EEG sleep in depressed adolescents

Sleep disturbances, including disturbances in REM sleep, are common among depressed adults; it is unclear if the same is true for depressed adolescents. The authors monitored the sleep of 13 depressed adolescents and 13 normal age-matched controls. They found that, as with depressed adults, REM latency was significantly shorter and REM density significantly greater in the depressed group. There was no correlation between reduced REM latency and severity of depression, but there was a significant negative correlation between REM latency and age.     

Temporal coherence in ultradian sleep EEG rhythms in a never-depressed, high-risk cohort of female adolescents.

BACKGROUND: Previous work has indicated that low temporal coherence of ultradian sleep electroencephalographic rhythms is characteristic of depressed patients and of depressed women, in particular. It may also be evident in one quarter of those at high risk, based on a family history of depression. METHODS: The present study evaluated temporal coherence of sleep electroencephalographic rhythms in 41 adolescent girls with a maternal history of depression (high risk) and 40 healthy controls (low risk). The entire sample was followed clinically every 6 months for 2 years. RESULTS: Temporal coherence was significantly lower among the high-risk girls than in controls. Regression analyses predicted group from coherence values and correctly classified 70% of the high-risk group with a false-positive rate of 5% among controls. Moreover, 54% of the high-risk girls were identified with extreme low coherence. On clinical follow up, 14 girls showed depressive symptoms, 9 in the high-risk group (22.5%) and 5 controls (12.2%). Six met DSM-IV criteria for first-episode major depressive disorder, five high-risk and one control. Most importantly, 41% of those identified as having the most abnormal coherence values either showed symptoms of depression or met diagnostic criteria upon follow up. CONCLUSIONS: Low temporal coherence is evident in adolescent girls at high risk for depression. The more abnormal the coherence, the greater the risk of a first episode of major depressive disorder within 2 years of sleep study, approximately 10 times greater than in controls.     

Sleep EEG findings in depressed children and adolescents

Sleep polysomnographic data on 17 juveniles (age 9 to 14) with major depression revealed abnormalities similar to those in depressed adults.     

Ultradian sleep rhythms of lateral EEG, autonomic, and cardiovascular activity are coupled in humans

This study compared the dynamics of multiple systems during sleep with earlier results during waking rest. Three consecutive nights of data were collected from three healthy adults for 10 variables: left and right central EEGs; the nasal cycle (NC); beat-to-beat measures of CO, SV, HR, SBP, DBP, MAP, and hemoglobin-oxygen saturation. Time series analysis detected periods at 280-300, 215-275, 165-210, 145-160, 105-140, 70-100, and 40-65 min bins with the greatest spectral power in longer periods. We found significance across subjects with all parameters at 280-300, 105-140 (except left EEG power, left minus right EEG power, and HR), 70-100, and 40-65 min. Significant periods were reported earlier during waking for the NC, pituitary hormones, catecholamines, insulin, and cardiovascular function in five bins at 220-340, 170-215, 115-145, 70-100, and 40-65 min, with 115-145, 70-100, and 40-65 min common across all variables. These results suggest that lateral EEG power during sleep has a common pacemaker (the hypothalamus), or a mutually entrained pacemaker, with the cardiovascular and autonomic nervous systems (ANS), and that the waking ultradians of the neuroendocrine and fuel regulatory hormones may also be coupled to lateral EEG activity. Taken together these results present a new perspective for the Basic Rest-Activity Cycle and the physiology of the ANS-central nervous system during both waking and sleep.     

Cerebral rhythms and temporal coherence

Some studies of scalp-conducted human EEG show a positive correlation between the temporal coherence of prestimulus activity in the theta, alpha, and beta passbands, on the one hand, and both target probability and subjective self-report about good performance, on the other. There remains an important ambiguity in these data: Are these changes in temporal coherence merely a reflection of changes in subjective relaxation, or do they index the timing of neural network convergences to terminal attractors? Other studies of human EEG during temporal conditioning paradigms suggest that the second alternative can be rigorously tested.     

Ultradian rhythms in pituitary and adrenal hormones: their relations to sleep

Sleep and circadian rhythmicity both influence the 24-h profiles of the main pituitary and adrenal hormones. From studies using experimental strategies including complete and partial sleep deprivation, acute and chronic shifts in the sleep period, or complete sleep-wake reversal as occurs with transmeridian travel or shift-work, it appears that prolactin (PRL) and growth hormone (GH) profiles are mainly sleep related, while cortisol profile is mainly controlled by the circadian clock with a weak influence of sleep processes. Thyrotropin (TSH) profile is under the dual influence of sleep and circadian rhythmicity. Recent studies, in which we used spectral analysis of sleep electroencephalogram (EEG) rather than visual scoring of sleep stages, have evaluated the temporal associations between pulsatile hormonal release and the variations in sleep EEG activity. Pulses in PRL and in GH are positively linked to increases in delta wave activity, whereas TSH and cortisol pulses are related to decreases in delta wave activity. It is yet not clear whether sleep influences endocrine secretion, or conversely, whether hormone secretion affects sleep structure. These well-defined relationships raise the question of their physiological significance and of their clinical implications.     

Paroxetine pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of paroxetine in children and adolescents and to explore the role of genetic polymorphisms in paroxetine pharmacokinetics. METHOD: Thirty depressed youths were enrolled. Samples for phenotyping with respect to cytochrome P450 2D6 (CYP2D6) and catechol-O-methyltransferase were collected. A single 10-mg dose of paroxetine was then administered followed by 5 days of blood and urine collection for pharmacokinetic analyses. Subjects subsequently received open treatment for 8 weeks, and weekly blood samples were obtained for plasma concentration measurements. RESULTS: There was tremendous interindividual variability in paroxetine disposition. The mean half-life of paroxetine was 11.1 +/- 5.2 (SD) hours. The average clearance was 88.7 +/- 66.4 mL/min/kg. The mean area under the plasma drug concentration curve was 0.09 +/- 0.10 microgram/mL.hr. Within-subject variability of plasma paroxetine concentrations was generally not significant. Clearance and fractional urinary excretion of paroxetine were found to correlate with CYP2D6 activity. Two subjects developed hypomania necessitating drug discontinuation. No clinically significant changes in any safety assessments were noted. CONCLUSIONS: Paroxetine is more rapidly cleared in youths than adults and may be given once daily in this population. Short-term treatment with paroxetine appears safe and well tolerated in this relatively small sample of pediatric patients.     

Premorbid polysomnographic signs in depressed adolescents: a reanalysis of EEG sleep after longitudinal follow-up in adulthood.

BACKGROUND: This is a report of a clinical follow-up study (10-15 years later as young adults) of adolescent major depressives and normal control subjects. Polysomnographic data were obtained during the original study period when the subjects were adolescent (time 1). With clinical follow-up (time 2) assessments in hand, our objective was to ascertain whether there were any premorbid polysomnographic signs associated with depression during adolescence. METHODS: Based upon initial (during adolescence) and follow-up clinical assessments (as adults), new subject groupings were generated: depression-free normal subjects and original normal subjects who experienced a depressive episode during the follow-up period (latent depressives). Suicidality and recurrence of depression were also examined. Multivariate analysis of covariance was used to analyze group differences in sleep measures and logistic regression for predicting three outcomes: lifetime depression, lifetime suicidality, and recurrence. RESULTS: Comparison of the depression-free normal subjects, the latent depressives, and the original major depressives revealed significant differences for sleep latency and sleep period time. Comparing all lifetime depressives (original major depressives and the latent depressives) to depression-free normal subjects revealed significantly more stages 3 and 4 combined (ST34) sleep and greater sleep period times among the depressives. An analysis involving the presence or absence of suicidality revealed no overall significant differences between the groups. Comparison of the lifetime depressives grouped by nonrecurrent and recurrent depressive course to the depression-free normal subjects revealed significant difference for sleep period time. Using logistic regression, we found that a longer sleep latency and sleep period time significantly predicted lifetime depression. Gender, ST34 sleep, and an interaction term for ST34 sleep and REM latency significantly predicted lifetime suicidality. CONCLUSIONS: There was evidence of premorbid sleep abnormalities during adolescence. A general pattern of sleep disruption around sleep onset and during the first 100 min of the sleep period and overall sleep was evident among the major and lifetime depressives, involving sleep latency (initial insomnia), sleep period time (hypersomnia), REM latency, and slow-wave sleep. This adds to the body of literature that highlights the importance of the first 100 min of the sleep period in depression.     

Pharmacotherapy in depressed children and adolescents

In children and adolescents, antidepressants are used in the treatment of depressive symptoms and several other psychiatric conditions. In the treatment of mild and moderate depressive symptoms, non-pharmacological approaches such as psychotherapy play a major role, a severe symptomatology may demand a combination with antidepressants. As first-choice medication for the treatment of juvenile depression, the selective serotonin reuptake inhibitor (SSRI) fluoxetine is recommended, due to its efficacy and approval. As second-choice antidepressants the SSRIs sertraline, escitalopram and citalopram might be used. Other antidepressants - such as tricyclic antidepressants, α(2)-adrenoceptor antagonists, selective noradrenalin reuptake inhibitors (SNRI) - may be alternatively used, but not as first- or second-choice medications. In the case of "off-label" use, patients and parents have to be carefully informed prior to the start of medication, after a thorough risk-benefit analysis. In the following overview we address a general framework, therapeutic strategies and the issues of antidepressant pharmacotherapy for the treatment of unipolar depression in childhood and adolescence.     

Platelet imipramine binding in depressed children and adolescents.

Kinetic constants of platelet imipramine binding were determined in youths with major depression, and a contrast group. Subjects actively depressed (N = 10) had significantly fewer imipramine binding sites (Bmax) (877 +/- 148 fmol/mg protein) than recovering depressives (N = 12) (1220 +/- 428 fmol/mg protein) and contrasts (N = 10) (1270 +/- 230 fmol/mg protein). Affinity constants (Kd) (1.14 +/- 0.36 nM, 0.97 +/- 0.31 nM, and 1.17 +/- 0.39 nM, respectively) were similar among the groups. Actively depressed males but not females had fewer imipramine binding sites than both their sex-matched comparison groups. Although actively depressed females' Bmax was significantly lower than recovering depressed and nondepressed males, neither age, Tannner stage, nor circannual rhythms influenced Bmax, but suicidality may be associated with low Bmax. A decrease in Bmax may be a state-specific marker of major depression in boys or associated with a depressive disorder with a suicidal history.     

Ultradian rhythms of alternating cerebral hemispheric EEG dominance are coupled to rapid eye movement and non-rapid eye movement stage 4 sleep in humans

Objective: To replicate the left minus right (L−R) hemisphere EEG power shifts coupled to rapid eye movement (REM) and non-rapid eye movement (NREM) sleep observed in 1972 by Goldstein (Physiol Behav (1972) 811), and to characterize the L−R EEG power spectra for total EEG, delta, theta, alpha and beta bands.Background: Ultradian alternating cerebral hemispheric dominance rhythms are observed using EEG during both waking and sleep, and with waking cognition. The question of whether this cerebral rhythm is coupled to the REM–NREM sleep cycle and the basic rest–activity cycle (BRAC) deserves attention.Methods: L−R EEG signals for ten young, normal adult males were converted to powers and the means were normalized, smoothed and subtracted. Sleep hypnograms were compared with L−R EEGs, and spectra were computed for C3, C4 and L−R EEG powers.Results: Significant peaks were found for all C3, C4 and L−R frequency bands at the 280–300, 75–125, 55–70 and 25–50 min bins, with power dominating in the 75–125 min bin. L−R EEG rhythms were observed for all bands. Greater right hemisphere EEG dominance was found during NREM stage 4 sleep, and greater left during REM for total EEG, delta and alpha bands (Chi-squares, P<0.001). Theta was similar, but not significant (P=0.163), and beta was equivocal.Conclusions: Earlier ultradian studies show that lateral EEG and L−R EEG power have a common pacemaker, or a mutually entrained pacemaker with the autonomic, cardiovascular, neuroendocrine and fuel-regulatory hormone systems. These results for L−R EEG coupling to sleep stages and multi-variate relations may present a new perspective for Kleitman's BRAC and for diagnosing variants of pathopsychophysiological states.     

Nefazodone pharmacokinetics in depressed children and adolescents

OBJECTIVE: To describe the pharmacokinetics and safety of nefazodone (NFZ) in depressed children and adolescents. METHOD: Depressed youths aged 7 to 17 years were eligible to participate. Intensive sampling for pharmacokinetic analyses of NFZ and 3 of its active metabolites was performed after single and multiple dose administration. Treatment was continued for 6 more weeks and titrated to maximize clinical response. RESULTS: Twenty-eight patients were enrolled. Systemic exposure to NFZ and 3 metabolites was generally higher in children than adolescents. NFZ and metabolite disposition profiles showed high intra- and interpatient variability. Compared to published data in adults, the half-life of NFZ and 2 of its metabolites appears shorter in children and adolescents. Meta-chlorphenylpiperazine pharmacokinetic parameters were different in 5 patients determined to be poor metabolizers of cytochrome P450 2D6 (CYP2D6). NFZ was well tolerated, and administration was associated with significant reductions (p < .001) in depressive symptoms. CONCLUSIONS: The pharmacokinetics of NFZ in pediatric patients is highly variable. NFZ appears to be safe in this small, short-term study. Pediatric patients who are poor metabolizers of CYP2D6 do not appear to be at increased risk for NFZ-associated adverse events. Open-label treatment of NFZ is associated with reductions in depressive symptoms.     

Correlation between EEG rhythms during sleep: surface versus mediotemporal EEG

We compared surface and intracranial electroencephalogram recordings of mediotemporal structures. These structures are critically involved in declarative memory formation and memory consolidation during sleep. As memory processing is suggested to involve the interplay between fast and slow oscillations, we hypothesized different correlations between frequency bands in surface versus mediotemporal electroencephalogram recordings. Polysomnographic recordings obtained in 10 patients with unilateral temporal lobe epilepsy were analyzed. In accordance with earlier studies, we observed that power density in surface electroencephalogram is organized reciprocally between delta/theta and fast frequencies above 16 Hz during non-rapid-eye-movement sleep (negative correlations). In contrast, we found that within the hippocampus delta/theta power alternated in parallel with fast oscillations above 16 Hz during non-rapid-eye-movement sleep (positive correlations).     

EEG power and coherence in children with educational problems.

SUMMARY: SUMMARY This study deals with the quantitative EEG (QEEG) of children attending schools for the mentally retarded and learning disabled. Questions are in which way do the EEGs of these children differ from normal development and whether deviations are restricted to a subgroup of children. The topographic distribution of EEG power is of particular interest. Based on a sample of n = 158 normal children, age-standardized values of absolute power (delta, theta, alpha 1, alpha 2, beta 1, beta 2 at F4, F3, C4, C3, CZ, PZ, O2, O1) and of coherence are computed for all children. The topographic distribution is assessed by analysis of variance (ANOVA) and by a principal component approach. The EEG of children with educational problems differs substantially from normal development in the slow bands and differs less in the fast bands. Deviations affect a subgroup of children, mainly children attending a school for the mentally retarded. Topographic distribution is an important factor in all bands. Coherence analysis leads to rather weak results that lack a clear interpretation. The QEEG is useful for understanding neurophysiological development in children with educational problems as a group more than individually. Parameters of topographic distribution provide strong additional information to power itself.     

Changes in EEG power density during sleep laboratory adaptation in depressed inpatients.

BACKGROUND: The aim of the present study was to evaluate the first-night effect in depressed inpatients, using standard sleep measures as well as all-night spectral analysis of the sleep electroencephalogram (EEG). METHODS: Eighteen drug-free, depressed inpatients were studied for 3 consecutive nights in the hospital sleep laboratory. RESULTS: Visual sleep scoring results showed a slight but measurable first-night effect, characterized by a reduction of rapid eye movement (REM) sleep amount and increased wakefulness. Sleep EEG spectral analysis showed significantly reduced delta (p <.01) and theta (p <.05) power density in non-REM (NREM) sleep of the first night compared with that of the second and third nights. These differences were limited to the early part of the sleep period, a time during the night that is particularly vulnerable to the effects of depressive disorder. In contrast to the NREM sleep findings, spectral REM variables studied did not significantly vary across the three nights. CONCLUSIONS: The results obtained suggest that first-night data should not be simply discarded but could be used in subsequent analyses and could be considered useful in the evaluation of the sleep of depressed patients.     

EEG sleep in elderly depressed, demented, and healthy subjects

In a prospective study of EEG sleep patterns in 25 elderly depressives, 25 elderly demented patients, and 25 healthy, elderly control subjects, the sleep of depressives was characterized by reduced REM sleep latency, increased REM percent and first REM period density, and altered temporal distribution of REM sleep, as well as by diminished sleep maintenance (correlated significantly with Hamilton ratings of depression: multiple R = -0.42, p less than 0.05). In contrast, the sleep of demented patients showed reduced REM sleep percent, but normal REM temporal distribution, increased loss of spindles and K-complexes (the latter correlating significantly with severity of cognitive impairment as measured by the Folstein score: multiple R = -0.59, p less than 0.01), and less severe sleep maintenance difficulty than for depressives. An examination of REM latency demonstrated a skewed distribution in depression (i.e., 42% of nights with sleep-onset REM periods), but a normal distribution in the controls and demented subjects. A REM latency cut-off score of 30 min correctly classified 68% of all patients (kappa = 0.36; p less than 0.005), compared with 78% correctly identified in our retrospective study (Reynolds et al. 1983).     

Sleep and sleep disorders in children and adolescents.

Pediatric sleep disorders are common, affecting approximately 25% to 40% of children and adolescents. Although there are several different types of sleep disorders that affect youth, each disorder can have a significant impact on daytime functioning and development, including learning, growth, behavior, and emotion regulation. Researchers are only beginning to uncover the interaction between sleep and psychiatric disorders in children and adolescents, including depression, attention-deficit/hyperactivity disorder, and autism. This article reviews normal sleep and sleep disorders in children and adolescents, the assessment of sleep in pediatric populations, common pediatric sleep disorders, and sleep in children who have common psychiatric disorders.     

Cortisol hypersecretion in depressed school-aged children and adolescents

A prospective longitudinal study has been carried out to determine the secretory pattern of cortisol in children (n = 10) with major depressive disorder. Salivary cortisol samples were collected at 4-hourly intervals over 24 hours when the subjects were depressed and again when they were recovered. Group comparison indicated that significant increases in mean cortisol output occurred during illness as compared with recovery. This difference occurred only at three points (midnight, 4 a.m., 8 a.m.) of six measured. Not all cases were showed hypersecretion, but when hypersecretion was present, it occurred in cases with more severe symptoms. In addition, marked differences existed within individuals in the depressed state vs. the recovered state. Hypersecretion appeared to be associated with a significant alteration in diurnal rhythm in some, but not all, cases. The degree of cortisol responsivity and the shape of the curve over 24 hours during the depressed state deserve further investigation and may have implications for the course and outcome of major depression in this age group.