86 VLADIMIR PISHKIN

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Tofranil, a new anti-depressant. Schweiz. med. Wchnschr., 1958,88,763. (Abstract) 6.

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KIELHOLZ, P. and BATTEGAY, R. The treatment of depressive states with special reference to

The treatment of deDressive states with G-22355 (Imipramine Hydrochloride). Amer. J.'Psychiat., 1958 116, 459.

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POLLACK, B. Clinical findings in the use of Tofranil in depressive and other psychiatric states. Amer. J . Psychiat., 1959, 116,312.

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12. PROCTOR, R. Clinical experience with Nialamide. Paper presented at Eastern Psychiatric Re- search Association, Kew YoEk June, 1959.

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Nialamide as a psychic energizer. Paper presented at Eastern Psychiatric Research Association, New York, June, 1959.

PHENOTHIAZINE EFFECTS I N CHRONIC SCHIZOPHRENIA* DAVID PEARL

Veterans Administration Hospital, Battle Creek, Michigan

P R o B L E M Tranquilizers belonging to the phenothiazine family may induce clinical im-

provement in schizophrenic patients, yet differ somewhat in their action on specific target symptoms. Some of these drugs have been reported as differentially depress- ing the excitability of the ascending reticular formation and posterior hypothalamus. To the extent that behavior is dependent on the activity of these neuro-physiological systems, various phenothiazines may effect differing changes on components of psychological functioning. This study reports the effects of various phenothiazines on moderately chronic schizophrenic subjects' functioning in conceptual, perceptual and psychomotor functions.

PROCEDURE Four widely used tranquilizers of the phenothiazine group, Chlorpromazine

(Thorazine) , Promazine (Sparine) , Prochlorperazine (Compazine) , and Perphenazine (Trilafon), were studied for their differential effects. Forty-eight subjects equally divided into these four drug groups and two control groups, each with eight subjects, were studied for twelve weeks. Drug and placebo patients were randomly selected from a larger group of moderately chronic patients who were to receive tranquilizers. Eight subjects who were receiving no phenothiazine medication during this period were similarly evaluated. All subjects had been prescribed tranquilizer following

*Based on a paper presented at the 6th Annual V. A. Research Conference on Research in Psy- chiatry, March 27, 1961, Cincinnati, Ohio.

PHENOTHIAZINE EFFECTS IN CHRONIC SCHIZOPHRENIA 87

their hospital admissions but had received no phenothiazines for at least one month. These patients were in fair to good reality contact, had been hospitalized an average of 2.8 years and were from three privileged wards. Their ages ranged between 25 and 55 years. Medication dosages were flexible and were adjusted by ward psychiatrists to what they judged optimum for individual subjects. Average daily dosages were: Chlorpromazine 600 mg. (range 400-1200 mg.), Promazine 600 mg. (range 400- 1200 mg.), Prochlorperaxine 75 mg. (range 40-100 mg.), and Perphenazine 24 mg. (range 12-36 mg.).

Subjects were evaluated for functioning in intellectual, memory, perceptual and psychomotor areas prior to and again after the twelve weeks period. The following procedures and measures were used in each behavioral area:

1. ZnteZZectuaZ. Comprehension, Similarities, Digit Span, Digit Symbol and Picture Com- pletion subtests of the Wechsler Adult Intelligence Scale (WAIS).

2. Memoy . Mental Control, Logical Memory and Associative Learning subtests of the Wechsler Memory Scale and the Benton Visual Retention Test.

3. Perceptual. Two tasks were used. The first was a Perceptual Span Test involving the tachistoscopic presentation of varying numbers of small circles to determine the accuracy of subjects’ apprehension of these stimuli. The second was a tachistoscopically administered visual field test in which subjects, given a foveal fixation point, were presented with simultaneous foveal and peripheral targets and scored for the accuracy of their peripheral perceptions.

4. Psychmotor. Five psychomotor tasks were given. Simple and complex reaction times were measured with specially constructed apparatus. The subject, given an auditory stimulus, lifts his fingers from a metallic rest a t the bottom of a test board and rapidly as possible touches a predesignated metallic plate of two situated at the top of the board. A verbal ready signal is given from one to five seconds before stimulation. The auditory stimulus activates a timer which is stopped w,hen the subject reacts in lifting his fingers from the rest plate. This then starts a second timer which is deactivated when the subject’s fingers hit the target plate. Thus, two measures are provided-lift reaction time which measures response latency and jump reaction time which gauges speed of motor response once initiated. For simple reaction time, one stimulus and one target plate are used. In the complex situation, a buzzer and a bell are randomly pre- sented, signaling jumps t o the right or the left target plates respectively. Twenty trials of the simple and ten trials of the complex situation were given. Through conversion by appropriate switches, the above apparatus was used to auge alternate tapping rates between the two metallic target plates for five-second periods. The pfacement of a one inch wooden barrier midway between the plates necessitated an arc of movement for this taks. Ten trials were given. The Insertion and Assembly subtests of the Purdue Pegboard rounded out the psychomotor measures. These evaluate the speed and precision which a subject displays in manipulating small objects on the pegboard. The first primarily involves the speed of insertion of pins into the pegboard; the assembly task requires the coordinated use of hands in sequentially assembling pin, two washers and a sleeve into a patterned unit.

RESULTS Analyses of variance of phenothiazine and control subjects’ score changes dis-

closed relatively few significant alterations. In the cognitive area, significant differ- ences between means were found only for the WAIS Similarities and Benton Visual Retention Tests. t tests revealed that only Prochlorperaxine (Compazine) effected significant positive alterations a t the .01 and .05 P levels for these two tests as com- pared to control changes and the other three phenothiazines. With the number of comparisons made, these positive results could have occurred by chance. Further- more, when the total number of changes for subjects over all the cognitive tests were subjected to a chi square analysis, no significant differences were found between any of the drug and control groups. It would therefore appear that these pheno- thiazine drugs did not effect any generalized intellectual or memory alterations.

Analyses of variance on the various psychomotor measures disclosed significant differences at the .01 level only for the tapping rate and Purdue Pegboard Assembly tasks. t test analyses indicated that the tapping rate result was due primarily to an increased tapping rate by subjects receiving Perphenazine (Trilafon) at the .05 to .01 levels. No significant differences were found between other phenothiazines and control subjects. All phenothiazine groups demonstrated impaired performance at the .01 or .02 levels of confidence on the Purdue Assembly Test compared to control

DAVID PEARL 88

subjects. Intra-phenothiazine differences were not significant. No difference was found between placebo and “no medication” groups on this procedure.

Of the two perceptual tasks, only the Perceptual Span Test showed significant sensitivity to phenothiazines. All drug groups exhibited significant decrements in score at the .01 level compared to control subjects. Insignificant differences were present in intra-phenothiazine comparisons and again, between thetwo control groups.

DISCUSSION I n the dosages used, these phenothiazines had little overall effect on intellectual

functioning. Subjects’ general intellectual efficiency and ability to concentrate were not increased. The Digit Span, Wechsler Memory subtests and Benton Visual Re- tention Tests which tap these processes generally I’ailed to show a positive gain for the phenothiazine subjects. This was also reflected by failure by these patients to show enhanced verbal learning on the paired associate subtest of the Memory Scale, contrary to findings reported by D a ~ t o n ( ~ ) for chronic schizophrenics receiving Chlorpromazine. The only WAIS subtest to show significant change was Similar- ities, Tvhich measures verbal conceptualisatmion. This was the only WAIS subtest affected by Chlorpromazine in a study reported by Abrams“). Verbal conceptual- ization may be sensitive to phenothiazines, but our psychometric procedures gen- erally may be too gross as change indicators.

All phenothiazine drugs effected Perceptual Span score reductions. Only 7 of 32 drug subjects achieved the same or a higher score upon retesting as contrasted by 15 of the 16 control subjects. This accords with our previous findings that pheno- thiazines reduce perceptual efficiencyc7’ and is consistent with Beck’s results@). Furthermore, perceptual thresholds seemed raised for many phenothiasine subjects, in that longer tachistoscopic exposure speeds were necesary before subjects ack- nowledged perceiving the presented stimuli. About 20 percent of stimuli configura- tions seen in the pre-drug trials a t speeds of .05 and .10 seconds were not seen sub- sequently a t these speeds. Such decrements may reflect the result of the depressing action of these phenothiazines on either the reticular activating system or the posterior hypothalamus. A study by F u ~ t e r ‘ ~ ) in which monkeys stimulated in the midbrain reticular formation were more accurate in a tachistoscopic perceptual discrimination problem than a control group, suggests that facilitation is associated with increased perceptual efficiency. It would seem that the converse, the depression of reticular activity by tranquilizers, would result in decreased capacity for per- ceptual discrimination, the effect being reported here. Gelhornt6) suggests that per- ceptions are quantitatively and possibly qualitatively altered by changes in the intensity of the hypothalamic-cortical discharge. Pearl and VanderKamp ( * a 9 ) using the Perceptual Span Test on subjects assessed for hypothalamic excitability through the mecholyl test, obtained data supporting this hypothesis of a relationship of perception and sympathetic nervous system excitability. Whether such perceptual decrement is related to the depressive effects of phenothiazines on either or both of the above loci remains to be definitively demonstrated.

Except for the increased tapping rate of Perphenazine subjects and the reduced Purdue Assembly Test performance of all phenothiazine subjects, no significant motor effects occurred. An increased tapping rate was also found in Perphenazine subjects but not in Chlorpromazine patients by Mason-Browne and Borthwick ( 6 ) .

These results suggest that these phenothiazines have little prolonged effect on relatively simple motor capabilities in moderately chronic schizophrenics. They do appear to affect adversely more complex motor skills which involve speed and GO- ordination of both hands.

SUMMARY Four phenothiazine I tranquilizers (Chlorpromazine, Promazine, Prochlorpera-

zine and Perphenazine) were evaluated for their differential effects on moderately chronic schizophrenic patients as compared to similar subjects receiving a placebo

PHENOTHIAZINE EFFECTS IN CHRONIC SCHIZOPHRENIA 89

or no drug therapy. Forty-eight subjects, equally divided into the above four drug and two control groups were studied for changes occurring in intellectual, memory, perceptual and psychomotor areas.

Results indicated that no generalized intellectual or memory alterations oc- curred for any drug. Simpie reaction times and speed of simple manipulative move- ments were unaffected. All phenothiazine subjects demonstrated impaired perform- ance on the more complex Purdue Pegboard Assembly test and showed significant decrements on the Perceptual Span Test. The only significant differential action occurred for tapping rates where Perphenazine alone was found to increase tapping rates.

REFERENCES 1. ABRAMS, J. Chlorpromazine in the treatment of chronic schizophrenia. Dis. New. Syst., 1958,191

2. BECK, E. C. Personal Communication. Also Newbrough, J. E. and Beck, E. C. A m r . Psychol.,

3. DASTON, P. G. Effects of two phenothiazine drugs on concentrative attention span of chronic

4. FUSTER, J. M. Effects of stimulation of brain stem on tachistoscopic perception. Science, 1958,

5. GELHORN, E. Autonomic Imbalame and the Hypothalamus. Minneapolis: Univ. Minn. Press,

6. MASON-BROWNE, N. L. and BORTHWICK, J. W. Effect of perphenazine on modification of crude

7. PEARL, D. Some cognitive, psychomotor and perceptual effects of phenothiazine drugs. Paper

8. PEARL, D. and VANDERKAYP, H. Mecholyl chloride autonomic indices and perception. Paper

9. PEARL, D. and VANDERKAYP, H. Unrelatedness of mechoyyl chloride autonomic reaction indices.

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DIFFERENTIAL EFFECTS OF VARIOUS TRANQUILIZING DRUGS ON SPEED OF TAPPING

SAMUEL F. KLUGMAN’

Veterans Administration Hospital, Coatesville, Pa.

PROBLEM The opportunity for this study arose when 18 newly-admitted male schizo-

phrenics a t Coatesville Hospital were designated as part of the nationwide pool of subjects in Veterans Administration Cooperative Studies of Chemotherapy, Project Number 3. During the 12-week period that these patients were under medication, as required in the Project 3 study plan (Veterans Administration, 1958), this writer had them perform a standard tapping task with (a) forefinger, (b) middle finger, (c) simultaneously with both fingers, and (d) alternating forefinger and middle finger. Medication was administered in a double blind procedure, three patients being randomly assigned to each of four experimental drugs : mepazine (Pacatal), perphena- zine (Trilafon) , proclorperazine (Compazine) and trifluoramazine (Vesprin) , and three each to two “base line” drugs: chlorpromazine (Thorazine) and phenobarbital. From data provided by the manufacturers, oral dosages were chosen to produce equal pharmacological effects. During the first four weeks specified increasing dosages were administered but during the final eight weeks the attending physicians were free to adjust dosage to elicit what they regarded as “the maximum thera- peutic response from each patient.”

‘This writer is indebted to Dr. James Diggory, Psychological Consultant to this hos ital from the University of Pennsylvania, for having suggested the statistical approach and for {is continued interest and helpful suggestions.