Platelet serotonin concentrations in medicated schizophrenic patients

l’q.

Neuro-P~ychophannam1.

& E?iol. Psych&X

2001, Vol. 25, pp. 983-992

Cqynght 0 2001 Elsevm Science Inc. Printed in the USA. All rights reserved 0278.5846/01/$kee front matter

PII: 50274%5846(01)00173-7

PLATELET SEROTONIN CONCENTRATIONS IN MEDICATED SCHIZOPHRENIC PATIENTS

YASUHIRO KANEDA ‘,*, AK&4 FUJI1 ’ AND ISA0 NAGAMINE ’

’ Department of Neuropsychiatry, The University of Tokushima School of Medicine, Tokushima, Japan and ’ Department of Neuropsychiatry, Fujii Hospital, Anan, Tokushima, Japan

(Final form, April 2001)

Abstract Kaneda, Yasuhiro, Akira Fujii and Isao Nagamine: Platelet serotonin concentrations in medicated schizophrenic patients. Prog. Neuro-Psychopharmacol. & Psychiat. 2001,25, pp. 983-992. a001 Elsevkr Science Inc. 1. The present study was conducted to investigate the effects of neuroleptic administration on platelet serotonin (5HT) levels, and the relationships between platelet 5-HT levels, extrapyramidal symptoms (EPS) and psychopathology in schizophrenia. 2. The subjects were 49 regularly medicated inpatients who were diagnosed according to the DSM-IV criteria for schizophrenia. Each patient gave informed consent for the research involved in this study. All patients were first considered as one group and then divided into two groups: those with lower levels (LL) and those with higher levels (HL), according to their platelet 5-HT levels. Psychotic symptoms and EPS were assessed using the Brief Psychiatric Rating Scale and the Drug Induced Extra-Pyramidal Symptoms Scale, respectively. 3. (1) The mean level of the platelet 5-HT in the schizophrenics with neuroleptic-treatment was significantly lower than that in the normal subjects. (2) The mean level of the blood monoamine oxidase (MAO) in the schizophrenics tended to be lower than that in the normal subjects. (3) There was no significant difference in the mean scores of the positive symptoms, negative symptoms, or EPS between the LL and HL groups. (4) Platelet 5-HT levels were not correlated with blood MAO concentrations. 4. Overall, these results seem to indicate that (i) administration of neuroleptics lowers platelet 5-HT levels, and (ii) platelet 5-HT levels in the schizophrenics with neuroleptic-treatment do not reflect psychopathology of schizophrenia or severity of neuroleptic-induced EPS.

Kevwords: extrapyramidal schizophrenia, serotonin

symptoms,

monoamine

oxidase,

neuroleptics,

psychopathology,

Brief Psychiatric Rating Scale (BPRS), dopamine (DA), Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS), extrapyramidal symptom (EPS), high platelet 5-HT level (HL), low platelet 5-HT level (LL), monoamine oxidase (MAO), negative symptom (NES), Parkinson’s disease (PD), positive symptom (POS), serotonin (5-HT) 983 Abbreviations:

Y.Kaneda et al.

984

Introduction

One of the main abnormalities

in schizophrenia is an increase in dopaminergic (DArgic) activity

(Hokfelt et al., 1974; Randrup and Munkvad, 1972). Meanwhile, the therapeutic success of serotonergic (5_HTergic)/DArgic antagonists has focused attention on the role of 5-HT in schizophrenia. Several studies have shown elevated whole blood or platelet 5-HT in schizophrenics who are off neuroleptic medications (Borcsiczky et al., 1996; Garelis et al., 1975). There are contradictory findings regarding the effects of neuroleptics on blood 5-HT (Garelis et al., 1975; Joseph et al., 1977). Some investigators (Joseph et al., 1977) have noted that neuroleptics may elevate blood 5-HT, while others (Garelis et al., 1975) have reported that neuroleptic medication seemed to decrease blood 5-HT. Platelet 5-HT function may parallel changes that occur in the brain, and therefore, the platelet has been proposed as a model to study central 5-HT neurons (Stahl, 1977). The present study was conducted to investigate the effects of neuroleptic administration on platelet 5-HT levels, and the relationships between platelet 5-HT levels and psychopathology in schizophrenia.

In addition, the blockade of DA Dr receptors by neuroleptics in the dorsolateral striatum induces Parkinsonism (Cohen and Scheife, 1977). Since a reduction in platelet 5-HT in Parkinson’s disease (PD) and an increase in 5-HT content by drug treatment have been reported (van Kempen et al., 1995), the relation between platelet 5-HT levels and extrapyramidal symptoms (EPS) was studied.

Monoamine oxidase (MAO) is the main enzyme in participating in the metabolism of 5-HT and other monoamines. The majority of studies shows MAO levels in drug-free schizophrenics are similar to controls, but that schizophrenics with neuroleptic-treatment have lower platelet MAO levels than controls (Marcolin and Davis, 1992). Therefore, the authors also investigated MAO levels, together with 5-HT concentrations, to evaluate the relationship between them.

Subjects

The study was carried out at the Department

of Neuropsychiatry,

Fujii Hospital. Forty-nine

schizophrenic inpatients (20 females, and 29 males) that met the DSM (Diagnostic and Statistical Manual of Mental Disorders)-IV (American Psychiatric Association, 1994) diagnostic criteria were obtained for the study. Nine normal subjects (3 females, and 6 males) were obtained as a control sample. Informed consent was obtained from all subjects for the research in this study. Table 1 shows the demographic

Serotonin and extrapyramidal symptoms in schizophrenics

985

characteristics of the subjects. Subjects were excluded if they presented with any organic central nervous

system disorder, significant substance abuse, and mental retardation. Normal subjects had no ongoing medication. All patients were first considered as one group and then divided into two groups according to their platelet S-HT levels.

Table 1

Demographic Characteristics of Subjects

Normals

N

Age (yrs) Adm. period (yrs)

Schizophrenics Total

LL Group

HL Group

Mean (SD)

Mean (SD)

Mean (SD)

Mean (SD)

9

49

24

25

51.7 (17.7)

54.0 (11.1)

53.8 (12.2)

54.3 (10.2)

24.3 (11.7)

23.8 (12.0)

24.8 (11.6)

POS

6.6 (2.9)

6.7 (2.9)

6.4 (3.0)

NES

7.8 (4.0)

7.5 (3.9)

8.0 (4.1)

EPS

1.0 (1.0)

0.9 (0.9)

1.2 (1.0)

0.24 (0.23)

0.25 (0.26)

0.23 (0.19) 0.234 (0.077)

Dosage (mg/daykg)t Plt. S-HT (pg/nL)

0.231 (0.049)

0.162 (0.098)*

0.086 (0.046)

Pit. (xl O%nL)

24.5 1 (4.78)

22.57 (5.72)

20.23 (5.45)

24.81 (5.12)

Pk. 5-HT (ng/x109plt.)

973.8 (278.5)

730.5 (416.1)*

495.0 (417.2)

956.5 (266.3)

MAO (W/L)

0.899 (0.277)

0.852 (0.265)

0.843 (0.256)

0.861 (0.280)

Administration (adm.); extrapyramidal symptoms (EPS); high-level of serotonin (HL); low-level of serotonin (LL); monoamine oxidase (MAO); negative symptoms (NES); platelet (pk.); positive symptoms (POS); serotonin (5-HT). thaloperidol-equivalent. *p < .05 versus normals by the Mann Whitney’s U-test.

Procedure

Since the patients had been prescribed neuroleptics with various chemical structures, each neuroleptic was converted to its haloperidol equivalent using the dosage comparability table (Inagaki et al., 1998a); for depot neuroleptics, the procedure adopted was based on the equivalence table for long-term therapy (Inagaki et al., 1998b). The mean converted dosage of the patients is shown in Table 1.

Y. Kaneda et al.

986

Psychiatric

ratings were done using the Brief Psychiatric

1962). The BPRS operationally

provided

a standardized

method

defined 7-point scales. Two symptoms,

formed

retardation,

using

behavior and unusual thought

et al., 1995). The POS scores were

of the POS. Three symptoms,

emotional

and blunted affect, were derived from this scale as negative symptoms

Guy, 1976; Nicholson

symptoms

(POS) based on previous groupings of BPRS

(Crow, 1985; Guy, 1976; Kitamura et al., 1989; Nicholson

using the sum of the ratings

18 psychiatric

namely hallucinatory

content, were derived from this scale as positive symptoms symptoms

Rating Scale (BPRS) (Overall and Gorham,

of assessing

withdrawal,

motor

(NES) (Crow, 1985;

et al., 1995). The NES scores were formed using the sum of the ratings of the

NES. The mean POS and NES scores in the patients are also shown in Table 1. EPS were assessed using the Drug Induced Extra-Pyramidal The DIEPSS

is composed

of eight individual

parameters

Symptoms

Scale (DIEPSS) (Inada, 1996).

and one global assessment

constructed

to

measure EPS, using 5-point scales. The mean rating of overall severity was 1.0 (SD = 1.0, range O-4) (Table 1).

Hormonal Assessments

Blood samples were once drawn from all subjects between 0600 and 0700 h. Platelet 5-HT levels were assayed by high-performance

liquid chromatography

with fluorimetric

detection

(Nebinger

and Koel,

1988). Serum MAO was assayed using the enzymatic assay described by Sato et al. (Sat0 et al., 1985).

Data Analvsis

Statistical analyses were carried out using parametric tests (e.g. student t-test, Pearson product-moment correlations),

if the data were normally

distributed.

Whitney’s U-test, Spearman’s rank correlations)

Otherwise,

the nonparametric

tests (e.g. Mann

were used.

Results

Concentrations

of Platelet 5-HT and MAO

The platelet 5-HT concentrations

for the normal group and group of schizophrenics

with neuroleptic-

treatment were 0.231 ug/nL (SD = .049, range 0.17-0.32) and 0.162 ug/nL (SD = ,098, range .Ol-0.45), respectively

(Table 1). Mann Whitney’s U-test showed that the mean level of the platelet

5-HT in the

Serotonin and extrapyramidal symptoms in schizophrenics

patient group was significantly significant when corrections

In the normal concentrations

987

lower than that in the normal group (p < .OS). This difference

remained

for platelet counts were made.

group and group of schizophrenics

with neuroleptic-treatment,

the serum

MAO

were 0.899 III/L (SD = 0.277, range 0.53-1.29) and 0.852 III/L (SD = 0.265, range 0.44-

1.72), respectively

(Table 1). There was no significant

difference

in the mean levels of the serum MAO

between the groups by Mann Whitney’s U-test.

Relations between Platelet 5-HT Levels and Variables

Based on their platelet

5-HT levels, the patients were classified

into two groups: those with lower

platelet 5-HT levels (< 0.16 pg/nL: LL, N = 24) and those with higher ones (> 0.16 pg/nL: HL, N = 25). In the LL and HL groups, the dosages of neuroleptic mg/day/kg (SD = 0.19, range .O-0.8), respectively significant difference

were 0.25 (SD = 0.26, range .O-1.1) and 0.23

(Table 1). By the Mann Whitney’s U-test, there was no

in the mean dosage of neuroleptic

between the groups (Fig. 1).

In the LL and HL groups, the POS scores were 6.7 (SD = 2.9, range 3-l 3) and 6.4 (SD = 3.0, range 313), respectively

(Table 1). By the Mann Whitney’s U-test, there was no significant

difference

in the

mean POS score between the groups (Fig. 1).

In the LL and HL groups, the NES scores were 7.5 (SD = 3.9, range 3-18) and 8.0 (SD = 4.1, range 315), respectively

(Table 1). By the Mann Whitney’s U-test, there was no significant

difference

in the

mean NES score between the groups (Fig. 1). In the LL and HL groups, the ratings of overall severity in the DIEPSS were 0.9 (SD = 0.9, range O-2) and 1.2 (SD = 1 .O, range O-4), respectively significant difference

(Table 1). By the Mann Whitney’s

U-test,

there was no

in the mean rating of overall severity in the DIEPSS between the groups (Fig. 1).

In the LL and HL groups, the blood MAO levels were 0.843 (SD = 0.256, range 0.47-l .66) and 0.861 III/L (SD = 0.280, range 0.44-l .72), respectively significant difference

Spearman’s rank correlations variables.

(Table 1). By the Mann Whitney’s U-test, there was no

in the mean blood MAO level between the groups (Fig. 1).

showed no significant

correlation

between the platelet 5-HT levels and

i

5-HT (xlO$g/nL)

***

Dosage (x10-‘mg/day/kg)

Patients with high 5-HT

Patients with low 5-HT

I

POS

T

EPS

. . .

.

. . . . . .

Fig. 1 Relations between platelet serotonin (5-HT) levels and variables Results are means with S.D. There was no significant difference in the variables between the groups. EPS = extrapyramidal symptoms; MAO = monoamine oxidase; NES = negative symptoms; POS = positive symptoms. *** p -C.OOl by the Mann Whitney’s U-test.

6

10

1El

Serotonin and extrapyramidal

symptoms in schizophrenics

Our results showed that (i) platelet 5-HT levels are decreased in the schizophrenics with neuroleptictreatment, and (ii) platelet S-HT levels do not reflect psychopathology of schizophrenia or severity of neuroleptic-induced EPS.

Platelet 5-HT and Neurolentics Do neuroleptics elevate platelet S-HT, or do they decrease it? The result of the present study that there was no significant difference in the mean dosages of neuroleptics between the LL and HL groups does not answer the question directly. However, considering the previous findings that whole blood or platelet 5-HT in schizophrenics who are off neuroleptic medications is elevated (Borcsiczky et al., 1996; Garelis et al., 1975) and our finding that the mean level of the platelet 5-HT in the schizophrenics neuroleptic-treatment

was significantly

with

lower than that in the normal subjects, we can suppose that

neuroleptics decrease platelet 5-HT. Therefore, our result seems to provide support for the previous finding of Garelis et al. (1973,

though some investigators

(Joseph et al., 1977) have noted that

neuroleptics may elevate the platelet 5-HT. The inhibitory effects of neuroleptics on 5-HT seem to be explained by the finding that neuroleptics

are potent inhibitors

of the uptake mechanism

of the

monoamines (Fuks et al., 1964). Because 5-HT is a good substrate for MAO-A, but not for MAO-B (Marcolin and Davis, 1992), it is not surprising that there was no significant difference in the mean blood MAO between the LL and HL groups. Nevertheless, the differences between our results and the results of previous reports (Joseph et al., 1977) regarding the possibility that neuroleptics may produce elevation of the platelet 5-HT are difficult to explain. Conflicting findings on the effects of neuroleptic administration on the platelet 5-HT might be related to type and/or dosage duration. Another reason for the differences may be the differences in patient characteristics between the present study group and those in previous studies, i.e., a strict subclassification of patients was not carried out in the present study because of the comparatively

small number of subjects. To clarify the effects of neuroleptic administration

on the

platelet 5-HT, well controlled, large prospective studies are required. Meanwhile, our result that blood MAO in the schizophrenics with neuroleptic-treatment

tended to be decreased is consistent with the

previous report (Marcolin and Davis, 1992). Platelet 5-HT and EPS The finding in the present study that the platelet 5-HT was significantly lower in the schizophrenics with neuroleptic-treatment than in the normal subjects is also consistent with the finding of a reduction in platelet 5-HT in PD (van Kempen et al., 1995). This consistency could be understood, as the blockade of DA Dr receptors by neuroleptics in the dorsolateral striatum induces Parkinsonism (Cohen and Scheife, 1977). At the same time, the consistency is interesting, since the main abnormality in PD is the loss of

Y. Kaneda et al.

990

DArgic neurons and a decrease in available DA. But, it is not surprising, because a reduced 5-HT concentration in a number of brain regions of PD patients has been demonstrated. It is not yet clear whether the observed decrease in platelet 5-HT in PD (van Kempen et al., 1995) is explained as a primarily existing generalized S-HT deficit and/or as a consequence of DA deficit. However, as 5-HTz is supported to decrease EPS (Kapur, 1996), 5-HTergic activity may be down to compensate the loss of DArgic activity. This might be another reason for the observed decrease in platelet 5-HT in the schizophrenics

with neuroleptic-treatment.

Anyway, 5-HT may play an important

role in the

pathogenesis of PD. Van Kempen et al. (1995) have reported an increase in platelet 5-HT of patients with PD by drug treatment. We investigated the possibility that platelet 5-HT levels in the schizophrenics with neuroleptic-treatment may reflect severity of neuroleptic-induced EPS, but it failed.

Platelet 5-HT and Psvchouatholozv As for role of 5-HT in schizophrenia, it has been hypothesized that 5-HT deficiency is responsible for schizophrenia (Wooley and Shaw, 1954). In contrast, however, 5-HTr antagonism is claimed to have beneficial effects on both POS and NES of the illness (Abi-Dargham

et al., 1997). Moreover, a

hypothesis of cortical-subcortical imbalance with an increase in subcortical 5-HT function responsible for POS and a decrease in prefrontal 5-HT function responsible for NES is proposed (Breier, 1995). Pivac et al. (1997) demonstrated the significantly higher platelet 5-HT concentrations in drug-free patients with predominantly POS of schizophrenia than in healthy controls and in patients with predominantly NES. However, our results that showing there was no significant difference in the mean scores of the POS symptoms or NES between the LL and HL groups do not show the relation between platelet 5-HT levels and psychopathology in schizophrenia. For more clear evaluation, we need a drug-free sample, since the relation might be masked by a treatment regimen of neuroleptics.

Conclusions

The results seem to indicate that (i) administration of neuroleptics lowers platelet 5-HT levels, and (ii) platelet 5-HT levels in the schizophrenics with neuroleptic-treatment

do not reflect psychopathology of

schizophrenia or severity of neuroleptic-induced EPS.

Acknowledgments

The authors are grateful for the comments of Professor Tetsuro Ohmori (Tokushima, Japan) and appreciate the cooperation of staffs in our department. Some of these results were presented at the 9th annual meeting September, 1999.

of the Japanese Society of Clinical Neuropsychopharmacology,

Beppu, Japan,

Serotonin and extrapyramidal

991

symptoms in schizophrenics

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Inquiries and reprint requests should be addressed to: Dr. Yasuhiro Kaneda Department of Neuropsychiatry, The University of Tokushima School of Medicine, 3-18-15 Kuramoto-Cho, Tokushima 770-8503, Japan Telephone number: +81-88-633-7130, Facsimile number: +81-88-632-3214 E-mail: [email protected]