Circadian Rest-activity Cycle Research Articles

AgRP Neurons Encode Circadian Feeding Time

Food intake follows a predictable daily pattern and synchronizes metabolic rhythms. Neurons expressing Agouti-related protein (AgRP) read out physiological energetic state and elicit feeding, but the regulation of these neurons across daily timescales is poorly understood. Using a combination of neuron-dynamics measurements and timed optogenetic activation in mice, we show that daily AgRP-neuron activity was not fully consistent with existing models of homeostatic regulation. Instead of operating as deprivation counter, AgRP-neuron activity primarily followed the circadian rest-activity cycle through a process that required an intact suprachiasmatic nucleus (SCN) and synchronization by light. Imposing novel feeding patterns through time-restricted food access or periodic AgRP-neuron stimulation was suffcient to resynchronize the daily AgRP-neuron activity rhythm and drive anticipatory-like behavior through a process that required DMHPDYN neurons. These results indicate that AgRP-neurons integrate time-of-day information of past feeding experience with current metabolic needs to predict circadian feeding time. This work is supported by NIH to D.A. R01DK126740. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Rest-Activity Circadian Rhythm and Light Exposure Using Wrist Actigraphy in ICU Patients

Actigraphy (ACTG) is easy to use and has proved reliable in non-critical populations of patients. It has been used to track circadian rest-activity cycles and to identify states of wakefulness and sleep [1]. A more recent study has found that ACTG have a moderate level of agreement with PSG in distinguishing between sleep and wakeful states which is more profound in non-ventilated patients [2].

Disrupted Circadian Rest-Activity Cycles in Inflammatory Bowel Disease Are Associated With Aggressive Disease Phenotype, Subclinical Inflammation, and Dysbiosis.

Patients with inflammatory bowel disease (IBD)—Crohn's disease (CD), and ulcerative colitis (UC), have poor sleep quality. Sleep and multiple immunologic and gastrointestinal processes in the body are orchestrated by the circadian clock, and we recently reported that a later category or chronotype of the circadian clock was associated with worse IBD specific outcomes. The goal of this study was to determine if circadian misalignment by rest-activity cycles is associated with markers of aggressive disease, subclinical inflammation, and dysbiosis in IBD. A total of 42 patients with inactive but biopsy-proven CD or UC and 10 healthy controls participated in this prospective cohort study. Subjects were defined as having an aggressive IBD disease history (steroid dependence, use of biologic or immunomodulator, and/or surgery) or non-aggressive history. All participants did two weeks of wrist actigraphy, followed by measurement of intestinal permeability and stool microbiota. Wrist actigraphy was used to calculate circadian markers of rest-activity– interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA). Aggressive IBD history was associated with decrease rest-activity stability (IS) and increased fragmentation compared to non-aggressive IBD and health controls at 0.39 ±.15 vs. 0.51 ± 0.10 vs. 0.55 ± 0.09 (P < 0.05) and 0.83 ± 0.20 vs. 0.72 ± 0.14 (P < 0.05) but not HC at 0.72 ± 0.14 (P = 0.08); respectively. There was not a significant difference in RA by IBD disease history. Increased intestinal permeability and increased TNF-α levels correlated with an increased rest activity fragmentation (IV) at R = 0.35, P < 0.05 and R = 0.37, P < 0.05, respectively; and decreased rest-activity amplitude (RA) was associated with increased stool calprotectin at R = 0.40, P < 0.05. Analysis of intestinal microbiota showed a significant decrease in commensal butyrate producing taxa and increased pro-inflammatory bacteria with disrupted rest-activity cycles. In this study, different components of circadian misalignment by rest-activity cycles were associated with a more aggressive IBD disease history, increased intestinal permeability, stool calprotectin, increased pro-inflammatory cytokines, and dysbiosis. Wrist activity allows for an easy non-invasive assessment of circadian activity which may be an important biomarker of inflammation in IB.

Can Extra Daytime Light Exposure Improve Well-Being and Sleep? A Pilot Study of Patients With Glaucoma.

Glaucoma damages retinal ganglion cells, including intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells modulate various non-visual physiological and psychological functions which are modulated by light. In patients with glaucoma, we assessed the effect of daily bright light exposure (LE) on several melanopsin-dependent functions, such as the pupil constriction, circadian rest-activity cycles, sleep and subjective well-being including relaxation, alertness and mood. Twenty patients participated in the study (9 women, 11 men, mean age = 67.6 ± 7.5 y). Pupillometry was performed before the LE weeks and repeated on the last day of LE. The post-illumination pupil response (PIPR) was calculated as a proxy for melanopsin-dependent activation. Participants continuously wore an activity monitor and self-assessed sleep quality, well-being and visual comfort for 7 days before and during 4 weeks of daily bright LE (30 min to 10,000 lux polychromatic bright white light). After the LE, there was a significantly greater PIPR and higher subjective sleep quality when compared to the pre-LE week (p < 0.05), but no significant changes in 24-h rhythms or sleep parameters. A greater PIPR was correlated with an increase in circadian amplitude and higher inter-daily stability (derived from rest-activity cycles; p < 0.05). In a small group of patients with glaucoma, scheduled daily bright light exposure could improve subjective sleep quality. These findings highlight the importance to evaluate and maintain non-visual functions at different levels in patients with progressive loss of ipRGCs.

Effects of a dawn-dusk simulation on circadian rest-activity cycles, sleep, mood and well-being in dementia patients.

Light is the most powerful "zeitgeber" signal to synchronize circadian sleep-wake cycles. In dementia, these rhythms are often fragmented - probably due to loss of neuronal function of the suprachiasmatic nuclei (the biological "master clock" in the brain) and/or weakness of external zeitgebers. We investigated the effects of a prototype dawn-dusk simulator (DDS) on circadian rest-activity cycles, sleep, mood and well-being in a balanced crossover design during fall and winter in 20 institutionalized patients with dementia (86 ± 6 y, 17 f). All participants had one baseline week followed by exposure to individually timed DDS over their beds for 7-8 weeks. They spent 8 weeks without DDS as a control. Mood, self-reliant daily activity, social behavior, agitation, and quality of life were assessed by standardized questionnaires and visual analogue scales, regularly rated by trained caregivers. Circadian and sleep characteristics of their rest-activity cycles were analyzed by actimetry over 17 weeks. DDS exposure led to significantly better mood in the morning hours after waking. The effects were most pronounced in the second 4 weeks with DDS, indicating that positive effects emerged gradually. Differences in circadian rest-activity cycles and sleep were mainly age-dependent. We found statistically significant correlations between measures of higher quality of life and better mood, greater alertness and circadian rhythm stability. We conclude that continuous, long-term application of dawn-dusk simulation at the sleep-wake transitions appears to increase external zeitgeber strength in institutionalized patients with dementia. The DDS may provide an effective, non-invasive tool to improve mood and ameliorate patients' quality of life.

Time of day effects of temperature and daylight on short term electricity load

Abstract This paper proposes a model for short-term electricity load with differentiated temperature and daylight effects by time of day, which are determined by variations in intraday economic activity. The relationship between electricity load and economic activity implies that the electricity demand response to changes in exogenous variables like temperature is non-linear as well as non-homogeneous along the day. The proposed framework, a smooth transition regression model with double threshold (LSTR2), models the observed intraday patterns in load curves to explicitly capture the effect of the circadian rest-activity cycle on the distinct responses of electricity demand to temperature and daylight variations throughout the day. The model shows that the sensitivity of demand to low temperatures is significantly larger in the “active” compared to the “rest” state. If temperatures decrease from 10 °C to 0 °C, electricity demand in the “active” state increases by 960.5 MW h per 1 °C decrease, but by only 26.6 MW h per 1 °C decrease in the “rest” state. When temperatures are higher, in the “rest state” demand decreases by 602.9 MW h per 1 °C if temperature falls from 26 °C to 21 °C, while in the “active” state demand only decreases by 323.6 MW h per 1 °C variation.

Modulation of Motoneuronal Activity With Sleep-Wake States and Motoneuronal Gene Expression Vary With Circadian Rest-Activity Cycle.

In both nocturnal and diurnal mammals, sleep and wake states differentially aggregate during the rest and active phases of circadian cycle. Closely associated with this rhythm are prominent changes in motor activity. Here, we quantified the magnitudes of electromyographic activity (EMG) measured separately during different sleep-wake states across the rest-activity cycle, thereby separating amplitude measurements from the known dependance of the timing of wake and sleep on the phase of circadian rest-activity cycle. In seven rats chronically instrumented for electroencephalogram and EMG monitoring, nuchal and lingual muscle EMGs were measured as a commonly used postural output in behavioral sleep studies and as a cranial motor output with potential clinical relevance in obstructive sleep apnea (OSA) syndrome, respectively. We found that, for both motor outputs, EMG measured during wake episodes was significantly higher during the active phase, than during the rest phase, of circadian cycle. The corresponding patterns observed during slow-wave sleep (SWS) and rapid eye movement sleep (REMS) were different. During SWS, lingual EMG was very low and did not differ between the rest and active phase, whereas nuchal EMG had pattern similar to that during wakefulness. During REMS, lingual EMG was, paradoxically, higher during the rest phase due to increased twitching activity, whereas nuchal EMG was very low throughout the rest and active periods (postural atonia). In the follow-up comparison of differences in transcript levels in tissue samples obtained from the medullary hypoglossal motor nucleus and inferior olive (IO) at rest onset and active period onset conducted using microarrays, we identified significant differences for multiple transcripts representing the core members of the molecular circadian clock and other genes important for the regulation of cell metabolism and activity (up to n = 130 at p < 0.001). Collectively, our data indicate that activity of motoneurons is regulated to optimally align it with the rest-activity cycle, with the process possibly involving transcriptional mechanisms at the motoneuronal level. Our data also suggest that OSA patients may be relatively better protected against sleep-related upper airway obstructions during REMS episodes generated during the rest phase, than during active phase, of the circadian cycle.

Melanopsin-Mediated Acute Light Responses Measured in Winter and in Summer: Seasonal Variations in Adults with and without Cataracts.

Seasonal adaptation is a ubiquitous behavior seen in many species on both global hemispheres and is conveyed by changing photoperiods. In humans this seasonal adaptation is less apparent, in part because changes in daylength are masked by the use of electrical lighting at night. On the other hand, cataracts which reduce light transmission, may compound seasonal changes related to the reduced daylength of winter. To better understand the effects of different photoperiod lengths in healthy adults without and with cataracts, we tested their melanopsin-mediated light responses in summer vs. winter. Fifty-two participants (mean age 67.4 years; 30 with bilateral cataracts and 22 age-matched controls with clear lenses; pseudophakes) were tested twice, once in summer and once in winter. At each test session we assessed the electroretinogram and pupil responses during daytime and we determined melatonin suppression, subjective sleepiness and mood in response to light exposure in the evening. Circadian rest-activity cycles and sleep from activity recordings were also analyzed for both seasons. Both groups had similar visual function. There were no seasonal differences in the electroretinogram. For the pupil responses to bright blue light, the post-illumination pupil response (PIPR) was greater in winter than summer in pseudophakes, but not in cataract participants, whereas melatonin suppression to acute light exposure showed no differences between both groups and seasons. Overall, intra-daily variability of rest-activity was worse in winter but participants felt sleepier and reported worse mood at the laboratory in evening time in the summer. Those with cataracts had poorer sleep quality with lower sleep efficiency, and higher activity during sleep in winter than summer. In this study, the PIPR showed a seasonal variation in which a larger response was found during winter. This variation was only detected in participants with a clear intraocular lens. In the cataract group, visual function was not impaired yet these participants showed a lack of seasonal changes in the pupil response to blue light and poorer sleep in winter. These findings raise the question for tailored lighting conditions for cataract patients in order to counter potentially deleterious effects of living with chronically lower light exposure.

Bright Light Delights: Effects of Daily Light Exposure on Emotions, Restactivity Cycles, Sleep and Melatonin Secretion in Severely Demented Patients.

We tested whether the effects of a dynamic lighting system are superior to conventional lighting on emotions, agitation behaviour, quality of life, melatonin secretion and circadian restactivity cycles in severely demented patients. As a comparison, an age matched control patient group was exposed to conventional lighting. For none of the output measures were significant differences between the two lighting conditions found during the 8 study weeks in fall/winter. Thus, we divided the patient cohort (n = 89) into two groups, solely based on the median of their daily individual light exposure. Patients with higher average daily light exposure (>417 lx) showed significantly longer emotional expressions of pleasure and alertness per daily observations than patients with lower daily light exposure. Moreover, they had a higher quality of life, spent less time in bed, went to bed later and initiated their sleep episodes later, even though the two groups did not differ with respect to age, severity of cognitive impairment and mobility. In general, men were more agitated, had shorter sleep with more wake episodes, had a lower circadian amplitude of relative rest-wake activity and interdaily circadian stability than women. In particular, lower daily light exposures significantly predicted lower circadian amplitudes of rest-activity cycles in men but not in women. This may indicate sex specific susceptibility to daily light exposures for rest-activity regulation in older demented patients. Our results provide evidence that a higher daily light exposure has beneficial effects on emotions and thus improved quality of life in a severely demented patient group.

Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on: data derived from a randomized clinical trial.

BackgroundPatients with severe mental illness often suffer from disruptions in circadian rest-activity cycles, which might partly be attributed to ongoing psychopharmacological medication. Benzodiazepines are frequently prescribed for prolonged periods despite recommendations of only short-term usage. Melatonin, a naturally occurring nocturnal hormone, has the potential to stabilize disrupted circadian rhythmicity. Our aim was to investigate how prolonged-release melatonin affects rest-activity patterns in medicated patients with severe mental illness and if benzodiazepine dose reduction is associated with changes in circadian rhythm parameters.MethodData were derived from a randomized, double-blinded clinical trial with 24 weeks follow-up. Participants were randomized to add-on treatment with prolonged-release melatonin (2 mg) or matching placebo, and usual benzodiazepine dosage was gradually tapered. Here we report the results of 72 h of actigraphic assessment of activity-rest cycles performed pre and post tapering. Changes in rest-activity rhythm parameters between the melatonin and placebo group were analyzed using the univariate general linear model. Change in activity counts per 6 h, from baseline to follow-up, in the whole sample was analyzed using paired samples t-test.ResultsA subsample of 48 patients participated in the actigraphic assessment: 20 in the melatonin group and 28 in the placebo group. Rest-activity cycles varied from regular to highly disrupted. Melatonin significantly increased the interdaily stability and at a trend level decreased the intradaily variability compared with placebo. Benzodiazepine dose reduction was not associated with these circadian rhythm parameters. Activity counts were generally higher after benzodiazepine dose reduction compared with pre tapering, but differences did not reach statistical significance.ConclusionOur data suggest melatonin as an aid during benzodiazepine withdrawal for patients distressed by disrupted circadian rest-activity cycles. Benzodiazepine tapering might result in diminished sedentary behavior but further research is needed.Trial registrationClinicalTrials NCT01431092, clinicaltrials.gov. Registered 31 August 2011.

Behavioral Periodicity Detection from 24 h Wrist Accelerometry and Associations with Cardiometabolic Risk and Health-Related Quality of Life.

Periodicities (repeating patterns) are observed in many human behaviors. Their strength may capture untapped patterns that incorporate sleep, sedentary, and active behaviors into a single metric indicative of better health. We present a framework to detect periodicities from longitudinal wrist-worn accelerometry data. GENEActiv accelerometer data were collected from 20 participants (17 men, 3 women, aged 35–65) continuously for 64.4 ± 26.2 (range: 13.9 to 102.0) consecutive days. Cardiometabolic risk biomarkers and health-related quality of life metrics were assessed at baseline. Periodograms were constructed to determine patterns emergent from the accelerometer data. Periodicity strength was calculated using circular autocorrelations for time-lagged windows. The most notable periodicity was at 24 h, indicating a circadian rest-activity cycle; however, its strength varied significantly across participants. Periodicity strength was most consistently associated with LDL-cholesterol (r's = 0.40–0.79, P's < 0.05) and triglycerides (r's = 0.68–0.86, P's < 0.05) but also associated with hs-CRP and health-related quality of life, even after adjusting for demographics and self-rated physical activity and insomnia symptoms. Our framework demonstrates a new method for characterizing behavior patterns longitudinally which captures relationships between 24 h accelerometry data and health outcomes.

The Zurich 3-step concept for the management of behavioral sleep disorders in children: a before-and-after study.

Several strategies have been found to be effective for the treatment of childhood behavioral sleep disorders. One which has yet to be evaluated is the Zurich 3-step concept, which combines basic notions of the two-process model of sleep regulation (introducing a regular rhythm and adjusting bedtime to sleep need) with behavioral strategies. This uncontrolled before-and-after study describes our concept and its step-wise approach, assesses changes in sleep-wake variables and behavior problems, and also examines associations between changes in sleep-wake variables and behavior problems. A total of 79 children with sleep problems (age range 6-47 months, 42% females) were included. Sleep problems were assessed by the Infant Sleep Questionnaire, sleep-wake variables by diary and actigraphy, and behavior problems of children ≥ 18 months by the Child Behavior Checklist. A significant decrease in nocturnal wake duration (Cohen's d = -0.34) and a significant increase in the duration of the longest continuous nocturnal sleep period (Cohen's d = 0.19) were found from before to after intervention (on average 2.7 months, SD 1.5). The variability for sleep onset and end time decreased, and actigraphically measured circadian rest-activity cycle measures improved. Parent-reported internalizing and total behavior problems also decreased (Cohen's d = 0.66). The findings of both objective and subjective assessment techniques suggest that the Zurich 3-step concept is effective. Thus, the intervention concept may be useful in clinical practice with sleep-disordered children.

A role for the habenula in the regulation of locomotor activity cycles.

Although much is known about the regulation of the circadian rest-activity cycle by the hypothalamic suprachiasmatic nucleus in nocturnal rodents, little is known about the neural substrates that regulate the temporal organization of nocturnal activity within the active phase. In this report, data are presented in Syrian hamsters to implicate the habenula - believed to be involved in motivation, reward and motor control--as a candidate site for such a role. First, by examining hamsters during the day and night and by introducing a 'novel' running wheel in order to induce daytime motor activity, we showed that immunoreactive c-Fos expression in the lateral and medial habenula is related to motor activity/arousal. Second, by transecting the habenula's major efferent pathway (fasciculus retroflexus), we showed that the interruption of habenula neural output alters the daily amount of motor activity, lengthens the period of the circadian rest-activity rhythm and disrupts the species-typical pattern of nocturnal motor activity, measured as either wheel-running behavior or general locomotor activity. Instead of the usual pattern of night-time locomotion, characterized by a prolonged bout of elevated activity in the early night followed by shorter sporadic bouts or the cessation of activity altogether, lesioned animals exhibited a more homogeneous, undifferentiated temporal profile extending across the night. These data suggest a previously unrecognized function of the habenula whereby it regulates the temporal pattern of activity occurring within a circadian rest-activity window set by the suprachiasmatic nucleus.

Efficacy of the Novel Antidepressant Agomelatine on the Circadian Rest-Activity Cycle and Depressive and Anxiety Symptoms in Patients With Major Depressive Disorder: A Randomized, Double-Blind Comparison With Sertraline

Efficacy of the Novel Antidepressant Agomelatine on the Circadian Rest-Activity Cycle and Depressive and Anxiety Symptoms in Patients With Major Depressive Disorder: A Randomized, Double-Blind Comparison With Sertraline

Increased Late Night Response to Light Controls the Circadian Pacemaker in a Nocturnal Primate

The mammalian endogenous circadian clock, the suprachiasmatic nuclei, receives environmental inputs, namely the light-dark cycle, through photopigments located in the eye and from melanopsin-expressing retinal ganglion cells. The authors investigated the influence of light wavelength and intensity on the synchronization of the rest-activity rhythm of the gray mouse lemur, a nocturnal Malagasy primate. Animals were tested at different irradiance levels (320, 45, 13, and 6 nmol x m(-2) x s(- 1)) under several light wavelengths (from 400 to 610 nm). Several parameters including circadian period, activity, and body temperature waveforms were used to assess synchronization to a 12:12 light-dark cycle in comparison to control treatments (12:12 white light or continuous darkness). Entrainment of the circadian rest-activity cycle increased with light intensity. It was more efficient for mid wavelengths relative to shorter or longer wavelengths but not coincident with melanopsin maximal sensitivity, suggesting other photoreceptors are likely involved in lemurs' photoentrainment. The authors obtained a novel synchronization pattern characterized by a clear synchronization to lights-on only without phasing to lights-off. Changes in photo-responsiveness at dusk and dawn highlight differential responses of evening and morning oscillators in the circadian clock.

Efficacy of the Novel Antidepressant Agomelatine on the Circadian Rest-Activity Cycle and Depressive and Anxiety Symptoms in Patients With Major Depressive Disorder

This study evaluates the efficacy of agomelatine, the first antidepressant to be an agonist at MT(1)/MT(2) receptors and an antagonist at 5-HT(2C) receptors, versus sertraline with regard to the amplitude of the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder (MDD). Outpatients with DSM-IV-TR-defined MDD received either agomelatine 25 to 50 mg (n = 154) or sertraline 50 to 100 mg (n = 159) during a 6-week, randomized, double-blind treatment period. The study was conducted from 2005 to 2006. The main outcome measure was the relative amplitude of the individual rest-activity cycles, expressed as change from baseline to week 6 and collected from continuous records using wrist actigraphy and sleep logs. Secondary outcome measures were sleep efficiency and sleep latency, both derived from actigraphy, and efficacy on depression symptoms (17-Item Hamilton Depression Rating Scale total score and Clinical Global Impressions scale scores) and anxiety symptoms (Hamilton Anxiety Rating Scale total score and subscores). A significant difference in favor of agomelatine compared to sertraline on the relative amplitude of the circadian rest-activity cycle was observed at the end of the first week (P = .01). In parallel, a significant improvement of sleep latency (P <.001) and sleep efficiency (P <.001) from week 1 to week 6 was observed with agomelatine as compared to sertraline. Over the 6-week treatment period, depressive symptoms improved significantly more with agomelatine than with sertraline (P <.05), as did anxiety symptoms (P <.05). The favorable effect of agomelatine on the relative amplitude of the circadian rest-activity/sleep-wake cycle in depressed patients at week 1 reflects early improvement in sleep and daytime functioning. Higher efficacy results were observed with agomelatine as compared to sertraline on both depressive and anxiety symptoms over the 6-week treatment period, together with a good tolerability profile. These findings indicate that agomelatine offers promising benefits for MDD patients. www.isrctn.org: ISRCTN49376288.

The Circadian Rest-Activity Cycle in Korsakoff Psychosis

Alzheimer disease (AD) has been associated with diminished function of the biological clock in the suprachiasmatic nuclei (SCN) and pronounced circadian sleep-wake cycle disturbances. Few studies have investigated other dementia etiologies. Because alcohol acts on the SCN and modifies circadian rhythms in animal studies, Korsakoff psychosis (KP) may also be associated with circadian rhythm abnormalities. This pilot study investigated the rest-activity cycle of KP to see whether there were sleep-wake cycle disturbances similar to those that the authors had observed in patients with AD. Cross-sectional observational study in a single academic medical center. PARTICIPANTS, MEASUREMENTS: The authors investigated the circadian rest-activity cycle of six moderately demented patients with KP who wore an activity/lux monitor for 10-26 days and compared these patterns with those of six home-living healthy individuals of the same age group. In addition, rest-activity cycle data from previous studies of patients with AD were examined. None. The rest-activity cycle of KP was remarkably well entrained, without the marked circadian and sleep disturbances found in patients with AD on the same ward. KP had a >2 hour earlier bedtime and rest onset than healthy subjects and a 30-minute earlier wake-up time, resulting in longer nocturnal rest duration. The major difference was a greatly diminished daytime activity level and extremely low light exposure. A stably entrained, although low-amplitude and phase-advanced rest-activity cycle may reflect the different neuropathology of demented patients with KP compared with patients with AD.

Treatment of behavioural, cognitive and circadian rest-activity cycle disturbances in Alzheimer's disease: haloperidol vs. quetiapine

This 5-wk, open-label, comparative study investigated the effects of quetiapine and haloperidol on behavioural, cognitive and circadian rest-activity cycle disturbances in patients with Alzheimer's disease (AD). Out of a total of 30 patients enrolled in the study, there were 22 completers, 11 in the quetiapine group (mean age 81.9+/-1.8 yr, mean baseline MMSE 19.9+/-1.3, mean dose 125 mg) and 11 in the haloperidol group (mean age 82.3+/-2.5 yr, mean baseline MMSE 18.1+/-1.3, mean dose 1.9 mg). As shown in the Neuropsychiatric Inventory, both medications reduced delusion and agitation, whereas quetiapine additionally improved depression and anxiety. Haloperidol worsened aberrant motor behaviour and caused extrapyramidal symptoms. In the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery which assessed cognitive parameters, quetiapine improved word recall; significant interaction terms revealed differences between quetiapine and haloperidol in word-list memory and constructional praxis. According to the Nurses' Observation Scale for Geriatric Patients (NOSGER) quetiapine improved instrumental activities of daily living. Actimetry documented the circadian rest-activity cycle before and after treatment. Sleep analysis revealed that patients receiving quetiapine had shorter wake bouts during the night, whereas patients receiving haloperidol had fewer though longer immobile phases. The study provides evidence that quetiapine at a moderate dose may be efficacious in treating behavioural disturbances in AD, with better tolerability than haloperidol.

Actigraphy in Patients with Seasonal Affective Disorder and Healthy Control Subjects Treated with Light Therapy

Abnormalities of the circadian rest-activity cycle are hypothesized to accompany the clinical picture of seasonal affective disorder (SAD). The purpose of this study was to investigate if bright light therapy (BLT) is able to reverse these disturbances. Seventeen SAD outpatients and 17 sex- and age-matched healthy control subjects were treated with BLT administered in the morning for 4 weeks. Activity levels were measured with wrist actigraphy. SAD patients had 33% lower total (p = .031) and 43% lower daylight activity (p = .006) in week 1 compared with control subjects. The relative amplitude of the sleep-wake cycle was attenuated by 6% in patients (p = .025); they were phase delayed by 55 minutes (p = .023) and had significantly lower sleep efficiency (p = .030). Total (p = .002) and daylight activity (p = .001) increased after 4 weeks of treatment in SAD patients. Moreover, BLT led to increase of relative amplitude (p = .005), advance of delayed rhythms (p = .036), and improved sleep efficiency (p = .011) in patients. Intradaily stability, measuring the strength of coupling of the rhythm to external zeitgebers, increased by 9% both in patients and healthy control subjects (p = .032). Treatment with BLT normalizes disturbed activity patterns and restores circadian rhythms in SAD patients. BLT might also stabilize the circadian rhythm in nondepressed individuals during the fall-winter season.

Cognitive performance, behavioural and psychological symptoms, and circadian rhythm disturbances in Alzheimer’s disease patients treated with quetiapine or haloperidol

Alzheimer’s Disease (AD) is characterised by cognitive decline, behavioural problems (BPSD) and sleep-wake cycle disturbances: the latter decrease the quality of life of patients and caregivers and result in earlier institutionalisation. 16 AD patients (10 women, 6 men, age:80±2 y, MMSE: 19±1) were enrolled in this 6-week, open, comparative study and randomly assigned to quetiapine or haloperidol. Before and after 4 weeks treatment, we assessed cognitive performance with CERAD, BPSD with NPI and NOSGER, and the circadian rest-activity cycle with actimetry for one week. Some cognitive functions (delayed word recall) improved with quetiapine (p<0.05). Haloperidol worsened depression scores (p<0.05) and increased abnormal motor activity as well as augmenting difficulties in self care, whereas quetiapine improved both symptoms of depression and anxiety (p<0.05). A significant fragmentation of the circadian rest-activity cycle was found after haloperidol, whereas quetiapine tended to consolidate circadian rhythm organisation. Overall, these results show a tendency for quetiapine to improve not only cognitive performance, but also BPSD and circadian rhythm disturbances, in contrast to haloperidol. (Funding: AstraZeneca)