Am J Psychiatry 136:12, December /979

Effect of Clozapine on Human Serum Prolactin Levels

BY HERBERT Y. MELTZER, M.D., DAVID J. GOODE, M.D., PAUL M. SCHYVE, M.D.,

MICHAEL YOUNG, PH.D., AND VICTOR S. FANG, PH.D.

exception and thus a challenge to the dopamine hy-

The authors determined serum prolactin levels in 13
pothesis of schizophrenia (8). Clozapine has been re-
patients receiving clozapine, an antipsychotic drug
ported to displace 3H-haloperidol from striatal binding
that does not produce extrapyramidal side effects.
sites in vitro at concentrations that appear to be pro-
Morning serumn prolactin levels, I I hours after the last
portional to its antipsychotic potency (9, 10). A recent
dose, it’ere not elevated during chronic treatment with
study indicated that its ability to displace 3H-spiperone
clozapine in any subject despite its therapeutic effects.
from striatal dopamine receptors is much less than
Serumn prolactin levels tt’ere moderately increased
would be expected on the basis of its clinical potency
bettt’een 90 minutes and 4 hours after administration
(1 1). Thus, there is still controversy concerning the
ofvery high doses oforal clozapine in 4 patients but
ability of clozapine to block dopamine receptors,
vere smaller than those produced by chlorpromazine
which is believed to be the basis of the antipsychotic
in other subjects. The authors suggest that clozapine
action of the neuroleptics.
may achieve its antipsychotic effect differently than do
The ability of neuroleptics to produce blockade of
classical neuroleptics and that sustained prolactin
dopamine receptors leads to augmented prolactin se-
increases are not essentialfor antipsychotic action.
cretion in vivo (12) and in vitro (13), since the release
of prolactin is inhibited by dopamine (14). This effect
of dopamine is almost certainly exerted at the pituitary
CLOZAPINE, A DIBENZODIAZEPINE, is an antipsychotic level (13). The ability of neuroleptics to stimulate pro-
drug that has attracted great interest because it may lactin secretion is proportional to antipsychotic po-
act via a mechanism different from that of classical tency in man (15) and in laboratory rats (16). Thus, it is
neuroleptics. It does not produce extrapyramidal side useful to consider the ability of clozapine to stimulate
effects in man ( 1-3) and its administration may not lead prolactin secretion in relation to its clinical potency.
to the development of tardive dyskinesia. In laborato- The mean (±SD) clinical antipsychotic dose of cloza-
ry animals, clozapine differs from classical neurolep- pine in 8 studies was 241 ± 162 mg/day (3, 17-23) com-
tics in its inability or limited ability to induce catalepsy pared with a mean of691±411 mg/day for chlorproma-
or block apomorphine-induced stereotypy (4), both of zine in 1 1 studies (24). This would suggest clozapine is
which are characteristic of classical neuroleptics and approximately three times more potent than chlor-
are believed to result from dopamine receptor block- promazine as an antipsychotic agent. The mean dose
ade (5). These differences have led various investiga- of clozapine administered in a recent study was 800 mg
tors to propose that clozapine may exert its antipsy- (25), which is in general agreement with our clinical
chotic effects by a means other than dopamine recep- experience; one would expect this dose ofclozapine to
tor blockade (6-8) and that it may represent an increase prolactin secretion at least as potently or
more potently than chlorpromazine. We have reported
clozapine can stimulate secretion of rat prolactin (7),
Received Oct. 23, 1978; revised Jan. 31, 1979; accepted March 14, but it is only about one-half as potent as chlorproma-
1979.
zine in this regard.
Dr. Meltzer is Professor of Psychiatry, University of Chicago Pritz- We have previously reported preliminary evidence
ker School of Medicine, 950 East 59th St., Chicago, Ill. 60637,
where Dr. Fang is Associate Professor, Department of Medicine. that clozapine has little or no effect on human serum
Dr. Meltzer is also Professor of Psychiatry, Illinois State Psychiatric prolactin levels (16). We wish to report additional data
Institute, Chicago, where Dr. Schyve is Associate Director, Labora-
tory of Biological Psychiatry, and Dr. Young is Research Psycholo-
that indicate clozapine can produce brief, small in-
gist. Dr. Goode is Associate Professor of Psychiatry, Bowman Grey creases in serum prolactin levels in chronic schizo-
School of Medicine, Winston-Salem, N.C. phrenics. Clozapine administration has been greatly
This research was supported in part by Alcohol, Drug Abuse, and restricted because of an unacceptable incidence of
Mental Health Administration grants MH-30938 and MH-29206 from agranulocytosis (26, 27); therefore, we have no further
the National Institute of Mental Health. Dr. Meltzer is the recipient
of Research Scientist Award MH-47808. opportunity for additional testing of its effects on
serum prolactin levels in man, but the consistency of
The authors wish to thank Dr. Justine Petrie of the Rochester State
Hospital, Rochester, Minn., for supplying blood samples and clini- our findings indicates our results are likely to be valid
cal data from several patients. and generalizable.

1550 0002-953X/79/ 13/ 1550/06/$00.55 © 1979 American Psychiatric Association

Am J Psychiatry 136:12, December /979 MELTZER, GOODE, SCHYVE, ET AL

METHOD els were 59± 17 ng/ml, and mean serum prolactin levels
while receiving clozapine were 57±20 ng/ml. Prolactin
The subjects included 6 male and 7 female chronic levels during clozapine treatment were 46±22 ng/ml
schizophrenic patients (diagnosed with the Research for the 6 patients for whom no placebo period samples
Diagnostic Criteria, 28) admitted to the Illinois State were available. This is not significantly different from
Psychiatric Institute or the Rochester State Hospital. that of the 7 patients for whom pretreatment prolactin
None had received long-acting neuroleptics for at least levels were available. Prolactin levels during placebo
1 month or short-acting neuroleptics for at least 1 week treatment or clozapine treatment, or both, slightly ex-
prior to receiving clozapine. All gave informed con- ceeded the upper limit of normal in 4 of the male pa-
sent for the drug trial and related endocrine studies. tients and 4 ofthe female patients. We have previously
The initial dose ofclozapine was increased from 10 mg reported slight elevations in serum prolactin levels in
b.i.d. up to a maximum of 400 mg b.i.d. The rate of untreated schizophrenic patients and attributed these
increase varied from subject to subject but maximum to stress effects or lingering increases from nocturnal
dose was usually reached by 4 weeks. Two of the pa- elevation in prolactin secretion (16).
tients also received standard neuroleptics following The mean peak serum prolactin levels for the 6 male
the clozapine trial. In addition, we will present serum schizophrenic patients receiving I 50-800 mg of cloza-
prolactin levels from other schizophrenic patients who pine were significantly less than those in 13 male schiz-
received chlorpromazine. ophrenic patients receiving 800 mg of chlorpromazine:
We will present two types of serum prolactin data. 49.3±23.3 ng/ml versus 85±35 ng/ml (t=2. 126, p<.O5).
First, blood samples were obtained between 8:00 and For 7 women receiving 150-800 mg clozapine, mean
8:30 a.m. (1 to 2 hours after waking) at the end of the serum prolactin levels were also significantly less than
placebo period or during the medication period. This those of7 women receiving 800 mg of chlorpromazine:
was generally 1 1 hours after the last dose of medica- 54.4±19.6 ng/ml versus 280±79 ng/ml (t=6.827,
tion, which was given at 9:00 a.m. and 9:00 p.m. Sec- p<.OOl).
ond, in 4 subjects, an indwelling catheter was placed in Serum prolactin levels were available from 2 female
an antecubital vein at 10:00 p.m., three blood samples subjects who received both clozapine and classical
were obtained at 20-minute intervals, and then oral neuroleptics. For I subject, mean serum prolactin at
clozapine or placebo was given. Thereafter, blood 800 mg/day of clozapine was 45 ±6 ng/ml (13 determi-
samples were obtained every 30 minutes over a 4-hour nations) compared with 130± 15 ng/ml (7 determina-
period. Identical studies were carried out in 13 patients tions) at 400 mg/day ofchlorpromazine and 125± 19 ng/
receiving various doses of chlorpromazine. ml at 10 mg/day of haloperidol (7 determinations). For
Prolactin levels were determined by a double anti- the other subject, mean serum prolactin at 600 mg/day
body radioimmunoassay as previously described (29). of clozapine was 58± 14 ng/ml (13 determinations);
Because of the nature of the standard used, the levels serum prolactin at 1200 mg/day ofchlorpromazine was
we report are 3.8 times those generally found using 239±40 ng/ml (7 determinations).
conventional standards. This less pure standard per- For 3 additional subjects, morning serum prolactin
mits the detection of relatively small changes in pro- levels were obtained Monday through Friday for the 3-
lactin levels. Upper limit of normal is 60 ng/ml for fe- to 4-week period of clozapine treatment. In none of
males and 35 ng/ml for males in morning samples. The these individuals was there evidence of an increase in
interassay variation is less than 13%. early morning serum prolactin levels at any time dur-
Clinical state was assessed twice during the placebo ing that period. Placebo and clozapine prolactin levels
period and weekly thereafter with the Brief Psychiatric for one of these subjects are given in figure 1.
Rating Scale (BPRS) (30) and the Clinical Global Im- We next compared the serum prolactin levels for 4
pressions (CGI). hours after drug ingestion in 3 patients who received
200 mg of clozapine b.i.d. and 1 who received 300 mg
ofclozapine b.i.d. with the increase in serum prolactin
RESULTS1 levels in 1 1 patients who received 200 mg of chlor-
promazine b.i.d. and 2 who received 300 mg b.i.d. of
The mean (± SD) clozapine dose in our study the latter drug. All subjects had received these doses
(458±228 mg/ml for females, 579±2 16 mg/ml for for at least I week at the time of study. The clozapine-
males) was considerably higher than that utilized in treated patients had the lowest baseline-on-drug serum
most previous studies (1-3, 17-23, 25). Despite the prolactin levels. None of the 4 clozapine-treated sub-
high dose of clozapine, serum prolactin levels were not jects had baseline-on-drug serum prolactin levels that
significantly different from baseline in the 7 subjects differed from serum prolactin levels during the placebo
for whom morning prolactin levels were available from period. All but 1 of the 13 patients receiving chlor-
the placebo period as well as during clozapine treat- promazine had elevated baseline-on-drug serum pro-
ment. For these 7 patients, pretreatment prolactin 1ev- lactin levels compared with placebo prolactin levels.
The difference between the clozapine-treated and
chlorpromazine-treated patients was highly significant
‘Tables are available on request from Dr. Meltzer. (Fisher exact probability=p<.01). This is in agree-

1551
CLOZAPINE AND PROLACTIN LEVELS Am J Psychiatry /36:12, December 1979

FIGURE 1 13 chlorpromazine-treated patients did not increase

Morning Serum Prolactin Levels in a Schizophrenic Man Given beyond baseline levels in the 4-hour period after chlor-
Placebo and Clozapine
promazine administration. The magnitude of the mean
50 increase in serum prolactin levels in the 4 clozapine-
treated patients was less than that in 9 of 13 chlor-
40 promazine-treated patients. However, because of the
30 relatively low baseline-on-drug serum prolactin levels
in the clozapine-treated patients, the ratio of peak
serum prolactin to baseline-on-drug serum prolactin
20
was higher in 2 of the clozapine patients than in all but
o 1-
1 of the chlorpromazine-treated patients. Thus, cloza-
10 200!
pine elevates serum prolactin levels in man, for at least
PLACEBO
a 4-hour period, but the magnitude of the increase is
F 10 15 20 2’5 30
slight and barely exceeds the 95% upper limit of nor-
DAYS mal.
All of the patients who received clozapine improved
FIGURE 2 during the drug trial period when compared with pla-
Serum Prolactin Levels Following Oral Administration of Clozapine in cebo, as evidenced by changes in total BPRS score
a Schizophrenic Woman Receiving Chronic Clozapinea and CGI. Before treatment with standard neuroleptics
60
was initiated, 2 of the patients had major exacerba-
tions of psychotic symptoms when clozapine treat-
ment was stopped.
50

DISCUSSION
40
E
Prolactin levels were not significantly different from
C

z 30
baseline-before-drug in serum samples obtained II
0 #{149}
Clozapine (400 mg p.o.) hours after the last dose in I 3 patients treated chroni-
-J A Placebo cally with relatively high doses ofclozapine. All 13 pa-
0
tients experienced moderate to marked therapeutic
benefit from clozapine; there is little question that at
antipsychotic dose levels clozapine differs qualita-
10
tively from the classical antipsychotic drugs in regard
to effects on prolactin secretion. The latter produce
30 60 90 120 150 180 210 240 persistent increases in serum prolactin levels in all
000
CJ subjects after a few days of treatment (29). We did not
TIME (minutes)
observe increases in serum prolactin in the initial days
of treatment with clozapine; therefore, lack of an in-
‘Note normal baseline prolactin levels.
crease in serum prolactin levels was not due to toler-
ance.
When we monitored serum prolactin levels for up to
ment with the data from 8:00 a.m. serum prolactin lev- 4 hours after ingestion of high doses of clozapine, we
els and indicates that clozapine did not produce pro- found that clozapine had a slight and transient ability
longed elevations in serum prolactin. to stimulate prolactin secretion. Serum prolactin in-
All 4 of the patients who received clozapine had an creased in all 4 subjects. The increases were less than
increase in serum prolactin levels during the 4-hour pe- those produced by relatively smaller doses of chlor-
riod after ingestion of clozapine. The increase began promazine. Placebo had no effect on prolactin levels in
45-90 minutes after clozapine administration and was I of the clozapine-treated patients and 6 of the chlor-
still present at 4 hours in all 4 subjects. The peak promazine-treated patients.
serum prolactin levels within 4 hours after clozapine The difference between the effects of clozapine and
treatment were significantly greater than observed chlorpromazine (and other neuroleptics) on serum pro-
baseline-on-drug serum prolactin levels (paired lactin is unlikely to be entirely due to decreased ab-
t=5.36, p<.Ol). The time course of the serum pro- sorption or rapid disappearance of clozapine. The ab-
lactin response in one of these subjects who was ad- sorption half-life of both drugs is similar: clozapine, 40
ministered clozapine and placebo is given in figure 2. minutes2; chlorpromazine, 1-2 hours (31). The elimi-
There was no increase in serum prolactin levels over nation of clozapine is biphasic with half-lives of 9.5
baseline-on-drug in this subject when given a placebo
whereas serum prolactin levels were clearly increased 2investigator’s Manual for Leponox,” Sandoz, Inc., East Han-
following clozapine. Serum prolactin levels in 2 of the over, N.J.

1552
Am J Psychiatry 136:12, December /979 MELTZER, GOODE, SCHYVE, ET AL

and 38 hours; for chlorpromazine, elimination half-life bility. More importantly, they observed a very marked
has recently been reported as 17.7 hours (31). Because inhibition of the apomorphine-induced increase in
of the extensive metabolism of chlorpromazine, this growth hormone in 6 or 7 subjects treated with 200 mg
figure may not reflect the functional half-life of chlor- ofclozapine over a 3-day period. These results suggest
promazine. The available data indicate that the lack of that clozapine can block the hypothalamic dopamine
effect of clozapine on serum prolactin levels at 1 1 receptors which mediate this apomorphine effect and
hours after the last dose is probably not solely the re- together with our data indicate an important difference
sult of an absence of clozapine from plasma. The per- in the dopamine receptors in pituitary and the hypo-
sistence of clozapine for at least 1 1 hours after the last thalamus. It would be of interest to determine whether
dose is suggested by drowsiness, hypotension, and se- clozapine inhibited the apomorphine-induced decrease
dation in some subjects, even though serum prolactin in serum prolactin levels in man.
levels are not elevated beyond placebo levels. It is well known that a variety of neurotransmitters
Clozapine appears to be a weaker blocker of pitui- (e.g., acetylcholine, serotonin, endorphins, GABA,
tary dopamine receptors in man than would be ex- and possibly norepmnephrine) can affect prolactin Se-
pected on the basis of its antipsychotic potency. We cretion (45-54) and that extrapituitary brain areas may
have found that the IC50 (concentration producing a participate in the regulation of prolactin secretion (12,
50% inhibition) for clozapine for displacement of 3H- 13, 16). Limbic region stimulation can promote pro-
spiroperidol from rat pituitary membranes is 1320±86 lactin secretion (55). Clozapine has clearly been shown
nmol compared to 72.6±4.7 nmol chlorpromazine (32). to affect cholinergic, serotonergic, and adrenergic neu-
For those classical neuroleptics studied to date, the rotransmission (8-12, 56, 57) and to have definite lim-
ability to stimulate prolactin secretion in man or rats is bic effects (34-42). Conceivably, these factors rather
correlated with antipsychotic potency (15, 16). than dopaminergic receptor blockade could account
The capacity of classical neuroleptics to displace for the ability of clozapine to stimulate prolactin secre-
3H-spiroperidol from calf pituitary dopamine receptors tion. so this would indicate a fundamental difference
in vitro is correlated with antipsychotic potency (33). between clozapine and classical neuroleptics and fur-
Clozapine is distinctly less potent in its in vivo effects ther support the thesis that clozapine should not be
on prolactin secretion in both rat and man and in its in considered just another neuroleptic. Whether a dif-
vitro effects on 3H-spiroperidol binding than would be ference in the mechanism by which prolactin secretion
predicted on the basis of its antipsychotic potency. is stimulated also indicates a difference in the means of
There is controversy concerning its potency to dis- antipsychotic action remains to be determined.
place 3H-spiroperidol from striatum in relation to its The proven efficacy ofclozapine as an antipsychotic
antipsychotic effect (9-Il). These apparent quantita- agent in the absence of any major effect on prolactin
tive differences between clozapine and classical neuro- secretion is additional evidence that the increase in
leptics raise the possibility that clozapine may achieve prolactin levels produced by neuroleptics has little sig-
its antipsychotic effects via a nondopaminergic mecha- nificance for their antipsychotic action. Because of the
nism. However, it is conceivable that clozapine might concern that prolactin elevations may increase the risk
selectively block dopamine receptors in the human of mammary carcinoma in women at high risk for this
dopaminergic limbic system. Determination of the abil- tumor (e.g., those with a strong family history or those
ity of clozapine to displace classical dopamine antag- who have had treatment for a prolactin-dependent
onists from human limbic dopamine receptors will be mammary carcinoma) (58), clozapine may be specifi-
helpful in testing this hypothesis. Animal studies mdi- cally indicated in the treatment of such individuals.
cate that clozapine can affect dopamine metabolism in This, however, has to be weighed against the greater
both the striatum and limbic regions, but results con- risk ofagranulocytosis from clozapine, which might be
flict as to whether clozapine has a greater effect on lim- a special problem following chemotherapy or radiation
bic (34-38) or striatal (39, 40) dopamine metabolism or for a prolactin-dependent carcinoma.
an equal effect in both areas (41, 42). Bartholini and
associates (43) and Wilk and associates (40) have
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CLOZAPINE AND PROLACTIN LEVELS Am J Psychiatry 136:12, December 1979

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