) sleep. The present investigations attempt to replicate the REM sleep/tricyclic plasma level relationships in a larger group of psychiatric hospitalized patients for depression and to study whether such relationships persist in a group of ambulatory patients studied longitudinally for 1 to 2 years. In an acute treatment study of 38 patients, REM sleep percent and average REM activity demonstrated a significant relationship with plasma levels, even when controlled for age and severity. The sleep-plasma level relationships seem more prominent with amitriptyline levels than with nortriptyline plasma levels. In a long term comparison of plasma levels, tricyclic plasma levels showed a significant correlation with REM latency, REM percent and average REM activity. Thus, it appears that changes in REM sleep such as REM suppression correlate significantly with tricyclic plasma levels both on a short (4 weeks) and long term basis (1 to 2 years). The implications of these findings are discussed.

Computerized analysis of rapid eye movement (REM) and delta electroencephalographic (EEG) sleep patterns in normal and depressed subjects offers opportunities to examine sleep more precisely than previously possible. In the present study, automated REM analyses demonstrated good reliability with traditional manual procedures in both normal and depressed subjects. However, automated delta analyses correlated well with traditional scoring in normal subjects, but not in depressed patients. These findings suggest the use of automated delta techniques similar to those employed in this report or spectral analytic techniques in the following types of studies: specificity of delta sleep in various psychiatric syndromes, changes in delta sleep produced by the administration of psychotropic agents, relationships between delta sleep and sleep-related neuro-endocrine patterns, and, finally, relationships between delta sleep patterns and other biological rhythms such as activity and temperature.

Abnormalities in a two-process model of sleep regulation (a sleep-dependent process, termed Process S, and a sleep-independent circadian process, termed Process C) have been proposed to account for sleep abnormalities in depressive states. The major tenets of the two-process model of sleep regulation as applied to depression are: the level of process S, as reflected by the electroencephalographic (EEG) slow-wave activity, corresponds to the sleep-dependent facet of sleep propensity; the pathognomonic changes of sleep in depressives are a consequence of a deficiency in the build-up of process S. The application of automated rapid eye movement (REM) and delta wave analyses in normal subjects and younger depressed patients supports the model to some extent: The time spent asleep is positively correlated with total delta waves (normals and depressives) and average delta waves (depressives); delta sleep is lower in depressives than in normals; the average delta wave count is significantly reduced in younger depressives over the total night and in non-REM period 1. The model also postulates that measures of phasic REM activity are inversely related to process S, suggesting that process S can be regarded as exerting an inhibitory influence on phasic REM activity.

Application of automated rapid-eye-movement (REM) analysis can characterize individual REM periods in depressed patients. Average REM count for the individual REM periods generally demonstrated considerable decreases in the second half of the REM period and differentiated patients who subsequently did not respond well to tricyclic antidepressants. These findings suggest that, even as late as six hours into a night of sleep, significant differences among depressed patients are present, based on treatment responder groups. Furthermore, a reevaluation of the previous emphasis on REM abnormalities in the first hour or two of the night may be indicated.

While shortened REM latency is now considered the most consistent sleep feature observed among patients suffering from primary depressive episodes, and one which has generated a variety of hypotheses regarding possible mechanisms, few studies have employed long-term longitudinal designs. In the present investigation, REM latency was examined in 22 hospitalized depressed patients who were studied nightly during a 5-week protocol were bimodally distributed medication during that period; REM latencies were bimodally distributed with peaks occurring shortly after sleep onset and again 30-40 min later. Very short REM latencies (less than or equal to 20 min) were neither uncommon nor isolated events and persisted over time in this patient sample. These findings are discussed in relation to findings on shortened REM latency in other study populations.

Electroencephalographic (EEG) sleep changes in affective disorders have been characterized by sleep continuity, slow wave sleep, and rapid eye movement (REM) abnormalities. The most commonly cited feature, however, has been shortened REM latency. Because the diagnostic and prognostic significance of shortened REM latency has been debated, this issue was reexamined in a group of 186 psychotic and nonpsychotic depressed inpatients and outpatients. The analyses suggest an increased frequency of sleep onset REM periods in psychotic depression and in elderly depressed patients (psychotic or nonpsychotic).

Since electro-oculographic (EOG) activity during human sleep appears to be of medical diagnostic and prognostic value, the vast amount of EOG data representative of even a single night's sleep warrants the development of automated pattern recognition and information extraction techniques. Such a technique for the analysis of sleep EOG rapid eye movement (REM) is presented in which the time of occurrence, area, height, duration and binocular symphrony for each REM are measured. This automated technique for sleep EOG analysis is currently used in the investigation of periodicities and values of REM parameters for normal subjects and in the differential diagnosis of affective disorders.

To date it has not been established whether the anticholinergic properties of imipramine are responsible for the drug's suppresion of REM and prolongation of REM induction. A cholinesterase inhibitor, physostigmine, was administered in conjunction with imipramine to determine if these effects of imipramine were cholinergically medicated. Sleep EEG recordings were observed in rats administered either physostigmine (1.0 mg/kg), or imipramine (1.25, 2.5 or 5.0 mg/kg), alone or in combination. The results indicate that physostigmine blocks the effects of imipramine on REM latency.

Although considerable attention has been paid to the accumulated body of data on sleep-related "markers" of affective illness, there has been ongoing controversy with respect to the application of these sleep measures. This report attempts to reexamine the data on the electroencephalographic sleep features of individuals with depressive illness from a different theoretical perspective. Our focus on rapid eye movement latency is intended to provide both a new interpretation of the available data and directions for future research.

The concurrent validity of different definitions of REM latency has been tested by comparing the ability of each definition to discriminate between primary depressives (outpatients and inpatients) and normal controls. In outpatients the percentage of cases correctly identified ranged from 62.5% to 70.8%; in inpatients, from 64.6% to 70.8%. REM latency definitions with the least stringent sleep-onset criteria yielded the lowest specificity. In contrast, the range of sensitivities yielded by different definitions was narrower and not clearly affected by sleep-onset criterion or exclusion/inclusion of wakefulness between sleep onset and first REM period. Furthermore, different definitions of REM latency correlated equally well (p less than 0.01) with Hamilton depression ratings. The shorter REM latencies in both outpatients and inpatients were associated with a later time of NREM sleep onset than in controls, rather than with an earlier REM sleep-onset time.

While concurrent monitoring of sleep is considered to be a necessary component of evaluating nocturnal penile tumescence (NPT), in order to ensure that NPT data are not invalidated by fragmented sleep or diminished REM sleep, it is not known whether NPT recording itself disrupts sleep beyond the expected first night effect. In this study of 42 outpatient men with major depression and 36 normal control subjects, we found no effect of NPT recording on measures of sleep continuity, proportion of NREM to REM sleep, or REM sleep in either depressed or healthy control subjects.

Both the visual examination of all-night sleep recordings in both normals and patients, generated by a delta wave analyzer, and spectral analysis have suggested that delta wave sleep often appear to rise gradually during a NREM period and then to cease abruptly. Such observations by minute-by-minute computer plots of delta wave activity have strengthened the notion of a REM generator and/or a delta sleep generator in the central nervous system. We now report observations on a sample of 23 normal subjects under the age of 45 in which we investigated the 'rise and fall' of delta sleep activity during successive NREM periods. For these 23 normal subjects, significantly greater maximal decreases throughout the night were noted in each of these 4 NREM periods as compared to the maximal increases. Furthermore, these findings have implications for the understanding of the physiology of sleep and particularly the on- and off-generator of REM and NREM sleep.

The internight variability in REM latency in 92 drug-free inpatients with major depressive illness was recorded for 4 consecutive nights and subsequently assessed. Individual coefficients of variation in REM latency [CV = (standard deviation of mean REM latency for 4 recording nights/4-night mean REM latency) X 100] ranged from 5.1 to 121.7, with a mean of 37.0 (SD = 27.3) and a median of 27.4. CV was positively correlated with both age (p less than 0.05) and age at onset of depressive illness (p less than 0.01). Male patients showed more variability in REM latency than female patients (p less than 0.05); likewise, the subgroups of patients who either were incapacitated or had bipolar II illness showed greater variability in REM latency in comparison with the remainder of the sample (p less than 0.05). When the entire patient sample was stratified by CV into three equal subgroups, the subgroup of patients defined by the highest CV presented the longest sleep latency (p less than 0.05) and the shortest REM latency (p less than 0.0001). No other clinical or polysomnographic correlates of REM latency variability were noted nor was REM latency variability related to severity of illness, other subtypes of illness, or clinical response to antidepressant therapy. In selecting REM latency data for assessment of diagnostic sensitivity, the use of the shortest REM latency from at least 3 consecutive nights yielded a higher sensitivity (74%-81%) than did the use of any one individually specified night (50%-56%) or different internight means (49%-52%). The same conclusion applied when patient age was taken into account. These results have implications for standardizing the use of REM latency as a biological correlate in major depression.

The REM sleep of 23 nonpsychotic patients with primary depression was studied by means of an automated REM analyzer during a drug-free period and again during amitriptyline administration. Initial drug administration (50 mg) was associated with an immediate reduction in the number, average frequency, and average size of the rapid eye movements. The average REM size remained suppressed with continued drug administration while the average REM frequency showed a rebound which was responsible for a partial recovery of the number of REMs and total REM intensity to predrug levels. With regard to individual REM periods, REM frequency and REM intensity were redistributed during tricyclic administration so that the second REM period became more "intense" than the first REM period. This automated REM analysis technique provides an objective set of measures for characterizing discrete aspects of REM sleep during a depressive episode and for evaluating the changes in REM sleep during psychotropic trials.