Pharmacological Reports 66 (2014) 1077–1082
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Original research article
Daytime sleepiness and EEG abnormalities in patients treated with second generation antipsychotic agents Łukasz Okruszek a, Wojciech Jernajczyk a, Aleksandra Wierzbicka a, Elz˙bieta Waliniowska a, Tomasz Jakubczyk a, Marek Jarema b, Adam Wichniak b,* a b
Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warszawa, Poland Third Department of Psychiatry, Institute of Psychiatry and Neurology, Warszawa, Poland
A R T I C L E I N F O
Article history: Received 5 November 2013 Received in revised form 15 May 2014 Accepted 16 July 2014 Available online 2 August 2014 Keywords: Excessive daytime sleepiness Electroencephalography Schizophrenia spectrum disorders Second generation antipsychotics
A B S T R A C T
Background: The aim of this study was to verify whether or not an increased prevalence of excessive daytime sleepiness (EDS) or EEG abnormalities is observed in patients with schizophrenia spectrum disorders (SSD), and to compare the effects of second generation antipsychotics (SGA) on patients’ daytime sleepiness level and EEG recordings. Methods: EEG recordings and self-reports of EDS, assessed with Epworth (ESS) and Stanford (SSS) Sleepiness Scales, were compared between 244 patients with SSD and 82 patients with anxiety, personality or behavioral disorders (non-psychotic disorders, NPD). To examine the effects of various SGA, patients treated in monotherapy with aripiprazole, olanzapine, clozapine, risperidone and sertindole were compared. Results: A higher prevalence of abnormal EEG recordings was observed in SSD patients. No significant differences in average daytime sleepiness were found between patients with SSD and NPD; however, patients with SSD had longer sleep duration. Aripiprazole treatment was associated with significantly smaller and less frequent EEG abnormalities than treatment with any other SGA, while treatment with clozapine and olanzapine was related to an increased prevalence of severe EEG abnormalities. Patients with SSD treated with SGA in monotherapy were less sleepy than unmedicated patients with NPD. Conclusions: Although antipsychotics may have profound effects on EEG patients with schizophrenia do not have higher daytime sleepiness than patients with anxiety/personality disorders. Patients with schizophrenia may compensate sedative effects of antipsychotic treatment with sleep duration prolongation and report even less sleepiness than non-psychotic patients. ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Introduction The introduction of chlorpromazine to the treatment of schizophrenia in the 1950s is considered as a major breakthrough in the field of psychiatry [1]. For a long time, the sedative effect of antipsychotics was seen as an important indicator of treatment efficacy. However, sedation soon became viewed as a side-effect
Abbreviations: EDS, excessive daytime sleepiness; ESS, Epworth Sleepiness Scale; MSLT, multiple sleep latency test; NPD, non-psychotic disorders; SGA, second generation antipsychotics; SSD, schizophrenia spectrum disorders; SSS, Stanford Sleepiness Scale. * Corresponding author. E-mail addresses: [email protected], [email protected] (A. Wichniak).
instead of the benefit of the antipsychotic treatment. Sedation was shown to be related not only to decreased quality of life, but also worsening of the patients’ social functioning and compliance to antipsychotic treatment [2]. Even though second generation antipsychotics (SGA) have been claimed to have more favorable effects on functioning than typical neuroleptics (e.g. fewer extrapyramidal side-effects), they may cause significant psychomotor or metabolic adverse effects [3]. Moreover, some SGA, for instance quetiapine and olanzapine, share the sedative properties of typical neuroleptics [4]. Both typical neuroleptics and SGAs have also been shown to modify the bioelectrical activity (EEG) of the brain [5,6]. Abnormalities have been found in about 20–60% of patients with schizophrenia when their EEG is analyzed with conventional qualitative methods.
http://dx.doi.org/10.1016/j.pharep.2014.07.007 1734-1140/ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
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Moreover, various quantitative EEG abnormalities have been shown to be associated with clinical symptoms observed in schizophrenia [7–9]. Multiple studies have proven that excessive daytime sleepiness (EDS) is significantly associated with an increased risk of road and work accidents [10–12]. Therefore, antipsychotics are frequently regarded as factors that impair driving ability [13]. Consequently, many patients with schizophrenia who are treated with antipsychotics are prohibited from driving or undertaking work activities that require unimpaired sustained attention. Such decisions are frequently made on the basis of common beliefs, that may be unjustified as the data obtained from validated methods is sparse to support the claim that patients with schizophrenia have higher levels of daytime sleepiness than other psychiatric patients. A recent study that used the multiple sleep latency test (MSLT), showed that mean sleep latency was more than 36% longer (i.e. sleep propensity was lower) in untreated patients with schizophrenia than in healthy controls [14]. The aim of the present study was to examine the differences in levels of daytime sleepiness and corresponding EEG between patients with schizophrenia or schizophrenia spectrum disorders (SSD) and non-psychotic mental disorders, and to compare the effects of various SGA on the level of daytime sleepiness and EEG recordings of these patients. Materials and methods
sociodemographic characteristics of the study sample, obtained from medical records of participants, are shown in Table 1. All patients were examined during their hospitalization, so they shared similar clinical daily routines, sleeping conditions and diet. Patients who had a history of brain trauma or any other psychiatric, neurological or general medical disorders which might affect EEG were excluded from the study. EEG recordings EEG recordings were performed according to the recommendations of the International Federation of Clinical Neurophysiology [15]. All of the patients were examined between 9 a.m. and 12 noon in the same acoustically and electrically shielded room. The examination was performed upon completion of the sleepiness scales. An EEG was recorded for at least 20 min; eye opening, hyperventilation and photic stimulation were used as activation procedures during the recording. All of the EEG recordings were assessed using standardized forms by the experienced rater who was blind to the patient’s diagnosis. At the first step of analysis, EEG recordings were classified as ‘‘within the norms’’ or ‘‘pathological.’’ After that, each of the abnormal recordings was classified into one of three categories, depending on the severity of abnormalities observed in the recording. The scoring system was adopted from the Centorrino et al. [6] study to allow direct comparison of the effects of the antipsychotics on EEG observed in both studies. Three levels of EEG abnormality were distinguished:
Patients Data from 244 patients who were referred for routine EEG examination were included in this study. Patients were diagnosed based on the International Classification of Diseases (ICD-10) criteria with SSD (196 with schizophrenia [F20], 27 with acute psychotic disorder [F23], 10 with schizoaffective disorder [F25] and 11 patients with other diagnoses from the schizophrenia group [F20–F29]). All patients were pharmacologically treated with antipsychotics (mostly with SGA), 164 in monotherapy and 80 in polytherapy. The five most frequently used antipsychotics were aripiprazole, clozapine, olanzapine, risperidone and sertindole. The control group (patients with non-psychotic disorders, NPD) consisted of 82 patients (37 treated pharmacologically, mainly with selective serotonin reuptake inhibitors [SSRIs], 45 without any medication) with anxiety, personality and behavioral disorders. There were no differences in age (mean age: 28.2 7.0 [SSD] vs. 30.3 8.9 [NPD] years old, n.s.) or gender structure (59% males [SSD] vs. 49% males [NPD], n.s.) between both groups. The
1 Mild abnormality – scored if generalized or frontal symmetrical theta slowing was observed, 2 Moderate abnormality – scored if theta and delta slowing, asymmetrical focal slow waves activity or sharp waves were observed and 3 Severe abnormality – scored if spike discharges or slow wavespike activity (alone or with the moderate abnormality traits) were observed. EEG score was computed for each group as a mean of the EEG ratings for all of the patients within a group. A rating of zero was given to all of the EEG recordings which were classified as normal. Sleepiness scales and sleep assessment The Epworth Sleepiness Scale (ESS) is a questionnaire for the self-assessment of average daytime sleepiness in various activities of daily life [16,17]. Eight situations are presented, some of which
Table 1 Descriptive statistics of sociodemographic characteristics, sleepiness scales and EEG scores of groups analyzed in the study. Group
SSD
NPD
SSD, monotherapy with SGA
NPD, unmedicated
Aripiprazole
Clozapine
Olanzapine
Risperidone
Sertindole
n Age Sex (M/F) Dosage (mg/d) ESSa EDSb (%) SSSc Sleep duration (min)d EEG scoree
244 28.2 7.0 144/100 – 7.6 4.2 26 3.1 1.3 526 115
82 30.3 8.9 40/42 – 8.5 4.2 36 3.7 1.2 424 118
121 27.3 6.1 66/55 – 7.5 4.3 24 3.2 1.3 538 97
46 28.6 8.6 24/21 – 9.3 4.5 47 3.6 1.4 415 129
17 26.6 6.1 7/10 17.3 4.7 7.4 5.2 29 2.5 0.9 562 119
9 30.3 8.6 6/3 458 105 5.2 3.5 11 3.3 1.2 522 130
42 27.0 6.1 23/19 16.2 5.7 6.8 3.8 19 3.2 1.4 540 86
34 26.7 6.3 23/11 4.5 1.6 7.6 4.0 21 3.3 1.3 543 90
19 28.1 4.2 7/12 16.3 2.7 9.8 4.9 42 3.7 0.8 509 96
0.71 0.94
0.45 0.78
0.80 0.98
0.47 0.76
0.06 0.25
1.22 1.20
1.07 1.11
1.03 1.03
0.68 0.89
ESS – Epworth Sleepiness Scale; EDS – excessive daytime sleepiness (ESS score > 10); SSS – Stanford Sleepiness Scale; EEG score – mean EEG score computed as instructed in Centorrino et al. [6]; SSD – schizophrenia and schizophrenia spectrum disorders, NPD – non-psychotic disorders; SGA – second generation antipsychotics. a SSD monotherapy with SGA < unmedicated NPD, p < 0.05. b SSD monotherapy with SGA < unmedicated NPD, p < 0.01. c SSD < NPD, p < 0.01; aripiprazole < sertindole, p < 0.05. d SSD > NPD, p < 0.01; SSD monotherapy with SGA > unmedicated NPD, p < 0.001. e SSD > NPD, p < 0.01; SSD monotherapy with SGA > unmedicated NPD, p < 0.05; aripiprazole < olanzapine, p < 0.01; aripiprazole < risperidone, p < 0.05.
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are more appropriate to fall asleep than others [18]. Results above the cutoff score of 10 points suggest EDS. The Stanford Sleepiness Scale (SSS) is a brief self-rating scale of sleepiness at a certain point in time. A seven-point Likert-type scale (1 = ‘‘feeling active, vital alert or wide awake’’ to 7 = ‘‘no longer fighting sleep, sleep onset soon and having dream-like thought’’) is given to participants and they are asked to choose the answer which best describes their current level of sleepiness [19,20]. The duration and quality of the patients’ sleep before the EEG recording were assessed with a selfconstructed form that included questions about bedtime and waking hours, sleep onset latency and number of awakenings during the night. Statistical analysis Patients with SSD and NPD were compared with respect to their ESS and SSS scores, as well as sleep duration, using two-sided ttests for independent variables. Chi-squared (x2) analysis was carried out to compare the prevalence of abnormal EEG recordings within the groups. All of the patients treated in monotherapy with any SGA were combined and compared with an analogical procedure to unmedicated patients with NPD to provide information on sleepiness and EEG abnormalities during antipsychotic treatment. After the above procedure, one-way ANOVAs and Tukey’s post hoc tests were used to analyze the level of sleepiness and EEG abnormalities between patients with SSD treated with various SGA (aripiprazole, olanzapine, clozapine, risperidone, sertindole). Results at p < 0.05 were considered as significant.
Results Daytime sleepiness in patients with SSD and NPD Analysis of the ESS scores did not show any significant differences in the level of average daytime sleepiness between SSD and NPD patients (ESS mean score: 7.6 4.2 vs. 8.5 4.2; n.s.). Moderate EDS (ESS score 11–15) was observed in 20.5% (n = 50) of patients with SSD and in 30.5% (n = 25) of NPD patients (n.s.). The
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prevalence of severe daytime sleepiness (ESS > 15) was very similar in both groups (SSD: n = 14, 5.7% vs. NPD: n = 5, 6.1%). Patients with SSD reported lower levels of sleepiness at the time of EEG recording than patients with NPD (SSS mean score: 3.1 1.3 vs. 3.7 1.2, t(324) = 3.99, p < 0.01). They also had longer sleep duration (mean length: 526 115 min vs. 424 118 min, t(324) = 6.90, p < 0.01). EEG in patients with SSD and NPD A significantly higher prevalence of abnormal EEG recordings was observed in patients with SSD compared to NPD (44% vs. 31%, x2 = 4.55, p = 0.033). When analyzing the degree of pathology in EEG recordings, the most marked intergroup differences were observed in patients with moderate EEG abnormalities (22.6% vs. 7.7%; x2 = 10.95, p = 0.012), while the prevalence of mild (14.5% vs. 19.2%) and severe (6.5% vs. 3.8%) abnormalities was similar in both groups (Fig. 1). Antipsychotics and daytime sleepiness Patients treated in monotherapy with any SGA agents reported lower levels of average daytime sleepiness than unmedicated patients with NPD (ESS score 7.5 4.3 vs. 9.3 4.5, t(164) = 2.44, p = 0.016). EDS was found in 24% of patients treated in monotherapy with SGA and in 47% of unmedicated NPD patients (x2 = 8.03, p = 0.005). Sleep duration was longer in patients treated in monotherapy with SGA than in NPD patients (sleep length in min.: 538 97 vs. 415 129, t(164) = 6.59, p < 0.001). One-way ANOVA did not reveal any significant differences in ESS scores between the investigated five types of SGA treatments. At the time of EEG recording a significant difference in the level of sleepiness was found between patients receiving aripiprazole (SSS: 2.5 0.9) and sertindole (SSS: 3.7 0.8; Tukey’s post hoc test p = 0.03). Patients treated with olanzapine (SSS: 3.2 1.4), risperidone (SSS: 3.3 1.3) and clozapine (SSS: 3.3 1.2) had similar levels of sleepiness at the time of EEG recording and did not differ significantly from patients treated with aripiprazole and sertindole. However, extreme sleepiness levels at the time of EEG recording were reported only by patients treated with olanzapine (n = 4, 9.6% of the
Fig. 1. Prevalence of EEG abnormalities and severe EEG abnormalities in patients with SSD and NPD and in SSD patients treated with various SGA. SSD – schizophrenia and schizophrenia spectrum disorders, NPD – non-psychotic disorders; SGA – second generation antipsychotics; EEG abnormalities: SSD < NPD, p < 0.05; aripiprazole < other SGA, p < 0.01.
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group) and clozapine (n = 1, 11.1% of the group; x2 = 38.15, p = 0.033). No significant differences were found when the five types of antipsychotic treatment were compared for sleep duration. Antipsychotics and EEG No statistically significant differences in the frequency of abnormal EEG recordings were observed between SSD patients treated in monotherapy with SGA and unmedicated NPD patients (46.3% vs. 33.3%, n.s.). However, the EEG score in patients treated with SGA was significantly higher than in unmedicated NPD patients (0.80 0.98 vs. 0.47 0.76, t(102.3) = 2.31, p = 0.023). Significant differences were observed between groups of patients treated with various SGA in the prevalence of abnormal EEG recordings (risperidone 55.9%, clozapine 55.6%, olanzapine 54.8%, sertindole 42.1%, aripiprazole 5.9%, x2 = 14.08, p = 0.004) and in the EEG score (F = 3.90, p = 0.005). The mean EEG score of aripiprazole-treated patients (0.06 0.25) was significantly lower than the EEG score of olanzapine-treated patients (1.07 1.11, Tukey’s test p = 0.006), risperidone-treated patients (1.03 1.03, p = 0.029) and tended to be lower than the EEG score of patients treated with clozapine (1.22 1.20, p = 0.068). The EEG score of patients treated with sertindole (0.68 0.89) did not significantly differ from EEG scores of patients treated with any other antipsychotic. EEG abnormalities and sleepiness No significant differences were found between groups of patients with different EEG scores in their ESS score, SSS score or sleep duration. Discussion Patients with SSD as a group did not differ in their average daytime sleepiness from patients with NPD. A subgroup of SSD patients that was treated with SGA in monotherapy reported even lower levels of average daytime sleepiness than NPD patients. However, significantly longer night sleep duration was observed in patients with SSD. This finding is in line with the results from a study by Hawley et al. [21], which showed that patients treated with antipsychotics reported lower levels of daytime sleepiness and a lower prevalence of EDS than psychiatric populations not treated with antipsychotics. The mean ESS score of 115 antipsychotic-treated patients reported by Hawley et al. (7.1 4.9) was similar to the ESS score found in our study of the 121 patients treated in monotherapy with SGA (7.5 4.3). The observation of prolonged sleep duration in patients treated with antipsychotics in this study supports the suggestion by Hawley et al. [21] that patients may take sedative medications before they go to bed at night, and thus sleep longer and do not report EDS. The SGA included in the present study vary strongly in sedative properties. Clozapine is considered as an antipsychotic drug with marked sedative properties; there has been strong evidence that clozapine is a stronger sedative than haloperidol and low potency first generation antipsychotic drugs [3]. At the same time, aripiprazole has been shown to be a weaker sedative antipsychotic drug than haloperidol and is often cited as an atypical antipsychotic with a low sedative potential [3,22]. Olanzapine has an even higher affinity for the histamine H1 receptors than clozapine, thus it shows a large sedative effect, irrespective of the fact that it is a high-potency drug [23]. Risperidone is also a high-potency drug; however, with a lower affinity for histamine receptors than clozapine and olanzapine, its sedative effects are considered mild [24]. However, in a CATIE study [25], hypersomnia was reported by patients treated with olanzapine (31%) and risperidone (28%) at a
similar frequency. Sertindole, due to its pharmacodynamic characteristic and minimal affinity for muscarinic or histaminic H1 receptors, is often cited as an atypical antipsychotic with no sedative side-effects [26]. Until now, only a few studies have examined the results of certain antipsychotics on the level of daytime sleepiness. Wichniak et al. [27] have shown that patients treated with olanzapine and risperidone reported similar levels of daytime sleepiness as healthy controls. Subjective reports of EDS occurred in this study with a similar frequency in the olanzapine-treated group (19% vs. 25%) and less frequently in the clozapine-treated group (11% vs. 33%) than in a study by Kluge et al. [14], which also showed that treatment with olanzapine or clozapine increases sleep propensity as measured with the MSLT [28]. In the present study, no type of treatment with SGA was strictly associated with pathological levels of average daytime sleepiness. The analysis of sleepiness at the time of EEG recording revealed an unexpected effect; treatment with sertindole was associated with higher sleepiness than the treatment with aripiprazole, the other investigated nonsedative antipsychotic drug. However, due to the risk of cardiac adverse effects (QTc prolongation in ECG), sertindole is recommended for use in Poland only in patients who have already been treated with at least one other antipsychotic and had poor tolerance of the treatment. One of the most common reasons for switching to sertindole is patients’ complaints about excessive sedation caused by the antipsychotic drug. Thus, it is plausible that some patients treated with sertindole in the current study were very sensitive to this side-effect of antipsychotics. The findings from the present study are contradictory to common belief that patients treated with antipsychotics, especially sedative antipsychotics like clozapine and olanzapine, are more sleepy than other psychiatric patients. Three complementary hypotheses may be provided to explain this observation. Firstly, it may be suggested that, due to the increased activity of the dopaminergic system, patients with SSD have lower levels of sleepiness not only compared to NPD patients, but also to healthy people. As previously mentioned, the study by Kluge et al. [14] has shown that sleep propensity in untreated patients with schizophrenia is lower than in healthy subjects [14]. There is no reason to believe that patients with personality or behavioral disorders would exhibit increased daytime sleepiness when compared to healthy subjects, and only limited evidence of the association between EDS and anxiety disorders is available [29]. Thus, it may be hypothesized that even after accounting for the sedative effects of antipsychotic treatment, SSD patients may still report similar levels of daytime sleepiness as NPD patients or healthy people. It may also be suggested that the subjective feeling of EDS is common in patients treated with antipsychotics, but patients’ complaints about excessive sleepiness are not reflected in objective measures of sleepiness [14] or standardized self-rating scales of sleepiness [30]. Moreover, EDS can be easily confused with fatigue which is often related to mental disorders [30]. Finally, it is plausible that patients with SSD have lower daytime sleepiness than patients with NPD, mainly due to their longer sleep duration. Both patient groups, SSD and NPD, shared similar daily clinical routines, sleeping conditions and diet; therefore, the differences in sleep duration observed in this study cannot be explained by any lifestyle factors. Hence, prolongation of nocturnal sleep time seems to be the primary mechanism with which SSD patients compensate for the sedative effects of antipsychotic medication. The hypothesis that prolongation of nocturnal sleep time may be a compensatory mechanism in SSD patients is supported by results from Ohayon’s [29] large scale (n = 8937) cross-sectional study. Ohayon found that in the general population, a long (>8 h) night-time sleep duration is significantly associated with a decreased risk of moderate, but not severe EDS.
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Thus, sleep prolongation may decrease the frequency of moderate, but not severe, EDS. In support of this hypothesis, SSD patients were found in the present study to have very similar frequency of severe EDS (5.7% vs. 6.1%) as NPD patients, but not the frequency of moderate EDS (20.5% vs. 30.5%). The analysis of EEG recordings revealed that in SSD patients, increased slow-wave activity can be frequently observed. This finding is in line with the results from previous studies on EEG abnormalities in schizophrenic patients [31]. While reviewing oscillatory abnormalities in schizophrenia, Moran and Hong [32] claimed that increased EEG theta/delta activity, which occurs locally and globally, is one of the more consistent observations in EEG/ERP studies of unmedicated, first episode and chronic patients with schizophrenia. The antipsychotics investigated in this study varied strongly in the extent to which they affected EEG. Some drugs strongly modified EEG (clozapine, olanzapine) but drugs with a minimal impact on EEG (aripiprazole) may also be important to point out. Some of the drugs were also more likely to provoke epileptiform activity (clozapine, olanzapine) than others (sertindole, aripiprazole). The gradation of EEG scores of atypical antipsychotic agents was the same in this study as the one revealed in a study by Centorrino et al. [6]: clozapine (EEG score in this study: 1.22 1.20, EEG score in the Centorrino et al. study: 0.94 1.09) had the most prominent influence on EEG, preceding that of olanzapine (EEG score in this study: 1.07 1.11, EEG score in the Centorrino et al. study: 0.77 1.09) and risperidone (EEG score in this study: 1.03 1.03, EEG score in the Centorrino et al. study: 0.56 0.96). Some of the properties of the second generation antipsychotics included in this study have been reported before, for instance, the association between epileptiform activity and treatment with olanzapine or clozapine [33–35]. However, to the best of the author’s knowledge, this is the first study in which the impact of sertindole on the brain’s bioelectrical activity was analyzed. In conclusion, this study has shown that despite the profound effects exerted by antipsychotics on EEG, patients with SSD treated with these drugs do not report higher levels of daytime sleepiness than patients with NPD. Neither antipsychotic treatment, nor any specific antipsychotic drug, was related to an increased frequency of EDS in the patients studied. Thus, in clinical practice, the level of sleepiness of each patient should be examined without any prior assumption that certain antipsychotics may or may not cause sedation. Our study has some limitations that have to be considered in the interpretation of its results and should be addressed in the future studies. The assessment of sleepiness in patients was based on self-report scales. In neurology and respiratory medicine, the assessment of sleepiness is an established problem; however, it has received minimal attention in psychiatry [36]. Sleep medicine provides methods for assessing sleepiness (MSLT, maintenance of wakefulness test) which may be considered superior to selfratings [16], and therefore should be considered in further studies. The lack of a control group of healthy subjects and the lack of an assessment of severity of psychopathological symptoms with clinical rating scales do not allow to conclude what is the level of daytime sleepiness of SSD patients in comparison to non-psychiatric population and what is the link between mental status and the reported subjective level of daytime sleepiness in those patients. It has also to be noted that all SSD patients and substantial part of patients with NPD were pharmacologically treated. To reduce the role of pharmacological treatment as a confounding factor we compared in the subanalysis only SSD patients treated with SGA in monotherapy with unmedicated NPD patients. This subanalysis also showed that SSD patients treated with SGA do not report higher levels of daytime sleepiness than NPD patients. Despite the above
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mentioned weaknesses of the present study we believe this is an interesting and valid result. Conflict of interest The authors declare that there is no conflict of interest. Acknowledgments Funding for this study was provided by Research Grant 2 P05B 124 29 from the Polish Ministry of Science and Higher Education (MNiSW) and Institute of Psychiatry and Neurology (IPiN) Intramural Grant Nos 13/2005 and 09/2008; the MNiSW and IPiN had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. References [1] Pieters T, Majerus B. The introduction of chlorpromazine in Belgium and the Netherlands (1951–1968); tango between old and new treatment features. Stud Hist Philos Sci 2011;42:443–52. [2] Hofer A, Kemmler G, Eder U, Honeder M, Hummer M, Fleischhacker WW. Attitudes toward antipsychotics among outpatient clinic attendees with schizophrenia. J Clin Psychiatry 2002;63:49–53. [3] Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373:31–41. [4] Hermes ED, Sernyak M, Rosenheck R. Use of second-generation antipsychotic agents for sleep and sedation: a provider survey. Sleep 2013;36:597–600. [5] Amann BL, Pogarell O, Mergl R, Juckel G, Grunze H, Mulert C, et al. EEG abnormalities associated with antipsychotics: a comparison of quetiapine, olanzapine, haloperidol and healthy subjects. Hum Psychopharmacol 2003; 18:641–6. [6] Centorrino F, Price BH, Tuttle M, Bahk WM, Hennen J, Albert MJ, et al. EEG abnormalities during treatment with typical and atypical antipsychotics. Am J Psychiatry 2002;159:109–15. [7] Hughes JR, John ER. Conventional and quantitative electroencephalography in psychiatry. J Neuropsychiatry Clin Neurosci 1999;11:190–208. [8] Koenig T, Lehmann D, Merlo MC, Kochi K, Hell D, Koukkou M. A deviant EEG brain microstate in acute, neuroleptic-naive schizophrenics at rest. Eur Arch Psychiatry Clin Neurosci 1999;249:205–11. [9] Winterer G, Ziller M, Dorn H, Frick K, Mulert C, Wuebben Y, et al. Frontal dysfunction in schizophrenia – a new electrophysiological classifier for research and clinical applications. Eur Arch Psychiatry Clin Neurosci 2000; 250:207–14. [10] Connor J, Norton R, Ameratunga S, Robinson E, Civil I, Dunn R, et al. Driver sleepiness and risk of serious injury to car occupants: population based case– control study. BMJ 2002;324:1125–30. [11] Gander PH, Marshall NS, Harris RB, Reid P. Sleep, sleepiness and motor vehicle accidents: a national survey. Aust N Z J Public Health 2005;29:16–21. [12] de Mello MT, Narciso FV, Tufik S, Paiva T, Spence DW, Bahammam AS, et al. Sleep disorders as a cause of motor vehicle collisions. Int J Prev Med 2013;4:246–57. [13] Brunnauer A, Laux G, Zwick S. Driving simulator performance and psychomotor functions of schizophrenic patients treated with antipsychotics. Eur Arch Psychiatry Clin Neurosci 2009;259:483–9. [14] Kluge M, Himmerich H, Wehmeier PM, Rummel-Kluge C, Dalal M, Hinze-Selch D, et al. Sleep propensity at daytime as assessed by multiple sleep latency tests (MSLT) in patients with schizophrenia increases with clozapine and olanzapine. Schizophr Res 2012;135:123–7. [15] Deuschl G, Eisen A. Recommendations for the practice of clinical neurophysiology: guidelines of the international federation of clinical neurophysiology. Electroenceph Clin Neurophysiol Suppl 1999;52:3–41. [16] Cluydts R, De Valck E, Verstraeten E, Theys P. Daytime sleepiness and its evaluation. Sleep Med Rev 2002;6:83–96. [17] Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep 1992;15:376–81. [18] Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14:540–5. [19] Hoddes E, Zarcone V, Smythe HR, Phillips R, Dement WC. Quantification of sleepiness: a new approach. Psychophysiology 1973;10:431–6. [20] Short M, Lack L, Wright H. Does subjective sleepiness predict objective sleep propensity? Sleep 2010;33:123–9. [21] Hawley CJ, Gale TM, Sivakumaran T, Paul S, Kondan VR, Farag A, et al. Excessive daytime sleepiness in psychiatric disorders: prevalence, correlates and clinical significance. Psychiatry Res 2010;175:138–41. [22] Canas F. Management of agitation in the acute psychotic patient – efficacy without excessive sedation. Eur Neuropsychopharmacol 2007;17:S108–14.
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Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep
Original research article
Daytime sleepiness and EEG abnormalities in patients treated with second generation antipsychotic agents Łukasz Okruszek a, Wojciech Jernajczyk a, Aleksandra Wierzbicka a, Elz˙bieta Waliniowska a, Tomasz Jakubczyk a, Marek Jarema b, Adam Wichniak b,* a b
Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warszawa, Poland Third Department of Psychiatry, Institute of Psychiatry and Neurology, Warszawa, Poland
A R T I C L E I N F O
Article history: Received 5 November 2013 Received in revised form 15 May 2014 Accepted 16 July 2014 Available online 2 August 2014 Keywords: Excessive daytime sleepiness Electroencephalography Schizophrenia spectrum disorders Second generation antipsychotics
A B S T R A C T
Background: The aim of this study was to verify whether or not an increased prevalence of excessive daytime sleepiness (EDS) or EEG abnormalities is observed in patients with schizophrenia spectrum disorders (SSD), and to compare the effects of second generation antipsychotics (SGA) on patients’ daytime sleepiness level and EEG recordings. Methods: EEG recordings and self-reports of EDS, assessed with Epworth (ESS) and Stanford (SSS) Sleepiness Scales, were compared between 244 patients with SSD and 82 patients with anxiety, personality or behavioral disorders (non-psychotic disorders, NPD). To examine the effects of various SGA, patients treated in monotherapy with aripiprazole, olanzapine, clozapine, risperidone and sertindole were compared. Results: A higher prevalence of abnormal EEG recordings was observed in SSD patients. No significant differences in average daytime sleepiness were found between patients with SSD and NPD; however, patients with SSD had longer sleep duration. Aripiprazole treatment was associated with significantly smaller and less frequent EEG abnormalities than treatment with any other SGA, while treatment with clozapine and olanzapine was related to an increased prevalence of severe EEG abnormalities. Patients with SSD treated with SGA in monotherapy were less sleepy than unmedicated patients with NPD. Conclusions: Although antipsychotics may have profound effects on EEG patients with schizophrenia do not have higher daytime sleepiness than patients with anxiety/personality disorders. Patients with schizophrenia may compensate sedative effects of antipsychotic treatment with sleep duration prolongation and report even less sleepiness than non-psychotic patients. ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Introduction The introduction of chlorpromazine to the treatment of schizophrenia in the 1950s is considered as a major breakthrough in the field of psychiatry [1]. For a long time, the sedative effect of antipsychotics was seen as an important indicator of treatment efficacy. However, sedation soon became viewed as a side-effect
Abbreviations: EDS, excessive daytime sleepiness; ESS, Epworth Sleepiness Scale; MSLT, multiple sleep latency test; NPD, non-psychotic disorders; SGA, second generation antipsychotics; SSD, schizophrenia spectrum disorders; SSS, Stanford Sleepiness Scale. * Corresponding author. E-mail addresses: [email protected], [email protected] (A. Wichniak).
instead of the benefit of the antipsychotic treatment. Sedation was shown to be related not only to decreased quality of life, but also worsening of the patients’ social functioning and compliance to antipsychotic treatment [2]. Even though second generation antipsychotics (SGA) have been claimed to have more favorable effects on functioning than typical neuroleptics (e.g. fewer extrapyramidal side-effects), they may cause significant psychomotor or metabolic adverse effects [3]. Moreover, some SGA, for instance quetiapine and olanzapine, share the sedative properties of typical neuroleptics [4]. Both typical neuroleptics and SGAs have also been shown to modify the bioelectrical activity (EEG) of the brain [5,6]. Abnormalities have been found in about 20–60% of patients with schizophrenia when their EEG is analyzed with conventional qualitative methods.
http://dx.doi.org/10.1016/j.pharep.2014.07.007 1734-1140/ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
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Moreover, various quantitative EEG abnormalities have been shown to be associated with clinical symptoms observed in schizophrenia [7–9]. Multiple studies have proven that excessive daytime sleepiness (EDS) is significantly associated with an increased risk of road and work accidents [10–12]. Therefore, antipsychotics are frequently regarded as factors that impair driving ability [13]. Consequently, many patients with schizophrenia who are treated with antipsychotics are prohibited from driving or undertaking work activities that require unimpaired sustained attention. Such decisions are frequently made on the basis of common beliefs, that may be unjustified as the data obtained from validated methods is sparse to support the claim that patients with schizophrenia have higher levels of daytime sleepiness than other psychiatric patients. A recent study that used the multiple sleep latency test (MSLT), showed that mean sleep latency was more than 36% longer (i.e. sleep propensity was lower) in untreated patients with schizophrenia than in healthy controls [14]. The aim of the present study was to examine the differences in levels of daytime sleepiness and corresponding EEG between patients with schizophrenia or schizophrenia spectrum disorders (SSD) and non-psychotic mental disorders, and to compare the effects of various SGA on the level of daytime sleepiness and EEG recordings of these patients. Materials and methods
sociodemographic characteristics of the study sample, obtained from medical records of participants, are shown in Table 1. All patients were examined during their hospitalization, so they shared similar clinical daily routines, sleeping conditions and diet. Patients who had a history of brain trauma or any other psychiatric, neurological or general medical disorders which might affect EEG were excluded from the study. EEG recordings EEG recordings were performed according to the recommendations of the International Federation of Clinical Neurophysiology [15]. All of the patients were examined between 9 a.m. and 12 noon in the same acoustically and electrically shielded room. The examination was performed upon completion of the sleepiness scales. An EEG was recorded for at least 20 min; eye opening, hyperventilation and photic stimulation were used as activation procedures during the recording. All of the EEG recordings were assessed using standardized forms by the experienced rater who was blind to the patient’s diagnosis. At the first step of analysis, EEG recordings were classified as ‘‘within the norms’’ or ‘‘pathological.’’ After that, each of the abnormal recordings was classified into one of three categories, depending on the severity of abnormalities observed in the recording. The scoring system was adopted from the Centorrino et al. [6] study to allow direct comparison of the effects of the antipsychotics on EEG observed in both studies. Three levels of EEG abnormality were distinguished:
Patients Data from 244 patients who were referred for routine EEG examination were included in this study. Patients were diagnosed based on the International Classification of Diseases (ICD-10) criteria with SSD (196 with schizophrenia [F20], 27 with acute psychotic disorder [F23], 10 with schizoaffective disorder [F25] and 11 patients with other diagnoses from the schizophrenia group [F20–F29]). All patients were pharmacologically treated with antipsychotics (mostly with SGA), 164 in monotherapy and 80 in polytherapy. The five most frequently used antipsychotics were aripiprazole, clozapine, olanzapine, risperidone and sertindole. The control group (patients with non-psychotic disorders, NPD) consisted of 82 patients (37 treated pharmacologically, mainly with selective serotonin reuptake inhibitors [SSRIs], 45 without any medication) with anxiety, personality and behavioral disorders. There were no differences in age (mean age: 28.2 7.0 [SSD] vs. 30.3 8.9 [NPD] years old, n.s.) or gender structure (59% males [SSD] vs. 49% males [NPD], n.s.) between both groups. The
1 Mild abnormality – scored if generalized or frontal symmetrical theta slowing was observed, 2 Moderate abnormality – scored if theta and delta slowing, asymmetrical focal slow waves activity or sharp waves were observed and 3 Severe abnormality – scored if spike discharges or slow wavespike activity (alone or with the moderate abnormality traits) were observed. EEG score was computed for each group as a mean of the EEG ratings for all of the patients within a group. A rating of zero was given to all of the EEG recordings which were classified as normal. Sleepiness scales and sleep assessment The Epworth Sleepiness Scale (ESS) is a questionnaire for the self-assessment of average daytime sleepiness in various activities of daily life [16,17]. Eight situations are presented, some of which
Table 1 Descriptive statistics of sociodemographic characteristics, sleepiness scales and EEG scores of groups analyzed in the study. Group
SSD
NPD
SSD, monotherapy with SGA
NPD, unmedicated
Aripiprazole
Clozapine
Olanzapine
Risperidone
Sertindole
n Age Sex (M/F) Dosage (mg/d) ESSa EDSb (%) SSSc Sleep duration (min)d EEG scoree
244 28.2 7.0 144/100 – 7.6 4.2 26 3.1 1.3 526 115
82 30.3 8.9 40/42 – 8.5 4.2 36 3.7 1.2 424 118
121 27.3 6.1 66/55 – 7.5 4.3 24 3.2 1.3 538 97
46 28.6 8.6 24/21 – 9.3 4.5 47 3.6 1.4 415 129
17 26.6 6.1 7/10 17.3 4.7 7.4 5.2 29 2.5 0.9 562 119
9 30.3 8.6 6/3 458 105 5.2 3.5 11 3.3 1.2 522 130
42 27.0 6.1 23/19 16.2 5.7 6.8 3.8 19 3.2 1.4 540 86
34 26.7 6.3 23/11 4.5 1.6 7.6 4.0 21 3.3 1.3 543 90
19 28.1 4.2 7/12 16.3 2.7 9.8 4.9 42 3.7 0.8 509 96
0.71 0.94
0.45 0.78
0.80 0.98
0.47 0.76
0.06 0.25
1.22 1.20
1.07 1.11
1.03 1.03
0.68 0.89
ESS – Epworth Sleepiness Scale; EDS – excessive daytime sleepiness (ESS score > 10); SSS – Stanford Sleepiness Scale; EEG score – mean EEG score computed as instructed in Centorrino et al. [6]; SSD – schizophrenia and schizophrenia spectrum disorders, NPD – non-psychotic disorders; SGA – second generation antipsychotics. a SSD monotherapy with SGA < unmedicated NPD, p < 0.05. b SSD monotherapy with SGA < unmedicated NPD, p < 0.01. c SSD < NPD, p < 0.01; aripiprazole < sertindole, p < 0.05. d SSD > NPD, p < 0.01; SSD monotherapy with SGA > unmedicated NPD, p < 0.001. e SSD > NPD, p < 0.01; SSD monotherapy with SGA > unmedicated NPD, p < 0.05; aripiprazole < olanzapine, p < 0.01; aripiprazole < risperidone, p < 0.05.
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are more appropriate to fall asleep than others [18]. Results above the cutoff score of 10 points suggest EDS. The Stanford Sleepiness Scale (SSS) is a brief self-rating scale of sleepiness at a certain point in time. A seven-point Likert-type scale (1 = ‘‘feeling active, vital alert or wide awake’’ to 7 = ‘‘no longer fighting sleep, sleep onset soon and having dream-like thought’’) is given to participants and they are asked to choose the answer which best describes their current level of sleepiness [19,20]. The duration and quality of the patients’ sleep before the EEG recording were assessed with a selfconstructed form that included questions about bedtime and waking hours, sleep onset latency and number of awakenings during the night. Statistical analysis Patients with SSD and NPD were compared with respect to their ESS and SSS scores, as well as sleep duration, using two-sided ttests for independent variables. Chi-squared (x2) analysis was carried out to compare the prevalence of abnormal EEG recordings within the groups. All of the patients treated in monotherapy with any SGA were combined and compared with an analogical procedure to unmedicated patients with NPD to provide information on sleepiness and EEG abnormalities during antipsychotic treatment. After the above procedure, one-way ANOVAs and Tukey’s post hoc tests were used to analyze the level of sleepiness and EEG abnormalities between patients with SSD treated with various SGA (aripiprazole, olanzapine, clozapine, risperidone, sertindole). Results at p < 0.05 were considered as significant.
Results Daytime sleepiness in patients with SSD and NPD Analysis of the ESS scores did not show any significant differences in the level of average daytime sleepiness between SSD and NPD patients (ESS mean score: 7.6 4.2 vs. 8.5 4.2; n.s.). Moderate EDS (ESS score 11–15) was observed in 20.5% (n = 50) of patients with SSD and in 30.5% (n = 25) of NPD patients (n.s.). The
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prevalence of severe daytime sleepiness (ESS > 15) was very similar in both groups (SSD: n = 14, 5.7% vs. NPD: n = 5, 6.1%). Patients with SSD reported lower levels of sleepiness at the time of EEG recording than patients with NPD (SSS mean score: 3.1 1.3 vs. 3.7 1.2, t(324) = 3.99, p < 0.01). They also had longer sleep duration (mean length: 526 115 min vs. 424 118 min, t(324) = 6.90, p < 0.01). EEG in patients with SSD and NPD A significantly higher prevalence of abnormal EEG recordings was observed in patients with SSD compared to NPD (44% vs. 31%, x2 = 4.55, p = 0.033). When analyzing the degree of pathology in EEG recordings, the most marked intergroup differences were observed in patients with moderate EEG abnormalities (22.6% vs. 7.7%; x2 = 10.95, p = 0.012), while the prevalence of mild (14.5% vs. 19.2%) and severe (6.5% vs. 3.8%) abnormalities was similar in both groups (Fig. 1). Antipsychotics and daytime sleepiness Patients treated in monotherapy with any SGA agents reported lower levels of average daytime sleepiness than unmedicated patients with NPD (ESS score 7.5 4.3 vs. 9.3 4.5, t(164) = 2.44, p = 0.016). EDS was found in 24% of patients treated in monotherapy with SGA and in 47% of unmedicated NPD patients (x2 = 8.03, p = 0.005). Sleep duration was longer in patients treated in monotherapy with SGA than in NPD patients (sleep length in min.: 538 97 vs. 415 129, t(164) = 6.59, p < 0.001). One-way ANOVA did not reveal any significant differences in ESS scores between the investigated five types of SGA treatments. At the time of EEG recording a significant difference in the level of sleepiness was found between patients receiving aripiprazole (SSS: 2.5 0.9) and sertindole (SSS: 3.7 0.8; Tukey’s post hoc test p = 0.03). Patients treated with olanzapine (SSS: 3.2 1.4), risperidone (SSS: 3.3 1.3) and clozapine (SSS: 3.3 1.2) had similar levels of sleepiness at the time of EEG recording and did not differ significantly from patients treated with aripiprazole and sertindole. However, extreme sleepiness levels at the time of EEG recording were reported only by patients treated with olanzapine (n = 4, 9.6% of the
Fig. 1. Prevalence of EEG abnormalities and severe EEG abnormalities in patients with SSD and NPD and in SSD patients treated with various SGA. SSD – schizophrenia and schizophrenia spectrum disorders, NPD – non-psychotic disorders; SGA – second generation antipsychotics; EEG abnormalities: SSD < NPD, p < 0.05; aripiprazole < other SGA, p < 0.01.
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group) and clozapine (n = 1, 11.1% of the group; x2 = 38.15, p = 0.033). No significant differences were found when the five types of antipsychotic treatment were compared for sleep duration. Antipsychotics and EEG No statistically significant differences in the frequency of abnormal EEG recordings were observed between SSD patients treated in monotherapy with SGA and unmedicated NPD patients (46.3% vs. 33.3%, n.s.). However, the EEG score in patients treated with SGA was significantly higher than in unmedicated NPD patients (0.80 0.98 vs. 0.47 0.76, t(102.3) = 2.31, p = 0.023). Significant differences were observed between groups of patients treated with various SGA in the prevalence of abnormal EEG recordings (risperidone 55.9%, clozapine 55.6%, olanzapine 54.8%, sertindole 42.1%, aripiprazole 5.9%, x2 = 14.08, p = 0.004) and in the EEG score (F = 3.90, p = 0.005). The mean EEG score of aripiprazole-treated patients (0.06 0.25) was significantly lower than the EEG score of olanzapine-treated patients (1.07 1.11, Tukey’s test p = 0.006), risperidone-treated patients (1.03 1.03, p = 0.029) and tended to be lower than the EEG score of patients treated with clozapine (1.22 1.20, p = 0.068). The EEG score of patients treated with sertindole (0.68 0.89) did not significantly differ from EEG scores of patients treated with any other antipsychotic. EEG abnormalities and sleepiness No significant differences were found between groups of patients with different EEG scores in their ESS score, SSS score or sleep duration. Discussion Patients with SSD as a group did not differ in their average daytime sleepiness from patients with NPD. A subgroup of SSD patients that was treated with SGA in monotherapy reported even lower levels of average daytime sleepiness than NPD patients. However, significantly longer night sleep duration was observed in patients with SSD. This finding is in line with the results from a study by Hawley et al. [21], which showed that patients treated with antipsychotics reported lower levels of daytime sleepiness and a lower prevalence of EDS than psychiatric populations not treated with antipsychotics. The mean ESS score of 115 antipsychotic-treated patients reported by Hawley et al. (7.1 4.9) was similar to the ESS score found in our study of the 121 patients treated in monotherapy with SGA (7.5 4.3). The observation of prolonged sleep duration in patients treated with antipsychotics in this study supports the suggestion by Hawley et al. [21] that patients may take sedative medications before they go to bed at night, and thus sleep longer and do not report EDS. The SGA included in the present study vary strongly in sedative properties. Clozapine is considered as an antipsychotic drug with marked sedative properties; there has been strong evidence that clozapine is a stronger sedative than haloperidol and low potency first generation antipsychotic drugs [3]. At the same time, aripiprazole has been shown to be a weaker sedative antipsychotic drug than haloperidol and is often cited as an atypical antipsychotic with a low sedative potential [3,22]. Olanzapine has an even higher affinity for the histamine H1 receptors than clozapine, thus it shows a large sedative effect, irrespective of the fact that it is a high-potency drug [23]. Risperidone is also a high-potency drug; however, with a lower affinity for histamine receptors than clozapine and olanzapine, its sedative effects are considered mild [24]. However, in a CATIE study [25], hypersomnia was reported by patients treated with olanzapine (31%) and risperidone (28%) at a
similar frequency. Sertindole, due to its pharmacodynamic characteristic and minimal affinity for muscarinic or histaminic H1 receptors, is often cited as an atypical antipsychotic with no sedative side-effects [26]. Until now, only a few studies have examined the results of certain antipsychotics on the level of daytime sleepiness. Wichniak et al. [27] have shown that patients treated with olanzapine and risperidone reported similar levels of daytime sleepiness as healthy controls. Subjective reports of EDS occurred in this study with a similar frequency in the olanzapine-treated group (19% vs. 25%) and less frequently in the clozapine-treated group (11% vs. 33%) than in a study by Kluge et al. [14], which also showed that treatment with olanzapine or clozapine increases sleep propensity as measured with the MSLT [28]. In the present study, no type of treatment with SGA was strictly associated with pathological levels of average daytime sleepiness. The analysis of sleepiness at the time of EEG recording revealed an unexpected effect; treatment with sertindole was associated with higher sleepiness than the treatment with aripiprazole, the other investigated nonsedative antipsychotic drug. However, due to the risk of cardiac adverse effects (QTc prolongation in ECG), sertindole is recommended for use in Poland only in patients who have already been treated with at least one other antipsychotic and had poor tolerance of the treatment. One of the most common reasons for switching to sertindole is patients’ complaints about excessive sedation caused by the antipsychotic drug. Thus, it is plausible that some patients treated with sertindole in the current study were very sensitive to this side-effect of antipsychotics. The findings from the present study are contradictory to common belief that patients treated with antipsychotics, especially sedative antipsychotics like clozapine and olanzapine, are more sleepy than other psychiatric patients. Three complementary hypotheses may be provided to explain this observation. Firstly, it may be suggested that, due to the increased activity of the dopaminergic system, patients with SSD have lower levels of sleepiness not only compared to NPD patients, but also to healthy people. As previously mentioned, the study by Kluge et al. [14] has shown that sleep propensity in untreated patients with schizophrenia is lower than in healthy subjects [14]. There is no reason to believe that patients with personality or behavioral disorders would exhibit increased daytime sleepiness when compared to healthy subjects, and only limited evidence of the association between EDS and anxiety disorders is available [29]. Thus, it may be hypothesized that even after accounting for the sedative effects of antipsychotic treatment, SSD patients may still report similar levels of daytime sleepiness as NPD patients or healthy people. It may also be suggested that the subjective feeling of EDS is common in patients treated with antipsychotics, but patients’ complaints about excessive sleepiness are not reflected in objective measures of sleepiness [14] or standardized self-rating scales of sleepiness [30]. Moreover, EDS can be easily confused with fatigue which is often related to mental disorders [30]. Finally, it is plausible that patients with SSD have lower daytime sleepiness than patients with NPD, mainly due to their longer sleep duration. Both patient groups, SSD and NPD, shared similar daily clinical routines, sleeping conditions and diet; therefore, the differences in sleep duration observed in this study cannot be explained by any lifestyle factors. Hence, prolongation of nocturnal sleep time seems to be the primary mechanism with which SSD patients compensate for the sedative effects of antipsychotic medication. The hypothesis that prolongation of nocturnal sleep time may be a compensatory mechanism in SSD patients is supported by results from Ohayon’s [29] large scale (n = 8937) cross-sectional study. Ohayon found that in the general population, a long (>8 h) night-time sleep duration is significantly associated with a decreased risk of moderate, but not severe EDS.
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Thus, sleep prolongation may decrease the frequency of moderate, but not severe, EDS. In support of this hypothesis, SSD patients were found in the present study to have very similar frequency of severe EDS (5.7% vs. 6.1%) as NPD patients, but not the frequency of moderate EDS (20.5% vs. 30.5%). The analysis of EEG recordings revealed that in SSD patients, increased slow-wave activity can be frequently observed. This finding is in line with the results from previous studies on EEG abnormalities in schizophrenic patients [31]. While reviewing oscillatory abnormalities in schizophrenia, Moran and Hong [32] claimed that increased EEG theta/delta activity, which occurs locally and globally, is one of the more consistent observations in EEG/ERP studies of unmedicated, first episode and chronic patients with schizophrenia. The antipsychotics investigated in this study varied strongly in the extent to which they affected EEG. Some drugs strongly modified EEG (clozapine, olanzapine) but drugs with a minimal impact on EEG (aripiprazole) may also be important to point out. Some of the drugs were also more likely to provoke epileptiform activity (clozapine, olanzapine) than others (sertindole, aripiprazole). The gradation of EEG scores of atypical antipsychotic agents was the same in this study as the one revealed in a study by Centorrino et al. [6]: clozapine (EEG score in this study: 1.22 1.20, EEG score in the Centorrino et al. study: 0.94 1.09) had the most prominent influence on EEG, preceding that of olanzapine (EEG score in this study: 1.07 1.11, EEG score in the Centorrino et al. study: 0.77 1.09) and risperidone (EEG score in this study: 1.03 1.03, EEG score in the Centorrino et al. study: 0.56 0.96). Some of the properties of the second generation antipsychotics included in this study have been reported before, for instance, the association between epileptiform activity and treatment with olanzapine or clozapine [33–35]. However, to the best of the author’s knowledge, this is the first study in which the impact of sertindole on the brain’s bioelectrical activity was analyzed. In conclusion, this study has shown that despite the profound effects exerted by antipsychotics on EEG, patients with SSD treated with these drugs do not report higher levels of daytime sleepiness than patients with NPD. Neither antipsychotic treatment, nor any specific antipsychotic drug, was related to an increased frequency of EDS in the patients studied. Thus, in clinical practice, the level of sleepiness of each patient should be examined without any prior assumption that certain antipsychotics may or may not cause sedation. Our study has some limitations that have to be considered in the interpretation of its results and should be addressed in the future studies. The assessment of sleepiness in patients was based on self-report scales. In neurology and respiratory medicine, the assessment of sleepiness is an established problem; however, it has received minimal attention in psychiatry [36]. Sleep medicine provides methods for assessing sleepiness (MSLT, maintenance of wakefulness test) which may be considered superior to selfratings [16], and therefore should be considered in further studies. The lack of a control group of healthy subjects and the lack of an assessment of severity of psychopathological symptoms with clinical rating scales do not allow to conclude what is the level of daytime sleepiness of SSD patients in comparison to non-psychiatric population and what is the link between mental status and the reported subjective level of daytime sleepiness in those patients. It has also to be noted that all SSD patients and substantial part of patients with NPD were pharmacologically treated. To reduce the role of pharmacological treatment as a confounding factor we compared in the subanalysis only SSD patients treated with SGA in monotherapy with unmedicated NPD patients. This subanalysis also showed that SSD patients treated with SGA do not report higher levels of daytime sleepiness than NPD patients. Despite the above
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mentioned weaknesses of the present study we believe this is an interesting and valid result. Conflict of interest The authors declare that there is no conflict of interest. Acknowledgments Funding for this study was provided by Research Grant 2 P05B 124 29 from the Polish Ministry of Science and Higher Education (MNiSW) and Institute of Psychiatry and Neurology (IPiN) Intramural Grant Nos 13/2005 and 09/2008; the MNiSW and IPiN had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. References [1] Pieters T, Majerus B. The introduction of chlorpromazine in Belgium and the Netherlands (1951–1968); tango between old and new treatment features. Stud Hist Philos Sci 2011;42:443–52. [2] Hofer A, Kemmler G, Eder U, Honeder M, Hummer M, Fleischhacker WW. Attitudes toward antipsychotics among outpatient clinic attendees with schizophrenia. J Clin Psychiatry 2002;63:49–53. [3] Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373:31–41. [4] Hermes ED, Sernyak M, Rosenheck R. Use of second-generation antipsychotic agents for sleep and sedation: a provider survey. Sleep 2013;36:597–600. [5] Amann BL, Pogarell O, Mergl R, Juckel G, Grunze H, Mulert C, et al. EEG abnormalities associated with antipsychotics: a comparison of quetiapine, olanzapine, haloperidol and healthy subjects. Hum Psychopharmacol 2003; 18:641–6. [6] Centorrino F, Price BH, Tuttle M, Bahk WM, Hennen J, Albert MJ, et al. EEG abnormalities during treatment with typical and atypical antipsychotics. Am J Psychiatry 2002;159:109–15. [7] Hughes JR, John ER. Conventional and quantitative electroencephalography in psychiatry. J Neuropsychiatry Clin Neurosci 1999;11:190–208. [8] Koenig T, Lehmann D, Merlo MC, Kochi K, Hell D, Koukkou M. A deviant EEG brain microstate in acute, neuroleptic-naive schizophrenics at rest. Eur Arch Psychiatry Clin Neurosci 1999;249:205–11. [9] Winterer G, Ziller M, Dorn H, Frick K, Mulert C, Wuebben Y, et al. Frontal dysfunction in schizophrenia – a new electrophysiological classifier for research and clinical applications. Eur Arch Psychiatry Clin Neurosci 2000; 250:207–14. [10] Connor J, Norton R, Ameratunga S, Robinson E, Civil I, Dunn R, et al. Driver sleepiness and risk of serious injury to car occupants: population based case– control study. BMJ 2002;324:1125–30. [11] Gander PH, Marshall NS, Harris RB, Reid P. Sleep, sleepiness and motor vehicle accidents: a national survey. Aust N Z J Public Health 2005;29:16–21. [12] de Mello MT, Narciso FV, Tufik S, Paiva T, Spence DW, Bahammam AS, et al. Sleep disorders as a cause of motor vehicle collisions. Int J Prev Med 2013;4:246–57. [13] Brunnauer A, Laux G, Zwick S. Driving simulator performance and psychomotor functions of schizophrenic patients treated with antipsychotics. Eur Arch Psychiatry Clin Neurosci 2009;259:483–9. [14] Kluge M, Himmerich H, Wehmeier PM, Rummel-Kluge C, Dalal M, Hinze-Selch D, et al. Sleep propensity at daytime as assessed by multiple sleep latency tests (MSLT) in patients with schizophrenia increases with clozapine and olanzapine. Schizophr Res 2012;135:123–7. [15] Deuschl G, Eisen A. Recommendations for the practice of clinical neurophysiology: guidelines of the international federation of clinical neurophysiology. Electroenceph Clin Neurophysiol Suppl 1999;52:3–41. [16] Cluydts R, De Valck E, Verstraeten E, Theys P. Daytime sleepiness and its evaluation. Sleep Med Rev 2002;6:83–96. [17] Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep 1992;15:376–81. [18] Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14:540–5. [19] Hoddes E, Zarcone V, Smythe HR, Phillips R, Dement WC. Quantification of sleepiness: a new approach. Psychophysiology 1973;10:431–6. [20] Short M, Lack L, Wright H. Does subjective sleepiness predict objective sleep propensity? Sleep 2010;33:123–9. [21] Hawley CJ, Gale TM, Sivakumaran T, Paul S, Kondan VR, Farag A, et al. Excessive daytime sleepiness in psychiatric disorders: prevalence, correlates and clinical significance. Psychiatry Res 2010;175:138–41. [22] Canas F. Management of agitation in the acute psychotic patient – efficacy without excessive sedation. Eur Neuropsychopharmacol 2007;17:S108–14.
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