Some Uses of Haloperidol in the Treatment of

Psychiatric Conditions

FARUK S. ABUZZAHAB, SR., M.D., Ph.D.

• Haloperidol (Haldol) is an effective neu-roleptic compound which is chemically dis­

tinct from the phenothiazine group of drugs(see Figure 1). It has been commerciallyavailable in Europe since 1960 and has beenextensively investigated both here and in Eu-

CI

Fig. 1: Structural Formula of Haloperidol.

rope1.". Recently marketed in the UnitedStates, this compound has been shown to havea high milligram potency but unfortunatelyis accompanied by a high incidence of extra­pyramidal side effects. Except for the high in­cidence of these effects the toxicity record ofthis compound is favorable. For example, it iswell tolerated by the elderly and is rarelyassociated with hypotension, liver disorders,skin photosensitivity, or blood dyscrasias.

Dr. Abuzzahah is Assistant Profe~::;or. Depart­ments of Psychiatry and Pharmacology, Univer­sity of Minneiiota Medical School. University ofMinnesota.

This investigation was supported, in part, byresearch grant # MYP-5106, from the NationalInstitute of Mental Health, U.S. Public HealthService. Haloperidol was supplied by McNeilLaboratories, Inc., Fort Washington Pennsylvania.

Paper presented at the Fifteenth Annual Meet­ing of the Academy of Psychosomatic Medicine.Miami Beach, Florida.

188

The appearance of such a potent and non­toxic drug is particularly welcome in the lightof the findings that long-term use of pheno­thiazines appear to result in increased melan­osis and possible cardiac lesions. The purposeof the present study was to evaluate the effec­tiveness of haloperidol in the treatment of avariety of psychiatric patients in which a po­tent neuroleptic is usually called for. Inparticular, schizophrenic or other psychoticpatients who have failed to respond to othertypes of treatment and patients having Gillesde la Tourette's Disease were selected.

METHOD

Patient Population

Forty-one patients, 18 males and 23 fe­males were treated. Sixteen patients had neverbeen previously hospitalized for a psychiatriccondition. Prior psychotropic drug therapywas given to 31 of the patients, and, exceptin six of these patients, the pretreatment pro­gress had been static (13) or deteriorating(12). Ages ranged from 7 to 57, with the meanage being 31 years. All patients were cauca­soid. Thirty-five began the study as inpatients,six as outpatients.

Design

Patients were treated for a maximum ofone year. The minimum treatment period wasfour weeks, and patients who completed lessthan this period were considered dropouts.Drug administration was on a nonblind basisand medications were dispensed in capsulescontaining 2.0 mg of the drug. Patients wereinitially given one capsule 2 or 3 times perday and dosage was adjusted at the discretionof the investigator in relation to the thera­peutic and side effects responses of the pa­tients to a maximum of 32 mg daily. Sideeffects were controlled by dosage reduction

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SOME USES OF HALOPERIDOL-ABUZZAHAB

and/or the addition of antiparkinsonian drugsrbenztropine mesylate (Cogentin) was usedin the majority of the cases] up to 4.0 mg perday.

Evaluations

Patients were evaluated by the investi­gator at pretreatment, 2 weeks, 4 weeks andat 2 - 4 week intervals thereafter on the BriefPsychiatric Rating Scale (BPRS)', theMcNeil Symptom Profile and a side effectschecklist. A judgment of global improvementwas made for each patient at termination.Hemoglobin, white and differential bloodcounts were obtained at pretreatment and atmonthly intervals. In addition, weight, pulseand temperature were monitored at eachevaluation period.

RESULTS

DropoutsTen patients were dropped out of the

study prior to completing four weeks treat-

ment with haloperidol. Four of these patientsremained on the study one week or less, threefor two weeks or less, and three for threeweeks or less.

Seven of the ten dropouts had been diag­nosed as schizophrenic, and one as havingchronic brain syndrome secondary to a con­vulsive disorder, one manic-depressive reac­tion, and one obsessive-compulsive disorder.Four of the ten were terminated as a result ofextrapyramidal side effects which could notbe adequately controlled with the additionof antiparkinsonian medication, and four be­cause of lack of improvement. One patientworsened, and one patient was lost to follow­up when he did not return for an outpatientappointment.

Global Improvement

Three patients were rated as markedlyimproved at termination, 19 were rated asmoderately improved, five as slightly im-

TABLE I

Global Improvement of the 31 Patients whoCompleted at Least 4 Weeks on Haloperidol

Degree ofImprore1lle?lt

Markell

Moderate

None

May-June 1970

No. ofPatients

3

19

5

4

Diagnostic Freq./ MeanCategories Tot. Freq. Max. Dose

Schizophrenia 1/13Gilles de la Tourette 1/4 14.0 mg/dayPsychoneurotic Anxiety Reaction 1/1

Schizophrenia 8/13 16.8 mg/dayGilles de la Tourette 2/4Acute Brain Syndrome 3/3Secondary to AlcoholismHuntington's Chorea 1/4Chronic Brain Syndrome 1/1Secondary to Convulsive DisorderPsychoneurotic-DissociativeReaction 1/1Torticollis 1/1Child Adjustment Reaction 1/1Acute Psychotic Reaction 1/1

Schizophrenia 2/13Gilles de la Tourette 1/4 20.8 mg/dayHuntington's Chorea 2/4

Schizophrenia 2/13Huntington's Chorea 1/4 24.5 mg/dayManic-Depressive 1/1

189

PSYCHOSOMATICS

proved and four as showing no change in theircondition. Table I presents the number of pa­tients obtaining the differential levels of globalimprovement at termination, the distributionof these patients according to diagnostic cate­gory, and the mean maximum dosage level ateach category of improvement.

A total of 27 out of the 31 patients whowere treated for at least four weeks showedsome degree of improvement. Eleven of the13 diagnosed as schizophrenic and three out ofthe four diagnosed as having Huntington'sChorea improved. All four of the Gilles de laTourette patients improved.

The mean maximum dosage prescribed topatients was inversely related to the level ofimprovement (refer to Table I). The meanmaximum dosage of the four patients whoshowed no improvement reached 24.5 mg perday, the highest mean daily dosage of all im­provement levels; in contrast, the patientsshowing marked improvement averaged only14.0 mg maximum daily dose. This findingsuggests that if patients have not respondedto 14 mg per day, it is unlikely that theywill respond to 24 mg per day.

BPRS Data

No BPRS ratings were available for onepatient who was verbally uncommunicative(severe Huntington's Chorea). Table II pre­sents the mean total BPRS scores across fiverating periods. As can be seen in this table,the mean total BPRS score decreased fromthe pretreatment high to a low score by the

six-week rating period, but was slightly higherwhen based on termination scores. At termi­nation the patients had been on the studyvarying lengths of time from four weeks totwelve months, and the slightly increasedmean at termination may be the result of theinclusion of some 4 week values.

Each of the 16 signs and symptoms onthe BPRS was analyzed individually at pre­treatment, two weeks, four weeks, six weeksand at termination as well. Table III showsthe mean scores on each scale for five ratingperiods. Similar to the total BPRS means, theindividual scale mea:1S tend to be slightlyhigher at termination than at six weeks. Thegreatest mean improvement for any two weekperiod occurred from pretreatment to the twoweek rating, and the maximum level of im­provement for most scales was achieved bythe end of six weeks.

A consideration of the mean change forthe 16 items from pretreatment to two weeks(see Table III) indicates that for Anxiety,Conceptual Disorganization, Tension, Man­nerisms and Posturing, and Unusual ThoughtContent one point or more improvement oc­curred. All five of these items showed an evengreater amount of improvement by termina­tion. In addition, a mean positive change ofone point or more from pretreatmentto termination was found for Somatic Con­cern, Emotional Withdrawal, Motor Retarda­tion and Blunted AffeCt. Thus, on nine of the16 BPRS signs and symptoms a mean change

TABLE II

Mean Total Scores on BPRS and McNeil Symptom Profile

Rating period

pre 2 wks 4 wks 6 wks term

BPRS 49.0 37.4 34.6 29.9 35.3

McNeil Symptom Profile 32.2 21.4 15.5 11.4 14.0

11= 40 36 28* 24 27

* 4-week ratings for three additional patients who completed at least 4 weeks werenot available.

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SOME USES OF HALOPERIDOL-ABUZZAHAB

of 1 point or greater occurred by terminationof treatment.

McNeil Symptom ProfileAll patients at each rating period were

evaluated on the McNeil Symptom Profile.Each patient was scored on 24 symptoms ineight categories (Affect, Social Behavior, Per­ception, Ideation, Sensorium, Orientation,Memory). Choice of items varied among pa­tients and depended upon the individualsymptomatology at pretreatment, but themajor symptom categories remained constantfrom patient to patient. Table II also pre­sents the mean scores on the McNeil Symp­tom Profile at five rating periods. The resultsare similar to those for the Total BPRS scoresin that the greatest amount of improvementwas achieved by six weeks. Also. as on theBPRS, the termination mean score is slightlyhio:her than that of six weeks (again Dossibly

a function of the inclusion of some 4-weekscores), and the largest two week change inmean score occurs between pretreatment andthe two week rating.

Side Effects

Extrapyramidal side effects were reportedin 24 patients and antiparkinsonian medica­tion was effective in controlling these effectsin 20 of the cases. The onset of these effectsoccurred in the first week of treatment in 18patients, and the majority of them appearedaround a daily haloperidol dose of 8-12 mg,although the dose at which they were firstreported ranged from 4 to 32 mg per day.

Aside from parkinsonian effects, only inco­ordination and constipation, appeared to betrue treatment emergent symptoms at twoweeks. At the end of four weeks, the incidenceof drowsiness among the completing patients

TABLE III

Mean Scores for 16 BPRS Signs and Symptoms in Patients

Treated with H aloperidol*

~ RATING~

PRE 2 WKS MEAN 4 I.'KS 6 WKS TERM** MEANCHANGE CHANGE

(Pre- 2 wks) (Pre-term. )

SOMATIC CONCERN 3.7 3.0 .8 2.9 2.5 2.9 1.0

ANXIETY 4.4 3.4 1.0 3.3 2.7 3.2 1.3

EMOTIONAL WITHDRAWAL 3.4 2.8 .5 2.3 2.4 2.5 1.2

CONCEPTUAL DISORGANIZATION 3.8 2.4 1.2 2.1 1.9 2.3 1.8

GUILT FEELINGS 2.5 2.0 .5 1.9 1.5 1.7 .9

TENSION 4.3 3.1 1.1 3.1 2.7 3.0 1.2

MANNERISMS, POSTURING 4.0 2.9 1.1 2.8 2.5 2.6 1.3

GRANDIOSITY 1.9 1.3 .5 1.3 1.3 1.5 .4

DEPRESSIVE MOOD 3.1 2.5 .6 2.3 1.8 2.2 .9

HOSTILITY 2.6 2.1 .3 1.8 1.4 1.8 .7

SUSPICIOUSNESS 2.5 1.8 .5 1.5 1.4 1.5 .0

HALLUCINATORY BEHAVIOR 1.4 1.4 .1 1.3 1.2 1.4 .2

MOTOR RETARDATION 3.0 2.3 .6 2.1 1.7 1.8 1.2

UNCooPERATIVENESS 1.8 1.6 .1 1.4 1.4 1.6 .7

UNUSUAL THOUGHT CONTENT 3.3 2.1 1.1 2.0 1.8 2.2 1.3

BLUNTED AFFECT 3.4 2.6 .4 2.5 2.0 2.6 1.0

n = 40 36 36 28*** 24 27 27

*Scoring was made along a 7-point scale from not present (I), very mild (2) , mild (3) , moderate (4) •moderately severe (5) • severe (6), to extremely severe (7).

**Termination ranged from 4 weeks to 12 months.

*** 4-week ratings for three additional patients who completed at least 4 weeks were not available.

May-June 1970 191

PSYCHOSOMATICS

was much higher than it had been at pretreat­ment (16-pre vs 5-post) and the reverse wastrue for insomnia (6-pre vs 14-post). Also byfour weeks, extrapyramidal side effects werereported by somewhat fewer patients thanat two weeks (8 vs 15, respectively). This,in part, may be attributed to the terminationprior to four weeks of four patients in whomthese effects could not be controlled by theconcurrent use of antiparkinsonian medica­tion. This was consistent with the finding thatat the two week rating a higher proportion ofthe eventual dropouts than patients whowould complete four weeks, reported extra­pyramidal side effects.

Laboratory Findings

Table IV presents the mean initial andmean final weight, pulse and temperature aswell as the mean initial and mean final valuesfor hemoglobin, WBC, neutrophils, lympho­cytes, monocytes, eosinophils and basophils.T-tests for the difference between correlatedmeans· were not significant in any case. How­ever, mild eosinophilia was reported in twopatients. One patient showed an increasedeosinophile count from a pretreatment countof 2% to 14% at 6 weeks, and a return to 3~at approximately 8 weeks. In a second patientan eosinophile count of 1% at pretreatmentincreased to 8% at 6 weeks. In both casesof eosinophilia, SGOT and alkaline phospha­tase were within normal limits.

Five patients showed elevated WBC's attermination. One patient underwent cervicalfusion surgery prior to the increased count,and a subsequent WBC showed a return tothe normal range. A second patient was diag­nosed as having acute pelvic inflammatory

disease at the time of the high WBC, but un­fortunately no post blood tests were avail­able. For a third patient, the elevated WBCat termination of treatment returned to nor­mal at a subsequent testing. Two additionaloutpatients for whom post WBC's were notavailable also had mild leukocytosis.

DISCUSSION

Haloperidol proved to be an effectivetreatment in 27 of 41 variously diagnosed pa­tients and to be especially and most dramati­cally effective in four patients suffering fromGilles de la Tourette's Disease.

That the onset of effect was rapid wasseen by the large degree of improvementwhich occurred on the BPRS and McNeilSymptom Profile by the end of two weeks, andby the rapid onset of extrapyramidal sideeffects, within one week for 18 patients. Theseside effects resulted in the dropout of fourpatients prior to four weeks, but for the major­ity of patients in whom these effects appeared,they were controlled by the concurrent ad­ministration of antiparkinsonian medication.Other treatment emergent symptoms werefew and mild and primarily consisted of anincreased incidence of drowsiness. No signifi­cant changes in blood pressure, pulse, or tem­perature were noted in contrast to the typicalfinding of decreased blood pressure and in­creased pulse rate in treatment with somephenothiazines. No significant peripheralblood value changes in these patients werediscerned except for two cases of transienteosinophilia.

These results are consistent with the largebody of literature on the use of this com­pound which suggests that haloperidol is a

TABLE IV

Laboratory and Vital Sign Data

Weight Pulse Temp. Hemoglobin WBe Pulys Lymph MOllos Eos BIJ,.~o

MeanInitial 139.2 85.8 38.4 14.5 9076 68 27 4 2 <1

MeanFinal 144.4 87.4 98.5 14.2 8670 67 27 4 2 1

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SOME USES OF HALOPERIDOL--ABUZZAHAB

potent and generally nontoxic neurolepticuseful over a wide range of psychiatric prob­lems and in particular, useful in controlIingthe manifestations of Gilles de la TouretteDisease.

SUMMARY

An open investigation of haloperidol wasconducted on 41 variously diagnosed psychiat­ric patients, the majority of whom were schizo­phrenic, but three individuals with Hunting­ton's Chorea and four suffering from Gillesde la Tourette syndrome were also included.Ten patients were dropped from the studyprior to the completion of four weeks of treat­ment. Of the 31 patients who completed thestudy, three showed marked improvement, 19moderate improvement, five slight improve­ment and four no change.

Extrapyramidal side effects appeared in24 patients and with the exception of four

cases were adequately controlled by the con­current administration of antiparkinsonianmedication.

Haloperidol, found to be a rapid actingand nontoxic agent, was felt to be valuablein the treatment of a wide variety of psychiat­ric problems.

REFERENCES

1. Jackman, A.I. (Ed.): Haloperidol. Int. J.Neurnpsychiat., 3: S10-S155, 1967.

2. Goldstein, B.J., Clyde, D.J., and Caldwell, J.M.:Clinical efficacy of butyrophenones as anti­psychotic drugs. In Psychopharmacology: Ar'C'l'iew ot progress, 1957-67, Efron, D.H.•(Ed. ) ,pp. 1085-91, Washington, D.C.: GPO,1968.

3. Overall. J. E., and Gorham, D. R.: The briefpsychiatric rating scale. Psychol. Rep., 10:799,1962.

4. Winer, B.J.: Statistical Prillciples in Experi­mental Design. New York: McGraw-Hill,1962.

J

For those who do not think, it is best at least to rearrange their prejudices oncein a while.

LUTHER BURBANK

Remember that to change your mind and follow him who sets you right is to benone the less free than you were before.

MARClIS Al'RELIUS ANTONINl'S

May-June 1970 193