Effects of chlorpromazine,secobarbital and sleep deprivation on attention in monkeys

Summary In order to develop a method for studying sustained attention in the monkey, animals were trained to perform a rapid, serially-presented visual discrimination task. Two versions of the task were developed, one dependent upon shock avoidance, the other on water reward. The effects of varying doses of chlorpromazine (0.075 to 0.6 mg/kg) and of secobarbital (5 to 25 mg/kg) were studied; the shock avoidance task was also used to measure the effects of continuous work-sleep deprivation for periods up to 48 hours.The results suggest that the task is a useful and reliable measure of attentive behavior and that there are similarities between the monkey attention task and the procedures designed to study attention in man; chlorpromazine produces more impairment in performance than secobarbital; impairment is manifest chiefly in increased errors of omission; chlorpromazine and sleep deprivation seem to share certain common effects which distinguish them from secobarbital. No marked differences in drug effects were found between the water and shock versions of the task. The relation between these findings and those obtained in human subjects was discussed.Supported by grants from the Foundations Fund for Research in Psychiatry (61–241) the National Science Foundation (G-21382) and the National Institute of Mental Health (MH-10324). Thanks are due to Mrs. Diane D. Arenella and Mrs. Ellen B. Stechler for their efficient and devoted technical assistance.Career Development Awardee, Level II of the National Institute of Mental Health K3-MH-14,915.     

The psychomotor effects of carbamazepine in epileptic patients and healthy volunteers

The effect of straight release carbamazepine monotherapy was studied in 12 well-controlled epileptic patients using adaptive tracking, smooth pursuit and saccadic eye movements, body sway, Digit Symbol Substitution Test (DSST) and Visual Analogue Scales. Patients were matched to healthy controls for age and gender. After patients had received their usual morning dose of carbamazepine, patient-control pairs were studied for 7 h. Compared to controls, the average DSST scores of patients were significant lower. No relationships were shown between DSST performance and plasma concentrations of carbamazepine and carbamazepine-epoxide. No significant differences were found for any of the other effect parameters. Variations in plasma concentrations were limited, contributing to the absence of systematic fluctuations in test results. Of the used tests, DSST is most clearly related to cognitive function. It is concluded that the difference in DSST performance appears to reflect a long-term small neurocognitive difference between subjects with and without epilepsy.     

Psychometric performance during withdrawal from long-term benzodiazepine treatment

Twenty-two patients were withdrawn from normal-dose, long-term benzodiazepine treatment and their data compared with those of two control groups. Patients and controls were assessed repeatedly on the Digit Symbol Substitution Test (DSST), Symbol Copying Test (SCT), Cancellation Task (CT), Auditory Reaction Time (RT) and Key Tapping Rate (KTR). A substantial and prolonged practice effect was found on all the tests except RT and KTR. Prior to withdrawal the patients did not show the performance decrement on the CT, RT and KTR customarily associated with the initial phases of benzodiazepine therapy. A rebound performance increment was observed on KTR during the withdrawal. Patients demonstrated impaired performance on tasks requiring the combined use of sensory and fine motor skills.     

Effects of psychotropic drugs on digit substitution: comparison of the computerized symbol-digit substitution and traditional digit-symbol substitution tests

The digit-symbol substitution test (DSST), performed with paper and pencil or computerized, is widely used to reveal decrements in human attention and cognition. We programmed sets of adjustable tasks (digit-symbol, digit-digit, symbol-digit, symbol-symbol) into a microcomputer and compared the symbol-digit substitution (SDST) and the digit copying test (DDCT) with the traditional DSST in two placebo-controlled double-blind studies of psychotropic drugs with pre-trained young healthy subjects. Performances were measured before drug intake and several times after it; matched, different codes were used at consecutive tests. DSST and SDST substitutions remained at the baseline level after placebo, while the simple DDCT performance improved during the placebo session. The prolonged (3 min) test was not exhaustive because interim counts at 90 s predicted the final performance well. In Trial I, 15 mg diazepam orally reduced DSST and SDST functions in a similar way, but it also impaired simple copying in the DDCT, though to a lesser extent. Ebastine, an H(1)-antihistamine, proved inert alone and failed to increase the effects of diazepam on these variables. In Trial II, 7.5 mg zopiclone, 0.4 mg suriclone and 50 mg chlorpromazine, alone and in combinations, impaired the DSST performance in the manner expected. The drug effects were similar in the SDST, and somewhat less in the DDCT, while the substitution errors were subject related and not altered significantly by any treatment. The simple correlation matrices (Pearson, Spearman), confirmed by analysis of covariance, showed that the results of DSST correlated fairly well with those of SDST after zopiclone, chlorpromazine and their combination, but not after suriclone or its combination with chlorpromazine. The DDCT results correlated with those of the substitution tests when analysing pooled baseline values, but not when analysing the performances after drug intake. Subjective visual analogue variables correlated poorly or not at all with objective performances. Our results suggest that manual dexterity in these computerized tests might contribute significantly to the total impairment of performance in response to different drugs. The DSST and SDST matched each other fairly well in their sensitivity to drug effects, yet this similarity may depend on the drug used.     

The effects of chlorpromazine and secobarbital on the reaction times of chronic schizophrenics

Summary Twelve male schizophrenics were given a simple visual reaction time test (RT) after single doses and chronic (11 days) administration of chlorpromazine and secobarbital. RT was tested under two conditions: irregular, in which preparatory intervals were presented randomly, and regular, in which the same preparatory intervals were given in consecutive order. Results under single doses indicated that secobarbital reduced intra-individual variability, while chlorpromazine did not significantly affect performance. Results under chronic administration indicated that neither drug had a significant effect on RT performance. These findings are different from those obtained by other investigators who have observed facilitation in schizophrenic psychomotor performance after chlorpromazine, and deficit in performance after barbiturates.This study is a revision of part of a dissertation submitted in partial fulfillment of the requirements for the degree Master of Arts, from the Catholic University of America, August 1957, by the senior author. Thanks are due Dr. John W, Stafford, who served as thesis advisor.This study was part of an N.I.M.H. research project run at St. Elizabeths Hospital, Washington, D.C., under the direction of the junior author, and reported elsewhere (Kornetsky, Pettit, Wynne, and Evarts 1959).This paper was presented in part at the 1958 meetings of the American Psychological Association.     

The effects of daily administration of carphenazine on attention in the schizophrenic patient

Summary Chronic schizophrenic patients on daily administrations of carphenazine were clinically rated by two separate methods and measured by two types of performance tests. One was an attention test (CPT) and one a cognitive or associative test (DSST). Before medication the subjects performed poorly on the attention test but showed significant improvement during the course of medication. They showed no similar improvement on the cognitive test. Clinical improvement was also manifested and this correlated positively with improvement on the attention test. No such significant correlation existed between the DSST scores and the clinical ratings.The results of the study were discussed in light of the hypothesis that schizophrenic patients are hyperaroused. The fact that patients showed improvement on the CPT and not the DSST gave further evidence to support the hypothesis that phenothiazines have an effect on the selective areas of the brain and that these areas may be inherently related to the underlying factors in schizophrenia.This work was supported in part by USPHS, NIMH Grant MHO3312.The medication carphenazine was supplied by The Wyeth Company.NIH Career Development Awardee 2K3-GM-1759.     

Effect of diazepam and chlorpromazine on memory functions in man

Summary The effect of a single oral dose of diazepam 10 mg or chlorpromazine 25 mg on memory in man was examined in a double-blind study, each drug being crossed-over against placebo, with 20 subjects for each drug. Kahn's Test for Symbol Arrangement and a paired association-learning task were used for assessment of acquisition, storage and retrieval, and state-dependency effects. A flicker-fusion test, two coordination tests, and a choice reaction task were used to evaluate alertness in the subjects. Diazepam significantly impaired acquisition, but slightly facilitated recall. Reaction time was shortened after acute diazepam treatment and coordination was impaired after two weeks treatment with diazepam. Acute treatment with chlorpromazine did not change memory or psychomotor performance.     

Changes in psychic and somatic well-being and cognitive capabilities of peri- and postmenopausal women after the use of a hormone replacement drug containing estradiol valerate and levonorgestrel

A multicenter, prospective, open-label postmarketing surveillance study examined to what extent 2-month oral hormone replacement therapy (estradiol valerate and levonorgestrel; Klimonorm) could produce changes in psychosomatic well-being, self esteem and cognitive capabilities in 78 peri- and postmenopausal women. The women included were 42-58 years of age and had approached the physician due to climacteric symptoms. The following tests were used: Kupperman index, Menopause Rating Scale (MRS II), General Depression Scale (ADS), Zerssen's Symptom List (B-L), Frankfurt Self-Concept Scales (FSAL, FSAP, FSEG, FSSW), Digit Symbol Substitution Test (DSST), d2 Test of Attention and Number Square Test. The results showed a clear improvement in subjective psychosomatic well-being and improvements to a lesser extent in the concentration and cognitive capabilities in women in the third treatment cycle.     

Acute effects of kava, alone or in combination with alcohol, on subjective measures of impairment and intoxication and on cognitive performance

Kava (Piper methysticum) and alcohol were administered either separately or in combination to human subjects. Self-reports of their levels of impairment and intoxication were collected, and performance skills on a number of cognitive and visuomotor tests were determined, before and three times after consumption of the experimental drink. Kava alone had no effect on reported condition. In contrast, alcohol produced marked changes in each of the five subjective measures, all of which were in the direction of lowered ability. The combination of these two substances produced even larger negative changes on these measures. In the cognitive tests, kava produced a decrement in performance on Digit Symbol Coding. Alcohol produced a significant decrease in performance on a divided attention test, which was almost entirely on the peripheral, discontinuous component of the test. The combination of kava and alcohol produced an even greater decrease in performance on this test, and in the same component. The present findings suggest that kava alone has little effect on reported condition and cognitive performance, but appears to potentiate both perceived and measured impairment when combined with alcohol.     

On the dissimilar effects of drugs on the digit symbol substitution and continuous performance tests

Summary A tentative hypothesis is presented to account for the dissociation of the effects of various centrally-acting drugs and other agents on performance of the Continuous Performance Test (C.P.T.) and the Digit Symbol Substitution Test (D.S.S.T.): L.S.D., secobarbital, pentobarbital meprobamate and phenobarbital produced significantly greater impairment of the D.S.S.T. than of the C.P.T., while chlorpromazine, sleep deprivation and centrencephalic epilepsy had the reverse effect. Psychological, neurophysiological, electroencephalographic and neuropharmacological data were cited which suggested that the tests were affected differently because they are dependent upon the functioning of somewhat different neural organizations which are, in turn, differentially sensitive to the action of various centrally-active agents.The studies referred to in this paper involving the Digit Symbol Substitution and Continuous Performance Tests were conducted in the Laboratory of Clinical Science, and in the Section on Neuropsychology, Laboratory of Psychology, National Institute of Mental Health, and in the Surgical Neurology Branch of the National Institute of Neurological Diseases and Blindness. The authors wish to express their appreciation to the numerous members of the staff of these laboratories who provided advice, assistance and facilities for these studies. Part of the costs of preparing this work for publication were borne by grant M-6015 from the National Science Foundation, grants GMK3-1759 and K3-14 915 from the National Institute of Mental Health and grant 61-241 from the Foundations Fund for Research in Psychiatry.     

Effects of d-amphetamine on the performance of rats in an animal analogue of the A-X continuous performance test

Schizophrenia patients subjected to the A-X Continuous Performance Test (A-X CPT) show cognitive deficits that are thought to reflect impaired representation and maintenance of context information. An issue deserving attention is to what extent the acute amphetamine model of schizophrenia also models these cognitive deficits. The present experiment examined the effect of acute d-amphetamine (AMP) on the performance of rats in an animal analogue of the A-X CPT. Subjects first learned to solve an A --> X+, B --> X-, A --> Y- discrimination task, with A and B representing visual features; X and Y designating auditory target stimuli; --> signifying a serial presentation; and + and - referring to food reinforcement and non-reinforcement, respectively. Frequency of food-magazine visits was the dependent measure. After mastering the discrimination, rats received test trials under either saline or 0.5 mg/kg AMP (s.c.). At test, the interval between feature and target presentation was varied; reinforcement contingencies were maintained. AMP significantly impaired performance on the A --> X+/B --> X- discrimination by increasing the response level on B --> X- trials. AMP did not significantly affect performance on the A --> X+/A --> Y- discrimination. However, AMP also increased magazine responding in the absence of the presentation of features and targets. A parsimonious conclusion based on these preliminary results is that acute AMP does not affect processing of context information provided by the visual features in this procedure. It rather has a more non-specific response-enhancing effect, especially with respect to stimuli associated with the delivery of food.     

Cognitive function during insulin-induced hypoglycemia in humans: Short-term cerebral adaptation does not occur

It has been suggested that cerebral adaptation may occur in response to short-term hypoglycemia. This was examined in the present study by measuring serial changes in cognitive function and symptoms after 60 min of continuous hypoglycemia. Hypoglycemia was induced with a hyperinsulinemic glucose clamp on two separate occasions in 24 non-diabetic human subjects. Cognitive function was assessed using the following cognitive test battery: Paced Auditory Serial Addition Test (PASAT), Rapid Visual Information Processing (RVIP), Trail-Making B (TMB), Digit Symbol Substitution Test (DSST) and Four Choice Reaction Time (CRT). In condition A the blood glucose was maintained at 4.5 mmol/l throughout. On two separate occasions (condition B and condition C) the blood glucose was stabilised at 4.5 mmol/l for 30 min, lowered to 2.5 mmol/l for 60 min and restored to 4.5 mmol/l for 30 min. In each condition the cognitive test battery was performed immediately after stabilisation of blood glucose at 4.5 mmol/l and the subsequent battery was repeated at different time intervals: condition A — after a further 40 min of euglycemia; condition B — after 5 min of hypoglycemia; condition C — after 40 min of hypoglycemia. Acute hypoglycemia induced a significant deterioration in cognitive function which was manifest in all tests except TMB (P<0.05), but performance ability did not differ between conditions B and C. Symptom scores, assessed by a scaled questionnaire, increased significantly during hypoglycemia (P<0.001) but no differences were detected between the scores at 30 min and 60 min. In non-diabetic humans, no improvement appears to occur either in cognitive function or in symptom score after 40–60 min of hypoglycemia (2.5 mmol/l), suggesting that cerebral adaptation does not occur during this period of time.     

Comparison of the spectrum of cognitive effects of alprazolam and adinazolam after single doses in healthy subjects

Single doses of alprazolam (0, 0.5, 1.5 mg) or adinazolam mesylate sustained release tablets (SR) (0, 15, 45 mg) were administered to separate groups of 12 healthy men in a crossover design. Psychomotor performance was assessed by digit symbol substitution (DSST), and memory was assessed using a test battery which reflects various aspects of memory, including attention/working memory, explicit memory (recall of categorically related words), semantic memory (fragmented picture recognition, generation of category exemplars), and implicit memory (time saved in resolving fragmented pictures on the second exposure). Maximal psychomotor performance and memory decrements for the highest active doses were significantly different from placebo for all tasks at some time after dosing. The maximum decrement in DSST was not significantly different between drugs at the high dose (P=0.288). Maximum attention/working memory decrements were significantly different between the high doses of the active compounds (P=0.031), and the difference in maximum category recall decrement was marginally significant (P=0.067). Access to knowledge memory was not significantly altered by these drugs; these results are similar to those obtained for other benzodiazepines. Both drugs exhibited slight effects on implicit memory. The results suggest that the sedative and memory effects of these triazolobenzodiazepines may not be closely related and suggest that adinazolam has a somewhat different spectrum of cognitive effects relative to alprazolam.     

The effects of chlorpromazine and secobarbital on matching from sample and discrimination tasks in monkeys

Summary Monkeys were trained in the performance of a matching from sample task and in two simultaneous visual discrimination tasks differing in level of difficulty. In the case of the matching task, four doses each of chlorpromazine and of secobarbital were administered to the animals according to a balanced design. The procedure was then replicated. The results of the matching task indicated that chlorpromazine produced many errors of omission and few errors of commission. The latter kind of error as well as other measures of confused responding were seen primarily with secobarbital. In the case of the visual discriminations, secobarbital produced greater impairment of the more difficult (pattern) task than of the simpler (color) task; chlorpromazine had equivalent effects on the two tasks. The similarity between the secobarbital action and the behavioral consequences of certain cortical lesions in the monkey was discussed.This work was supported by the following grants from the National Institute of Mental Health, Public Health Service: Research Grant MH-12568; Special Fellowship 1-F3-25,128 (Dr. Bakay Pragay); Research Scientist Award 5-KO-5MH-14,915 (Dr. Mirsky); Predoctoral Fellowship 1-F2-NB-32-103 (Dr. Abplanalp).     

Ecological relevance of memory tests and the prediction of relapse in alcoholics

In an inpatient alcoholism rehabilitation program, 56 men were administered two 10-min memory tests: the Product Recall Test (PRT), designed to assess memory for familiar stimuli (assumed to be relatively high in ecological relevance), and the Memory-for-Designs Test (MFD), a test of memory for novel patterns of stimuli (assumed to be relatively low in ecological relevance). Approximately 74% of subjects who recalled less than or equal to half the items of the PRT relapsed at 3 months compared to only 33% of the subjects who recalled more than half the items. Performance on the MFD was not related to relapse rate. PRT performance was almost as predictive of relapse at 3 months as aftercare attendance, and combining both of these variables further improved predictability. The results suggest that the familiarity of the stimuli employed in memory tests may be important in tapping cognitive deficits of alcoholics that place these subjects at increased risk for relapse. The implication of these findings for the time-effective identification of early relapsers from alcoholism treatment programs are discussed.     

Effects of chlordiazepoxide on the acquisition of avoidance learning and its transfer to the normal state and other drug conditions

Summary Rats trained after injection of chlordiazepoxide (CDP), 15 mg/kg, acquired the conditioned avoidance response significantly faster than saline controls. When tested in the undrugged state, CDP trained animals showed virtually no retention of the learned response. Conversely, normally trained rats showed a significant decrement in performance with CDP, whether or not they had received a series of CDP injections following the period of training. CDP trained animals performed much worse than controls on tests with chlorpromazine and amphetamine, despite continued perfect performance on intercurrent CDP tests. Both the rapid learning and the dissociation of learning are discussed with reference to the diminution by drug of the spectrum of behavioral responses to novel stimuli, as well as the elimination of the electrical response of hippocampus which normally accompanies these responses to novelty.Librium.This research was supported in part by funds made available by the National Institute of Mental Health under grants MY-2811 and MH-08519. awarded to Dr. E. R. John.     

阿立哌唑与氯丙嗪对慢性精神分裂症认知功能的影响

目的比较阿立哌唑与氯丙嗪对慢性精神分裂症认知功能的影响。方法入组60例慢性精神分裂症患者,其中随机分成阿立哌唑组和氯丙嗪各30例治疗12周,采用韦氏成人智力量表（WAIS—RC）,韦氏记忆量表（WMS）,威斯康星卡片分类测验（WCST）及持续操作测验（Crq9在治疗前及治疗12周后进行认知功能测定。结果治疗12周后阿立哌唑组WAIS、WCST、WMS、CPT中绝大多数指标评分均较治疗前有显著改善（P〈0．05或P〈0．01）,而氯丙嗪组各项认知功能评分元显著改善（P〉0．05）。两组治疗后的比较除WCST中正确反应数、WMS中背数、CPT中正确数及反应时间外,其余各项认知功能指标中阿立哌唑组均较氯丙嗪组有显著改善（P〈0．05）。结论阿立哌唑对慢性精神分裂患者认知功能障碍有良好的改善,更有利于患者整体康复,值得临床推广。     

Zolpidem and triazolam do not affect the nocturnal sleep-induced memory improvement

Rationale It is widely accepted that sleep facilitates memory consolidation. Hypnotics (e.g., benzodiazepines), which reportedly increase sleep efficiency but also modify sleep architecture, could affect memory improvement that occurs during sleep. Objectives The present study examined the effects of single doses of two short half-life hypnotics, zolpidem and triazolam, on sleep-induced improvement of memory. Methods Twenty-two healthy volunteers participated in this randomized, double-blind, crossover study. All subjects received a single oral dose of zolpidem (10 mg), triazolam (0.25 mg) or placebo at 9 p.m. and slept for 7.5±0.2 h. The effect of sleep on memory was investigated by comparing the performance of this group of volunteers with a group of 21 subjects in wakefulness condition. Declarative memory was evaluated by using a free-recall test of ten standard word and seven nonword lists. Subjects memorized the word and nonword lists 1 h before dosing and they were asked to recall the memorized lists 10 h after dosing. Digit symbol substitution test (DSST) and forward and backward digit tests were also given 1 h before and 10 h after dosing. Results Subjects who slept remembered more nonwords than those in wakefulness condition, but they did not recall significantly more standard words. Neither zolpidem nor triazolam affected the enhanced nonword recall observed after sleep. Finally, none of the hypnotics affected the improvement in the DSST performance of subjects who slept. Conclusions The hypnotics tested did not interfere with the nocturnal sleep-induced improvement of memory.     

Subjective effects of caffeine among introverts and extraverts in the morning and evening.

In previous studies of psychomotor performance, the stimulant effects of caffeine differed by personality characteristics. For example, caffeine improved the task performance of extraverts but overaroused introverts and thus impaired their performance. The present study compared the effects of caffeine on subjective arousal among introverts and extraverts. Seventeen introverts and 19 extraverts drank coffee that contained doses of 0, 2, and 4 mg/kg caffeine during morning and evening sessions in a within-subjects, randomized, double-blind, crossover design. At 30-min intervals for 180 min after drinking, participants completed the Profile of Mood States, a battery of self-report visual analog scales, and the Digit Symbol Substitution Test (DSST). Caffeine effects on mood and task performance did not significantly interact with extraversion, except for nonsignificant trends for caffeine to increase happiness and vigor more among extraverts than introverts. No 3-way interactions of group, time, and dose were found on any scales or on the DSST. Results do not support the hypothesis that caffeine differentially affects extraverts and introverts, particularly at different times of the day.     

Effects of single and multiple doses of a new reversible MAO-A inhibitor,befloxatone, on psychomotor performance and memory in healthy subjects

The effects on memory, psychomotor performance and mood of two dosage regimens of befloxatone, a new reversible and selective MAO-A inhibitor were assessed in a randomized, double-blind, cross-over, placebo-controlled study involving 12 healthy young male volunteers. Befloxatone and a placebo were orally administered as single (5 and 10 mg) and repeated doses (10 mg once daily and 5 mg twice daily) at one week wash-out intervals. Objective tests evaluated both memory (working memory, immediate and delayed free recall of a word list, dual coding and faces recognition) and vigilance continuous performance task (CPT), and digit symbol substitution (DSST). Subjective mood and sleep were assessed using visual analogue scales and the Leeds Sleep Evaluation Questionnaire. Statistical analysis was conducted using an ANOVA with pairwise comparisons using the Student Newman Keuls procedure. Both dosage regimens of befloxatone (10 mg once daily or 5 mg twice daily) were free of any detrimental effect on vigilance (CPT) and information processing (DSST) and did not significantly disrupt short- and long-term memory (working memory, free recall of words, dual coding and faces recognition). In addition, no subjective sedation or sleep disturbances were recorded. In conclusion, this study gives no evidence to suggest that befloxatone, at a daily dose which shows potent MAO-A inhibition, has any sedative or amnestic properties likely to interfere with the activities of everyday-life in young subjects and therefore may be safely administered in depressed outpatients.