Int J Psychiatry Clin Pract 2014; Early Online: 1–8. © 2014 Informa Healthcare ISSN 1365-1501 print/ISSN 1471-1788 online. DOI: 10.3109/13651501.2014.907919
ORIGINAL ARTICLE
Assessment of the effects of antihistamine drugs on mood, sleep quality, sleepiness, and dream anxiety
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Pinar Guzel Ozdemir1, Ayşe Serap Karadag2, Yavuz Selvi3, Murat Boysan4, Serap Gunes Bilgili5, Adem Aydin6 & Sevda Onder5 Department of Psychiatry, Yuzuncu Yil University Medicine Faculty, Van, Turkey, 2Department of Dermatology, Medeniyet Unversity, Faculty of Medicine, Göztepe Research and Training Hospital, Istanbul, Turkey, 3Department of Psychiatry, Selcuk University, Medicine Faculty, SUSAB (Neuroscience Unit), Konya, Turkey, 4Department of Psychology, Yuzuncu Yil University, School of Science and Arts, Van, Turkey, 5Department of Dermatology, Yuzuncu Yil University Medicine Faculty, Van, Turkey, and 6 Department of Psychiatry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey Int J Psych Clin Pract Downloaded from informahealthcare.com by Ryerson University on 06/18/14 For personal use only.
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Abstract Objective. There are limited comparative studies on classic and new-generation antihistamines that affect sleep quality and mood. The purpose of this study was to determine and compare the effects of classic and new-generation antihistamines on sleep quality, daytime sleepiness, dream anxiety, and mood. Methods. Ninety-two patients with chronic pruritus completed study in the dermatology outpatient clinic. Treatments with regular recommended therapeutic doses were administered. The effects of antihistaminic drugs on mood, daytime sleepiness, dream anxiety, and sleep quality were assessed on the first day and 1 month after. Results. Outpatients who received cetirizine and hydroxyzine treatments reported higher scores on the depression, anxiety, and fatigue sub-scales than those who received desloratadine, levocetirizine, and rupatadine. Pheniramine and rupatadine were found to be associated with daytime sleepiness and better sleep quality. UKU side effects scale scores were significantly elevated among outpatients receiving pheniramine. Classic antihistamines increased daytime sleepiness and decreased the sleep quality scores. New-generation antihistamines reduced sleep latency and dream anxiety, and increased daytime sleepiness and sleep quality. Conclusion. Both antihistamines, significantly increased daytime sleepiness and nocturnal sleep quality. Daytime sleepiness was significantly predicted by rupadatine and pheniramine treatment. Cetirizine and hydroxyzine, seem to have negative influences on mood states. Given the extensive use of antihistamines in clinical settings, these results should be more elaborately examined in further studies. Key words: Antihistamines, sleep quality, mood, dream anxiety, daytime sleepiness (Received 23 December 2013; accepted 20 March 2014)
Introduction Histamine is the main mediator of pruritus in many disorders (Ständer et al. 2007). Classic and new-generation antihistamines are equally effective and mainly used for its treatment. Chronic pruritus that lasts longer than 6 weeks is often intractable and has a high impact on the patient’s quality of life (Grundmann and Ständer 2011). It can become severe enough to interfere with work and restful sleep. New-generation antihistamines (e.g., cetirizine, loratadine, fexofenadine) cause fewer adverse effects, leading to improved patient compliance (Reamy et al. 2011). H1-antihistamines are inverse agonists that combine with and stabilize the inactive conformation of H1-receptors and therefore interfere with the actions of histamine (Herman and Vender 2003). The wake-promoting effects of histamine are believed to be mediated via histamine H1 receptors in the central nervous system (CNS). They penetrate the blood– brain barrier. They have poor receptor selectivity and often Correspondence: Dr. Pinar Guzel Ozdemir, Department of Psychiatry, Yuzuncu Yil University Medicine Faculty, Van 65200, Van-Turkey, Turkey. Tel: ⫹ 905056179746. Fax: ⫹ 904322167519. E-mail: [email protected]
interact with receptors of other biologically active amines that lead to antimuscarinic, anti-a-adrenergic, and antiserotonin effects. Their proclivity to interfere with neurotransmission by histamine at CNS H1-receptors potentially leads to drowsiness, sedation, somnolence, and fatigue leading to impairment of cognitive function, memory, and psychomotor performance (Church et al. 2010). Classical H1-antihistamines increase the latency to the onset of rapid eye movement (REM) sleep at night and reduce the duration of REM sleep. Residual effects are still present in the next morning. Such effects include impairment in divided attention, vigilance, working memory and sensory-motor performance, and reduced latency to daytime sleep. New-generation antihistamines are also more H1 selective than the classic antihistamines, have no anticholinergic effects, and also may result in less sedation and few other antihistaminic side effects (Church et al. 2010). They have known minimally sedating or non-sedating because of their limited penetration of the blood–brain barrier. It is well established that classic H1-antihistamines in doses commonly recommended for treatment frequently lead to somnolence, sedation, drowsiness, fatigue and impaired memory, and psychomotor performance (Church et al. 2010).
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Classic and new-generation antihistamines are nearly equally effective for the resolution of pruritus. The use of classical antihistamines, such as diphenhydramine and chlorpheniramine, is often related to a number of adverse effects, with sedation being the most addressed. These adverse effects can interfere with the performance of daytime activities and place the patient at risk of occupational injuries and traffic accidents (Theunissen et al. 2006). Classic H1-antihistamines cause drowsiness, especially with initial doses. They have long elimination half-life values with consequential hang-over effects the following morning (Church et al. 2010; Simons 2004; Kay et al. 1997a). New-generation antihistamines (e.g., cetirizine, loratadine, fexofenadine) cause fewer adverse effects, leading to improved patient compliance (Reamy et al. 2011). As second-generation antihistamines are less permeable to the brain than first-generation H1-antihistamines, their ability to induce sleep is still poorly understood. A large number of trials with an even larger number of tests have been carried out to assess the sedative effect of the newer H1 antagonists. However, many of these tests lack validity and the results are not reproducible. In a study that involves only the test drug and placebo, data showing no change in test scores may indicate either that the drug does not produce impairment, or that the tests lacked sufficient sensitivity to detect the impairment. Experimental studies have shown that single therapeutic doses of new-generation antihistamines produce little or no impairment of attention, memory, vigilance, psychomotor performance, or driving (Kay et al. 1997b; Hindmarch and Shamsi 2001). Higher doses have been occasionally found to produce significant sedative effects, although less pronounced than those of classic antihistamines (Riedel et al. 1990). There are limited prospective and comprehensive comparative studies about both classic and new-generation antihistamines. The purpose of this study was to determine and compare the effect of classic and new-generation antihistamines on sleep quality, daytime sleepiness, dream anxiety, and mood in patients with chronic pruritus. Methods Study protocol and drug assignment The study population consisted of 120 chronic pruritus cases that were presented to a university hospital dermatology clinic. According to the International Forum for the Study of Itch (IFSI) diagnostic criteria, patients suffering from itching for 6 weeks or longer were diagnosed with chronic pruritus and were included in the study. The inclusion criteria were as follows: had pruritus for the last month; no organic cause; no use of antihistamine drugs in the last month; aged between 18 and 60 years; and volunteer to be included in the study. The exclusion criteria were severe neurological or psychiatric disorders; pregnancy or breastfeeding; chronic psychotropic drug use; and hypnotic drug use. The participants were selected in a random sampling method; however, 28 patients dropped out of the study. Therefore, 92 patients completed all the study sessions. The participants were interviewed by physicians with questionnaires including the Pittsburgh Sleep Quality Index (PSQI),
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Epworth Sleepiness Scale (ESS), Van Dream Anxiety Scale (VDAS), and Profile of Mood States (POMS) before drug administration. They were evaluated with ESS, POMS, and psychological side effects with Udvalg für Kliniske Undersogelser (UKU) 1 day after beginning treatment. Antihistamine treatment, either with classic or with new-generation antihistamines, was carried out for over a month’s period regularly once a day, and at the end of the month the patients were evaluated with the ESS, PSQI, VDAS, POMS, and UKU scale as well. The patients visited our outpatient clinic a day and 1 month after the treatment. Treatment consisted of regular therapeutic doses and, preferably mentioned, the specific drugs that were given as follows: 15 patients were given pheniramine maleate 22.7 mg 3 times a day; 16 patients: hydroxyzine 25 mg/day; 15 patients: cetirizine 10 mg/day; 15 patients: desloratadine 5 mg/day; 15 patients: levocetirizine 5 mg/day; and 16 patients: rupatadine 10 mg/day. Assessment instruments Pittsburgh sleep quality index. The PSQI developed by Buysse et al. (1989) is a self-administered questionnaire that assesses sleep quality and disturbances over a 1-month period. Nineteen equally weighted individual items are scored on a 0– 3 scale which generates seven component scores to assess subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, medication use for sleep, and daytime dysfunction. The sum of the scores for these seven components yields one global score, which has a range of 0–21. A global PSQI score ⬎ 5 is considered to be a sensitive and specific measure of poor sleep quality. The PSQI was demonstrated to have good validity and reliability in Turkish population (Agargun et al. 1996). The van dream anxiety scale. VDAS assesses nightmare frequency and dream anxiety treatment response in subjects who have had nightmares during the preceding month (Agargun et al. 1999). There are 17 self-rated questions in the scale. Four questions (7–10) are used for clinical information only and not tabulated in the global scoring of the VDAS. The items are weighted equally on a 0–4 scale and summed to yield a global VDAS score, which has a range of 0–42. In the validity study, the VDAS could discriminate between patients with a nightmare disorder and healthy controls Cronbach’s alpha for the instrument was α ⫽ 0.87 (Agargun et al. 1999). The Epworth Sleepiness Scale. The ESS is a brief selfadministered questionnaire with eight items used to assess global symptoms of sleepiness. The ESS asks patients to rate the likelihood that they will doze off, on a scale from 0 (“no chance”) to 3 (“definitely would doze”). A total ESS score of 10 points or higher is indicative of clinically significant excessive sleepiness (Johns 1991). Izci et al. (2008) reported good reliability and validity for the ESS in Turkish population. Profile of mood states. POMS was developed to assess transient distinct mood states (McNair et al. 1981). The original form of the instrument consists of 65 adjectives rated on a 5-point scale from “not at all” to “extremely.” Six
Effects of antihistamine drugs on mood and sleep 3
DOI: 10.3109/13651501.2014.907919
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sub-scales were derived: Tension-anxiety, depressiondejection, anger-hostility, fatigue-inertia, vigor-activity, and confusion-bewilderment. A seventh score of total mood disturbance is also calculated by subtracting the score on the one positively scored sub-scale, vigor-activity, from the sum of the other five sub-scales. The validity and reliability of the Turkish version of the POMS were good (Selvi et al. 2011). Assessment of side effects from the antihistaminic drugs. To assess the presence of side effects, we used the Turkish version of UKU scale. We used a sub-scale of adverse psychological effects (Lingjaerde et al. 1987). The scores were assessed the first day after the treatment and after the first month of treatment. The possible causal relationship of the drug with the symptoms was assessed from 0 to 2 points to these items (0 ⫽ improbable; 1 ⫽ possible; and 2 ⫽ probable). Approval by the ethics committee This study was approved by the Clinical Ethics and Research Committee of the Yuzuncu Yil University, Faculty of Medicine. All participants signed a consent form declaring that they had been properly informed of the purposes of the study. They were not paid for their participation. Statistical analysis Descriptive statistics were computed. Temporal changes on the POMS subscale scores were measured at three timepoints: before treatment, a day after treatment, and a month after treatment, and were assessed by running the repeated measures of analysis of variance models. Temporal changes on the PSQI, ESS, and VDAS scores were measured at two time-points: before treatment and a month after treatment, and were assessed by running the repeated ANOVAs as well. Comparisons of the POMS subscales, PSQI, ESS, and VDAS scores between classic and new-generation antihistamines
were computed by utilizing one-way ANOVA models. Statistical significance threshold was held at p ⬍ 0.05. Results There were 92 patients that completed the study: 61 (66.3%) females and 31 (33.7%) males. Classic antihistamines were administered to 31 patients, and 61 patients received newgeneration antihistamine drugs. The subjects were aged from 18 to 60 years (36.93 ⫾ 13.29). Sleep characteristics before and after antihistamine treatments Temporal changes on the PSQI sub-scales for the classic and new-generation antihistamines were evaluated by using repeated measure ANOVAs. Statistical significance of temporal changes through two time-points, before and 1 month after treatment, were separately analyzed for the classic and new-generation antihistamines. The scores of sleep latency in new-generation antihistamine drugs were significantly decreased 1 month after the treatment. Sleep disturbances in each group were significantly decreased. The global PSQI score that significantly decreased after 1 month meant good sleep quality. Global ESS scores were significantly increased in both groups 1 month after administration. There were no significant differences in the global VDAS scores for both groups. Results are presented in Table I. Sleep characteristics of classic and new-generation antihistamine treatment groups The PSQI sub-scale scores, which were reported by the outpatients at two time-points, before and 1 month after antihistaminic medication, were compared between classic and new-generation antihistamines. It was found that the
Table I. Repeated measure ANOVAs for the temporal change in sleep characteristics after antihistaminic medication in chronic pruritus. Before PSQI components Subjective quality of sleep Sleep latency Sleep duration Sleep efficiency Sleep disturbances Medication use for sleep Daytime dysfunction Global PSQI score Global ESS score Global VDAS score
Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines
A Month After
Mean
SD
Mean
SD
Partial η2
df
F
P
1.32 1.25 1.77 1.59 0.52 0.53 0.52 0.54 1.55 1.31 0.19 0.18 1.07 0.85 6.90 6.22 4.21 3.68 10.33 7.20
0.98 0.83 1.71 1.54 0.96 0.91 0.96 0.94 0.72 0.65 0.40 0.39 0.89 0.91 4.42 3.77 2.59 2.71 8.32 7.94
1.36 1.23 1.42 1.20 0.32 0.44 0.25 0.43 1.32 1.11 0.16 0.23 1.00 0.80 5.84 5.44 5.25 4.79 10.93 6.78
0.88 0.69 1.39 1.14 0.70 0.79 0.51 0.83 0.70 0.61 0.38 0.42 0.89 0.75 3.47 3.05 2.40 2.90 7.70 7.11
0.001 0.001 0.118 0.110 0.083 0.009 0.103 0.016 0.176 0.118 0.005 0.013 0.008 0.005 0.158 0.092 0.216 0.167 0.012 0.008
1.30 1.60 1.30 1.60 1.30 1.60 1.30 1.60 1.30 1.60 1.30 1.60 1.30 1.60 1.30 1.60 1.27 1.46 1.26 1.54
0.042 0.047 4.024 7.400 2.714 0.529 3.453 1.000 6.391 8.030 0.139 0.816 0.244 0.330 5.610 6.088 7.442 9.238 0.304 0.437
0.839 0.829 0.054 0.009 0.110 0.470 0.073 0.321 0.017 0.006 0.712 0.370 0.625 0.568 0.025 0.016 0.011 0.004 0.586 0.511
PSQI, Pittsburgh Sleep Quality Index; ESS, Epworth Sleepiness Scale; VDAS, Van Dream Anxiety Scale; SD, Standard deviation
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Table II. Comparison of sleep characteristics between first and second generation antihistaminic medication in chronic pruritus. Classic antihistamines PSQI components Subjective quality of sleep Sleep latency Sleep duration Sleep efficiency Sleep disturbances
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Medication use for sleep Daytime dysfunction Global PSQI score Global ESS score Global VDAS score
Before A month after Before A month after Before A month after Before A month after Before A month after Before A month after Before A month after Before A month after Before A month after Before A month after
New-generation antihistamines
Mean
SD
Mean
SD
Partial η2
df
F
P
1.32 1.35 1.77 1.42 0.52 0.32 0.52 0.26 1.55 1.32 0.19 0.16 1.06 1.00 6.90 5.84 4.21 5.25 10.33 10.93
0.98 0.88 1.71 1.39 0.96 0.70 0.96 0.51 0.72 0.70 0.40 0.37 0.89 0.89 4.41 3.47 2.59 2.40 8.32 7.70
1.25 1.23 1.59 1.20 0.51 0.44 0.54 0.43 1.31 1.11 0.18 0.23 0.85 0.80 6.23 5.44 3.68 4.79 7.20 6.78
0.83 0.69 1.54 1.14 0.91 0.79 0.94 0.83 0.65 0.61 0.39 0.42 0.91 0.75 3.77 3.05 2.71 2.90 7.94 7.12
.002 .006 .003 .007 .000 .006 .000 .012 .028 .023 .000 .006 .012 .014 .006 .003 .010 .007 .033 .068
1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.73 1.73 1.80 1.80
0.155 0.560 0.272 0.678 0.002 0.514 0.014 1.071 2.547 2.161 0.023 0.575 1.131 1.242 0.584 0.316 0.702 0.507 2.735 5.817
0.695 0.456 0.603 0.412 0.969 0.475 0.906 0.304 0.114 0.145 0.879 0.450 0.290 0.268 0.447 0.576 0.405 0.479 0.102 0.018
PSQI, Pittsburgh Sleep Quality Index; ESS, Epworth Sleepiness Scale; VDAS, Van Dream Anxiety Scale; SD, Standard deviation
PSQI sub-scale scores of outpatients who were medicated with classical antihistaminic drugs did not significantly differ from the scores of outpatients who were medicated with new-generation antihistaminic drugs. Also, differences on the ESS scores between the two types of antihistaminic drugs were not substantial. However, the dream anxiety scores of outpatients who were medicated with new-generation drugs were significantly decreased when compared to outpatients who were medicated with first generation drugs after 1 month (p ⬍ 0.05). Findings are indicated in Table II. Profile of mood states Statistical significance of temporal changes on the POMS through three time-points were separately analyzed for the classic and new-generation antihistamines. There was no significant difference in the sub-scales between the groups on day 1 and 1 month after the treatment. The POMS, PSQI, ESS, VDAS, and UKU scores of outpatients measured after 1 month were compared between six antihistaminic drugs. ANOVA models indicated that differences between the six antihistaminic drugs on depressiondejection (F (5, 82) ⫽ 2.763; p ⬍ 0.05), tension-anxiety (F (5, 82) ⫽ 2.655; p ⬍ 0.05), and fatigue-inertia (F (5, 82) ⫽ 4.191; p ⬍ 0.01) scores after 1 month of medication were significant. Multiple group comparisons were run by using the Duncan test. Outpatients who received cetirizine treatment reported higher scores on the depression-dejection sub-scale than outpatients who received desloratadine, levocetirizine, and rupatadine treatment. Differences between pheniramine maleate, hydroxyzine, and cetirizine treatments were not significant. Outpatients who received cetirizine treatment reported higher scores on the tension-anxiety sub-scale than outpatients who received desloratadine, levocetirizine, rupatadine, and pheniramine treatment. Differences between
hydroxyzine and cetirizine treatments were not significant. Finally, outpatients who received cetirizine and hydroxyzine treatment reported higher scores on the fatigue-inertia subscale than outpatients who received desloratadine, levocetirizine, rupatadine, and pheniramine treatment. Differences between hydroxyzine and cetirizine treatments were not significant. Results are illustrated in Figures 1–3. UKU scores were significantly elevated among outpatients receiving pheniramine medication (F (1, 14) ⫽ 4.884; p ⬍ 0.05). Sleep latency was significantly improved among patients medicated with levocetirizine (F (1, 14) ⫽ 6.137; p ⬍ 0.05). Rupadatine also brought about significant improvement on the PSQI Global scores (F (1, 15) ⫽ 4.951; p ⬍ 0.05). Moreover, daytime sleepiness was significantly increased by rupadatine (F (1, 13) ⫽ 6.121; p ⬍ 0.05) and pheniramine treatments (F (1, 13) ⫽ 4.944; p ⬍ 0.05). Significant results are presented in Table III. Discussion Results of this study showed that antihistaminic drugs had significant sleepiness effects. Furthermore, no significant mood changes accompanied their use. The global PSQI scores which mean better sleep quality, significantly decreased after 1 month. Global ESS scores, indicating daytime sleepiness, were significantly increased in both groups 1 month after the treatment. PSQI sub-scale scores of outpatients medicated with classical antihistaminic drugs did not significantly differ from the scores of outpatients medicated with new-generation antihistaminic drugs. Our findings suggest that both antihistamine groups have a higher risk for sleepiness. When the six drugs were separately compared with each other it revealed that outpatients who received cetirizine reported higher scores on the depression, anxiety, and fatigue sub-scale than outpatients who received
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DOI: 10.3109/13651501.2014.907919
Figure 1. Mean and 95% standard error of the depression-dejection subscale score of POMS after 1 month medication by six antihistaminic drugs.
desloratadine, levocetirizine, and rupatadine. Hydroxyzine and cetirizine did not differ from each other. Sleep latency was significantly improved among patients medicated with levocetirizine. Daytime sleepiness was significantly predicted by rupadatine and pheniramine. UKU scores were significantly elevated among outpatients receiving pheniramine. The most common approach to managing chronic pruritus is to prevent the release of histamine or to block its effects at receptor sites on nerves. Therefore, H1 antihistamines are the cornerstone of pruritus treatment. Classic and new-generation antihistamines are equally effective for the resolution of pruritus (Crownover et al. 2004). Furthermore, new-generation agents are widely preferred as first-line drugs for chronic pruritus due to their proven efficacy and safety profiles (O’Donoghue and Tharp 2005). There are many studies performed on the effects of antihistamines on sleepiness, cognition and psychomotor performance, and many studies have used comparable tests
Figure 2. Mean and 95% standard error of the tension-anxiety subscale score of POMS after 1 month medication by six antihistaminic drugs.
Effects of antihistamine drugs on mood and sleep 5
Figure 3. Mean and 95% standard error of the fatigue-inertia subscale score of POMS after 1 month medication by six antihistaminic drugs.
again. An investigation was conducted to evaluate the initial effects of loratadine on mood and self-reported sleepiness (Kay 1997a). The study involved 98 healthy volunteers randomized into three treatment groups: loratadine 10 mg once daily, placebo, or an initial dose of diphenhydramine 50 mg, followed by subsequent doses of diphenhydramine 25 mg (all medications and placebo were given for 5 days). Comparison of the three groups showed that those who received the 50 mg dose of diphenhydramine reported more sedation and negative mood (p ⬍ 0.01) than did subjects who administered loratadine or placebo. Subjects who received diphenhydramine performed less well than subjects who received placebo on days 3 and 5 on a test of tracking errors that reflects lapses of attention. On day 3, group differences were still evident on self-report measures of mood and sedation. Subjects who received diphenhydramine reported greater fatigue and rated the quality of their test performance as lower, and reported lower motivation compared with subjects who received loratadine (Kay and Harris 1999). The original change over time in our study was focused on sleep quality. Specifically, second-generation antihistamine drugs reduced sleep latency; classic and new-generation antihistamine drugs decreased the sleep disturbances, the fifth component of PSQI. The total scores indicating poor quality of sleep and sleep disturbances were decreased in time. The ESS scores showed daytime sleepiness increased over time. Also, there were no significant differences between the two generations in sleep quality and ESS before treatment and 1 month after. However, we have detected significant differences in the scale of VDAS showing anxiety of dreams after 1 month of treatment. There was no significant difference in the sub-scale of adverse psychological effects between groups on day 1 and 1 month after the treatment. Histamine has a major role in the control of arousal and the sleep–wake cycle (Brown et al. 2001; Haas and Panula 2003). In the brain, histaminergic neuronal cell bodies are located in the tuberomammillary nucleus (TMN) of the posterior hypothalamus (Onodera et al. 1994) from where
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Table III. Repeated measure ANOVAs for the temporal change in affective and sleep characteristics by antihistaminic drugs after medication. Before Variables
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Depression-dejection Tension-anxiety Anger-hostility Fatigue-inertia UKU Sleep latency Sleep efficiency Sleep disturbances PSQI global PSQI global Epworth Epworth
A day after
A month after
Drugs
Mean
SD
Mean
SD
Mean
SD
Partial η2
df
F
P
Cetirizine Cetirizine Cetirizine Cetirizine Pheniramine Levocetirizine Pheniramine Pheniramine Rupatadine Pheniramine Rupatadine Pheniramine
16.90 14.70 14.20 8.10 – 1.60 0.47 1.80 7.00 7.67 3.79 3.71
13.33 7.78 9.19 5.67 – 1.55 0.84 0.56 4.84 4.56 2.08 2.89
20.00 15.40 15.100 9.90 1.53 – – – – – – –
14.65 7.31 9.61 6.76 3.441 – – – – – – –
27.80 19.20 21.90 13.50 3.80 1.07 0.07 1.40 5.38 6.13 5.36 5.00
5.35 3.58 4.46 3.81 4.945 1.16 .26 .74 3.20 3.46 2.34 2.80
0.344 0.317 0.511 0.442 0.259 0.305 0.300 0.400 0.352 0.261 0.320 0.276
2.18 2.18 2.18 2.18 1.14 1.14 1.14 1.14 1.15 1.14 1.13 1.13
4.722 4.176 9.414 7.132 4.884 6.137 6.000 9.333 8.151 4.951 6.121 4.944
0.022 0.032 0.002 0.005 0.044 0.027 0.028 0.0009 0.012 0.043 0.028 0.045
UKU, Udvalg für Kliniske Undersogelser; SD, Standard deviation
they project to practically all brain regions, with the ventral areas (ventrolateral preoptic nucleus [VLPO] in hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation (Brown et al. 2001). The NA-inhibited neurons containing γ-aminobutyric acid (GABA) are sleeppromoting neurons and project to the histamine-releasing neurons in the TMN. These neurons release GABA into the TMN, thus inhibiting the activity of this arousal-producing nucleus and reducing the release of histamine to elicit the onset of sleep (Liu et al. 2010). The release of histamine during the day causes arousal, whereas its decreased production at night results in a passive reduction of the arousal response (Church et al. 2010). Classical antihistamines increase the latency to the onset of REM sleep and reduce the duration of REM sleep at night. Furthermore, residual effects are still present the next morning. These effects include impairment in divided attention, vigilance, working memory, sensory-motor performance, and reduced latency to daytime sleep (Rojas-Zamorano et al. 2009; Boyle et al. 2006). In our study, classic antihistamines increased daytime sleepiness and decreased the scores of subjective sleep quality. New-generation antihistamines reduced sleep latency, increased daytime sleepiness and subjective sleep quality. Furthermore, both antihistamine groups decreased sleep disturbances and improved the quality of sleep. In the clinical practice, new-generation antihistamines are believed to minimally effect or have no effect on sleepiness and are prescribed primarily rather than firstgeneration antihistamines. However, according to our results, new-generation antihistamines had sleepiness side effects. Bender et al.’s meta-analysis with diphenhydramine (the most commonly used classic antihistamine) and newgeneration antihistamines reveals that the average sedating effect of diphenhydramine was modest, and in some instances the results of tests of performance in the diphenhydramine group showed less sedation than in the control or newgeneration antihistamine groups. A significant (p ⬍ 0.05) average effect size indicated a mild sedating effect caused by new-generation antihistamines in comparison with placebo (Bender et al. 2003). In another study, loratadine and fexofenadine resulted in a significantly lower incidence of sedation than cetirizine and acrivastine (Mann et al. 2000).
Classic antihistamines, such as chlorpheniramine, cyproheptadine, diphenhydramine, and hydroxyzine are known to bind not only to H1-receptors but also to muscarinic, α-adrenergic, dopamine, or serotonin receptors and have a central sedative effect (Presa 1999). Due to side effects, the application of classic antihistamines is limited nowadays. New-generation antihistamines like cetirizine, levocetirizine, desloratadine, fexofenadine, and loratadine have minimal activity on non-histaminic receptors, fewer side effects, and a longer duration of action compared to the first generation (Weisshaar 2011). According to the results of our study, there were no differences between groups in terms of side effects. There were no differences between classic and newgeneration antihistamines (especially cetirizine) influencing the mood (depression-dejection, tension-anxiety, fatigue-inertia). Therefore, we found that cetirizine was no safer than classic antihistamines on the mood profile. Furthermore, the serotonergic effect of cetirizine should be further explored. The second-generation antihistamines—desloratadine, levocetirizine, and rupatadine—which are new-generation antihistamines (called third-generation antihistamines in some sources) had little change on the mood profile and are better than cetirizine. Therefore, we conclude that the selection of new-generation antihistamines is safer. Mann et al. and their prescriptionevent monitoring study showed the extent to which second-generation antihistamines affect driving. It varies with the drug, its dose, and its dosing regimen. Acrivastine, cetirizine, and mizolastine slightly affected driving performance when given at therapeutic doses. Ebastine, fexofenadine, loratadine, and terfenadine did not have clinically significant effects after recommended doses but did have at least measurable effects after doses that were twice as high (Mann et al. 2000). Sedation and performance-impairing effects accompanying new-generation antihistamine use have been a matter of debate. That is, some studies found evidence for sedation and performance impairment after using the recommended dose (10 mg) of cetirizine, and other studies did not (Ramaekers et al. 1992; Schweitzer et al. 1994; Salmun et al. 2000). As a result, the search for improved antihistaminic drugs has continued.
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DOI: 10.3109/13651501.2014.907919
Additionally, according to our knowledge, this current study was the primary study evaluating both hypnotic effects and mood states between two groups and six antihistaminic drugs. We compared all six antihistaminic drugs separately for sleep quality and mood states. We found significant differences of these drugs on depression-dejection, tension-anxiety, and fatigue-inertia scores after 1 month of treatment. Cetirizine was the most influential drug on mood changes followed by hydroxyzine. As we know, cetirizine is the carboxylic acid metabolite of hydroxyzine. Levocetirizine, the S enantiomer of racemic cetirizine, seems to have a smaller volume of distribution than cetirizine, providing for better safety and efficacy. There were no differences in sleep parameters between the six drugs. In the literature, in comparison with loratadine and fexofenadine, cetirizine had been shown to be associated with increased somnolence and less motivation to perform activities during the workday (Salmun et al. 2000; Tashiro et al. 2004). Daytime sleepiness was significantly predicted by rupadatine and pheniramine treatments. UKU scores were significantly elevated among outpatients receiving pheniramine, which was expected as it is a classic antihistamine. The major limitations of our study are firstly, that it was a single-centered, small sample size study; secondly, it was not placebo-controlled; thirdly, the patients were only admitted after a physician had confirmed the diagnosis of chronic pruritus; fourthly, the study did not dose escalation to drugs; and finally, we did not compare sleep architecture and sleep diary as they are confounding factors in the assessment of sleepiness. According to the results of the study; classic and newgeneration antihistamines significantly increase sleepiness, but there is no significant difference between them for this side effect. Upon examining the drug differences, cetirizine and hydroxyzine seem to have negative influences on mood states. Pheniramine and rupatadine appear to be related more to daytime sleepiness and better nocturnal sleep quality. Since the sample size of each drug group was small, the current results should be re-examined in further studies among larger patient groups. Key points • • •
• •
Antihistamines, mainly used to treat chronic pruritus, affect sleep quality and mood. We compared the effects of classic and new-generation antihistamines on sleep quality, daytime sleepiness, dream anxiety, and mood states. We found that outpatients received cetirizine treatment reported higher scores on depression, anxiety, and fatigue subscales of the POMS than outpatients who received desloratadine, levocetirizine, and rupatadine treatment. Hydroxyzine and cetirizine did not differ from each other. Sleep latency was significantly improved among patients medicated with levocetirizine. Daytime sleepiness was significantly predicted by rupadatine and pheniramine treatment. Both classic and new-generation antihistamines significantly increased daytime sleepiness as well as nocturnal sleep quality.
Effects of antihistamine drugs on mood and sleep 7 Acknowledgments None. Statement of interest None of the authors reports conflicts of interest. References Agargun MY, Kara H, Anlar O. 1996. The validity and reliability of the Pittsburgh Sleep Quality Index. Turk Psikiyatri Derg 7: 107–115. Agargun MY, Kara H, Bilici M, Cilli AS, Telci M, Semiz UB, et al. 1999. The Van Dream Anxiety Scale: a subjective measure of dream anxiety in nightmare sufferers. Sleep Hypn 4:204–211. Bender BG, Berning S, Dudden R, Milgrom H, Tran ZV. 2003. Sedation and performance impairment of diphenhydramine and second-generation antihistamines: a meta-analysis. Allergy Clin Immuno 111:770–776. Boyle J, Eriksson M, Stanley N, Fujita T, Kumagi Y. 2006. Allergy medication in Japanese volunteers: treatment effect of single doses on nocturnal sleep architecture and next day residual effects. Curr Med Res Opin 22:1343–1351. Brown RE, Stevens DR, Haas HL. 2001. The physiology of brain histamine. Prog Neurobiol 63:637–672. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. 1989. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 28:193–213. Church MK, Maurer M, Simons FE, Bindslev-Jensen C, Cauwenberge P, Bousquet J, et al. 2010. Risk of first-generation H(1)-antihistamines: a GA(2)LEN position paper. Allergy 65:459–466. Crownover BK, Jamieson B, Mott TF. 2004. First- or second-generation antihistamines: which are more effective at controlling pruritus? J Fam Pract 53:742–744. Grundmann S, Ständer S. 2011. Chronic pruritus: clinics and treatment. Ann Dermatol 23:1–10. Haas H, Panula P. 2003. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 4: 121–130. Herman SM, Vender RB. 2003. Antihistamines in the treatment of dermatitis. J Cutan Med Surgb 7:467–473. Hindmarch I, Shamsi Z. 2001. The effects of single and repeated administration of ebastine on cognition and psychomotor performance in comparison to triprolidine and placebo in healthy volunteers. Curr Med Res Opin 17:273–281. Izci B, Ardic S, Firat H, Sahin A, Altinors M, Karacan I. 2008. Reliability and validity studies of the Turkish version of the Epworth sleepiness scale. Sleep Breath 12:161–168. Johns MW. 1991. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 14:540–545. Kay GG, Berman B, Mockoviak SH, Morris CE, Reeves D, Starbuck V, et al. 1997a. Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood, and psychomotor performance. Arch Intern Med 157:2350–2356. Kay GG, Harris AG. 1999. Loratadine: a non-sedating antihistamine. Review of its effects on cognition, psychomotor performance, mood and sedation. Clin Exp Allergy 29:147–150. Kay GG, Plotkin KE, Quig MB, Starbuck VN, Yasuda S. 1997b. Sedating effects of AM/PM antihistamine dosing with evening chlorpheniramine and morning terfenadine. Am J Man Care 3:1843–1848. Lingjaerde O, Ahlfors U, Bech P, Dencker S, Elgen K. 1987. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand 334:1–100. Liu YW, Li J, Ye JH. 2010. Histamine regulates activities of neurons in the ventrolateral preoptic nucleus. J Physiol 588: 4103–4116.
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Mann RD, Pearce GL, Dunn N, Shak S. 2000. Sedation with “nonsedating” antihistamines: four prescriptionevent monitoring studies in general practice. Gen Pract BMJ 320:1184–1187. McNair D, Lorr M, Droppleman L. 1981. Profile of mood states manual. San Diego: Educational and Industrial Testing. O’Donoghue M, Tharp MD. 2005. Antihistamines and their role as antipruritics. Dermatol Ther 18:333–340. Onodera K, Yamatodani A, Watanabe T, Wada H. 1994. Neuropharmacology of the histaminergic neuron system in thebrain and its relationship with behavioral disorders. Prog Neurobiol 42: 685–702. Presa IJ. 1999. H1 antihistamines: a review. Alergol Immunol Clin 14:300–312. Ramaekers JG, Uiterwijk MM, O’Hanlon JF. 1992. Effects of loratadine and cetirizine on actual driving and psychometric test performance and EEG during driving. Eur J Clin Pharmacol 42: 363–369. Reamy B, Bunt C, Fletcher S. 2011. A diagnostic approach to pruritus. Am Fam Physician 84:195–202. Riedel WJ, Ramaekers G, Uiterwijk MM, O’Hanlon JF. 1990. Higher doses of terfenadine and loratadine: acute and subchronic effects on psychomotor and actual driving performance. Maastricht: Institute for Drugs, Safety and Behavior, University of Limburg. Rojas-Zamorano JA, Esqueda-Leon E, Jimenez-Anguiano A, Cintra-Mc Glone L, Mendoza Melendez MA, Velazquez MJ. 2009. The H1 histamine receptor blocker, chlorpheniramine, completely prevents the increase in REM sleep induced by immobilization stres in rats. Pharmacol Biochem Behav 9:291–294.
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Salmun LM, Gates D, Scharf M, Greiding L, Ramon F, Heithoff K. 2000. Loratadine versus cetirizine: assessment of somnolence and motivation during the workday. Clin Ther 22:573–582. Schweitzer PK, Muehlbach MJ, Walsh JK. 1994. Sleepiness and performance during three-day administration of cetirizine or diphenhydramine. J Allergy Clin Immunol 94:716–724. Selvi Y, Gulec M, Aydin A, Besiroglu L. 2011. Psychometric evaluation of the Turkish language version of the Profile of Mood States (POMS). J Mood Dis 1:152–161. Simons FE. 2004. Advances in H1-antihistamines. N Engl J Med 351:2203–2217. Ständer S, Weisshaar E, Mettang T, Szepietowski JC, Carstensm E, Ikoma A, et al. 2007. Clinical classification of itch: a position paper of the International Forum for the Study of Itch. Acta Derm Venereol 87:291–294. Tashiro M, Sakurada Y, Iwabuchi K, Mochizuki H, Kato M. 2004. Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography. J Clin Pharmacol 44:890–900. Theunissen EL, Vermeeren A, Ramaekers JG. 2006. Repeated-dose effects of mequitazine, cetirizine and dexchlorpheniramine on driving and psychomotor performance. Br J Clin Pharmacol 61: 79–86. Weisshaar E, Szepietowski JC, Darsow U, Misery L, Wallengren J, Mettang T, et al. 2011. EDF-Guidelines for Chronic Pruritus In cooperation with the European Academy of Dermatology and Venereology (EADV) and the Union Européenne des Médecins Spécialistes (UEMS).
ORIGINAL ARTICLE
Assessment of the effects of antihistamine drugs on mood, sleep quality, sleepiness, and dream anxiety
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Pinar Guzel Ozdemir1, Ayşe Serap Karadag2, Yavuz Selvi3, Murat Boysan4, Serap Gunes Bilgili5, Adem Aydin6 & Sevda Onder5 Department of Psychiatry, Yuzuncu Yil University Medicine Faculty, Van, Turkey, 2Department of Dermatology, Medeniyet Unversity, Faculty of Medicine, Göztepe Research and Training Hospital, Istanbul, Turkey, 3Department of Psychiatry, Selcuk University, Medicine Faculty, SUSAB (Neuroscience Unit), Konya, Turkey, 4Department of Psychology, Yuzuncu Yil University, School of Science and Arts, Van, Turkey, 5Department of Dermatology, Yuzuncu Yil University Medicine Faculty, Van, Turkey, and 6 Department of Psychiatry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey Int J Psych Clin Pract Downloaded from informahealthcare.com by Ryerson University on 06/18/14 For personal use only.
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Abstract Objective. There are limited comparative studies on classic and new-generation antihistamines that affect sleep quality and mood. The purpose of this study was to determine and compare the effects of classic and new-generation antihistamines on sleep quality, daytime sleepiness, dream anxiety, and mood. Methods. Ninety-two patients with chronic pruritus completed study in the dermatology outpatient clinic. Treatments with regular recommended therapeutic doses were administered. The effects of antihistaminic drugs on mood, daytime sleepiness, dream anxiety, and sleep quality were assessed on the first day and 1 month after. Results. Outpatients who received cetirizine and hydroxyzine treatments reported higher scores on the depression, anxiety, and fatigue sub-scales than those who received desloratadine, levocetirizine, and rupatadine. Pheniramine and rupatadine were found to be associated with daytime sleepiness and better sleep quality. UKU side effects scale scores were significantly elevated among outpatients receiving pheniramine. Classic antihistamines increased daytime sleepiness and decreased the sleep quality scores. New-generation antihistamines reduced sleep latency and dream anxiety, and increased daytime sleepiness and sleep quality. Conclusion. Both antihistamines, significantly increased daytime sleepiness and nocturnal sleep quality. Daytime sleepiness was significantly predicted by rupadatine and pheniramine treatment. Cetirizine and hydroxyzine, seem to have negative influences on mood states. Given the extensive use of antihistamines in clinical settings, these results should be more elaborately examined in further studies. Key words: Antihistamines, sleep quality, mood, dream anxiety, daytime sleepiness (Received 23 December 2013; accepted 20 March 2014)
Introduction Histamine is the main mediator of pruritus in many disorders (Ständer et al. 2007). Classic and new-generation antihistamines are equally effective and mainly used for its treatment. Chronic pruritus that lasts longer than 6 weeks is often intractable and has a high impact on the patient’s quality of life (Grundmann and Ständer 2011). It can become severe enough to interfere with work and restful sleep. New-generation antihistamines (e.g., cetirizine, loratadine, fexofenadine) cause fewer adverse effects, leading to improved patient compliance (Reamy et al. 2011). H1-antihistamines are inverse agonists that combine with and stabilize the inactive conformation of H1-receptors and therefore interfere with the actions of histamine (Herman and Vender 2003). The wake-promoting effects of histamine are believed to be mediated via histamine H1 receptors in the central nervous system (CNS). They penetrate the blood– brain barrier. They have poor receptor selectivity and often Correspondence: Dr. Pinar Guzel Ozdemir, Department of Psychiatry, Yuzuncu Yil University Medicine Faculty, Van 65200, Van-Turkey, Turkey. Tel: ⫹ 905056179746. Fax: ⫹ 904322167519. E-mail: [email protected]
interact with receptors of other biologically active amines that lead to antimuscarinic, anti-a-adrenergic, and antiserotonin effects. Their proclivity to interfere with neurotransmission by histamine at CNS H1-receptors potentially leads to drowsiness, sedation, somnolence, and fatigue leading to impairment of cognitive function, memory, and psychomotor performance (Church et al. 2010). Classical H1-antihistamines increase the latency to the onset of rapid eye movement (REM) sleep at night and reduce the duration of REM sleep. Residual effects are still present in the next morning. Such effects include impairment in divided attention, vigilance, working memory and sensory-motor performance, and reduced latency to daytime sleep. New-generation antihistamines are also more H1 selective than the classic antihistamines, have no anticholinergic effects, and also may result in less sedation and few other antihistaminic side effects (Church et al. 2010). They have known minimally sedating or non-sedating because of their limited penetration of the blood–brain barrier. It is well established that classic H1-antihistamines in doses commonly recommended for treatment frequently lead to somnolence, sedation, drowsiness, fatigue and impaired memory, and psychomotor performance (Church et al. 2010).
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Classic and new-generation antihistamines are nearly equally effective for the resolution of pruritus. The use of classical antihistamines, such as diphenhydramine and chlorpheniramine, is often related to a number of adverse effects, with sedation being the most addressed. These adverse effects can interfere with the performance of daytime activities and place the patient at risk of occupational injuries and traffic accidents (Theunissen et al. 2006). Classic H1-antihistamines cause drowsiness, especially with initial doses. They have long elimination half-life values with consequential hang-over effects the following morning (Church et al. 2010; Simons 2004; Kay et al. 1997a). New-generation antihistamines (e.g., cetirizine, loratadine, fexofenadine) cause fewer adverse effects, leading to improved patient compliance (Reamy et al. 2011). As second-generation antihistamines are less permeable to the brain than first-generation H1-antihistamines, their ability to induce sleep is still poorly understood. A large number of trials with an even larger number of tests have been carried out to assess the sedative effect of the newer H1 antagonists. However, many of these tests lack validity and the results are not reproducible. In a study that involves only the test drug and placebo, data showing no change in test scores may indicate either that the drug does not produce impairment, or that the tests lacked sufficient sensitivity to detect the impairment. Experimental studies have shown that single therapeutic doses of new-generation antihistamines produce little or no impairment of attention, memory, vigilance, psychomotor performance, or driving (Kay et al. 1997b; Hindmarch and Shamsi 2001). Higher doses have been occasionally found to produce significant sedative effects, although less pronounced than those of classic antihistamines (Riedel et al. 1990). There are limited prospective and comprehensive comparative studies about both classic and new-generation antihistamines. The purpose of this study was to determine and compare the effect of classic and new-generation antihistamines on sleep quality, daytime sleepiness, dream anxiety, and mood in patients with chronic pruritus. Methods Study protocol and drug assignment The study population consisted of 120 chronic pruritus cases that were presented to a university hospital dermatology clinic. According to the International Forum for the Study of Itch (IFSI) diagnostic criteria, patients suffering from itching for 6 weeks or longer were diagnosed with chronic pruritus and were included in the study. The inclusion criteria were as follows: had pruritus for the last month; no organic cause; no use of antihistamine drugs in the last month; aged between 18 and 60 years; and volunteer to be included in the study. The exclusion criteria were severe neurological or psychiatric disorders; pregnancy or breastfeeding; chronic psychotropic drug use; and hypnotic drug use. The participants were selected in a random sampling method; however, 28 patients dropped out of the study. Therefore, 92 patients completed all the study sessions. The participants were interviewed by physicians with questionnaires including the Pittsburgh Sleep Quality Index (PSQI),
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Epworth Sleepiness Scale (ESS), Van Dream Anxiety Scale (VDAS), and Profile of Mood States (POMS) before drug administration. They were evaluated with ESS, POMS, and psychological side effects with Udvalg für Kliniske Undersogelser (UKU) 1 day after beginning treatment. Antihistamine treatment, either with classic or with new-generation antihistamines, was carried out for over a month’s period regularly once a day, and at the end of the month the patients were evaluated with the ESS, PSQI, VDAS, POMS, and UKU scale as well. The patients visited our outpatient clinic a day and 1 month after the treatment. Treatment consisted of regular therapeutic doses and, preferably mentioned, the specific drugs that were given as follows: 15 patients were given pheniramine maleate 22.7 mg 3 times a day; 16 patients: hydroxyzine 25 mg/day; 15 patients: cetirizine 10 mg/day; 15 patients: desloratadine 5 mg/day; 15 patients: levocetirizine 5 mg/day; and 16 patients: rupatadine 10 mg/day. Assessment instruments Pittsburgh sleep quality index. The PSQI developed by Buysse et al. (1989) is a self-administered questionnaire that assesses sleep quality and disturbances over a 1-month period. Nineteen equally weighted individual items are scored on a 0– 3 scale which generates seven component scores to assess subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, medication use for sleep, and daytime dysfunction. The sum of the scores for these seven components yields one global score, which has a range of 0–21. A global PSQI score ⬎ 5 is considered to be a sensitive and specific measure of poor sleep quality. The PSQI was demonstrated to have good validity and reliability in Turkish population (Agargun et al. 1996). The van dream anxiety scale. VDAS assesses nightmare frequency and dream anxiety treatment response in subjects who have had nightmares during the preceding month (Agargun et al. 1999). There are 17 self-rated questions in the scale. Four questions (7–10) are used for clinical information only and not tabulated in the global scoring of the VDAS. The items are weighted equally on a 0–4 scale and summed to yield a global VDAS score, which has a range of 0–42. In the validity study, the VDAS could discriminate between patients with a nightmare disorder and healthy controls Cronbach’s alpha for the instrument was α ⫽ 0.87 (Agargun et al. 1999). The Epworth Sleepiness Scale. The ESS is a brief selfadministered questionnaire with eight items used to assess global symptoms of sleepiness. The ESS asks patients to rate the likelihood that they will doze off, on a scale from 0 (“no chance”) to 3 (“definitely would doze”). A total ESS score of 10 points or higher is indicative of clinically significant excessive sleepiness (Johns 1991). Izci et al. (2008) reported good reliability and validity for the ESS in Turkish population. Profile of mood states. POMS was developed to assess transient distinct mood states (McNair et al. 1981). The original form of the instrument consists of 65 adjectives rated on a 5-point scale from “not at all” to “extremely.” Six
Effects of antihistamine drugs on mood and sleep 3
DOI: 10.3109/13651501.2014.907919
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sub-scales were derived: Tension-anxiety, depressiondejection, anger-hostility, fatigue-inertia, vigor-activity, and confusion-bewilderment. A seventh score of total mood disturbance is also calculated by subtracting the score on the one positively scored sub-scale, vigor-activity, from the sum of the other five sub-scales. The validity and reliability of the Turkish version of the POMS were good (Selvi et al. 2011). Assessment of side effects from the antihistaminic drugs. To assess the presence of side effects, we used the Turkish version of UKU scale. We used a sub-scale of adverse psychological effects (Lingjaerde et al. 1987). The scores were assessed the first day after the treatment and after the first month of treatment. The possible causal relationship of the drug with the symptoms was assessed from 0 to 2 points to these items (0 ⫽ improbable; 1 ⫽ possible; and 2 ⫽ probable). Approval by the ethics committee This study was approved by the Clinical Ethics and Research Committee of the Yuzuncu Yil University, Faculty of Medicine. All participants signed a consent form declaring that they had been properly informed of the purposes of the study. They were not paid for their participation. Statistical analysis Descriptive statistics were computed. Temporal changes on the POMS subscale scores were measured at three timepoints: before treatment, a day after treatment, and a month after treatment, and were assessed by running the repeated measures of analysis of variance models. Temporal changes on the PSQI, ESS, and VDAS scores were measured at two time-points: before treatment and a month after treatment, and were assessed by running the repeated ANOVAs as well. Comparisons of the POMS subscales, PSQI, ESS, and VDAS scores between classic and new-generation antihistamines
were computed by utilizing one-way ANOVA models. Statistical significance threshold was held at p ⬍ 0.05. Results There were 92 patients that completed the study: 61 (66.3%) females and 31 (33.7%) males. Classic antihistamines were administered to 31 patients, and 61 patients received newgeneration antihistamine drugs. The subjects were aged from 18 to 60 years (36.93 ⫾ 13.29). Sleep characteristics before and after antihistamine treatments Temporal changes on the PSQI sub-scales for the classic and new-generation antihistamines were evaluated by using repeated measure ANOVAs. Statistical significance of temporal changes through two time-points, before and 1 month after treatment, were separately analyzed for the classic and new-generation antihistamines. The scores of sleep latency in new-generation antihistamine drugs were significantly decreased 1 month after the treatment. Sleep disturbances in each group were significantly decreased. The global PSQI score that significantly decreased after 1 month meant good sleep quality. Global ESS scores were significantly increased in both groups 1 month after administration. There were no significant differences in the global VDAS scores for both groups. Results are presented in Table I. Sleep characteristics of classic and new-generation antihistamine treatment groups The PSQI sub-scale scores, which were reported by the outpatients at two time-points, before and 1 month after antihistaminic medication, were compared between classic and new-generation antihistamines. It was found that the
Table I. Repeated measure ANOVAs for the temporal change in sleep characteristics after antihistaminic medication in chronic pruritus. Before PSQI components Subjective quality of sleep Sleep latency Sleep duration Sleep efficiency Sleep disturbances Medication use for sleep Daytime dysfunction Global PSQI score Global ESS score Global VDAS score
Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines Classic antihistamines New-generation antihistamines
A Month After
Mean
SD
Mean
SD
Partial η2
df
F
P
1.32 1.25 1.77 1.59 0.52 0.53 0.52 0.54 1.55 1.31 0.19 0.18 1.07 0.85 6.90 6.22 4.21 3.68 10.33 7.20
0.98 0.83 1.71 1.54 0.96 0.91 0.96 0.94 0.72 0.65 0.40 0.39 0.89 0.91 4.42 3.77 2.59 2.71 8.32 7.94
1.36 1.23 1.42 1.20 0.32 0.44 0.25 0.43 1.32 1.11 0.16 0.23 1.00 0.80 5.84 5.44 5.25 4.79 10.93 6.78
0.88 0.69 1.39 1.14 0.70 0.79 0.51 0.83 0.70 0.61 0.38 0.42 0.89 0.75 3.47 3.05 2.40 2.90 7.70 7.11
0.001 0.001 0.118 0.110 0.083 0.009 0.103 0.016 0.176 0.118 0.005 0.013 0.008 0.005 0.158 0.092 0.216 0.167 0.012 0.008
1.30 1.60 1.30 1.60 1.30 1.60 1.30 1.60 1.30 1.60 1.30 1.60 1.30 1.60 1.30 1.60 1.27 1.46 1.26 1.54
0.042 0.047 4.024 7.400 2.714 0.529 3.453 1.000 6.391 8.030 0.139 0.816 0.244 0.330 5.610 6.088 7.442 9.238 0.304 0.437
0.839 0.829 0.054 0.009 0.110 0.470 0.073 0.321 0.017 0.006 0.712 0.370 0.625 0.568 0.025 0.016 0.011 0.004 0.586 0.511
PSQI, Pittsburgh Sleep Quality Index; ESS, Epworth Sleepiness Scale; VDAS, Van Dream Anxiety Scale; SD, Standard deviation
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Table II. Comparison of sleep characteristics between first and second generation antihistaminic medication in chronic pruritus. Classic antihistamines PSQI components Subjective quality of sleep Sleep latency Sleep duration Sleep efficiency Sleep disturbances
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Medication use for sleep Daytime dysfunction Global PSQI score Global ESS score Global VDAS score
Before A month after Before A month after Before A month after Before A month after Before A month after Before A month after Before A month after Before A month after Before A month after Before A month after
New-generation antihistamines
Mean
SD
Mean
SD
Partial η2
df
F
P
1.32 1.35 1.77 1.42 0.52 0.32 0.52 0.26 1.55 1.32 0.19 0.16 1.06 1.00 6.90 5.84 4.21 5.25 10.33 10.93
0.98 0.88 1.71 1.39 0.96 0.70 0.96 0.51 0.72 0.70 0.40 0.37 0.89 0.89 4.41 3.47 2.59 2.40 8.32 7.70
1.25 1.23 1.59 1.20 0.51 0.44 0.54 0.43 1.31 1.11 0.18 0.23 0.85 0.80 6.23 5.44 3.68 4.79 7.20 6.78
0.83 0.69 1.54 1.14 0.91 0.79 0.94 0.83 0.65 0.61 0.39 0.42 0.91 0.75 3.77 3.05 2.71 2.90 7.94 7.12
.002 .006 .003 .007 .000 .006 .000 .012 .028 .023 .000 .006 .012 .014 .006 .003 .010 .007 .033 .068
1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.73 1.73 1.80 1.80
0.155 0.560 0.272 0.678 0.002 0.514 0.014 1.071 2.547 2.161 0.023 0.575 1.131 1.242 0.584 0.316 0.702 0.507 2.735 5.817
0.695 0.456 0.603 0.412 0.969 0.475 0.906 0.304 0.114 0.145 0.879 0.450 0.290 0.268 0.447 0.576 0.405 0.479 0.102 0.018
PSQI, Pittsburgh Sleep Quality Index; ESS, Epworth Sleepiness Scale; VDAS, Van Dream Anxiety Scale; SD, Standard deviation
PSQI sub-scale scores of outpatients who were medicated with classical antihistaminic drugs did not significantly differ from the scores of outpatients who were medicated with new-generation antihistaminic drugs. Also, differences on the ESS scores between the two types of antihistaminic drugs were not substantial. However, the dream anxiety scores of outpatients who were medicated with new-generation drugs were significantly decreased when compared to outpatients who were medicated with first generation drugs after 1 month (p ⬍ 0.05). Findings are indicated in Table II. Profile of mood states Statistical significance of temporal changes on the POMS through three time-points were separately analyzed for the classic and new-generation antihistamines. There was no significant difference in the sub-scales between the groups on day 1 and 1 month after the treatment. The POMS, PSQI, ESS, VDAS, and UKU scores of outpatients measured after 1 month were compared between six antihistaminic drugs. ANOVA models indicated that differences between the six antihistaminic drugs on depressiondejection (F (5, 82) ⫽ 2.763; p ⬍ 0.05), tension-anxiety (F (5, 82) ⫽ 2.655; p ⬍ 0.05), and fatigue-inertia (F (5, 82) ⫽ 4.191; p ⬍ 0.01) scores after 1 month of medication were significant. Multiple group comparisons were run by using the Duncan test. Outpatients who received cetirizine treatment reported higher scores on the depression-dejection sub-scale than outpatients who received desloratadine, levocetirizine, and rupatadine treatment. Differences between pheniramine maleate, hydroxyzine, and cetirizine treatments were not significant. Outpatients who received cetirizine treatment reported higher scores on the tension-anxiety sub-scale than outpatients who received desloratadine, levocetirizine, rupatadine, and pheniramine treatment. Differences between
hydroxyzine and cetirizine treatments were not significant. Finally, outpatients who received cetirizine and hydroxyzine treatment reported higher scores on the fatigue-inertia subscale than outpatients who received desloratadine, levocetirizine, rupatadine, and pheniramine treatment. Differences between hydroxyzine and cetirizine treatments were not significant. Results are illustrated in Figures 1–3. UKU scores were significantly elevated among outpatients receiving pheniramine medication (F (1, 14) ⫽ 4.884; p ⬍ 0.05). Sleep latency was significantly improved among patients medicated with levocetirizine (F (1, 14) ⫽ 6.137; p ⬍ 0.05). Rupadatine also brought about significant improvement on the PSQI Global scores (F (1, 15) ⫽ 4.951; p ⬍ 0.05). Moreover, daytime sleepiness was significantly increased by rupadatine (F (1, 13) ⫽ 6.121; p ⬍ 0.05) and pheniramine treatments (F (1, 13) ⫽ 4.944; p ⬍ 0.05). Significant results are presented in Table III. Discussion Results of this study showed that antihistaminic drugs had significant sleepiness effects. Furthermore, no significant mood changes accompanied their use. The global PSQI scores which mean better sleep quality, significantly decreased after 1 month. Global ESS scores, indicating daytime sleepiness, were significantly increased in both groups 1 month after the treatment. PSQI sub-scale scores of outpatients medicated with classical antihistaminic drugs did not significantly differ from the scores of outpatients medicated with new-generation antihistaminic drugs. Our findings suggest that both antihistamine groups have a higher risk for sleepiness. When the six drugs were separately compared with each other it revealed that outpatients who received cetirizine reported higher scores on the depression, anxiety, and fatigue sub-scale than outpatients who received
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Figure 1. Mean and 95% standard error of the depression-dejection subscale score of POMS after 1 month medication by six antihistaminic drugs.
desloratadine, levocetirizine, and rupatadine. Hydroxyzine and cetirizine did not differ from each other. Sleep latency was significantly improved among patients medicated with levocetirizine. Daytime sleepiness was significantly predicted by rupadatine and pheniramine. UKU scores were significantly elevated among outpatients receiving pheniramine. The most common approach to managing chronic pruritus is to prevent the release of histamine or to block its effects at receptor sites on nerves. Therefore, H1 antihistamines are the cornerstone of pruritus treatment. Classic and new-generation antihistamines are equally effective for the resolution of pruritus (Crownover et al. 2004). Furthermore, new-generation agents are widely preferred as first-line drugs for chronic pruritus due to their proven efficacy and safety profiles (O’Donoghue and Tharp 2005). There are many studies performed on the effects of antihistamines on sleepiness, cognition and psychomotor performance, and many studies have used comparable tests
Figure 2. Mean and 95% standard error of the tension-anxiety subscale score of POMS after 1 month medication by six antihistaminic drugs.
Effects of antihistamine drugs on mood and sleep 5
Figure 3. Mean and 95% standard error of the fatigue-inertia subscale score of POMS after 1 month medication by six antihistaminic drugs.
again. An investigation was conducted to evaluate the initial effects of loratadine on mood and self-reported sleepiness (Kay 1997a). The study involved 98 healthy volunteers randomized into three treatment groups: loratadine 10 mg once daily, placebo, or an initial dose of diphenhydramine 50 mg, followed by subsequent doses of diphenhydramine 25 mg (all medications and placebo were given for 5 days). Comparison of the three groups showed that those who received the 50 mg dose of diphenhydramine reported more sedation and negative mood (p ⬍ 0.01) than did subjects who administered loratadine or placebo. Subjects who received diphenhydramine performed less well than subjects who received placebo on days 3 and 5 on a test of tracking errors that reflects lapses of attention. On day 3, group differences were still evident on self-report measures of mood and sedation. Subjects who received diphenhydramine reported greater fatigue and rated the quality of their test performance as lower, and reported lower motivation compared with subjects who received loratadine (Kay and Harris 1999). The original change over time in our study was focused on sleep quality. Specifically, second-generation antihistamine drugs reduced sleep latency; classic and new-generation antihistamine drugs decreased the sleep disturbances, the fifth component of PSQI. The total scores indicating poor quality of sleep and sleep disturbances were decreased in time. The ESS scores showed daytime sleepiness increased over time. Also, there were no significant differences between the two generations in sleep quality and ESS before treatment and 1 month after. However, we have detected significant differences in the scale of VDAS showing anxiety of dreams after 1 month of treatment. There was no significant difference in the sub-scale of adverse psychological effects between groups on day 1 and 1 month after the treatment. Histamine has a major role in the control of arousal and the sleep–wake cycle (Brown et al. 2001; Haas and Panula 2003). In the brain, histaminergic neuronal cell bodies are located in the tuberomammillary nucleus (TMN) of the posterior hypothalamus (Onodera et al. 1994) from where
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Int J Psychiatry Clin Pract 2014;Early Online:1–9
Table III. Repeated measure ANOVAs for the temporal change in affective and sleep characteristics by antihistaminic drugs after medication. Before Variables
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Depression-dejection Tension-anxiety Anger-hostility Fatigue-inertia UKU Sleep latency Sleep efficiency Sleep disturbances PSQI global PSQI global Epworth Epworth
A day after
A month after
Drugs
Mean
SD
Mean
SD
Mean
SD
Partial η2
df
F
P
Cetirizine Cetirizine Cetirizine Cetirizine Pheniramine Levocetirizine Pheniramine Pheniramine Rupatadine Pheniramine Rupatadine Pheniramine
16.90 14.70 14.20 8.10 – 1.60 0.47 1.80 7.00 7.67 3.79 3.71
13.33 7.78 9.19 5.67 – 1.55 0.84 0.56 4.84 4.56 2.08 2.89
20.00 15.40 15.100 9.90 1.53 – – – – – – –
14.65 7.31 9.61 6.76 3.441 – – – – – – –
27.80 19.20 21.90 13.50 3.80 1.07 0.07 1.40 5.38 6.13 5.36 5.00
5.35 3.58 4.46 3.81 4.945 1.16 .26 .74 3.20 3.46 2.34 2.80
0.344 0.317 0.511 0.442 0.259 0.305 0.300 0.400 0.352 0.261 0.320 0.276
2.18 2.18 2.18 2.18 1.14 1.14 1.14 1.14 1.15 1.14 1.13 1.13
4.722 4.176 9.414 7.132 4.884 6.137 6.000 9.333 8.151 4.951 6.121 4.944
0.022 0.032 0.002 0.005 0.044 0.027 0.028 0.0009 0.012 0.043 0.028 0.045
UKU, Udvalg für Kliniske Undersogelser; SD, Standard deviation
they project to practically all brain regions, with the ventral areas (ventrolateral preoptic nucleus [VLPO] in hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation (Brown et al. 2001). The NA-inhibited neurons containing γ-aminobutyric acid (GABA) are sleeppromoting neurons and project to the histamine-releasing neurons in the TMN. These neurons release GABA into the TMN, thus inhibiting the activity of this arousal-producing nucleus and reducing the release of histamine to elicit the onset of sleep (Liu et al. 2010). The release of histamine during the day causes arousal, whereas its decreased production at night results in a passive reduction of the arousal response (Church et al. 2010). Classical antihistamines increase the latency to the onset of REM sleep and reduce the duration of REM sleep at night. Furthermore, residual effects are still present the next morning. These effects include impairment in divided attention, vigilance, working memory, sensory-motor performance, and reduced latency to daytime sleep (Rojas-Zamorano et al. 2009; Boyle et al. 2006). In our study, classic antihistamines increased daytime sleepiness and decreased the scores of subjective sleep quality. New-generation antihistamines reduced sleep latency, increased daytime sleepiness and subjective sleep quality. Furthermore, both antihistamine groups decreased sleep disturbances and improved the quality of sleep. In the clinical practice, new-generation antihistamines are believed to minimally effect or have no effect on sleepiness and are prescribed primarily rather than firstgeneration antihistamines. However, according to our results, new-generation antihistamines had sleepiness side effects. Bender et al.’s meta-analysis with diphenhydramine (the most commonly used classic antihistamine) and newgeneration antihistamines reveals that the average sedating effect of diphenhydramine was modest, and in some instances the results of tests of performance in the diphenhydramine group showed less sedation than in the control or newgeneration antihistamine groups. A significant (p ⬍ 0.05) average effect size indicated a mild sedating effect caused by new-generation antihistamines in comparison with placebo (Bender et al. 2003). In another study, loratadine and fexofenadine resulted in a significantly lower incidence of sedation than cetirizine and acrivastine (Mann et al. 2000).
Classic antihistamines, such as chlorpheniramine, cyproheptadine, diphenhydramine, and hydroxyzine are known to bind not only to H1-receptors but also to muscarinic, α-adrenergic, dopamine, or serotonin receptors and have a central sedative effect (Presa 1999). Due to side effects, the application of classic antihistamines is limited nowadays. New-generation antihistamines like cetirizine, levocetirizine, desloratadine, fexofenadine, and loratadine have minimal activity on non-histaminic receptors, fewer side effects, and a longer duration of action compared to the first generation (Weisshaar 2011). According to the results of our study, there were no differences between groups in terms of side effects. There were no differences between classic and newgeneration antihistamines (especially cetirizine) influencing the mood (depression-dejection, tension-anxiety, fatigue-inertia). Therefore, we found that cetirizine was no safer than classic antihistamines on the mood profile. Furthermore, the serotonergic effect of cetirizine should be further explored. The second-generation antihistamines—desloratadine, levocetirizine, and rupatadine—which are new-generation antihistamines (called third-generation antihistamines in some sources) had little change on the mood profile and are better than cetirizine. Therefore, we conclude that the selection of new-generation antihistamines is safer. Mann et al. and their prescriptionevent monitoring study showed the extent to which second-generation antihistamines affect driving. It varies with the drug, its dose, and its dosing regimen. Acrivastine, cetirizine, and mizolastine slightly affected driving performance when given at therapeutic doses. Ebastine, fexofenadine, loratadine, and terfenadine did not have clinically significant effects after recommended doses but did have at least measurable effects after doses that were twice as high (Mann et al. 2000). Sedation and performance-impairing effects accompanying new-generation antihistamine use have been a matter of debate. That is, some studies found evidence for sedation and performance impairment after using the recommended dose (10 mg) of cetirizine, and other studies did not (Ramaekers et al. 1992; Schweitzer et al. 1994; Salmun et al. 2000). As a result, the search for improved antihistaminic drugs has continued.
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DOI: 10.3109/13651501.2014.907919
Additionally, according to our knowledge, this current study was the primary study evaluating both hypnotic effects and mood states between two groups and six antihistaminic drugs. We compared all six antihistaminic drugs separately for sleep quality and mood states. We found significant differences of these drugs on depression-dejection, tension-anxiety, and fatigue-inertia scores after 1 month of treatment. Cetirizine was the most influential drug on mood changes followed by hydroxyzine. As we know, cetirizine is the carboxylic acid metabolite of hydroxyzine. Levocetirizine, the S enantiomer of racemic cetirizine, seems to have a smaller volume of distribution than cetirizine, providing for better safety and efficacy. There were no differences in sleep parameters between the six drugs. In the literature, in comparison with loratadine and fexofenadine, cetirizine had been shown to be associated with increased somnolence and less motivation to perform activities during the workday (Salmun et al. 2000; Tashiro et al. 2004). Daytime sleepiness was significantly predicted by rupadatine and pheniramine treatments. UKU scores were significantly elevated among outpatients receiving pheniramine, which was expected as it is a classic antihistamine. The major limitations of our study are firstly, that it was a single-centered, small sample size study; secondly, it was not placebo-controlled; thirdly, the patients were only admitted after a physician had confirmed the diagnosis of chronic pruritus; fourthly, the study did not dose escalation to drugs; and finally, we did not compare sleep architecture and sleep diary as they are confounding factors in the assessment of sleepiness. According to the results of the study; classic and newgeneration antihistamines significantly increase sleepiness, but there is no significant difference between them for this side effect. Upon examining the drug differences, cetirizine and hydroxyzine seem to have negative influences on mood states. Pheniramine and rupatadine appear to be related more to daytime sleepiness and better nocturnal sleep quality. Since the sample size of each drug group was small, the current results should be re-examined in further studies among larger patient groups. Key points • • •
• •
Antihistamines, mainly used to treat chronic pruritus, affect sleep quality and mood. We compared the effects of classic and new-generation antihistamines on sleep quality, daytime sleepiness, dream anxiety, and mood states. We found that outpatients received cetirizine treatment reported higher scores on depression, anxiety, and fatigue subscales of the POMS than outpatients who received desloratadine, levocetirizine, and rupatadine treatment. Hydroxyzine and cetirizine did not differ from each other. Sleep latency was significantly improved among patients medicated with levocetirizine. Daytime sleepiness was significantly predicted by rupadatine and pheniramine treatment. Both classic and new-generation antihistamines significantly increased daytime sleepiness as well as nocturnal sleep quality.
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