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Psychiatry Research 189 (2011) 62–66 Contents lists available at ScienceDirect Psychiatry Research Schizophrenia patients with predominantly positive symptoms have more disturbed sleep–wake cycles measured by actigraphy Pedro Afonso a,⁎, Sofia Brissos a, Maria Luísa Figueira b, Teresa Paiva ba Lisbon's Psychiatric Hospitalar Center (CHPL), Lisbon, Portugalb Hospital Santa Maria, Faculty of Medicine, University of Lisbon, (FMUL), Lisbon, Portugal Sleep disturbances are widespread in schizophrenia, and one important concern is to determine the impact of Received 28 February 2010 this disruption on self-reported sleep quality and quality of life (QoL). Our aim was to evaluate the sleep–wake Received in revised form 20 December 2010 cycle in a sample of patients with schizophrenia (SZ), and whether sleep patterns differ between patients with Accepted 31 December 2010 predominantly negative versus predominantly positive symptoms, as well as its impact on sleep quality andQoL. Twenty-three SZ outpatients were studied with 24 h continuous wrist-actigraphy during 7 days. The quality of sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI), and the self-reported QoL was Pittsburgh Sleep Quality Index evaluated with the World Health Organization Quality of Life — Abbreviated version (WHOQOL-Bref). About half of the studied population presented an irregular sleep–wake cycle. We found a trend for more disrupted Negative symptoms sleep–wake patterns in patients with predominantly positive symptoms, who also had a trend self-reported worse quality of sleep and worse QoL in all domains. Overall, patients with worse self-reported QoLdemonstrated worse sleep quality. Our findings suggest that SZ patients are frequently affected with sleep andcircadian rhythm disruptions; these may have a negative impact on rehabilitation strategies. Moreover, poorsleep may play a role in sustaining poor quality of life in SZ patients.
2011 Elsevier Ireland Ltd. All rights reserved.
Although sleep architecture improves with antipsychotic treatment, sleep remains mostly fragmented and fails to establish its normal Sleep is an important restorative physiologic process (Suresh Kumar pattern (Kupfer et al., 1970). This suggests that sleep physiology might et al., 2007). The sleep–wake cycle is a circadian rhythm generated and share a common substrate with SZ symptoms (Boivin, 2000; Poulin regulated by the suprachiasmatic nucleus of the hypothalamus, et al., 2003; Cohrs, 2008). Furthermore, worse sleep quality has been synchronized by internal (body) and external (environment) stimuli associated with poorer quality of life (QoL), even after correcting for (Albrecht, 2002; Van Gelder, 2004).
depression and drug effects (Hofstetter et al., 2005; Ritsner et al., 2004).
Patients with schizophrenia (SZ) frequently experience sleep Positive and negative symptoms, neurocognitive impairment and brain problems (Keshavan et al., 1990; Taylor et al., 1991; Tandon et al., structure may also correlate with important sleep variables such as sleep 1992; Monti and Monti, 2004; Cohrs, 2008), like advanced sleep phase latency, sleep efficiency, SWS, and REM sleep parameters (Cohrs, 2008).
syndrome and hypersomnia with short naps (Wirz-Justice et al., REM density was inversely correlated with positive, cognitive, and 2001). Reduced sleep efficiency and total sleep time, increased sleep emotional discomfort symptoms as well as the total score on the Positive latency, decrease in slow wave sleep (SWS) and rapid eye movement and Negative Syndrome Scale (Yang and Winkelman, 2006).
(REM) latency have also been reported in most patients with SZ However, because of the limited number of methodologically (Tandon et al., 1992; Zarcone et al., 1987; Keshavan et al., 1998). This is rigorous studies, no clear statement can be made about the influence especially true during psychotic episodes (Kupfer et al., 1970), but also of these variables on sleep structure (Cohrs, 2008). Actigraphy has been in the prodromal phase (Donlon and Blacker, 1975; Cohrs, 2008).
used in SZ to study sleep and circadian rhythms (Haug et al., 2000; It remains unclear whether sleep problems in SZ are secondary Poyurovsky et al., 2000; Shamir et al., 2000; Hofstetter et al., 2005; to social withdrawal and reclusive behavior, to medication, or to an Martin et al., 2005; Wulff et al., 2006), but studies have been limited, abnormality of the neuroendocrine systems regulating sleep and probably for methodological feasibility reasons (Vanelle, 2009).
wakefulness (Wulff et al., 2006).
One of the most important goals in SZ treatment is social and professional rehabilitation. To accomplish this, physiologic sleep,compatible with work routines and timetables is necessary.
We aimed to evaluate the sleep–wake cycle in a sample of SZ ⁎ Corresponding author. Lisbon Psychiatry Hospital Center, Av. do Brasil n°. 53, 1749- 002 Lisbon, Portugal. Tel.: +351 217917000; fax: +351 217 952 989.
patients, and whether sleep patterns differed between patients with E-mail address: (P. Afonso).
predominantly negative versus predominantly positive symptoms.
0165-1781/$ – see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.psychres.2010.12.031 Author's personal copy
P. Afonso et al. / Psychiatry Research 189 (2011) 62–66 Moreover, we hypothesized that worse quality and sleep patterns, would be associated with poorer self-reported QoL.
Sociodemographic and clinical characteristics.
2. Material and methods positive symptoms) negative symptoms) 2.1. Participants Gender (men:women) Data herein reported is based on an ongoing investigation on sleep characteristics of SZ patients at Lisbon's Psychiatric Hospital Center. Twenty-three patients with SZ,aged 19–52 yrs, were diagnosed according to DSM-IV criteria (APA, 2000), ascertained from interview with a psychiatrist and medical chart review. Patients were evaluated with the Positive and Negative Syndrome Scale — PANSS (Kay et al., 1989). Based on Educational level (yrs) the PANSS scores, patients were divided into two groups according to symptom Illness duration (yrs) preponderance: Group 1 (n = 11) included patients with predominant positive Number of admissions symptoms, and Group 2 (n= 12) included patients with predominant negative Legend: yrs: years; S.D.: standard deviation.
⁎ p b0.05.
At the time of evaluation all patients had been on a stable medication regimen for at least 1 month. Patients taking benzodiazepines in daily doses lower than the equivalentof diazepam 15 mg (never taken after 18h00) were accepted. A minimum washoutperiod of 72 h was obligatory for hypnotic medication. The daily dosage of (iii) mean duration (s) of uninterrupted immobility (MIP)(activity =0). The mean antipsychotics and diazepam used in each treatment group was as follows. (1) Group duration of uninterrupted immobility periods (MIP) provides a global measure 1; olanzapine (n=4), mean 18.8 mg; quetiapine (n=1), mean 600 mg; risperidone of the distribution and number of immobility periods.
(n=3), mean 6 mg; clozapine (n=3), mean 367 mg; diazepam (n=2) mean 7.5 mg;(2) Group 2: olanzapine (n=4), mean 17.5 mg; quetiapine (n=1), mean 400 mg; 2.4. Statistical analysis risperidone (n=2), mean 4.5 mg; clozapine (n=4), mean 362.5 mg; ziprasidone(n=1), mean 120 mg; diazepam (n=3) mean 8.3 mg.
Both groups were compared in sociodemographic, and clinical variables using Schizoaffective disorder, organic impairment, previous head trauma or neurolog- nonparametric Mann–Whitney test, Chi-Square and contingency (symmetry). Correla- ical disorders, or substance abuse/dependence were considered exclusion criteria.
tions of sociodemographic and clinical variables, WHOQOL-BREF, PSQI, and actigraphy Patients working night-shifts were also excluded.
data were calculated through Spearman correlation. We used SPSS 17.0 (SPSS Inc., The local Ethics committee approved the study, and all participants provided Chicago, IL, USA).
written informed consent.
2.2. Assessment instruments The quality and patterns of sleep were measured with the Pittsburgh Sleep Quality Social, demographic, and clinical characteristics of our sample are Index (PSQI) (Buysse et al., 1989). This self-report questionnaire rates sleep quality and presented in Table 1. Significant statistical differences were found patterns during the previous month, and evaluates 7 components of sleep: subjective only in professional activity, patients with preponderant negative quality, latency, duration, usual efficiency, sleep disturbances, medication use, anddaytime dysfunction. The score is given through a Likert-like scale, between 0 and 3, symptoms being all inactive.
with a cut-off value of 5, higher scores meaning worse sleep quality.
There was no difference in PANSS total (Group 1, mean 89.4, S.D.
Subjective quality of life (QoL) was assessed using the WHO Quality of Life Measure — 19.3; Group 2, mean 82, S.D. 22.6) or general psychopathology results Abbreviated version (WHOQOL–BREF–PT), Portuguese version. The 26-item version between both groups (Group 1, mean 48.5, S.D. 10.5; Group 2, mean WHOQOL–BREF (W.H.O.Q.O.L. Group, 1994) provides measurement on four domains: 44, S.D. 11.0). Because of the patients' allocation, the positive physical, psychological, social relationships, and environment. Higher scores meanbetter QoL.
symptom's PANSS subscale results were higher in Group 1 (mean Wrist-actigraphy was used for sleep–wake cycle assessment. Actigraphy provides 24.2, S.D. 5.4) than in Group 2 (mean 12.3, S.D. 3.2). On the other the recording of continued limb motor activity during 24 h or longer periods and is a hand, negative symptom's PANSS subscale results were higher in the useful and validated instrument for sleep studies (Ancoli-Israel et al., 2003). Actimeters latter (mean 26.1, S.D. 9.2) than in Group 1 (mean 16.6, S.D. 5.2). For (SomnoWatch® actigraphy system) were strapped on the patients' nondominantwrists. Movement counts of the actigraph were stored in 1 second interval, with the these results, there was statistical significance.
signal sampled at 32 Hz with 12 Bit ADC, allowing continuous recording for 168 h Both groups presented a score above of 5 on the PSQI, which is (7 days) on the 16 MB memory. We chose the smallest possible interval to achieve considered as poor sleep quality (Table 2). Group 2 subjects self- maximum temporal resolution. Since actigraphy cannot distinguish between sleep and reported better QoL in all domains, compared to Group 1, but the sedentary activities, subjects recorded in a diary, bed and wake times, awakenings differences were not statistically significant (Table 2).
at night, day naps, and other activities. During the study period all participants usedthe equipment at all times, except when bathing. In these situations we asked No significant differences were found in motor activities measure- the participants to mark this period by pressing a button to mark events on the ments during wakefulness (day) and sleep (night) between the two SomnoWatch® (before and after bathing). Data during these periods were treated as groups (Table 3).
2.3. Sleep/wake variables and actigraphic parameters Table 2Quality of sleep and quality of life in both patient groups.
Sleep latency was considered as the time period between turning-off the light and falling asleep. The actigraph contains a light sensor that measures the time between the instant when the light goes off and the reduction of motor activity (typical of sleep onset). To score sleep onset we used the 5 min of actigraphic immobility criterion (Chae positive symptoms) negative symptoms) Test et al., 2009). To assess sleep–wake cycles the actogram was visually analysed and confronted with the sleep log information given by the patients. The sleep–wakerhythm was considered regular when there was a clear distinction between sleep/ inactivity occurring at night and wake/activity periods occurring during the day, and regular occurrences of both during the week.
Using the sleep log information, and the light sensor information, we divided the WOQOL — physical data between night (period between lights off and wake) and day period. Data were transferred to our own EXCEL® templates for further analyses. We chose to extract WOQOL — psychological three variables from the data that had previously been described (Middelkoop et al., 1997). Actigraphy measures were calculated as follows: WOQOL — social domain 40.4 (20.7) WOQOL — environmental 59.7 (17.5) (i) movement index (MI) (%), indicating the percentage of epochs with an activity Legend: PSQI: Pittsburgh Sleep Quality Index; WHOQOL: World Health Organization (ii) activity level (AL), number of activity counts per hour.
Quality of Life.

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P. Afonso et al. / Psychiatry Research 189 (2011) 62–66 Actigraphy results between the patient groups.
Our results show that there is a trend for more disrupted sleep– wake patterns and circadian activity rhythms in SZ patients with positive symptoms) negative symptoms) predominant positive symptoms. In fact, Group 1 patients self- reported worse quality of sleep as compared to Group 2, except forone item (hypnotic use). Moreover, Group 1 patients self-reported Sleep latency (min) Movement index (%) worse QoL in all domains as compared to patients with predominant negative symptoms, indicating that worse sleep patterns may lead to worse subjective quality of sleep and QoL. Our results support Activity level (number of counts/hour) previous findings that SZ patients show more disrupted sleep–wake patterns and circadian activity compared to healthy subjects (Martin Uninterrupted immobility duration (s) et al., 2005).
An important aspect in actigraphy results was sleep latency; in both groups sleep latency proved to be quite long (usually, sleep latency Regular sleep–wake should take about 30 min), as confirmed by the patients' subjective opinion of worse quality of sleep.
Legend: min: minutes; s: seconds; S.D.: standard deviation.
We found differences, although not statistically significant, b Chi-square test.
between the groups regarding regular sleep–wake rhythms; 11 outof 23 subjects showed an irregular sleep–wake rhythm. We verified arelative absence of a circadian pattern of the sleep–wake cycle. The Group 1 presented worse actigraphy patterns with 7 patients (64%) actogram and the sleep log showed that sleep times were randomly presenting an irregular sleep–wake cycle (Fig. 2) and only 4 patients distributed throughout the day and night and sleep duration and showing regular sleep–wake cycles (Table 3 and Fig. 1). Sleep latency wake-up episodes were variable and unpredictable during the 24 h was higher in Group 1 (Table 3), but these differences were not period. Actigraphy confirmed daytime napping and nighttime statistically significant. Only 36% of Group 1 patients presented fragmentation, a common finding in SZ patients (Yamadera et al., normal alternation between sleep/wake states, as compared to 67% in Group 2; however, these differences were not statistically significant.
We found a significant association between psychopathology and In Group 2, 4 patients (33%) presented irregular sleep–wake pattern, general symptoms, and quality of sleep, but no significant correlations while 8 showed regular sleep–wake cycles; these differences were with positive and negative symptoms, and quality of sleep. Other not significant (Chi2=2.112; p=0.220), but the contingency analysis symptoms, namely depressive, could possibly influence more the showed symmetry among them (p=0.146).
quality of sleep, than positive or negative symptoms. We were able to Significant negative correlations were found between PANSS sub- replicate earlier findings showing that in schizophrenia self-reported scales' scores and WHOQOL-BREF and PSQI scores, indicating that QoL is associated with quality of sleep (Ritsner et al., 2004; Hofstetter higher symptom levels correlate with lower self-reported QoL and et al., 2005; Xiang et al., 2009). In our sample, patients with worse quality of sleep (Table 4). However, we found no significant predominant negative symptoms reported better quality of sleep correlations between sleep/wake variables and quantitative motor and better QoL. Patients with negative syndrome present low motor activity on actigraphy, and scores on any PANSS subscales, and/or any activity levels (Walther et al., 2009), possibly facilitating sleep. On the QoL domain (data not shown).
other hand, hallucinations and delusions may cause difficulty in falling Fig. 1. Regular sleep–wake rhythm (actogram obtained by actigraphy over a 7-day period).

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P. Afonso et al. / Psychiatry Research 189 (2011) 62–66 Fig. 2. Irregular sleep–wake rhythm (actogram obtained by actigraphy over a 7-day period).
asleep, and thereby having a negative impact on both sleep quality and fetal organs such as the brain and pineal gland (Richardson-Andrews, 2009). Moreover, lesions of the suprachiasmatic nucleus have been Evidence shows that when circadian rhythm sleep is disturbed, postulated to play an important role in the aetiology of SZ (Trbovic, daytime sleepiness, insomnia, and displacement of social timetables 2010). Therefore, future studies should explore the relation between occur (APA, 2000). This contributes negatively to rehabilitation sleep–wake cycles and melatonin levels in SZ patients.
interventions. Interestingly, we found an association between having The inclusion of patients who were taking benzodiazepines before a daily occupation, and better sleep quality and lower sleep latency, 18h00 is a study limitation, since activity levels are significantly indicating that social and professional rehabilitation could reflect reduced following an acute administration of lorazepam 2.5 mg positively in the patients' circadian rhythms.
(Dawson et al., 2008). Despite that, in our sample all the 4 patients Unexpectedly, we found no significant correlations between had been taking diazepam (medium dose=8 mg) for long-term. Our psychopathology, self-reported QoL and quality of sleep, and sleep/ patients presented elevated symptom levels, and therefore our results wake variables registered by actigraphy, possibly due to the small may not be applicable to patients in remission.
sample size. Also, our sample consisted of rather symptomatic patients, Previous studies reported lower quantitative motor activity possibly with low insight into their quality of sleep and QoL.
parameters than those of the present study (Walther et al., 2009; Atypical antipsychotics tend to improve sleep induction and/or Farrow et al., 2005; Farrow et al., 2006). This can probably be explained sleep maintenance in SZ patients (Monti and Monti, 2004), and most by differences in algorithms used for calculation of activity and by atypical antipsychotics demonstrate an increase in total sleep time differences between the actigraphs, since they have different sensor and/or sleep efficiency in SZ patients, with the exception of risperidone types, sampling rates and storage rates. Furthermore, the American (Cohrs, 2008). To disentangle the effects of schizophrenia itself Academy of Sleep Medicine (AASM) referred some problems when from the influence of medication on sleep is difficult (Cohrs, 2008), comparing actigraphy data. According to the "AASM Standards and but it seems unlikely that treatment only could explain the differences Practice", additional research is needed which compares results from between the groups.
different actigraphy devices and the variety of algorithms used to The causes for the present findings remain unknown. The tendency evaluate actigraphy data in order to further establish standards of for more daytime inactivity sleepiness periods in Group 2 patients actigraphy technology (Morgenthaler et al., 2007).
may be explained by social withdrawal, reclusive behavior, and Quantitative motor activity parameters during wakefulness were low motor activity levels associated with the negative syndrome related to the clinically assessed negative syndrome in schizophrenia (Walther et al., 2009). On the other hand, positive symptoms, namely (Walther et al., 2009). In our study we didn't replicate these findings, suspiciousness, hallucinations and hyperactivity, could make it harder probably because of the small sample size. Furthermore, we didn't for the patients to fall asleep, due to an increased neurophysiologic find a relation between motor activity parameters and sleep–wake arousal, explaining the longer sleep latency, and lower total sleep time rhythm. This could be explained by the fact that schizophrenia found in this group.
is a heterogeneous disease with significant differences in activity or Another good candidate to explain changes in the sleep–wake immobility periods. Therefore, the volume of specific executive brain rhythm is melatonin, a hormone produced by the pineal gland, and an structures may affect motor behaviors. Cumulative motor activity endogenous synchronizer of circadian rhythms. Nocturnal plasma over a 20 h period was correlated with the volume of left anterior melatonin levels have been reported to be reduced in SZ patients as cingulate cortex in schizophrenia patients (Farrow et al., 2005).
compared with normal controls (Shamir et al., 2000; Viganò et al., 2001; Finally, our results are preliminary and due to the small sample Mann et al., 2006; Suresh Kumar et al., 2007), probably due to changes size, and lack of a control group, need further replication.
of the pineal gland (Sandyk et al., 1990). Some theories have proposed In summary, our findings show a trend for more disrupted sleep– that SZ is caused by a damage produced in utero, to zinc dependent wake patterns and circadian activity rhythms in SZ patients with Author's personal copy
P. Afonso et al. / Psychiatry Research 189 (2011) 62–66 predominant positive symptoms; these patients also self-reported Martin, J.L., Jeste, D.V., Ancoli-Israel, S., 2005. Older schizophrenia patients have more worse quality of sleep and worse QoL in all domains as compared to disrupted sleep and circadian rhythms than age-matched comparison subjects.
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