Circadian phase in adults of contrasting ages.

There is evidence that aging may impair phase-shifting responses to light synchronizers, which could lead to disturbed or malsynchronized circadian rhythms. To explore this hypothesis, 62 elder participants (age, 58 to 84 years) and 25 young adults (age, 19 to 40 years) were studied, first with baseline 1-wk wrist actigraphy at home and then by 72 h in-laboratory study using an ultra-short sleep-wake cycle. Subjects were awake for 60 minutes in 50 lux followed by 30 minutes of darkness for sleep. Saliva samples were collected for melatonin, and urine samples were collected for aMT6s (a urinary metabolite of melatonin) and free cortisol every 90 minutes. Oral temperatures were also measured every 90 minutes. The timing of the circadian rhythms was not significantly more variable among the elders. The times of lights-out and wake-up at home and urinary free cortisol occurred earlier among elders, but the acrophases (cosinor analysis-derived peak time) of the circadian rhythm of salivary melatonin, urinary aMT6s, and oral temperature were not significantly phase-advanced among elders. The estimated duration of melatonin secretion was 9.9 h among elders and 8.4 h among young adults (p < 0.025), though the estimated half-life of blood melatonin was shorter among elders (p < 0.025), and young adults had higher saliva melatonin and urinary aMT6s levels. In summary, there was no evidence for circadian desynchronization associated with aging, but there was evidence of some rearrangement of the internal phase-angles among the studied circadian rhythms.

Long-term follow-up of sleep disordered breathing in older adults.

OBJECTIVE: The current study was designed to determine whether, with increasing age, sleep apnea improves, becomes worse, or stays the same. BACKGROUND: There is a high prevalence of sleep disordered breathing (SDB) in older adults, but little is known about longitudinal changes. This study followed older adults to examine the natural history of SDB. METHODS: Subjects were randomly selected community-dwelling elderly (n=427). A subset of subjects was studied approximately every 2 years over an 18-year period. Overnight sleep recordings and sleep questionnaires were completed at each time point. RESULTS: Multiple linear regression showed that three variables were associated with change in respiratory disturbance index (RDI):body mass index (BMI) at initial visit (P=0.001), change in BMI (P=0.02), and a consistent self-report of high blood pressure (P=0.005). RDI increase was associated with BMI increase and presence of self-reported high blood pressure. CONCLUSIONS: The changes in RDI that occurred were associated only with changes in BMI and were independent of age. This underscores the importance of managing weight for older adults, particularly those with hypertension.

An open-label, 12-week clinical and sleep EEG study of nefazodone in chronic combat-related posttraumatic stress disorder.

BACKGROUND: We examined the effects of nefazodone on polysomnographic sleep measures and subjective reports of sleep quality and nightmares. as well as other symptoms, in patients with chronic combat-related posttraumatic stress disorder (PTSD) during a 12-week, open-label clinical trial. To our knowledge, this is the first polysomnographic study of treatment in patients with PTSD. METHOD: The subjects were 12 male veterans (mean age = 54 years) who met DSM-IV diagnostic criteria for PTSD (mean duration = 30 years). All but I patient also met DSM-IV criteria for major depressive disorder. Patients were evaluated weekly with clinical ratings in an open-label clinical trial. Polysomnographic recordings for 2 consecutive nights were obtained before treatment and at 2, 4, 8, and 12 weeks. The dose of nefazodone was adjusted according to individual clinical needs. Final mean daily dose was 441 mg. RESULTS: The patients reported significantly fewer nightmares and sleep problems during treatment. Nevertheless, contrary to studies in depressed patients, nefazodone did not significantly affect polysomnographic sleep measures compared with baseline. In addition, the patients showed significant improvement in the Clinical Global Impressions of PTSD symptoms (global score, hyperarousals and intrusions subscales), the Clinician-Administered PTSD Scale (global, hyperarousal, and intrusions subscales), the Hamilton Rating Scale for Depression (HAM-D). and the Beck Depression Inventory (BDI). CONCLUSION: These patients with chronic, treatment-resistant, combat-related PTSD showed significant improvement of subjective symptoms of nightmares and sleep disturbance, as well as depression and PTSD symptoms. in this 12-week open-label clinical trial. Nevertheless, objective polysomnographic sleep measures did not change. Further studies, including double-blind. placebo-controlled trials, are needed to extend these findings and to understand the relationships between the physiology of sleep and symptoms of poor sleep and nightmares.

Circadian rhythms of agitation in institutionalized patients with Alzheimer's disease.

Agitation is a common problem in institutionalized patients with Alzheimer's disease (AD). "Sundowning," or agitation that occurs primarily in the evening, is estimated to occur in 10-25% of nursing home patients. The current study examined circadian patterns of agitation in 85 patients with AD living in nursing homes in the San Diego, California, area. Agitation was assessed using behavioral ratings collected every 15 minutes over 3 days, and activity and light exposure data were collected continuously using Actillume recorders. A five-parameter extension of the traditional cosine function was used to describe the circadian rhythms. The mean acrophase for agitation was 14:38, although there was considerable variability in the agitation rhythms displayed by the patients. Agitation rhythms were more robust than activity rhythms. Surprisingly, only 2 patients (2.4%) were "sundowners." In general, patients were exposed to very low levels of illumination, with higher illumination during the night being associated with less robust agitation rhythms with higher rhythm minima (i.e., some agitation present throughout the day and night). Seasonality was examined; however, there were no consistent seasonal patterns found. This is the largest study to date to examine agitation rhythms using behavioral observations over multiple 24 h periods. The results suggest that, although sundowning is uncommon, agitation appears to have a strong circadian component in most patients that is related to light exposure, sleep, and medication use. Further research into the understanding of agitation rhythms is needed to examine the potential effects of interventions targeting sleep and circadian rhythms.

Illumination levels in nursing home patients: effects on sleep and activity rhythms.

Studies examining levels of illumination in adult populations have demonstrated that the level and amount of light exposure are lower in the elderly compared with younger adults, particularly in institutionalized patients with dementia. Although insufficient light exposure has been implied as a cause of sleep fragmentation, evidence for such a relationship is scant. Sixty-six institutionalized elderly had their activity and light exposure monitored for a 3-day period. Mean and median light levels, minutes spent over 1000 and over 2000 lux, percent sleep and wake, and number of naps were computed for daytime intervals, defined as 07.00-18.59. Percentages of sleep and wake, number of awakenings and mean duration of wake periods were computed for night-time intervals, defined as 22.00-05.59. Mesor, amplitude and acrophase of activity and of light were determined by cosinor analysis. A mixed linear model was used to assess the effects of daytime Actillume measures on subsequent night-time measures, and vice versa. Spearman correlations were computed, and multiple regression analyses were carried out with light variables and dementia level as predictors and sleep-wake and activity measures as dependent variables. The median light level was 54 lux and a median of only 10.5 min were spent over 1000 lux. Higher light levels predicted fewer night-time awakenings, and severe dementia predicted more daytime sleep and lower mean activity. Increased bright light exposure predicted later activity acrophase. There was an association between the acrophases of light and of activity, with maximum illumination preceding peak activity. These results suggest that daytime light exposure has an impact on both night-time sleep consolidation and timing of peak activity level.

Circadian rhythm of vital signs, norepinephrine, epinephrine, thyroid hormones, and cortisol in schizophrenia.

Changes in the circadian rhythmicity in vital signs, catecholamines, thyroid hormones, and cortisol have been observed in psychiatric disorders, most notably in depression. With respect to schizophrenia, the literature is scanty. We report here on the circadian parameter estimates of the vital signs, epinephrine, norepinephrine, triiodothyronine, thyroxine, thyroid stimulating hormone, and cortisol in the blood of 34 healthy subjects, 89 drug-free schizophrenic patients, and 25 neuroleptic-treated schizophrenic patients. The analyses are based on the cosine model to fit the experimental data. The circadian profiles of heart rate, blood pressure, and oral temperature are similar among schizophrenic patients and healthy subjects. Neuroleptic-treated patients have significantly higher MESORs (the daily mean) of serum norepinephrine and epinephrine than healthy subjects. The TSH MESOR is significantly lower in schizophrenic patients; the MESOR of triiodothyronine also shows a tendency to be nonsignificantly lower in schizophrenic patients compared with control subjects. The circadian serum thyroxine and cortisol profiles are similar in the three groups. The data show that the circadian profiles of vital signs in drug-free chronic schizophrenic patients who are not chronically hospitalized are similar to those of healthy subjects and that the increase in serum catecholamines and the apparent lowering in some thyroid indices might induce a down-regulation in the noradrenergic receptor system that could contribute to the pathophysiology of schizophrenia.

Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia.

Circadian rhythm abnormalities have been described mostly with respect to manic-depressive illness; little information is available concerning circadian rhythms and schizophrenia or their influence on neuroleptic drugs. We showed previously that the MESOR of dopamine is higher in schizophrenic patients than in healthy subjects and that women who are drug-free schizophrenic have lower prolactin MESORs and lower amplitudes than healthy women. We now report the data of a cosinor analysis of tryptophan, serotonin, melatonin, and pituitary hormones in the blood of 34 healthy subjects, 90 drug-free schizophrenics, and 25 neuroleptic-treated schizophrenic patients. This data indicated a significant phase advance of serum tryptophan, prolactin, and melatonin concentrations, a trend toward a phase advance in serotonin. Thyroid stimulating hormone (TSH), and growth hormone concentrations, and decreases in the TSH MESORs among patients compared to healthy subjects. These results suggest that circadian changes, such as phase advances and alterations in MESOR, are not only present in depression but also in schizophrenia. Although neuroleptic treatment raised the prolactin MESOR and amplitude, it did not elicit any change in circadian rhythmicity among the other parameters.

Hyperdopaminergia in schizophreniform psychosis: a chronobiological study.

Circadian rhythm abnormalities have been described in various psychiatric disorders, but they have not received much attention in studies of schizophrenia and schizophreniform psychosis. The present study used the cosine model to determine the circadian patterns of amino acids, dopamine, and prolactin concentrations, which were analyzed over a 24-hour period in serum of healthy subjects, drug-free schizophrenic patients, and neuroleptic-treated schizophrenic patients. The mesor (the daily mean) of phenylalanine was lower in drug-free schizophrenic women than in healthy women. The mesors of the ratio of phenylalanine or tyrosine to competing amino acids were similar in healthy subjects and patients. The ratio of phenylalanine/competing amino acids showed a phase advance (i.e., earlier onset of the time of highest concentration) in drug-free patients compared with healthy subjects. Schizophrenic patients displayed a higher dopamine mesor than healthy subjects. Female drug-free schizophrenic patients had lower prolactin mesors and lower amplitudes (i.e., half of the total predictable change in rhythm) than healthy women. Compared with healthy subjects, schizophrenic patients showed a phase advance of circadian prolactin concentrations. Neuroleptics raised the prolactin mesor and amplitudes but did not elicit any phase change in amino acids, dopamine, or prolactin. These data confirm the indirect pharmacologic evidence of increased dopaminergic activity in schizophrenic patients that relates to dopamine's precursors and to the neuroendocrine regulation of prolactin.

Prenatal alcohol exposure and preschool physical growth: a longitudinal analysis.

This report examines the effects of fetal alcohol exposure on size and growth in an urban cohort followed prospectively through early childhood. Indices of prenatal drinking were related to measurements of weight, stature (length), and head circumference obtained at birth and during five subsequent in-home assessments. Small but statistically significant relationships were detected between short-term recall estimates of drinking during pregnancy and weight and length at birth. The strength of these relationships diminished during the preschool assessments. However, estimates of catch-up growth associated with alcohol exposure were not statistically significant. With the exception of a single case with a profile of signs characteristic of fetal alcohol syndrome, an adverse effect of prenatal alcohol exposure on head circumference was not indicated.

Personality pathology in bulimics versus controls.

The Millon Clinical Multiaxial Inventory (MCMI) was administered to 37 bulimic women, as well as 32 female general psychiatric outpatients and 30 normal women in order to assess contrasts in prevalence of various types of personality pathology among the three groups. Bulimic women displayed significantly greater pathology on scales measuring dependent and avoidant characteristics. However, they were not significantly different from female psychiatric outpatients with regard to most types of personality pathology. Results are discussed within the framework of previous literature on personality characteristics and disorders within the bulimic population.

Desipramine lowers tritiated para-aminoclonidine binding in platelets of depressed patients.

Platelet adrenergic receptor binding has been studied by several groups of investigators as a possible marker for depression and other psychiatric conditions. Although some of the findings have been discrepant, the results of the majority of studies that have used imidazoline compounds as ligands have confirmed elevated alpha 2-adrenergic receptor binding in depression. We have emphasized the advantages of obtaining platelet-purified plasma membranes and using tritiated para-aminoclonidine as the ligand of choice. By using "site-selective" concentrations of tritiated para-aminoclonidine, we have identified two high-affinity-binding sites of the platelet alpha 2-adrenergic receptor that appear to be upregulated in depression before treatment. Depressed patients were treated with desipramine hydrochloride for 6 to 8 weeks, and platelet binding was reassessed. Desipramine reduced binding to nearly normal levels at both site-selective concentrations of tritiated para-aminoclonidine. The concentrations of plasma catecholamines could play a role in the downregulation of binding at posttreatment. We discuss these findings in the context of platelet imidazoline-binding sites being a possible state-dependent marker for depression.

The 4-5-6 configuration on the MMPI in bulimics vs. controls.

The 4-5-6 configuration on the MMPI for females has been associated with problems in the direct expression of anger, as well as excessive dependency and affectional needs (Greene, 1980). Because these characteristics frequently have been ascribed to bulimic women, we hypothesized that the incidence of the 4-5-6 configuration would be greater for bulimic women (n = 26) than for female outpatients (n = 40) or a nonpsychiatric population (n = 31). We did not find the predicted differences in incidence of the 4-5-6 configuration in a study that used conventional cut-offs and treated the configuration as a discrete variable. However, when the characteristic was measured as a continuous variable, the nonpsychiatric population differed significantly from both clinical populations. Results are discussed in terms of feminine role conflict as a factor that differentiates women who seek psychiatric treatment from those who do not.

Elevated 3H-para-aminoclonidine binding to platelet purified plasma membranes from depressed patients.

Purified platelet plasma membranes were used to compare 3H-para-aminoclonidine binding in 18 depressed patients and 24 sex- and age-matched, healthy control subjects. Two site-selective concentrations of the radioligand were used (0.06 and 1.5 nmol/L) to investigate two high-affinity 3H-para-aminoclonidine binding sites. Radioligand binding was significantly elevated in platelets of depressed patients at both concentrations of 3H-para-aminoclonidine whether expressed per milligram protein, per platelet, or per square micrometer of platelet surface area (each p less than 0.02). These data agree with most previous studies, suggesting that a subset of platelet alpha 2 adrenoceptors, recognized by clonidine and its derivative para-aminoclonidine, is upregulated in depressed patients. By using purified plasma membranes, our data rule out the possibility that an inhibitor may have masked receptor binding in previous studies which used total platelet lysates. The present findings thus support the alpha 2 adrenoceptor hypersensitivity theory of depression.

MHPG circadian rhythmicity in blood of healthy subjects.

An earlier study showed that plasma concentrations of total 3-methoxy-4-hydroxyphenylglycol (MHPG), the major metabolite of norepinephrine, display a circadian rhythm in 6 male healthy subjects. In the previous study, the period of the rhythm was not fixed to 24 h thereby undermining the reliability of the cosinor parameter estimates. The present study extends the findings to a larger group of 12 clinically healthy male volunteers. Plasma total MHPG concentrations were determined every 3h for one full day. The data were fitted to a cosinor model fixing the period of the putative MHPG rhythm at 24 h. Several estimation techniques were utilized including Fourier analysis and time domain analysis with 4 variations. It is concluded that a circadian rhythm indeed characterizes MHPG blood concentrations. The concordance among the various parameter estimates is discussed.

MCMI characteristics of DSM-III-R bulimics.

The literature on bulimia has suggested that bulimic women exhibit a number of pathological personality characteristics. However, the Millon Clinical Multiaxial Inventory (MCMI), an objective measure of personality functioning, has not previously been utilized to assess the personality characteristics of a bulimic population. The MCMI was administered to 37 female bulimics, 32 female general psychiatric outpatients, and 30 normal female controls in order to assess the relationship between bulimia and pathological personality traits. Bulimic women were found to score higher than the other groups on MCMI Scales 1 (Schizoid), 2 (Avoidant), and 3 (Dependent). They also scored lower than the other two groups on Scale 6 (Antisocial). Results are discussed within the framework of parallels between the MCMI profiles of bulimics and the existing literature on bulimics' personality characteristics.

Apparent phase advance in diurnal MHPG rhythm in depression.

Several investigators have proposed that diurnal rhythms, particularly that of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), show abnormalities in affective disorders. The present study compared diurnal MHPG rhythms in the plasma of 18 male depressed patients and 12 healthy male volunteers. A diurnal rhythm of MHPG closely fit to a cosine model was observed in volunteers and, to a lesser extent, in depressed patients. Patients, especially those with endogenous depression (N = 11), demonstrated an earlier acrophase (mean +/- SD = 12.53 +/- 3.38 hours), and treatment with desipramine was associated with a significant (3-hour) phase delay. This study confirms and extends previous reports of apparent phase advances in circadian noradrenergic rhythms in depressed patients.

The statistical analysis of treatment effects in 24-hour ambulatory blood pressure recordings.

This paper presents a statistical analysis of treatment effects in 24-hour ambulatory blood pressure recordings. The statistical models account for circadian rhythms, subject effects, and the effects of treatment with drugs or relaxation therapy. In view of the heterogeneity of the subjects, we fit a separate linear model to the data of each subject, use robust statistical procedures to estimate the parameters of the linear models, and trim the data on a subject by subject basis. We use a meta-analytical method to combine the results of all subjects in the study.

Low level lead exposure in the prenatal and early preschool periods: early preschool development.

The hypothesis that low level lead exposure in the fetal and early preschool years is related to neuropsychological deficit was examined in a prospective study of child development. We also tested the hypothesis of reverse causality, i.e., that lead level is a function of prior developmental status. Fetal lead exposure was measured in maternal and cord blood while preschool lead level was measured in venous blood samples at ages six months, two years and three years. These blood lead measures (PbB) were related to concurrent and ensuing scores on developmental measures at six months, one year, two years, and three years. With statistical control of covariate measures (age, sex, race, birth weight, birth order, gestational exposure to other toxic substances, maternal intelligence, and several indicators of the quality of the caretaking environment) as well as potentially confounding risk factors (gestational exposure to alcohol and other toxic substances), most statistically significant associations of PbB with concurrent and later development were completely attenuated. Effects of lead exposure, significant or not, were not consistent in direction. In reverse-causality analyses, PbB was not related significantly to prior measures of developmental retardation or acceleration. It was concluded that the relationship of lead level and measures of development in these early years was primarily a function of the dependence of each on the quality of the caretaking environment.