ANTEROGRADE AMNESIA INDUCED BY THE HYPNOTIC DIAZEPAM IS NOT ASSOCIATED WITH SLEEPINESS
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1 ANTEROGRADE AMNESIA INDUCED BY THE HYPNOTIC DIAZEPAM IS NOT ASSOCIATED WITH SLEEPINESS Agnieszka Unrug l, Marielle Gorissen 2, Gilles van Luijtelaar l, Anton Coenen l 1 NICI, Department of Psychology, University of Nijmegen, PO Box 9104, 6500 HE Nijmegen, The Netherlands 2 Psychiatric Hospital Veldwijk, Ermelo, The Netherlands ABSTRACT The question whether the sedative effects of diazepam, lowering the level of vigilance and inducing sleepiness, can be held responsible for the memory impairments expressed in anterograde amnesia, was evaluated. This was done in two ways. The influence of diazepam was compared with the effects of sleep deprivation on memory. Sleep deprivation is an alternative method to reduce vigilance and induce sleepiness. Furthermore, effects on memory of methylphenidate were studied. Methylphenidate is a drug which induces an increase in the level of vigilance. It was suggested that if the amnestic effects of benzodiazepines are related to the reduction in vigilance, then sleep deprivation would impair memory similar to diazepam, while methylphenidate would improve memory. Memory was clearly impaired after diazepam intake. On the contrary, anterograde amnesia was not present in the sleep deprived group, although the lack of sleep indeed lowered the level of vigilance. Memory improvement was not found after methylphenidate, although a clear indication of an increase in vigilance after drug intake was found. In all, memory impairments in the diazepam group, and the lack of memory impairments in the sleep deprived group, as well as the lack of memory improvement in the methylphenidate group, indicate that the level of vigilance plays not a decisive role in anterograde amnesia after diazepam. intake. INTRODUCTION Benzodiazepines (BZDs), with diazepam (Valium) as the best know representative, are frequently used as psychoactive drugs to induce sleep or to suppress anxiety and stress. Although BZDs are efficient and safe, they also produce side effects. The most unwanted side effects are sedation, as seen in a decrease in vigilance, and impairments in memory. The recall of the information learned under the influence of BZDs is impaired. This phenomenon is called anterograde amnesia (Curran, 1986; Coenen et al, 1989; Coenen and van Luijtelaar, 1997; Ghoneim and Mewaldt, 1990). The mechanism behind the effects of BZDs on memory is still not clear. Some authors suggest that anterograde amnesia might be due to the lowered level of alertness (Preston et al, 1988; Roth et al, 1990; Roehrs et al, 1994). Others argue, that the 123
2 amnestic effects of BZDs can be separated from those related to sedation (Curran et al, 1991; File, 1992). The aim of this paper is centered on the question whether sedation induced by BZD is the factor responsible for the drug-induced memory impairments. The analysis of the relation between the sedative and amnestic effects was done in two ways. In the first experiment the effects of the reduction in alertness by diazepam on memory were compared with the reduction in alertness by a non-pharmacological way, sleep deprivation (Gorissen et al, 1997). Sleep deprivation is known as a technique which decreases the level of vigilance and induces sleepiness. The question was addressed whether sleep deprivation induces similar memory effects to those found after diazepam intake. The second experiment was aimed towards a comparison between the effects on memory of the sedative diazepam and the stimulant drug, methylphenidate (Ritalin) (Unrug et al, 1997). Methylphenidate is a representative of a group of centrally stimulating drugs. The goal was to find whether methylphenidate can induce opposite effects on memory, such as anterograde facilitation. In all, it was supposed that when sleep deprivation induces anterograde amnesia just as diazepam and methylphenidate induces opposite effects on memory, than the amnestic effects of benzodiazepines might be related to the reduction of the level of alertness. EFFECTS OF DIAZEPAM AND SLEEP DEPRIVATION ON MEMORY The question whether memory impairment is related to reduction of alertness induced by diazepam was addressed firstly (Gorissen et al, 1997). Drug effects on memory were compared to those after sleep deprivation. Twelve healthy psychology students of both sexes, years of age, participated in this open study. Each subject was tested in three sessions: diazepam (15 mg), placebo and 24 hours of sleep deprivation. Experimental sessions were separated by an one-week break. The level of alertness was measured both objectively with alertness tests and subjectively with questionnaires. A 20-word test was used for memory evaluation. Subjects were asked to recall as many words as possible immediately after the presentation of the list of words. The delayed recall was assessed 20 minutes after the presentation of the list. The results showed that alertness measured subjectively as well as objectively was reduced by both drug intake and by sleep deprivation. Subjects reported more fatigue, less alertness and more tiredness after diazepam in comparison with placebo. Interestingly, the subjective level of alertness was even more reduced in the sleep deprivation group than in the diazepam group. The performance on a vigilance task was similar after sleep deprivation and diazepam. The results of the memory test and the statistics are presented in Figure 1. Similar to what was reported by others (Curran, 1986; Mewaldt et al, 1983; Ghoneim and Mewaldt, 1990), diazepam did not affect the immediate recall of the 20-word test. Sleep deprivation had also no effects on the immediate recall of the memory test. The results of the delayed recall showed that subjects under influence of diazepam recalled less words in comparison with the delayed recall in the placebo group, 124
3 as well as in the sleep deprived group. Anterograde amnesia was found after diazepam intake only. There was no difference between the delayed recall after placebo and sleep deprivation (figure 1). The lack of differences between the placebo and the sleep deprived group was remarkable considering the fact that the level of vigilance in the sleep deprived group was even lower than after diazepam. Therefore, the lowered level of alertness might not always induce memory impairments. Figure 1: Number of words recalled (means and standard errors) in the immediate and delayed recall of the 20-word test, in the placebo, sleep deprivation and diazepam condition. An ANOVA showed no effects on the immediate recall scores, while significant effects of condition on the delayed recall scores were found (p<0.005). Planned contrasts showed that subjects recalled fewer words after diazepam compared to placebo (p<0.002), as well as compared to sleep deprivation (p<0.02). Data are taken from Gorissen et al (1997). EFFECTS OF DIAZEPAM AND METHYLPHENIDATE ON MEMORY The question whether memory impairments induced by diazepam. intake are related to the drug-reduced level of alertness was further investigated in a second experiment (Unrug et al, 1997). Six female and six male subjects with an average age of 24 years (range 19-27) participated in this double-blind experiment. Subjects received an oral dose of 10 mg diazepam, 20 mg methylphenidate or placebo. The level of alertness was determined by a subjective alertness scale, AD-ACL (Thayer, 1986). 125
4 A 15-word test served as memory test. Similar to the first experiment, subjects were asked to recall as many words as they could recall directly after presentation and after a delay of 20 minutes. The general question in this experiment was whether opposite effects of diazepam and methylphenidate might be observed with respect to memory. Diazepam and methylphenidate induced opposite effects on subjective alertness as was expected (Roehrs et al, 1994; Strauss et al, 1984). Diazepam reduced and methylphenidate increased the level of vigilance. The level of deactivation on the AD-ACL associated with sleep was higher in the diazepam group ( ) in comparison with the methylphenidate ( ) group, and the placebo group ( ) in comparison with the stimulant drug. The level of general activation was lower after diazepam ( ) in comparison with both methylphenidate ( ) and placebo ( ). The results of the 15-word test are presented in Table 1. Table 1: Means and standard errors of the scores from the 15-word test in the diazepam, methylphenidate and placebo group. N of all groups is 12. (ns= not significant, d = diazepam, in = methylphenidate and p = placebo, vs = versus). Data are taken from Unrug et al (1997). Diazepam methylphenidate placebo d vs m d vs p m vs p immediate recall 6.8 ± ± ± 0.8 n.s ns ns delayed recall 8.8 ± ± ± 0.5 d < m d < p n.s Diazepam did not affect the immediate recall of the 15-word test. The results of the delayed recall indicate anterograde amnesia induced by diazepam. The results of the second experiment were thus similar with respect to diazepam to those obtained by Gorissen et al (1997). However, in contrast to what was expected, methylphenidate did not improve memory performance, in spite of the fact that the level of alertness was increased. It could not be totally excluded that a lack of improvement in performance after methylphenidate was due to ceiling effects. The subjects of the placebo and the methylphenidate group were able to recall almost all of the presented words. In order to verify this possibility a modified version of the 15-word test was used. In a second part of the experiment 20 mg of methylphenidate and placebo were compared. Twenty words were presented and the presentation time was shorter. Again, methylphenidate increased the level of alertness, but there was no effect of this drug on the performance of the immediate and delayed recall of the memory test. The means and standard deviations of the immediate recall after methylphenidate and after placebo intake were respectively and The means and standard deviations of the immediate recall after methylphenidate and after placebo were respectively and The data indicate that the enhanced level of alertness does not improve the recall of memory. 126
5 DISCUSSION The general purpose of both experiments was to evaluate whether memory impairments may be related to a decrease in alertness. The level of alertness was pharmacologically manipulated by diazepam and alternatively by a non-pharmacological way, by sleep deprivation. Alertness was reduced by diazepam intake and by sleep deprivation. An increase of the level of alertness was obtained by methylphenidate. It was hypothesized that memory impairments such as anterograde amnesia will be associated with a reduced level of alertness and memory facilitation such as anterograde facilitation, with an increased level of alertness. The phenomenon of anterograde amnesia was easily demonstrated after diazepam intake in both experiments. Memory was clearly impaired after diazepam intake and anterograde amnesia was demonstrated. Subjects under the influence of the drug recalled less items in comparison to the placebo, the methylphenidate as well as the sleep deprived group. In spite of the elevated alertness by methylphenidate, the expected anterograde facilitation was not obtained. Despite of the reduced level of vigilance in the sleep deprived group, memory impairments after 24 hour sleep deprivation were also not found. However, it seems to be clear that it is difficult to increase alertness in healthy and fully alert subjects. Considering this difficulty and the putative ceiling effects, the investigation of the effects of methylphenidate on the performance of memory tests should be further continued. The lack of memory impairments in the sleep deprived group indicates that subjects are able to perform a memory task as good as the placebo group, even when their subjective level of alertness is more reduced than the level of alertness in the diazepam group. In all, these results jeopardizes the suggestion that a reduction in alertness can be held responsible for the diazepam-induced memory impairments. REFERENCES Coenen AML, van Poppel HCAJM, Gribnau FWJ, Vossen JMH, van Luijtelaar ELJM (1989). Benzodiazepines and cognition: effects on intentional and incidental learning. In: J Home (Ed.), Sleep 88, (pp ), Stuttgart, New York: Gustav Fischer Verlag. Coenen AML, van LuiJtelaar EUM (1997). Effects of benzodiazepines, sleep and sleep deprivation on vigilance and memory. Acta Neurologica Belgica 97: Curran HV (1986). Tranquillising memories: a review of the effects of benzodiazepines on human memory. Biological Psychology 23: Curran HV, Schivy W, Lader M (199 1). Differential amnestic properties of benzodiazepines: a dose-response comparison of two drugs with similar elimination halflives. Psychopharmacology 92: File SE (1992). A comparison of the effects of a secondary task and lorazepam on cognitive performance. Journal of Psychopharmacology 6: Ghoneim MM, Mewaldt SP (1990). Benzodiazepines and human memory: a review. Anaesthesiology 72:
6 Gorissen M, Tielemans M, Coenen A. (1997). Alertness and memory after sleep deprivation and diazepam intake. Journal of Psychopharmacology 11: Mewaldt SP, Hinrichs JV, Ghoneim MM (1983). Diazepam and memory: support for a duplex model of memory. Memory and Cognition 11: Preston CG, Broks P, Traub M, Ward C, Poppelton P, Stahl SM (1988). Effects of lorazepam on memory, attention and sedation in man. Psychopharmacology 95: Roehrs TA, Merlotti L, Zoric F, Roth T (1994). Sedative, memory and performance effects of hypnotics. Psychopharmacology 116: Roth T, Roehrs TA, Stepanski EJ, Rosenthal L (1990). Hypnotics and behavior. American Journal of Medicine 88: 43S-46S. Strauss J, Lewis JL, Klorman R, Peloquin LJ, Perlmutter RA, Salzman LF (1984). Effects of methylphenidate on young adults performance and event-related potentials and a paired-associates learning test. Psychophysiology 21: Thayer R (1986). Activation-Deactivation Adjective Check List: current overview and structural analysis. Psychological Reports 58: Unrug A, Coenen A, van Luijtelaar EUM (1997). Effects of the tranquillizer diazepam and the stimulant methylphenidate on alertness and memory. Neuropsychobiology 36:
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