Prog. Neuro-Psychophermucol. & Biol. Psychk]t. 1988, Vol. 12, pp. 511-522 0278-5846/88 $0.00 + .50 Printed in Great Britain. All rights reserved Copyright ~) 1988 Pergamon Press plc

EFFECTS OF CERULETIDE ON CLINICAL SYMPTOMS AND EEGS IN SCHIZOPHRENIA

YASUSHI MIZUKI, ITSUKO USHIJIMA, KENSUKE HABU, KOHJI NAKAMURA and MICHIO YAMADA

Department of Neuropsychiatry, Yamagnchi University School of Medicine, Kogushi, Ube, Japan

(Final form, September 1987)

Abstract

Mizuki Yasushi, Itsuko Ushijima, Kensuke Habu, Kohji Nakamura and Michio Yamada: Effects of ceruletide on clinical symptoms and EEGS in schizophrenia. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1988, 12:511-522

I. The efficacy of ceruletide as a supplement in treating schizophrenics was tested by monitoring the Brief Psychiatric Rating Scale (BPRS) and the EEG.

2. Eight male inpatients with schizophrenia were administered fixed doses of neuroleptics during the study.

3. A control EEG recording and BPRS scoring were done before ceruletide administration.

4. Doses of 0.8 ~g/kg/week of ceruletide and of placebo were given intramuscu- larly in a double-blind, crossover design for 3 consecutive weeks, and no treatment followed for I week.

5. EEG recordings and BPRS scoring were carried out once weekly. There were no significant differences in the total BPRS scores or the scores of each item between ceruletide and placebo.

6. With ceruletide treatment, the power values of the frontal EEGs increased in the whole bands but only in the first week.

7. The EEG values in the occipital area increased in e and B activities slightly in the third week and markedly in the fourth week.

8. The power values in the right temporal area decreased in fast 8 activity in the second and third weeks but increased in ~ activity in the third and fourth week.

9. The power of the left temporal area increased in both ~ and 8 bands in the second week, and this continued to the fourth week.

10. These results suggest that treatment with ceruletide might fail to improve the symptoms of schizophrenics but does affect their EEGs, and that cerule- tide may have a delayed effect.

Keywords: BPRS, ceruletide, EEG, neuropeptide, schizophrenia.

Abbreviations: Brief Psychiatric Rating Scale (BPRS), cholecystokinin (CCK), 3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), electroencephalogram (EEG), homovanillic acid (HVA).

Introduction

Recently, various neuropeptides have been found in the brain and their roles as

neuromodulators or neurotransmitters in the central nervous system have been

investigated. The effectiveness of these peptides in the treatment of mental

511

512 Y. Mizuki et al.

illness has been suggested (Swaab 1982).

Ceruletide diethylamine is a decapeptide chemically related to cholecystokinin

(CCK) octapeptide, which has a similar spectrum of biological activity to the

CCK-gastrin family of peptides (Rehfeld 1978). It has been reported that CCK

increases the affinity and decreases the number of central dopamine (DA) recep-

tors (Fuxe et al 1981), and that this peptide modifies DA release and turnover

in the limbic regions of the mammalian brain (Fekete et al 1981). These results

suggest that CCK and its related peptides are involved in the pathophysiology of

schizophrenia (Meltzer and Stahl 1976) and in the therapeutic actions of anti-

psychotic drugs (H~kfelt et al 1980 a,b). Moroji et al (1982) and Nair et al

(1982) found that a single administration of ceruletide or CCK produced a marked

improvement in both positive and negative symptoms in chronic schizophrenic

patients. However, Hommer et al (1984) and Mattes et al (1985) also reported

that ceruletide possesses only slight antipsychotic action in the treatment of

schizophrenia. Thus, previous clinical studies on CCK and ceruletide have

presented conflicting results.

The present study was undertaken to investigate the possible efficacy of

ceruletide as a supplement in treating schizophrenic patients by monitoring both

the Brief Psychiatric Rating Scale (BPRS) and the electroencephalogram (EEG).

Methods

Subjects

The subjects in this trial were 8 male inpatients ranging in age from 23 to 44

years (mean age of 30.5 years), who were diagnosed as having schizophrenic

disorders by DSM-III (APA, 1980) criteria. Prior to the study, informed consent

was obtained from all the patients or their relatives. The patients continued

to receive their regular maintenance doses of neuroleptics throughout the study.

The backgrounds of the patients are summarized in Table I.

Druqs

Ceruletide, 0.8 ~g/kg body weight, or an equivalent volume of saline (placebo)

was given intramuscularly in this study. The doses of ceruletide were determin-

ed on the basis of available human data (Kato et al 1984).

Clinical Assessment

The BPRS (Overall and Gorham 1962) was used to assess symptoms, and was

recorded by the same 2 psychiatrists at every examination.

EE9

Resting EEGs, taken while the patients had their eyes closed, were recorded

Ceruletide in schizophrenia 513

for 3 min using bipolar leads, i.e., Fz-Cz, Oz-Cz, T3-Cz, T4-Cz (International

10-20 Electrode System). The recording conditions were: paper speed of 1.5

cm/sec, time constant of 0.1 sec, and sensitivity of 10 ~v/mm. The 60 Hz high-

cut filter was the only one used. EEGs were recorded simultaneously on paper

and on an analog tape recorder (FRC-1402N) and were analyzed for the requirement

of the power spectrum by a digital computer (HR-1000) using Fast Fourier Trans-

formation. Each 10-sec epoch was analyzed with 102.4 points/sec, which permitt-

ed the analysis of high frequencies up to 50 Hz. Time samples of 60 sec were

used.

Table I

Backgrounds of the Patients

Age Medication Sex Age at DSM-III (mg/day)

onset

Male 30 28 Paranoid type

Male 34 15 Paranoid type

Male 25 15 Disorganized type

Male 44 16 Disorganized type

Male 23 17 Disorganized type

Male 25 20 Disorganized type

Male 36 19 Catatonic type

Male 27 26 Disorganized type

Haloperidol 9 mg

Haloperidol 9 mg

Sulpiride 600 mg Oxypertine 120 mg

Haloperidol 9 mg

Timiperone 20 mg Clocapramine 150 mg Chlorpromazine 650 mg Zotepine 300 mg Levomepromazine 50 mg

Haloperidol 10 mg Levomepromazine 250 mg

Haloperidol 30 mg

Experimental Procedure

Scoring of the BPRS, EEG recording, and the administration of ceruletide and

placebo were done in a double-blind, crossover design. Seven consecutive days

of EEG recordings at 1300 hr and one BPRS scoring at 1000 hr were done before

ceruletide or placebo treatment. Subsequently, 0.8 ~g/kg of ceruletide or

placebo was given intramuscularly once weekly at 0800 hr for 3 consecutive

weeks. A period of no ceruletide or placebo treatment followed for the next I

week. The BPRS scoring and EEG recordings were performed 8 times at l-week

intervals after the initiation of ceruletide or placebo treatment.

Table 2

Effects of Ceruletide and Placebo on the BPRS

After

ist Week

2nd Week

3rd Week

4th Week

Items

Control

Control

EEG

Ceruletide

Placebo

Ceruletide

Placebo

Ceruletide

Placebo

Ceruletide

Placebo

Somatic Concern

3.00±0.68

2.13±0.52

2.25±0.41

2.00±0.50

2.50±0.50

2.00±0.38

2.38±0.53

1.38±0.26

1.88±0.35

1.50±0.27

Anxiety

2.63±0.63

3.00±0.63

2.50±0.60

2.63±0.63

2.50±0.46

2.75±0.53

2.75±0.65

2.50±0.42

2.75±0.49

2.38±0.53

Emotional

3.75±0.68

4.38±0.60

4.00t0.63

4.00±0.63

4.13±0.69

3.75±0.68

3.38±0.60

3.50±0.63

3.63±0.68

3.25±0.59

Withdrawal

Conceptual

2.13t0.52

2.00±0.53

1.75±0.41

2.13±0.58

1.88±0.52

2.00±0.50

1.63±0.33

2.13±0.52

1.88±0.48

1.75±0.31

Disorganization

Guilt Feelings

2.25±0.62

1.88±0.64

1.25±0.16

1.50±0.38

1.25±0.25

1.63±0.63

1.38±0.37

1.63±0.63, 1.38±0.37

1.38±0.37,

Tension

3.00±0.38

2.38±0.46

2.13±0.23

2.13±0.40

1.88±0.23" 2.13±0.40

1.88±0.29" 1.75±0.31

1.75±0.31" 1.75±0.25

Mannerisms and

2.13±0.58

2.25±0.56

1.88±0.58

1.88±0.58

1.88±0.58

1.88±0.58

2.25±0.65

1.88±0.58

1.88±0.58

1.88±0.58

Posturing

Grandiosity

1.63±0.63

1.63±0.63

1.38±0.37

1.75±0.62

1.63±0.63

2.00±0.63

1.63±0.63

2.00±0.63

1.13±0.12

1.38±0.37

Depressive Mood

2.13±0.48

2.25±0.56

2.38±0.63

1.88±0.48

1.75±0.49

2.13±0.55

1.75±0.49

1.88±0.48

1.50±0.50

1.75±0.41

Hostility

2.38±0.73

2.50±0.63

1.88±0.35, 2.63±0.57

2.38±0.50

2.00±0.50

2.50±0.46

2.00±0.42

1.75±0.31

2.38±0.65

Suspiciousness

5.25±0.53

5.00±0.63

4.50±0.57

4.38±0.65

4.50±0.63

4.38±0.73

4.38±0.60

4.25±0.75

4.00±0.63

4.00±0.73

Hallucinatory

4.75±0.68

4.38±0.68

3.75±0.62

4.25±0.80

3.50±0.53

4.38±0.84

4.13±0.67

4.25±0.86

3.50±0.63

3.75±0.75

Behavior

Motor Retardation 4.00±0.73

4.00±0.71

4.13±0.72

4.13±0.64

3.88±0.79

4.13±0.64

3.88±0.72

3.88±0.64

4.25±0.70

4.00±0.65

Uncooperativeness

2.25±0.62

2.38±0.60

2.13±0.55

2.38±0.63

2.00±0.46

2.50±0.63

2.25±0.45

2.25±0.56

2.50±0.68

1.88±0.48

Unusual Thought

5.25±0.68

5.00±0.65

4.88±0.64

4.38±0.71

4.50±0.68

4.50±0.82

4.50±0.68

4.50±0.82

3.75±0.59

4.00±0.73

Content

Blunted Affect

4.13±0.58

4.38±0.57

4.25±0.59

4.38±0.53

3.88±0.67

4.25±0.49

4.00±0.68

4.00±0.57

4.13±0.69

3.63±0.60

Excitement

2.50±0.38

2.25±0.41

1.88±0.35

1.88±0.29

1.75±0.37

2.38±0.53

1.25±0.25

2.13±0.61

1.50±0.27

1.50±0.27

Disorientation

1.00±0.00

1.00±0.00

1.00±0.00

1.00±0.00

1.00±0.00

1.00±0.00

1.00±0.00

1.00±0.00

1.00±0.00

1.00±0.00

Total

54.13

52.75

47.88*

49.25

46.75

49.75

46.88

46.88

44.13"

43.13"

± 3.45

± 4.43

± 3.37

± 3.93

± 4.47

± 4.84

± 4.49

± 4.36

± 4.40

± 4.42

All scores of BPRS are expressed as the mean ~

S.E.M.

Statistical analysis was performed in comparison with control values

because there were no significant differences

in all scores between ceruletide and placebo treatment.

*: p~O.05.

Ceruletide in schizophrenia 515

Laboratory Examinations

In order to monitor the patients' physical state, the following laboratory

tests were done before, during and after ceruletide or placebo treatment: liver

function tests, hematological examination, urinalysis, kidney tests and blood

pressure.

Statistical Analysis

The Wilcoxon matched-pairs signed-ranks test (two tailed) was used for statis-

tical analysis of the BPRS scores and Student's t test (two tailed) for the EEG

results.

Frontal Area 1 s t Week

PI

| I

s ,0 ,s

0.2 F

• I

6 5 ,~> is

, , , ~ ' ; ' 20 25 30 5 40 5 50 (Hz)

2 nd W e e k

i - - r

I I I

~'o ~5 ~o 35 ,o ,~ ~oc~> 0.2 r 3 rd W e e k

-

' ' ' ' 2' 2' 0 5 10 15 0 5 3'o 3'5 4'o A s'oc~i 0.2 [ . . . . . 4 t h W e e k

- - . 2

< 20 ~ 0 % 0 5 10 15 5 3 3 40 45 50 (Hz)

Fig I. Effects of ceruletide and placebo on the EEG in the frontal area. The figures are based on a comparison of the EEGs of patients on ceruletide and placebo treatment and the power values of the first, second, third, and fourth week from the upper to lower rows, respectively. Ordinate: the values obtained by subtracting the control values from those after medication; abscissa: EEG frequency. The control values were calculated in accordance with the mean of EEGs recorded for 7 days. The solid line shows the placebo value (PI), and the dotted line the ceruletide power values (Cr). The shaded area of the figure ~ndicates where the dotted line is above the solid line. A: P<0.10; *: P<0.05; ,: P<0.01.

516 Y. Mizuki et al.

Results

BPRS Scores

In both the total BPRS scores and the scores for each item, there were no

significant differences in any week between ceruletide and placebo treatment

(Table 2). When ceruletide was given (Table 2), the total scores in the first

and fourth week, and scores for suspiciousness in the first week and for tension

in the second, third and fourth week were significantly decreased as compared

with the control values. When placebo was administered (Table 2), the total

scores in the fourth week, and scores for tension in the third and fourth week

were markedly decreased as compared with the control values.

EEG Findinqs

In the frontal area, in patients receiving ceruletide (Fig I), the power

values of the whole bands increased markedly in the first week, whereas those of

all bands showed no remarkable changes in the second and third week as compared

with placebo. Conversely, the power values of the 8, ~ and B bands slightly

decreased in the fourth week.

O2 L

0

Occipital Area - - P I

1 S t W e e k . . . . . Cr

I I I 2 I I I f I I i

5 10 15 0 25 30 35 40 45 50 (Hz) 0.2 f ~ ~ 2 n d W e e k ~

O0 -..- ....... <.~_~ -- .2

0 5 10 15 20 25 30 35 40 45 50 (Hz)

0.2I ~ 3rd Week

- - .2 I I I I J

0 5 10 ,5 2'0 2'5 ~0 ~5 20 25 5o(.z)

0'2 I

-~.2 6 ; ,b ,~ 2'0 2% 3'0 a; 4b 4; 5b (.z)

Fig 2. Effects of ceruletide and placebo on the EEG in the occipital area. The details are in the legend for Fig I.

Ceruletide in schizophrenia 517

L t . T e m p o r a l A r e a

1 s t Week - - P I r

-0.2 ,, , , . . . , , , , 0 5 10 15 20 25 30 35 40 45

I. ° -'- ... __° ___ _

-0.2

6 ; lb 1'5 ~0 ~5 :~0 ;5 i0 ~s

I

50 (Hz)

I

50 (Hz)

I

0

0'2 I

-~.2 &

0

I I I | I

s ;0 ;5 2'o :~s ;0 3s ,~0 45 5'0 (.,) . : 4thWeek

; ;% ,'s 2'o :~5 3'o 3'5 4'0 & 5b (~)

Fig 3. Effects of ceruletide and placebo on the EEG in the left temporal area. The details are in the legend for Fig 1.

R t . T e m p o r a l A r e a PI

1 s t W e e k . . . . . Cr °

-- .2 I I I I

o 5 ,b ;'s" :~o ~;5 ;o ;5 4o ;,5 sO(.z)

0.2I 2nd Week ,

- - . 2

I 3 rd Week 0.2 ~. * ~. , ~,s ,~ ,~ -", * * * :~

6 5 I0 15 210 2'5 30 35 20 45 50 (H,) [ 4 t h Week

° 2 f ~ * . . , - _ 1 - . . . . . . . . . . . . . . . . . . . . . ~ . . . . . . . . .

- - . 2 L . . . . . . . . . i i i i i

o 5 ;'o i'~ 2o 25 3'0 3'5 ;o A 5O(.z)

Fig 4. Effects of ceruletide and placebo on the EEG in the right temporal area. The details are in the legend for Fig I.

518 Y. Mizuki eta].

In the occipital area of patients receiving ceruletide treatment (Fig 2), no

power values of any band indicated any significant changes in the first and

second week as compared with placebo. However, the values of the u and B activ-

ities increased slightly in the third week and markedly in the fourth week.

In the left temporal area of patients on ceruletide (Fig 3), the power values

of all bands showed no remarkable changes in the first week, whereas those of

the 8, u and B activities markedly increased in the second and third week as

compared with placebo. In the fourth week, however, only u activity increased

significantly.

In the right temporal area of patients on ceruletide (Fig 4), only the power

values of u activity decreased slightly in the first week as compared with

placebo. Those of the 8 and ~ activities increased slightly but those of the

fast 8 activity decreased slightly in the second week, whereas the ~ activity

increased slightly. The fast 8 activity, however, decreased markedly in the

third week. In the fourth week, only the u activity increased slightly.

Laboratory Findings

Laboratory findings were always within normal limits in all patients receiving

ceruletide or placebo treatment.

Discussion

Distribution of CCK in brain

In animal studies, specific CCK receptors have been identified in the rat

brain. The density of these binding sites is the highest in the cerebral cortex

and the lowest in the cerebellum (Innis and Snyder 1980). In a human brain

autopsy study (Vanderhaeghen et al 1981) and a study using biopsies of the

human cortex (Rehfeld 1978), it has also been reported that the highest concen-

tration of CCK-immunoreactivity is in the cerebral cortex. Moderate amounts are

present in the basal ganglia and hypothalamus, and the concentration in the

frontal cortex is 3.6 times that of the hypothalamus. CCK-containing neuronal

pathways are widely distributed in the brain.

Co-localization of CCK and DA

From recent findings that CCK-immunoreactivity is localized with DA in some

neurons in the ventral tegmental area, which projects to various limbic struc-

tures, it is suggested that CCK and its related peptides modulate DA function

and may be relevant to the pathophysiology of schizophrenia (H6kfelt et al

1980 a,b).

Ceruletide in schizophrenia 519

Clinical aspects of ceruletide in schizophrenia

Indeed, CCK-related peptides have shown a neuroleptic-like action in several

behavioral tests (Van Ree et al 1983; Zetler 1983), and show a therapeutic

effect in schizophrenia (Moroji et al 1982; Nair et al 1982). However,

conflicting results such as an inhibitory effect of CCK-related peptides on DA

turnover (Fekete et al 1981), a DA release effect (Markstein and H~kfelt

1984), and an enhancing effect on DA function (Hamilton et al 1984) have been

presented, and the negative studies showing no improvement in schizophrenia have

been also reported (Hommer et al 1984; Mattes et al 1985).

In the present study, ceruletide failed to show a decrease in either total

BPRS scores or scores on any individual item at all times. Only the total

scores in the first and fourth week, and the scores for suspiciousness in the

first week and for tension in the second, third and fourth week decreased as

compared with the control values. Moroji et al (1982) and Nair et al (1982)

reported reduction in some symptoms after administration of CCK-related peptides

to patients with chronic schizophrenia. The patients in this study had both

acute and chronic symptoms. Thus, positive results would not be expected after

brief ceruletide treatment. Yamagami et al (1986) reported that the optimal

dose of ceruletide in terms of both efficacy and safety is in the range of 1.0

to 1.2 ~g/kg body weight, so it is possible that the dose of ceruletide used in

the present study was not large enough to affect the clinical symptoms.

Furthermore, Matsumoto et al (1984) showed that peripherally administered

ceruletide reduces homovanillic acid (HVA) and 3, 4-dihydroxyphenylacetic acid

(DOPAC) only in the striatum of the rat brain without changing those neurotrans-

mitters in the mesolimbic and mesocortical DA systems. Another possibility is

that the mesolimbic and mesocortical DA systems are not be involved in the

antipsychotic action of ceruletide.

Effects of ceruletide on EEG

Itil et al (1975) reported that drug-refractory schizophrenic patients showed

more potent negative symptoms than positive symptoms, as well as some fast 8

activity and much slow u and slow wave activities on the EEG in the right occip-

ital area. Furthermore, patients who responded to conventional neuroleptics

showed strong positive symptoms, much fast 8 activity, and slight u activity.

Itil (1980) also noted that an increase in u activity and a decrease in fast B

activity were observed after amelioration of the positive symptoms. The rela-

tionship between the improvement of some symptoms after ceruletide administra-

tion and the increase in e activity in the occipital area was not always paral-

lel in this study, whereas the occipital fast 8 activity also showed higher

values in the patients given ceruletide than in those on placebo in the third

520 Y. Mizuki et al.

and fourth week. Considering the results of studies on CCK-immunoreactivity

(Rehfeld 1978; Vanderhaeghen et al 1981) and our previous studies on some

neuropeptides'~Mizuki et al 1985, 1986), we suggest that EEGs in the frontal

area partially reflect changes in the total BPRS scores. Namely, the increase

of ~ activity and decrease of 8 activity is shown in the first and fourth week

at the same times as the decrease in the total scores. The partial improvement

in tension in the patients on ceruletide in the second, third and fourth week

coincided with changes in the right temporal EEGs such as an increase of

activity and a decrease of fast B activity. There are many reports concerning

the functional laterality of the cerebral hemispheres in schizophrenia, and it

has been suggested that the left hemisphere shows a functional disturbance or

hyperactivity in this disorder (Gur 1978). Our findings are in close agreement

these reports; however, the present data suggest that the changes in the right

temporal region were more prominent than those on the left. This indicates a

lack of flexibility in the left hemisphere either due to a functional disturban-

ce or hyperactivity in this region. Furthermore, changes in the EEGs of all

areas continued even in the fourth week without ceruletide administration. This

may show that ceruletide has a long-lasting central effect.

Side effects of ceruletide

The laboratory findings did not reveal any abnormalities. Therefore, it may

be assumed that ceruletide is a comparatively safe neuropeptide with minimal

side effects.

Conclusion

Although a more definitive study without other medication and with a larger

population will be necessary, the present study suggests that treatment with

ceruletide fails to improve the symptoms of schizophrenics but does affect theiz

EEGs, and that ceruletide may have a delayed effect.

Acknowledgements

The authors would like to thank to Dr. Gary B. Glavin, Associate Professor of

Pharmacology and Therapeutics, University of Manitoba, for his helpful comments

and suggestions. Gratitude is also due to Shionogi & Co. Ltd., Osaka, Japan for

the generous supply of ceruletide.

Ceruletide in schizophrenia 521

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Inquiries and reprint requests should be addressed to:

Dr. Yasushi Mizuki Department of Neuropsychiatry Yamaguchi University School of Medicine 1144 Kogushi, Ube 755, Japan