Reduced cortisol latency in depressive illness.

Depressed patients commonly have disturbances in their sleep and cortisol secretory patterns. When the sleep-related changes in plasma cortisol concentration were measured in 14 patients with a primary major depressive illness, they differed significantly from the changes measured in 14 age- and sex-matched healthy control subjects. The nadir of the nocturnal plasma cortisol concentration was significantly greater in the group of depressed patients, and the nocturnal increase in the plasma cortisol concentration occurred significantly closer to sleep onset in these patients. The circadian activity within the hypothalamic-pituitary-adrenal axis of these depressed patients showed a subtle but significantly disturbed temporal relationship to sleep onset. This reduced time between sleep onset and the nocturnal increase in cortisol secretion suggests a possible biologic correlate of a depressive illness that might be useful as an illness marker in depressed patients.

Application of automated REM analysis in depression.

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.

Electroencephalographic sleep of younger depressives. Comparison with normals.

The electroencephalographic sleep of younger depressives (aged 20 to 44 years) was compared with that of an age-matched group of normals. The patients demonstrated many of the typical sleep changes reported for older depressed populations: shortened rapid-eye-movement (REM) latency; REM sleep activity alterations, with a shift to the early portion of the night (first REM period); reduced delta sleep; and sleep efficiency reductions marked by sleep-onset difficulties. The traditional scoring procedures were supplemented by automated REM and delta-sleep analyses that provided more precise delineation of these differences between patients and normals, particularly the distributions of REM activity and delta-wave patterning.

"Paradoxical" shortening of REM latency on first recording night in major depressive disorder: clinical and polysomnographic correlates.

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.

Distribution of REM latency in depression.

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.

Nortriptyline and EEG sleep in depressed patients.

The effect of nortriptyline was assessed on the EEG sleep of 20 inpatients with major depressive syndrome. While 25 mg of nortriptyline had an immediate effect on REM sleep variables, relatively little influence on sleep continuity measures was noted. Subsequent administration of 75 and 100 mg of nortriptyline produced continued REM sleep suppression over several weeks. In summary, nortriptyline altered EEG sleep in a pattern similar to that of amitriptyline. REM latency and REM sleep time were consistently reduced by drug administration, while REM activity was only transiently altered as with amitriptyline. The comparison with amitriptyline showed, for the most part, similar influences on REM sleep without the sedative effects of amitriptyline.

REM latency in depression: is there one best definition?

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.

Neuropsychological assessment and EEG sleep in affective disorders.

The neuropsychological test performance of 76 hospitalized, depressed patients meeting RDC for the presence of affective disorder was assessed as part of a protocol involving amitryptyline (n = 53) or placebo (n = 23). Tests included the Trail-making Test (TMT), the Benton Visual Retention Test, and the Shipley-Hartford Scale. Clinical ratings and data concerning the characteristics of EEG sleep were also obtained. Analysis of data collected after a drug-free period of 2 weeks and again at the end of the protocol yielded the following conclusions. Base-line performance was inferior to norms for these tests, but for the TMT, scores were not as poor as that expected for brain-damaged patients. Poor performance was often associated with older age, the presence of psychotic features, and prolonged sleep latencies. Baseline Hamilton Rating Scale (HRS) was predicted best by TMT part B. However, this association was not as strong as that between HRS and poor sleep efficiency. Treatment with drug or placebo had little differential effect upon test performance over the course of the protocol. It is suggested that further research should utilize tests which have specificity in localizing cerebral lesions, so that any focal deficits in brain function in depression might be identified.

Sleep, gender, and depression: an analysis of gender effects on the electroencephalographic sleep of 302 depressed outpatients.

Gender-related differences in electroencephalographic (EEG) sleep were examined in 151 pairs of men and women with major depression, all outpatients, matched for age and severity of depression. Across five decades (age 21-69), depressed men had less slow-wave sleep than did depressed women. Gender differences were small with respect to visually scored measures of slow-wave sleep time and percent, but moderate for gender differences in automated measures of slow-wave density. The time constant of the polygraph preamplifier significantly affected both visually scored and automatically scored slow-wave sleep. Other measures such as REM sleep latency, first REM period duration, sleep efficiency, and early morning awakening, showed robust age effects, but no main effects for gender or gender-by-age interactions. Gender effects on slow-wave sleep and delta-wave counts in depression parallel gender effects seen in healthy aging. The possibility of occult alcohol use by depressed male outpatients cannot be definitely excluded as a partial explanation of the current findings. However, covarying for past alcohol abuse did not negate the statistical significance of the observed gender effects on slow-wave sleep and delta-wave density. The possibility of gender differences in slow-wave regulatory mechanisms is suggested, but similarity in temporal distribution of delta-wave density between the first and second non-rapid-eye-movement (NREM) periods does not support gender differences in slow-wave sleep regulation.

EEG sleep, depression, and aging.

To date little attention has been paid to the possible age-dependent relationships of EEG sleep measures in depression or to the implications of such relationships for diagnostic sensitivity and specificity. In a study of 108 patients with major depressive disorders (67 inpatients, 41 outpatients), age was shown to be a very powerful determinant of electroencephalographic (EEG) sleep patterns. Thus, among other sleep variables, sleep efficiency, delta sleep percent, and REM latency all showed significant linear declines with increasing age. Similar trends were seen in both inpatients and outpatients. Some variables were without age trends (age-stable), including sleep latency, REM sleep percent, and REM activity. These findings confirm those of an earlier report from our laboratory [45] and suggest that age-corrected sleep variables can be developed for clinical diagnostic application. Thus, using normative data from Gillin et al. [19] for comparison, a sensitivity level of 65% for age-corrected REM latency was demonstrated, together with a specificity of 95% and a diagnostic confidence of 92%. Data from a pilot study comparing EEG sleep measures in depression and dementia are also presented; these data suggest the potential utility of EEG sleep measures in the differential diagnosis of these two disorders, especially in patients with mixed symptoms. Additional areas for further research are reviewed with enumeration of specific testable hypotheses.

Differential effects of amitriptyline and of zimelidine on the sleep electroencephalogram of depressed patients.

The effects of amitriptyline (n = 14) or zimelidine (n = 13) on the sleep electroencephalogram of hospitalized depressed patients were assessed in a double-blind protocol involving 28 days of active dosing. Zimelidine induced no immediate improvement in sleep continuity, and even after 3 wk on zimelidine subjects tended to have longer sleep latency, more awakenings, and lighter non-rapid eye movement (REM) sleep than before taking the drug. Zimelidine did, however, induce a rapid and persistent alteration of sleep architecture and selected REM measures. REM sleep, which was suppressed over the first two nights on zimelidine, was maximally suppressed after 1 wk, but by 3 wk there was some tolerance for selected REM measures. While zimelidine induced none of the sedative effects of amitriptyline, both were equivalent in their REM-suppressant effects. These findings are discussed in terms of the differences in uptake blockade and anticholinergic potency in these two drugs.

Subtyping DSM-III-R primary insomnia: a literature review by the DSM-IV Work Group on Sleep Disorders.

OBJECTIVE: The authors review the usefulness, reliability, and validity of recently proposed subtypes of primary insomnia. DSM-III uses "primary insomnia" to indicate chronic insomnia not associated with other diagnosable mental or medical disorders, whereas the International Classification of Sleep Disorders (ICSD) recognizes three subtypes: psychophysiological insomnia, idiopathic insomnia, and sleep state misperception. METHOD: After reviewing all of the primary source references for each insomnia disorder in the ICSD and all of the additional primary sources cited in each of these, the authors conducted an automated literature search using Medline. Of the 48 primary sources located, the authors selected 27 studies that were reported in peer-reviewed journals, had the largest available subject groups, used diagnostic reliability procedures, and included control groups. RESULTS: The studies reviewed contained limited empirical support for the proposed distinction between idiopathic and psychophysiological insomnia. Sleep state misperception appears, however, to be a highly prevalent feature of chronic insomnia generally, rather than only a specific disorder per se. CONCLUSIONS: The authors conclude that there is not yet sufficient empirical evidence to warrant the abandonment of DSM-III-R "primary insomnia" and the adoption of the ICSD subtypes in DSM-IV. However, they affirm the heuristic value of the ICSD subtypes and the need for field trials to compare the performance characteristics of the DSM-III-R and ICSD systems with respect to 1) interrater reliability, 2) effects of rater expertise (generalist versus specialist) on rates of agreement, and 3) effects of polysomnographic data on rates of agreement.

Sleep and treatment prediction in endogenous depression.

The prediction of clinical response in depression has been based primarily on clinical symptoms and history. Recently, psychobiologic measures have been used to increase the accuracy of clinical prediction. In 34 drug-free patients with primary endogenous depression treated with amitriptyline, the application of EEG-monitored sleep criteria alone was more significant than clinical status alone in the prediction of clinical response. Prolonged REM latency and reduced difficulty in sleep onset following the administration of amitriptyline were the main sleep variables contributing to this prediction equation. These data suggest a strong relationship between clinical outcome and psychobiologic profile in patients with endogenous depression after a "pharmacologic probe" with a tricyclic antidepressant.

Persistent psychophysiologic insomnia: preliminary Research Diagnostic Criteria and EEG sleep data.

Some patients with persistent psychophysiologic insomnia have a history of generalized anxiety, minor depression, or drug misuse. Their sleep resembles sleep of patients with generalized anxiety (except for night 2 improvement in the insomniacs' sleep continuity) but differs from sleep of patients with major depression.

EEG sleep evaluation of depression in borderline patients.

In this study the sleep of borderline patients and patients with primary nondelusional depression showed sleep continuity disturbance and greater REM activity and density (particularly during the first REM period) than that of normal control subjects. First-night REM latencies were more variable in the borderline than in the depressed group, but by the second night both groups showed shorter REM latencies than the controls. The similarities in EEG sleep suggest a relationship between borderline disorder and the affective spectrum and cast doubt on the definition of the borderline disorder as a pure character type.

EEG sleep alterations in olivopontocerebellar degeneration.

All-night polygraphic recordings of the electroencephalogram, horizontal electrooculogram, and submental electromyogram were performed in two patients with familial olivopontocerebellar degeneration. Sleep was characterized by subnormal measurements of both rapid eye movement (REM) and delta (slow-wave) sleep. Phasic eye movements were reduced out of proportion to tonic components of REM sleep. These findings lend further support to theories linking the pontine nuclei to the primary regulation of sleep in both experimental animals and humans.

Electroencephalographic sleep of healthy children. Part II: Findings using automated delta and REM sleep measurement methods.

Using earlier developed computer-based measurement methods, delta and REM activity were examined during sleep as a function of age, gender, and time of night in 85 healthy, 6- to 16-year-old children. Chronological age was found to account most strongly for differences in automated delta and REM count measures in this age range. Increasing age was shown to be associated with a significant decline in both automated measures, but the effect was much greater for the delta count measure. The age-related decline in delta wave activity was reflected primarily in a linear decline in 2.0-3.0 Hz delta activity, that is, in the faster end of the delta frequency band. Examination of these measurements in successive NREM and REM sleep periods confirmed that, in children as in adults, delta activity decreases and REM activity increases across the night. Findings are discussed relative to those obtained in the same children using standard measurement methods.

EEG sleep of normal healthy children. Part I: Findings using standard measurement methods.

Despite the increasing application of all-night electroencephalographic (EEG) sleep studies to children for clinical as well as for research purposes, readily available normal EEG sleep standards for the period of childhood have remained sparse and, at present, reflect data on only approximately 100 children 6 to 16 years of age. As part of a large scale study examining various aspects of EEG sleep among children, findings derived using standard recording and scoring methods are reported for a new sample of nearly 100 normal, healthy children and are compared with existing standards. Data obtained add substantially to the existing database and generally confirm findings of previous normative reports on children in this age range.

Concordance between habitual sleep times and laboratory recording schedules.

The validity of laboratory-based studies of sleep depends, in part, upon good concordance between habitual sleep schedule and laboratory recording schedule. Without good concordance, error variance due to the circadian misplacement of sleep and to different amounts of time in bed is probable. In an assessment of scheduling concordance in 1,762 research patient nights over two time intervals, we observed good concordance (< 30-minute discrepancy) in 71.2-77.3% of bedtimes and waketimes, discrepancy (difference of > or = 30 minutes) in 14.9-24.2% of bedtimes and waketimes, and missing data in 4.6-7.5% of times. Waketime differences were consistently in the direction of earlier laboratory than habitual waketimes, whereas differences in bedtime were about equally divided between earlier and later (laboratory vs. habitual). Subjects with schedule discordance averaged 19.5 minutes less time in bed during laboratory sessions as compared with their habitual sleep schedule, whereas subjects with schedule concordance averaged only 3.6 minutes less (p < 0.001). Our experience suggests that it may be more difficult to achieve higher rates of concordance among young adult and middle-aged subjects than among elders and that patient requests related to external constraints on scheduling were a frequent reason for discrepancy. We strongly recommend a policy of routinely including data on laboratory versus habitual sleep times in peer-reviewed publications.

Diagnostic classification of sleep disorders: implications for psychiatric practice.

We have applied a diagnostic classification of sleep and arousal disorders (Association of Sleep Disorders Centers - ASDC) to a group of 174 patients in order to assess its usefulness. In our population, there were over twice as many disorders of initiating and maintaining sleep (DIMS) as there were disorders of excessive sleepiness (DOES). We found that 68.1% of diagnoses in DIMS were psychiatric (particularly affective disorders) and that 37.8% of diagnoses in DOES were either sleep apnea or narcolepsycataplexy. Furthermore, drug/alcohol abuse was much more strongly associated with DIMS, while medical disorders were more often found to be associated with DOES. Since only 58% of our sample could be adequately classified with one diagnosis, we expect that the ASDC nosology will need to evolve further. Nevertheless, the nosology should facilitate comparability and pooling of data across centers.