Prolactin responses to domperidone in chronic schizophrenia

159

Psychiatry Research, 42:159-169 Elsevier

Prolactin Responses to Domperidone Schizophrenia

in Chronic

Dina Nerozzi, Armando Magnani, Corrado Dastoli, Edoardo Ferri, Giampiero Capesciotti, halo Antonozzi, Gaetano Frajese, and Herbert Y. Meltzer Received April I, 1991; revised version received February 20, 1992; accepted April 7, 1992, Abstract. The prolactin response to 20 mg of domperidone, a peripheral dopamine receptor antagonist, was evaluated in a group of 17 male, drug-free, elderly, chronic schizophrenic patients and 8 age-matched male normal control subjects. Both groups of subjects were receiving a variety of nonpsychotropic medications not known to affect the prolactin response to dopamine receptor antagonists. Basal plasma prolactin levels did not differ between the two groups. However, the prolactin response following domperidone was significantly greater in the schizophrenic patients, although plasma domperidone levels did not differ between the two groups. This effect is opposite to the previously reported effect of domperidone in young schizophrenic patients compared with age-matched control subjects (Nerozzi et al., 1990). The prolactin response to domperidone was markedly smaller in the old compared with the young normal control subjects, whereas the young and old schizophrenic patients had identical responses. Possible explanations for these results are considered, especially the possibility of abnormalities in the release of dopamine and pituitary D, dopamine receptors in the elderly schizophrenic patients compared with age-matched normal control subjects. Key Words. Psychoneuroendocrinology, age, pituitary hormones.

domperidone,

dopamine, D, receptors,

Both clinical and preclinical findings suggest an abnormality of the dopaminergic system in schizophrenia (for review, see Losonczy et al., 1987). Secretion of prolactin from the anterior pituitary gland is under inhibitory dopaminergic control (McLeod, 1976; Meltzer et al., 1978). Dopamine receptor antagonists block the inhibitory effect of dopamine on prolactin release and thereby stimulate prolactin secretion. There have been numerous studies comparing the ability of antipsychotic drugs to stimulate prolactin secretion in unmedicated schizophrenic patients and normal

Dina Nerozzi, M.D., is Assistant Professor in the Department of Experimental Medicine, University of Rome “La Sapienza.” Armando Magnani, M.D., is Research Fellow in the Institute of Clinica Medica V, University oi Rome “La Sapienza.” Corrado Dastoli, M.D., Edoardo Ferri, M.D., Giampiero Capesciotti, M.D.. are Psvchiatrists at the S. Giovanni di Dio Hosoital. Genzano (Rome). ltalo Anionozzi, M.D., is Dire&or of the Service for Genetic and Metadolic ‘Diseases, cepartkent of Experimental Medicine, University of Rome “La Sapienza.” Gaetano Frajese, M.D., is Professor of Endocrinology, University of Rome “La Sapienza.” Herbert Y. Meltzer, M.D., is Director, Laboratory of Biological Psychiatry, Case Western Reserve University, Cleveland, Ohio. (Reprint requests to Dr. D. Nerozzi, Via di Porta Pinciana, 4, 00187 Rome, Italy.) 0165-1781/92/$05.00

@ 1992 Elsevier Scientific

Publishers

Ireland

Ltd.

160

control subjects. Thus, Asnis et al. (1979) found no difference in the prolactin response to haloperidol(0.5 mg, i.m.) in six unmedicated schizophrenic patients and 13 normal control subjects. Similarly, no difference in the prolactin response to chlorpromazine (25 and 50 mg, i.m.) was found in 6 male normal control subjects and 14 unmedicated schizophrenic patients (Meltzer et al., 1981). However, Keks et al. (1987) reported a smaller prolactin response to haloperidol (0.5 mg., i.v.) in 14 drug-free male schizophrenic patients compared with 14 age- and sex-matched normal control subjects. Recently, Copolov et al. (1990) also reported a significantly blunted prolactin response to haloperidol in schizophrenic patients as well as in patients with other psychiatric disorders. We have reported that the prolactin response following domperidone, a peripheral dopamine-blocking agent, was significantly blunted in 16 drug-free, acute, young schizophreniform and schizophrenic males (Nerozzi et al., 1990). The prolactin response was significantly smaller in the schizophreniform patients than in the schizophrenic patients. However, both groups had significantly blunted responses in comparison with the normal control subjects. It should be noted that the mean age of the control subjects in that study was 20.4 years and that of the patients was also 20.4. Because domperidone does not penetrate the blood-brain barrier (Laduron and Leysen, 1979) it may provide a more specific test of the responsivity of pituitary dopamine receptors than does a drug like haloperidol, which acts both centrally and peripherally. In this study, we report the results of a study of the effect of domperidone on prolactin levels in elderly male schizophrenic patients who had been withdrawn from neuroleptic medication for prolonged periods of time in comparison with a group of age-matched normal control subjects. Methods Subjects. The subjects were 20 relatively healthy, nonobese, male schizophrenic patients (mean age = 64.7 years, SD = 7.2). They were hospitalized in a long-term psychiatric unit of the hospital San Giovanni Di Dio near Rome. The duration of hospitalization ranged from 17 to 34 years. The duration of illness averaged nearly 45 years. All patients had been free of neuroleptic drugs for at least 10 years because of the residual nature of their symptomatology. The control group consisted of IO males (mean age = 62.6 years, SD = 4.0) who had no history of psychiatric illness on the basis of an interview as well as the Minnesota Multiphasic Personality Inventory (Hathaway and McKinley, 1951). Some of the patients and control subjects were receiving medication for hypertension, diabetes, or cardiovascular disorders (Table 1). Written informed consent was obtained in 18 of the 30 subjects. It was not possible to obtain written consent in the other I2 subjects, but verbal assent was obtained. Diagnoses were made by consensus of two psychiatrists according to DSM-III criteria (American Psychiatric Association, 1980). Psychopathology was rated with the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962) as well as by the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1985) and the Scale for the Assessment of Positive Symptoms (SAPS; Andreasen, 1985). Patients were divided into three groups according to their age: (I) 50-59; (2) 60-69; and (3) > 70 years. Procedure. Both patients and control subjects were studied in parallel at the same time of day. The protocol began with the insertion of an i.v. catheter between 8:30 and 9:00 a.m. after an overnight fast. Patients were kept at bed rest and were awake for at least I-1 1%hours before the test began. Control subjects entered the hospital the day of the challenge study. The first three baseline blood samples were taken at 15-minute intervals. Subsequent blood sampling

54

54

58

58

62

63

63

65

67

67

68

70

72

73

76

76

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

72

7c

8c

17

-

25

26

30

18

29

28

34

28

30

30

27

34

27

21

33

30

-

38

39

35

45

33

42

41

39

44

33

37

49

41

38

33

43

53

BPRS total score

2

4

-

-

-

-

1

1

0

1

-

1

1

1

1

1

1

1

-

4

4

2

4

1

1

1

1

0

1

1

1

0

1

0

1

1

2

-

4

2

2

3

2

2

3 5

1

2

4 1

1

1

1

1

0

1

1

1

5

4

5

5

4

5

4

5

5

2

1

4

4

4

4

5

3

4

4

4

4

2

0

2

2

1

3

1

0

2

0

1

2

3

2

1

1

2

3

SAPS subscales

-

4

4

3

4

2

3

2

3

2

3

1

4

2

2

5

2

3

2

2

4

4

13

0

1 1

3

2

2

4

4 4

4

3

4

4

4 4

5

4

3

5

3

2

3

0

2

4

3

3

4

4

2

1

SANS subscales

1

1

3

3

2

2

1

4

3

2

3

4

2

3

1

4

1

4

100

550

-

-

-

H2 antagonist40 -

H2 antagonist40

FANS

FANS

Ami, Dig 250x2, Ver 80 -

Met 250x2

Phb 100

Dig 125, The 100x2

Dig 125, Phb 100

Cap 25x2, Chl 25

-

Phe2,5,Bro3,Ran 150x2 -

Ran 150x2, Mex 200x2

Hyd 25x2 -

Phe 2.5,Dig 250

Dig 250 -

-

Present treatment drug/dose (mg)

Note. Ami = amiloridum + hydrochlorothiazidum. Mex = mexiletinum. Bro = bromazepamum. Phb = phenobarbitalum. Cap = captopnlum. Phe = phenforminum. Chl = chlortalidonum. Ran = ranitidinum. Dig = digoxinum. The = theophyllinum. Hyd = hydroxyzinum. Ver = verapamilum. Met = methyldopum. FANS = naproxenum. H2 antagonist = famotidinum.

51

68

6c

73

68

58

3c

5c

61

4c

67

lc

2c

Controls

51

1

Age W)

2

Patients

Subject No.

Duration of hospitalization (yr)

Table 1. Subject characteristics

162 was performed at 60,90, 105, and 120 minutes after oral administration of 20 mg of domperidone. Two patients and two control subjects received placebo instead of domperidone. Blood was drawn into heparinized tubes, centrifuged, and frozen at -20 ‘C until prolactin levels were determined by double antibody radioimmunoassay (Fraioli and Isidori, 1977). The intra-assay and interassay coefficients of variations were 4% and 6.5%, respectively. To evaluate the possibility of a stress response to the challenge procedure, plasma growth hormone and cortisol levels were also determined by radioimmunoassay. Plasma domperidone levels were measured by high pressure liquid chromatography by Janssen Laboratories in Beerse (Belgium). Statistical Analysis. Analysis of variance (ANOVA) was used to assess differences between groups with time as an independent factor. Post hoc tests were also performed with the least significant difference method of Fisher to confirm results obtained by ANOVA.

Results Analysis of plasma prolactin levels revealed that one patient was an outlier. Results for that patient were not included in further analyses. The total number of the patients suitable for the study is therefore 17. Table 1 summarizes the age, current treatment, length of hospitalization, BPRS, SANS, and SAPS data. Table 2 presents the time course of individual plasma prolactin values before and after domperidone, along with domperidone plasma levels. Fig. 1 shows the plasma prolactin levels before and after domperidone administration in schizophrenic patients and normal control subjects. Fig. 1 also shows plasma prolactin levels following placebo administration in two normal control subjects and two schizophrenic patients. Table 3 summarizes the results for prolactin values obtained from the two-way ANOVA. Basal plasma prolactin levels did not differ between patients and control subjects. There was no significant correlation between age and basal plasma prolactin levels for either group. There was a significantly increased prolactin response in the schizophrenic patients compared with normal control subjects as indicated by the significant group effect (p < 0.001). There was a significant time effect but no time X group interaction (Table 3). Both patients and control subjects were divided into three groups according to their age: 50-59, 60-69, and > 70 years. Table 4 presents mean prolactin levels of the area under the curve (AUC). ANOVA indicated that prolactin levels in schizophrenic and normal subjects did not differ significantly within the three age groups. Mean domperidone levels in patients and control subjects did not differ significantly at any time point (data not shown). No correlation was found between domperidone plasma levels and prolactin values at any time point. Inspection of the data in Table 2 suggests that 5 of the 17 schizophrenic patients had peak prolactin plasma levels which exceeded those of any of the normal control subjects. The prolactin responses following placebo administration in two normal control subjects and two schizophrenic patients did not differ significantly (Fig. 1). The great majority of the patients had only mild positive symptoms as indicated by the SAPS (Table l), while negative symptoms, as indicated by the SANS (Table l), ranged from moderate to severe in all subjects. Basal prolactin and the prolactin response (peak - baseline) to domperidone correlated significantly with BPRS total,

163 SANS or SAPS global score. Only scale 4 of the SAPS showed a trend toward correlation with prolactin response to domperidone 0, < 0.06). The mean prolactin response following domperidone administration in elderly normal control subjects was compared with that of young normal control subjects reported in a previous study (Nerozzi et al., 1990) and was found to be significantly reduced (p < 0.000). By contrast, no significant difference was found in the prolactin response to domperidone between young acute and old chronic schizophrenic patients (p < 0.806) (Fig. 2; Table 5). It is not possible to compare domperidone plasma levels in the two studies because we did not measure domperidone levels in our previous study. Basal growth hormone levels were higher in the normal control

Table 2. Plasma prolactin (nglml) responses to domperidone in chronic schizophrenic patients and control subjects Subject No.

me (yr)

0

f60

+90

+105

+120

Patients 1

51

2

1a-1

22(4.3)

40(8.3)

57(9.3)

2

54

4

68(23.0)

67(13.1)

55(7.0)

38(8.4)

3

54

6

47(22.6)

50(16.4)

50(17.0)

37(20.7)

4

58

5

68(30.8)

72(17.1)

77( 9.8)

51( 7.7)

5

58

6

39( 6.6)

39( 3.6)

40( 3.0)

42( 3.6)

6

62

7

15( 8.9)

45(21.4)

97(25.7)

64(28.7)

7

63

32(15.2)

49(34.7)

39(15.1)

30(22.2)

8

63

14 -

6( 1.3)

lO( 3.4)

24( 4.3)

23(14.7)

29(12.6)

87( 8.5)

83( 7.3)

27(-) 132( 7.2)

9

65

3

7(-) 27(29.7)

10

67

4

32( 4.7)

11

67

3

10( 2.5)

18( 2.9)

19( 4.1)

12

68

2

26( 3.9)

13

70

8

16(-l 11l-1

14

72

6

37( 3.8)

16(-l -

29( 1.5) -

15

73

4

55(18.8)

56(15.0)

71(14.5)

16

76

11

16( 3.3)

44(10.9)

52(15.3)

76

5

31( 4.0)

53( 6.2)

5.70

IO(-) 28.22

25( 1.5)

64.53

38.47

44.88

42.94

7.69

3.13

20.43

23.20

25.17

27.69

21( 6.2)

23( 4.0)

17 Mean SD

31( 2.5)

20( 7.8) 30( 3.9) 30( 5.1) 21( 1.2) 73(16.0) 35( 9.5)

Controls lc

50

7

5( 1.7)

2c

54

6

16(26.8)

18(13.1)

16(12.7)

17(12.5)

3c

58

4

17(22.4)

53(13.2)

58( 7.6)

59( 2.8)

4c

61

6

37(18.8)

33( 9.9)

32( 9.7)

28( 4.9)

5c

67

6

6c

67

4

4(ND) 3( 2.6)

7c

72

4

8c

72

4

62.62

5.12

8.21

1.24

Mean SD

7( 4.1)

4( 2.1)

4( 2.0)

8( 5.6)

13( 6.3)

11( 3.3)

21(10.2)

44( 6.1)

44( 3.8)

45( 2.8)

9(14.1)

19( 8.4)

19( 7.1)

20( 6.7)

14.00

23.12

25.87

25.87

11.45

18.37

17.77

18.08

Domperidone plasma levels aregivenInparentheses.

3WD)

164 Fig. 1. Plasma prolactin (PRL) levels following domperidone (20 mg at time and age-matched control subjects 0) in chronic schizophrenic

-

Schizophrenics

Table 3. Analvsis

-I- Controls

-W Placebo Group

of variance on prolactin

levels

df

F

P

Time

4

12.424

0.000

Group

1

11.695

0.001

Times X group

4

0.708

0.588

Source

of variation

120

Residual

Table 4a. Analysis of variance of area under the curve (ng/ml X 120’) of plasma prolactin levels df

F

P

Age

2

0.992

0.389

Groups

1

4.677

0.044

2

0.636

0.540

Source

of variation

2-way interactions: Age, groups

Table 4b. Analysis and controls Source Groups

of variation of age

Times Groups Residual

of age X times

of variance df

between

patients

F

P

2

0.462

0.631

4

12.813

0.001

8

0.278

0.972

110

165

Fig. 2. Plasma prolactin (PRL) levels following domperidone (20 mg at time 0) between elderly normal controls compared with young normal controls and between young acute and old chronic schizophrenic patients W8lW-Q LI-, , “,

--young

subjscts

+ slderly

subjscts

-young

,.-

SubJscts

+ sgsd

rubJscts

Table 5. Analysis of variance on prolactin responses to domperidone in elderly and young subjects Source of variation

df

F

P

Controls Groups

1

1.263

0.264

Times

3

22.795

0.000

3

0.287

0.835

Groups

X times

Residual

101

Patients Groups

1

0.061

0.806

Times

3

0.001

0.971

3

0.046

0.830

Groups Residual

X times

132

subjects (Fig. 3), but the difference (p < 0.004) disappeared over time. No significant difference in growth hormone levels was detected after domperidone administration in either schizophrenic patients or normal control subjects (p < 0.378). Basal cortisol levels were 122.88 (SD = 36.70) ng/ml and 135.25 (SD = 47.05) ng/ml in the schizophrenics and control subjects, respectively.

Discussion The major finding in this study is that plasma prolactin levels in unmedicated, elderly, chronic schizophrenic patients following domperidone administration were significantly greater than those in the age-matched normal control subjects. There were no significant differences in basal plasma prolactin levels between the two groups.

166 Fig. 3. Plasma schizophrenic

growth hormone (GH) and normal subjects

levels

following

domperidone

in

w((W-Jl)

-

Schizophrenics + normals

Many of the patients and normal control subjects were receiving nonpsychotropic drugs for various age-related ailments. With the exception of the a2 blockers, none is known to affect prolactin levels in man. We found no association between domperidone response and these agents. The fact that control subjects had to walk to the hospital while schizophrenic patients did not could have influenced this study. Increased basal growth hormone levels in the control subjects, which decreased over time, could reflect a stress effect due to mobilization. Since basal prolactin levels were similar in the two groups, it seems unlikely that the morning walk could account for differences in response to domperidone. We next considered the possibility of a stress reaction. The absence of a prolactin response to placebo in subjects from both groups who had a placebo study (data not presented) argues against the possibility of a stress-induced prolactin response. It would have been desirable to carry out a placebo study in all subjects, but this was not feasible. We next considered the possibility that there was a difference in plasma domperidone levels between the two groups. The fact that no significant difference was found in domperidone plasma levels in the two groups rules out differences in absorption and metabolism of domperidone. In this regard, we have to underline the presence of a high standard deviation and the lack of a correlation between plasma domperidone levels and prolactin values (see Table 2). We did not find any correlation between the duration of withdrawal from neuroleptic drugs and the magnitude of the prolactin response. There was no correlation between age and the magnitude of the prolactin response in either the control subjects or the schizophrenic patients. We next considered the issue of the correlation between psychopathology and

167 prolactin response. First, we looked for a correlation between basal prolactin levels and BPRS total, SANS, and SAPS scores. There was no significant correlation between these parameters and basal prolactin levels. We next looked for a correlation between change in prolactin levels in response to domperidone and BPRS total, SANS, and SAPS scores. No significant correlation was noted except for scale 4 of the SAPS, as previously mentioned. A number of other studies have been performed to investigate prolactin responses to antidopaminergic agents: Asnis et al. (1979) and Meltzer et al. (1981) found no difference between schizophrenic patients and control subjects, while Keks et al. (1987), Copolov et al. (1990), and Nerozzi et al. (1990) found a blunted prolactin response either to haloperidol or to domperidone. In the present study, we found an increased prolactin response to domperidone in elderly chronic schizophrenic patients compared with age-matched control subjects. On the basis of our previous study of young control subjects (mean age = 20.4) and the present study of older control subjects (mean age = 62.6), the prolactin response to domperidone apparently declines with age (Fig. 2). Therefore, the age issue appears to be a crucial one in studies of prolactin responses to antidopaminergic agents. If we consider the six schizophrenic patients in the study of Asnis et al., the mean age of the patients was 37.2 (range = 26-52). In the study carried out by Meltzer et al., the age of the patients ranged from 19 to 40. The studies of Keks et al., Copolov et al., and Nerozzi et al. dealt with a more homogeneous younger patient population of 27.3, 28.1, and 20.4 it would seem that the prolactin response to years, respectively. Therefore, antidopaminergic agents is blunted in young schizophrenic patients and is enhanced in older patients. There are no data on the prolactin response of middle-aged schizophrenic patients compared with age-matched control subjects. This could explain the different results obtained by Asnis et al. and Meltzer et al., who studied middle-aged patients or patients of mixed ages. A study of patients in the 30- to 40-year-old age range could be useful to characterize prolactin response to antidopaminergic agents in schizophrenic subjects over the full lifespan. The enhanced prolactin response in the drug-free elderly chronic schizophrenic patients could have several interpretations. It could be that these patients have enhanced stores of prolactin in the anterior pituitary and that blockade of the dopamine-dependent inhibitory mechanism can then release more prolactin into the circulation. The absence of a difference in basal prolactin levels argues against this hypothesis, but more specific study is needed. It is also possible that chronic schizophrenic patients have a weak dopamine-dependent inhibitory system despite the absence of a difference in basal prolactin levels. It would, therefore, be possible for domperidone more easily to antagonize this dopamine-dependent inhibition of prolactin secretion. A dose-response study in normal control subjects may be able to test this hypothesis. As mentioned above, the prolactin response to domperidone in the elderly normal control subjects was significantly less than that observed in the normal control subjects (mean age = 20.4) in our previous study (Nerozzi et al., 1990). This suggests either a diminished prolactin reserve in the elderly normal control subjects or an enhanced dopaminergic inhibition in this group. The former possibility appears

168 more likely since there is evidence that at least some dopaminergic mechanisms decrease with age (McGeer, 1978). Conversely, the mean prolactin response in the elderly schizophrenic patients in this study did not differ significantly from that of the younger schizophrenic patients in our previous study (Fig. 2). This could indicate that dopaminergic inhibition in the elderly schizophrenic patients does not decrease with age as it does in normal control subjects, or at least that it decreases to a lesser extent. In conclusion, we have found that the plasma prolactin response in elderly chronic schizophrenic patients who had not received neuroleptic drugs for 10 years or longer did not differ from that of younger schizophrenic patients but was significantly higher in comparison with that of age-matched normal control subjects. Older normal control subjects, on the other hand, had a significantly blunted prolactin response in comparison with younger normal control subjects. Therefore, the expected decrease in the prolactin response to a dopamine receptor blocking drug was not observed in elderly chronic schizophrenic patients. This could be due to weaker antagonism of the effect of domperidone in the elderly compared with the young schizophrenic patients if they also had lower prolactin stores in the pituitary. The reversal of the prolactin response relative to normal control subjects in young and old schizophrenic patients is a noteworthy finding of this and our previous study. These results point toward the need for longitudinal study of dopaminergic parameters within schizophrenic patients as compared with age-matched control subjects. Acknowledgments. The present study was supported by C.N.R. grant #89.04004.CT04. The authors thank all patients and control subjects for their patience and collaboration. Gratitude is expressed to Professor Renato Lazzari, Professor and Chairman of Psychology of the University of Rome “La Sapienza” for performing the statistical analysis. A portion of the research was supported in part by USPHS MH-41684, GCRC hlOl RR00080, the Department of Veterans Affairs, and the Elisabeth Severance Prentiss and John Pascal Sawyer Foundations. H.Y.M. is the recipient of a USPHS Research Career Scientist Award MH47808. Janssen Laboratory in Beerse, Belgium, provided domperidone determinations. The authors appreciate the experienced preparation of the manuscript by Patrizia Severin.

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American

Disorders. Bulletin,

11:380-389,

1985.

Asnis, G.M.; Sachar, E.J.; Langer, G.; Halpern, F.S.; and Fink, M. Normal prolactin responses in tardive dyskinesia. Psychopharmacology, 66:247-250, 1979. Copolov, D.L.; Keks, N.A.; Kulkarni, J.; Singh, B.S.; McKenzie, D.; McGorry, P.; and Hill, C. Prolactin response to low-dose haloperidol challenge in schizophrenic, psychotic, and control subjects. Psychoneuroendocrinology. 15:225-23 I, 1990. Fraioli, F., and Isidori, A. Sistemi h radioligandi in endocrinologia. Rome: Societa Editrice Universale SEU, 1977. Hathaway, S.R., and McKinley, J.C. Minnesota Multiphasic Personality Inventory (M.M. P.I.). Minneapolis: University of Minnesota, 1951. Keks, N.A.; Copolov, D.L.; and Singh, B.S. Abnormal prolactin response to haloperidol challenge in men with schizophrenia. American Journal of Psychiatry, 144: 1335-l 337, 1987.

169 Laduron, P.M., and Leysen, J.E. Domperidone, a specific in vitro dopamine antagonist, devoid of in vitro central dopaminergic activity. Biochemical Pharmacology, 28:2627-2665, 1979. K.L. The dopamine hypothesis of Losonczy, M.F.; Davidson, M.; and Davis, schizophrenia. In: Meltzer H.Y., ed. Psychopharmacology: The Third Generation of Progress. New York: Raven Press, 1987. pp. 715-726. McGeer, E. Aging and neurotransmitter metabolism in the human brain. In: Katyman, R.; Terry, R.O.; and Bick, K., eds. Alzheimerk Disease: Senile Dementia and Related Disorders. Vol. 7. New York: Raven Press, 1978. pp. 427-440. McLeod, R.M. Regulation of prolactin secretion. In: Martini, L., and Ganong, W.F., eds. Frontiers in Neuroendocrinology. Vol. 4. New York: Raven Press, 1976. pp. 169-I 74. Meltzer, H.Y.; Busch, D.A.; Creese, I.R.; Snyder, S.H.; and Fang, V.S. Effect of intramuscular chlorpromazine on serum prolactin levels in schizophrenic patients and normal controls. Psychiatry Research, 5:95-105, 1981. Meltzer, H.Y.; Goode, D.J.; and Fang, V.S. The effect of psychotropic drugs on endocrine function: 1. Neuroleptics, precursor and agonists. In: Lipton, M.A.; DiMascio, A.; and Killam, K.F., eds. Psychopharmacology: A Generation of Progress. New York: Raven Press, 1978. pp. 509-529. Nerozzi, D.; Magnani, A.; Sforza, V.; Scaramucci, E.; Cerilli, M.; Moretti, C.; Frajese, G.; Antonozzi, I.; and Meltzer, H.Y. Plasma prolactin response to domperidone in acute schizophrenia and schizophreniform illness. Psychiatry Research, 34: 139-47, 1990. Overall, J.E., and Gorham, D.R. The Brief Psychiatric Rating Scale. Psychological Reports, 10:799-8 12, 1962.