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Pii: s0165-1781(00)00191-8

Piyarat Govitraponga,U, Jaturaporn Chagkutipa, Wanpen a Neuro-Beha¨ioural Biology Center, Institute of Science and Technology for Research and De¨elopment, Mahidol Uni¨ersity, Salaya, Nakornpathom 73170, Thailand bDepartment of Psychiatry, Faculty of Medicine, Srinakarinwirot Uni¨ersity, Bangkok, Thailand c Department of Physiology, Faculty of Medicine, Chulalongkorn Uni¨ersity, Bangkok, Thailand Received 17 August 1999; received in revised form 5 April 2000; accepted 16 June 2000 Abstract
It has been suggested that abnormal function of the serotonergic system may be implicated in the pathophysiology of schizophrenia. In order to examine the role of this system in schizophrenia, we have determined 5-HT on human platelets of 20 control subjects and 37 schizophrenic patients by using w3 x data showed that the maximum number Ž B receptors for schizophrenic patients without neuroleptic therapy was significantly higher than that for control subjects. The B of schizophrenic patients on butyrophenone, phenothiazine, benzisoxazole and thioxanthene therapies were signifi-cantly lower than those obtained from the drug-free group, but were comparable to control values. The effect ofvarious medication periods on platelet 5-HT receptors was also examined. We found that after 2᎐4 weeks, 1᎐4 months, 4᎐12 months and more than 1 year of neuroleptic treatments, the B when compared with values in the drug-free group. The present results indicate that treatment with various types ofneuroleptics decreases the hypersensitivity of platelet 5-HT receptors. Significant clinical improvements occurred in all types of neuroleptic-treated groups and for all different treatment durations in this study. The precisemechanisms of how neuroleptics achieve their therapeutic effects still need to be further delineated. ᮊ 2000 ElsevierScience Ireland Ltd. All rights reserved.
receptor; Schizophrenia; Neuroleptics; Platelet U Corresponding author. Fax: q662-9310472.
E-mail address: ŽP.
0165-1781r00r$ - see front matter ᮊ 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 1 6 5 - 1 7 8 1 Ž 0 0 . 0 0 1 9 1 - 8 P. Go¨itrapong et al. r Psychiatry Research 96 ( 1. Introduction
cleotide 120. These data suggest that the regula-tion of 5-HT Schizophrenia is one of the most important the same in both platelets and brain. A cDNA forms of psychiatric illness, but its cause remains encoding the human platelet 5-HT uptake site mysterious. Among the various hypotheses put has been isolated and sequenced. It has been forth to account for the etiology of schizophrenia, demonstrated that the human platelet 5-HT up- the neurochemical imbalance hypothesis has re- take site is identical to the human brain 5-HT cently gained marked acceptance ŽAshton, The search for an underlying neurochemical dis- order has gone on, despite so-far unsuccessful take sites in platelets and brain suggests that the attempts to discover specific biochemical abnor- study of serotonergic dysfunction in platelets is a malities in schizophrenic patients, the hope being useful model for such dysfunctions in the brain.
that a biochemical understanding of the mecha- This study attempts to investigate the pharma- nism would provide the basis for a rational drug treatment. In fact, the biochemical theories have blood platelets and their relevance to the come mainly from analysis of the actions of drugs pathogenesis of schizophrenia. Knowledge is found by chance to be effective, rather than vice sought in this study to better understand the role of serotonin in schizophrenia, which may then be used as a basis to select the most appropriate neuroleptic drugs for schizophrenic patients.
throughout the central nervous system. The roleof 5-HT in schizophrenia is still unclear. A rapidlygrowing body of data suggests that serotonergic 2. Materials and methods
dysfunction may be involved in the pathophysi-ology of schizophrenia, and that pharmacological agents for this illness have their therapeutic ef-fects mediated through a serotonergic mechanism was purchased from Amersham International similarities between blood platelets and central 5-HT synaptosomes, and because of data showing All other chemicals used were of the purest that virtually all 5-HT in blood is associated with commercially available grade, purchased mainly the platelets, platelets have been widely used as a from E. Merck ŽDarmstadt, Germany. and Sigma minimally invasive means of studying 5-HT in the containing the drugs were freshly prepared for tion, platelets offer a suitable peripheral source subjects because pharmacological properties of Schizophrenic patients diagnosed according to DSM-IV criteria ŽAmerican Psychiatric Associa- tion, 1994 from the Psychiatric Clinic, Wachira the brain are under the same genetic control and Phra Mongkutklao Hospitals were studied after having given informed consent. This study was approved by the Mahidol University Ethics Committee and performed in accordance with sequence is identical to that reported for human ethical standards laid down in the 1964 Declara- tion of Helsinki. Complete medical and family P. Go¨itrapong et al. r Psychiatry Research 96 ( histories were obtained from the patients and The membrane pellets were resuspended in 15 ml informants when available. Behavioral ratings of ice-cold 50 mM Tris᎐HCl buffer, pH 7.5 Žcon- were completed with the Brief Psychiatric Rating taining: 120 mM NaCl; 5 mM KCl; 2 mM CaCl ; and 1 mM MgCl . and homogenized for 15 s with patients Ž6 males and 3 females. received butyro- phenones Žhaloperidol, haloperidol decanoate or bromperidol , 10 Ž5 males and 5 females. received formed by the addition of 400 ␮l platelet mem- phenothiazines Žtrifluoperazine, chlorpromazine, brane suspension Žto give a final protein concen- fluphenazine or perphenazine., 7 Ž3 males and 4 contained 50 ␮l incubation buffer either with or 6 Ž4 males and 2 females. received thioxanthenes without 100 ␮M ketanserin in the buffer. The Ž cis-flupenthixol, cis-flupenthixol decanoate. The reactions were started by adding 50 ␮l of H spiperone to give a final concentration of patients who had never received any neuroleptic 0.2᎐10 nM in a final incubation volume of 0.5 ml.
drug before blood sampling. All patients had not made any recent suicide attempt. Healthy adults ing agent to define non-specific binding. The as- were recruited as a control group. They had no say mixtures were incubated at 37ЊC for 30 min, history of neurological or psychiatric illness, in- during which time binding equilibrium was cluding no serious or infectious diseases such as reached. The reaction was terminated by rapidly HIVrAIDS or hepatitis, they were drug-free, and filtering the reaction mixture through Whatman they were matched with the schizophrenic patients GFrC filters under vacuum. The filters were washed twice with 3 ml of ice-cold 50 mMTris᎐HCl buffer ŽpH 2.3. Platelet membrane preparation and receptor-bound radioactivity trapped on thefilters was counted in 5 ml of scintillation fluid containing Triton X-100rtoluene base flour Ž tal vein with a 21-gauge needle into plastic sy- ringes and transferred to plastic centrifuge tubes counting efficiency for tritium was approximately containing 0.38% Žfinal concentration. sodium citrate as the anticoagulant. Platelet-rich plasma PRP was obtained by centrifugation at 200 =g for 20 min. PRP was isolated and mixed with half of its original volume of ice-cold 50 mM Tris᎐HClŽpH 7.5 and homogenized for 15 s with a poly- Saturation curves were analyzed by using the nonlinear least-squared regression analysis com- suspension was centrifuged at 40 000 =g for 20 puter program, LIGAND ŽMunson and Robard, min at 4ЊC in a refrigerated centrifuge ŽDoupont, 1980 . The dissociation equilibrium constant Ž K .
Sorvall RC 26 plus. The supernatant was de- and the maximum number of binding sites Ž B canted and the membrane pellet was resuspended were obtained. The data are expressed as mean " S.D. derived from n experiments indicated and homogenized and centrifuged at 40 000 =g for 20 were analyzed by ANOVA, and then statistical min. The final pellet was kept frozen at y80ЊC evaluation of the results was performed by using the Tukey᎐Kramer multiple comparison test.
2.6. Determination of platelet protein The binding assays were carried out according The concentration of protein in the platelet to a technique modified from Biegon et al. Ž membranes was determined by the method of P. Go¨itrapong et al. r Psychiatry Research 96 ( patients were auditory hallucinations, signs of delusion, and incoherence or mutism.
3. Results
patients with different neuroleptic medications 3.1. General features of schizophrenic patients Analysis of the saturation data was carried out using the non-linear least squares regression The mean ages of control, unmedicated, buty- analysis program, LIGAND. The results gathered rophenone-, phenothiazine-, benzisoxazole- and from this computer-assisted analysis were consis- thioxanthene-treated groups were 31.7"2.2, 24.8 tent with the presence of only one binding site on "2.3, 32.7"3.5, 33.7"3.6, 33.4"4.8 and 28.2" the platelets of control subjects and schizophrenic 2.9 years, respectively. The mean durations of patients. The present data were comparable to illness for the unmedicated, butyrophenone, our previous report ŽGovitrapong et al., phenothiazine, benzisoxazole and thioxanthene groups were 3.1 "1.5, 9.9"2.8, 5.20"1.1, 9.9" ing to platelets of normal control subjects and 1.9 and 4.8"1.2 years, respectively. The mean durations of treatment on butyrophenones, patients are shown in Table 1. The data indicated phenothiazines, benzisoxazoles and thioxanthenes significantly Žt s3.35, P- were 10.7"12.9, 5.2"8.7, 3.1"3.7 and 8.6"9.6 H spiperone binding to the blood platelets of months, respectively. The mean ages of patients schizophrenic patients without neuroleptic ther- taking drugs for 2᎐4 weeks, 1᎐4 months, 4᎐12 apy, compared with normal control subjects months and more than 1 year were 28.7"4.1, Ž347.3 " 118.6 and 214.4" 74.0 fmolrmg protein, 30.1"2.5, 39.7"4.7 and 31.3"5.8 years, respec- tively. The number of patients on butyrophenone, patients on butyrophenone, phenothiazine, ben- phenothiazine, benzisoxazole and thioxanthene zisoxazole or thioxanthene medications Ž154.5" medications in the 2᎐4-week group was 1, 0, 1 56.5, 173.4"44.4, 172.7"78.4 and 178"54.8 and 4, respectively; in the 1᎐4-month group, it fmolrmg protein, respectively. were significantly was 3, 7, 4 and 1, respectively; in the 4᎐12-month lower than those in the untreated group; how- group, it was 2, 2, 2 and 0, respectively; and in the ever, they were comparable to values in the con- more than one year group, it was 3, 1, 0 and 0, respectively. The main clinical features of the various treatment groups, including and excluding receptors in schizophrenic patients with different types of neuroleptic treatments values were analyzed by comparing the B values: Ži. between treatment groups including controls, treatment effect: F s6.383, d.f.s5, P-0.001; Žii. between treatment groups excluding controls, treatment effect: F s8.032, d.f.s4,P -0.001; Žiii. between gender: F s1.594, d.f.s1, Ps0.212; and Ž .
iv between age: F s0.802, d.f.s5, Ps0.554.
P. Go¨itrapong et al. r Psychiatry Research 96 ( Fig. 1. Distribution of individual and mean "S.D. B H spiperone binding to blood platelets of: Ž .
5 , benzizoxazole-treated group; and Ž .
control subjects, the treatment effect showed a tions of neuroleptic medications are shown in significant difference Ž F s6.383, d.f.s5, P- Table 2. After 2᎐4 weeks of neuroleptic therapy, 0.001, and F s8.032, d.f.s4, P-0.001, respec- was significantly decreased Žt s2.76, P- with gender indicated no significant difference when compared with the drug-free group Ž347.3 "118.6 fmolrmg protein.; however, this value was comparable to that of the control group groups with age, indicated no significant differ- Ž214.7 " 74.0 fmolrmg protein. The B ence Ž F s0.802, d.f.s5, Ps group was further decreased significantly Žt s5.0, patients, as well as in the normal control subjects, group. The degree of decrease in B highest in the 4᎐12-month group Ž121.6"59.6 significantly altered in any group in this study.
fmolrmg protein., and this value was significantlydecreased Žt s2.797, P- with the control group. After 1 year of neurolep- patients with different durations of neuroleptic fmolrmg protein. was significantly decreased Žt s2.09, P - group; however, it was comparable to the control binding to platelets of normal control subjects and schizophrenic patients with different dura- values between various durations of medication P. Go¨itrapong et al. r Psychiatry Research 96 ( receptors in schizophrenic patients with different durations of neuroleptic treatments values were analyzed by comparing the B values between various duration of treatment groups as including control subjects, duration of treatment effect: F s7.813, d.f.s5, P-0.001; and Žii. excluding control subjects, duration oftreatment effect: F s10.433, d.f.s4, P-0.001.
groups including and excluding the control group, ent types of neuroleptics or among different dura- the duration of treatment showed a significant difference Ž F s7.813, d.f.s5, P-0.001, and F s10.433, d.f.s4, P-0.001, respectively. Thedistribution 4. Discussion
patients in different duration of treatment groups, as well as in the normal control subjects, is illus- trated in Fig. 2. As is evident in the statisticalanalysis H spiperone binding in schizophrenic patients The present data show that the maximum num- related to duration of medication, there was no higher in the blood platelets of unmedicated schizophrenic patients compared with normalcontrol subjects. These results were compatible 3.4. The beha¨ioral rating in schizophrenic patients with several previous reports. For example,Pandey et al. Ž The mean "S.D. behavioral rating scores by w125IxLSD binding to 5-HT receptors in platelets BPRS in the unmedicated group and in the buty- of unmedicated schizophrenic patients was sig- rophenone-, phenothiazine-, benzisoxazole- and nificantly higher than that in normal control sub- thioxanthene-treated groups were 37.2"6.3, 12.4 jects, and that there was no significant difference "3.1, 13.6"2.8, 14.9"4.9 and 15.6"4.6, re- spectively. The scores from the four neuroleptic- and normal control subjects. An increase of 5-HT2 treated groups were significantly Ž P - than in the unmedicated group. The mean "S.D.
BPRS scores in 2᎐4-week, 1᎐4-month, 4᎐12- month and more than 1-year medications were found both in schizophrenic patients who had 17.0" 3.5, 14.4"3.3, 12.0"1.8 and 10.5"4.1, made suicide attempts and in non-suicidal respectively. They were significantly Ž P - schizophrenic patients compared with normal lower than in the unmedicated group. Significant control subjects. Postmortem studies also indi- clinical improvements occurred in all types of neuroleptic-treated groups and for all different ing in unmedicated chronic schizophrenic patients durations of treatments in this study. However, who had been drug-free for 1 year before death there was no significant difference among differ- P. Go¨itrapong et al. r Psychiatry Research 96 ( quantitative receptor autoradiography, reported role in cell signaling, and the observed changes may reflect an abnormality in signal transduction labeled 5-HT receptors in the temporal and pos- mediated through the 5-HT -receptor event.
terior cingulate, frontal and parietal cortices, theventral putamen, nucleus accumbens and hip- pocampus. In contrast, 5-HT receptors in post- patients with different classes of neuroleptic mortem brains of unmedicated schizophrenic patients were decreased in the reports of Bennettet al. Ž ceptors in schizophrenic patients under different neuroleptic Žbutyrophenone, phenothiazine, ben- zisoxazole and thioxanthene. treatments were sig- Data supporting receptor hypersensitivity in nificantly reduced when compared with the schizophrenic patients may also be obtained from unmedicated group. These values were compara- ble to those in normal control subjects.
Our results are in agreement with several pre- platelets from schizophrenic patients contained a vious studies. For example, there was no differ- significantly increased amount of PIP compared with controls. The agonist-stimulated hydrolysis frontal cortex found in medicated schizophrenic of PIP in platelets from the schizophrenic group patients ŽMackay et al., 1978; Owen et al., 1981; was also significantly greater than that in platelets Reynolds et al., 1983; Mita et al., 1986; Laruelle from the control group. PIP plays an important et al., 1991 . Pandey et al. 1993 examined the Fig. 2. Distribution of individual and mean "S.D. B H spiperone binding to blood platelets of: Ž .
schizophrenic patients without neuroleptic treatment; Ž .
schizophrenic patients with 2᎐4-week neuroleptic treatment; Ž .
schizophrenic patients with 1᎐4-month neuroleptic treatment; Ž .
5 schizophrenic patients with 4᎐12-month neuroleptic treatment; 6 schizophrenic patients with more than 1-year neuroleptic treatment.
P. Go¨itrapong et al. r Psychiatry Research 96 ( effect of treatment with neuroleptics on platelet in patients after receiving neuroleptics. Taken together, it is reasonable to assume that agents ment with haloperidol nor treatment with thio- that are thought to decrease 5-HT function have thixine caused a significant change in platelet shown antipsychotic effects, particularly when po- tent 5-HT antagonists have been used.
ing. However, both fluphenazine and trifluopera- The pharmacological activities of haloperidol zine significantly increased the B and other typical neuroleptics have long been binding without any significant change in K considered to depend upon the blockade of D dopamine receptors, whereas the ‘atypical’ neu- platelet 5-HT receptor numbers in schizophrenic roleptics show a higher occupancy of 5-HT patients who had been treated with depot pheno- receptors. Two recent studies ŽKapur, 1998; thiazine for long periods, but not in patients who were receiving non-phenothiazine neuroleptics. It has been reported that chronic treatment with F setoperone found that both clozapine and high doses of chlorpromazine blocked the 5-HT2A haloperidol, causes down-regulation of 5-HT re- receptor, suggesting that the distinct clinical pro- ceptors in rat brain ŽPeroutka and Snyder, 1980; files of both drugs were unrelated to 5-HT2A blockade itself. The present finding suggests that 1989 reported in a study on the effect of acute haloperidol might affect the serotonergic system treatment with seven atypical and four typical as well. In addition, elucidating the interactions between several neurotransmitter systems might cerebral cortex, that clozapine, fluperlapine, lead to a significantly better understanding of the RMI-81582 and setoperone decreased the density psychopathologic mechanisms in schizophrenia.
one did not. Loxapine decreased the B chlorpromazine and cis-flupenthixol had no effectŽMeltzer et al., reported that 5-HT receptor binding in human various durations of neuroleptic treatment was brain was decreased, when compared with that in also performed. Different groups of schizophrenic control subjects. This occurred in both patients patients who had been under neuroleptic treat- who were receiving neuroleptic medication at the ment for 2᎐4 weeks, 1᎐4 months, 4᎐12 months time of death and in those who had not had such and more than 1 year were studied. The results treatment for at least 2 months prior to death.
ceived neuroleptic drugs for every treatment pe- who were treated with haloperidol in our study riod, when compared with drug-free patients. Af- were markedly reduced when compared with the unmedicated group, and slightly reduced when numbers declined to normal control levels. Fur- compared with normal control subjects. The pres- ent data are comparable to those reported by 4᎐12-month period, was further reduced to a level that was significantly lower than normal control subjects. However, after more than 1 year brains of schizophrenic patients might be due to previous neuroleptic exposure. The reduction in restored close to control levels again. Presumably, agents that are thought to decrease 5-HT func- effect of neuroleptic treatment that induced a tions have shown antipsychotic effects, and then decrease in the receptor numbers to control lev- the therapeutic efficacy was reached within a els. Concomitantly, an improvement was observed P. Go¨itrapong et al. r Psychiatry Research 96 ( Obviously, the presumed dysfunction of each Mongkutklao Hospital and the staff at Psychiatric neurotransmitter system should be considered in Clinic, Wachira Hospital and Phra Mongkutklao relation to the dynamic interactions among the Hospital for their help. This research was sup- systems rather than as independent processes.
ported in part by a Mahidol University Research Optimal pharmacotherapy of schizophrenia might Grant and a Dr Chantana Sukwaj Research Grant.
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