Use of Haloperidol in a “Hard-Core” Chronic Schizophrenic Population

Use of Haloperidol in a

~~Hard-Core"

Chronic

Schizophrenic Population HAROLD

• Haloperidol o is the first commercially available major tranquilizer of a new chemical class, the butyrophenones. It has been available in Europe since 1959, and is now available in the United States. At the time we began our evaluation of haloperidol we were eager to try the drug in chronic schizophrenic patients because its effectiveness in these patients was not well defined. The chronic schizophrenics in our study were long term patients whose treatment with other psychotherapeutic agents had not been very successful. The evaluation was based on 1) global change as observed in clinical interviews and 2) patients' results on the Medfield Step Ratings during a special work rehabilitation program. \Ve also compared the effectiwness of the tablet and liquid forms. In addition, we observed those patients with chlorpromazine-induced lenticular and corneal opacities to determine if there was any change in their eye lesions on haloperidol. Haloperidol was administered in a controlled fashion to 29 hospitalized psychiatric patients, most of whose conditions were either static or deteriorating prior to treatment with the drug. The patients consisted of 8 males and 21 females, ranging in age from 14 to 57 years, with all average age of 39.7 years. Table I shows the breakdown of patients according to diagnosis and age. Therapy was divided into four treatment periods. In the first period, the patients received haloperidol in the form of tablets. In the second period, the patients received an Dr. Lee's paper is being published posthumously. He was the Superintendent-Assistant, \fedfield State Hospital, Harding, l\lassachusetts. • HALDOL® (haloperidol) supplied by \fcNeil Laboratories, Inc., Fort \Vashington, Pennsylvania. Sl'pkmher-Odoher 196H

LEE, M.D.

odorless, colorless, and tasteless liquid form of haloperidol with routine oral fluids. In the third period, five patients received placebo and the remainder continued to receive the liquid (haloperidol study medication) in a double-blind comparison of haloperidol with placebo. In the fourth period, the patients were again placed on tablets. The average total therapy period was six months. Table II shows the average duration of the 4 periods. TABLE 1. BREAKDOWN OF PATIENTS ACCORDING TO DIAGNOSIS AND AGE No. of Age Average Patients Range Age

Diagnosis

Schizophrenia 24 Affective Psychosis 2 Psychosis with Mental Deficiency 2 Childhood Aut! sm I

26-57 34-44 30-38 14

41.3 39.0 34.0 14.0

29

14-57

39.7

Total

TABLE II. AVERAGE TREATMENT PERIODS

Treatment Period

Number of Patients on Drug

I. Tablets 2. Drops 3 a. Haloperidol Study Medication 3b. Placebo 4. Tablets

Average Duration of Period in Weeks

Range in Weeks

27 19

16 6

3 ·26

13 5 16

2 2 5

1*·25

2 • 4 1-3 I - 6

.One day, one patient; four days. one patient.

TABLE ill. REASONS FOR DiSCONTINUANCE OF HALOPERIDOL Cause Worsening of condition Weight loss Vomiting No improvement on drug Decreased blood pressure Akathisia Seizure and 108s of consciousness Detection of diabetes mellitus Woraening of depression in a patient with affective psychosis Total Total Patients Dropped From Study

No. of Incidents.

5

3 3 2

2 1

I I

I 19 II

267

PSYCHOSO\IATICS TABLE IV. DOSAGE FOR EACH TREATMENT PERIOD Dosage (mg/day) Number of Patients On Drug

Treatment Period

1. Tablets

27

2. Drops

19

3. Haloperidol Study Medication

13

4. Tablets

16

Average Initial Dose (Range)

Average Maximum Dose (Range)

Average Maintenance Dose (Range)

2.9 (2.0-3.0) 7.\ (0.1-12.0) 8.6 (2.2-12.0) 8.9 (3.0-12.0)

7.0 (2.0-11.5) 8.\ (1.9-12.0) 8.7 (2.2-12.0) 9.3 (3.5-12.0)

7. I· (3.0-\1.5) 8.1·· (1.3·12.0) 8.7 (2.2-12.0) 9.2 (3.5-12.0)

.. Calculated for the 17 patients who were maintained on tablets in period # 1. ··Calculated (or the 18 patients who were maintained on drops in period #2.

Eleven patients were dropped during the course of treatment due to the severity of side effects, the lack of improvel1l('J1t, or the worsening of their condition on the
II

4 6

5 3

Unknown

Total

29

lAalnS

38 14 21 17 10 100

I"'auTS

IMP OVEO NOI IMPROVEO

2S PAIJ£NTS

19'AIIlNIS

t6'AIIlNTS

Figure 1. Comparison of improvement on tablets and drops.

261)

the average maintenance dose increases slightly in succeeding treatment periods. The therapeutic response of the patients during the entire study is shown in Table V. The overall effects of treatment with haloperidol were the following: 52 percent of tIlt' patients showed some form of improvement on the drug; 38 percent of the patients showed either marked or moderate improvement. We viewed this unexpected incidence of improvement among mainly chronic schizophrenics as very good. Figure 1 compares the incidence of improvement among the various treatment periods. That is, it compares the effectiveness of the two dosage fonns. Improved for each category means either the patient improved compared to the previous treatment period or the patient maintained an improved state he had developed in the previous treatment period. Conversely, not improved for each category means either the patient became worse compared to the previous treatment period or the patient maintained a regressed state he had developed in the previous treatment period. Twenty-five of the 29 patients were evaluated on haloperidol tablets in the first treatment period. Sixteen of these patients (64%) improved. Nineteen of the 29 patients were evaluated on haloperidol drops. Fourteen of these patients (74$) improved. Sixteen of the 29 patients were evaluated on haloperidol tablets again. Eleven of these patients (69%) improved. These results suggest that haloperidol tablets and drops are equally effective. In the third treatment period, haloperidol was compared with placebo in a special twoVolume IX

)

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HALOPERIDOL-LEE

week double-blind study. Figure 2 shows results obtained with 11 patients who received haloperidol study medication (actually a continuation of regular haloperidol drops) and five patients who received placebo. Two other patients received haloperidol study medication but these patients were not evaluated. Immediately prior to this double-blind study, all of the patients had been receiving haloperidol drops. The percent of improved patients in the placebo group was similar to that in the haloperidol study medication group. At the end of the double-blind study, among the patients receiving haloperidol the same percent were in an improved state. In contrast, only one patient receiving placebo was still in an improved state. In fact, three of the four who regressed on placebo, regressed so quickly that they were all back on haloperidol within six days. Although the number of patients is small, the sharp difference between the results in the two groups suggests haloperidol was effective. All of the patients who regressed when they received placebo improved when placed on the drug. As another measure of the effect of haloperidol, we used the Medfield Step System.' This is an evaluation system for chronic psychotic patients participating in a special work rehabilitation program. The evaluation system consists of 17 achievement levels, called steps, ranging from the lowest, step 0, to the highest, step 16. The higher the step level a patient can attain the more he has improved. The step level is calculated from three values: the patient's score on a work supervisor's evaluation; the patient's score on a ward evaluation; and the number of hours per day the patient has been able to work. Ratings for 10 patients were obtained on the first or second day they received haloperidol (pre-drug) and at the end of three months of treatment. For seven of these patients, ratings were also obtained at the end of six months of treatment. Figure 3 shows the mean step level of the evaluated patients at these times. There was an increase in mean step level between the beginning of treatment and three months and between three months and six months. i'\either of these increases was statistically significant. But the fact that the step level was higher with succeeding evaluations September-October 1968

HALOPERIDOL STUDY MEDICATION C.ONDIlIO

At (NO

U(#INNINO

•

/I

Figure 2. Placebo vs Haloperidol study medication. 6

.......> ...... :;; ~

(5.4)

5

4

(4.3) ,..... (3.4)

3

Z

~ 2 ~

-P....~

3 Month. Treatment

Figure 3.

~redfield

6 Month. T.eatment

stpp ('valuation.

suggests some effect of the drug and suggests also that therapy longer than 6 months might have resulted in further increases in step level. Greiner and Berry, in 1964, first reported the detection of a new side effect of one of the phenothiazines, ocular change after longterm chlorpromazine therapy.2 This change consists of opacities produced by the deposition of granules in the lens and cornea. Susceptible individuals may develop ocular changes after receiving large doses of chlorpromazine for prolonged periods. In 269

PSYCHOSO~'IATICS

TABLE VI. RESULTS OF SLIT-LAMP EXAMINATIONS Examination #1 Before Therapy Average-7 Months 1-12 Months

Examination 112 During Therapy Average-6 Months t-6 Months

Examination 113 After Therapy Average-5 Months 4-5 Months After

+3 +3 +4

+3 +3 +4

4

+1

+t

5 6 7 8 9 to II t2

+t

+1

+4

+4 +t +4 +3 +2 +t +2

+3 +3 +4 +t +t +4 +t

Patient No. t

2 3

+t +4 +3 +2 +1

+2

some of the cases of intense opacification, impairment of visual acuity has occurred." In some instances, the effects of chlorpromazine on the eye may be reversed, but the clearing of deposits is slow because of their locatiou in avascular tissue.' One report gives the results of seven investigators who performed slitlamp surveys on patients following long-term phenothiazine therapy. Thirty-two percent of 1,632 patients who underwent ophthalmologic examination were discovered to have drugrelated eye lesions." Prior to our study with haloperidol, phenothiazines had to be discontinued in 22 of the 29 patients because of drug-induced eye changes. Twelve were examined by slit-lamp biomicroscopv and funduscopy to determine if there was 'a progression of their lenticular and corneal opacities on haloperidol. Slitlamp examinations were not performed on the remaining 10 patients due to the discontinuance of therapy. Three examinations were performed. Examination # 1 was performed at an average of 7 months prior to treatment with haloperidol. Examination #2 was performed an average of 6 months after the start of haloperidol. In 7 of 12 patients, the third slit-lamp examination was performed at an average of 5

TABLE VII. ADVERSE REACTIONS Type

No. of Patients

No. of Incidents

Extrapyramidat Ga.trointestinal Cardiovascular Miscellaneous

It 6 6 13

22 to 7 2t

Totals

36"

60·

"Some patients exhibited more than one kind of adverse "eaction.

270

Examination #3 Extended Therapy Average-14 Months 12-t4 Months

+4 +3 +2 +t

+2

months after the termination of treatment. The remaining five patients, who were found to be refractory to all other tranquilizers, were continued on haloperidol after the termination of the study for at least 12 months. In these five patients, the third slit-lamp examination was performed at an average of 14 months after start of the drug. The average maximum dose of haloperidol for these twelve patients during the treatment period was 8.8 mg/day; no dose exceeded 12.0 mg/day. Table VI shows the results of the three slit-lamp examinations. The intensity of opacification was graded from 1-4, grade 4 representing the most intense opacification. No changes in opacification occurred in any of the periods for which slit-lamp examinations were carried out, even the 14-month period. Table VII shows the number and type of side effects encountered during the treatment with haloperidol. Since haloperidol is often compared with the phenothiazines in terms of the incidence of extrapyramidal reactions, it was expected that a large majority of the patients would develop such reactions during the course of our study. It was noted, however, that only 11 of the 29 patients developed extrapyramidal reactions. In some of the patients, these disappeared either spontaneously or with the administration of benztropine mesylate, diphenhydramine, or trihexyphenidyl; in others the reactions persisted, but were mild. One patient developed a severe extrapyramidal reaction which was not controlled with antiparkinson medication and which persisted even after haloperidol was discontinued. The Volume IX

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HALOPERIDOL-LEE

low incidence of extrapyramidal reactions was probably due to tbe very slow increase in dosage throughout the study. Other medications administered along with haloperidol were hypnotic-sedatives ( glutethimide, ethchlorvynol, sodium amobarbital), tolbutamide, tetracycline, elixir of terpin hydrate, aspirin, and a compound 0 containing ephedrine, phenobarbital, theophylline, and potassium iodide, used in the treatment of chronic respiratory diseases. Eight patients received hypnotic-sedatives for disturbed behavior, assaultiveness, or restlessness. As mentioned previously, six of these patients discontinued haloperidol. Lack of improvement was one reason for removal of five of these six. I feel that it is also necessary to mention the increase in hostility exhibited by 10 of the patients during the treatment period with haloperidol. This may be considered a positive rather than a negative reaction to the drug, since a schizophrenic who is chronically withdrawn may actually be improving when he expresses his emotions. Some of the patients, however, developed hostility to such a degree that the drug was discontinued. Laboratory tests consisting of complete blood count, SCOT, and urinalysis were performed on all patients before the start of treatment, at the start of treatment and at approximately three-month intervals during treatment. Results showed that no abnormal

°Quadrinal

values developed except in one patient who developed a leukocytosis, the cause of which was not attributed to haloperidol. These results suggest that the drug does not cause laboratory abnormalities at the doses employed. In summary it appears that a six-month course of treatment with haloperidol resulted in significant improvement in a population of chronic schizophrenic patients; this was indicated by patients' global improvement and patients' improvement on the Medfield Step Ratings. On the basis of this study, it also appears that haloperidol tablets and drops are equally effective. Finally, since no progression of chlorpromazine-induced eye lesions occurred during haloperidol therapy, we think that haloperidol may be a chemotherapeutic agent which may eliminate the ocular risks associated with long-term chlorpromazine therapy.

REFERENCES

1. Isaac, D. M., and Lafave, H. C.: An EvaluationIncentive System for Chronic Psychotics. Psychiat. Quart. 38: Suppl.: 33-47, 1964.

2. Mathalone, M. B. R.: Eye and Skin Changes in Psychiatric Patients Treated with Chlorpromazine. Brit.]. Ophtlllll. 51 :86-93, 1967. 3. Phenothiazines: Skin and Eye Complications. Int. Dru.g Ther. Newslet. 1: No.1, 1966. 4. Prolonged Pharmacotherapy and the Eye. Int. Drug Ther. Newslet. 1: No.9. 1966.

Medfield State Hospital Harding, Massachusetts 02042

The attainment of proper self love must be the concern of religion hecause as long as human )wings arc ('nslaved to wrong attitudes toward themselves, they cannot help l'xpH'ssing wrong attitudes toward others.-}osHUA LOTH LIEBMAN

September-October 1968

271