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Biogenic amine metabolites in plasma of drug-naive schizophrenic patients: Associations with symptomatology
288
BIOL PSYCHIATRY 1992;32:288-292
B iogenic Amine Metabolites in Plasma of DrugNaive Schizophrenic Patients: Associations with Symptomatology Manolis Markianos, Alexander Botsis, and Yannis Arvanitis
The main metabolites of dopamine, noradrenaline, and serotonin, homovanillic acid, methoxyhydroxyphenylglycol (MHPG), and 5.hydro,~indoleacetic acid (5-HIAA), were estimated in plasma of 20 drug-naive young male schizophrenic patients and 21 healthy controls. Although there were no significant differences between the two groups, multiple regression analysis revealed strong associations of the patients' 5-HIAA and MHPG plasma levels to their scores in the Brief Psychiatric Rating Scale items. 5-HIAA levels were mainly related positively to hostility and negatively to somatic concern, and MHPG positively to disorientation and negatively to emotional withdrawal and uncooperativeness. The result., suggest that levels of the neurotransmitter metabolites may be related to certain psychological dysfunctions of the patients rather than to disease entities.
Introduction The estimation of the principal neurotransmitter metabolites in cerebrospinal fluid (CSF) has been proven to be a fruitful strategy for assessing central neuronal activity of biogenic amines in neuropsychiatric disorders, In recent years, methods for the estimation of the metabolite levels in plasma have been developed with adequate accuracy. Data collected from such measurements indicate that plasma concentrations may well reflect not only changes in peripheral, but also in central monoamine turnover. Changes in the main dopamine metabolite homovanillic acid (HVA) in CSF of psychotic patients treated with neuroleptics paralleled changes in plasma HVA (pHVA) (Sharma et al 1989). Neuroleptic treatment influences pHVA (Pickar et al 1984; Sharm,aet al 1989; Khan et al 1990), and baseline pHVA levels have been connected to the therapeutic response to neuroleptics (Bowers et al 1984, Davila et al 1988). Recently, positive correlations between pHVA and positive symptoms ratings have been reported in schizophrenic patients (Pickar et al 1990). Plasma concentrations of the main noradrenaline metabolite metboxyhydroxyphenylglycol (pMHPG) have been reported to be elevated in psychotic patients, especially in paranoid schizophrenics (Ko et ai 1988), and negative symptoms were correlated with pMHPG (Pickar et al 1990). In addition, reductions in both pHVA and pMHPG were found in psychotic patients after treatment with neuroleptics (Bowers et al 1989). From the Athens University Medical School, Psychiatric Clinic, Eginition Hospital (MM, YA), and the Department of Psychiatry, 41 ! General Army Hospital (AB), Greece. Address reprint requests to Dr. M. Markianos, Athens UniversityMedical School, PsychiatricClinic, Eginition Hospital, Vas. Sophias 74, Athens 11528, Greece. Received May 11, 1991; revised August 30, 1991. © 1992 Society of Biolosical Psychiatry
0006-3223/92/$05.Q0
Biogenic Amine Metabolites in Schizophrenia
BIOLPSYCHIATRY 1992;32:288-292
289
Regarding the main serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), there are only a few studies on its plasma concentrations, presumably because it is believed that it reflects central parent amine turnover less than HVA or MHPG, although there are indications that it acts in a similar manner. Alfredsson and Wiesel (1990) studied recently a group of 24 acutely ill schizophrenics and reported that patients with higher plasma 5-HIAA (pS-HIAA) had lower scores for autistic and depressive symptoms, and that responders to treatment with sulpiride had significantly higher pSHIAA levels during treatment than the nonresponders. Because of these data it seems meaningful to study plasma levels of dopamine, noradrenaline, and serotonin metabolites in relation to psychotic illness and its symptomatology, because all three amines have been implicated in schizophrenia (Meltzer 1987; Bleich et al 1988). In this study, we estimated the main dopamine, noradrenaline, and serotonin metabolites HVA, MHPG, and 5-HIAA of plasma in a group of drug-naive young male schizophrenic patients, and in a group of healthy male subjects in the same age range. We addressed the following questions: (1) were there differences in the metabolite concentrations between patients and controls, and (2) were the concentrations within the patient group related to the psychopathology as expressed in the EPRS items?
Subjects and Methods The patients were all recruits who had been hospitalized in the Psychiatric Clinic of the Army Hospital during an exacerbation of their illness. The age range was 19-24 years, and the duration of illness 1-5 years. They had never received treatment with psychotropic drugs. Twenty patients were examined, eight with paranoid, six with disorganized, four with undifferentiated, and two with catatonic subtype of schizophrenia, according to DSM-III-R criteria. Twenty-one controls known to manifest no psychopathology were selected by the psychiatrist (AB). All subjects were physically healthy. Blood samples were taken from the patients 2-4 days after their hospitalization, between 9 and 10 AM. Every time a blood sample was taken from a patient, samples were also taken from one or two control subjects. Blood was drawn (12 ml) wJth EDTA as coagulant, the plasma separated by centrifugation, and stored at - 30°C until analysis. The metabolites were estimated by high pressure liquid chromatography (HPLC) with electrochemical detection. The acids (HVA and 5-HIAA) were extracted from 0.5 ml acidified plasma into ethyl ether, and MHPG into ethyl acetate. After evaporation of the solvent, the residue was taken in 0. l ml mobile phase (acetate buffer with 10% methanol) and injected into a HPLC system with a Spberisorb ODS-2 column connected to electrochemical detector operating at a potential of 0.7 V and sensitivity 10 nA. For each estimation, 2 ml plasma was used for HVA and 5-HIAA, and 2 ml for MHPG, each in four portions of 0.5 ml, two without and two with 10 ng pure substances added at the beginning of the procedure. The differences in peak height between the samples with and without standards were used for calculations. The coefficients of variation were between 10% and 20%. For statistical evaluation of the data we used one-way analysis of variance (ANOVA) to compare the variables of the patient group to the control group. Further, the multiple linear regression model was applied for detecting possible associations between the plasma levels of the three metabolites (dependent variables), and the scores in the BPRS items (independent variables). Linear regression and Spearman correlation coefficients were also calculated.
290
BIOLPSYCHIATRY
M. Markianos et al
1992;32:288-292
Table 1. Age and Biogenic A m i n e Metabolites (ng/ml) in Plasma o f 21 Healthy Males and 20 Drug-Naive Male Schizophrenic Patients Variable
Controls
Age HVA 5-HIAA MHPG
20.9 12.6 16.6 5.5
Patients
(2.3) (5.4) (9.8) (!.9)
20.6 11.0 12.4 5.4
(1.7) (4.3) (6.5) (1.8)
F
p
0.23 1.10 2.55 0.03
0.64 0.30 0. I 1 0.84
Mean values and SD; one-way ANOVA.
Results and Discussion The concentrations of the three metabolites measured in the patient and the centre! groups are given in Table 1. No differences between the groups could be detected in any of these parameters. Thus, drug-naive male schizophrenic patients show normal levels of the biogenic amine metabolites in plasma during an exacerbation of their illness. Further statistical analysis of the data revealed some interesting points. We first applied the linear regression model for possible associations of the ratings in BPRS and the plasma levels of ~he three metabolites. This analysis (Table 2) revealed an association of the BPRS scc'~ to p5-HIAA. The linear regression coefficients between BPRS and the three metab~lites were not significant for pHVA and pMHI:'G, but showed a significant positive co relation to p5-HIAA (r = 0.4651, p = 0.039). from the 20 patients studied, 8 were paranoid and 12 had other types of the illness, as ,~aentioned in Subjects and Methods. Paranoid schizophrenics are expected to have hibher BPRS scores, and this was the case in our study group. The subgroup of patients with paranoid schizophreni ~ had a mean BPRS score of 76 (SD = 9), and the nonparanoid subgroup had 61 (SD = 9); the difference is significant (F = 14.51, p = 0.002). Comparison of the three m,~tabolite plasma levels between the subgroups revealed higher p5HIAA levels in the paranoid subgroup (F = 4.49, p = 0.046), whereas there were no significant differences in pHVA and pMHPG levels. Further, we used the multiple regression model to test the hypothesis of associations of the metabolite concentrations measured in plasma to the scores in the separate items of the BPRS. Because of the relatively small number of cases in relation to the number of BPRS items, we used the forwara stepwise model. The results are shown in Table 3. pHVA had a weak negative association with depressive mood and unusual
Table 2. Multiple Regression Analysis with Dependent Variable (DV) the Total BPRS Score, and IndependentVariables the Plasma Levels of HVA, 5-HIAA, and MHPG HVA DV BPRS
R
F
0,544 2,24 Linear regression: BPRS versus p~tVA BPRS versus p3-HIAA BPRS versus pI4HPG
p 0.12 r -0.0564 0.4051 - O.3484
5-HIAA
MHPG
Beta
p
Beta
p
Beta
p
-0.146 p
0,50
0,433
0.07
-0.247
0.27
0.813 0,039 0,132
The linear regressioncoefficientsof the BPRS score to the metabolitelevels are also given.
BiogenicAmine Metabolitesin Schizophrenia
BIOLPSYCHIATRY 1992;32:288-292
291
Table 3. Stepwise Multiple Linear Regression (forward, F to enter = 1.00) with Dependent Variables of the Plasma Concentrations of 5-HIAA, MHPG, and HVA, and the Independent Scores in the 18 Items of the BPRS R
df
F
p
pHVA
0.4046
2,17
1.66
0.22
p5-HIAA
0.9085
7,12
8. I !
0.0009
pMHPG
0.9031
7,12
7.58
0.00013
Beta Depressive mood Unusual thought content Hostility Somatic concern Conceptual disorganiz. Blunted affect Depressive mood Emotional withdrawal Disorientation Uncooperativeness Hostility Somatic concern
p
-0.449 -0.357
0.I0 0.19
0.619 - 0.503 0.388 0.281 - 0.275 !.057 - 0.716 - 0.598 0.341 - 0,374
0.0007 0.0025 0.07 0.085 0.093 ,0015 ,0009 .01 I .039 .06
F, forward to enter -- 1.00 The beta weights and the significance for each BPRS item entered are given,
thought centent, p5-HIAA showed highly significant associations with a number of items, the most significant being hostility and somatic concern, pMHPG had most significant associations with the score in disorientation, emotional withdrawal, and uncooperative attitude. Although these results deserve speci~d consideration, they cannot be considered definitive, because of the relatively small number of patients in relation W the number of variables One confounding factor in this type of analysis is the existence of intercorrelations between the BPRS item scores. We examined this issue and found that from the items inserted in the stepwise regression analyses no significant intercorrelations existed, except between the items uncooperative attitude and hostility inserted m the equation for pMHFq3. With a larger patient group, we could perform cluster and factor analysis with the variables being the concentrations of the three metabolites plus the scores in the BPRS items. This is especially so because the items found to relate to the plasma levels of the metabolites (Table 3) do not coincide with the BPRS subscales positive-negative-neutral symptoms, or the subscales depression-thought disorder-anergiaexcitation/disorientation. The discussion of the present findings in light of the existing reports is difficult, mainly because different scales and subscales were used for the assessment of the patients' psychopathology. Alfredsson and Wiesel (1990) used the Comprehensive Psychopathological Rating Scale, and found no correlations with pHVA and pMHPG, whereas patients with high p5HIAA levels had lower scores for autistic and depressive symptoms than those with lower p5-HIAA levels. No correlations of pHVA to any BPRS items score was found by Kirch et al (1988) in chronic schizophrenis, and by Sharma et al (1989) in a mixed psychotic patient group. On the other hand, in the study of Pickar et al (1990), pHVA correlated positively with psychosis and positive symptoms, whereas pMHPG correlated with negative symptoms. In summary, the main findings of the study indicate that although the concentrations of the main metabolites of dopamine, serotonin, and noradrenaline found in the plasma of drug-naive, schizophrenic patients are not different from healthy controls, there are
292
BIOLPSYCHIATRY
M. ~larkianos et al
1992;32:288-292
significant associations of certain BPRS item scores to serotonin and nora~;enaline metabolites and less to that of dopamine. The results indicate that ~%sma ;.evels of the neurotransmitter metabolites may reflect central turnover, and may be m o e related to particular psychological dysfunctions than to disease entities, as suggested b~: van Praag et al (1987) for seroton;~n. The correlations of serotonin and noradrenaline metabolites to certain psychopathology found in the present work support the hypothesis that these two biogenic amines are implicated in schizophrenia (Meltzer 1987; Bleich et ai 1988).
References AIfredsson G, Wiesel F-A (1990): Relationships between clinical effects and monoamine metabolites and amino acids in sulpiride-treated schizophrenic patients. Psychopharmacology 101:324-331. Bleich A, Brown S-L, Kahn R, van Praag HM (1988): The role of semtonin in schizophrenia. Schizophr Bull 14:297-315. Bowers MB, Swigar ME, Jatlow PI, Goicoechea N (1984): Plasma catecholamine metabolites and early response to haloperidol. J Clin Psychiatry 45:248-25 I. Bowers BB, Swigar ME, Jatiow PI, Hoffman FJ (1989): Plasma catecholamine metabolites and treatment response at neurnleptic steady :;tare. Biol Psychiatry 25:734-'/38. Davila R, Manero E, Zumarraga M, Andia I, $chweitzer JW, Friedhaff AJ (1988): Plasma homovanillic acid as predictor of response to neuroleptics. Arch Gen Psychiatry 45:564-567. Khan RS, Amin F, Powchik P, et al (1990): Increments in plasma homovaniilic acid concentrations after neuroleptk discontinuation are associated with worsening of schizophrenic symptoms. Prog NeuropsychopharmacolBiol Psychiatry 14:879-884. Kirch DO, Jaskiw G, Linnoila M, Weinberger DR, Wyatt RJ (1988): Plasma amine metabolites before and after withdrawal from neuroleptic treatment in chronic schizophrenic inpatients. Psyct:tatry Res 25:233-242. Ko GN, Jimerson DC, Wyatt RJ, Bigelow LB (1988): Plasma 3-methoxy-4-hydroxyphenylglycol changes associated with clinical state and schizophrenic subtype. Arch Gen Psychiatry 45:842846. Meltzer HY ( 1987): Biological studies in schizophrenia. Schizophr Bull 13:77-111. Pickar D, Laba,'ca R, Linnoila M, ct al (1984): Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients. Science 225:954-957. Pickar D, Breier A, Hsiao JK, et al (1990): Cerebrospinal fluid and plasma monoamine me~abolites and their relation to psychosis. Arch Gen Psychiatry 47:641-.648. Sharma R, Javaid JI, lanicak P, Faull K, Comaty .I, Davis ,IM (1989): Plasma and CSF HVA before and after pharmacological treatment. Psychiatry Res 28:97-104. van Praag HM, Kahn RS, Asnis GM, et al (1987): Denosologization of biological psychiatry or the specificity of 5-HT disturbs.aces in psychiatric disorders. J Ajfective Disord 13:1-8.
BIOL PSYCHIATRY 1992;32:288-292
B iogenic Amine Metabolites in Plasma of DrugNaive Schizophrenic Patients: Associations with Symptomatology Manolis Markianos, Alexander Botsis, and Yannis Arvanitis
The main metabolites of dopamine, noradrenaline, and serotonin, homovanillic acid, methoxyhydroxyphenylglycol (MHPG), and 5.hydro,~indoleacetic acid (5-HIAA), were estimated in plasma of 20 drug-naive young male schizophrenic patients and 21 healthy controls. Although there were no significant differences between the two groups, multiple regression analysis revealed strong associations of the patients' 5-HIAA and MHPG plasma levels to their scores in the Brief Psychiatric Rating Scale items. 5-HIAA levels were mainly related positively to hostility and negatively to somatic concern, and MHPG positively to disorientation and negatively to emotional withdrawal and uncooperativeness. The result., suggest that levels of the neurotransmitter metabolites may be related to certain psychological dysfunctions of the patients rather than to disease entities.
Introduction The estimation of the principal neurotransmitter metabolites in cerebrospinal fluid (CSF) has been proven to be a fruitful strategy for assessing central neuronal activity of biogenic amines in neuropsychiatric disorders, In recent years, methods for the estimation of the metabolite levels in plasma have been developed with adequate accuracy. Data collected from such measurements indicate that plasma concentrations may well reflect not only changes in peripheral, but also in central monoamine turnover. Changes in the main dopamine metabolite homovanillic acid (HVA) in CSF of psychotic patients treated with neuroleptics paralleled changes in plasma HVA (pHVA) (Sharma et al 1989). Neuroleptic treatment influences pHVA (Pickar et al 1984; Sharm,aet al 1989; Khan et al 1990), and baseline pHVA levels have been connected to the therapeutic response to neuroleptics (Bowers et al 1984, Davila et al 1988). Recently, positive correlations between pHVA and positive symptoms ratings have been reported in schizophrenic patients (Pickar et al 1990). Plasma concentrations of the main noradrenaline metabolite metboxyhydroxyphenylglycol (pMHPG) have been reported to be elevated in psychotic patients, especially in paranoid schizophrenics (Ko et ai 1988), and negative symptoms were correlated with pMHPG (Pickar et al 1990). In addition, reductions in both pHVA and pMHPG were found in psychotic patients after treatment with neuroleptics (Bowers et al 1989). From the Athens University Medical School, Psychiatric Clinic, Eginition Hospital (MM, YA), and the Department of Psychiatry, 41 ! General Army Hospital (AB), Greece. Address reprint requests to Dr. M. Markianos, Athens UniversityMedical School, PsychiatricClinic, Eginition Hospital, Vas. Sophias 74, Athens 11528, Greece. Received May 11, 1991; revised August 30, 1991. © 1992 Society of Biolosical Psychiatry
0006-3223/92/$05.Q0
Biogenic Amine Metabolites in Schizophrenia
BIOLPSYCHIATRY 1992;32:288-292
289
Regarding the main serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), there are only a few studies on its plasma concentrations, presumably because it is believed that it reflects central parent amine turnover less than HVA or MHPG, although there are indications that it acts in a similar manner. Alfredsson and Wiesel (1990) studied recently a group of 24 acutely ill schizophrenics and reported that patients with higher plasma 5-HIAA (pS-HIAA) had lower scores for autistic and depressive symptoms, and that responders to treatment with sulpiride had significantly higher pSHIAA levels during treatment than the nonresponders. Because of these data it seems meaningful to study plasma levels of dopamine, noradrenaline, and serotonin metabolites in relation to psychotic illness and its symptomatology, because all three amines have been implicated in schizophrenia (Meltzer 1987; Bleich et al 1988). In this study, we estimated the main dopamine, noradrenaline, and serotonin metabolites HVA, MHPG, and 5-HIAA of plasma in a group of drug-naive young male schizophrenic patients, and in a group of healthy male subjects in the same age range. We addressed the following questions: (1) were there differences in the metabolite concentrations between patients and controls, and (2) were the concentrations within the patient group related to the psychopathology as expressed in the EPRS items?
Subjects and Methods The patients were all recruits who had been hospitalized in the Psychiatric Clinic of the Army Hospital during an exacerbation of their illness. The age range was 19-24 years, and the duration of illness 1-5 years. They had never received treatment with psychotropic drugs. Twenty patients were examined, eight with paranoid, six with disorganized, four with undifferentiated, and two with catatonic subtype of schizophrenia, according to DSM-III-R criteria. Twenty-one controls known to manifest no psychopathology were selected by the psychiatrist (AB). All subjects were physically healthy. Blood samples were taken from the patients 2-4 days after their hospitalization, between 9 and 10 AM. Every time a blood sample was taken from a patient, samples were also taken from one or two control subjects. Blood was drawn (12 ml) wJth EDTA as coagulant, the plasma separated by centrifugation, and stored at - 30°C until analysis. The metabolites were estimated by high pressure liquid chromatography (HPLC) with electrochemical detection. The acids (HVA and 5-HIAA) were extracted from 0.5 ml acidified plasma into ethyl ether, and MHPG into ethyl acetate. After evaporation of the solvent, the residue was taken in 0. l ml mobile phase (acetate buffer with 10% methanol) and injected into a HPLC system with a Spberisorb ODS-2 column connected to electrochemical detector operating at a potential of 0.7 V and sensitivity 10 nA. For each estimation, 2 ml plasma was used for HVA and 5-HIAA, and 2 ml for MHPG, each in four portions of 0.5 ml, two without and two with 10 ng pure substances added at the beginning of the procedure. The differences in peak height between the samples with and without standards were used for calculations. The coefficients of variation were between 10% and 20%. For statistical evaluation of the data we used one-way analysis of variance (ANOVA) to compare the variables of the patient group to the control group. Further, the multiple linear regression model was applied for detecting possible associations between the plasma levels of the three metabolites (dependent variables), and the scores in the BPRS items (independent variables). Linear regression and Spearman correlation coefficients were also calculated.
290
BIOLPSYCHIATRY
M. Markianos et al
1992;32:288-292
Table 1. Age and Biogenic A m i n e Metabolites (ng/ml) in Plasma o f 21 Healthy Males and 20 Drug-Naive Male Schizophrenic Patients Variable
Controls
Age HVA 5-HIAA MHPG
20.9 12.6 16.6 5.5
Patients
(2.3) (5.4) (9.8) (!.9)
20.6 11.0 12.4 5.4
(1.7) (4.3) (6.5) (1.8)
F
p
0.23 1.10 2.55 0.03
0.64 0.30 0. I 1 0.84
Mean values and SD; one-way ANOVA.
Results and Discussion The concentrations of the three metabolites measured in the patient and the centre! groups are given in Table 1. No differences between the groups could be detected in any of these parameters. Thus, drug-naive male schizophrenic patients show normal levels of the biogenic amine metabolites in plasma during an exacerbation of their illness. Further statistical analysis of the data revealed some interesting points. We first applied the linear regression model for possible associations of the ratings in BPRS and the plasma levels of ~he three metabolites. This analysis (Table 2) revealed an association of the BPRS scc'~ to p5-HIAA. The linear regression coefficients between BPRS and the three metab~lites were not significant for pHVA and pMHI:'G, but showed a significant positive co relation to p5-HIAA (r = 0.4651, p = 0.039). from the 20 patients studied, 8 were paranoid and 12 had other types of the illness, as ,~aentioned in Subjects and Methods. Paranoid schizophrenics are expected to have hibher BPRS scores, and this was the case in our study group. The subgroup of patients with paranoid schizophreni ~ had a mean BPRS score of 76 (SD = 9), and the nonparanoid subgroup had 61 (SD = 9); the difference is significant (F = 14.51, p = 0.002). Comparison of the three m,~tabolite plasma levels between the subgroups revealed higher p5HIAA levels in the paranoid subgroup (F = 4.49, p = 0.046), whereas there were no significant differences in pHVA and pMHPG levels. Further, we used the multiple regression model to test the hypothesis of associations of the metabolite concentrations measured in plasma to the scores in the separate items of the BPRS. Because of the relatively small number of cases in relation to the number of BPRS items, we used the forwara stepwise model. The results are shown in Table 3. pHVA had a weak negative association with depressive mood and unusual
Table 2. Multiple Regression Analysis with Dependent Variable (DV) the Total BPRS Score, and IndependentVariables the Plasma Levels of HVA, 5-HIAA, and MHPG HVA DV BPRS
R
F
0,544 2,24 Linear regression: BPRS versus p~tVA BPRS versus p3-HIAA BPRS versus pI4HPG
p 0.12 r -0.0564 0.4051 - O.3484
5-HIAA
MHPG
Beta
p
Beta
p
Beta
p
-0.146 p
0,50
0,433
0.07
-0.247
0.27
0.813 0,039 0,132
The linear regressioncoefficientsof the BPRS score to the metabolitelevels are also given.
BiogenicAmine Metabolitesin Schizophrenia
BIOLPSYCHIATRY 1992;32:288-292
291
Table 3. Stepwise Multiple Linear Regression (forward, F to enter = 1.00) with Dependent Variables of the Plasma Concentrations of 5-HIAA, MHPG, and HVA, and the Independent Scores in the 18 Items of the BPRS R
df
F
p
pHVA
0.4046
2,17
1.66
0.22
p5-HIAA
0.9085
7,12
8. I !
0.0009
pMHPG
0.9031
7,12
7.58
0.00013
Beta Depressive mood Unusual thought content Hostility Somatic concern Conceptual disorganiz. Blunted affect Depressive mood Emotional withdrawal Disorientation Uncooperativeness Hostility Somatic concern
p
-0.449 -0.357
0.I0 0.19
0.619 - 0.503 0.388 0.281 - 0.275 !.057 - 0.716 - 0.598 0.341 - 0,374
0.0007 0.0025 0.07 0.085 0.093 ,0015 ,0009 .01 I .039 .06
F, forward to enter -- 1.00 The beta weights and the significance for each BPRS item entered are given,
thought centent, p5-HIAA showed highly significant associations with a number of items, the most significant being hostility and somatic concern, pMHPG had most significant associations with the score in disorientation, emotional withdrawal, and uncooperative attitude. Although these results deserve speci~d consideration, they cannot be considered definitive, because of the relatively small number of patients in relation W the number of variables One confounding factor in this type of analysis is the existence of intercorrelations between the BPRS item scores. We examined this issue and found that from the items inserted in the stepwise regression analyses no significant intercorrelations existed, except between the items uncooperative attitude and hostility inserted m the equation for pMHFq3. With a larger patient group, we could perform cluster and factor analysis with the variables being the concentrations of the three metabolites plus the scores in the BPRS items. This is especially so because the items found to relate to the plasma levels of the metabolites (Table 3) do not coincide with the BPRS subscales positive-negative-neutral symptoms, or the subscales depression-thought disorder-anergiaexcitation/disorientation. The discussion of the present findings in light of the existing reports is difficult, mainly because different scales and subscales were used for the assessment of the patients' psychopathology. Alfredsson and Wiesel (1990) used the Comprehensive Psychopathological Rating Scale, and found no correlations with pHVA and pMHPG, whereas patients with high p5HIAA levels had lower scores for autistic and depressive symptoms than those with lower p5-HIAA levels. No correlations of pHVA to any BPRS items score was found by Kirch et al (1988) in chronic schizophrenis, and by Sharma et al (1989) in a mixed psychotic patient group. On the other hand, in the study of Pickar et al (1990), pHVA correlated positively with psychosis and positive symptoms, whereas pMHPG correlated with negative symptoms. In summary, the main findings of the study indicate that although the concentrations of the main metabolites of dopamine, serotonin, and noradrenaline found in the plasma of drug-naive, schizophrenic patients are not different from healthy controls, there are
292
BIOLPSYCHIATRY
M. ~larkianos et al
1992;32:288-292
significant associations of certain BPRS item scores to serotonin and nora~;enaline metabolites and less to that of dopamine. The results indicate that ~%sma ;.evels of the neurotransmitter metabolites may reflect central turnover, and may be m o e related to particular psychological dysfunctions than to disease entities, as suggested b~: van Praag et al (1987) for seroton;~n. The correlations of serotonin and noradrenaline metabolites to certain psychopathology found in the present work support the hypothesis that these two biogenic amines are implicated in schizophrenia (Meltzer 1987; Bleich et ai 1988).
References AIfredsson G, Wiesel F-A (1990): Relationships between clinical effects and monoamine metabolites and amino acids in sulpiride-treated schizophrenic patients. Psychopharmacology 101:324-331. Bleich A, Brown S-L, Kahn R, van Praag HM (1988): The role of semtonin in schizophrenia. Schizophr Bull 14:297-315. Bowers MB, Swigar ME, Jatlow PI, Goicoechea N (1984): Plasma catecholamine metabolites and early response to haloperidol. J Clin Psychiatry 45:248-25 I. Bowers BB, Swigar ME, Jatiow PI, Hoffman FJ (1989): Plasma catecholamine metabolites and treatment response at neurnleptic steady :;tare. Biol Psychiatry 25:734-'/38. Davila R, Manero E, Zumarraga M, Andia I, $chweitzer JW, Friedhaff AJ (1988): Plasma homovanillic acid as predictor of response to neuroleptics. Arch Gen Psychiatry 45:564-567. Khan RS, Amin F, Powchik P, et al (1990): Increments in plasma homovaniilic acid concentrations after neuroleptk discontinuation are associated with worsening of schizophrenic symptoms. Prog NeuropsychopharmacolBiol Psychiatry 14:879-884. Kirch DO, Jaskiw G, Linnoila M, Weinberger DR, Wyatt RJ (1988): Plasma amine metabolites before and after withdrawal from neuroleptic treatment in chronic schizophrenic inpatients. Psyct:tatry Res 25:233-242. Ko GN, Jimerson DC, Wyatt RJ, Bigelow LB (1988): Plasma 3-methoxy-4-hydroxyphenylglycol changes associated with clinical state and schizophrenic subtype. Arch Gen Psychiatry 45:842846. Meltzer HY ( 1987): Biological studies in schizophrenia. Schizophr Bull 13:77-111. Pickar D, Laba,'ca R, Linnoila M, ct al (1984): Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients. Science 225:954-957. Pickar D, Breier A, Hsiao JK, et al (1990): Cerebrospinal fluid and plasma monoamine me~abolites and their relation to psychosis. Arch Gen Psychiatry 47:641-.648. Sharma R, Javaid JI, lanicak P, Faull K, Comaty .I, Davis ,IM (1989): Plasma and CSF HVA before and after pharmacological treatment. Psychiatry Res 28:97-104. van Praag HM, Kahn RS, Asnis GM, et al (1987): Denosologization of biological psychiatry or the specificity of 5-HT disturbs.aces in psychiatric disorders. J Ajfective Disord 13:1-8.