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Alpidem and Psychological Performance in Elderly Subjects l. Hindmarch Head of Human Psychopharmacology Research Unit, Department of Psychology, University of Leeds, Leeds, England

With increasing age there is a concurrent increase in the side efTects following psychotropic medication. The necessity of measuring the magnitude of the extent of the side efTects using a properly constructed psychometric test battery is illustrated with reference to a dose ranging study compared to acute dose efTects of 25, 50 and 100 mg alpidem in a population of elderly volunteers. The study was both placebo and verum (Iorazepam 2 mg) controlled and the treatments were administered according to a crossover design with each subject acting as their own contro\. The efTects of the verum were evident on all the tests and under these conditions there was no efTect on psychological difTerences following doses of 25 and 50 mg alpidem. There was an initial deterioration one hour after dosing following 100 mg alpidem which was readily attenuated by three hours. No difTerences with any ofthe doses of alpidem were able to be detected at any other time point even though the verum continued to show the sensitivity of the battery to tests to sedative amnestic sensori-motor and information processing activities.

Ageing, in psychological performance terms is reflected by a gradual, age related impairment of sensorimotor skills, reaction time, information processing capacity, short term memory and flexibility of thought. Individuals are less able to concentrate and are more easily distracted as they grow older and increase in daytime tiredness, due to nocturnal fragmentation of sleep reduces overall levels of perceptual, cognitive and psychomotor ability in an age related manner (Wattis& Hindmarch, 1988).

A1pidem und psychologische Leistungsbewertung älterer Menschen Mit fortschreitendem Alter nehmen gleichzeitig die Nebenwirkungen nach der Verabreichung von Psychopharmaka zu. Die Notwendigkeit, das Ausmaß der Nebenwirkungen mit Hilfe einer Abfolge psychometrischer Tests zu bestimmen, wurde durch einen abgestuften Dosie-rungs-Vergleichstest belegt, bei dem die akuten Wirkungen von 25, 50 und 100 mg Alpidem an älteren Probanden festgestellt wurden. Der Test war sowohl Plazebo- als auch Verum-(Lorazepam 2 mg)-kontrolliert, und die Behandlung erfolgte im OberKreuz-Schema, wobei jeder Proband seine eigene Kontrollperson war. Die Wirkungen des Verum waren in allen Tests erkennbar; unter den vorliegenden Versuchsbedingungen ergaben sich keine Auswirkungen auf die psychologischen Veränderungen nach Verabreichung von 25 und 50 mg Alpidem. Nach Verabreichung einer Dosierung von 100 mg Alpidem zeigte sich eine anfängliche Verschlechterung eine Stunde nach der Gabe, die jedoch nach 3 Stunden spontan abgeklungen war. Zu keinem anderen Zeitpunkt ergaben sich irgendweIche Veränderungen nach der Verabreichung der Alpidemgaben, wenn auch das Verum nach wie vor die Empfindlichkeit der Testreihe für die Feststellung sedativer, gedächtnisverlustbewirkender, sensomotorischer und informationsverarbeitender Wirkungen bestätigte.

cognitive, mnestic and psychomotor functions. As the elderly sufTer from more disease and disability than younger patients it is expected that they will receive more prescribed medicines (Moir & Dingwall-Fordyce, 1980). Side efTects of medications must be minimised in the elderly patient as they have been shown to increase with age (Hurwitz, 1969; Seidl et a\., 1966) and furthermore, have been shown to be one of the major reasons for admission to geriatric hospitals (Williamson & Chopin, 1980).

Psychotropic drug use increases with increasing age (Hindmarch & Wattis, 1988) and age related changes in metabolic and pharmacokinetic variables have also been reported. lt is necessary to investigate the psychopharmacological impact of psychotropic agents in the older patient to determine the behavioural toxicity of compounds on measures of psychological performance which are analogues of everyday

lt is first essential to find a battery ofvalid tests that reflect the range of psychological abilities relevant to the elderly patient. This battery of tests should also be a reliable index of the efTects of the psychoactive agents under investigation and, perhaps most importantly, performance on the test assessments must be within the skilllevel of elderly subjects.

Pharmacopsychiatry 23 124-128 (1990) (Supplement) © Georg Thieme VerlagStuttgart· New York

lt is evident (Hindmarch, 1980) that many putative psychometric tests are unreliable, not valid, insensitive to the efTects of psychoactive drugs and weil beyond the intel-

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Summary

lectual and/or motor capacities of elderly patients (Hindmarch & Wattis, 1988). Some demand substantial attention spans for up to two hours and others require subjects to use computer keyboards and other electronic technology which might appear both threatening to an old subject and difficult to use with those suffering from arthritic or musculo-skeletal problems and poor eyesight. The time taken to complete some psychogeriatric assessments makes them impossible to inc1ude in repeated measure designs where pharmacodynamic profiles of drug action are to be determined using hourly test sessions. Many tests, originally developed and validated as c1inical ratings for the severity of psychological and psychomotor decline in the elderly are not reliable when used in repeated measure designs, since parallel forms do not exist and the rating scales have not been validated for repeated administration or shown to be sensitive to the effects of psychotropic drugs. However, a careful consideration of the literature identifies a test battery which a) reflects the age related dec1ine in ecologically valid measures of psychomotor and cognitive functions, b) is a sensitive and reliable indicator of the effects of psychopharmacological agents and c) meets the pragmatic criterion that old subjects can perform the sub-tests easily and without the necessity of complex training schedules.

Psychometrie test batteryJor use with elderly patients A consideration of the information processing model (Hindmarch, 1980) identifies four aspects of psychological functioning which are important indicators of the effects of psychoactive compounds in man viz. information processing capacity and/or general CNS arousal, attention and speed of reaction to a sensory stimulus, sensori-motor co-ordination and short term memory storage and retrieval of information. A psychometric test battery should reflect these aspects. A typical exemplar is given below: Critical Flicker Fusion Threshold (CFFT) is used as a measure of information processing capacity i.e. as a general index of the overall level of CNS arousal and activity. CFFf is a sensitive index ofthe action ofa wide range ofCNS active drugs (Hindmarch, 1982). It correlates weil with other measures of a1ertness and mental capacity (Parrott, A. C. 1982), it is a useful indicator of circadian changes in arousal (Hindmarch, 1988a), it paraIleIs CNS activity changes during the menstrual cycle (Hindmarch, 1988b) and, most importantly CFFf reflects age related changes in overall cognitive performance (Hindmarch, 1981).

Recent c1inical studies (Ponciano et al., 1981; Hill et a1., 1981; Gringas & Beaumont, 1985) have shown that a patient's response to the therapeutic activity of antianxiety preparations was reflected in concordant changes in CFFT. The side effects of antidepressant therapy, particularly sedation and tiredness, have been reflected in CFFT ratings in hospitalised patients (Khan et al., 1984; Hanks, 1984). The technique has also been shown to be sensitive enough to mirror the c1inical response of patients treated with no-otropic agents (Parrott & Hindmarch, 1982).

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Choice Reaction Time (CRT) is a commonly used assessment of psychomotor performance (Hindmarch, 1980), but in a format whereby the motor component of the task (MRT) is separated from the overall reaction time; the latency of response to the sensory stimulation (RRT) can be measured (Hindmarch, 1975; Frewer & Hindmarch, 1988).

This technique has proven useful in discriminating between the residual sequelae of nocturnal hypnotics (Hindmarch, 1975) and between the "sedative" potential of different anti-anxiety therapies (Hindmarch, 1979). As CRT increases with increasing age (Frewer & Hindmarch, 1988) it is important to separate the relative contribution of an augmentation of motor reaction time from changes in the speed of sensory stimulus detection and reaction. Otherwise it is difficult to identify the locus of a drug induced change in CRT. Clear differences in the RRT of elderly compared to young subjects and between anxious and not anxious age matched controls have been established (Frewer & Hindmarch, 1988): further extending the validity of RRT as a relevant psychometric for profiling potential antianxiety therapies. Short Term Memory and Information Retrieval (STM) is an essential executive function of an intact cognitive system. The holding of discrete "bits" of information in the STM or working memory is an habitual feature of daily intellectual activity. Some nootropics are able to improve STM, without having any effect on CFF or CRT (Hindmarch & Subhan, 1985; Subhan & Hindmarch, 1984a; Subhan & Hindmarch, 1985) suggesting that measures of short-term storage, input and retrieval of information are independent of overall changes in CNS arousal and/or speed of stimulus processing.

Tests of STM using object recall, were able to discriminate between the significant amnestic properties of lorazepam and the lack of amnesia following c10bazam in a group of elderly (mean age 77 years) anxious patients treated for four weeks (Paes de Sousa et a1., 1981). Memory tasks have been found to be sensitive and reliable measures for distinguishing between a variety of psychoactive drugs including benzodiazepine receptor ligands (Hindmarch, 1988b) antidepressants (Hindmarch & Subhan, 1986; Hindmarch, I, 1988lJ) and nootropic agents (Subhan & Hindmarch, 1984a; Subhan & Hindmarch, 1985). Efficient assessment of mnestic function is a sine qua non of pharmacodynamic studies in the elderly as memory impairment as a consequence of drug administration is a particularly serious "side-effect". Sensori-motor Coordination (SMC) is usually assessed by a tracking task where the mean deviation of the subject's attempt to follow a moving target is the experimental measure recorded. The greater the deviation from the target the poorer the sensori-motor coordination and the poorer, therefore, the underlying CNS integration. SMC is a well established measure in pschopharmacological research (Nicholson & Ward, 1984) being particularly sensitive to the sedative activity of a wide range of psychoactive drugs including antianxiety agents (Nicholson, 1981), hypnotics (Nicholson & Stone, 1982), antidepressants (Hindmarch, 1988c) and antihistaminics (Nicholson, 1979). Furthermore, SMC is a valid analogue of the integrity of coordinated behaviour, an essen-

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Alpidem and Psychological Performance in Elderly Subjects

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126 Pharmacopsychiatry 23 (1990) -CFF (Hz): Change from baseline. The mean change from pretreatment values for critical flicker fusion thresholds

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tial feature of the daily environment of elderly patients. The use of this psychometrie battery will be iIIustrated by reference to work in a population of elderly volunteers where the pharmacodynamics of alpidem were to be investigated (Hindmarch et al., 1988).

The pharmacodynamic profile 0/ alpidem in elderly subjects As weil as using a test battery which has been previously shown to be a reliable and valid measure of performance it is important to anchor any changes observed with the test compound within the framework of values folowing placebo and verum (positive internal contro\) treatments. It is also important to use a range of doses of the investigational compound to avoid the possibility of missing a dose dependent effecL It is not usual to reflect the magnitude of c1inieal dose regimens or the chronic nature of administration as it is not the purpose of pharmacodynamic studies to measure the c1inical efficacy of the drug under evaluation but rather to measure and define the parameters of the action of the drug, per se, on c1inically relevant variables. The c1inically relevant variables are defined by the tests which comprise the assessment battery.

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Alpidem has been shown to be a c1inically effective anxiolytic (Bassi et al., 1989; Pancheri et al., 1989) at daily doses between 100 and 150 mg. In young volunteers (Lader et al., 1988) acute doses of alpidem 25, 50 and 100 mg showed a dose related increase in sedative activity; as measured on a variety of psychometrie tests; with 25 mg having no effect and 100 mg being significantly sedative and approximately equivalent to 2 mg lorazepam. To see if increasing aged altered these pharmacodynamic profiles, acute doses of 25, 50 and 100 mg alpidem were compared against placebo and an internat positive control (Iorazepam 2 mg) in a group of 20 physically and psychologically healthy elderly volunteers. The study was a double blind crossover design with each subject acting as his own control. Subjects were tested at baseline and I, 3, 5, 8 and 24 hours after dosing on a battery of psychometrie tests including those detailed above (CFFf, RRT, STM and SMC). The results were obtained from complete scores in 19 subjects. The changes in CFF threshold, with respect to pre-treatment baselines are presented in Fig. I. The reduction in CFF values produced by the verum is evident confirmation of the sensitivity of this measure to reductions in information

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Pharmacopsychiatry 23 (1990) 127

Alpidem and Psychological Performance in Elderly Subjects

Memory performance was measured on a computer assisted task based on a previously validated theoretical and practical technique (Subhan & Hindmarch, 1984b; Subhan & Hindmarch, 1984c) using reaction time to measure information processing aspects of STM. The amnestic properties of the verum for the 8 hours following administration are evident in Fig. 3. Apart from an interference ofSTM by 100 mg a1pidem there is no evidence that any dose of alpidem at any test time has any noticeable efTect on STM. Sensori-motor coordination as measured on a tracking task shows an initial impairment of SMC at one hour after dosing with 100 mg alpidem. There are no other observable efTects of a1pidem at any dose or time, even though the verum shows the test system to be sensitive to SMC changes for up to 5 hours post treatment (Fig. 4). Overall this pharmacodynamic study in elderly volunteers shows acute doses of alidem 25 and 50 mg to be free from disruptive efTects on a battery of tests historically proven to be sensitive and reliable indices of psychotropic activity and made valid in this particular instance by demonstrating the known efTects of averum treatment. The highest dose of 100 mg alpidem shows a significant initial impairment on most of the test measures. This initial impairment is fleeting and there is no evidence of any significant changes or noticeable trends towards impairment after the one hour post-treatment testing session. However, the test battery remains sensitive to drug induced reductions in the integrity of psychological functions as evidenced by the significant verum induced impairments on all test measures. The results obtained in this population of elderly volunteers are in complete accord with those obtained from young subject populations (Saletu et al., 1986; Allen et al., 1988; Curran et al., 1987) and it can thus be assumed that increasing age does not modify the acute dose pharmacodynamics of a1pidem and that there is little likelihood of disruptive efTects on the integrity of psychological performance in the elderly following acute doses ofup to 50 mg alpidem. With doses in excess of 50 mg there might weil be an initial "sedative response" but this verum-controlled study shows this response to be transitory and completely assimilated some three hours post dose. The lack of side effects following psychoactive medication in the elderly is important as elderly patients already have an age-related disadvantage in cognitive, perceptual and mnestic skills and further drug induced impairment of these abilities would only exacerbate the severity of an underlying psychological ilIness and be counter-therapeutic in delaying the patient's return to normality.

References Allen, D., A. Baylav, M. Lader: A Comparative Study of the Interaction of Alcohol with Alpidem, Lorazepam and Placebo in Normal Subjects. International Clinical Psychopharmacology 3 (1988) 327-341 Bassi, S.. M. G. Albizzati, C. Ferrarese, L. Frattola, B. Cesana, R. Piolti, A. Farolfi: Alpidem, a Novel Anxiolytic Drug: A Double-Blind, Placebo-Controlled Study in Anxious Outpatients. C1inical Neuropharmacology 12 (I), Raven Press Ltd., New York (1989) pp. 67-74 Curran, H. v.: Tranquillising memories: a review of the efTects of benzodiazepines on human memory. Biological Psychiatry 23 (1986) 179-213 Curran, v., D. Allen, M. Lader: The efTects of single doses of a1pidem (SL800342-00), lorazepam and placebo on memory and psychomotor performance in healthy human volunteers. Journal of Psychopharmacology I (1987) 81-89 Frewer, L. J., I. Hindmarch: The EfTects of Time of Day, Age, and Anxiety on a Choice Reaction Task. In: Hindmarch, 1., B. Aufdembrinke, H. Ott (eds.): Psychopharmacology and Reaction Time. J. Wiley & Sons, Chichester (1988) pp 103-114 Gringras. M., G. Beaumont: The EfTectiveness of Repeated Nocturnal Doses of Clobazam and Dipotassium Clorazepate on C1inical Measures of Anxiety, Patient Ratings of Mood and Sieep and Objective Assessments of CNS Activity. In: Hindmarch, 1., P. D. Stonier, M. R. Trimble (eds.): Clobazam: Human Psychopharmacology and C1inical Applications. Royal Society of Medicine International Symposium Series. No. 74, Oxford University Press, Oxford( 1985)73 -79 Hanks, G. W: The efTect of amitriptyline and nomifensine on critical flicker fusion threshold in an elderly patient population. In: Linford-Rees, W., R. G. Priest (eds.): Nomifensine: A Pharmacological and Clinical Profile. Royal Society of Medicine International Congress and Symposium Series. No. 70, Oxford University Press, Oxford( 1984)95-97 Hill, A. J., I. Hindmarch, R. D. Walsh: Tolerability of Nocturnal Doses of Clobazam in Anxious Patients in General Practice. In Hindmarch, 1., Stonier, P. D. (eds.): Clobazam: Royal Society of Medicine International Congress and Symposium Series No. 43, AcademicPress,London(1981) 133-140 Hindmarch, I.: A 1,4-Benzodiazepine, Temazepam (K3917), its Effect on Some Psychological Parameters of Sleep and Behaviour. Arzneimittel-Forschung (Drug Research) 25 (11) (1975) 18361839 Hindmarch, I.: Some Aspects of the EfTects of Clobazam on Human Psychomotor Performance. British Journal of C1inical Pharmacology7,Suppl.l (1979)77-82 Hindmarch, I.: Psychomotor Function and Psychoactive Drugs. BritishJournalofClinical Pharmacology 10 (3)(1980) 189-209 Hindmarch, I.: Measuring the Effect of Psychoactive Drugs on Higher Brain Activity. In: Burrows, G., J. S. Werry (eds.): Advances in Human Psychopharmacology, Vol. 2, JAI Press, Connecticut (1981)99-127 Hindmarch, I.: Critical Flicker Fusion Frequency (CFFF): The Effects of Psychotropic Compounds. Pharmacopsychiatrica 15, Suppl.l (1982)44-48 Hindmarch, I.: Critical F1icker Fusion Thresholds as a Useful Measure of Circadian Rhythmicity. In: Marks, V., S. W. Parker (eds.): The Biological Clock - Current Approaches. Duphar, Southampton(1988a) 57 -61 Hindmarch, I.: Information Processing, Critical Flicker Fusion Threshold and Benzodiazepines: Results and Speculations. In: Hindmarch, 1., H. Ott (eds.): Benzodiazepine Receptor Ligands, Memory and Information Processing. Psychometric, Psychopharmacological and C1inical Issues. Psychopharmacology Series 6, Springer-Verlag, Heidelberg(l988b) 169-179 Hindmarch, I.: Cognitive and Behavioural Consequences of Antidepressants. In: Leonard, B. E., S. W. Parker (eds.): Risks/Benefits of Antidepressants - Current Approaches, Duphar, Southampton (l988c)18-24

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processing capacity. At one hour post administration there is a dose related efTect of alpidem on CFFf with 100 mg alpidem showing a significant disruptive activity. However, after this test time there are no significant placeboJalpidem difTerences to be seen, a1though the verum indicates that this psychometrie is still sensitive to drug efTects. The speed of stimulus recognition reaction time (RRT) (Fig. 2) is significantly increased by the verum for the five hours following administration. None of the doses of a1pidem produce any significant augmentation of RRT, a1though there is an evident increase at one hour post treatment with the highest dose (100 mg).

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128 Pharmacopsychiatry 23 (J 990)

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J. Hindmarch, M.D.

Human Psychopharmacology, Research Unit Department of Psycho10gy University ofLeeds Leeds, LS2 9JT England

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Hindmarch, I., C. A. Shillingford, J. Shillingford, A. Baksi, D. Graham, Ph. Guillel: The Pharmacodynamic EfTects of Alpidem in Elderly Subjects. Journal ofDrug Development I (2) (1988) 77 - 85 Hindmarch, I., Z Subhan: A preliminary Investigation of "Albert 285" (HWA 285) on Psychomotor Performance, Mood and Memory. Drug Development Research 5 (4) (1985) 379- 386 Hindmarch, I.. Z Subhan: The EfTects of Antidepressants taken with and without Alcohol on Information Processing, Psychomotor Performance and Car Handling Ability. In: O'Hanlon, J. F., J. F. de Gier (eds.): Drugs and Driving, Taylor and Francis, London (1986)231- 239 Hindmarch, I., J. P. Wallis: Measuring the efTects of Psychoactive Drugs. In: Wattis, J. P., I. Hindmarch (eds.): Psychologieal Assessment of the Elderly. Churchill Livingstone, Edinburgh (1988) 180-197 Hurwilz, N: Predisposing factors in adverse reactions to drugs. British MedicalJournal1 (1969)536-549 Khan, M. C, S. N Mahapalra, P. D. Slonier, E. M. Thomas: Nomifensine and Mianserin: Non-trieyclie Antidepressants with Distinct Clinical Profiles: A Randomised Double-blind Study. In: Linford-Rees, W., R. G. Priest (eds.): Nomifensine: A Pharmacological and Clinical Profile. Royal Society of Medieine International Congress and Symposium Series No. 70, Oxford University Press, Oxford(1984)71-76 Lader, M., V. Curran, D. Allen, A. Baylav: EfTects of single doses of alpidem on psychologieal functioning in normal subjects (Abstract). Acta Pharmacologiea et Toxieologiea 59 (1986) 118 Moir, D. C, I. Dingwall-Fordyce: Drug taking in the elderly at horne. Journal ofClinical and Experimental Gerontology 2 (1980) 329 Nicholson, A. N: EfTect of the Antihistamines, Brompheniramine Maleate and Triprolidine HydrocWoride, on performance in man. British Journal ofClinieal Pharmacology 11 (1979) 321 Nicholson, A. N: Studies of the efTects of 1,4 and I, benzodiazepines on sleep in man. In: Hindmarch, 1., P. d. Stonier (eds.): Clobozam: Royal Society of Medicine International Congress and Symposium Series No. 43, Academic Press, London (1981) 67-71 Nicholson, A. N, B. M. Slone: Hypnotic Activity and EfTects of Performance of Lormetazepam and Camazepam - Analogues of Temazepam. British Journal of Clinieal Pharmacology 13 (1982) 433-439 Nicholson, A. N, 1. Ward: Psychotropie Drugs and Performance. British Journal ofClinieal Pharmacology 18 (suppl. I) (1984) 2s Paes de Sousa, M., M.-L. Figuiera, F. Loureiro, I. Hindmarch: Lorazepam and Clobazam in Anxious Elderly Patients. In: Hindmarch, 1., P. D. Stonier (eds.): Clobazam: Royal Soeiety of Medieine International Congress and Symposium Series No. 43, AcademicPress, London(1981) 119-123 Pancheri, P., P. Pede, M. Donnini, A. Farolfi, V. Ascalone, P. Priore: Alpidem, a novel anxiolytic drug: a double-blind comparison versus Diazepam. New Trends in Experimental and C1inieal Psychiatry, YoI.Y-N, I( 1989)23-30 Parroll, A. c.: Critical F1icker Fusion Thresholds and their Relationship to Other measures of Alertness. Pharmacopsychiatrica 15 (I) (1982)39-44 Parroll, A. C, I. Hindmarch: The EfTects of Hydergine upon Psychomotor Performance, Indices of Alertness and Behavioural Ratings in Studies Involving Normal and Geriatrie Subjects. British Journal ofClinical Practice 16 (1982) 18 - 20 Ponciano, E., 1. Relvas, F. Mendes, A. Lameiras, A. Vaz Serra, I. Hindmarch: C1inieal EfTects and Sedative Activity of Bromazepam and Clobazam in the Treatment of Anxious Out-patients. In: Hindmarch, 1., P. D. Stonier (eds.): Clobazam: Royal Soeiety of International Congress and Symposium Series No. 43, Academic Press, London(l98 I) 125-131 Salelu, B., J. Grunberger, L. Linzmaler: Pharmacokinetic and dynamic studies with a new anxiolytic imidazopyridine a1pidem utilising pharmaco-EEG and psychometry. International C1inieal Psychopharmacology I (1986) 145-164 Seidl, L., G., G. F. ThornlOn, J. W. Smilh, L. E. ClifI Studies on the epidemiology of adverse drug reactions. Bull. John Hopkins Hospital 119(1966)299-315