Journal of Psychopharmacology
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`1Histamine H
`
`-receptor blockade in humans affects psychomotor performance but not memory
`P. van Ruitenbeek, A. Vermeeren and WJ Riedel
`
` 2008; 22; 663 originally published online Jan 21, 2008; J Psychopharmacol
`DOI: 10.1177/0269881107081526
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`AVENTIS EXHIBIT 2213
`Mylan v. Aventis, IPR2016-00712
`
`

`
`Original papers
`
`Histamine H1-receptor blockade in
`humans affects psychomotor
`performance but not memory
`
`Journal of Psychopharmacology
`22(6) (2008) 663–672
`© 2008 British Association
`for Psychopharmacology
`ISSN 0269-8811
`SAGE Publications
`Los Angeles, London,
`New Delhi and Singapore
`10.1177/0269881107081526
`
`P van Ruitenbeek Experimental Psychopharmacology Unit, Department of Neuropsychology and Psychopharmacology, Brain and Behaviour Institute,
`Faculty of Psychology, Maastricht University, Maastricht, The Netherlands.
`A Vermeeren Experimental Psychopharmacology Unit, Department of Neuropsychology and Psychopharmacology, Brain and Behaviour Institute, Faculty of
`Psychology, Maastricht University, Maastricht, The Netherlands.
`WJ Riedel Experimental Psychopharmacology Unit, Department of Neuropsychology and Psychopharmacology, Brain and Behaviour Institute, Faculty of
`
`Psychology, Maastricht University, Maastricht, The Netherlands.
`Abstract
`
`Results from recent animal studies suggest an important role for histamine in
`memory functioning. Histaminergic drugs might prove beneficial for people
`suffering from memory impairment. To determine if histamine is involved in
`memory functioning this study evaluates the effects of histaminergic dysfunc-
`tion on memory performance by administrating a H1-antagonist to humans.
`The study was conducted according to a 4-way, double-blind, crossover design
`in 20 healthy female volunteers, aged 18–45 years. On each test day subjects
`completed three test sessions: before and around 2 and 4 h after administra-
`tion of single oral doses of dexchlorpheniramine 2 mg or 4 mg, scopolamine
`1 mg or placebo. Drug effects were assessed using tests of memory, psychomo-
`tor and attention performance, and subjective alertness. Results showed that
`
`dexchlorpheniramine impaired performance in tests of spatial learning, reac-
`tion time, tracking and divided attention but showed no effects on working
`memory, visual memory, word learning or memory scanning. Scopolamine
`induced a similar pattern of effects. In addition, both drugs decreased subjec-
`tive alertness. In conclusion results show that dexchlorpheniramine and scopo-
`lamine clearly impaired performance on psychomotor and attention tasks but
`do not suggest a specific role of the histaminergic system in learning and
`memory in humans.
`
`Keywords
`cognition, memory, psychomotor performance, histamine, acetylcholine, H1-
`antagonist, muscarinic antagonist
`
`Introduction
`
`Recently interest in the role that histamine might play in cognition
`has increased (Bacciottini et al., 2001; Blandina et al., 2004).
`Especially the cognitive domain of learning and memory is of inter-
`est. Animal studies have shown that increases in histaminergic
`functioning improve memory performance and decreases impair it
`[c.f.(Giovannini et al., 1999; Hancock and Fox, 2004; Komater
`et al., 2005; Meguro et al., 1995; Orsetti et al., 2001; Witkin and
`Nelson, 2004)].
`Currently, evidence supporting a role of histamine in learning
`and memory is mainly on the basis of studies in animals. So far
`there are hardly any studies specifically addressing this subject in
`humans. Although there are many studies assessing the behavioural
`effects of histaminergic blockade by centrally acting
`H1-antagonists in humans, they provide little support for the
`hypothesis that decreased histaminergic functioning is associated
`
`with impaired memory functions. This is largely because of the fact
`that most of these studies simply did not include tests for memory
`functioning. Most of them have been conducted in the context of
`behavioural safety of anti-histamines with an emphasis on car-
`driving [for reviews see: (Hindmarch and Shamsi, 1999; O’Hanlon
`and Ramaekers, 1995; Shamsi and Hindmarch, 2000; White and
`Rumbold, 1988)]. As driving performance is more strongly
`dependent on perceptual-motor and attentional functions than on
`memory, only a few studies included memory tests.
`The studies that did assess the effects of H1 blockade on mem-
`ory, show inconsistent results. The majority found no significant
`effects on memory (Acons et al., 2006; Bower et al., 2003; Curran
`et al., 1998; De Brabander, 1990; Kerr et al., 1994; Lee et al., 1988;
`Turner et al., 2006), whereas others did (Hindmarch et al., 2001;
`Katz et al., 1998; Sands et al., 1997; Vuurman et al., 1994). Two
`studies (Katz et al., 1998; Sands et al., 1997) found significant
`effects of diphenhydramine 50 mg on memory performance in
`
`Corresponding author: P. van Ruitenbeek, Experimental Psychopharmacology Unit, Department of Neuropsychology and Psychopharmacology, Brain & Behaviour Institute, Faculty of
`Psychology, Maastricht University, Maastricht, The Netherlands PO Box 616, 6200 MD Maastricht, The Netherlands. Email: p.vanruitenbeek@psychology.unimaas.nl
`
`Downloaded from at Universiteit Maastricht on August 28, 2008 http://jop.sagepub.com
`
`
` © 2008 British Association for Psychopharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
`
`
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`

`
`664 Histamine H1-receptor blockade in humans
`
`healthy elderly subjects. Vuurman et al., (1994; 1996) found signif-
`icant learning impairment in children and adolescents after the use
`of diphenhydramine, and Hindmarch and Shamsi, (2001) found a
`significant effect of triprolidine 10 mg on performance of healthy
`young volunteers in a memory scanning task.
`The contradictory results may be partly explained by the
`methods used. The use of insensitive memory tests and assessing
`memory functions before or after the time of peak behavioural
`impairments might explain the absence of effects. Alternatively, the
`significant effects found in some studies might be because of the
`anti-muscarinic effects of the anti-histamines used.
`The aim of the present study was therefore, to assess the effects
`of the relatively selective H1-antagonist dexchlorpheniramine
`(2 and 4 mg) on performance of healthy female volunteers. The
`decision to select only female subjects was based on results from
`a number of previous studies suggesting that females are more
`sensitive to effects of H1-antagonists than males (Ramaekers and
`O’Hanlon, 1994; Robbe, 1990; Vermeeren et al., 2002; Vuurman
`et al., 1994). The effects were to be compared with those of the
`muscarinic antagonist scopolamine that was included as a verum.
`To detect potential effects of the dexchlorpheniramine on mem-
`ory, a number of tests were selected that had previously been shown
`sensitive to detect drug induced impairments and together covered
`a range of important aspects of memory function, such as short-
`term or working memory, long-term memory, memory for verbal
`and visual material and implicit and explicit (declarative) memory
`(Ramaekers et al., 1992; Riedel et al., 1990; Rubinsztein et al.,
`2001; Vermeeren et al., 1995; Vuurman et al., 1994). A word learn-
`ing test and a pattern recognition test were included to assess
`effects on short- and long-term memory for verbal and visual mate-
`rial respectively; a memory scanning task and a syntactic reasoning
`task were included to assess integrity of working memory func-
`tions; and a spatial paired associate learning test was included to
`assess effects on implicit memory and learning. A simple reaction
`time test and a choice reaction test were added to the battery for the
`purpose of measuring effects on response speed without the cogni-
`tive components of the memory tests. To assess time of peak
`impairment of dexchlorpheniramine two tasks were included that
`have repeatedly been shown to be among the most sensitive tests to
`assess the impairing effects of H1-antagonists; that is a critical
`tracking test, and a divided attention test (Burns and Moskowitz,
`1980; Hindmarch and Shamsi, 1999; Meltzer, 1991; Theunissen
`et al., 2004; Vermeeren and O’Hanlon, 1998; Verster et al., 2003).
`Dexchlorpheniramine was selected as a tool drug, because it is
`a first generation H1-antagonist having a moderately high-binding
`affinity for the H1-receptors, but relatively low affinities for mus-
`carinic, alpha-1, alpha-2 and beta-receptors. The affinity for the
`muscarinic receptor is especially low (Kd ⫽ 3300 for chlorpheni-
`ramine) as compared with scopolamine (Kd ⫽ 0.1) (Wiech and
`Martin, 1982). The half-life of chlorpheniramine is approximately
`28 h (range 19–43 h) and maximum plasma concentrations are
`reached at 2.8 h (range 2–4 h) after oral doses (Huang et al., 1982;
`Paton and Webster, 1985). Two studies have shown that single oral
`doses of 4 mg chlorpheniramine produced significant performance
`impairment, which was most pronounced shortly after tmax (Kamei
`et al., 2003; Witek et al., 1995). Yet, in a third study performance
`
`was significantly impaired only at 1.5 h after drug administration
`(Clarke and Nicholson, 1978). On the basis of these results it was
`decided to measure the effects of dexchlorpheniramine at both
`times reported for peak impairment that is between 1.5 and 2.5 h
`and between 3.5 and 4.5 h after administration.
`Scopolamine 1 mg in oral doses (p.o.) was included as an active
`control because the drug is well known for its impairing effects on
`learning and memory (Bartus et al., 1985). Oral doses of 1 mg or
`above have been reported to impair cognitive functioning (Kennedy
`et al., 1990; Rammsayer et al., 2000). Peak plasma concentrations
`are reached at approximately 0.8 h after oral intake and scopo-
`lamine has an average elimination half-life of 4.3 h (Golding et al.,
`1991).
`
`Methods
`
`Subjects
`
`Twenty healthy female volunteers aged between 18 and 45 years
`were recruited as subjects for the study by means of advertisements
`in local newspapers and paid for their participation. Subjects were
`screened using a medical history questionnaire and a physical
`examination, including a 12-lead electrocardiogram, blood chem-
`istry and haematology and urinary tests for pregnancy and drugs of
`abuse (opiates, benzodiazepines, cocaine, tricyclic anti-depressants
`and cannabis). Exclusion criteria were pregnancy or lactation, a
`history or presence of any mental or physical disorder; gastroin-
`testinal, hepatic, renal, cardiovascular or neurological. Also, drug
`abuse, a body mass index (BMI) value outside the limits of 18 and
`28 kg/m2, blood pressure outside the limits of 100 and 150 Hg sys-
`tolic and 60 and 90 Hg diastolic and drinking more than 20 standard
`alcoholic units per week or more than five beverages containing
`caffeine per day, were regarded as exclusion criteria. No drugs or
`medication except oral contraceptives, aspirin and acetaminophen,
`were allowed to be taken from a week before the first test-day until
`the end of the study. Smoking and use of caffeine was prohibited on
`test-days and the use of alcohol from 24 h before and during each
`test-day.
`Three volunteers did not complete the study for reasons unrelat-
`ed to treatment. Two of them withdrew before the second treatment
`session and the third subject was excluded for smoking on the first
`test-day as determined by measurement of carbon monoxide in
`expired air, using a Smokerlyzer Micro® (Bedfont Scientific Ltd).
`These subjects were replaced. Mean ⫾ SD age of the 20 subjects
`who completed the study was 23.7 ⫾ 7.3 years. Their mean ⫾ SD
`BMI was 21.6 ⫾ 3.0 kg/m2. Five subjects were smokers, who on
`average (⫾SD) smoked 4.6 (⫾2.1) cigarettes and no more that 10
`per day. Eighty percent of the subjects were in college or had a sim-
`ilar level of education. The remaining 20% had all at least finished
`high school at an average level of education.
`All subjects received written information about the study proce-
`dures and were able to ask questions. They signed an informed con-
`sent form prior to enrolment. The study was approved by the Ethics
`Committee of Maastricht University and University Hospital
`Maastricht and carried out in accordance with the World Medical
`Association Declaration of Helsinki (Edinburgh, 2000).
`
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` © 2008 British Association for Psychopharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
`
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`

`
`Histamine H1-receptor blockade in humans
`
`665
`
`Study design and treatments
`
`The study was conducted according to a double-blind, placebo-
`controlled, four-way crossover design. Treatments were single oral
`doses of dexchlorpheniramine 2 and 4 mg, scopolamine 1 mg (all
`immediate release formulations) and placebo. Treatments were
`spaced apart by a washout period of at least 7 days.
`
`Procedure
`
`Subjects were individually trained to perform all psychomotor and
`memory tests within 2 weeks prior to their first treatment day.
`On treatment days they arrived at the University around 9:00 h.
`Between 9:45 and 10:45 h, a battery of psychometric tests was
`completed to obtain baseline performance scores. At 11:00 h, sub-
`jects ingested the study medication. Thereafter the test battery was
`repeated at 12:30 and 14:30 h that is between 1.5 and 2.5 h, and 3.5
`and 4.5 h after ingestion, henceforth indicated as t2 and t4.
`The duration of the test battery was approximately 1 h and
`consisted of the tasks and assessments in the following sequence:
`critical tracking, divided attention, subjective alertness, syntactic
`reasoning, immediate pattern recognition, memory scanning, sim-
`ple reaction time, choice reaction time, spatial paired associate
`learning, delayed pattern recognition and critical tracking. The t4
`test battery included a 30-words learning task, that was completed
`only once per test day to prevent interference of the previously
`learned words that same day. The immediate recall part was done
`following the syntactic reasoning test and delayed recall part was
`done following the spatial paired associate learning test. At 0.5 h
`after drug intake an additional critical tracking task was performed,
`with performance on this test then assessed at hourly intervals after
`drug administration. This allowed better monitoring of the time of
`peak impairment induced by both drugs.
`
`Assessments
`
`Memory performance 30-Words learning task – The 30-words
`learning test (Klaassen et al., 2002; Rey, 1964; Riedel et al., 1999)
`assesses short- and long-term verbal memory. Thirty Dutch mono-
`syllabic meaningful nouns and adjectives are presented for 1000 ms
`at a rate of 1 per 2 s and subjects are required to read them aloud.
`When the presentation ends, subjects are required to verbally recall
`as many words as possible (immediate recall). This procedure is
`repeated three times, with the same words presented in the same
`sequence. After a 45 min delay subjects are requested again to
`recall as many words as possible (delayed recall). Finally, subjects
`are presented a series of 30 words on a computer screen that
`include 15 words from the original list and 15 comparable but new
`words. Subjects are asked to indicate as quickly as possible whether
`the presented words are from the original list or not by pressing one
`of two buttons (delayed recognition). Dependent variables were the
`total number of words correctly recalled over the three immediate
`recall trials, the number of correctly recalled words after the delay
`and median reaction time (ms) of correct answers during recogni-
`tion. Since the distribution of reaction times is generally skewed to
`the right, the median RT was selected as dependent variable in all
`
`tasks except when indicated otherwise. The median is less sensitive
`to the presence of one sided outliers as compared with the mean.
`Pattern recognition task – The pattern recognition task assesses
`short- and long-term memory for visual information. In this test
`subjects are presented a series of 15 randomly generated black and
`white block patterns of a 6 ⫻ 4 grid, at a rate of 1 pattern per 3 sec.
`Subjects are asked to memorize the patterns. The same series of
`patterns is presented three times in the same order. Immediately
`thereafter a series of 30 patterns is presented, including 15 patterns
`from the original set and 15 new patterns. Subjects are asked to
`indicate as quickly as possible, whether the presented patterns are
`from the original list or not by pressing one of two buttons. After
`approximately 30 min this recognition procedure is repeated. The
`dependent measures are the median reaction time and the number
`of patterns correctly recognized in the immediate and delayed
`recognition tests.
`Memory scanning task – The memory scanning task (Sternberg,
`1969) measures the time it takes to scan items held in memory as
`part of working memory integrity, separating it from other process-
`es required to respond. When subjects judge whether a test symbol
`is contained in a short memorized sequence of symbols, their mean
`reaction time increases linearly with the length of the sequence.
`The linearity and slope of the function imply the existence of an
`internal serial comparison process whose average rate is between
`20 and 30 items per second. In this test the subjects are presented
`with a set of 1, 2 or 4 consonants, which they are asked to memo-
`rize. Hereafter, a series of 48 consonants is presented on a comput-
`er screen of which 24 are targets and 24 are nontargets. The
`subjects’ task is to indicate as fast as possible whether or not the
`presented letter was one from the memory set by pressing one of
`two buttons. The task consists of six blocks of 48 stimuli with
`different memory sets. The order of the blocks is 1, 2, 4, 4, 2 and 1
`letters, respectively. The median reaction time for correct respons-
`es is recorded and used to calculate individual linear regression
`lines between reaction time and memory set size. The slope of this
`line is a measure of speed of scanning short-term memory, where-
`as the intercept is a measure of psychomotor speed. Both slope
`(ms/letter) and intercept (ms) are outcome measures.
`Spatial paired associate learning – Spatial memory and learn-
`ing is assessed by the spatial paired associate learning task. In this
`task the subject is presented with two highly discriminative pictures
`flanking a central crosshair on a computer screen for 1000 ms.
`Hereafter, one of the two original stimuli (target) or a third (new
`picture) is presented in the centre of the screen and subjects were
`asked to indicate the original location (left or right) of the stimulus
`by pressing a corresponding button as fast as possible. Targets
`appear either left or right with a 50% probability. In total there are
`32 different targets of which 16 targets are presented only once and
`16 targets are presented eight times at the same location with ran-
`dom intervals over the test. Reaction time following repeated pres-
`entation of a target is hypothesized to diminish during the test as a
`result of implicit learning of the location associated with each tar-
`get picture. Therefore, the median reaction time following the
`repeated items should be lower than that following the nonrepeated
`items. The dependent variables are the median reaction times (ms)
`for repeated and nonrepeated targets.
`
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`
`666 Histamine H1-receptor blockade in humans
`
`Syntactic reasoning task – The syntactic reasoning task
`(Baddeley, 1968) assesses speed and accuracy of logical reasoning
`processes in working memory (Repovs and Baddeley, 2006). The
`task consists of 32 short sentences each describing the order of the
`letters ‘A’ and ‘B’ and belonged to one of four categories: active
`positive, active negative, passive positive and passive negative (e.g.,
`A follows B, A does not follow B, A is followed by B, A is not fol-
`lowed by B, respectively). The sentence is immediately followed by
`a letter-pair (‘A–B’ or ‘B–A’) in the same or opposite order as in the
`sentence. The required response is to indicate as quickly as possi-
`ble whether or not the letters are in the same order as in the sen-
`tence. Dependent variables are the number of correct responses and
`the mean reaction time (ms). The mean reaction time was chosen,
`because the categories differed to a large extend in terms of diffi-
`culty and the median is very sensitive to fluctuations in perform-
`ance on the different categories.
`
`Psychomotor performance and attention Simple and choice reac-
`tion time tasks – The simple and choice reaction time tasks assess
`the speed of perceptual-motor processing without the cognitive
`components of the other tests. The simple reaction time test con-
`sists of a white square that appears on a computer screen and turns
`red after a variable interval. The subject has to press a single button
`as fast as possible. The choice reaction time task is similar to the
`simple reaction time task, with the exception that two squares are
`presented and the subject should press one of two buttons corre-
`sponding to the left or right square turning red. Both tasks consist
`of 48 trials and the dependent measure is the median reaction time
`(ms).
`Critical tracking task – The critical tracking task measures the
`ability to control an unstable triangle, which is displayed on a hor-
`izontal axis on a computer screen, using a joystick (Jex et al.,
`1966). An error signal causes the triangle to become increasingly
`unstable and therefore, it tends to diverge from the centre of the
`axis. The subject has to make compensatory movements to null the
`error in order to keep the triangle in the middle. As the correction
`frequency of the cursor deviations increases as a stochastic function
`of time, the subject is required to make compensatory movements
`with an increasingly higher frequency to the limit of her ability,
`whereupon control is lost. This frequency decreases under the influ-
`ence of sedating drugs. The dependent measure is the average
`frequency at which control is lost of five trials after removing
`the lowest and highest score. This is called the ‘critical frequency’
`or ‘lambdac’ (rad/s).
`Divided attention task – The divided attention task (Moskowitz,
`1973) assesses the ability to perform two tasks simultaneously and
`evaluates cognitive processing resources. The primary task is simi-
`lar to the critical tracking task described above, with the exception
`that the level of difficulty is held constant at 50% of that which is
`just controllable by the subject. Tracking error is measured by the
`absolute distance (in mm) between the cursors position and the
`centre. The secondary task involves the monitoring of 24 digits
`(0–9) that are arranged around the display’s periphery. The
`digits change asynchronously every 5 s. The requirement is to
`respond as rapidly as possible by lifting her foot from a pedal any-
`time the digit ‘2’ appears. Because relative long reaction times are
`
`recorded, outliers are expected to be present at both ends of the dis-
`tribution. Therefore, average reaction time to targets is recorded as
`the response measure in this task. Performance scores in the sub-
`tasks were combined to overall performance scores before analysis,
`because performance in the two subtasks is related within subjects
`and tests. First, average reaction times and tracking error of each
`test were transformed to z-scores using data from all subjects, test
`days and test sessions. Secondly, the standardized scores of the
`subtasks were summed to yield an overall performance score for
`each subject, test day and test session. Overall scores were used
`for further analysis.
`Subjective alertness – Subjective alertness was assessed using a
`mood rating scale consisting of 16 visual analogue scales (i.e.,
`100 mm lines) each representing a continuum between two
`extremes of a certain mood [e.g., alert and drowsy (Bond and
`Lader, 1974)]. Subjects are required to indicate how they feel by
`placing a vertical line on the scale corresponding to their mood at
`that moment. Together these scales provide three factor-analytically
`defined summary scores– ‘alertness’, ‘contentedness’ and ‘calm-
`ness’, of which the factor ‘alertness’ was of primary interest.
`
`Statistical analysis
`
`After unblinding treatments turned out to be not completely
`balanced over periods, due to errors in the ordering of replacement
`medication. Since baseline scores of some tasks showed significant
`Period effects in spite of prior training, assessments at t2 and t4 were
`analysed as changes from baseline at the same day. This is a valid
`method of analysing the data (Van Breukelen, 2006). Changes from
`baseline were screened for normality of the distributions. No sig-
`nificant deviations were found.
`Dependent variables expressed as differences from baseline
`were analysed in repeated measures multivariate analysis of vari-
`ance, according to a 2 (Time) ⫻ 4 (Treatment) factorial model to
`test the main effect of Treatment and the interaction of Treatment
`and Time. The data from the critical tracking task were analysed
`according to a 5 (Time) ⫻ 4 (Treatment) factorial model, but
`otherwise in a similar fashion. Regardless of the outcome of the
`overall F-tests, three planned univariate comparisons were carried
`out between the treatments and placebo for t2 and t4 separately. This
`is a legitimate procedure as the comparisons are suggested by the
`theoretical basis of the experiment (Winer, 1971). All data
`were analysed using SPSS for Windows (version 12.0.1).
`
`Results
`
`Memory
`A summary of mean (⫾SE) performance scores of tasks assessing
`memory performance is presented in Table 1.
`No significant main effects of Treatment or interactions between
`Treatment and Time were found in any memory test except for the
`simplified spatial paired associate learning task. Analysis showed
`that there was a main effect of Treatment on speed of responses to
`⫽ 5.5, P ⬍ 0.008). Longer reaction times
`repeated stimuli. (F3,17
`as compared with placebo were observed after administration of
`
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` © 2008 British Association for Psychopharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
`
`
`
`

`
`Histamine H1-receptor blockade in humans
`
`667
`
`Table 1 Summary of data obtained from tests assessing memory performance after administration of placebo (PLA) dexchlorpheniramine 2 mg (D2), dex-
`chlorpheniramine 4 mg (D4) and scopolamine 1 mg (S1)
`
`Overall analyses of
`changes from baseline
`
`Mean (⫾SEM) scores
`
`Main effect of
`Treatment
`
`P ⫽
`
`Interaction of
`Treatment ⫻
`Time
`P ⫽
`
`Test Session
`
`Treatment
`PLA
`
`D2
`
`D4
`
`S1
`
`Syntactic reasoning task
`Number correct (#)
`
`0.620
`
`0.253
`
`Mean reaction time (ms)
`
`0.865
`
`0.509
`
`Spatial paired associate learning task
`Median reaction time (ms)
`repeated items
`
`0.008
`
`0.176
`
`Median reaction time (ms)
`non-repeated items
`
`0.097
`
`0.432
`
`Word learning task
`Immediate recall (# words correct)
`Delayed recall (# words correct)
`Recognition (ms)
`Pattern recognition task
`Immediate recognition
`Patterns correct (#)
`
`0.075
`
`0.767
`
`Median reaction time (ms)
`
`0.056
`
`0.663
`
`Delayed recognition
`Patterns correct (#)
`
`0.760
`
`0.308
`
`Median reaction time (ms)
`
`0.135
`
`0.370
`
`Sternberg memory scanning task
`Slope (ms/letter)
`
`0.880
`
`0.337
`
`Intercept (ms)
`
`0.379
`
`0.340
`
`Baseline
`t2
`t4
`Baseline
`t2
`t4
`
`Baseline
`t2
`t4
`Baseline
`t2
`t4
`
`t4
`t4
`t4
`
`Baseline
`t2
`t4
`Baseline
`t2
`t4
`
`Baseline
`t2
`t4
`Baseline
`t2
`t4
`
`Baseline
`t2
`t4
`Baseline
`t2
`t4
`
`28.4 ⫾ 1.0
`28.4 ⫾ 1.0
`29.2 ⫾ 1.0
`1651 ⫾ 169
`1594 ⫾ 138
`1582 ⫾ 141
`
`509 ⫾ 15
`501 ⫾ 16
`479 ⫾ 12
`521 ⫾ 22
`504 ⫾ 19
`472 ⫾ 15
`
`28.1 ⫾ 1.0
`27.8 ⫾ 1.0
`29.0 ⫾ 1.0
`1591 ⫾ 163
`1546 ⫾ 155
`1464 ⫾ 139
`
`495 ⫾ 15
`520 ⫾ 20*
`485 ⫾ 16
`501 ⫾ 16
`502 ⫾ 20
`489 ⫾ 19
`
`28.2 ⫾ 1.0
`28.4 ⫾ 1.1
`28.9 ⫾ 0.0
`1652 ⫾ 118
`1654 ⫾ 124
`1629 ⫾ 115
`
`503 ⫾ 18
`512 ⫾ 17
`488 ⫾ 17
`494 ⫾ 16
`514 ⫾ 22
`481 ⫾ 16
`
`29.2 ⫾ 1.1
`28.3 ⫾ 1.0
`29.3 ⫾ 1.0
`1614 ⫾ 121
`1544 ⫾ 105
`1556 ⫾ 120
`
`481 ⫾ 13
`504 ⫾ 16*
`497 ⫾ 17*
`487 ⫾ 15
`503 ⫾ 14
`495 ⫾ 18
`
`45.3 ⫾ 1.8
`15.1 ⫾ 1.0
`647 ⫾ 20
`
`42.9 ⫾ 1.9
`14.6 ⫾ 0.8
`644 ⫾ 17
`
`46.9 ⫾ 1.7
`15.6 ⫾ 0.9
`652 ⫾ 17
`
`44.7 ⫾ 1.5
`14.6 ⫾ 0.8
`643 ⫾ 13
`
`26.5 ⫾ 0.5
`26.6 ⫾ 0.7
`27.1 ⫾ 0.5
`972 ⫾ 59
`916 ⫾ 42
`880 ⫾ 50
`
`25.8 ⫾ 0.5
`24.8 ⫾ 0.7
`24.5 ⫾ 0.7
`1033 ⫾ 74
`1004 ⫾ 63
`986 ⫾ 59
`
`44 ⫾ 4
`47 ⫾ 3
`44 ⫾ 3
`345 ⫾ 11
`338 ⫾ 9
`333 ⫾ 10
`
`26.9 ⫾ 0.5
`26.5 ⫾ 0.7
`27.3 ⫾ 0.5
`904 ⫾ 51
`905 ⫾ 46
`858 ⫾ 60
`
`25.7 ⫾ 0.9
`24.5 ⫾ 0.8
`24.4 ⫾ 0.9
`995 ⫾ 65
`1039 ⫾ 78
`965 ⫾ 67
`
`49 ⫾ 3
`50 ⫾ 4
`50 ⫾ 4
`334 ⫾ 9
`338 ⫾ 1
`317 ⫾ 9
`
`26.7 ⫾ 0.5
`25.5 ⫾ 0.8
`26.8 ⫾ 0.6
`928 ⫾ 70
`936 ⫾ 57
`886 ⫾ 68
`
`25.5 ⫾ 0.8
`23.8 ⫾ 0.8
`24.3⫾ 0.7
`970 ⫾ 74
`1022 ⫾ 70
`993 ⫾ 63
`
`52 ⫾ 5
`56 ⫾ 5
`49 ⫾ 5
`331 ⫾ 10
`336 ⫾ 12
`328 ⫾ 10
`
`27.4 ⫾ 0.5
`25.2 ⫾ 1.0
`26.7 ⫾ 0.5
`945 ⫾ 46
`871 ⫾ 43
`891 ⫾ 48
`
`25.9 ⫾ 0.6
`23.3 ⫾ 0.9
`24.2 ⫾ 0.9
`961 ⫾ 47
`1022 ⫾ 82
`978 ⫾ 64
`
`47 ⫾ 4
`53 ⫾ 5
`50 ⫾ 4
`332 ⫾ 11
`338 ⫾ 8
`329 ⫾ 9
`
`Significant (P ⬍ 0.05) a-priori drug-placebo contrasts are indicated as asterisk.
`
`Downloaded from at Universiteit Maastricht on August 28, 2008 http://jop.sagepub.com
`
`
` © 2008 British Association for Psychopharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
`
`
`
`

`
`668 Histamine H1-receptor blockade in humans
`
`dexchlorpheniramine 2 mg at t2 (F1,19 = 14.5, P < 0.001), and after
`⫽ 12.7, P ⬍ 0.002)
`administration of scopolamine 1 mg at t2 (F1,19
`⫽ 13.6, P ⬍ 0.002).
`and t4 (F1,19
`
`Psychomotor performance and attention
`A summary of mean (⫾SE) performance scores of tasks assessing
`psychomotor functioning and attention is presented in Table 2.
`Analysis of variance of simple reaction time showed a signifi-
`cant main effect of Treatment and a significant interaction between
`⫽ 4.9,
`⫽ 5.2, P ⬍ 0.010, F3,17
`Treatment and Time (F3,17
`P ⬍ 0.012, respectively). Drug-placebo comparisons showed that
`dexchlorpheniramine 2 mg, dexchlorpheniramine 4 mg and scopo-
`lamine 1 mg all significantly increased reaction times at t2
`⫽ 15.5,
`⫽ 5.3, P ⬍ 0.032; F1,19
`⫽ 8.4, P ⬍ 0.009; F1,19
`(F1,19
`P ⬍ 0.001, respectively). These differences were no longer signifi-
`cant at t4.
`Similar results were obtained from the choice reaction time
`task. The main effect of Treatment on response speed was nearly
`⫽ 2.7, P ⬍ 0.078) and drug-placebo comparisons
`significant (F3,17
`at t2 showed significantly longer reaction times after administration
`⫽ 6.3, P ⬍ 0.021), dexchlor-
`of dexchlorpheniramine 2 mg (F1,19
`⫽ 5.9, P ⬍ 0.025) and scopolamine 1 mg
`pheniramine 4 mg (F1,19
`⫽ 10.4, P ⬍ 0.004).
`(F1,19
`
`A main effect of Treatment was also found on critical tracking
`⫽ 3.3, P ⬍ 0.044). Tracking was impaired at
`performance (F3,17
`both 1.5 h as 2.5 h following the administration of dexchlorpheni-
`⫽ 5.5, P ⬍ 0.030), dex-
`⫽ 7.6, P ⬍ 0.012, F1,19
`ramine 2 mg (F1,19
`⫽ 14.7, P ⬍ 0.001, F1,19
`⫽ 7.8,
`chlorpheniramine 4 mg (F1,19
`P ⬍ 0.012) and scopolamine 1 mg (F1,19
`⫽ 13.7, P ⬍ 0.001,
`⫽ 12.3, P ⬍ 0.002). The effects were no longer significant at
`F1,19
`3.5 and 4.5 h after administration (Figure 1).
`Owing to a technical error, reaction times in the visual search
`task of the divided attention test were not recorded for one subject
`during baseline measurements before administration of dexchlor-
`pheniramine 4 mg. Her data were excluded from all analyses of
`performance in this task.
`A significant main effect of Treatment was found on the
`⫽ 7.7, P ⬍ 0.002).
`overall performance measure
`(F3,16
`Dexchlorpheniramine 4 mg produced a significant impairment
`⫽ 7.4, P ⬍ 0.014).
`⫽ 9.9, P ⬍ 0.006) and at t4 (F1,18
`at t2 (F1,18
`Similarly, scopolamine 1 mg impaired performance at both times of
`⫽ 15.6, P ⬍ 0.001).
`⫽ 19.9, P ⬍ 0.001 and F1,19
`assessment (F1,19
`
`Subjective alertness
`
`There were significant main effects of Treatment and a significant
`interaction between Treatment an