Sleep Medicine xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
Narcolepsy–cataplexy and schizophrenia in adolescents Yu-Shu Huang a,b,c, Christian Guilleminault d,⇑, Chia-Hsiang Chen c,e,f, Ping-Chin Lai g, Fan-Ming Hwang h a
Sleep Center, Chang Gung Memorial Hospital and University, Linkou, Taiwan Child Psychiatry Department, Chang Gung Memorial Hospital and University, Linkou, Taiwan c Psychiatry Department, Chang Gung Memorial Hospital and University, Linkou, Taiwan d Stanford University Sleep Medicine Division, Stanford, CA, USA e Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan f Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan g Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital and University, Linkou, Taiwan h Department of Education, National Chia-Yi University, Chiayi, Taiwan b
a r t i c l e
i n f o
Article history: Received 1 January 2013 Received in revised form 21 September 2013 Accepted 24 September 2013 Available online xxxx Keywords: Narcolepsy Cataplexy Adolescent Schizophrenia HLA Chinese and HLA DQ B1-03:01
a b s t r a c t Background: Despite advances in the understanding of narcolepsy, little information the on association between narcolepsy and psychosis is available, except for amphetamine-related psychotic reactions. Our case-control study aimed to compare clinical differences and analyze risk factors in children who developed narcolepsy with cataplexy (N–C), schizophrenia, and N–C followed by schizophrenia. Methods: Three age- and gender-matched groups of children with N–C schizophrenia (study group), N–C (control group 1), and schizophrenia only (control group 2) were investigated. Subjects filled out sleep questionnaires, sleep diaries, and quality of life scales, followed by polysomnography (PSG), multiple sleep latency tests (MSLT), routine blood tests, HLA typing, genetic analysis of genes of interest, and psychiatric evaluation. The risk factors for schizophrenia also were analyzed. Results: The study group was significantly overweight when measuring body mass index (BMI) (P = .016), at narcolepsy onset compared to control group 1, and the study group developed schizophrenia after a mean of 2.55 ± 1.8 years. Compared to control group 2, psychotic symptoms were significantly more severe in the study group, with a higher frequency of depressive symptoms and acute ward hospitalization in 8 out of 10 of the subjects. They also had poorer long-term response to treatment, despite multiple treatment trials targeting their florid psychotic symptoms. All subjects with narcolepsy were HLA DQ B1⁄0602 positive. The study group had a significantly higher frequency of DQ B1⁄-03:01/06:02 (70%) than the two other groups, without any significant difference in HLA-DR typing, tumor necrosis factor a (TNFa) levels, hypocretin (orexin) receptor 1 gene, HCRTR1, and the hypocretin (orexin) receptor 2 gene, HCRTR2, or blood infectious titers. Conclusion: BMI and weight at onset of narcolepsy as well as a higher frequency of DQ B1⁄-03:01/06:02 antigens were the only significant differences in the N–C children with secondary schizophrenia; such an association is a therapeutic challenge with long-term persistence of severe psychotic symptoms. Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction Narcolepsy with cataplexy (N–C) [1] is associated with daytime somnolence, disrupted nocturnal sleep, and episodes of abrupt complete or partial loss of muscle tone; the loss of muscle tone is mostly triggered by laughter or abrupt emotional involvement, with the disappearance of deep tendon reflexes during cataplexy. Hypnopompic and hypnagogic hallucinations and sleep paralysis are observed at various frequencies [2]. Nocturnal polysomnography ⇑ Corresponding author. Address: Stanford University Division of Sleep Medicine, 450 Broadway St, MC 5704, Redwood City, CA 94063, USA. Tel.: +1 650 723 6601; fax: +1 650 725 8910. E-mail address: [email protected] (C. Guilleminault).
(PSG) may uncover sleep-onset rapid eye movement periods (SOREMPs), though the multiple sleep latency test (MSLT) on the following day shows two or more SOREMPs during the five 20-min naps and less than 8 min mean sleep latency. N–C is associated with the presence of the HLA DQB1⁄06:02 allele, independent of ethnicity in at least 92% of the cases [3]; in addition, the cerebrospinal fluid analysis often reveals absence of or pathologically low levels of hypocretin. Presence of the HLA DQB1⁄06:02 allele has a sensitivity of 89.3% and a specificity of 76%; the presence of two or more SOREMPs at MSLT has a sensitivity of 87.9% and a specificity of 96.9%; and the complete absence of or low levels of hypocretin has a sensitivity of 83.3% and a specificity of 100% in patients with narcolepsy [4].
1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.09.018
Please cite this article in press as: Huang Y-S et al. Narcolepsy–cataplexy and schizophrenia in adolescents. Sleep Med (2013), http://dx.doi.org/10.1016/ j.sleep.2013.09.018
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Y.-S. Huang et al. / Sleep Medicine xxx (2013) xxx–xxx
Autopsy material shows destruction of the hypocretin (orexin) neurons that produce peptide hypocretin (orexin) in the lateral hypothalamus [5]. The notion that N–C may be an autoimmune disease has received more and more support due to further genetic analyses [6]. N–C is now frequently recognized in prepubertal and young teenagers due to systematic investigation and the emphasis on recent reports switches to the understanding of the health problems associated with hypocretin deficiency, not limited to sleepiness and cataplexy. Despite previous work indicating an association of narcolepsy in adult schizophrenics and the absence of recognition of narcolepsy syndrome [7–10], we still have little knowledge on the relationship between N–C and schizophrenia to date. The prevalence of N–C combined with schizophrenia has been previously estimated to be in 1–18 cases in a population of 2 million based on independent prevalence rates [11]. Stimulants and amphetamine-like drugs in particular have been used in the treatment of narcolepsy and the development of psychotic disorders in association with drug intake in narcoleptics also has been implicated in the literature [12]. Many studies have emphasized the strong association between narcolepsy and HLA, particularly the HLA-DQ and the HLA-DR protein [3]. In addition, a genetic association between specific HLA-DR genes and schizophrenia also has been shown [6,9,11,13], but the association between HLA alleles and schizophrenia is a field with continuous research efforts [14,15]. The question of a potential interaction between narcolepsy and schizophrenia, especially in children diagnosed with N–C, has mostly been unexplored particularly when looking at the chronologic development of the two syndromes and also questioning if the clinical presentation of the first syndrome gave any clue on occurrence of the second morbidity. We present the results of a retrospective investigation of our prospectively collected narcoleptic cases. We compared our findings obtained from N–C children who also developed schizophrenia to findings of age-matched children with N–C and age-matched children with schizophrenia only.
2. Methods 2.1. Subjects Our pediatric sleep center is the only pediatric sleep center for Taiwan (23 million inhabitants) and is the referring center for all children with abnormal sleepiness. The center is responsible for treatment and follow-up of all diagnosed children. During the 4 year prospective study, 151 children fulfilled all the International Classification of Sleep Disorders, second edition, criteria for diagnosis of Narcolepsy [16], but only 102 children presented with N–C. The prospectively collected 102 N–C children represented our total clinical initial group. Out of the 102 N–C children, 10 (9.8%) developed schizophrenia. Most of the children were diagnosed with hypersomnia and N–C first and subsequently developed Schneider first-rank symptoms within 3 years’ duration (mean time of schizophrenia onset, 2.55 ± 1.8 y). As shown below, the diagnosis of schizophrenia was based on thorough clinical evaluation by a child psychiatrist and positive testing on different scales. The children with N–C and schizophrenia (n = 10) comprised our study group. We also formed two control groups: control group 1 comprised age- and gender-matched N–C children without schizophrenia (n = 37/92); and control group 2 comprised a group of age- and gender-matched schizophrenic children without N–C (n = 13). In reviewing past teenage schizophrenia cases seen during the last 10 years in our large university pediatric psychiatric clinic, no schizophrenic child developed narcolepsy thereafter. Because the pediatric sleep laboratory and clinic are both part of the pediatric psychiatric division, all of these
previous patients received a similar evaluation as those in the study group. Children in the control and study groups completed similar testing procedures. Study approval was obtained from the Institutional Review Boards of Chang Gung Hospital, Taiwan. Written informed consent was obtained from subjects and their legal representatives following a detailed explanation of the study. 2.2. Diagnostic evaluation 2.2.1. N–C evaluation All cases underwent a standardized evaluation based on the international recommendations (International Classification of Sleep Disorders, second edition) for the diagnosis of N–C and hypersomnia [16]. Children underwent a general pediatric clinical evaluation. Body weight and height of subjects were assessed in a standardized fashion to calculate body mass index (BMI). Complete neurologic evaluation including electroencephalogram (EEG) (while awake and while asleep) and brain magnetic resonance imaging were systematically performed. Routine blood tests (complete blood cell count with differential count and biochemical blood tests [i.e., blood sugar, thyroid-stimulating hormone, thyroxine, liver function, and renal function]) were obtained. Systematic HLA typing was performed on all children. Blood also was drawn for other potential genetic studies. Parents and children filled out the following sleep questionnaires (validated in Mandarin): the Pediatric Daytime Sleepiness Scale (PDSS) [17], the Epworth Sleepiness Scale (ESS) if the child was old enough to drive [18], sleep diaries for 14 days, and the Stanford Narcolepsy Questionnaire [19]. They also were asked to fill out sleep diaries for a minimum of 14 successive days, with notation of indicators, triggers, and duration of each cataplexy attack; and four daily visual analog scales (VAS) (scored 1–100), which observed excessive daytime sleepiness (EDS), presence of hypnagogic/hypnopompic hallucination, and sleep paralysis. Each patient underwent 14 days of actigraphy tests, which observed the amount of sleep inactivity during the night and during the daytime. Nocturnal PSG also was observed for a minimum of 7 h, with monitoring of the following variables: EEG (C3/A2, C4/A1, Fz/A1–A2, and O1/A2); right and left electrooculogram; chin and legs electromyography; electrocardiography with a modified V2 lead; nasal cannula pressure transducer; mouth thermistor; chest and abdomen inductive plethysmography bands; neck microphone; and finger oximetry, from which oximetry curve and finger plethysmography were extracted and recorded. The following morning, an MSLT was administered to each patient at 2-h intervals consisting of five 20-min naps; mean sleep-latency and presence of SOREMPs were calculated. After the PSG, patients were submitted to video-monitored challenges reported by family members to trigger cataplectic attacks; such video monitoring allowed the observers to replay the attacks to determining the presence of complete and partial attacks, investigate the segments of the body involved during an ‘‘attack,’’ and to affirm the presence of cataplexy. Interaction with family members usually was successful in inducing cataplectic attacks. Attacks provoked in the sleep medicine facilities were witnessed by a physician expert in narcolepsy, and deep tendon reflexes were checked during the attack and just after recovery when the attack was of sufficiently long duration [20]. 2.2.2. Schizophrenia evaluation A structured psychiatric interview was conducted using the Schedule for Affective Disorder and Schizophrenia for school-aged children, adolescent version (K-SADS-E) [21] by experienced child psychiatrists. Schizophrenia was diagnosed based on Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Text
Please cite this article in press as: Huang Y-S et al. Narcolepsy–cataplexy and schizophrenia in adolescents. Sleep Med (2013), http://dx.doi.org/10.1016/ j.sleep.2013.09.018
Y.-S. Huang et al. / Sleep Medicine xxx (2013) xxx–xxx
Revision (DSM-IV-TR) diagnostic criteria [22]. Inventories used to assess psychiatric health included the Positive and Negative Symptom Scale (PANSS), the Beck Depression Inventory, the Beck Anxiety Inventory, and the Clinical Global Impressions severity scale (CGI-S) [23–25]. Children also had a clinical evaluation performed by a sleep specialist and demonstrated absence of features suggestive of narcolepsy at PSG testing. All children were regularly followed over a minimum of 6 years, with adjustment of respective treatment as needed. 2.2.3. Medications All patients with N–C except for one received medication to control EDS. The Taiwan health recommended guidelines for treatment of EDS in narcolepsy are as follows: children are initially treated with methylphenidate (MPH) for 1–2 months at a dose of 0.3–0.7-mg/kg daily. Thereafter, the recommendation is to switch narcoleptic patients to 200 mg of modafinil in the morning. In addition, subjects with N–C also may receive anticataplectic treatment. Patients with schizophrenia were treated with antipsychotic medications as needed. 2.2.4. Family history evaluation Positive family history of narcolepsy was affirmed based on demonstration of EDS and cataplexy in siblings, parents, or second-degree relatives. We asked for medical documentation of the reported problems. Similarly, positive family history of psychiatric disorders was based on the presence of a DSM-IV-TR-documented psychiatric diagnosis in subsequent family members. 2.3. Statistical analysis 2.3.1. Data scoring Questionnaires were scored according to the recommended scales [17–19,21,23–25]. PSG and MSLT data were analyzed following the recommendations of the American Academy of Sleep Medicine [26]. Sleep–wake data were obtained by identifying slow-wave sleep (nonrapid eye movement [NREM] sleep stage 3) and dissociation of stage 3 and 4 NREM sleep following the international criteria from the Rechtschaffen and Kales atlas [27]. Short EEG arousals were scored following the American Sleep Disorders Association guidelines [28], and mean sleep latency and presence of SOREMPs were extracted from MSLTs. 2.3.2. Comorbid associations Comorbidities were determined following DSM-IV-TR criteria. The statistical analyses were presented as mean, standard deviation, and percentages. Comparisons of quantitative variables were performed using the nonparametric Mann–Whitney U test and the Student t test for independent samples. The statistics from the v2 test were used to compare percentages. We first performed an analysis of variance across all three groups and a post hoc test with Bonferroni adjustment for comparison. If a variable was not normally distributed, a Kruskal–Wallis analysis of variance on ranks and a Dunn test were performed. Pearson product moment correlation coefficients were obtained to determine the relationship between BMI and different sleepiness scales. Risk factors for schizophrenia were analyzed using multiple logistic regression analyses. The adjusted odds ratios (OR) for each significant factor are reported. 3. Results Demographics and clinical symptoms of the three groups of children are presented in Table 1. All narcoleptic patients revealed no abnormalities on neurologic evaluation (i.e., EEG, brain magnetic resonance imaging) on entry into the study. All blood tests
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were within reference range, including tumor necrosis factor a (TNF-a) cytokines and IL-6. A significant difference in body weight and BMI at time of diagnosis of N–C was found. Most of the N–C children with schizophrenia were much more overweight on entry into the study, sometimes at the level of obesity, than the other two groups (BMI, P = .002; body weight, P = .026). A positive family history of narcolepsy was shown in four subjects in the narcolepsy with schizophrenia group, and a positive psychiatry family history was found to be higher in the narcolepsy with schizophrenia group (n = 4; sibling [n = 2], second-degree relatives [n = 2]) than in the pure narcolepsy control group (n = 2; sibling [n = 1], parent [n = 1]). 3.1. Timing of schizophrenia onset in subjects with narcolepsy Except for one subject who developed hypersomnia, cataplexy, and schizophrenia in that order but at nearly the same time, schizophrenic symptoms appeared much later than symptoms of N–C, and the diagnosis of schizophrenia was given an average of 2.55 ± 1.8 years following the onset of N–C. Before developing schizophrenia, narcoleptic subjects in the study group were no different than any of the other narcoleptic subjects in reports of hallucinations shown by the prospectively collected follow-up data, with systematic follow-up evaluation at least every 6 months. However, at the onset of psychotic symptoms, narcoleptic subjects with schizophrenia presented several more visual hallucinations of psychotic type than those with schizophrenia in the control group 2; delusions were more frequent and more severe in the schizophrenia control group 2, but there was no statistic significant difference compared to the study group (P = .67). Comorbidities observed in the three groups are presented in Table 2. The percentage of subjects with N–C and schizophrenia who presented with major depression was significantly higher than that noted in the other two control groups (P = .034). The results from various administered scales are presented in Table 3. As expected, schizophrenic control subjects showed no evidence of sleepiness (ESS, 6.08 ± 2.4; PDSS, 10.38 ± 3.12), though N–C controls had lower scores on the PANSS and CGI-S in psychotic symptoms. On the other hand, N–C subjects with schizophrenia and control subjects with isolated schizophrenia presented with similar scores on the PANSS-P (PANSS positive subscale), the ESS, and the PDSS at the onset of psychotic symptoms (Table 3). However, greater severity was noted in the study group: psychotic symptoms were severe from the onset of the schizophrenia in the narcoleptic study subjects (CGI-S, 4.90 ± 1.37; PANSS-P, 24.7 ± 4.06; PANSS-N [PANSS negative subscale], 25.7 ± 5.06). Eight out of 10 subjects had to be admitted to the acute psychiatry ward, with florid auditory hallucination and delusional behaviors. Subjects were followed for a mean of 3.45 ± 2.02 years since the onset of schizophrenia and were noted to have responded poorly to several antipsychotic medications and electroconvulsive therapy. To date, psychotic symptoms in these subjects have persisted and are still poorly controlled. 3.2. Results of specific investigations 3.2.1. Physical evaluation of BMI Significant correlations between BMI and CGI-S and PANSS scores were found in the study group but not in the two control groups (Table 4); higher BMI was associated with a greater severity on the PANSS-P (r = 0.632), PANSS-G (PANSS general psychopathologic subscale) (r = 0.644), and the CGI-S (r = 0.669) (psychotic symptoms). Risk factors for schizophrenia were analyzed by multiple logistic regression analyses and cross-tabulations of OR (see Table 5). The adjusted OR of each significant factor are reported, showing that BMI was the higher risk factor for schizophrenia (OR, 1.506; P = .002).
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Table 1 Demographics and clinical symptoms. Variable
Study group (n = 10) mean ± SD (count) (%)
Control group 1 (n = 37) mean ± SD (count) (%)
Control group 2 (n = 13) mean ± SD (count) (%)
P value
Current age (y) Boys Girls Age of narcolepsy onset (y) Age of schizophrenia onset (y) BMI (kg/m2) Family history of narcolepsy Family history of psychiatric disease
18.54 ± 2.99 5 (50.0%) 5 (50.0%) 11.25 ± 3.92 15.80 ± 1.36 27.39 ± 7.17a,c 4 (40.0%)c 4 (30.0%)a
18.82 ± 3.54 21 (56.8%) 16 (43.2%) 12.59 ± 3.41 – 23.62 ± 4.86a 5 (13.5%)b 2 (5.4%)a,b
18.38 ± 3.65 6 (46.2%) 7 (53.8%) – 16.38 ± 0.84 20.32 ± 3.13c 0 (0.0%)b,c 3 (23.1%)b
.268 .703
Symptoms and sign at time of diagnosis Hypersomnia Cataplexy Hypnogogic hallucination Sleep paralysis Parasomnia Delusion Auditory hallucination or visual hallucination
10 (100%)c 10 (100%)c 10 (100%) 10 (100%)a,c 8 (80.0%) 7 (70.0%)a 9 (90.0%)a
37 (100%)b 37 (100%)b 30 (81.1%) 25 (67.6%)a,b 22 (59.5%) 0 (0.0%)a,b 0 (0.0%)a,b
3 (23.1%)b,c 0 (0.0%)b,c 9 (69.2%) 2 (15.4%)b,c 6 (46.2%) 13 (100%)b 13 (100.0%)b
.0001 .0001 .166 .0001 .258 .0001 .0001
.269 .572 .002 .027 .016
Abbreviations: SD, standard deviation; y, years; BMI, body mass index. Study group: narcolepsy–cataplexy with schizophrenia.. Control group 1: narcolepsy–cataplexy without schizophrenia. Control group 2: only schizophrenia. Comparison of means: Kruskal–Wallis H test. Comparison of counts (%): v2 test. a Post hoc analysis showed significance of study group and control group 1. b Post hoc analysis showed significance of control group 1 and control group 2. c Post hoc analysis showed significance of control group 2 and study group. a,b BMI: Mann–Whitney U test (1 tailed).
Table 2 Comorbidity. Variable
Experimental group (n = 10) mean ± SD (count) (%)
Major depression Obesity (BMI =25 kg/m2) ADHD history ODD Asperger syndrome PLMS OSA OCD Insomnia
5 9 3 1 2 0 4 0 3
(50.0%)a,c (75.0%)a,c (30.0%) (8.3%) (20.0%) (0.0%) (40.0%) (0.0%) (30.0%)
Control group 1 (n = 37) mean ± SD (count) (%)
Control group 2 (n = 13) mean ± SD (count) (%)
5 (21.6%)a 14 (37.8%)a,b 2 (5.9%) 4 (10.8%) 1 (2.7%) 4 (10.8%) 8 (21.6%) 0 (0.0%) 11 (29.7%)
2 2 2 0 0 1 2 1 5
(15.4%)c (15.4%)b,c (15.4%) (0.0%) (0.0%) (7.7%) (15.4%) (7.7%) (38.5%)
P value .034 .026 .357 .264 .289 .545 .355 .159 .838
Abbreviations: SD, standard deviation; BMI, body mass index; ADHD, attention-deficit/hyperactivity disorder; ODD, oppositional defiant disorder; PLMS, periodic limb movements during sleep (PLMI >5/h with daytime symptoms); OSA, obstructive sleep apnea (apnea–hypopnea index >5 events/h); OCD, obsessive–compulsive disorder. Comparison of means: Kruskal–Wallis H test. Comparison of counts (%): v2 test. Major depression was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria. The diagnosis of insomnia was made according to criteria of DSM-IV-TR. a Post hoc analysis showed significance of study group and control group 1. b Post hoc analysis showed significance of control group 1 and control group 2. c Post hoc analysis showed significance of control group 2 and study group.
3.2.2. Sleep data In Table 3, analysis of variance showed a significant reduction of stage 2 NREM sleep in the N–C with schizophrenia group compared to the control group 2 (P = .006) on PSG. When compared to the group of schizophrenic control subjects, the two N–C subject groups showed significantly different mean sleep latency (1.74 ± 1.61; 2.97 ± 3.81 min) and number of SOREMPs (3.70 ± 1.34; 3.51 ± 1.38) compared to control group 2 schizophrenia in the MSLT, as expected. 3.2.3. HLA typing and blood tests All N–C patients were HLA DQB 1-0602 positive. There were three subjects (8.1%) with a homozygote for DQB1⁄06:02/⁄06:02 in the narcoleptic control group. There was no homozygote for
DQB1⁄06:02/⁄06:02 in the N–C subjects with schizophrenia and the schizophrenia-only control group 2, but there was a significant difference (P = .012) for DQB1⁄03:01/0 6:02 between the study group (70%), control group 1 (37.8%), and control group 2 (n = 0). Another interesting finding was the higher frequency of DQB1⁄06:01 in the schizophrenia control group 2. The results of the v2 test showed significant differences (P = .01) in the control group 2 schizophrenia subjects (46.1%), in the control group 1 narcolepsy subjects (8.1%), and the study group (10%). Analyses of the TNF-a cytokine and the hypocretin (orexin) receptor 1 gene, HCRTR1, and the hypocretin (orexin) receptor 2 gene, HCRTR2, showed no difference in any of the three investigated groups. We sequenced all exons of the dopamine D2 receptor gene, DRD2, investigating the possible mutations in the N–C subjects with schizophrenia, but no mutation in the
Please cite this article in press as: Huang Y-S et al. Narcolepsy–cataplexy and schizophrenia in adolescents. Sleep Med (2013), http://dx.doi.org/10.1016/ j.sleep.2013.09.018
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Y.-S. Huang et al. / Sleep Medicine xxx (2013) xxx–xxx Table 3 Comparison of different administered scales and of sleep data. Variable
Experimental group (n = 10; a) mean ± SD (count) (%)
PANSS-P PANSS-N PANSS-G CGI-S ESS
24.70 ± 4.06) 25.70 ± 5.06 53.00 ± 7.23 4.90 ± 1.37 17.70 ± 2.00
PDSS
25.70 ± 4.60
VAS
Sleep variables MSLT variable Mean sleep latency (min) Number of sleep latency55 min Number of REM sleep (times) PSG variable AHI (times/h) AI (times/h) HI (times/h) Sleep efficiency % Awake % REM sleep % Stage 1% Stage 2% SWS % TST (min) Sleep latency (min)
Control group 1 (n = 37; b) mean ± SD (count) (%) – – – – 16.16 ± 3.00 22.19 ± 3.99 )
Control group 2 (n = 13; c) mean ± SD (count) n(%)
.018 .019 .004 .010 .0001
10.38 ± 3.12
.0001
23.08 ± 12.51
.0001
81.49 ± 12.18
1.74 ± 1.61
2.97 ± 3.81
10.24 ± 6.81
4.60 ± 0.97
4.03 ± 1.59
3.70 ± 1.34
3.51 ± 1.38
2.88 ± 3.97 0.38 ± 0.80 2.11 ± 3.13 83.81 ± 12.96 14.56 ± 12.08 18.18 ± 7.85 16.16 ± 9.27 40.13 ± 12.56 18.18 ± 11.11 378.35 ± 86.91 9.27 ± 15.47
P value
20.83 ± 3.16 19.77 ± 4.23 44.00 ± 4.24 3.69 ± 0.63 6.08 ± 2.40
92.50 ± 8.25
5.76 ± 7.60 1.43 ± 2.93 4.00 ± 5.57 76.32 ± 11.44 18.85 ± 10.87 20.44 ± 14.32 18.20 ± 4.84 28.25 ± 8.74 22.75 ± 10.17 324.10 ± 93.46 10.10 ± 15.80
F
Post hoc analysis
a > b,a > c, b>c a > b,a > c, b>c a > b, a > c, b>c
11.04
.0001
a < c, b < c
1.50 ± 1.52
9.00
.0001
a > c, b > c
0.57 ± 0.79
15.68
.0001
a > c, b > c
12.35 ± 3.20 2.11 ± 5.30 12.11 ± 8.38 79.93 ± 10.12 14.87 ± 12.75 16.84 ± 7.90 23.11 ± 23.77 49.39 ± 15.52 10.58 ± 17.04 385.13 ± 57.73 24.44 ± 16.64
7.69 1,84 8.71 1.56 0.462 0.35 1.14 5.71 0.03 2.70 3.14
.001 .170 .001 .219 .633 .708 .329 .006 .972 .077 .052
a < c, b < c NS a < c, b < c NS NS NS NS a
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
Narcolepsy–cataplexy and schizophrenia in adolescents Yu-Shu Huang a,b,c, Christian Guilleminault d,⇑, Chia-Hsiang Chen c,e,f, Ping-Chin Lai g, Fan-Ming Hwang h a
Sleep Center, Chang Gung Memorial Hospital and University, Linkou, Taiwan Child Psychiatry Department, Chang Gung Memorial Hospital and University, Linkou, Taiwan c Psychiatry Department, Chang Gung Memorial Hospital and University, Linkou, Taiwan d Stanford University Sleep Medicine Division, Stanford, CA, USA e Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan f Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan g Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital and University, Linkou, Taiwan h Department of Education, National Chia-Yi University, Chiayi, Taiwan b
a r t i c l e
i n f o
Article history: Received 1 January 2013 Received in revised form 21 September 2013 Accepted 24 September 2013 Available online xxxx Keywords: Narcolepsy Cataplexy Adolescent Schizophrenia HLA Chinese and HLA DQ B1-03:01
a b s t r a c t Background: Despite advances in the understanding of narcolepsy, little information the on association between narcolepsy and psychosis is available, except for amphetamine-related psychotic reactions. Our case-control study aimed to compare clinical differences and analyze risk factors in children who developed narcolepsy with cataplexy (N–C), schizophrenia, and N–C followed by schizophrenia. Methods: Three age- and gender-matched groups of children with N–C schizophrenia (study group), N–C (control group 1), and schizophrenia only (control group 2) were investigated. Subjects filled out sleep questionnaires, sleep diaries, and quality of life scales, followed by polysomnography (PSG), multiple sleep latency tests (MSLT), routine blood tests, HLA typing, genetic analysis of genes of interest, and psychiatric evaluation. The risk factors for schizophrenia also were analyzed. Results: The study group was significantly overweight when measuring body mass index (BMI) (P = .016), at narcolepsy onset compared to control group 1, and the study group developed schizophrenia after a mean of 2.55 ± 1.8 years. Compared to control group 2, psychotic symptoms were significantly more severe in the study group, with a higher frequency of depressive symptoms and acute ward hospitalization in 8 out of 10 of the subjects. They also had poorer long-term response to treatment, despite multiple treatment trials targeting their florid psychotic symptoms. All subjects with narcolepsy were HLA DQ B1⁄0602 positive. The study group had a significantly higher frequency of DQ B1⁄-03:01/06:02 (70%) than the two other groups, without any significant difference in HLA-DR typing, tumor necrosis factor a (TNFa) levels, hypocretin (orexin) receptor 1 gene, HCRTR1, and the hypocretin (orexin) receptor 2 gene, HCRTR2, or blood infectious titers. Conclusion: BMI and weight at onset of narcolepsy as well as a higher frequency of DQ B1⁄-03:01/06:02 antigens were the only significant differences in the N–C children with secondary schizophrenia; such an association is a therapeutic challenge with long-term persistence of severe psychotic symptoms. Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction Narcolepsy with cataplexy (N–C) [1] is associated with daytime somnolence, disrupted nocturnal sleep, and episodes of abrupt complete or partial loss of muscle tone; the loss of muscle tone is mostly triggered by laughter or abrupt emotional involvement, with the disappearance of deep tendon reflexes during cataplexy. Hypnopompic and hypnagogic hallucinations and sleep paralysis are observed at various frequencies [2]. Nocturnal polysomnography ⇑ Corresponding author. Address: Stanford University Division of Sleep Medicine, 450 Broadway St, MC 5704, Redwood City, CA 94063, USA. Tel.: +1 650 723 6601; fax: +1 650 725 8910. E-mail address: [email protected] (C. Guilleminault).
(PSG) may uncover sleep-onset rapid eye movement periods (SOREMPs), though the multiple sleep latency test (MSLT) on the following day shows two or more SOREMPs during the five 20-min naps and less than 8 min mean sleep latency. N–C is associated with the presence of the HLA DQB1⁄06:02 allele, independent of ethnicity in at least 92% of the cases [3]; in addition, the cerebrospinal fluid analysis often reveals absence of or pathologically low levels of hypocretin. Presence of the HLA DQB1⁄06:02 allele has a sensitivity of 89.3% and a specificity of 76%; the presence of two or more SOREMPs at MSLT has a sensitivity of 87.9% and a specificity of 96.9%; and the complete absence of or low levels of hypocretin has a sensitivity of 83.3% and a specificity of 100% in patients with narcolepsy [4].
1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.09.018
Please cite this article in press as: Huang Y-S et al. Narcolepsy–cataplexy and schizophrenia in adolescents. Sleep Med (2013), http://dx.doi.org/10.1016/ j.sleep.2013.09.018
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Autopsy material shows destruction of the hypocretin (orexin) neurons that produce peptide hypocretin (orexin) in the lateral hypothalamus [5]. The notion that N–C may be an autoimmune disease has received more and more support due to further genetic analyses [6]. N–C is now frequently recognized in prepubertal and young teenagers due to systematic investigation and the emphasis on recent reports switches to the understanding of the health problems associated with hypocretin deficiency, not limited to sleepiness and cataplexy. Despite previous work indicating an association of narcolepsy in adult schizophrenics and the absence of recognition of narcolepsy syndrome [7–10], we still have little knowledge on the relationship between N–C and schizophrenia to date. The prevalence of N–C combined with schizophrenia has been previously estimated to be in 1–18 cases in a population of 2 million based on independent prevalence rates [11]. Stimulants and amphetamine-like drugs in particular have been used in the treatment of narcolepsy and the development of psychotic disorders in association with drug intake in narcoleptics also has been implicated in the literature [12]. Many studies have emphasized the strong association between narcolepsy and HLA, particularly the HLA-DQ and the HLA-DR protein [3]. In addition, a genetic association between specific HLA-DR genes and schizophrenia also has been shown [6,9,11,13], but the association between HLA alleles and schizophrenia is a field with continuous research efforts [14,15]. The question of a potential interaction between narcolepsy and schizophrenia, especially in children diagnosed with N–C, has mostly been unexplored particularly when looking at the chronologic development of the two syndromes and also questioning if the clinical presentation of the first syndrome gave any clue on occurrence of the second morbidity. We present the results of a retrospective investigation of our prospectively collected narcoleptic cases. We compared our findings obtained from N–C children who also developed schizophrenia to findings of age-matched children with N–C and age-matched children with schizophrenia only.
2. Methods 2.1. Subjects Our pediatric sleep center is the only pediatric sleep center for Taiwan (23 million inhabitants) and is the referring center for all children with abnormal sleepiness. The center is responsible for treatment and follow-up of all diagnosed children. During the 4 year prospective study, 151 children fulfilled all the International Classification of Sleep Disorders, second edition, criteria for diagnosis of Narcolepsy [16], but only 102 children presented with N–C. The prospectively collected 102 N–C children represented our total clinical initial group. Out of the 102 N–C children, 10 (9.8%) developed schizophrenia. Most of the children were diagnosed with hypersomnia and N–C first and subsequently developed Schneider first-rank symptoms within 3 years’ duration (mean time of schizophrenia onset, 2.55 ± 1.8 y). As shown below, the diagnosis of schizophrenia was based on thorough clinical evaluation by a child psychiatrist and positive testing on different scales. The children with N–C and schizophrenia (n = 10) comprised our study group. We also formed two control groups: control group 1 comprised age- and gender-matched N–C children without schizophrenia (n = 37/92); and control group 2 comprised a group of age- and gender-matched schizophrenic children without N–C (n = 13). In reviewing past teenage schizophrenia cases seen during the last 10 years in our large university pediatric psychiatric clinic, no schizophrenic child developed narcolepsy thereafter. Because the pediatric sleep laboratory and clinic are both part of the pediatric psychiatric division, all of these
previous patients received a similar evaluation as those in the study group. Children in the control and study groups completed similar testing procedures. Study approval was obtained from the Institutional Review Boards of Chang Gung Hospital, Taiwan. Written informed consent was obtained from subjects and their legal representatives following a detailed explanation of the study. 2.2. Diagnostic evaluation 2.2.1. N–C evaluation All cases underwent a standardized evaluation based on the international recommendations (International Classification of Sleep Disorders, second edition) for the diagnosis of N–C and hypersomnia [16]. Children underwent a general pediatric clinical evaluation. Body weight and height of subjects were assessed in a standardized fashion to calculate body mass index (BMI). Complete neurologic evaluation including electroencephalogram (EEG) (while awake and while asleep) and brain magnetic resonance imaging were systematically performed. Routine blood tests (complete blood cell count with differential count and biochemical blood tests [i.e., blood sugar, thyroid-stimulating hormone, thyroxine, liver function, and renal function]) were obtained. Systematic HLA typing was performed on all children. Blood also was drawn for other potential genetic studies. Parents and children filled out the following sleep questionnaires (validated in Mandarin): the Pediatric Daytime Sleepiness Scale (PDSS) [17], the Epworth Sleepiness Scale (ESS) if the child was old enough to drive [18], sleep diaries for 14 days, and the Stanford Narcolepsy Questionnaire [19]. They also were asked to fill out sleep diaries for a minimum of 14 successive days, with notation of indicators, triggers, and duration of each cataplexy attack; and four daily visual analog scales (VAS) (scored 1–100), which observed excessive daytime sleepiness (EDS), presence of hypnagogic/hypnopompic hallucination, and sleep paralysis. Each patient underwent 14 days of actigraphy tests, which observed the amount of sleep inactivity during the night and during the daytime. Nocturnal PSG also was observed for a minimum of 7 h, with monitoring of the following variables: EEG (C3/A2, C4/A1, Fz/A1–A2, and O1/A2); right and left electrooculogram; chin and legs electromyography; electrocardiography with a modified V2 lead; nasal cannula pressure transducer; mouth thermistor; chest and abdomen inductive plethysmography bands; neck microphone; and finger oximetry, from which oximetry curve and finger plethysmography were extracted and recorded. The following morning, an MSLT was administered to each patient at 2-h intervals consisting of five 20-min naps; mean sleep-latency and presence of SOREMPs were calculated. After the PSG, patients were submitted to video-monitored challenges reported by family members to trigger cataplectic attacks; such video monitoring allowed the observers to replay the attacks to determining the presence of complete and partial attacks, investigate the segments of the body involved during an ‘‘attack,’’ and to affirm the presence of cataplexy. Interaction with family members usually was successful in inducing cataplectic attacks. Attacks provoked in the sleep medicine facilities were witnessed by a physician expert in narcolepsy, and deep tendon reflexes were checked during the attack and just after recovery when the attack was of sufficiently long duration [20]. 2.2.2. Schizophrenia evaluation A structured psychiatric interview was conducted using the Schedule for Affective Disorder and Schizophrenia for school-aged children, adolescent version (K-SADS-E) [21] by experienced child psychiatrists. Schizophrenia was diagnosed based on Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Text
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Revision (DSM-IV-TR) diagnostic criteria [22]. Inventories used to assess psychiatric health included the Positive and Negative Symptom Scale (PANSS), the Beck Depression Inventory, the Beck Anxiety Inventory, and the Clinical Global Impressions severity scale (CGI-S) [23–25]. Children also had a clinical evaluation performed by a sleep specialist and demonstrated absence of features suggestive of narcolepsy at PSG testing. All children were regularly followed over a minimum of 6 years, with adjustment of respective treatment as needed. 2.2.3. Medications All patients with N–C except for one received medication to control EDS. The Taiwan health recommended guidelines for treatment of EDS in narcolepsy are as follows: children are initially treated with methylphenidate (MPH) for 1–2 months at a dose of 0.3–0.7-mg/kg daily. Thereafter, the recommendation is to switch narcoleptic patients to 200 mg of modafinil in the morning. In addition, subjects with N–C also may receive anticataplectic treatment. Patients with schizophrenia were treated with antipsychotic medications as needed. 2.2.4. Family history evaluation Positive family history of narcolepsy was affirmed based on demonstration of EDS and cataplexy in siblings, parents, or second-degree relatives. We asked for medical documentation of the reported problems. Similarly, positive family history of psychiatric disorders was based on the presence of a DSM-IV-TR-documented psychiatric diagnosis in subsequent family members. 2.3. Statistical analysis 2.3.1. Data scoring Questionnaires were scored according to the recommended scales [17–19,21,23–25]. PSG and MSLT data were analyzed following the recommendations of the American Academy of Sleep Medicine [26]. Sleep–wake data were obtained by identifying slow-wave sleep (nonrapid eye movement [NREM] sleep stage 3) and dissociation of stage 3 and 4 NREM sleep following the international criteria from the Rechtschaffen and Kales atlas [27]. Short EEG arousals were scored following the American Sleep Disorders Association guidelines [28], and mean sleep latency and presence of SOREMPs were extracted from MSLTs. 2.3.2. Comorbid associations Comorbidities were determined following DSM-IV-TR criteria. The statistical analyses were presented as mean, standard deviation, and percentages. Comparisons of quantitative variables were performed using the nonparametric Mann–Whitney U test and the Student t test for independent samples. The statistics from the v2 test were used to compare percentages. We first performed an analysis of variance across all three groups and a post hoc test with Bonferroni adjustment for comparison. If a variable was not normally distributed, a Kruskal–Wallis analysis of variance on ranks and a Dunn test were performed. Pearson product moment correlation coefficients were obtained to determine the relationship between BMI and different sleepiness scales. Risk factors for schizophrenia were analyzed using multiple logistic regression analyses. The adjusted odds ratios (OR) for each significant factor are reported. 3. Results Demographics and clinical symptoms of the three groups of children are presented in Table 1. All narcoleptic patients revealed no abnormalities on neurologic evaluation (i.e., EEG, brain magnetic resonance imaging) on entry into the study. All blood tests
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were within reference range, including tumor necrosis factor a (TNF-a) cytokines and IL-6. A significant difference in body weight and BMI at time of diagnosis of N–C was found. Most of the N–C children with schizophrenia were much more overweight on entry into the study, sometimes at the level of obesity, than the other two groups (BMI, P = .002; body weight, P = .026). A positive family history of narcolepsy was shown in four subjects in the narcolepsy with schizophrenia group, and a positive psychiatry family history was found to be higher in the narcolepsy with schizophrenia group (n = 4; sibling [n = 2], second-degree relatives [n = 2]) than in the pure narcolepsy control group (n = 2; sibling [n = 1], parent [n = 1]). 3.1. Timing of schizophrenia onset in subjects with narcolepsy Except for one subject who developed hypersomnia, cataplexy, and schizophrenia in that order but at nearly the same time, schizophrenic symptoms appeared much later than symptoms of N–C, and the diagnosis of schizophrenia was given an average of 2.55 ± 1.8 years following the onset of N–C. Before developing schizophrenia, narcoleptic subjects in the study group were no different than any of the other narcoleptic subjects in reports of hallucinations shown by the prospectively collected follow-up data, with systematic follow-up evaluation at least every 6 months. However, at the onset of psychotic symptoms, narcoleptic subjects with schizophrenia presented several more visual hallucinations of psychotic type than those with schizophrenia in the control group 2; delusions were more frequent and more severe in the schizophrenia control group 2, but there was no statistic significant difference compared to the study group (P = .67). Comorbidities observed in the three groups are presented in Table 2. The percentage of subjects with N–C and schizophrenia who presented with major depression was significantly higher than that noted in the other two control groups (P = .034). The results from various administered scales are presented in Table 3. As expected, schizophrenic control subjects showed no evidence of sleepiness (ESS, 6.08 ± 2.4; PDSS, 10.38 ± 3.12), though N–C controls had lower scores on the PANSS and CGI-S in psychotic symptoms. On the other hand, N–C subjects with schizophrenia and control subjects with isolated schizophrenia presented with similar scores on the PANSS-P (PANSS positive subscale), the ESS, and the PDSS at the onset of psychotic symptoms (Table 3). However, greater severity was noted in the study group: psychotic symptoms were severe from the onset of the schizophrenia in the narcoleptic study subjects (CGI-S, 4.90 ± 1.37; PANSS-P, 24.7 ± 4.06; PANSS-N [PANSS negative subscale], 25.7 ± 5.06). Eight out of 10 subjects had to be admitted to the acute psychiatry ward, with florid auditory hallucination and delusional behaviors. Subjects were followed for a mean of 3.45 ± 2.02 years since the onset of schizophrenia and were noted to have responded poorly to several antipsychotic medications and electroconvulsive therapy. To date, psychotic symptoms in these subjects have persisted and are still poorly controlled. 3.2. Results of specific investigations 3.2.1. Physical evaluation of BMI Significant correlations between BMI and CGI-S and PANSS scores were found in the study group but not in the two control groups (Table 4); higher BMI was associated with a greater severity on the PANSS-P (r = 0.632), PANSS-G (PANSS general psychopathologic subscale) (r = 0.644), and the CGI-S (r = 0.669) (psychotic symptoms). Risk factors for schizophrenia were analyzed by multiple logistic regression analyses and cross-tabulations of OR (see Table 5). The adjusted OR of each significant factor are reported, showing that BMI was the higher risk factor for schizophrenia (OR, 1.506; P = .002).
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Table 1 Demographics and clinical symptoms. Variable
Study group (n = 10) mean ± SD (count) (%)
Control group 1 (n = 37) mean ± SD (count) (%)
Control group 2 (n = 13) mean ± SD (count) (%)
P value
Current age (y) Boys Girls Age of narcolepsy onset (y) Age of schizophrenia onset (y) BMI (kg/m2) Family history of narcolepsy Family history of psychiatric disease
18.54 ± 2.99 5 (50.0%) 5 (50.0%) 11.25 ± 3.92 15.80 ± 1.36 27.39 ± 7.17a,c 4 (40.0%)c 4 (30.0%)a
18.82 ± 3.54 21 (56.8%) 16 (43.2%) 12.59 ± 3.41 – 23.62 ± 4.86a 5 (13.5%)b 2 (5.4%)a,b
18.38 ± 3.65 6 (46.2%) 7 (53.8%) – 16.38 ± 0.84 20.32 ± 3.13c 0 (0.0%)b,c 3 (23.1%)b
.268 .703
Symptoms and sign at time of diagnosis Hypersomnia Cataplexy Hypnogogic hallucination Sleep paralysis Parasomnia Delusion Auditory hallucination or visual hallucination
10 (100%)c 10 (100%)c 10 (100%) 10 (100%)a,c 8 (80.0%) 7 (70.0%)a 9 (90.0%)a
37 (100%)b 37 (100%)b 30 (81.1%) 25 (67.6%)a,b 22 (59.5%) 0 (0.0%)a,b 0 (0.0%)a,b
3 (23.1%)b,c 0 (0.0%)b,c 9 (69.2%) 2 (15.4%)b,c 6 (46.2%) 13 (100%)b 13 (100.0%)b
.0001 .0001 .166 .0001 .258 .0001 .0001
.269 .572 .002 .027 .016
Abbreviations: SD, standard deviation; y, years; BMI, body mass index. Study group: narcolepsy–cataplexy with schizophrenia.. Control group 1: narcolepsy–cataplexy without schizophrenia. Control group 2: only schizophrenia. Comparison of means: Kruskal–Wallis H test. Comparison of counts (%): v2 test. a Post hoc analysis showed significance of study group and control group 1. b Post hoc analysis showed significance of control group 1 and control group 2. c Post hoc analysis showed significance of control group 2 and study group. a,b BMI: Mann–Whitney U test (1 tailed).
Table 2 Comorbidity. Variable
Experimental group (n = 10) mean ± SD (count) (%)
Major depression Obesity (BMI =25 kg/m2) ADHD history ODD Asperger syndrome PLMS OSA OCD Insomnia
5 9 3 1 2 0 4 0 3
(50.0%)a,c (75.0%)a,c (30.0%) (8.3%) (20.0%) (0.0%) (40.0%) (0.0%) (30.0%)
Control group 1 (n = 37) mean ± SD (count) (%)
Control group 2 (n = 13) mean ± SD (count) (%)
5 (21.6%)a 14 (37.8%)a,b 2 (5.9%) 4 (10.8%) 1 (2.7%) 4 (10.8%) 8 (21.6%) 0 (0.0%) 11 (29.7%)
2 2 2 0 0 1 2 1 5
(15.4%)c (15.4%)b,c (15.4%) (0.0%) (0.0%) (7.7%) (15.4%) (7.7%) (38.5%)
P value .034 .026 .357 .264 .289 .545 .355 .159 .838
Abbreviations: SD, standard deviation; BMI, body mass index; ADHD, attention-deficit/hyperactivity disorder; ODD, oppositional defiant disorder; PLMS, periodic limb movements during sleep (PLMI >5/h with daytime symptoms); OSA, obstructive sleep apnea (apnea–hypopnea index >5 events/h); OCD, obsessive–compulsive disorder. Comparison of means: Kruskal–Wallis H test. Comparison of counts (%): v2 test. Major depression was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria. The diagnosis of insomnia was made according to criteria of DSM-IV-TR. a Post hoc analysis showed significance of study group and control group 1. b Post hoc analysis showed significance of control group 1 and control group 2. c Post hoc analysis showed significance of control group 2 and study group.
3.2.2. Sleep data In Table 3, analysis of variance showed a significant reduction of stage 2 NREM sleep in the N–C with schizophrenia group compared to the control group 2 (P = .006) on PSG. When compared to the group of schizophrenic control subjects, the two N–C subject groups showed significantly different mean sleep latency (1.74 ± 1.61; 2.97 ± 3.81 min) and number of SOREMPs (3.70 ± 1.34; 3.51 ± 1.38) compared to control group 2 schizophrenia in the MSLT, as expected. 3.2.3. HLA typing and blood tests All N–C patients were HLA DQB 1-0602 positive. There were three subjects (8.1%) with a homozygote for DQB1⁄06:02/⁄06:02 in the narcoleptic control group. There was no homozygote for
DQB1⁄06:02/⁄06:02 in the N–C subjects with schizophrenia and the schizophrenia-only control group 2, but there was a significant difference (P = .012) for DQB1⁄03:01/0 6:02 between the study group (70%), control group 1 (37.8%), and control group 2 (n = 0). Another interesting finding was the higher frequency of DQB1⁄06:01 in the schizophrenia control group 2. The results of the v2 test showed significant differences (P = .01) in the control group 2 schizophrenia subjects (46.1%), in the control group 1 narcolepsy subjects (8.1%), and the study group (10%). Analyses of the TNF-a cytokine and the hypocretin (orexin) receptor 1 gene, HCRTR1, and the hypocretin (orexin) receptor 2 gene, HCRTR2, showed no difference in any of the three investigated groups. We sequenced all exons of the dopamine D2 receptor gene, DRD2, investigating the possible mutations in the N–C subjects with schizophrenia, but no mutation in the
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Y.-S. Huang et al. / Sleep Medicine xxx (2013) xxx–xxx Table 3 Comparison of different administered scales and of sleep data. Variable
Experimental group (n = 10; a) mean ± SD (count) (%)
PANSS-P PANSS-N PANSS-G CGI-S ESS
24.70 ± 4.06) 25.70 ± 5.06 53.00 ± 7.23 4.90 ± 1.37 17.70 ± 2.00
PDSS
25.70 ± 4.60
VAS
Sleep variables MSLT variable Mean sleep latency (min) Number of sleep latency55 min Number of REM sleep (times) PSG variable AHI (times/h) AI (times/h) HI (times/h) Sleep efficiency % Awake % REM sleep % Stage 1% Stage 2% SWS % TST (min) Sleep latency (min)
Control group 1 (n = 37; b) mean ± SD (count) (%) – – – – 16.16 ± 3.00 22.19 ± 3.99 )
Control group 2 (n = 13; c) mean ± SD (count) n(%)
.018 .019 .004 .010 .0001
10.38 ± 3.12
.0001
23.08 ± 12.51
.0001
81.49 ± 12.18
1.74 ± 1.61
2.97 ± 3.81
10.24 ± 6.81
4.60 ± 0.97
4.03 ± 1.59
3.70 ± 1.34
3.51 ± 1.38
2.88 ± 3.97 0.38 ± 0.80 2.11 ± 3.13 83.81 ± 12.96 14.56 ± 12.08 18.18 ± 7.85 16.16 ± 9.27 40.13 ± 12.56 18.18 ± 11.11 378.35 ± 86.91 9.27 ± 15.47
P value
20.83 ± 3.16 19.77 ± 4.23 44.00 ± 4.24 3.69 ± 0.63 6.08 ± 2.40
92.50 ± 8.25
5.76 ± 7.60 1.43 ± 2.93 4.00 ± 5.57 76.32 ± 11.44 18.85 ± 10.87 20.44 ± 14.32 18.20 ± 4.84 28.25 ± 8.74 22.75 ± 10.17 324.10 ± 93.46 10.10 ± 15.80
F
Post hoc analysis
a > b,a > c, b>c a > b,a > c, b>c a > b, a > c, b>c
11.04
.0001
a < c, b < c
1.50 ± 1.52
9.00
.0001
a > c, b > c
0.57 ± 0.79
15.68
.0001
a > c, b > c
12.35 ± 3.20 2.11 ± 5.30 12.11 ± 8.38 79.93 ± 10.12 14.87 ± 12.75 16.84 ± 7.90 23.11 ± 23.77 49.39 ± 15.52 10.58 ± 17.04 385.13 ± 57.73 24.44 ± 16.64
7.69 1,84 8.71 1.56 0.462 0.35 1.14 5.71 0.03 2.70 3.14
.001 .170 .001 .219 .633 .708 .329 .006 .972 .077 .052
a < c, b < c NS a < c, b < c NS NS NS NS a
