Clinical significance of sleep EEG abnormalities in chronic schizophrenia

Schizophrenia Research 82 (2006) 251 – 260 www.elsevier.com/locate/schres

Clinical significance of sleep EEG abnormalities in chronic schizophrenia Changkook Yang a, John W. Winkelman b,* b

a Department of Psychiatry, Dong-A University College of Medicine, Busan, Korea Brigham & Women’s Hospital, Divisions of Sleep Medicine and Psychiatry, Harvard Medical School, Boston, MA 02115, U.S.A.

Received 1 July 2005; received in revised form 26 October 2005; accepted 31 October 2005 Available online 27 December 2005

Abstract This study aimed to investigate the relationship between measures of clinical symptom severity and sleep EEG parameters in a relatively diagnostically homogeneous group of patients with schizophrenia. We obtained sleep EEG data in 15 drug-free inpatients who met DSM-IV-R criteria for schizophrenia, undifferentiated type, with 15 age- and sex-matched normal controls over two consecutive night polysomnographic recordings. Clinical symptoms were assessed by the Positive and Negative Symptom Scale (PANSS) and Hamilton Rating Scale for Depression. Characteristic features of sleep disturbance were seen in patients with schizophrenia: profound difficulties in sleep initiation and maintenance, poor sleep efficiency, a slow wave sleep (SWS) deficit, and an increased REM density. SWS was inversely correlated with cognitive symptoms. REM density was inversely correlated with positive, cognitive, and emotional discomfort symptoms as well as PANSS total score. Our data demonstrate that drug-free patients with chronic undifferentiated type schizophrenia suffer from profound disturbances in sleep continuity and sleep architecture. Both the SWS deficit and cognitive impairment found in schizophrenics in this study may relate to similar underlying structural brain abnormalities. D 2005 Elsevier B.V. All rights reserved. Keywords: Sleep EEG; SWS deficit; Cognitive impairment; Schizophrenia

1. Introduction Sleep EEG research in schizophrenia during the past several decades has focused on the relationship * Corresponding author. Tel.: +1 617 527 2227x119; fax: +1 617 527 2098. E-mail address: [email protected] (J.W. Winkelman). 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.10.021

between sleep parameters and underlying clinical symptoms. Schizophrenia is associated with a number of sleep EEG abnormalities, including difficulty in sleep initiation and maintenance (Tandon et al., 1992; Hudson et al., 1993; Lauer et al., 1997; Keshavan et al., 1998), decreased total sleep time (Tandon et al., 1992; Keshavan et al., 1998), poor sleep efficiency (Tandon et al., 1992; Lauer et al., 1997; Keshavan et al., 1998), a slow wave sleep (SWS) deficit (Hiatt et

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al., 1985; Ganguli et al., 1987; Keshavan et al., 1998; Poulin et al., 2003), and shortened REM latency (Hiatt et al., 1985; Tandon et al., 1992; Hudson et al., 1993; Poulin et al., 2003). Not all studies, however, have shown consistent findings. Such disparities may relate to differences in sample size, demographic features, phase of illness, type of treatment being received at the time of study (drug-naive vs. drug-free, drug-free duration), and diagnostic criteria for schizophrenia, as well as the definition of sleep parameters. Discrepant findings may also relate to the underlying pathophysiological and phenotypic heterogeneity of schizophrenia. Therefore, an investigation of sleep EEG in a homogeneous schizophrenia sample with control for additional confounding factors, would be of value. Sleep EEG abnormalities in schizophrenia may provide insight into the anatomical and/or neurophysiological pathophysiology of schizophrenia. For instance, particular sleep variables provide the bridge between clinical dimensions of schizophrenia and their underlying biological basis. There is little consensus regarding the relationship of sleep abnormalities to clinical symptoms of schizophrenia (Ganguli et al., 1987; Van Kammen et al., 1988; Tandon et al., 1989, 1992; Keshavan et al., 1995; Lauer et al., 1997; Zarcone and Benson, 1997). Although some studies suggested that a SWS deficit (Ganguli et al., 1987; Van Kammen et al., 1988; Tandon et al., 1989) or a decrease in REM latency (Tandon et al., 1989) was correlated with negative symptoms, others reported that total delta count (a marker of SWS) was negatively associated with positive symptoms (Keshavan et al., 1995). Other investigators failed to find any such relationships (Lauer et al., 1997). Comprehensive models of schizophrenia have increasingly included symptoms of cognitive impairment as a distinctive feature of this disorder, independent of positive and negative symptoms (Bell et al., 1994; Lanc¸on et al., 2000). Bell et al. (1994) performed a factor analysis of the Positive and Negative Syndrome Scale (PANSS, Kay et al., 1987) in patients with schizophrenia or schizoaffective disorder and found 5 symptom clusters: positive, negative, cognitive, hostility, and emotional discomfort. Several factor analytic studies have supported this model (Lanc¸on et al., 2000). To our knowledge, there is no study examining the relationship between cognitive symptoms derived from PANSS and sleep parameters.

The present study was designed to investigate the relationship between measures of clinical symptom severity, in particular cognitive symptoms, and sleep EEG parameters in a relatively diagnostically homogeneous group of patients with schizophrenia.

2. Methods 2.1. Subjects The subjects were recruited from a long-term facility of a regional metropolitan hospital according to their free will. They were given an explanation of the study processes and it was explained that they were allowed to discontinue study participation freely anytime they wanted and further, that the withdrawal from study would not affect any aspect of their treatment or hospital life. All patients were withdrawn from their routine medication solely for this study. Twenty-two patients were recruited for this study. Among them, 2 patients declined to participate during drug withdrawal without specific reasons and one patient was dropped out because his psychotic symptoms aggravated when his medication was withdrawn. Thus, 19 patients were included in this study. All patients met Diagnostic and Statistical Manual for Mental Disorders—Fourth Edition (APA, 1994) criteria for schizophrenia, undifferentiated type, based on diagnostic interviews using the Structured Clinical Interview for DSM-IV Axis I (Korean version) (Han and Hong, 2000). Diagnostic evaluation included a review of clinical records, an interview of family members, and clinical observations. None of the patients fulfilled current or lifetime diagnostic criteria for any other psychiatric disorders. Patients with a life-time history of alcohol or other substance abuse were excluded, as were those with current or recent evidence of a significant medical disorder, those with a history of electroconvulsive therapy, and those with a history of head injury with loss of consciousness. None of the patients had movement disorders including tardive dyskinesia. Patients with first-degree relatives with a current or life-time history of mood disorder were excluded. The mean age was 40.6 F 3.7 years (range 33–45). The mean age of onset was 23.4 F 3.0 years (range 18–30). The mean duration of illness was 17.3F 3.7 years (range 12–

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23). As indicated in Table 1, our patients were chronically ill and negative symptoms predominant. Patients were free of psychotropic medications for a minimum 2 weeks. Pharmacological intervention was only allowed for sleep onset insomnia, and only within the first 5 days of initial neuroleptic discontinuation. Three patients took zolpidem 10 mg at bedtime one to three times during this initial stage. Twelve of 15 patients (80.0%) were smokers who smoked 12 or less cigarettes a day. Coffee was disallowed during hospitalization by hospital regulations. The patients were asked to stop smoking tobacco 6 h prior to polysomnographic recording. Daytime naps were not allowed on the polysomnographic recording day. Seventeen healthy men, mean age of 40.2 F 4.1 years (range 35–47) with no personal or family history of psychiatric disorders served as a normal control group. No significant age difference was noted between patients and normal controls. All normal controls were hospital personnel and were not shift workers. Three of 15 normal controls (20.0%) were smokers who smoked 10–20 cigarettes a day. No alcoholic beverages were allowed for the normal controls for 1 week before polysomnographic recording. The normal controls were also asked to stop drinking coffee after noon on the polysomnographic recording day and to stop smoking tobacco 6 h prior to polysomnographic recording. Among 19 patients with schizophrenia, two patients refused to continue with the second night of polysomnographic recording. Two patients and two of

Table 1 Demographic and clinical characteristics of patients with schizophrenia Mean Age (year) Age of onset (year) Illness duration (year) PANSS Positive symptoms Negative symptoms Cognitive symptoms Hostility symptoms Emotional discomfort symptoms Total HRSD

SD

Range

40.6 23.4 17.3

3.7 3.0 3.7

33~45 18~30 12~23

13.8 33.0 23.8 8.7 12.0 94.5 12.0

4.3 6.8 5.9 2.6 2.9 18.2 3.5

7.0~21.0 23.0~44.0 16.0~38.0 5.0~15.0 8.0~17.0 65.0~131.0 6.0~17.0

PANSS: Positive and Negative Symptom Scale. HRSD: 17-item Hamilton Rating Scale for Depression.

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17 normal controls each had sleep apnea and periodic limb movement disorder. Thus, each group included 15 evaluable subjects for this study. All participants provided written informed consent prior to study inclusions and were compensated for study participation. This study was approved by the Institutional Review Board at Dong-A Medical Center. 2.2. Clinical ratings The Positive and Negative Symptom Scale (PANSS, Kay et al., 1987) and the 17-item Hamilton Rating Scale for Depression (HRSD, Hamilton, 1960) were used to assess the severity of clinical symptoms. Two trained psychiatrists rated these scales independently using a semi-structured clinical interview during the same session. These clinical ratings were obtained on the day of the first night polysomnographic recording. For both scales, item by item scores were obtained by averaging the two raters’ independent ratings. The PANSS consists of a 30-item scale: each item is rated discretely from d1T (not present) to d7T (extremely severe). Separate scores were determined for positive, negative, cognitive, hostility, and emotional discomfort clusters, according to Bell et al. (1994). These symptom clusters were chosen because their sample was similar to ours with regard to the subjects’ age, chronicity, and gender. In our study, interrater reliability (intraclass r) was 0.97 for positive symptoms, 0.91 for negative symptoms, 0.96 for cognitive symptoms, 0.71 for hostility symptoms, 0.76 for emotional discomfort symptoms, and 0.93 for PANSS total score. Interrater reliability for the HRSD was 0.85. 2.3. Polysomnographic recording All polysomnographic recordings were obtained after a minimum drug-free period of 2 weeks. All subjects slept in the sleep laboratory unit for two consecutive nights and were allowed to retire and wake up at their habitual sleeping and waking times. A fullmontage polysomnogram was recorded using Embla (Flaga, Iceland), consisting of an EEG (C4/A1, C3/A2, O2/A1, O1/A2), EOG, submental EMG, snoring microphone, nasal–oral airflow, abdominal and chest respiratory efforts, EKG, finger oximetry, and anterior tibialis EMG. The first night served as an adaptation night and as an additional screening for primary sleep

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Table 2 Comparison of sleep structure between patients with schizophrenia and normal controls Sleep architecture

Patients (mean F SD)

Controls (mean F SD)

df

Stage 1 (min) Stage 1 (%) Stage 2 (min) Stage 2 (%) Stage 3 (min) Stage 3 (%) Stage 4 (min) Stage 4 (%) Slow wave sleep (min) Slow wave sleep (%) Stage REM (min) Stage REM (%)

96.5 F 55.4 26.4 F 12.5 157.6 F 64.1 43.3 F 13.8 15.2 F 10.8 4.6 F 4.0 7.0 F 9.0 2.2 F 3.0 22.1 F15.8 6.8 F 5.6 85.0 F 33.6 23.5 F 6.6

38.8 F 14.6 10.6 F 4.1 190.9 F 31.3 51.5 F 6.4 26.3 F 13.1 7.2 F 3.7 28.4 F 18.9 7.8 F 5.2 54.8 F 22.2 14.9 F 6.1 85.2 F 14.4 23.0 F 3.2

15.9 17.1 20.3 19.7 28 28 20.1 22.4 25.3 27.8 19 20.2

disorders including sleep apnea and periodic limb movement disorder. The sleep records were scored visually according to standard criteria (Rechtschaffen and Kales, 1968) by a trained technician who was blind to group and to the clinical data. The authors defined sleep apnea syndrome and periodic leg movement of sleep according to the International Classification of Sleep Disorders criteria (ASDA, 1997), in which a respiratory disturbance index (RDI) greater than 5 and a periodic leg movements index greater than 5 are regarded as abnormal. Four patients and one control, however, who had RDI ranging from 5.5 to 5.9 were included because they reported no daytime sleepiness and their RDI in the first night study was lower than 5. The definition of the sleep parameters was as follows: sleep latency was defined as the time from lights off to first occurrence of three consecutive epochs of stage 1 sleep, or an epoch of any other sleep stage. Total sleep time was defined as total minutes of sleep obtained during the recording period. Sleep efficiency was defined as the percent of time spent asleep divided by the total

t

p-value 3.90 4.67 1.81 2.07 2.55 1.82 3.96 3.59 4.63 3.79 0.02 0.27

0.0013 0.0002 0.0850 0.0515 0.0167 0.0790 0.0008 0.0016 b0.0001 0.0007 0.9833 0.7903

recording period. SWS was the sum of stages 3 and 4 sleep. SWS latency was defined as the time between sleep onset and the first occurrence of stage 3 or 4 sleep. REM sleep latency was defined as the time between sleep onset and the first occurrence of a REM period of 3 min or more in duration, minus the time awake during the first non-REM period. REMs were counted visually and REM density was defined as the number of REMs divided by the total REM time, in minutes. 2.4. Statistics The data was analyzed using SAS program (version 6.12). Comparison of sleep parameters between patients and normal controls was made using the Student t-test. Intercorrelations among variables were analyzed by computing Pearson correlation coefficients. 3. Results No significant differences between groups were observed for respiratory indices. Mean apnea-hypopnea index was

Table 3 Comparison of sleep continuity between patients with schizophrenia and normal controls Sleep continuity

Patients (N = 15) mean F SD

Controls (N = 15) mean F SD

df

Time in bed (min) Sleep latency (min) Total sleep time (min) Waking time after sleep onset (min) Sleep efficiency (%) Slow wave sleep latency (min) Arousal index Awakening index (b60 s) Awakening index (z60 s)

555.9 F 28.2 63.8 F 56.3 367.8 F 92.6 130.0 F 77.8 64.4 F 15.3 40.6 F 28.2 14.1 F10.9 8.2 F 4.5 4.2 F 2.8

374.2 F 42.0 4.6 F 4.2 369.9 F 26.1 19.6 F 9.5 93.9 F 2.7 16.1 F12.9 6.6 F 2.4 3.3 F 1.2 0.9 F 0.6

28 14.2 16.2 14.4 14.8 17.9 15.4 16 15.2

t

p-value 13.92 4.05 0.09 5.46 7.34 2.98 2.58 4.06 4.55

b0.0001 0.0012 0.9326 b0.0001 b0.0001 0.0080 0.0206 0.0009 0.0004

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Table 4 Comparison of REM sleep measures between patients with schizophrenia and normal controls REM sleep measures

Patients (N = 15) mean F SD

Controls (N = 15) mean F SD

df

REM latency (min) First REM period (min) Second REM period (min) First REM density Second REM density Total REM density

66.4 F 37.4 14.8 F 12.0 14.6 F 9.6 9.5 F 6.7 9.9 F 5.9 10.2 F 3.6

66.5 F 24.1 20.8 F 14.4 18.9 F 10.8 4.7 F 3.2 7.7 F 6.6 7.3 F 3.6

28 28 28 20.1 28 26

t

p-value 0.01 1.24 1.16 2.55 0.95 2.10

0.9897 0.2248 0.2541 0.0191 0.3484 0.0452

REM sleep latency was defined as the time between sleep onset and the first occurrence of a REM period of 3 min or more in duration, minus the time awake during the first non-REM period. REM density is the number of REM divided by stage REM minutes.

they had much more of that time spent awake after initially falling asleep, leading to an equivalent total sleep time.

2.0 F 2.0 (range 0.4–5.9) for patients and 2.4 F 1.8 (range 0.5–5.5) for normal controls. Mean lowest arterial oxygen saturation was 87.7 F 2.1% (range 83.0–91.0) for patients and 88.9 F 2.1% (range 84.0–92.0) for normal controls. Periodic leg movement of sleep index was 0.5 F 1.1 (range 0–4.3) for patients and 0.3 F 0.4 (range 0–1.2) for normal controls ( p N 0.1).

3.2. REM sleep parameters REM latency did not show a significant difference between patients and normal controls. However, two of 15 patients with schizophrenia (13.3%), and none of 15 normal controls had REM latencies of shorter than 10 min, and 4 of 15 patients with schizophrenia (26.7%) and 1 of 15 normal controls (6.7%) had REM latencies of shorter than 40 min. Patients with schizophrenia showed significantly greater REM densities during the first REM period and in total REM than normal controls (Table 4).

3.1. Sleep architecture and continuity Stage 1 sleep percentage was significantly increased, while stages 3 and 4 percentages, and total slow wave sleep percentage, were all significantly decreased in patients with schizophrenia as compared with normal controls (Table 2). Four of 15 patients (26.7%) and none of 15 normal controls had no scorable stage 4 sleep. Seven of 15 patients (46.7%) and 1 of 15 normal controls (6.7%) had less than 2 min of stage 4 sleep in the entire night. As a group, patients with schizophrenia showed significant disturbances of sleep continuity as compared with normal controls (Table 3). Waking time after sleep onset, arousal index, and awakening index were all significantly increased, and sleep efficiency was significantly decreased, in patients with schizophrenia. Patients with schizophrenia had substantially longer time in bed than controls. In addition,

3.3. Clinical symptoms and selected sleep parameters Pearson’s correlation coefficients between clinical symptoms and sleep parameters of interest are presented in Table 5. Stage 1 sleep percentage was positively correlated with positive symptoms (r = 0.53, p b 0.05), negative symptoms (r = 0.60, p b 0.02), cognitive symptoms (r = 0.64, p = 0.01), and PANSS total score (r = 0.57, p b 0.03). SWS percentage (r = 0.63, p b 0.01) was inversely correlated with cognitive symptoms (Fig. 1). Total REM density was

Table 5 Pearson correlation coefficients between sleep parameters and clinical symptoms Sleep parameters

PANSS Positive symptoms r ( p-value)

Stage 1 (%) Stage 2 (%) Slow wave sleep (%) Stage REM (%) REM latency (min) Total REM density

0.534 0.316 0.249 0.142 0.134 0.624

(0.040) (0.251) (0.370) (0.614) (0.634) (0.017)

Negative symptoms r ( p-value) 0.595 0.508 0.330 0.211 0.037 0.320

PANSS: Positive and Negative Symptom Scale.

(0.019) (0.053) (0.229) (0.450) (0.896) (0.265)

Cognitive symptoms r ( p-value) 0.644 0.476 0.626 0.303 0.082 0.559

(0.010) (0.073) (0.013) (0.272) (0.770) (0.038)

Hostility symptoms r ( p-value) 0.360 0.447 0.038 0.289 0.251 0.305

(0.187) (0.095) (0.893) (0.296) (0.366) (0.289)

Emotional symptoms r ( p-value) 0.398 0.258 0.350 0.072 0.130 0.615

(0.142) (0.354) (0.202) (0.798) (0.645) (0.019)

Total score r ( p-value) 0.572 0.378 0.489 0.116 0.073 0.645

(0.026) (0.165) (0.064) (0.680) (0.796) (0.010)

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Fig. 1. Correlation between slow wave sleep (%) and cognitive symptoms. Cognitive symptoms, derived from the PANSS, consist of difficulty in abstract, stereotyped thinking, cognitive disorganization, lack of judgment and insight, poor attention, tension, and mannerisms and posturing.

inversely correlated with positive symptoms (r = 0.62, p b 0.02), cognitive symptoms (r = 0.56, p b 0.04), emotional discomfort symptoms (r = 0.62, p b 0.02), and PANSS total score (r = 0.65, p = 0.01). HRSD total score was unrelated to any clinical symptoms.

4. Discussion Our data showed the characteristic features of sleep disturbance seen in many studies of patients with schizophrenia. As a group, patients had profound difficulties in sleep initiation and maintenance, reduced SWS, and an increased REM density. We found that SWS and REM density were both inversely correlated with clinical symptoms. Our data are the first to establish a relationship between specific sleep abnormalities (reduced SWS and reduced REM density) and cognitive deficits extracted from the PANSS in schizophrenia. Nearly all sleep studies in patients with schizophrenia have documented increased stage 1 sleep, increased wake time after sleep onset, and a marked increase in sleep onset latency, which result in poor sleep efficiency (Ganguli et al., 1987; Hudson et al., 1993; Benson and Zarcone, 2000). Our data reconfirmed these findings. These findings are also frequently found in other psychiatric disorders as well as in primary sleep disorders (Lauer et al., 1991; Hudson et al., 1993).

Our patients showed a profound SWS deficit, which was more confined to the stage 4 sleep component of SWS. Approximately one-fourth of our patients had no scorable stage 4 sleep at all and almost half of patients had less than 2 min of stage 4 sleep in the entire night. This SWS deficit is thought to be a characteristic feature of the sleep EEG of patients with schizophrenia, and has been reported in acute, chronic, and remitted patients with schizophrenia (Feinberg et al., 1969; Hiatt et al., 1985; Keshavan et al., 1996, 1998) and drug-naive patients with schizophrenia (Poulin et al., 2003), though other studies have failed to find this deficit in either drugnaive (Ganguli et al., 1987; Tandon et al., 1992) or drug-free schizophrenia (Tandon et al., 1992; Hudson et al., 1993; Lauer et al., 1997). The paucity of stage 4 sleep is comparable to the report of Benson et al. (1991) and is regarded as the most consistent abnormality of sleep in schizophrenia (Feinberg et al., 1969; Hiatt et al., 1985; Zarcone and Benson, 1997). Many researchers have been interested in the REM sleep of patients with schizophrenia because of the similarity between psychotic symptoms (hallucinations in particular) and dreams. We observed no differences between schizophrenic patients and normal controls in REM sleep time or its percentage. The amounts of REM sleep in patients with schizophrenia vary. Keshavan et al. (1996) reported that REM parameters seem to change in relation to phase of illness and treatment, suggesting state-related alterations in schizophrenia. We failed to find significant difference in REM latencies between patients with schizophrenia and normal controls, which is consistent with some previous studies (Feinberg et al., 1969; Ganguli et al., 1987; Lauer et al., 1997; Keshavan et al., 1998). However, many studies of sleep EEG in schizophrenia have observed that mean REM latencies are shortened compared to normal controls (Hiatt et al., 1985; Zarcone et al., 1987; Tandon et al., 1992; Benson and Zarcone, 1993; Hudson et al., 1993; Poulin et al., 2003). Our patients had a mean REM latency of 66.4 min, which is similar to the REM latency observed in other studies of patients with schizophrenia (Tandon et al., 1992; Lauer et al., 1997). Therefore, our inability to observe significant difference in REM latency between two groups may have resulted from a

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shortening of REM latency in our sample of normal controls, who may have been sleep deprived prior to entry into the study. Our study did replicate the finding of an increased number of sleep onset REM (SOREMs) in patients with schizophrenia. Researchers have reported that a subset of their sample with schizophrenia had REM latencies less than 10–15 min (Feinberg et al., 1965; Taylor et al., 1991; Tandon et al., 1992; Zarcone et al., 1987). In our sample, two of 15 patients with schizophrenia (13.3%) and none of 15 normal controls had REM latencies of less than 10 min. REM density has not been as extensively investigated in schizophrenia as it has been in major depression. Some studies observed that the REM density in schizophrenia was higher than normal controls (Zarcone et al., 1987; Tandon et al., 1992; Hudson et al., 1993), though many studies found no difference (Feinberg et al., 1965; Ganguli et al., 1987; Benson and Zarcone, 1993; Lauer et al., 1997; Keshavan et al., 1998; Poulin et al., 2003). Tandon et al. (1992) reported that increased REM density may be related to medication withdrawal because it was observed only in patients with who were drug-free for 2 to 4 weeks, whereas drug-naive patients and those drug-free for more than 4 weeks showed REM density comparable to normal controls. On the other hand, Rotenberg et al. (1997) found that REM density depended on symptom dimensions. Our patients consisted of chronic schizophrenia who had predominantly negative symptoms and mild positive symptoms which were similar to the group which showed the highest REM density in the study of Rotenberg et al. (1997). Most studies investigating the relationship between clinical symptoms and sleep parameters in schizophrenia have focused on positive and negative dimensions extracted from the BPRS or PANSS. Positive symptoms have been linked to increased REM density (Feinberg et al., 1965; Benson and Zarcone, 1993), short REM latency (Taylor et al., 1991; Tandon et al., 1992; Lauer et al., 1997), poor sleep efficiency (Neylan et al., 1992), and prolonged sleep latency (Zarcone and Benson, 1997). On the other hand, negative symptoms have been associated with a SWS deficit (Ganguli et al., 1987; Van Kammen et al., 1988; Tandon et al., 1989; Keshavan et al., 1995), which may represent a trait-like feature

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in schizophrenia (Benson et al., 1996; Keshavan et al., 1996). These previous studies did not consider the cognitive dimension of schizophrenia, which cuts across traditional positive and negative symptom clusters of the disease (Bell et al., 1994; Lanc¸on et al., 2000). Cognitive symptoms derive from the negative symptom (difficulty in abstract and stereotyped thinking), positive symptom (cognitive disorganization), and general symptom (lack of judgment and insight, poor attention, tension, and mannerisms and posturing) subscales of the PANSS (Bell et al., 1994). Our finding of a significant inverse correlation between cognitive symptoms (extracted from the PANSS) and SWS is consistent with what is known about the anatomical bases of both cognitive impairment of schizophrenia and of SWS generation. Evidence for frontal lobe dysfunction in schizophrenia comes from neurocognitive (Conklin et al., 2005; Wong and van Tol, 2003), neurophysiological (Bagary et al., 2004; Molina et al., 2005), and neuroanatomical studies (Tan et al., 2005). The prefrontal cortex seems to play an important role in the generation of synchronized SWS activity (Jones, 2000), and SWS is most intense in the frontal cortex (Buchsbaum et al., 1982; Finelli et al., 2001). Investigators also have suggested that SWS may mediate a critical role in memory consolidation (Gais and Born, 2004a,b). In fact, Keshavan and Tandon (1993) suggested that impaired frontal lobe functioning may be involved in the mediation of the SWS deficit in schizophrenia. Our findings are consistent with earlier reports of an inverse relationship between impairment in sustained attention and SWS (Orzack et al., 1977), between disorganization symptoms and total delta counts (Keshavan et al., 1995), and the positive relationship between impairment of visuospatial memory and the SWS deficit (Goder et al., 2004). As cognitive impairments in schizophrenia are predictive of poor functional outcome (Sharma and Antonova, 2003), it is possible that the SWS deficit may have predictive value in the clinical course of schizophrenia. The clinical significance of the REM sleep abnormalities in schizophrenia remains unclear. Feinberg et al. (1965) reported that patients with schizophrenia who were actively hallucinating had shorter REM latencies than nonhallucinating patients. Similarly,

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Tandon et al. (1992) found that short REM latencies were significantly associated with more severe psychotic symptoms, and Taylor et al. (1991) also observed that patients with SOREMs, compared with those without SOREMs, had more negative symptoms and poorer clinical outcome. However, our data showed no relationship between clinical symptoms and REM latencies. We did observe a significant inverse relationship between total REM density and the severity of positive symptoms, cognitive symptoms, emotional discomfort symptoms, and PANSS total score. These findings suggest that REM density is closely associated with symptom severity in schizophrenia. Several researchers have reported a relationship between REM densities and schizophrenic symptoms: REM density was positively correlated with ratings of hallucinatory behavior (Feinberg et al., 1965; Benson and Zarcone, 1993); REM density was positively correlated with the severity of negative symptoms (Tandon et al., 1989). REM density was negatively correlated with the BPRS total score (Poulin et al., 2003). We failed to observe any significant relationship between HRSD total score and sleep parameters including REM latency and REM density. Other studies that assessed the relationship between REM latency and depression in schizophrenia also failed to observe any correlation (Tandon et al., 1989, 1992). When we employed the PANSS emotional discomfort symptoms (consisting of depression, anxiety, guilt, and active social avoidance) that is comparable with the HRSD, there were positive correlation between REM density and emotional discomfort symptoms. There were several limitations in this study. First of all, a 2-week drug-free period may not have been enough to eliminate the effects of neuroleptic withdrawal. Tandon et al. (1992) reported that measurements of sleep EEG change over the first 4 weeks of medication withdrawal and tend to stabilize after more than 4 weeks of medication withdrawal. Therefore, our data may have been biased by pharmacological effects of prior neuroleptic treatment. Second, we did not utilize comprehensive neuropsychological testing to investigate cognitive impairment in our sample, but used the cognitive factor derived from the PANSS factor analysis. However, the cognitive factor of PANSS correlates well with neuropsychological tests (Bell et al., 1994). Third,

the present investigations were obtained in a highly selected study group, which is not representative of the general population of schizophrenia (e.g., all of them were investigated during the chronic phase, and were negative symptom predominant schizophrenia). Therefore, we are unable to generalize our findings to the general population of patients with schizophrenia. Fourth, our patients were chronic institutionalized schizophrenics who often show erratic sleeping habits and low levels of activity, which may independently affect the results of sleep studies. Finally, the study participants were asked not to smoke cigarette 6 h prior to polysomnographic recording. It is well known that smoking, as well as nicotine withdrawal, may affect sleep. In summary, the present findings in a diagnostically homogeneous sample of 15 drug-free chronic inpatients with schizophrenia demonstrate sleep patterns which are characterized by markedly delayed sleep onset, poor sleep efficiency, disturbed sleep continuity and architecture, SWS deficit, and increased REM density indices. Our data also show that SWS is inversely correlated with cognitive symptoms, and REM density is negatively correlated with positive, cognitive, and emotional discomfort symptoms as well as overall schizophrenic symptoms. References American Psychological Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, (4th ed. rev.). American Psychological Association Press, Washington, DC, pp. 273 – 290. American Sleep Disorders Association, 1997. The International Classification of Sleep Disorders—Revised: Diagnostic and Coding Manual. American Sleep Disorders Association, pp. 52–58, 65–68. Bagary, M.S., Hutton, S.B., Symms, M.R., Barker, G.J., Mutsatsa, S.H., Barnes, T.R., Joyce, E.M., Ron, M.A., 2004. Structural neural networks subserving oculomotor function in first-episole schizophrenia. Biol. Psychiatry 56, 620 – 627. Bell, M.D., Lysaker, P.H., Milstein, R.M., Beam-Goulet, J.L., 1994. Concurrent validity of the cognitive component of schizophrenia: relationship of PANSS scores to neuropsychological assessment. Psychiatry Res. 54, 51 – 58. Benson, K.L., Zarcone Jr., V.P., 1993. Rapid eye movement sleep eye movements in schizophrenia and depression. Arch. Gen. Psychiatry 50, 474 – 482. Benson, K.L., Zarcone Jr., V.P., 2000. Schizophrenia. In: Kryger, M.H., Roth, T., Dement, W.C. (Eds.), Principles and Practice of Sleep Medicine, (3rd ed.). W.B. Saunders, Philadelphia, pp. 1159 – 1167.

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