John R. Hofstetter

Quality of sleep in patients with schizophrenia is associated with quality of life and coping

BackgroundWhile sleep disturbance is widespread in schizophrenia it is less clear whether sleep disturbance is uniquely related to impaired coping and perceived quality of life.MethodsWe simultaneously assessed sleep quality, symptoms, and coping in 29 persons with schizophrenia or schizoaffective disorder in a post acute phase of illness. Assessment instruments included the Pittsburgh Sleep Quality Index; the Positive and Negative Symptom Scale; the Heinrichs Quality of Life Scale; and the Ways of Coping Scale. Multiple regressions were performed predicting quality of life and coping from sleep quality controlling for age and symptom severity. On a subset of seven subjects non-dominant wrist actigraphy was used as an objective check of their self-reported poor sleep.ResultsAnalyses revealed that poor sleep quality predicted low quality of life (r = -0.493; p = .022) and reduced preference for employing positive reappraisal when facing a stressor (r = -0.0594; p = 0.0012). Actigraphy confirmed poor sleep quality in a subset of subjects. They had shorter sleep duration (p < .0005), shorter average sleep episodes (p < .005) and more episodes of long awakening (p < 0.05) than community norms.ConclusionThe results are consistent with the hypotheses that poor sleep may play a unique role in sustaining poor quality of life and impaired coping in patients with schizophrenia. These associations may hold for community controls as well.

Sleep and daily activity preferences in schizophrenia: associations with neurocognition and symptoms.

Research suggests that an unusually high percentage of persons with schizophrenia prefer to be awake during the night and to sleep during the day (Benson and Zarcone, 1994). In general, it is widely held that such disturbances in the timing of sleep cycles limit how well people are able to function. For instance, several studies have found that community control subjects who prefer to be awake at night, generally referred to as “owls,” sleep more poorly (Carrier et al., 1997), are more isolated, and possibly experience more emotional distress (Taillard et al., 2001) than those of other chronotypes. Another study found that owls have greater cognitive capacity than those who prefer to be awake early (Roberts and Kyllonen, 1999). Yet, is this true for patients with schizophrenia? Is chronotype (i.e., when in the day one prefers to be active) associated with similar difficulties and abilities in patients with schizophrenia? Answering these questions may help unravel the mysteries surrounding prolonged dysfunction in patients with schizophrenia. It is known that sleep disturbances are prevalent among persons with schizophrenia (Benson and Zarcone, 1994; Doi et al., 2000; Royuela et al., 2002). They can be a prodromal symptom and have been associated with symptom exacerbation and relapse (Tan and Ang, 2001). Zarcone and Benson (1997) found that persons with schizophrenia take longer to fall asleep, awaken more frequently after going to sleep, experience reduced deep or slow-wave sleep, and have shorter REM latencies, even when not in a period of acuity, than community control subjects. They also found that difficulties falling asleep correlate with a measure of thought disorder. Yet, it is unclear what types of sleep difficulties are related to outcome. To address these issues, we correlated symptom levels, an assessment of executive function, and sleep quality with self-reported chronotype. To assess chronotype, we used the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ; Horne and Ostberg, 1976), which generates a rating of activity preference for morning (larks), evening (owls), and neither. We predicted that there would be disproportionately more owls in our sample than a similar sample of community control subjects and that owls would have a) higher levels of excitement and emotional discomfort symptoms, b) poorer sleep quality, and c) better cognitive function than larks.

Circadian activity rhythms in high-alcohol-preferring and low-alcohol-preferring mice

The circadian periods of high-alcohol-preferring (HAP) and low-alcohol-preferring (LAP) selected lines of mice were compared. The mice were ethanol-naive. Circadian periods were calculated from records of running-wheel activity in constant dark. The number of daily wheel revolutions and body weights of the two lines of mice were also compared. The HAP line had a shorter period of wheel running than that of the LAP lines. The HAP mice also had a tendency to run more on wheels than did LAP mice. These findings support the suggestion that genes affecting ethanol consumption in mice have pleiotropic effects on circadian period.

New Quantitative Trait Loci for the Genetic Variance in Circadian Period of Locomotor Activity between Inbred Strains of Mice

Provisional quantitativetrait loci (QTL) for circadian locomotor period and wheel-running period have been identified in recombinant inbred (RI) mouse strains. To confirm thoseQTLand identify newones, the geneticcomponent of variance of the circadian period was partitionedamongan F2 intercross of RI mouse strains (BXD19 and CXB07). First, a genomic survey using 108 SSLP markers with an average spacing of 15 cM was carried out in a population of 259 (BXD19 · CXB07)F2 animals. The genome-wide survey identified two significant QTLfor period of locomotor activity measured by infrared photobeam crossings on mousechromosomes 1 (lod score5.66) and 14 (lod score4.33). TheQTL on distal chromosome 1 confirmed a previous report based on congenic B6.D2-Mtv7a/ Ty mice. Lod scores greater than 2.0 were found on chromosomes 1, 2, 6, 12, 13, and 14. In a targeted extension study, additional genotyping was performed on these chromosomes in the full sample of 341 F2 progeny. The 6 chromosome-wide surveys identified 3 additional QTL on mouse chromosomes 6, 12, and 13. The QTLon chromosome 12 overlaps with circadian period QTLidentified in several prior studies. For wheel-running period, the chromosome-wide surveys identified QTLon chromosomes 2 and 13 and one highly suggestive QTLon proximal chromosome 1. The results are compared to other published studies of QTL of circadian period.

Provisional QTL for Circadian Period of Wheel Running in Laboratory Mice: Quantitative Genetics of Period in RI Mice

Wheel running was monitored in B x D recombinant inbred (RI) mice under dark-dark (DD) conditions, and the mean circadian period was calculated for each strain. There were significant differences for this trait among B x D recombinant inbred strains (p < .0001) and a narrow-sense heritability of 21%. Analysis of strain means and variances indicates that at least four segregating loci contribute to the genetic variance for the free-running circadian period in this population. Correlation of the strain means for the circadian period of wheel running for each RI strain against the distribution of markers at over 1500 loci along the mouse genome identified a number of provisional quantitative trait loci (QTL). There were provisional QTL for wheel running at p < .001 on chromosome 11 and at p < .01 on chromosomes 1, 6, 9, 17, and 19. Most were in agreement with a second analysis done under similar conditions.

Intermittent long-wavelength red light increases the period of daily locomotor activity in mice

Background We observed that a dim, red light-emitting diode (LED) triggered by activity increased the circadian periods of lab mice compared to constant darkness. It is known that the circadian period of rats increases when vigorous wheel-running triggers full-spectrum lighting; however, spectral sensitivity of photoreceptors in mice suggests little or no response to red light. Thus, we decided to test the following hypotheses: dim red light illumination triggered by activity (LEDfb) increases the circadian period of mice compared to constant dark (DD); covering the LED prevents the effect on period; and DBA2/J mice have a different response to LEDfb than C57BL6/J mice. Methods The irradiance spectra of the LEDs were determined by spectrophotometer. Locomotor activity of C57BL/6J and DBA/2J mice was monitored by passive-infrared sensors and circadian period was calculated from the last 10 days under each light condition. For constant dark (DD), LEDs were switched off. For LED feedback (LEDfb), the red LED came on when the mouse was active and switched off seconds after activity stopped. For taped LED the red LED was switched on but covered with black tape. Single and multifactorial ANOVAs and post-hoc t-tests were done. Results The circadian period of mice was longer under LEDfb than under DD. Blocking the light eliminated the effect. There was no difference in period change in response to LEDfb between C57BL/6 and DBA/2 mice. Conclusion An increase in mouse circadian period due to dim far-red light (1 lux at 652 nm) exposure was unexpected. Since blocking the light stopped the response, sound from the sensors electronics was not the impetus of the response. The results suggest that red light as background illumination should be avoided, and indicator diodes on passive infrared motion sensors should be switched off.

Effects of indirect light and propranolol on melatonin levels in normal human subjects.

An indirect lighting protocol was developed to measure nocturnal melatonin suppression by light in normal human subjects. Goals were to minimize both discomfort due to staring intensely at a bright light source, and behavioral variation due to wandering gaze. Subjects sat with a bank of five full-spectrum light sources placed behind them. Lights reflecting off the surfaces before each subject produced a hemisphere of light that measured 500 lx +/- 5%. Subjects retired to bed in darkness by midnight and then sat in the hemisphere of light from 02.00 h to 04.00 h. Blood for melatonin was drawn at 20-30-min intervals from midnight to 06.00 h. Plasma melatonin was measured by radioimmunoassay. The indirect lighting protocol was used to compare the effects of 500 lx light to dark (21 subjects) and to study varying light intensities from 300 to 2000 lx (7 subjects). We studied the effects of the sitting posture in very dim light of 20-30 lx (6 subjects). We also studied the effects of propranolol plus dark and propranolol plus 500 lx light on melatonin levels. Subjects received placebo, 10 mg propranolol or 40 mg propranolol orally at 23.00 h, and were then exposed to either the dark or light condition. Melatonin levels obtained with the indirect lighting protocol were consistent with studies using direct lighting; light of 500 lx significantly suppressed nocturnal melatonin and suppression was dose related between 300 and 2000 lx. Sitting in dim light had no significant effect on melatonin suppression when compared with the supine posture in the dark in six subjects. Propranolol caused a dose-dependent decrease in melatonin levels in both the dark and the light. There was no relationship between suppression of melatonin by propranolol and suppression by light.

Provisional Quantitative Trait Loci (QTL) for the Aschoff Effect in RI Mice

Mice of the CXB recombinant inbred (RI) panel were phenotyped for period of locomotor activity in continuous dark (tau) and in continuous 10-lux light (tauLL). There were significant differences in the effect of light on period, delta tau (tauLL-tau), among CXB RI strains and their progenitors. By comparing strain means for delta tau in the CXB RI strains with typed genetic loci using a product moment correlation, it was possible to hypothesize quantitative trait loci (QTL) important to the genetic variance in the effect of constant low-level light on circadian period. Some of the candidate genes linked to statistically associated markers are neuropharmacologically interesting. Provisional QTL for delta tau were found on proximal Chromosome 8 and mid Chromosome 11 in regions near QTL identified in a similar analysis of the BXD RI panel. This provides additional evidence for the importance of loci on Chromosomes 8 and 11.

A Locus for Circadian Period of Locomotor Activity on Mouse Proximal Chromosome 3

Lengthened circadian period of locomotor activity is a characteristic of a congenic strain of mice carrying a nonsense mutation in exon 5 of the carbonic anhydrase II gene, car2. The null mutation in car2 is located on a DBA/2J inbred strain insert on proximal chromosome 3, on an otherwise C57BL/6J genomic background. Since reducing the size of the congenic region would narrow the possible candidate genes for period, two recombinant congenic strains (R1 and R2) were developed from the original congenic strain. These new congenic strains were assessed for period, genetic composition, and the presence of immunoreactive carbonic anhydrase II. R1 mice were homozygous DBA/2J for the distal portion of the original DBA/2J insert, while R2 mice were homozygous DBA/2J for the proximal portion. R1 mice had a significantly lengthened period compared to R2 mice and wild-type C57BL/6J mice, indicating that the gene(s) affecting period is likely found within the reduced DBA/2J insert (˜1 cM) in the R1 mice. The R1 mice also possessed the null mutation in car2. This study confirmed the presence of a gene(s) affecting period on proximal chromosome 3 and significantly reduced the size of the congenic region and the number of candidate genes. Future studies will focus on identifying the gene influencing period.

Sleep and Quality of Life in Schizophrenia

Patients with schizophrenia have severe and persistent sleep disturbance. Multiple mechanisms contribute to poor sleep in patients with schizophrenia, including high brain dopamine levels, high anxiety, and medication side effects. Persons with psychoses generally rate their QOL worse than both the general population and physically ill patients. Although patients with schizophrenia can self-rate their QOL, the most complete picture of QOL includes assessment by family members and professionals. Negative symptoms, depressed mood, anxiety, medication side effects, and stigma correlate with low QOL in patients with schizophrenia. Positive mood, high self esteem, good social support, a sense of personal control and empowerment, and an extroverted, agreeable personality promote QOL. Sleep deprivation may foster poor functioning and high levels of thought disorder, hostility, and excitement. Improving sleep in patients with schizophrenia is likely to improve their psychiatric symptoms.