Prostaglandin E1 suppression of platelet aggregation response in schizophrenia

Schizophrenia Research, 5 (1991) 67-80 Elsevier

SCHIZO

67

00 168

Prostaglandin

E, suppression of platelet aggregation response in schizophrenia Hisanobu Kaiya

Department of Neurology and Psychiatry, Gifu University School of Medicine, 40 Tsukasamachi, Gifu 500, Japan (Received

27 February

1990, revised received

6 November

1990, accepted

19 November

1990)

The inhibitory effects of prostaglandin E, (PGE,) on the platelet aggregation response (PAR) to adenosine diphosphate (ADP) in 103 schizophrenics, 55 patients with other mental disorders, and 71 controls were examined. The three groups did not differ in PAR to ADP. However, schizophrenic patients, especially in the acute state, showed a significant reduction in the inhibitory effects of PGE, on PAR compared to the other two groups. These results suggest PGE, hyposensitivity exists in some schizophrenic patients, which may result from PGE, deficiency. As clinical characteristics of the subgroup showing platelet PGE, subsensitivity, relatively successful heterosexual relations, less anergia, and a more severe activation factor on BPRS were identified. Furthermore, the relationship between platelet sensitivity to PGE, and brain morphology, using magnetic resonance imaging on 39 male schizophrenics was examined. Of 11 parameters obtained from MRI measurements, only callosum: brain ratio showed a significant negative correlation with a platelet sensitivity to PGE,. The current study suggested existence of a subgroup of schizophrenia having platelet hyposensitivity and a definite clinical feature as state markers and small corpus callosum as a trait marker. Key words: Platelet

aggregation

response;

Prostaglandin

E,; Clinical

INTRODUCTION

Prostaglandins are found in the brain and are thought to be involved in neuronal transmission (for review, see Chiu and Richardson, 1985). Roles for these substances in the pathophysiology of psychiatric disorders have been postulated (for review, see Gross et al., 1977; Ragheb and Ban, 1982). In schizophrenia, both PGE excess (Feldberg, 1976) and deficiency (Horrobin, 1977) hypotheses have been proposed; however, there is little direct evidence to support either view. Increased CSF PGEs immunoreactivity (Mathe et al., 1980) and elevated plasma PGE, levels in schizophrenic patients (Kaiya et al., 1989) were Correspondence to: H. Kaiya, Department of Neurology and Psychiatry, Gifu University School of Medicine, 40 Tsukasamachi, Gifu 500, Japan.

0920-9964/91/$03.50

0

1991 Elsevier

Science Publishers

B.V.

characteristics;

Corpus

callosum:brain

ratio; (Schizophrenia)

reported, while another study showed no differences in CSF PGE levels between schizophrenia and controls (Gerner and Merrill, 1983). Since platelets have biochemical characteristics resembling those of neurons, this peripheral tissue has been studied extensively as a model for possible neurochemical abnormalities in neuropsychiatric disorders (Stahl, 1977). Some studies demonstrated hyposensitivity of the PGE, receptor in the platelets of schizophrenic subjects by showing reduced PGE,-stimulated CAMP accumulation in comparison to normal controls (Kafka et al., 1979, 1986; Rotrosen et al., 1980; Garver et al., 1982; Kafka and Van Kammen, 1983; Kanof et al., 1986, 1987; Kaiya et al., 1990). The PGE, receptor in the platelet membrane is coupled to a guanosine triphosphate binding nucleotide which in turn stimulates adenyl cyclase catalytic unit (Rodbell, 1980). PGE,, stimulating this enzyme, has an inhibitory

68

effect on the platelet aggregation response (PAR) by increasing CAMP (Mills and Smith, 1971). We previously reported a reduction in the inhibitory effects of PGEl on PAR elicited by ADP in schizophrenic patients, as compared with normal controls (Kaiya et al., 1983). The study suggested decreased sensitivity to PGE, in platelet membrane in schizophrenia. In the case of PGE,, a decrease in PGE, can lead to hyposensitivity of the PGEl receptor (Vincent et al., 1974). Namely, hyposensitivity to PGE, in schizophrenia may be thought to result from decreased formation of PGE,. This is in agreement with the PGE, deficiency hypothesis of schizophrenia. The present study tests the hypothesis by reproducing our previous findings in a larger population, by comparing the inhibitory effects of PGE, on PAR in a large number of normal controls, patients with schizophrenia, and patients with other psychiatric disorders. We found that marked hyposensitivity to the effects of PGE, on PAR exists in patients with schizophrenia. The current study, furthermore, attempts to identify clinical characteristics of those patients showing platelet PGEl hyposensitivity by examining demographical variables, mental symptoms, and neuromorphological changes using magnetic resonance imaging (MRI).

SUBJECTS

All subjects consenting to this study were physically healthy adults under 60 years of age, who were not receiving aspirin or any other drugs significantly affecting PAR at the platelet examination. The control group consisted of 71 volunteers (46 men and 25 women with a mean&SD age of 33.5 f 9.2 years) recruited from hospital personnel in whom mental disorders could be excluded in a brief interview (Table 1). 103 patients (73 men and 30 women with mean _+SD age of 35.0+ 9.1 years old) meeting the DSM-III-R criteria (American Psychiatric Association, 1987) for schizophrenia, including both inpatients and outpatients, were divided into subgroups according to their clinical state (Table 1). 25 schizophrenic patients were examined during an acute exacerbation. 78 schizophrenic patients were considered chronic, having no sig-

nificant change in symptoms for at least 3 months. Conventional neuroleptics were administered to all schizophrenics except for seven patients, five acute and two chronic ones, who had been free of drugs for at least 3 months. 55 patients (29 men and 26 women with mean age + SD of 36.5 f 11.3 years old) with other mental disorders were also subjected to the PAR examination. This group included 14 patients with bipolar disorder; 11 with major depression; seven with atypical psychosis; four with paranoid disorders; 19 with miscellaneous mental disorders, all diagnosed according to DSM-III-R criteria (American Psychiatric Association, 1987).

METHODS PAR study

Using a plastic syringe containing 1 ml of 3.8% sodium citrate, 9 ml of blood were drawn between 10 a.m. and 1 p.m. Platelet-rich plasma (PRP) was prepared by centrifuging the titrated blood at 150 x g at room temperature for 10 min. Plateletpoor plasma (PPP) was obtained by centrifugation at 1500 x g under the same conditions as used for PRP. PAR was determined photometrically at 37°C for 5 min, with stirring (1000 rpm), using a four-channel aggregometer (Kyoto Daiichikagaku, PA-3210). Before the examination, 250 ~1 of PRP was incubated for 5 min at 37°C and 0% light transmission was assumed when PRP was measured without any stimulation. PPP was used to adjust for 100% light transmission. Platelet aggregation in response to ADP, purchased from Sigma (no. 885-3) in a final concentration of 1, 2, 3, and 4 PM was determined by maximum light transmission. The PGE, suppression test for PAR was performed as follows: 50 ~1 of PGE, in various concentrations or physiological saline solution was added during incubation at 37°C with stirring 1 min before determination of PAR to 3 PM of ADP. The inhibitory effect of PGE, on PAR to ADP was quantified as the ICsO concentration of PGE, that decreased the rate of maximum light transmission (%).

69 TABLE Results

1

of the PAR study in all subjects N

MjF

Age

PAR to 3 pM

of ADP (96)

IC,,

of PGE, IwlmU

Mean

SD

Mean

SD

Mean

SD

Schizophrenia Acute Chronic

103 25 78

73130 14/l I 59119

35.0 33.8 35.4

9.1 10.5 8.6

64.0 66.1 63.8

24.1 21.4 25.0

74.4a 124.6b 58.4

16.3 126.5 40.6

Other mental disorders

55

29126

36.5

11.3

68.7

20.3

65.5

41.1

71

46125

33.5

Control

“Significant difference from control (Welch’s t = 2.50, p <0.05). %gnificant difference from control (Welch’s f=2.77, p
Clinical history and symptoms 100 patients (70 men and 30 women with mean& SD age of 35.Ok9.1 years old) out of 103 schizophrenics who had undergone PAR study were subjected to the clinical evaluation. Five demographic variables were documented for all patients with schizophrenia: (1) age at onset; (2) duration of illness (in months); (3) number of hospitalizations; (4) cumulative duration of hospitalization (in months); and (5) hospitalization/ duration of illness rate (%). Three other variables, relating to the genesis of the disease, were investigated: (1) family history of schizophrenia in first and second degree relatives, determined by analysis of information collected from patients, from patients’ families, and from case notes, then subjected to DSM-III-R criteria for schizophrenia; (2) birth in winter; and (3) birth complications, including premature birth, body weight under 2.5 kg, asphyxia, toxemia during pregnancy, and induced labor. Three variables related to social adjustment were also scored: (1) highest academic grade completed; (2) heterosexual relations (4: married without divorce or separation or date regularly; 2: marriage with divorce or separation or date occasionally; 0: never married, never date) (Strauss and Carpenter, 1974); and (3) employment prior to last episode (4: regular full-time employment holding a job for a year or more; 2: part-time employment usually full-time about half of the time) (Strauss and Carpenter, 1974). Five mental syndromes were rated, using the

63.5

from chronic

schizophrenia

(Welch’s

t=2.57,

p
and from

Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) score (each of the 18 symptoms was scored by assigning equal interval values of O-6): (1) anxiety-depression syndrome (somatic concern, anxiety, guilt feelings, depressive mood); (2) anergia syndrome (emotional withdrawal, motor retardation, blunted affect, disorientation); (3) thought disturbance syndrome (conceptual disorganization, grandiosity, hallucinatory behavior, unusual thought content); (4) activation syndrome (tension, mannerisms and posturing, excitement); and (5) hostile-suspiciousness

70

Type 3 1) through diafilms made from the originals, traced on paper and analyzed by a fixed-arm planimeter or clipper. Analysis was performed blindly without previous knowledge of the subjects, and was repeated five times to obtain a mean value (V). The reliability using the intrarater correlation coefficient was 0.97 (p
WIDTH OF CALLOSUM FRONTAl

I

CALLOSUM FDURTH

VENTRICLE

VERMIS

Fig. 1. Schema of mid-sagittal MRI measurement.

brain

features

and method

for

appears in conjunction with their maximum areas, and the ventricle/brain ratio (VBR) was calculated according to the method reported by Synek and Reuben (1976). Statistical treatment All data were presented as the mean k SD unless otherwise noted. When the PGE, suppression test was repeatedly performed on a subject, the value of the first examination was used in the statistical analysis. In the data analysis, the two-tailed Welch’s t test, Wilcoxon’s T test, ANOVA, Pearson’s and Spearman’s correlation coefficient, Fisher’s intraclass correlation coefficient, and x2 analysis with Fisher’s correction were employed, using a microcomputer (PC 9801VM). Also, a multiple regression analysis with a backward elimination method or a forward entering method employing Akaike’s information constant (Akaike, 1974) was carried out using the ‘MREGZ’ program from Kyouritsu Shuppan (Tokyo). The significance level was 0.05, and 0.1 for a multiple regression analysis. For testing multiple hypotheses, we set the p value for significance at 0.01, using Bonferroni’s inequality (Grove and Andreasen, 1982) because the number of multiple comparisons in a family was 5 at maximum.

RESULTS PAR study PAR examinations were performed 88 times in controls, 217 times in schizophrenics, and 73 times in patients with other mental disorders. The stability of the PGE, suppression test, with repeated determinations over time, in normal controls, was high. The intraclass correlation coefficient for the PAR to 3 pM of ADP was 0.81 (Fisher’s intraclass correlation: n= 50, F=9.56, pO.l) and between age

71

significantly associated with the diagnosis (partial correlation = 0.185, F= 5.84, p < 0.05). To eliminate drug effects on the results, untreated patients were compared with the same number of age- and gender-matched controls. Seven untreated schizophrenics showed significantly higher IC,, values for PGE, than controls (Table 2). To learn more about the effects of neuroleptic medication on the results in the PAR study, changes in IC,, values for PGE, in 5 untreated schizophrenics, after starting neuroleptic medication, were followed. These changes showed no clear trend. Since most untreated schizophrenics (5/7) were in the acute in state, IC,, values of PGE, were compared untreated schizophrenics and medicated schizophrenics in the acute state, and no differences were found (147.6f 128.0 ng/ml (n= 5) vs. 118.8 k 128.8 ng/ml (n = 20) Welch’s t = 0.45, NS). If an IC,, value for PGE, greater than the mean k4 SDS of normal controls (168.6 ng/ml) is defined as abnormal, those subjects showing ab-

and the TC,, value for PGE, (Spearman’s correlation: r=0.31, t=2.8l,p<0.01) in normal controls. These age- and gender-based effects do not need to be taken into account when comparing data among normal controls, schizophrenics, and patients with other mental disorders because these groups did not differ significantly in age (ANOVA: F= 1.49, df= 2,224, NS)- or gender-based ratios (x2 = 5.2, df= 2, NS) (Table 1). The IC,, values for PGE, were significantly elevated in schizophrenics, especially in the acute state, compared to controls (Fig. 2). In contrast, the PAR to ADP did not differ among the groups (Table 1). Even though without statistical significance, a slight correlation between the IC,, value of PGE, and PAR to 3 ,uM ADP was seen, therefore, a multiple regression analysis was performed, using the IC,, value of PGE, as the dependent variable and age, gender, diagnosis (schizophrenia vs control) and PAR to 3 ,uM ADP as independent variables. Subsequently, the IC,, value was still

1000’

.

. 500

-

loo

-

88,

50 -

10 -

s-

.

.

1

,L Schizophrenia (n = 103)

p < 0.01

I I

P e 0.05

Acute Schizophrenia (n

I

as)

Chronic Schizophrenia (n

-

78)

Other (n

Mental Disorders P 55)

Controls (n

-

71)

Fig. 2. IC,, of PGE, for the platelet aggregation response elicited by ADP in patients with schizophrenic disorders including acute and chronic, and patients with other mental disorders, and normal controls. The open circle represents the case not receiving neuroleptic medication.

12 TABLE

2

Results I$’ the PAR study in untreated patients with .schizophrenia or major depression N

Schizophrenia Control Major Depression Control “Significant

difference

7 7 8 8 from control

M/F

4/3 413 3i5 315

Age

PAR to 3pM

of’ADP (%)

IC,,

of PGE, (ndmll

Mean

SD

Mean

SD

Mean

SD

31.4 32.0 39.8 39.8

10.5 9.5 10.2 10.2

78.4 54.1 73.6 75.3

14.8 33.8 22.8 25.8

150.0” 48.7 98.8 75.4

104.6 30.9 71.2 33.8

(Welch’s I = 2.46, pi

0.05).

normal values at least once during repeated examinations included: 12 schizophrenics, nine acutely exacerbated, and three chronic patients, one patient with major depression with hypochondrical delusions, and one patient with a manic episode accompanied by paranoid delusions. The occurrence rate showing abnormal IC,, values for PGE, was significantly higher in acute schizophrenics than chronic ones (9/25 vs. 3/78, x2= 16.0, df= 1, p
adjustment, the score of heterosexual relations significantly correlated with IC,, values of PGE, (Spearman’s r=0.29, t = 3.02, p
73

TABLE

3

Correlation

between

IC,,

value of PGE,

and clinical variables Correlation

Demographical variables Age of onset Duration of illness Number of hospitalizations Cumulative duration of hospitalization Hospitalization: ill duration rate

Pearson’s Pearson’s Pearson’s Pearson’s Pearson’s

Variables related to social adjustment Employment Heterosexual relations

Spearman’s Spearman’s

Mental symptoms rates by BPRS Anxiety depression Anergia Thought disturbance Activation Hostile suspiciousness

Spearman’s Spearman’s Spearman’s Spearman’s Spearman’s

TABLE

in 100 patients coejicient

r =0.02 r =0.02 r = 0.04 r = - 0.12 r = - 0.15

with schizophrenia

t

P

0.17 0.17 0.37 1.17 1.47

NS NS NS NS NS

r= -0.07

t=0.66

NS

r = 0.29

t=3.02

pt0.005

r = 0.02

t=0.23

NS

r = - 0.29

t=3.05

p
r = 0.15 r = 0.13 r = 0.21

t= 1.56

NS

i= 1.30

NS

t=2.15

NS

4

Incidence

of abnormal

IC,,

values of PGE,

in 100 patients Incidence

with schizophrenia

rate

x2

P

(Xi Demographical Sex Clinical

State

Variables Family

variables female male practice Out-patient In-patient acute chronic

23.3 7.1

3.79

NS

0.11

NS

9.5 13.8 37.5 3.9

related to genesis history + _

Birth in winter

+ _

Birth complications

+

11.1 13.3 13.2 10.2 20.0 12.2

The abnormal platelet hyposensitivity to PGE, seen in patients with schizophrenia was not a steady change. We were able to follow the time course of IC,, values and total BPRS scores in 11 schizophrenics exhibiting the abnormality (eight acutely exacerbated and three chronic stable patients). While the abnormality was seen irrespective of clinical state in chronic patients, in acutely ill patients a global temporal parallelism was seen between clinical exacerbation and elevation of IC,,

16.40

p
0.00

NS

0.02

NS

0.04

NS

value of PGE, (Table 6). Clinical exacerbation preceded PGE, hyposensitivity. Thus, a maximum score on the BPRS was seen prior to the emergence of the maximum IC,O value of PGE, (the time lag ranged from 0 to 11 weeks, mean, 5.4 24.3 weeks). And the normalization of PGE, hyposensitivity occurred after clinical improvement. Thus, the mean period from the maximum IC,, value of PGE, to its return to levels within the mean + 2SDs of normal controls (111.4 ng/ml) was 27.2f 15.0

74 TABLE

5

C&kzl

chnracteristics

qf’uc.ute schizophrenics

Demographical variables Age of onset (year) Duration of illness (month) Number of hospitalizations Cumulative duration of hospitalization Hospitalization: ill duration rate (%) State of examination Rate of outpatients Rate of patients unmedicated

with OY w,ithout abnormal

(month)

IC,,

value of PGE,

IC,, vulue qf PGE, Abnormal Normul in=91 in = 15)

Statistic

22.3 k4.8 121.3k93.0 4.1*3.s 25.4 + 34.9 19.s+ 14.9

Wilcoxon Wilcoxon Wilcoxon Wilcoxon Wilcoxon

33.3% 11.1%

23.1 i5.2 121.1i96.1 3.0* 1.7 40.1 k60.3 28.1 i28.7

26.1% 26.1%

anulysi.~

T= T= T= T= T=

P

109.50 1 11.OO 116.50 106.50 105.00

NS NS NS NS NS

x2=0.01, x2=0.15,

df= 1 df= 1

NS NS

Variables related to social adjustment Employment Heterosexual relations Highest academic grade

2.3 i 1.3 2.2i 1.6 2.9+ 1.8

1.8*1.6 0.x*1.5 3.5k1.8

Wilcoxon Wilcoxon Wilcoxon

T= 98.00 T= 146.00 T= 100.00

NS NS NS

Mental symptoms rated Anxiety-depression Anergia Thought disturbance Activation Hostile-suspiciousness

3.9k4.2 5.6k5.5 7.Ok5.5 6.Ok3.3 6.2+5.1

6.9k4.2 5.6 i4.0 6.7k4.0 2.Ok2.6 6.3 k 5.3

Wilcoxon Wilcoxon Wilcoxon Wilcoxon Wilcoxon

T= T= T= T= T=

NS NS NS p < 0.005 NS

by BPRS

weeks (6640 weeks), while the mean duration in which the BPRS score became half the maximum score was 8.8 f6.4 weeks. The time-lag ranged from 2 to 32 weeks (mean 10.4f 13.3 weeks).

vs. 8.02+0.73, (Fig. 3).

Wilcoxon

86.50 110.50 114.50 156.50 110.10

T=34.00,

~~0.01)

DISCUSSION A4RI study

To examine the relationship between platelet PGE, sensitivity and neuroanatomical measures, a multivariate analysis was performed. The multiple regression model was made employing eleven MRI parameters as independent variables and IC,, values of PGE, as a dependent variable. Table 7 shows the results. High IC,, values of PGE, were associated with a shortened corpus callosum and a low callosum:brain ratio (CBR). VBR did not correlate with IC,, of PGE,. When the value of the IC,, of PGE, exceeding the mean+SD of schizophrenic patients (90.06 ng/ml) was considered as a high value, six patients (mean f SD age of 35.3 + 10.8 years old) displayed high values. The mean CBR of these six patients was significantly higher than those in the remaining 33 patients (6.86f0.72 vs. 8.52+ 1.11, Wilcoxon T=39.00, p
Is platelet PGE, schizophrenia.7

hyposensitivity

spec$c

to

Schizophrenic patients as a group demonstrated decreased sensitivity to the effects of PGE, on the PAR as compared to normal controls and patients with other psychiatric disorders. This change was particularly striking in acute schizophrenics. The decreased platelet sensitivity to PGE, does not seem due to neuroleptic effects, because no differences in the IC,, value for PGE, were found between medicated and unmedicated schizophrenics in the acute state. Furthermore, unmedicated patients who started drug therapy during the course of the study did not demonstrate definite changes in IC,, of PGE,. It would also seem that hospitalization had no effect on this measure, since the abnormality was found in both inpatients and outpatients. The abnormality in the PGE, suppres-

(0)134-B (23)245-25

(Op5c25c~

(0)592-s (10.5)262-14 (32)460&15

(0)139-l I (13)320-14 (80)54-6

(0)138&2J (30)80-6

4/21/M

5/32/M

6/30/F

7/51/F

8/22/M

“Unmedicated

(0)370-40 (4)94&10 (26)305-g

3/39/F”

case. ND, not determined

(1)192-22 (32)65-5

(2)200-27 (15)182-19

(1.5)700-24 (14.5)700&12 (40)410-6

(4)=-6 (37)38&6

(8)258% 19 (23)101-5

(2.5)180-l 1 (19)445S12 (56)27?8

(12)149%21 (83)45-14

(10)294-33 (31)97718

(0.5)185-29

(2)460-3 1 (9)260-30

(1)250-29 (7)600-30 (54)266- 18

(6)250-29 (19)260-20 (51)108-12

(4)112-26 (16)294-15 (40)250&21 (92)52-10

(O)“ND-48 (1 l)a-25 (28)280- 13 (67)61-14

2/36/M

(34)256-3 1 (73)63- 11

(0)51-23 (42)143310

1/17/F

(5)l lo-16 (52)33-5

(Week(s) after starting the test) ICY,,-total BPRS scores

Case/age/sex

(10)79%6 (65)75-5

(11)170-16 (39)85-5

(4.5)74013 (24)6 16- 12 (80)276-g

( 15)2OOG15

(3)700- 13 (21)470-g

(8)109-22 (25)97-12 (55)73%12

(38)131-21 (101)46-6

26

6

4

51.5

7

21

?

40

18

Time ,for IC,, normalization (week)

11

4.5

0

10

3

11

0

Time d@erence between maximum value of ICsO and maximum BPRS scores (week)

Results of repeated PGE, suppression test in acute schizophrenic patients with abnormal findings

TABLE 6

4

21

2.5

_

15

3

8

8

Duration 10 become half for maximum BPRS

Dependent variable

R2

AIC”

AN0 VA(F)

IC,,

0.2613

385.738

6.19**

Independcw >,ariahles

B israndard error)

Partial correlarion

F

Length CBRb

-33.92(16.42) -9.15(5.32)

-0.33 -0.28

4.27* 2.96

values of PGE,

of corpus

callosum

*p
sion test seemed not to be an unspecific finding due to stress in acute psychotic states, because the abnormality was also seen in chronic schizophrenics and continued for more than a year in one case. This conclusion is, also, supported by the evidence that the elevation in the IC,, of PGE, was not found in the acute state of major depression. Subjects other than schizophrenics, in whom the abnormality in the PGE, suppression test was demonstrated, were also considered to be psychotic (mood disorders with mood-congruent psychotic features). Therefore, it could be concluded that the marked reduction in the inhibitory effect of PGE, on PAR is a state-dependent finding for some psychotic conditions, mainly schizophrenia. When the abnormal value of the IC,, of PGE, was defined as greater than the mean + 4 SDS of normal controls, specificity for the diagnosis of schizophrenia was high (96.4%), while sensitivity was low (11.7%). Most schizophrenic patients showing the abnormality were seen in acute exacerbated conditions. 44% of acute schizophrenics showed the abnormality.

CBR

11

10

9

8

.

I

. . .

6

qlf‘platelet PGE, hyposensitivity In the case of PGE,, it is suggested that exposure of a receptor to low level of the agonist reduces the sensitivity of the receptor (Vincent et al., 1974). Therefore, the hyposensitivity of platelet membrane to PGE, could be due to a PGE, deficiency. Abdulla and Hamadah (1975) demonstrated a drastic decrease in ADP-stimulated PGE, synthesis in blood platelet of schizophrenic patients. In the current study, emergences of elevation of IC,, Mechanism

?

I

8.02~0.73

Control (nz171

6.86f0.72

6.49f

I. I!

Scnlzaphrenia with high values of ICSB of PCE: ln=G)

remai

rider

(n=?3)

Fig. 3. Distribution of callosum:brain ratio (CBR) in normal controls, schizophrenics showing high IC,, values of PGE,, and the remaining schizophrenics.

77

values of PGE, in schizophrenic patients were late for clinical exacerbation. In another words, PGE, hyposensitivity developed to the highest degree after the extremely exacerbated clinical state ceased. The time-lag may be a period in which PGE, hyposensitivity will be completed as a result of down-regulation through PGE, deficiency. It will be also considered that delay in normalization of PGE, hyposensitivity to clinical improvement which may directly be involved in recovery of PGE, deficiency is a period of up-regulation. If PGE, deficiency exists in schizophrenia, PGE, should increase in the disease, because PGE, inhibits the mobilization of arachidonic acid into a free form, which is a precursor of PGE, (Horrobin, 1980). Indeed, PGE, has recently been found to be increased in the plasma (Kaiya et al., 1989) and saliva (Ohishi et al., 1986) of schizophrenics. Decreased PGE,-stimulated CAMP formation in platelets from schizophrenics (Kafka et al., 1979, 1986; Rotrosen et al., 1980; Garver et al., 1982; Kafka and Van Kammen, 1983; Kanof et al., 1986, 1987; Kaiya et al., 1990) and depressive patients (Kanof et al., 1986) may be one of the underlying pathophysiologies of the present results. However, this finding is not entirely relevant to our results, because our previous study demonstrated no parallelism between PGE,-stimulated CAMP formation and IC,, of PGE, in PAR examination (Kaiya et al., 1990) and in the current study depressive patients did not show any abnormality in IC,, of PGE,. This suggests that PAR is based on more complicated mechanisms than CAMP formation in platelets. Other studies that assess the density of PGE, and a,-adrenergic receptors (Rice et al., 1984; Kafka et al., 1985) on the platelets that reacted abnormally in the PGE, suppression tests of PAR, or a study of the phosphatidylinositol cycle (Kaiya et al., 1989) may help to elucidate the basis of our results. PGE, hyposensitivity and clinical state Abnormal PGE, hyposensitivity was mainly seen in acute exacerbated state. Schizophrenic patients with PGE, hyposensitivity showed relatively good heterosexual relations. Platelet PGE, hyposensitivity was related to poverty of the BPRS anergia factor in both acutely and chronically ill patients with schizophrenia. Acute schizophrenics with abnormal PGE, hyposensitivity showed significantly

higher BPRS activation factor and a non-significant decreased BPRS anxiety-depression factor. To see the results of the relevant studies, schizophrenic patients with high plasma PGE, levels have been shown to have more guilt feelings and hallucinatory behavior on the BPRS, relatively successful heterosexual relations, and a higher incidence of birth complications (Kaiya et al., 1989). Among these clinical features, relatively good heterosexual relations have been regarded as one of the clinical characteristics of patients with PGE, hyposensitivity. PGE,-stimulated platelet CAMP accumulation, another parameter indicating PGE, sensitivity, did not discriminate among exacerbated, remitted, and poor-prognosis schizophrenic patients. However, CAMP response to PGE, was negatively correlated with global symptom severity in actively ill schizophrenic patients (Kanof et al., 1986). This study showed significant negative correlations between CAMP response to PGE, and BPRS thought disturbance factor or BPRS positive symptoms (Kanof et al., 1987). Activation syndrome, shown as a clinical characteristic in acute patients with platelet hyposensitivity to PGE, in the current study, is reminiscent of the hyperarousal phenomenon of schizophrenia which implicates the central noradrenergic function (for review, see Hornykiewicz, 1982). PGEs were shown to inhibit noradrenaline not only in peripheral tissues (Horton, 1973), but also in brain (Dray and Heaulime, 1984). Decreased function of PGE, could cause hyperactivity of norepinephrine in the brain, contributing some of the mental symptoms of schizophrenia with platelet PGE, hyposensitivity as described here. We tried PGE, supplementary treatment based on PGE, deficiency hypothesis of schizophrenia as mentioned above, and found some cases well responded (Kaiya, 1984, 1987; Kaiya et al., 1985). It would be of interest to see if in future prospective studies the current PAR test will be useful in identifying groups of patients that differ in their clinical response to PGE, treatment. PGE, hyposensitivity and MRIjindings The current study demonstrated that schizophrenic patients having platelet subsensitivity to PGE, showed no lateral ventricular abnormality but a significantly smaller corpus callosum than the remaining schizophrenics or the normal controls.

78

Our previous study, using larger subjects including the same samples as in the current study, demonstrated that schizophrenic patients overall showed a significantly larger corpus callosum in the one third anterior portion (Uematsu and Kaiya, 1988). This finding was not related to age, duration of illness, birth complication, or other morphological alterations, and, therefore, was considered as a change occurring before onset of the illness (Uematsu and Kaiya, 1988). Because it has been suggested that the size and shape of the corpus callosum seen in the adult is decided by selective elimination of callosal colaterals or neurons during the postnatal period (Bleier et al., 1986) therefore, an enlarged corpus callosum seen in a subgroup of schizophrenia might result from post-natal failure in reshaping callosal connections. An original autopsy study reported an increased mean thickness of the corpus callosum (Rosenthal and Bigelow, 1972) and a subsequent study found significantly greater mean corpus callosum mid sections in 21 early onset chronic schizophrenic brains when compared with eight subjects with late onset schizophrenia, 13 patients with neurological diagnoses, and 14 patients with other psychiatric diagnoses (Bigelow et al., 1983). Nasrallah et al. (1986) found increased callosal thickness only in schizophrenic women. A recent MRI study (Rossi et al., 1988) reported a smaller corpus callosum:brain ratio in 15 male schizophrenics than in 15 normal male controls. All these findings suggested the existence of not only a subgroup of schizophrenic patients having a large corpus callosum but also of a subgroup having a small one. Although the corpus callosum, especially in the anterior half of normal controls, was reported to suffer from aging atrophy (Yoshii and Duara, 1989) the small corpus callosum, demonstrated in the current study, could not be attributed to aging because there were no age differences in the three groups compared. A small corpus callosum shown in the current study might be due to hypoplasia of callosal fibres, and be a trait marker for platelet PGE, hyposensitivity dependent on the clinical state. CONCLUSION The results of the current study supports PGE, deficiency hypothesis of schizophrenia at least in

a subgroup of the disease. The PGE, suppression test for PAR to ADP seems to have certain advantages as a clinical diagnostic tool. It has highly stable results, a high magnitude of abnormality as represented as one order difference from normal controls. The PGE, suppression test has a possibility to diagnose a subgroup of schizophrenia having defined clinical characteristics. This is a state marker of acute schizophrenic patients with a relatively small corpus callosum, possibly as a trait marker. It seems likely that PGE, supplementary treatment will be indicated to this subgroup of schizophrenia in future.

ACKNOWLEDGEMENTS

Presented at the 15th C.I.N.P. Congress, San Juan, Puerto Rico, December 15, 1986. Supported by the Grant-in-Aid for Science Research of the Japanese Ministry of Education, Science and Culture (no. 60570497). The author thanks H. Yoshida, M.D. (Director of Inuyama Hospital) for supporting this work, and T. Kondo (Inuyama Hospital) and M. Uematsu, M.D. (Hashima City Hospital) for technical assistance. Prostaglandin E, was a gift from Ono Pharmaceutical Co. Ltd.

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