Schizophrenic patients with deficit syndrome have higher plasma homovanillic acid concentrations and ventricular enlargement

Schizophrenic Patients with Deficit Syndrome Have Higher Plasma Homovanillic Acid Concentrations and Ventricular Enlargement Masashi Nibuya, Shigenobu Kanba, Utako Sekiya, Eiji Suzuki, Yoko Matsuo, Norihisa Kinoshita, Futoshi Shintani, Gohei Yagi, and Masahiro Asai

hi order to investigate the biological characteristics of deficit syndrome in schi=ophrenia (Carpenter et al 1988), we examined eerebroventricular ratios (CVRs) and plasma concentrations of homovanillie acid (HVA) in a group of schizophrenic inpatients with deficit syndrome (n = 20) and in a control group of age- and sex-matched schi=ophrenic inpatients without deficit syndrome (n = 20). Symptoms and intelligence levels were measured using the Brief Psychiatric Rating Scale (BPRS) and the Wechsler Adult Intelligence Scale (WA1S), respectively. Patients in the deficit group had significantly higher CVRs as well as significantly elevated plasma HVA concentrations when compared with patients in the nondefieit group. We also found that the mean total WA1S seore i, the deficit group was significantly lower than that in the nondeficit group. These findings suggest the biological heterogeneity (~f schizophrenia. Increased central dopaminer,~ic turnover, as indicated by higher plasma HVA concentrations, may partially account for the pathogenesis (~['defieit syndrome.

Key Words: Schizophrenia, deficit syndrome, plasma homovanillic acid, computed tomography, Wechsler Adult Intelligence Scale, negative symptoms

Introduction In recent years, negative symptoms of schizophrenia have gained more attention (Strauss et al 1974), and some investigators have attempted to categorize schizophrenia according to the severity of positive and negative symptoms. Andreasen et al (1982a), based on a cross-sectional clinical

From the Department of Neuropsychiatry, Keio University Schmd of Medicine. (MN. SK, US, ES. NK, FS, GY. MAI, and the Department ol Psychiatry. Jiundo Hospital, Tokyo, Japan (MN, US, YM, NKI Address reprint requests to Shigenobu Kanba. M.D., Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi. Shinjuku ku Tokyo 160. Japan. Received July 7, 1993: revised July 19, 1994.

© 1995 Society of Biological Psychiatr5

observation, identified three types of schizophrenia: one type characterized by predominantly positive symptoms (positive schizophrenia), another type characterized by predominantly negative symptoms (negative schizophrenia), and a third type characterized by mixed positive and negative symptoms (mixed schizophrenia). Crow (1980, 1985) has described two types of schizophrenia: type I, characterized by predominantly positive symptoms and a good response to neuroleptics; and type II, characterized by predominantly negative symptoms, a poor response to neuroleptics, and lateral ventricular enlargement. More recently, Carpenter et al (1988) proposed that the primary enduring negative symptoms of schizophrenia, termed deficit symptoms, should be distinguished from transient nega0006-3223/95/$09.50 SSDI (X)06-3223(94)00216-P

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tire symptoms resulting from anxiety, depression, the adverse effects of medication, or the deprivation of environmental stimuli. According to Carpenter et al (1988), the diagnosis of deficit syndrome cannot be made unless negative symptoms have been present for at least the preceding 12 months. This deficit versus nondeficit classification has excellent temporal diagnostic stability (Fenton and McGlashan 1992). To date, few biological investigations of the deficit/nondeficit distinction in schizophrenics have been performed. We measured cerebroventricular ratios (CVRs) and plasma homovanillic acid (HVA) concentrations and used them as biological markers in schizophrenic inpatients with deficit and nondeficit syndromes in an attempt to define a pathophysiologic basis for this distinction.

uncooperativeness); 3) withdrawal retardation (emotional withdrawal, motor retardation, and blunted affect); and 4) depressive disturbance (somatic concern, anxiety, guilt feelings, and depressive mood). In addition, positive symptoms were assessed using the total scores of the following seven BPRS items: conceptual disorganization, mannerisms and posturing, hostility, suspiciousness, hallucinatory behavior, unusual thought content, and excitement (Tandon et al 1989). The intelligence level of subjects was evaluated using the Wechsler Adult Intelligence Scale (WAIS; Wechsler 1958) by a trained psychologist (YM), blind to background information on the patients. Two subjects in the deficit group and two subjects in the nondeficit group refused to take the test.

Measurements of Cerebroventricular Ratios

Subjects and Methods Deficit and Nondeficit Classification The subjects investigated in our study were all schizophrenic patients who had been hospitalized in a mental hospital for a minimum of 12 months. Patients who had been earlier diagnosed as having schizophrenia according to DSM-III-R criteria (American Psychiatric Association 1987) and who had provided written consent to participate in the study were independently interviewed by two psychiatrists (MN and US) and diagnosed as having either a deficit syndrome or a nondeficit syndrome, according to the Schedule for Deficit Syndrome (Carpenter et al 1988). In cases where the two psychiatrists differed in their diagnosis, patients were excluded from the study. So, too, were patients whose dose of neuroleptics had been changed within the last 8 weeks prior to the study. No patient had a history of neurological illness, including mental retardation, alcoholism, substance abuse, or other physical disease. No patients had received neuroleptics in depot form. Twenty patients with deficit syndrome (17 males and 3 females) and 20 ageand sex-matched patients with nondeficit syndrome (17 males and 3 females) were selected as subjects. The mean age of deficit group subjects was 43.7 _+ 14.1 years (range, 21~54 years), and the mean age of the nondeficit group subjects was 45.0 _+ 13.2 years (range 21-61 years).

Assessment of Symptoms and hltelligence Once subjects were enrolled in the study, their symptoms were rated on the 18-item Brief Psychiatric Rating Scale (BPRS) (Overall 1988) by their primary physician. This was based on an earlier four-dimensional model of BPRS clusters developed by Overall et at (1967), which includes the dimensions of I) thinking disturbance (conceptual disorganization, hallucinatory behavior, and thought content): 2) interpersonal disturbance (hostility, suspiciousness, and

Computed tomography (CT) was performed on all subjects except for one subject in the nondeficit group. At the level of superior collicus, the ratio of the maximum distance between the tips of the anterior horns to maximum transverse inner diameter of the skull along the line of the maximum distance between the tips of the anterior horns was measured as the first CVR. The second CVR was measured as the ratio of the maximum distance of the celiac mediae at the level of the caudate nuclei just anterior to the third ventricle, to the maximum transverse inner diameter of the skull along the line of the bicaudate diameter at the same slice level (Haug 1977).

Blood Collections and Plasma HVA Measurements Blood samples were collected on the day of symptom assessment. High-monoamine diets, alcohol, and caffeine, all of which are known to influence plasma HVA concentration, were restricted for all patients from 3:00 eM on the day before blood collection (Davidson et al 1987). Five milliliters of blood were obtained by venipuncture and collected in a glass tube containing ethylenediamine tetraacetic acid (EDTA)-2Na (l mg/ml) at about 7:00 AM before breakfast and the oral administration of morning medications, to minimize the effects of diurnal variation, food (Davidson et al 1987), and medication (Davila et al 1989) on plasma HVA concentration. Plasma was obtained by centrifugation at 800 g for 10 minutes and stored in a deep freezer (-80°C) until assay. High-performance liquid chromatography with electrochemical detection (HPLC-ECD) analysis was performed to measure the plasma HVA concentration. The assay method employed was a modified version of that reported by Change et al (1983). Thus, for deproteinization, plasma was added to 2/10 volume of 4 N-perchloric acid and centrifuged at 3200 g for 15 minutes. Supernatant was filtrated using a nylon flter (pore size, 0.45 p~m; Cameo, USA), and

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Table 2. Demographic Features of Schizophrenic Subjects with and Without Deficit Syndrome

Table 1. Levels of Plasma HVA for High or Low Groups in Various Items

Deficit g r o u p (n = 20)

H V A concentration (ng/ml) Items Positive s y m p t o m s cluster Thinking disturbance cluster Interpersonal disturbance cluster W i t h d r a w a l retardation cluster Depressive s y m p t o m cluster CPequivalent B P R S total score

High group',

(n)

Lowgroup',

(n)

12.7 _+ 5.3 13.4 _+ 5.2 12.5 -+ 4.8 14.9 ± 4.4 13.6-+4.3 12.7 _+ 4.4 14.2-+4.8

(16) (24) (22) (21) (11) (21) (12)

13.7 _+ 4.5 13.0 + 4.1 14.2 -+ 4.7 I 1.5 -+ 4.6* 13.1 -+5.0 13.8-+ 5.2 12.9_+4.8

(24) (16) (18) (19) (29) (19) (28)

CP = chlorpromazine: BPRS = Brief Psychiatric Rating Scale. "A patient with a mean score in each subscale item > 2.0 or a patient whose CP equivalent dose was > 400 mg/day was placed in a higher group *p < ,05; Scheffe's multiple comparison test.

each sample (20 ~1) was injected directly into the HPLCECD system. A polyoctadecylsilica column (C-18, 4.6 × 250 mm; Niko, Japan) was used as the solid phase for the separation of monoaminergic metabolites. The HPLC-ECD system consisted of a pump system (JASCO, 880-PU, Japan) with a degasser (JASCO, 880-51), a damper (EICOM, PL 100, Japan), an autosampler (JASCO, 851AS), and an amperometric detector (Coulochem-II, USA). The mobile phase of HPLC consisted of 0.04 M Na2HPO40.04 M citrate with 85 mM sodium l-octanesulphonic acid, 10 mM EDTA-2Na and 8% (v/v) methanol adjusted to pH = 4.5. Separation was carried out at 33°C using a columnoven (JASCO, 880-CO) at a flow rate of 0.6 ml/min. The plasma HVA concentration was calculated from the area under the curve (AUC) using a Chromatocorder-12 (SIC, Japan). The retention time of the HVA peak was about 34 min, and the entire fraction appeared as a single, distinct peak.

Data Analysis The Mann-Whitney U test was used to compare the means of each BPRS subscale, WA1S scores, and the patients' social background. Student's unpaired t test was used to compare mean plasma HVA concentrations and CVRs. Scheffe's multiple comparison test was applied to post-hoc data to compare plasma HVA concentrations between high and low groups (Table I). All probability values were calculated as two-tailed. P < .05 was considered significant.

Results Table 2 shows subjects' demographic background. No significant difference in age of onset, duration of hospitalization, number of hospitalizations, level of education, or administered neuroleptic dose (chlorpromazine (CP) equivalent dose) was found between the deficit and the nondeficit groups. In all subjects, treatment depended

Age(yr) Age of onset (yr) Duration of hospitalization (yr) No. of hospitalizations Education (yr) O c c u p a t i o n (yr) D r u g administration

43.7 22.9 15.9 2.7 10.9 2.1 667.8

_+ 14.1 -+ 6.4 + 13.7 _+ 1.8 -+ 2.5 +- 3.3* _+ 587.9

Nondeficit g r o u p (n = 20) 45.0 24.7 12.9 3.6 12.2 6.1 456.1

+ 13.2 -+ 7.7 _+ 14.1 _+ 3.7 -+ 2.7 + 5.2 --- 435.3

(mg CP/day) CP = chlorpromazine. *p < .01 ; the Mann-Whitney U test.

mainly on neuroleptic medication, so the duration of hospitalization and the duration of time on medication were identical; however, the work history was shorter in the deficit group than the nondeficit group (p < .01; Mann-Whitney U test). These findings were consistent with the data published by Andreasen et al (1982b) stating that patients with prominent negative symptoms had poor social adjustment. No subjects received mediations other than the regular medications at 0730, 1200, 1800, 2030. Subjects had been administered neuroleptics, including phenothiazines (chlorpromazine, levomepromazine, thioridazine, or propericiazine) and butyrophenones (haloperidol, bromperidol, or pimozide) and antiparkinsonian drugs (promethazine or bipedden) as regular medications, and had been administered benzodiazepines as hypnotics before sleep. No significant changes were found in the administered oral dose of phenothiazines, butyrophenones, antiparkinsonian drugs, and benzodiazepines between the deficit and nondeficit groups. Thinking disturbance (p < .01; Mann-Whitney U test) and withdrawal retardation (p < .001; Mann-Whitney U test) were significantly worse in the deficit group. No significant intergroup difference existed in the positive symptom cluster (Figure 1). The first and second CVRs in the deficit group were 0.32 ± 0.06 and 0.16 ± 0.04, and were 0.28 ± 0.05 and 0.13 ± 0.02 in the nondeficit group, respectively. Both differences in the CVRs between the two groups were significant (p < .05 and p < .01, respectively; Student's unpaired t test) (Figures 2 and 3). The WAIS scores are shown in Table 3. The deficit group had lower scores in most categories, with highly significant differences in verbal (p < .01), performance (p < .001), and full-scale IQ (p < .001) when the Mann-Whitney U test was used for data analysis. The deficit group had a significantly higher mean plasma concentration of HVA (14.8 --- 4.5 ng/ml) than the nondeficit group (11.7 ± 4.6 ng/ml, p < .05; Student's unpaired t test) (Figure 4). Plasma HVA concentrations did not corre-

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positive symptom thinking disturbance interpersonal disturbance withdrawal disturbance depressive disturbance

.~ficil ~a vula

total BPRS

*~

0

1

2

~ deficit g r o u p

;

'~

5

mean score (score / item) Figure I. Comparison of scores for each BPRS subscale in schizophrenic subjects with and without deficit syndromes. Thinking disturbance (p < .01 ) and withdrawal retardation (p < .001) were significantly worse in the deficit group. No significant intergroup difference existed in the positive symptom cluster. **p < .01, ***p < .001 ; the Mann-Whitney U test.

late with the first or second CVRs or WA1S scores in the deficit group. Finally, subjects were divided into two groups based on whether their mean score was greater than or less than 2.0 for each BPRS cluster, and whether drug dose was greater than or less than a CP equivalent dose of 400 rag/day. Then, the plasma HVA concentrations between groups were compared (Table 1). The difference was significant only for withdrawal retardation (p < .05; Scheffe's multiple comparison test).

Discussion In this study, the deficit group had significantly higher CVRs as compared with the nondeficit group (p < .05: Student's unpaired t test). Ventricular enlargement has been found more consistently in the negative type of schizophrenia than the mixed or positive subtypes by both computed tomography (Andreasen et al 1982b; Pearlson et al 1984; Nasrallah et al 1982; Williams et al 1980: Klausner JD 1992) and magnetic resonance imaging (MRI) (Andreasen et al 1990). The intelligence levels evaluated with the WAIS in both the deficit and the nondeficit groups were generally lower than those reported by Wagman et al (1987). This difference may be due in part to the fact that all subjects in that study were outpatients, while most of our subjects had been hospitalized for a number of years. Therefore, long-term institutionalization and social deprivation might have influenced the WAIS scores: however, both studies are con-

sistent in demonstrating that patients with deficit syndrome have significantly lower WAIS scores than those without deficit syndrome. The presence of enlarged ventricles and lower WAIS scores in the deficit group may allow us to speculate that neuronal atrophy producing intellectual deterioration may underlie deficit syndrome. The plasma HVA has been accepted as a good index of central dopaminergic activity; several authors have reported a significant correlation between the change in the plasma HVA concentration and the neuroleptic response (Bowers et al 1984; Davila et al 1988, Pickar et al 1984, 1986), and have suggested that the plasma HVA is useful for predicting the response to neuroleptics and it could be a biological marker for subtyping schizophrenia (Chang et al 1988). The deficit group in this study had higher plasma HVA concentrations than the nondeficit group, which may imply higher dopaminergic turnover in the central nervous system in spite of long term pharmacotherapy. It has been reported that more symptomatic, drug-free schizophrenics have higher plasma HVA concentrations (Davidson et ali 988) and that plasma HVA concentration is positively correlated with total BPRS score and positive symptom score in patients after 5 weeks of neuroleptic treatment from a drug-free state (Pickar et al 1986). In the present study we were unable to find a positive correlation between plasma HVA concentration and the score of total or positive symptom cluster in BPRS. One possible reason for this discrepancy arises from the fact that our subjects had been consecutively administered neuroleptics without a

54

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M. Nibuya et al

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Figure 2. Comparison of the first cerebroventricular ratio in schizophrenic subjects with deficit and without deficit syndromes. The first CVR for the deficit group was 0.32 _+0.06 and 0.28 -+ 0.05 for the nondeficit group. *p < .05: Student' s unpaired t test. drug-free period. Moreover, the subjects in the present study tend to have moderate positive symptoms with or without severe negative symptoms compared to these reports. For this reason we do not necessarily consider that the present study contradicts to previous reports. These findings should be interpreted cautiously until replicated. Other studies have shown a significant positive correlation between reduction in negative symptoms and decrease in the plasma HVA concentrations in response to administration of a neuroleptic drug (Pickar et al 1986; Suzuki et al 1992). In addition, the effectiveness of the relatively specific D2 antagonist pimozide in the treatment of negative symptoms in schizophrenia has been demonstrated in a placebo-controlled double-blind study (Opler et al 1991). These studies indicate that negative as well as positive symptoms are associated with higher dopaminergic turn-

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non-deficit group

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Figure 3. Comparison of second cerebroventricular ratio in schizophrenic subjects with and without deficit syndromes. The second CVR lk)rthe deficit group was 0.16 _+0.04 and 0.13 + 0.02 for the nondeficit group. **p < .01 ; Student's unpaired t test.

over, and these results coincide well with our results; however, a significant negative relationship between the severity of the negative symptoms and cerebrospinal fluid HVA concentrations has been reported in a drug-free patients (van Kammen et al 1986; Lindstr6m 1985). Thus, the relationship between the central dopaminergic turnover and negative systems remains to be established conclusively. Available evidence suggests that at least some schizophrenic patients with deficit syndrome have elevated central dopaminergic activity.

This work was supported in part by Ohme Keiyu Hospital Research Grant (Dr. Nobuo Otsuka, Director) and a Research Grant for Nervous and Mental Disorders from the Ministry of Health and Welfare.

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Table 3. Comparison of Intellectual Function in Schizophrenic Subjects with and without Deficit Syndrome Deficit group (n= 18)

Nondeficit group (n= 18)

WAIS-verbal (raw scores) Information Comprehension Arithmetic Similarities Digit span Vocabulary

5.8 5.6 5.3 5.7 5.9 4.4

+ 3.4 _+ 3.7** -+ 2.1"* + 4.1"** _+ 3.0** + 4.1"

8.2 _+ 2.6 8.3 -+ 3.6 7.4 _+ 2.0 9.2 + 2.6 8.2 _+ 1.9 6.2 + 2.8

WAlS-performance (raw scores) Digit symbol Picture completion BIockdesign Picture arrangement Object assembly

5.3 4.8 5.4 5.2 4.8

_+ 3.0" + 3.4** + 3.2* _+ 2.8*** + 3.2**

7. I 7.4 7.5 8.0 7.3

WAIS-summary VerballQ Performance lQ Full scale IQ

71.0 : 14.2**~ 69.6 + 14.0* 68.2 + 14.1 ~

_+2.1 + 2.4 _+ 2.5 -+ 3.0 _+ 2.7

89.2 + 12.6 87.7 _+ 13.0 87.4 _+ 13.2

WAIS = Wechsler Adult Intelligence Scale *p < . l , * * p < .05,***p < .01,~p <.(X) l:the Mann Whitney Utest.

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I

non-deficit

deficit

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group

Figure 4. Comparison of plasma homovanillic acid concentrations in schizophrenic subjects with and without deficit syndromes. The deficit group had a significantly higher mean plasma HVA concentration ( 14.8 -4- 4.5 ng/ml) than the non-deficit group ( 1 1 . 7 - 4.6 ng/ml). *p < .05; Student's unpaired t test.

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