Theoretical and practical importance of plasma levels of haloperidol. correlations with clinical and computerized EEG data

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THEORETICAL AND PRACTICAL IMPORTANCE OF PLASMA LEVELS OF HALOPEIUDOL. CORRELATIONS WITH CLINICAL AND COMPuTEREED EEG DATA .*. RENE P.DE BUCK; NORBERTO ZELASCHI: CHRISTIAN GILLES;.JACQUES DURDU**and HENRI BRAUMAN * Clinical ** Neurology Brugmann

Psychopharmacology Research Unit. Institute Dpt. l ** Clinical Biochemistry Dept. University Hospital. Brussels. Belgium. (Final

form,

April

of Psychiatry.

1981)

Abstract 1. 2. 3.

4.

Haloperidol plasma levels, after long acting haloperidol i.m. injection, are analyzed and compared with clinical evolution and EEG modifications. Haloperidol plasma levels were determined by radioinununoassay. Clinical status was assessed weekly and computerized EEG were performed daily from day 3 to 7 after haloperidol decanoate injection. The plasma level-dose relationship during oral treatment and 4 weeks after haloperidol decanoate injection are very similar. After injection, the plasma level attains its highest value within 3 to 10 days and decreases along a logarithmic curve. An inverse relationship with B.P.R.S.scores is found in many patients. EEG changes are related to clinical status rather than to plasma levels. The results obtained by these three methods are proposed as criteria for the assessment of the reinjection time.

Key words Abbreviation

: computerized evolution.

EEG, depot

neuroleptics,

haloperidol

decanoate,

: Brief Psychiatric Rating Scale (B.P.R.S.); computerized Haloperidol Decanoate (H.D.) ; Radioimmunoassay (RIA).

psychotic

patients

EEG (cEEG);

Introduction The extending use of depot neuroleptics has improved the treatment of psychotic patients, leading to a shortening of hospitalization periods (Johnson, 19771. Haloperidol is one of the most widely used neuroleptics, and its efficacy has been well It has been tested in established (Ayd, 1978). H.D. is a long acting form of haloperidol. 1979) and used in hospitalized, chronic psychotic patients dogs (Heykants and Niemegeers, (Deberdt et al., 1980). RIA allows the assessment of haloperidol plasma levels during oral chronic treatment (Rubin et al., 1980) and after H.D. injection. cEEG offers another approach to the response to neuroleptic treatment (Itill, 1980). The results obtained by these two methods, when compared with the clinical evolution could provide good criteria for the time of H.D. reinjection. Methods 29 psychotic Patients. 16 to 60 (mean 42) years, Drug.

13 patients

in and out patients, 16 males were included in the study.

were treated

by oral

haloperidol

499

and 13 females (2-15

mg/d.)

in the age range

; 5 patients

of

were direct-

R.P. De Buck et al.

SOD

ly intramuscularly injected with H.D.(75-300 mg) after a wash-out period of 4 days. Another 11 patients were equilibrated with oral haloperidol, and then injected with H.D. The calculation of the H.D.doses was based on the fact that the bioavalability of oral haloperidol is 60-70 % (Forssman and Ohman, 1977). Thus, a monthly dose of H.D. is 20 times the daily were made 21 to 30 days after the first one, as required oral dose. Subsequent injections by the patient's clinical status. Other medications, except neuroleptics, were allowed. All the patients received anticholinergic drugs at constant doses. Plasma levels determinations. Blood samples were taken once a week in orally treated samples were taken each two days during the first week, and patients. After H.D. injection, once a week thereafter. Dsterminations were performed by RIA, using a commercial kit containing an ~tiiSel'Um SpefiCity Of vbich has not been fully assessed and which could cross react with some non active metabolites of haloperidol. The sensitivity of the assay is 0.02 ng/SCO ul. Clinical ted using

evaluation. the B.P.R.S.

In some cases,

the clinical

status

at days of sampling

was estima-

CEEG. cEEG were performed, when possible, the day before H.D.injection and at days 3 to 7 after. A five minute resting EEG was recorded from the left and right temporal and occipital regions. From the tape recording (H.P 3960 FM recorder), the FFT analysis was perforspectrum was obtained med off line on PDP 11/05 computer (TEKTRONIX DPO system). A modified by convolution of the average spectrum by the inverse spectrum of the selected channel. The influence of the drug is evaluated by the ratio between the spectrum during and before the treatment. Results The comparison of the dose-plasma level relationship during oral treatment and after H.D. injection shows that the correlation is good in both instances (Fig. 1). The relationship obtained after a ten day period of eqilibration during the oral treatment is very similar the one found during the 4th week after H.D.injection (a = 0.8)

PER OS

rz0.91

PLASMA rig/ml

LEVELS

DECA NOATE

60

100

200 OOSES

2630 38 300mg

Fig. 1. Haloperidol plasma levels (n&-d) to dose relationship during oral treatment in 24 patients (top) and during the 4th week after H-D-injection (16 patients). The two lines have the same slope (a = 0.8).

Fig. 2. Haloperidol plasma levels (m&-d) after H.D.injection (16 patients). A peak develops during the 1st week, and the plasma level decreases following a logarithmic curve (r = 0.90).

After between

18

a single injection of H.D.(Fig. 21, the plasma the 3rd and the 10th day, and somewhat earlier

level attains if the patient

46

64 60 DAYS

its highest value has been equilibrated

Haloperidol

plasma

levels,

cEEG and clinical

evolution

501

previously with oral haloperidol (2nd to 5th day). Then, it decreases, following a logarithmic curve (r=0.90). When oral equilibration preceded the injection, plasma levels comparable to those reached during oral treatment are found during the 4th week. After reinjection, the plasma levels follow the same curve. The reinjections were not given strictly 30 days after the first one. The criterion for reinjection was the patients'clinical status. When it was assessed by B.P.R.S., an inverse (Fig.3). relationship is observed between the B.P.R.S. scores and the plasma levels cEEG (Fig. 4) shows an increase in the theta spectrum power from day 3 to 6 after H.D. injection. The spectrum ratio is already about 200 % at day 4 and increases until1 day 6.

PLAShA nglml 30-1

LEVELS

ms

&ORES

IHC300mg(15myldl

t60

L

DAYS

80 60 40 t 20 80 60 f 40

30: 2010-i

5

Jil. 15

25

35

45

IJAYS

Fig. 3. Clinical evolution. B.P.R.S. scores (dotted line) and plasma levels (solid line) in 4 patients injected after equilibration with oral haloperidol (daily dose in brackets), except the 4th one, who was directly injected.

FREQUENCIES

b

Fig. 4. cEEG. Left : rise in the theta spectrum power (4 to 8 cycles/set.) from day 3 to 6. Right : spectrum ratio, increasing from day 3 to 6 after injection.

Discussion The plasma levels attained after H.D.injection are as well predictable as the ones reached under oral treatment. The similarity between the dose-plasma level relationship during oral treatment and after H.D.injection indicates that the "20 fold rule" is good, at least when the 4th week is considered. However, if the goal is to obtain the same plasma levels in both instances, it is noteworthy that this is true only during the 4th week, after 3 weeks of much higher levels. The poor specificity of the method can lead to an overestimation of the plasma levels during the 1st week, but a careful evaluation of short-and longterm side effects will be necessary to assess the risk of such a profile. The time-plasma levels relationship seems to be more reliable after H.D.injection than It should be confirmed by a broader study. If it is, the extrapoladuring oral treatment. tion of the curve obtained in one patient after 15 days would allow to predict the best time for reinjection. A regular assessment of the patients clinical status also appears as a good way to evato establish a more precise luate the reinjection time. A broader study must be performed, plasma levels. In this rescorrespondance between the B.P.R.S. scores and the haloperidol

R.P. De Buck et al.

502

pect, it would be preferable to use an item-by-item rather than a global cotation. is another par;meter The evolution of the theta spectrum power, and if the spectrum ratio to take into consideration. It seems to be more related to the clinical status than to the and could provide the most sensitive appreciation of the treatment. plasma levels, Conclusion When it is possible, the combined use of RIA, cEEG and clinical assessment will allow it is not possible in most a very,fine follow up of H.D. treated patients. Unfortunately, cases, and the physician must have recourse to a simpler method, especially for the out the patient's clinical status requires a reinjecpatients. In our experience, most often, tion about three weeks after the first one, and the delay seems to be longer for the following ones. Acknowledqement The authors wish to thank recording. They are grateful

Mr R. Devos for his perfect technical assistance in EEG to the whole nurses team for their daily collaboration. References

AYD, F.J. (1978) Haloperidol : Twenty years' clinical experience. J.Clin.Psychiat. 2, 807-814. DEBERDT, R., ELENS, P., BERGHMANS, W., HEYKANTS, J., NOESTENBORGHS, R., DRIESENS, F., REYNTJENS,A. and WLJNGAARDEN, I. (1980) Intramuscular haloperidol decanoate for neuroleptic maintenance therapy. Efficacy, dosage schedule and plasma levels. Acta Psychiat. Stand. 62, 356-363. FORSSMPI,A.and OHMAN, R. (1977) Applied phannacokinetics of haloperidol in man. Curr. Ther.Res. 2, 396-411. HEYKANTS, J. and NIEMEGEERS, C.J.E. (1979) Pharmacokinetics of haloperidol after intramuscular injection of haloperidol decanoate in dogs. Basic medical information, haloperidol decanoate, Janssen Phannaceutica, Beerse, Belgium. ITIL, T.M. (1980) Computer-analysed electroencephalogram to predict the therapeutic outin Schizophrenia Research, C. Baxter and come in schizophrenia. In : Perspectives T. Melnechuk (eds), pp 61-75, Raven Press, New York. JOHNSON, D.W.M. (1977) Practical considerations in the use of depot neuroleptics for the treatment of schizophrenia. British J. Hosp. Med., June 1977, 546-558. RUBIN, R.T., FORSSMAN, A., HEYKANTS, J. OHMAN, R., TOWER, B., MICHIELS, M. (1980) Serum haloperidol determinations in psychiatric patients. Comparison of methods and correlation with serum prolactin levels. Arch.Gen.Psychiatrv, 37, 1069-1074. Inquiries Dr R.P. Clinical Institute Brugmann Pl. Van B-1020

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