Prolactin response to single and multiple doses of haloperidol in schizophrenic patients

Psychiatry Research, 11,6 1-69 Elsevier

61

Prolactin Response to Single and Multiple Haloperidol in Schizophrenic Patients G.K. Ravichandran, Ru-Band Lu, Alla Shvartsburd. T. Ho, Myrna Kahn, and Robert C. Smith Received 1983.

March

25, 1983; revised

version

received

October

Doses

of

Chandra l-l. Misra. Beng

24, 1983; accepted

December

5,

Abstract. Serum prolactin and blood levels of haloperidol were assessed in schizophrenic patients after single acute oral doses of haloperidol and during fixed dose treatment with this medication. Although significant intrapatient correlations between prolactin responses to different doses of haloperidol were found, no statistically significant interpatient relationship between haloperidol dose and prolactin response emerged. There were statistically significant relationships between steady-state plasma and red cell haloperidol levels (measured by radioreceptor orgas liquid chromatographic techniques) and serum prolactin response, but not between blood levels after the acute haloperidol dose and prolactin response. Key Words. Prolactin.

haloperidol,

schizophrenia

The increase in prolactin (PRL) induced by neuroleptic drugs is believed to be mediated by dopaminergic receptors in the tuberoinfundibular tracts. Several studies of psychiatric patients have attempted to elucidate the clinical utility and biological importance of the effects of neuroleptics in stimulating prolactin secretion. The utility of using plasma or serum prolactin as an index of neuroleptic blood levels at doses administered clinically to patients with psychosis remains controversial (see Smith et al., 1979; Rao et al., 1980; Rubin and Hayes, 1980; Meltzer et al., 1981). To explore the question further, we studied the PRL response in schizophrenic patients treated with an acute dose and several fixed doses of haloperidol over a period of 3-6 weeks. Methods Patients. Patients who had a diagnosis of schizophrenia or schizoaffective disorder by Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) were included in the study. Mean age of patients (+ SD) was 28.7 f 7.8 years (range 18-45). Most of the patients were relapsing schizophrenics who had been hospitalized on several occasions but were not chronically hospitalized in long-term state facilities. We did not have accurate data on the amount of

G.K. Ravichandran. M.D., Ru-Band Lu, M.D.. Alla Shvartsburd, M.S., Chandra H. Misra, Ph.D., and Robert C. Smith, M.D.. Ph.D., are in the Section of Biological Psychiatry, and Beng T. Ho, Ph.D., and Myrna Kahn, M.S.. are in the Section of Neurochemistry and Nemopharmacology, Texas Research Institute of Mental Sciences. Houston, TX. Drs. Misra and Smith are also in the Department of Psychiatry and Pharmacology, Baylor College of Medicine. Dr. Lu is now with Tri-Service General Hospital, Taipei, Taiwan. (Reprint requests to Dr. R.C. Smith, Biological Psychiatry. TRIMS, 1300 Moursund. Texas Medical Center, Houston, TX 77030. USA.) 0165-1781;84:$03.00

@ 1984 Elsevier Science Publishers

B.V

neuroleptic drugs administered to the patients over the course of their illness. Since most of our patients were chronic or subchronic schizophrenics who had several hospitalizations, we assume that they have been treated with neuroleptics on a continuous or frequent intermittent basis during the course of their prolonged illness. Therefore, we chose years since onset of illness as a crude measure of years of neuroleptic treatment. Design. Patients who had not received neuroleptics or antidepressant medication in the preceding 2 weeks had a drug-free period of at least 1 week, and patients who had recently received neuroleptics had a I$$- to 2-week drug-free period before beginning treatment with haloperidol. After the drug-free washout period, patients received a single oral dose of 20 mg haloperidol, administered in liquid form on day 1 of drug therapy. They then received a fixed reduced dose for the next 2 days, followed by a higher fixed dose of haloperidol (usually twice the reduced dose) for 3 weeks. The first 24 patients received a fixed dose of haloperidol of 20 mg/ day (10 mg b.i.d.), 11patients received a fixed dose of 10 mg/ day, and 7 patients received a fixed dose of 25 mg/day. Haloperidol was administered in liquid concentrate form on the b.i.d. fixed dose schedule at 9 a.m. and 9 p.m. If significant parkinsonian symptoms developed, patients were treated with benztropine mesylate, l-2 mg b.i.d. Other accessory drugs were not administered, except for occasional aspirin or laxatives. The numbers of patients for specific comparisons differ (see tables) because not all patients cooperated at all the blood sampling times discussed below. Study

Blood Sampling. During regular dosage with haloperidol, blood samples for haloperidol assay were drawn twice a week at 8:30 a.m. about 11% hours after the last dose, and before the morning dose. Blood samples were drawn twice during the washout period (at 9 a.m.), and 3 and 23 hours after the first acute haloperidol dose. Haloperidol blood was drawn in EDTA (ethylenediaminotetraacetate) tubes from which the rubber tip was removed, covered with parafilm, spun to separate plasma and packed red blood cells (RBCs), and the buffy coat was discarded. Sodium metabisulfate was added as a preservative. Samples were stored at -20°C until analysis. Blood samples for serum PRL determination were drawn in syringes and transferred to integrated serum separator (ISS) tubes. The serum was separated and frozen at -20°C. Blood samples were collected twice during the washout period (day 7 and day 14), 3 hours and 23 hours after the first haloperidol acute dose, and 2 weeks after beginning treatment with a fixed dose of neuroleptic (steady-state sample). All steady-state samples were drawn between 8:30 and 9:00 a.m. Patients were seated when blood samples were drawn into the syringe.They had completed their normal breakfast served between 7 and 8 a.m. Chemical Assays. Analysis of plasma levels and RBC levels of haloperidol was performed on a 5830A Hewlett-Packard gas liquid chromatograph (GLC) equipped with a dual nitrogenphosphorus flame ionization detector and area integrator. We followed the procedures described by Javaid et al. (1979) with modifications as described in detail elsewhere (Smith et al., 1982; Shvartsburd et al., 1983). The coefficient of variation of triplicate assays was less than 2%. Radioreceptor assay (RRA) of plasma haloperidol was carried out following the general procedures of Creese and Snyder (1977), with modifications as described in detail in a previous publication (Smith et al., 1980). Serum PRL levels were determined by radioimmunoassay (RIA) using the human prolactin RIA kit from Immune-Nuclear Corporation. The assay was run directly in the scintillation minivials using an overnight incubation. After addition of the second antibody precipitation reagent, the minivials were centrifuged and the supernatant aspirated. The bound fractions were dissolved in 9.5 ml of distilled water and 5 ml of Instagel (Packard Instrument Co.) were added to each vial. The samples were counted in a Packard Tri-Carb Liquid Scintillation Counter. The coefficient of variation of PRL determinations was 6.95% at 13 ng/ ml and 6.39% at 44 ngj ml. Statistical

baseline

Analysis.

(washout)

For most analyses, PRL values during drug treatment were corrected for PRL, and these values are labeled delta prolactin (A PRL). For some

63 analyses, male and female PRL values were analyzed separately. In other analyses, male and female values were combined, but adjusted for sex differences by the following calculation: adjusted

APRLi = APRLi X APRL,,,

for each sex separately

L

Steady-state haloperidol levels reported here for each patient are mean values calculated from blood level measurements of four to six individual samples drawn between day 6 and day 24 after the start of drug administration. An analysis of variance (ANOVA) was used to assess dose effects on APRL. Pearson correlation coefficients were used to determine the relationship between two variables. For some analyses, PRL values were log transformed, and the analyses were performed both on the original and the log-transformed values.

Results Baseline

serum

PRL

The 20 female patients male patients.

levels

were generally

had a mean baseline

Table 1. Effects of halooeridol Patients All

Baseline PRL

in females than in males (Table 1). PRL which was about twice that of the 20

higher

on serum orolactin (PRLIl APRL2 3 hours

23 hours

patients 22.4 k 17.6

n3

n4

94.4 + 80.9

15.9 + 19.2

40

23

22

20.6 + 20.0

102.9 k 79.5

15.6 + 19.6

21

21

21

30.0 f 19.5

151.3 i 84.5

24.8 k 23.1

20

11

11

32.4 f 22.4

166.6 s 71.2

25.0 k 24.4

10

10

10

Females

n3

n4 Males

15.2 + 12.8

n3

20 10.0 k 10.6

n4 1. 2. 3. 4

There females.

11

42.3 k 19.6

7.0 t

44.9 2 18.3

a.1

11

12

7.0 t

a.1

11

11

Data are presented as mean k SD of baseline prolactin or A PRL (ng/ml) Prolactin response to 20 mg acute dose of haloperidol. All patients from whom we have data at the specific time point indicated. Patients who had blood drawn at all the time points indicated.

were also differences in the serum PRL response Both males and females showed a mean increase

to haloperidol in males and in serum PRL 3 hours after

64 the 20 mg acute dose of haloperidol, but the increase in PRL response in females was about three times the increase in males (Table 1). Females also had significantly higher levels of PRL during fixed dose treatment with haloperidol (Fig. 1). Females also showed more variability than males. We did not have reliable data on phase of menstrual cycle to investigate the influence of this variable on PRL levels in our female patients. No patient failed to show a PRL increase either 3 hours after haloperidol or during regular dosing with haloperidol. There were no significant correlations between APRL or adjusted APRL after the acute dose or regular dosing with haloperidol and years since onset of psychosis, our crude measure of duration of neuroleptic treatment. Fig. 1. Relatonship

between dose of haloperidol

1.40-

and prolactin response

175.0 1

3

B

LSS-

150.0-

.=ALLPATIENTS

f

g

1*so

B

1.65-

E w

i!

. 0

3 2

16&O-

1.60-

% p: i

lOO.O-

1.15-

E w

75.0-

I 0 7)

E l.lOR

i

B 8

50.0-

65.0 l.oo-

I61

z

l.OI-

y

ii

tL1

Ii% 0.05 10

16

60

06

DOSE EALOPERIDOL (mg/day)

'e

i

“-“+T7kTz7

DOSE HALOPERIDOL (mg/day)

Each l 0 represents mean (f SEMi of APRL or sex-adjusted (adj. I APRL based on Indicated (nl. Dose refers to fixed dose of haloperidol (see text for details). Analyses of variance of APRL, adj. APRL. log APFIL, and log adj. APRL all show no significant Fs (p > 0.101 for dose effects.

What was the relationship between the dose of haloperidol and serum PRL response? In a comparison of PRL levels in patients treated with different fixed doses of haloperidol, there was not a significant dose effect of haloperidol on serum PRL (APRL); there was a slight trend for patients receiving higher doses to have higher PRL levels, especially among females (Fig. 1). Results were similar for analyses done on the original APRL values and log-transformed APRL values. On the other hand, there were significant intrasubject correlations between haloperidol dose and PRL response. A patient’s PRL response to haloperido13 hours and 23 hours after the acute

65 20 mg dose was positively fixed doses of haloperidol. (Table 2).

correlated with PRL levels during regular administration of These correlations were stronger for females than for males

Table 2. Relationship between prolactin haloperidol in the same patients

responses

to different

dosages of

HaloDeridol dose condition Acute dose

Acute dose (23 hrs)

patients

3 hours

0.591

(n = 18-23)

23 hours

Patients All

Males

3 hours

(n = 9-12) Females

3 hours

(n=9-111

Pearson correlation

0.762

0.601

0.612

-0.22

-

0.32

0.583

0.18

0.41

0.34

0.614

-

0.473

0.483

23 hours

Each number represents other indicated times.

0.631

0.423

23 hours

Fixed dose

Reduced dose

coefficient

(r) between APRL at 3 hours or 23 hours and APRL at

l.p
Steady-state plasma and RBC levels of haloperidol, estimated by the GLC method, were significantly correlated with PRL response to haloperidol (Table 3). The correlations were higher for male than for female patients. There were no significant correlations between serum PRL and plasma or RBC haloperido13 hours or 23 hours after the acute dose of haloperidol. In some patients, steady-state samples of plasma haloperidol were assayed by RRA as well as the GLC methods. Overall, GLC haloperidol correlated slightly better with PRL response, and this was especially true for males (Table 4). There was a moderate correlation between GLC and RRA haloperidol levels (r = 0.78,~ < O.OOl), but these could not be interchanged (Fig. 2). Table 3. Relationship between peridol and serum prolactin

blood levels of halo-

Acute dose 3 hours

23 hours

Fixed dose

Plasma haloperidol

n

-0.02

-0.33

0.471

23

22

40

-0.05

-0.04

0.432

14

13

Red cell haloperidol

n

36

Each number represents Pearson correlation coefficient lr) between plasma or red cell level of haloperidol. determined by GLC procedure, and increase in serum prolactin level (adjusted APRL) in the same patients at the indicated time and dose conditions. 1. p < 0.001. 2. p < 0.01.

66

Table 4. Comparison of correlation of GLC vs. RRA halooeridol olasma levels with serum orolactin Correlation between steady-state haloperidol levels and plasma prolactin All patients

Males

Females

0.461

0.642

0.32

29

12

17

0.322

0.423

0.373

29

12

17

Mean GLC haloperidol plasma level n Mean RRA haloperidol

plasma level

n

Each number represents Pearson correlation coefficient ir) between steady-state plasma haloperidol, determined by GLC or RRA procedure. and increase in serum prolactin level (adjusted APRLI in the same patients. 1. p c 0.001, 2. p < 0.05. 3. p < 0.10.

Fig. 2. Relationship and RRA

between plasma level of haloperidol

determined

by GLC

25.0

r=.78 p<.OOOl

0

.

.

.

. 0

b 0

“‘.l~ko &s&k-SI;ATGkR I~,A&A EALOPERIDOL (q/ml)

Each point represents

mean steady-state

plasma level when patient was treated with fixed dose of haloperidol.

67 Discussion This is the first study to compare separately the relationship of plasma versus red cell haloperidol levels to serum PRL, and also the first to compare the correlations of GLC versus RRA methods of measuring haloperidol with the serum PRL response produced by this drug. The correlations between steady-state haloperidol blood levels and PRL response are considerably stronger than the relationship between butaperazine blood levels and plasma PRL response that we previously reported in chronic schizophrenic patients (Smith et al., 1979). Although the correlations we report between plasma or red cell haloperidol, assayed by GLC or RRA methods, and serum PRL were statistically significant, they are considerably lower than those obtained using an RIA method to measure plasma or serum haloperidol. Rubin et al. (1980), Rubin and Forster (1980) and Poland and Rubin (1981) reported a correlation of 0.83 to 0.87 between serum haloperidol and PRL using RIA procedures to measure haloperidol and PRL, and Rao et al. (1980) reported a very similar correlation (I 0.83) between plasma haloperidol and plasma PRL. The correlation that we report is more similar in magnitude to that reported by Kolakowska et al. (1975) in their study of chlorpromazine and plasma PRL (r = 0.67) in which they used a GLC method to measure chlorpromazine. Furthermore, we found no correlation between serum PRL and plasma or red cell levels of haloperidol at 3 hours or 23 hours after the acute dose of haloperidol, whereas with the neuroleptic butaperazine there was a significant correlation between the plasma butaperazine and the plasma PRL 2 hours after an acute 40 mg dose (Smith et al., 1979). These findings point out the complexity of the relationship between blood levels of neuroleptics and PRL response to neuroleptics in man. The degree of concordance between neuroleptic drug levels and PRL response may vary considerably depending on the specific neuroleptic studied and the method chosen for drug assay. The results of our current studies, which demonstrated only a moderate correlation between steady-state serum PRL and plasma or red cell haloperidol, suggest that the measurement of serum PRL cannot be substituted for measurement of drug levels of haloperidol, assayed by GLC or RRA techniques, in patients being treated with clinical doses of this medication. The correlations between PRL responses to the acute dose and fixed dose of haloperidol in the same patient were of equal or greater magnitude than the correlation between haloperidol blood levels and serum PRL. These findings suggest that PRL responses of a given patient to a different dose of a neuroleptic drug are predictable, and may provide a guide to choosing the optimum dosage. Ohman and Axelsson (1978) presented evidence that mathematical treatment of PRL responses to different doses of thioridazine given to the same patients using equilibrium enzyme kinetic equations yielded results which predicted dosage requirements for efficacious treatment of schizophrenic psychosis. The peak PRL response to an acute 20 mg dose of haloperidol that we report is considerably higher than the peak PRL response reported by Langer et al. (1977) and Gruen et al. (1978) to 1.O mg or 1.5 mg of haloperidol administered intramuscularly; the mean peak increase in PRL reported by Gruen et al., in male subjects, was 18.9 ng/ ml, whereas the mean increase in PRL in our male subjects was 42.3 ng/ ml. The PRL increase in our male subjects is also considerably higher than the mean 3-hour PRL peak reported by Rubin et al. (1976) who administered 0.25 mg to 0.5 mg q

68 haloperidol to male subjects. However, in a later study by Rubin and Hayes (1979) three of seven subjects who received 0.5 mg haloperidol intramuscularly or intravenously did have APRL values that were greater than 40 ng/ ml. Our findings suggest that for many subjects the PRL response to an acute oral dose of haloperidol may continue to increase at doses in the range used clinically, beyond the PRL response obtained at small doses of the drug administered by the intramuscular or intravenous route. The lack of correlation between haloperidol blood levels and PRL response after the acute haloperidol dose that we reported here contrasts with the moderately high correlations reported by Rubin and Hayes (1979) 1 to 4 hours after an intramuscular dose of haloperidol, and also the high correlation (r = 0.92) reported by Meltzer et al. (1981) between serum PRL response to low intramuscular doses of chlorpromazine and serum blood levels of this neuroleptic assayed by an RRA procedure. These contrasting results may be due to differences in drug assay methods (GLC procedures in our study vs. RRA or RIA procedures in the other studies), limited time sampling after the acute dose in our study, or differences in the relationship between blood levels and PRL response when subjects are given low acute doses of neuroleptics (0.5 mg haloperidol, 25-50 mg chlorpromazine) administered intramuscularly, compared to more standard clinical doses (20 mg haloperidol) administered orally. The contrast between our findings of a lack of relationship between blood levels of haloperidol and PRL response after the acute dose, compared with the significant correlations between haloperidol blood levels and PRL response during regular dosing with this neuroleptic, suggests that different factors may regulate the degree of PRL response to neuroleptics after single vs. multiple dosing with these drugs in man. References Creese, I., and Snyder, S.H. A simple and sensitive radioreceptor assay for antischizophrenic drugs in blood. Nature, 270, 180 (1977). Gruen, P.H., Sachar, E.J., Largen, G., Altman, N., Leifer, M., Frantz, A., and Halpern, F.S. Prolactin response to neuroleptics in normal and schizophrenic subjects. Archives of General Psychiatry,

35, 108 (1978).

Javaid, J.T., Dekirmenjian, H., Leskevych, V., and Davis, J.M. Determination of butaperizine in biological fluids by gas chromatography using nitrogen specific detection system. Journal of Chromatographic Science, 17, 666 (1979). Kolakowska, T., Wiles, D.H., McNeilly, A.S., and Gelder, M.G. Correlation between plasma levels of prolactin and chlorpromazine in psychiatric patients. Psychological Medicine, 5,214 (1975).

Langer, G., Sachar, E.J., Halpern, F.S., Gruen, P.H., and Solomon, M. The prolactin neuroendocrine response to neuroleptic drugs, a test of neuroendocrine blockade: Neuroendocrine studies in normal men. Journal of Clinical Endocrinology and Metabolism, 45,996 (1977). Meltzer, H.Y., Busch, D.A., and Fang, V.S. Effects of neuroleptics on serum prolactin levels in relation to clinical response and neuroleptic blood levels. In: Usdin, E., and Davis, J.M., eds. Clinicnl Pharmacology in Psychiatry. Elsevier, New York, p. 25 1 (198 I). Ohman, R., and Axelsson, R. Relationship between prolactin response and antipsychotic effect of thioridazine in psychiatric patients. European Journal of Clinical Pharmacology, 14, 1I1 (1978). Poland, R.E., and Rubin, R.T. Radioimmunoassay of haloperidol in human serum: Correlation of serum haloperidol with serum prolactin. Life Sciences, 29, 1837 (1981).

69

Rao, R., Bishop, M., and Cooper, A. Clinical state, plasma level of haloperidol and prolactin: A correlation study in chronic schizophrenia. British Journnl of Psychiatry. 137, 518 (1980). Rubin, R.T., and Forster, B. Haloperidol stimulation of prolactin secretion: How many. blood samples are needed to define the hormone response. Communications in Psychopharmacology,

4,4

I ( 1980).

Rubin, R.T., Frosman, haloperidol determination

A., Heykants, in psychiatric

J., Ohman, R., Tower, B., and Michlels, M. Serum patients. Archives of General Psychiurry, 37, 1069

(1980).

Rubin, R.T., and Hayes, S.E. Variability of prolactin response to intravenous and intramuscular haloperidol in normal adult men. Psychopharmacology, 1, 17 ( 1979). Rubin, R.T., and Hayes, S.E. The prolactin response to neuroleptic drugs; mechanisms, applications and limitations. Psychoneuroendocrinology, 5, 12 I (1980). Rubin, R.T., Poland, R.E., O’Connor, T., Govin, P.R., and Tower, B.B. Selective neuroendocrine effects of low-dosage haloperidol in normal adult men. Psychopharmacology, 47, 135 (1976).

Shvartsburd, A., Dekirmenjian, H., and Smith, R.C. Blood levels of haloperidol in psychiatric patients. Journal of Clinical Psychopharmacology, 3,7 (1983). Smith, R.C., Tamminga, C.A., Crayton, J.W., Dekirmenjian, F., and Davis, J.M. Relationship of butaperazine blood levels to plasma prolactin in chronic schizophrenic patients. Psychopharmacology,

66,29

(1979).

Smith, R.C., Vroulis, G., Misra, C.H., Schoolar, J.C., DeJohn, C., Korivi, P., Leelavathi, D.E., and Arzu, D. Receptor techniques in the study of plasma levels of neuroleptics and antidepressant drugs. Communications in Psychopharmacology, 4,45 I (1980). Smith, R.C., Vroulis, G., Shvartsburd, A., Allen, R., Schoolar, J.C., Chojnacki, M., and Johnson, R. RBC and plasma levels of haloperidol and clinical response in schizophrenia. American

Journal

Spitzer, reliability.

R.L.,

of Psychiatry,

Endicott,

Archives

139, 1054 (1982).

J., and Robins,

of General

Psychiatry,

E. Research 35, 773 (1978).

Diagnostic

Criteria:

Rationale

and