Br. J. clin. Pharmac. (1986), 21, 647-653 Zopiclone produces effects on human performance similar to flurazepam, lormetazepam and triazolam A. N. GRIFFITHS', D. M. JONES2 & A. RICHENS1 'Department of Pharmacology and Therapeutics, University of Wales College of Medicine, Cardiff and 2Department of Applied Psychology, University of Wales Institute of Science and Technology, Cardiff 1 The cognitive function and psychomotor performance of 10 healthy male volunteers were measured following single oral doses of: zopiclone (7.5 mg), flurazepam (15 mg), lormetazepam (1 mg), triazolam (0.25 mg) and placebo. 2 The performance tests selected (stroop task, five choice serial reaction time, memory span, logical reasoning, mood and saccadic eye movement analysis) were thought to reflect aspects of normal daily activity. 3 The tests demonstrated a clear reduction of performance for all active treatments. No drug emerged as the most potent sedative overall, as each of the tests was affected to a different degree by each drug. 4 Drug effects were not qualitatively different between active treatments so that zopi- clone was indistinguishable from the three benzodiazepines with which it was compared. Keywords zopiclone benzodiazepines human performance saccadic eye movements Introduction Zopiclone is a cyclopyrrolone derivative which, (7.5 mg) has been shown to be effective as an although structurally unrelated to the benzodia- hypnotic (Wickstrom & Giercksky, 1980), zepines, shares their pharmacological profile. and furthermore, Lader & Denney (1983) Binding studies have shown that zopiclone binds reported this dose to be the preferred hypnotic to brain benzodiazepine receptors but is not dose. recognised by peripheral (renal) benzodiazepine The marketed benzodiazepines selected for receptors. Blanchard et al. (1983) investigating use in this study provided a cross section of the modulating action of GABA and barbiturates elimination half-lives varying from the very short on zopiclone binding have shown differences 2 h half-life of triazolam through lormetazepam between zopiclone and benzodiazepines. They with a 9-15 h half-life to flurazepam whose active suggest that zopiclone may bind, in rat brain, to metabolite, N-desalkylflurazepam, has a half- sites that do not correspond exactly to the ben- life of 65 h. Doses were selected with reference zodiazepine sites. This was confirmed by Trifilletti to those recommended by the manufacturers. & Snyder (1984) who reported that zopiclone The present study used the effects of the drugs bound to a novel site linked allosterically to on saccadic eye movements as a measurement benzodiazepine receptors. of the time course of sedative drug action. In man zopiclone is well tolerated and is rapidly This approach has been previously reported and efficiently absorbed (> 75%). The plasma (Bittencourt et al., 1981, Tedeschi et al., 1983). kinetics of zopiclone are generally well described Into this framework, specific tasks of cognitive by a two compartment open model with a half and psychomotor performance have been fitted life of 5-6 h (Houghton etal., 1984); a large total to provide a more detailed insight into the nature body clearance of 300 ml min7l and a low renal of the induced sedation. clearance of 10 ml min-' (Gaillot et al., 1983). The aim of the study was to compare the The dose of zopiclone selected for this study effect of zopiclone with three marketed 647 648 A. N. Griffiths et al. benzodiazepines using a battery of tasks to The Stroop test assess psychomotor and cognitive performance. This test measured the time taken to read a colour word when printed in an incongruous ink. Methods For example, the word 'green' might be printed in red ink. The task of the subject was to give the Protocol response 'red' even though the natural and com- pelling tendency was to give the colour word Ten male volunteers aged 20-22 years of age 'green'. The time taken to make the response to were recruited. All were declared healthy after a a number of such items arranged on a card is full medical examination and had normal usually considerably longer than to a similar haematological and blood biochemical screening number of colour words which do not involve tests both before and after the study. The treat- such conflict. The task is thought to measure the ments, zopiclone (7.5 mg), flurazepam (15 mg), degree to which the individual is able to suppress lormetazepam (1 mg), triazolam (0.25 mg) and the conflict between the two types of response. placebo, were matched for size, shape and colour The effect of a drug on these response times by encapsulation. They were administered in a might be due to the effects on the speed of random order (using a conjugate latin square) reading rather than on the interference per se. and in a double-blind manner. Treatments were To control for this possibility, two other types of separated by at least 7 days. Volunteers were material were also presented along with the instructed to abstain from ethanol and caffeinated interfering material (the CW card). Their beverages for 24 h and 12 h respectively before purpose was to give some indication of any effects treatment and throughout treatment days. On on reading speed. In one (the W card), colour test days volunteers reported to the department words were presented in black ink on a white at 08.00 h, drug intake was at approximately background. In the other (the C card), patches 09.30 h. A standard diet was provided for of colour (of the same size as the material on the volunteers on test days. Volunteers were asked CW card) were presented. This gave a measure to perform the task battery before drug admini- of the speed of colour naming. stration and 1, 4 and 10 h after. Saccadic eye The version of this test used consisted of three movements were measured before and 0.5, 1, 2, cards (C, W and CW); each arranged in a 10 x 10 3, 4, 6, 8 and 10 h after drug intake. matrix of colours or colour words as appropriate. The study was granted ethical approval by the The colour names (four colours) used were red, Joint Ethics Committee, University of Wales green, yellow and blue, these being the least College of Medicine. Written informed consent, ambiguous in their naming. For the CW card witnessed by an independent person, was ob- each of the four colour words was represented tained from each volunteer. on a roughly equal number of occasions in each colour. Subjects were asked to name colours Saccadic eye movements aloud as quickly as possible and to read each card in a systematic fashion from left to right. Saccadic eye movements are rapid conjugate For each card the total time to read the hundred shifts of gaze, the dynamics of which are con- items and the number of errors were noted. trolled by groups of neurones situated in the brain stem. Peak saccade velocity has been Logical reasoning shown to be a good marker ofdrug induced CNS depression. Drug effects in normal volunteers This task measured performance at a relatively have been observed with barbiturates, opiates, high level of abstraction (Baddeley, 1968). On benzodiazepines, carbamazepine, amphetamine each trial subjects were presented with, first, a and ethanol (Griffiths et al., 1984). statement of a relation between two objects (for Volunteers were instructed to follow the move- example, 'A follows B'), which was followed by ments of a target presented to them on a televi- an exemplar ('AB'). The subject was asked to ion screen. Their eye movements were recorded decide whether each statement was true or false by electro-oculography. The target moved hori- (the case just given is, of course, false). Other zontally through a sequence of jumps of 30°40' more complex instances included 'A does not amplitude, with respect to the volunteer's nasion. precede B' and 'B is preceded by A'. A total Subsequently computer analysis of the recorded of twenty five trials were given on each occa- eye movements was carried out by a method sion and performance was measured in terms of described elsewhere (Griffiths etal., 1984). Each total time to perform all trials and number of measurement session lasted 3 min. errors. Zopiclone and human performance 649 All the materials were presented and Memory span the responses timed and scored on a micro- computer. The test was composed of strings of consonants presented individually on the screen of the Serial reaction microcomputer at a rate of one item per second. The length of each list was between 20 and 40 Subjects were required to make a speeded letters. Each list ended unpredictably. In this response to an unpredictable sequence of signals. way, subjects were unable to recruit themselves The task consisted of a display board with five to concentrate for a relatively short period as lights (light emitting diodes) mounted in the they might with a list of fixed length. In each shape of a pentagon. The display board was experimental session twenty lists were presented. inclined at approximately 400 to the horizontal Two versions of the list were deployed over the and immediately behind the response board. period of the experiment to minimize learning of Keys on the response board were arranged in a the lists. pentagonal pattern identical to the layout of the The subjects were asked to write down as lights on the display board. The subject was many as they could ofthe last few items in the list required to press the key on the response board after the list was stopped. Emphasis was placed corresponding to the position of the illuminated on reporting the items in the correct order on a light on the display board. Only one light was response blank which was provided for each illuminated at a time.