Comparison of Sernyl With Other Drugs

7/31/2019 Comparison of Sernyl With Other Drugs

1/6

Comparison of Sernyl with Other DrugsSimulation of Schizophrenic Performance with Sernyl, LSD-25, and Amobarbital

(Amytal) Sodium; I. Attention, Motor Function, and Proprioception

GERALD ROSENBAUM, Ph.D.; BERTRAM D. COHEN, Ph.D.; ELLIOT D. LUBY, M.D.;

JACQUES S. GOTTLIEB, M.D., and DONALD YELEN, B.A., Detroit

Study of the pathological mechanismsimplicated in schizophrenia has recently beenaccelerated by the production of modelpsychoses through the use of Psychotomi-metic drugs. Our laboratories have previous-ly reported6 Psychotomimetic effects withSernyl, l-(l-phenylcyclohexyl) piperidinemonohydrochloride. This drug is one of aclass of new chemical compounds whichfunction as sensory blocking agents, withanesthetic and sedative properties. It wasfound to produce severe disturbances in bodyimage, affect, attention, and thinking whichclosely approximated the primary symptomsof schizophrenia. Depersonalization, feel-ings of isolation and estrangement, concrete-ness, hypnagogic states, and repetitive motorbehavior occurred in patients following intra-venous infusion of this drug.

The present studies were conducted in an

attempt to isolate the mechanism responsiblefor the effects of Sernyl and its relevanceto the psychopathology of schizophrenia. Anumber of psychological functions charac-

teristically associated with the primarypathology of schizophrenia were system-atically evaluated in schizophrenic patientsand in normal subjects receiving Sernyl andother drugs. This report presents compara-tive data on the relative effectiveness of

Sernyl, lysergic acid diethylamide (LSD-25),and amobarbital (Amytal) sodium in simu-lating attention and motor deficits character-

istically found in schizophrenia. Additionaldata are reported showing the effects ofschizophrenia and of these drugs onproprioception. It is hypothesized that block

ing of the proprioceptive inputs required fornormal behavioral integration may be thepathological mechanism mediating impairments found in schizophrenia and thoseproduced by Sernyl.

Method

Experimental Design.Ten chronic schizophrenicpatients with illnesses of at least three years' duration were compared with three groups of normal

subjects. Of these normal subjects, 10 later received Sernyl ; 10 received LSD-25, and 5 receivedamobarbital sodium. All subjects were tested ona battery which included measures of attention(reaction time), motor function (rotary pursuit),and proprioceptive acuity (weight discrimination).LSD-25 was used to permit comparison of Sernylwith a well-known psychotomimetic drug. Theamobarbital sodium group provided a control index for the sedative effects of Sernyl. All normalsubjects were pretested before drug administrationto provide a base line against which the drug ef

fects could be evaluated. Schizophrenic patientswere tested only without drugs. This design permitted comparisons of the relative effects of thethree drugs and the extent to which performanceunder each drug simulated schizophrenic performance.

Administration of Drugs.Sernyl was administered intravenously in a subanesthetic dose of0.1 mg. per kilogram in 150 cc. of 5% dextroseover a period of 12 minutes. One microgram ofLSD-25 in 50 cc. of water per kg. of body weightwas administered orally. An average dose of 500

mg. of amobarbital sodium and 15 mg. of amphetamine sulfate mixed in a 21 cc. solution wasadministered intravenously to the point of slurringof speech and lateral nystagmus. The test batterywas begun immediately following injection for theSernyl and amobarbital groups and three hours

Submitted for publication May 5, 1959.From the Lafayette Clinic and Wayne State

University College of Medicine.The authors wish to express their gratitude to

Parke, Davis & Company for supplying the Sernylused in this study and subsidizing the normal con-trols.

113/651

Downloaded From: http://archpsyc.jamanetwork.com/ on 06/05/2012


2/6

. . . ARCHIVES OF GENERAL PSYCHIATRY

following injection for the LSD-25 group, at theheight of the LSD-25 reaction." The dosages ofthe comparative drugs were based on an attemptto produce maximum sedative and psychotomimeticeffects without profound disturbance in consciousness.

Testing Procedure.The postdrug test batterywas administered to the normal subjects two tofour hours following the pretest battery. Theadministration of the predrug test battery requiredone hour, while the postdrug battery required oneto two hours. Schizophrenic subjects usually required one to two hours to complete the battery,which they received only once without drugs. Thecomplete battery contained a number of tests ofthinking functions and questionnaires designed toevaluate subjective reactions to the drugs. Thetotal battery included six psychological tests presented serially so that the weight-discriminationtest occurred fourth, the reaction-time test fifth,and the rotary-pursuit task sixth. In the postdrugtest sequence, these tests occurred 30, 60, and 75minutes after the onset of testing.

Measurement of Attention.A modification ofthe reaction-time technique previously employedby Huston and Senfl for measuring deficits inlevel and maintenance of attention in schizophreniawas used in the present study. The reaction-timeapparatus employed has been described elsewhere."

Subjects were required to release a telegraph keyat the sound of a buzzer following a 10-secondpreparatory interval. All subjects were given 20reaction-time trials. On the first 10 trials, subjectswere socially motivated by instructions to react asrapidly as possible, whereas the last 10 trials werebiologically motivated by a 50-volt shock to thereacting finger accompanying the buzzer signal toreact. Median reaction times obtained on the firstand last 10 trials served as measures of attentionunder the two conditions of motivation.

Measurement of Motor Function.A rotary-pursuit task was employed to evaluate motor performance. This task has previously been used toshow that schizophrenic patients perform belowthe level of manic-depressive and normal subjects,both in initial level of motor functioning and inimprovement with practice.6 The apparatus was aLafayette Instrument Co. Pursuit Rotor. The taskrequires the subject to keep a prod-stylus in contact with a small metallic target, set in a phonograph-type disk, revolving at 60 rpm. Score ona given trial is the total time on target during a20-second period, the trial being followed immediately by 20 seconds of rest. In order to assessseveral attributes of motor performance, the complete motor task consisted of 2 initial trials withthe nonpreferred hand; then 10 trials with thepreferred hand, interrupted by one min. of restbetween the 5th and the 6th trial, and, finally, 2

additional trials with the nonpreferred hand. Thisprocedure provided separate scores for total motorefficiency, motor learning, reminiscence effects, andbilateral transfer.

Measurement of Proprioception.A weight-discrimination procedure was employed to measureproprioceptive acuity. The procedure was a modification of the method of constant stimuli, in whichupper difference thresholds were obtained from a44 gm. standard weight. Subjects received eighttrials with each of four comparison weights of 52,50, 48, and 46 gm., respectively, in that order. Oneach trial, subjects were required to "heft" thestandard stimulus and comparison weight successively and to designate whether the first or thesecond weight was heavier. The order of presentation of the standard stimulus as the first or

second weight was randomized within each blockof eight trials. The time requirements of the totaltest battery precluded obtaining difference thresholds in more than one direction. The present procedure proved satisfactory for obtaining reasonablystable thresholds over a wide-enough range ofstimuli to reflect individual changes in proprioceptive acuity.

Results

Reaction Time (RT).The effects of

schizophrenia and the three drugs on attention are shown in the RT data, presented asFigure 1. The upper portion of the Figureshows the medians obtained from the fourgroups under ordinary social motivation toreact without shock. Inspection of theFigure and analysis of variance of thesedata indicate that the nonshock RT scoresof the schizophrenic group were significantlyslower (P


3/6

SERNYL, LSD-25, AMOBARBITAL SODIUM

the figure, the Serynl, LSD-25, andamobarbital groups differed significantly(.P


4/6


R 60

4 6 8 2 4 6

COMPARISON DIFFERENCE IN GRAMS

WITHOUT DRUG WITH DRUG

Fig. 3.Weight discrimination of schizophrenicand drug groups.

drop in performance from their predruglevel (P


5/6

SERNYL, LSD-25, AMOBARBITAL SODIUM

impairment in proprioception, pain, andtouch add further credence to this hypothesis. It has also been suggested in a previouspaper6 that the body-image disturbance

typically found with schizophrenia andSernyl may be a direct reflection of disturbances in proprioception.

While these data suggest that the proprioceptive deficit produced by Sernyl may alsobe present in schizophrenia, the nature ofthe performance deficits obtained is alsoconsonant with a social-learning theory ofschizophrenia. In a previous study, Rosen-baum, Mackavey, and Grisell10 have shown

that schizophrenic disturbances in attentionon a reaction-time task performed undersocial motivation can be eliminated by thearousal of biological-pain motivation. Similarly, Cohen2 and Huston and Shakow5have shown that defective motor learning inthe chronic schizophrenic patient may beattributable to poor social cooperation andinsufficient drive arousal. The present results confirm these previous findings on the

nature of the performance deficit in schizophrenia, but indicate further that Sernylproduces an almost identical deficit in theseperformance functions.If schizophrenia is conceptualized as the

end-product of a long-term process of socialdisarticulation, as suggested in the theoriesof Cameron 1 and Sullivan,12 how could adrug like Sernyl have produced immediateeffects closely simulating the primary pa

thology of this illness? Our findings onthe effects of Sernyl suggest that it tends toblock and disorganize the basic proprioceptive mechanism through which social meanings and motives are normally integrated.This formulation means, in effect, that theacquisition of social motives ordinarily requires the development of habitual acts andthoughts which elicit response-produced proprioceptive stimuli, serving, in turn, to

energize and direct appropriate social behavior. These stimuli, arising from the feedback of motor, linguistic, and perceptualreactions, presumably serve as the locus ofsocially shared meanings and provide the

motivation for effective interpersonal communication.* Disturbances in this systemof socially acquired meanings and motivescould then result either (a) from inadequate

social reinforcement of these mediating reactions in the social development of theschizophrenic or (b) from the direct actionof Sernyl on the proprioceptive mechanism.

An alternative formulation of the processof social disarticulation in the schizophrenicpatient would assume that the proprioceptivedeficit represents a primary biological defect,constitutionally or genetically based. Disturbance in the acquisition of social motives

and meanings would then arise from physiologically determined distortions in theproprioceptive system.

The assumption that reduced proprioceptive stimulation results in the performancedeficits found in schizophrenia suggests theadditional possibility that increases in proprioceptive stimulation could reverse theseeffects. Techniques for directly modifyingthe amount and type of proprioceptive stimu

lation and its effects on performance andmeaning in schizophrenic patients are currently being developed.

SummaryThe performance of a group of chronic

schizophrenic patients on attention (reactiontime), motor function (rotary pursuit), andproprioception (weight discrimination) wascompared with the corresponding functionsof groups of normal subjects receivingSernyl, lysergic acid diethylamide (LSD-25),and amobarbital (Amytal) respectively.Sernyl was the only one of the three drugswhich produced disturbances in these functions approaching the deficit level shown bythe schizophrenics. It is concluded thatSernyl results in schizophrenic-like impairments of primary attention and motor functions, whereas LSD-25 simulates only thesecondary symptoms of schizophrenia. Thedata are interpreted as evidence for the

*This notion is further elaborated in personalitytheory by Dollard and Miller3 and in the analysisof language and meaning by Osgood.7

Rosenbaum et al. 117/655



6/6


hypothesis that disturbances in proprioception may be the pathological mechanismmediating impairments in performance andmotivation found in schizophrenia and produced by Sernyl.

Lafayette Clinic, 951 E. Lafayette St. (Dr. Gottlieb).

REFERENCES

1. Cameron, N.: : The Functional Psychoses, inPersonality and the Behavior Disorders, edited byJ. McV. Hunt, New York, The Ronald PressCompany, 1944, pp. 861-921.

2. Cohen, B. D. : Motivation and Performancein Schizophrenia, J. Abnorm. & Social Psychol.

52:186-190, 1956.3. Dollard, J., and Miller, N. E. : Personalityand Psychotherapy : An Analysis in Terms ofLearning, Thinking, and Culture, New York,McGraw-Hill Book Company, 1950.

4. Huston, P. E., and Senf, R. : Psychopathologyof Schizophrenia and Depression: I. Effect ofAmytal and Amphetamine Sulfate on Level andMaintenance of Attention, Am. J. Psychiat. 109:131-138, 1952.

5. Huston, P. E., and Shakow, D.: : Learning inSchizophrenia : I. Pursuit Learning, J. Personality17:52-74, 1948.

6. Luby, E. D.; ; Cohen, B. D.; ; Rosenbaum, G.; ;Gottlieb, J. S., and Kelley, R.: : Study of a NewSchizophrenomimetic

Drug\p=m-\Sernyl,Sernyl,A.M.A. Arch.

Neurol. & Psychiat. 81:363-369, 1959.7. Osgood, C. E.: : The Nature and Measurement

of Meaning, Psychol. Bull. 49:197-237, 1952.8. Rodin, E. A.; Luby, E. D., and Meyer, J. S.:

Electroencephalographic Findings Associated withSernyl Infusion, Electroencephalog. & Clin. Neuro-physiol., to be published.

9. Rosenbaum, G.; Grisell, J. L., and Mackavey,W. R.: The Relationship of Age and PrivilegeStatus to Reaction Time Indices of SchizophrenicMotivation, J. Abnorm. & Social Psychol. 55 :202-207, 1957.

10. Rosenbaum, G.; Mackavey, W. R., andGrisell, J. L.: Effects of Biological and SocialMotivation on Schizophrenic Reaction Time, J.Abnorm. & Social Psychol. 54:364-368, 1957.

11. Salvatore, S., and Hyde, R. W.: Progressionof Effects of Lysergic Acid Diethylamide (LSD),A.M.A. Arch. Neurol. & Psychiat. 76:50-59, 1956.

12. Sullivan, H. S.: Conceptions of ModernPsychiatry, Washington, D.c., William AlansonWhite Psychiatric Foundation, 1947.

118/656


Comparison of Sernyl With Other Drugs

Documents

Transcript of Comparison of Sernyl With Other Drugs