Drug effects and initial severity of symptomatology

Summary A recurring question appearing in clinical psychopharmacological research concerns the nature of the relationship between initial severity of symptomatology and the magnitude of a drug effect. Data are presented to show that, with meprobamate and placebo in neurotic outpatients, the magnitude of the pharmacological effect remains constant across all levels of initial severity.These data were collected as part of an investigation supported by two special U.S.P.H.S. research grants to the University of Pennsylvania (MH-04731, Rickels) and to Johns Hopkins University (MH-04732, Uhlenhuth and Park); the over-all project was coordinated by the Psychopharmacology Service Center of N.I.M.H. (Fisher and Lipman). The three participating clinics were: Henry Phipps Psychiatric Clinic at Johns Hopkins, the Functional Clinic at the University of Pennsylvania, and the Neuropsychiatric Clinic at the Philadelphia General Hospital (Dr. John Mock was particularly helpful at PGH). Preparation of this report is in part supported additionally by MH-08954.     

The effects of amphetamines upon judgments and decisions

Summary D-amphetamine sulfate, dl-amphetamine sulfate, and placebo were orally administered to 93 college student volunteers who served as their own controls in a Latin Square design. Dosages were adjusted to the two-thirds power of body weight with the proportionality constant set for 14 mg/70 kg with each drug. Effects were measured upon performances in a mathematical reasoning test, upon self-appraisals of these performances, and in a task which attached monetary payments to the accuracy of self-appraisals (Decision Score). The objectives of this research were (1) to reassess the biases in performance self-appraisals reported by Smith and Beecher (1964), and (2) to determine whether these biases represent mere verbal expansiveness or whether they are reflected by changes in decision behavior. Smith and Beecher's effect upon self-appraisals was confirmed (at p<.02). Decision Score also was affected (at p<.01) in the predicted direction. Performance scores were not significantly affected.This research was supported by Grant No. MH-11294-01 from the National Institute of Mental Health. Dr. Nel Kopp of State College, Pennsylvania, was the Medical Supervisor. The authors wish to thank Dr. Herbert T. Glenn, Director of the Pennsylvania State University Health Center, and his staff for their generous cooperation in providing medical records for screening student volunteers. The drugs were donated by Smith, Kline and French Laboratories.     

Urinary excretion of epinephrine,norepinephrine, dopamine and tryptamine during sleep and wakefulness

Summary Twenty normal male Ss spent 6 h a night in the laboratory on 4 nights a week apart. In a balanced design, on two nights they received, p.o. and double blind, a dextroamphetamine sulfate spansule 15 mg and sodium pentobarbital 100 mg and on two others pentobarbital plus placebo. Fifteen of the Ss spent an additional two nights on which they received placebos. Continuous EEG and EOG recordings were taken on all nights. Overnight (6 h) and postsleep (1 h) urine collections taken from 17 Ss on drug nights and 13 Ss on placebo nights were analyzed for epinephrine, norepinephrine, dopamine and tryptamine.Results with placebo suggested that wakefulness produces the greatest amine and urine outputs, nonactivated sleep the least and activated sleep intermediate amounts. Epinephrine excretion was greater in the AM than overnight. The results were thought consistent with a hierarchical ordering of physiological activity where wakefulness > activated sleep > nonactivated sleep.After corrections were made for their effects on wakefulness, neither dextro-amphetamine sulfate nor pentobarbital appeared to have any effect on amine excretions during sleep.Significant correlations were found between amine excretions and urine volume both during sleep and wakefulness.This study was supported by grants from the United States Public Health Service, nos. MH-23,901, MH-10088, MH-07336, and MH-07219.Abbott Laboratories supplied the pentobarbital (Nembutal) placebos and Smith, Kline & French the dextroamphetamine sulfate (Dexedrine) placebos used in this study.Drs. Donald R. Goodenough and Donald McMillan made valuable comments during the preparation of this paper.     

Effects of chlordiazepoxide and secobarbital on film-induced anxiety

Summary Normal college students were given a single dose of chlordiazepoxide, secobarbital or placebo 85 min before being shown an anxiety-inducing film. Measures of sedation and of subjective anxiety were taken before and after the film. Results indicate that chlordiazepoxide and secobarbital had a measurable sedative action compared with placebo. Neither medication showed a significant anti-anxiety effect.This project was supported by NIMH grants MH-7753, MH-08954, a GRS grant to University Hospital, and by Roche Laboratories through Dr. Stanley Gould who also kindly supplied the chlordiazepoxide (Librium). The authors are pleased to acknowledge the assistance of Kim Atkinson, Susan Saaz, Betsy Janes, Andrew Strasfogel, George Fishman, and Mary Sheldon. Medical screening was done by Robert Rood, M.D. Films were borrowed from Audio-Visual Support Center, Mr. R. A. Cudworth, Director, First Army Base, Boston, and from the Boston Public Library.     

Psychiatric diagnosis and a typology of clinical drug effects

Summary Analyses of clinical drug effects have largely been derived from univariate rating scale or global improvement scale data. In general, global improvement scales have proved more sensitive and clinically useful than univariate scales. Another approach, presented here, is to use qualitative outcome categories to which patients are assigned on the basis of the configuration of multiple changes. Such a systematic qualitative outcome typology is presented as used in an experimental study of 309 non-chronic voluntary psychiatric patients who, regardless of symptomatology or diagnosis, were randomly assigned to placebo, imipramine or chlorpromazine-procyclidine, in a fixed dosage double-blind study.This outcome typology is compared with a global improvement scale and related to diagnosis. In general, the drug outcome categorization was equal or superior to the global improvement scale in detecting the differences between drugs and placebo. Furthermore, by utilizing the author's diagnostic schema, as well as the qualitative outcome typology, the prediction of specific drug induced qualitative outcomes by diagnosis was demonstrated. Max Fink, M.D. and Max Pollack, Ph.D. were Principal Investigators in the initial study. Aethur Willner, Ph.D. participated in the clinical evaluations. Mr. Sydney Feldman did the statistical analyses.Supported, in part, by grants MH 02715, MH 04798 and MH 08004 of the National Institute of Mental Health, U.S.P.H.S. The cooperation of Geigy Pharmaceuticals, Smith, Kline and French Laboratories and Burroughs Wellcome and Co. is gratefully acknowledged. The unfailing collaboration of the staff of Hillside Hospital made these studies possible.     

EEG profiles of fenfluramine,amobarbital and dextroamphetamine in normal volunteers

A quantitative EEG study in volunteer adults was undertaken to distinguish single oral administrations of 50 and 100 mg amobarbital, 10 mg dextroamphetamine, 40 mg fenfluramine and placebo. Four hour EEG recordings were monitored by frequent auditory reaction time tasks. The EEG changes were measured by digital computer period analysis.In the analysis, each drug was distinguished from placebo, and from each other, with the best discriminations for 50 mg amobarbital and dextroamphetamine, and the poorest discrimination of fenfluramine from 50 mg amobarbital.These observations are consistent with the clinical pharmacology of the compounds and suggest further applications of quantitative EEG for the classification of psychoactive drugs.Aided, in part, by USPHS grants MH-11358, 13003 and 13358; the Psychiatric Research Foundation of Missouri, Smith Kline and French Laboratories and A. H. Robins, Inc.This report summarizes data of a second quantitative EEG study undertaken in 1965–1966. Earlier progress reports dated April 1965 and May 1967 are available.The cooperation of Connie Hickman, B.S.E.E. and the nursing and technical staff of the Missouri Institute of Psychiatry are gratefully acknowledged.     

Differential effects of chlordiazepoxide and fluphenazine in two anxious patient populations

Summary Fluphenazine and chlordiazepoxide were evaluated for therapeutic effectiveness in a double-blind study carried out with anxious neurotic patients attending either a hospital clinic or a general practitioner's office.All patients had significantly lower psychopathology scores after treatment than before, the general practice sample improving significantly more than the hospital clinic sample. While there was no significant difference in the degree of improvement produced by each drug in the general practice sample, in the hospital clinic sample, chlordiazepoxide was significantly more effective than fluphenazine, but only when using the somatic symptom cluster of the Physician Questionnaire as improvement criterion.Differences in population characteristics, primarily in social class and its related variables, but also in treatment set were suggested as important non-specific factors, which, by interactions with specific drug effects, influenced significantly the results observed in the present study. This study thus confirms the 2 hypotheses stated earlier in the introduction.Research reported in this paper was supported by USPHS Grants MH-08957 and MH-08958 (Principal Investigator: Dr. Rickels). All medication was supplied by Dr. Michael Barry, White Laboratories, Inc. Permitil is the trade name for fluphenazine and Librium for chlordiazepoxide.     

The effects of methamphetamine and pentobarbital on the running memory span

Summary The effects of two drugs on the running memory span were tested in 18 young men who served as their own control under double blind conditions. Each of the three treatments-methamphetamine, pentobarbital, and saline placebo-was administered intravenously and repeated in a balanced design. Ss were tested on strings of digits, varying in length from 8 to 20 items, the first eight presented at the rate of one item per second, another eight at the rate of one every four sec. The instruction was to reproduce the last five items in the original order.Performance at the slower rate confirms the conclusion of an earlier experiment, conducted at the rate of one digit per two sec., i.e., that pentobarbital narrows and methamphetamine exerts no detectable effect on the running digit span. No significant drug effects were found at the fast rate of presentation.It is proposed that two components determine the running digit span; one involves shifts of attention as the input changes, the other its organization, rehearsal, and other strategies by which the information is stored and made available for recall. Pentobarbital, in the dose used and under the conditions of this study, impairs the latter and does not affect the former.This research was supported in part by a project grant (MH-03996) and research career grants MH 15418 (George A. Talland) and M-1608 (Gardner C. Quarton) from the U.S. Public Health Service.     

Effects of d-amphetamine on performance under a multiple schedule in the rat

Summary d-amphetamine in doses of 0.50, 1.0, 2.0, and 4.0 mg/kg, i.m., was administered to rats performing on a multiple schedule containing S (extinction), fixed-interval (FI) and fixed-ratio (FR) components. Both time course and dose-effect data are presented for each schedule component. High control rates of responding under FR were decreased as a function of dose. Intermediate FI rates were slightly increased at the lowest dose. Low rates under S increased as a function of dose. Under all schedule-components the control pattern of responding was disrupted by the drug. 2 mg/kg or more produced steady moderate rates characterized by alternating short bursts and pauses. This pattern appeared in all schedule-components, reducing or abolishing the differentation between schedule performances at the larger doses. Extended pauses, during which animals were observed to be hyperactive, also appeared in the first 1 to 2 hours after large doses. Related experimental findings are discussed, and the results are interpreted as supporting the hypothesis of an interaction between amphetamine dosage and control rate of responding.Supported by Grant MH-05863 from the National Institutes of Mental Health. We are indebted to Dr. Milton H. Anderson, Medical Superintendent, Evansville State Hospital, for his continuing support. Dr. Roger T. Kelleher and Dr. Robert K. Chalmers kindly read an earlier draft, but are not responsible for statements appearing here. d-amphetamine was supplied by Smith Kline & French Laboratories, Inc.     

The effects of some psychotropic drugs on conditioned avoidance and aggressive behaviors

Summary Chlorpromazine, chlordiazepoxide, meprobamate, and pentobarbital were evaluated for their ability to alter 3 behaviors: 1. unconditioned escape, 2. conditioned avoidance, and 3. isolation-induced aggression, in the same species of mouse. A comparison of the dose of each drug necessary to alter these behaviors revealed quantitative differences between the drugs by which chlorpromazine and chlordiazepoxide may be differentiated from each other as well as from pentobarbital and meprobamate.Supported by a research grant from the National Institute of Mental Health (MH-07397-02), U.S. Public Health Service.Portion of a thesis presented by Henry F. Cole in partial fulfillment of the requirements for the Master of Science Degree at The Ohio State University.Predoctoral Fellow 1964–65, National Institutes of Health, U.S. Public Health Service.     

Some effects of d-amphetamine on the behavior of pigeons under intermittent reinforcement

Summary The effects of d-amphetamine (0.25 to 8.0 mg/kg) were studied on key-pecking behavior under variable interval (high response rate) and DRL reinforcement (low response rate) in pigeons. Doses of 2.0 mg/kg and above progressively decreased VI responding, as was the case for DRL with doses 4.0 mg/kg and above. No consistent increases in response output on either reinforcement schedule were observed with any dose of the drug, even though prior studies have suggested that amphetamine ought to increase DRL behavior. When their behavior was reduced by d-amphetamine, DRL birds often earned many more grain reinforcements than usual, but frequently did not consume them. No effects of d-amphetamine were observed on a color discrimination tested in the VI birds.We acknowledge the advice of Dr. William B. Morse and Dr. Evalyn Segal, and the expert technical assistance of Peter Gorinsky. This research was performed at the Dept. Pharmacology, Royal College of Surgeons of England and was supported in part by a Public Health Service Special Fellowship (No. MH 25608) to the first author from the National Institute of Mental Health and by NIMH Grant-Number MH-06635 to the Royal College of Surgeons.     

Doxepin and diazepam in general practice and hospital clinic neurotic patients: A collaborative controlled study

Summary Doxepin and diazepam were evaluated for therapeutic effectiveness in a double blind study carried out with 69 primarily anxious neurotic outpatients attending either a municipal hospital clinic or a general practitioner's office.Doxepin produced more clinical improvement than diazepam in several questionnaire clusters measuring depressive symptomatology, but not in clusters measuring anxious symptomatology.According to several outcome criteria, doxepin tended to produce more clinical improvement in general practice than in clinic patients, while diazepam produced either equal improvement in both populations or slightly more improvement in the clinic.Possibly contributing to the present results are low daily dosage of diazepam, differential pharmacological drug effects, population differences in levels of anxiety and depression, and differences in population characteristics, primarily as related to social class.This work was supported by USPHS Grants MH-08957-8 and by Pfizer Laboratories, who provided all medications. The authors wish to thank Miss Reita Brandt and Mrs. Jane Eveland for carrying out the computer analyses, and Mr. Peter Hesbacher for coordinating the data collection phase.     

A research report on the anti-fatigue effects of magnesium pemoline

Summary The effects of magnesium pemoline were compared to those of caffeine and methylphenidate on the performance of a nonmotivated task which required continuous attention over a two hour testing period. The drug treatment consisted of: 25 or 50 mg magnesium pemoline, 100 or 200 mg caffeine, 15 mg methylphenidate or a placebo. Ten unhospitalized volunteers were each tested six times, once on each treatment. The significant increase in errors which occured under placebo conditions did not occur with 50 mg magnesium pemoline, or 200 mg caffeine or 15 mg methylphenidate. These results support the contention of others that magnesium pemoline acts as a nonspecific CNS stimulant.Part support by Grant from Abbott Laboratories and by USPHS, NIMH Grant MH 12568.NIH Career Award Program 5-K3-GM-1759.This work was performed at the Medfield Foundation, Medfield State Hospital, Medfield, Mass., under the medical supervision of Dr. Nizamettin Oktem and Dr. Harry Freeman, Director.     

Counterconditioning and extinction of fear fail to transfer from amobarbital to nondrug state

Summary Three dosages of amobarbital sodium all aided albino rats to resume a previously punished lever-pressing response. This finding was obtained in a test of counterconditioning and extinction of fear-motivated avoidance, with 108 animals divided into groups which were given placebo or one of three dosages of amobarbital (10, 20, or 30 mg/kg). In a subsequent test for transfer of counterconditioning and extinction to the nondrug state, with placebo given to all the animals, the superior performance under the drug failed to transfer to the nondrug state. On the contrary, there was the suggestion of an inverse relationship between performance in the test for transfer to the nondrug state and drug dosage during the prior test for effect of amobarbital. This experiment demonstrates that the stimulus-change decrement produced by a shift from the drugged to the nondrug state may prevent the therapeutic retraining under the drug from transferring to the nondrug state.Research grants from the National Institute of Mental Health, U.S. Public Health Service supported this research (MY 2949) and the preparation of the article (MH 07824). Some of the replications were tested by Phyllis Miller and by Roberta Pritzker. A brief report of part of the findings was included in Miller 1961 and 1964.     

The apparent failure of ethyl alcohol to inhibit the formation of conditioned eyeblink responses in man

Summary Prior experience with central depressants lead to the expectation that alcohol would inhibit eyeblink conditioning. A similar prediction could also be generated from Eysenck's drug postulate. In a study involving normal male subjects no differences were obtained between the conditioned eyeblink response behavior of placebo and alcohol treatment groups. Possible reasons for this finding are offered in terms of suggestion and the nature of the placebo group. Ways of examining these possibilities are considered.The writer is indebted to the United States Public Health Service, under whose Research Grant No. M 2720 a large part of this investigation was carried out, and to Leslie E. H. Lindahl, Mary Bigelow, Edward Holden and Judy Lindahl who assisted in various ways with the testing, recruitment of subjects and scoring of data. Trenton State Police Headquarters generously loaned us a Harger Drunkometer and provided training in its use.     

Pentobarbital and dextroamphetamine sulfate: Effects on the sleep cycle in man

Summary Twenty Ss received, double blind, either a 15-mg dextroamphetamine sulfate (DA) spansule and pentobarbital (PB) 100 mg p.o. before bed on two nights or PB and a placebo (PL) on two other nights, all a week apart, in a balanced design. Fifteen of the Ss received DA and PB placebos on two additional nights. EEG and EOG recordings were obtained over a six-hour observation period on all nights.DA + PB produced more body movements, spontaneous awakenings and stage-2 sleep and less delta sleep (stages 3 + 4) than did PB, while PB reduced time to sleep onset and produced less body movements and spontaneous awakenings than did PL. These findings were thought to indicate that DA decreases soundness and depth of sleep while PB increases them.A decrease in emergent stage-1 sleep (activated sleep, AS) over the six-hour observation period with DA + PB was made up for by a corresponding increase in wakefulness (stage 0), while a decrease both in AS and stage 0 with PB was compensated for by a corresponding increase in nonactivated sleep (NAS).Both DA + PB reduced per cent AS sleep time and first AS period (ASP) latencies, DA + PB more markedly than PB. DA appeared to produce this effect primarily by increasing first ASP latencies, while PB did so as well by shortening the first two ASPs.The tendency of PB to reduce rapid eye-movement (REM) density within ASPs (DA did not do so), to produce periods of emergent stage 1 without REMs, to shorten ASPs without changing the intervals between successive ASPs and to produce a maximum in the concentration of body movements in the 60–90 min interval after sleep onset suggested that it does not induce a basic alteration in the sleep cycle but rather suppresses certain manifestations of the first ASP (REMs and stage-1 sleep), while leaving others, such as body movements, unchanged to persist as a REM-period residue. Since DA was always administered with PB, it is not clear by what mechanisms the former delayed the appearance of first ASPs.This study was supported by grants from the National Institutes of Health, United States Public Health Service, nos. MH-23,901, MH-10088 and MH-7336.This paper is based in part on a thesis submitted to the Department of Psychiatry, Graduate Educational Program, State University of New York, Downstate Medical Center, Brooklyn, New York, in partial fulfillment of the requirements for the degree of Doctor of Medical Science.Drs. Donald R. Goodenough and Arthur Shapiro gave helpful advice in both the design of this experiment and the data analysis.Abbott Laboratories provided the pentobarbital (Nembutal) placebos, and Smith, Kline and French Laboratories furnished the dextroamphetamine sulfate (Dexedrine) placebos.     

Antagonism between physostigmine and atropine on the behavior of the pigeon

Summary The effects of physostigmine upon food-maintained operant behavior of the pigeon were investigated. Physostigmine completely suppressed responding for a period up to 180 minutes and small doses of atropine could antagonize this suppression. Neostigmine produced a similar suppression of behavior of shorter duration. Methylatropine, much less potent than atropine in antagonizing behavioral suppression by physostigmine, was more potent in antagonizing neostigmine. Nicotine produced a suppression of behavior similar to that produced by the two anticholinesterases, but neither methylatropine nor atropine antagonized this effect. These findings support the general supposition that suppression of behavior by physostigmine is in part mediated by muscarinic receptors in the central nervous system.With 5 Figures in the TextDedicated to Professor Otto Krayer on his 65th birthday.Thus study was supported by grants MH-02645, MH-02094 and 2M-7084 from the United States Public Health Service.     

Variation in effects of chlorpromazine in three strains of mice

Summary Mice of strains C3HeB/J, C57BL/6J and RF/J were trained in nondiscriminated avoidance (Sidman type). Experimental subject could terminate or defer shock by crossing between cage components. Controls received shock but could not control it. Chlorpromazine in doses up to 4 g/g body weight had no effect on the activity of controls. Avoidance activity, defined as the excess activity of experimentals, was reduced by the drug, particularly in C57BL. C3H avoided best at all drug levels. The poorest strain at low dosage was RF, at higher dosage, C57BL. The results suggest need for care in the choice of phenotypes in experimental pharmacogenetics.This investigation was supported in part by Public Health Service Grant MH-01775 from the National Institutes of Health.The author gratefully acknowledges the technical assistance of Jane Harris.     

The mechanism of fixation prevention and “Dissociation” learning with chlordiazepoxide

Summary This experiment investigated the possibility that chlordiazepoxide (CDP) has unique properties that account for state dependent learning, and prevention of conflict-induced behavior fixations.One group of rats were given a discrimination problem on a Lashley jumping stand, but on even days all responses were punished. Another group were treated the same way except than on even days all responses were rewarded. Each of these groups were subdivided, half of the Ss were given CDP on even days, the other half no drug. The results showed that punishment on even days for the response to be learned disrupted learning more than reward for responses that were to be avoided. CDP practically eliminated these disruptive effects and aided learning for the punishment group, but led to a slower rate of learning for the reward group. These findings confirmed the hypothesis that CDP attenuates the effects of negative incentives, and that this property accounts for the drug's cue value in discrimination learning and for its fixation prevention characteristics.This experiment was supported by Research Grant MH-01061, United States Public Health Service. Chlordiazepoxide was generously supplied by HoffmannLaRoche Inc., Nutley, New Jersey. The animals were run by Pieper Toyama and Nancy F. Feldman. The statistical analysis was done by Dennison Smith. Nancy F. Feldman also composed and drew the figures.     

Effects of d-amphetamine sulfate on time and brightness perception in human subjects

Summary This report describes the development of psychophysical fractionation techniques to assess the effects of drugs. Each of five subjects gave 1/2 estimates of several time and brightness standards, first without drugs, and then under the oral administrations of a placebo and damphetamine sulfate (15 mg) in randomized order.Time fractionations without drugs were, in general, accurate and reliable, especially for the shorter time standards. Placebo and damphetamine sulfate did not affect the accuracy of time estimations, but both tended to increase the variability of these estimations within standards, especially for the longer time standards. The brightness fractionations of the subjects with or without drugs, on the other hand, underestimated the standards generally. The reliability of these estimations did not appear to be related differentially to the magnitude of the brightness standards. Both placebo and d-amphetamine sulfate tended to produce increases in the estimates of the brightness standards, relative to control curves, without affecting the reliability of these estimates in any systematic way.The views expressed herein are those of the authors and do not necessarily reflect the opinion of Saint Elizabeths Hospital or The American Psychological Association.This study was supported in part by research grant, MY-1604, from the National Institute of Mental Health to the University of Maryland. We thank Dr. L. M. Dyke, Director of the Student Health Service, for his cooperation and Smith, Kline, and French Laboratories for supplying the drug and placebo.