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0 1993 Elsevier Science Publishers B.V. All rights reserved 0920-9964/93/$06.00 SCHRES 00318

Plasma homovanillic acid and treatment response in a large group

of schizophrenic patients*

Wen-Ho Chang”qb, Hai-Gwo Hwubya, Teng-Yi Chen”, Shi-Kwang Lin”, For-Wei Lung’, Horng Chen”, Wen-Long Lin”, Wei-Herng Hu”, Hsin-Nan Linbg” and Ching-Piao Chien”gb “Laboratory of Biological Psychiatry and Department of Adult Psychiatry, Taipei City Psychiatric Center, Taipei, Taiwan and bDepartment of Psychiatry, Medical College, National Taiwan University, Taipei, Taiwan and ‘Military 818 Psychiatric Hospital,

Taipei, Taiwan

(Received 12 September 1992; revision received 26 January 1993; accepted 28 January 1993)

Plasma levels of homovanillic acid (pHVA), a metabolite of dopamine, were measured in ninety-five Chinese schizophrenic patients free of neuroleptics for at least four weeks. These patients were treated with classical antipsychotics for six weeks. Pretreatment pHVA was positively correlated with the subsequent clinical response (r = 0.408, p < 0.0001). Good responders (BPRS improvement > 50%, n = 47) had higher pretreatment pHVA levels than poor responders (BPRS improvement < 50%, n = 48) (15.7 f 8.4 ng/ml versus 9.9* 3.7 ng/ml, p<O.OOOl). A higher than 15 ng/ml pretreatment pHVA level was associated with a more consistent clinical response to the subsequent treatment. Using a pHVA level of 12 ng/ml as a demarcation point, 72% of patients (34 of 47) who had pHVA >, 12 responded whereas 65% (31 of 48) who had < 12 did not respond (chi-square= 13.02, p< 0.0001). These results suggest that higher pretreat- ment pHVA levels may predict a better clinical response to antipsychotics. Based upon the pHVA findings, two hypothetical subtypes of schizophrenia are proposed.

Key words: Plasma homovanillic acid; Neuroleptic response; Subtype; (Schizophrenia)

INTRODUCTION

The dopamine (DA) hypothesis of schizophrenia which proposes that enhanced central dopa- minergic activity is causally related to this mental disorder has been one of the most important and enduring concepts in biological psychiatry in the last two decades. The measurement of the DA metabolite homovanillic acid (HVA) in body fluids has been one of the most widely used strategies for studying aspects of DA function in neuropsy- chiatric disorders. This approach has been based,

Correspondence to: Wen-Ho Chang, Laboratory of Biological Psychiatry, Taipei City Psychiatric Center, 309 Sung-Te Road Taipei, Taiwan 10510, ROC.

*Presented at the 7th International Catecholamine Symposium, June 22-26, 1992.

in part, on the possibility that metabolite pro- duction reflects neurotransmitter release and turn- over in the brain. Even though no more than 25% of plasma HVA (pHVA) appears to be of central origin according to current estimates (Amin et al., 1992), plasma may still be the most useful body fluid for HVA measurement as a correlate of clinical state. Based on both lines of reasoning, pHVA studies in psychiatric patients have been conducted in a number of research centers (Bowers et al., 1984; Pickar et al., 1984; Davis et al., 1985; Chang et al., 1988; Davila et al., 1988).

Several reports of pHVA concentrations in schiz- ophrenic patients have produced interesting, yet inconsistent, results. Pickar et al. (1984) found that pHVA levels in schizophrenic patients are signifi- cantly higher than those in normal control volun- teers, whereas Davidson and Davis (1988) reported the reverse. In addition, significant positive correla-

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the Student’s t-test, Pearson’s product-moment correlation and the chi-square test.

RESULTS

Forty-seven patients were rated as having a good clinical response, and 48 a poor clinical response. As shown in Table 1, the two groups did not differ significantly in terms of age, gender, or pretreat- ment BPRS rating. However, the pretreatment pHVA in the good responder group was signifi- cantly higher than that in the poor responder group (15.7k8.4 ng/ml versus 9.9f 3.7 ng/ml, t= 4.44, p<O.OOOl). Moreover, there was a positive correlation between baseline pHVA and clinical improvement after 6 weeks of antipsychotic treat- ment (Y= 0.408, p< 0.0001) (Fig. 1). Nineteen of twenty-one patients with > 15 ng/ml baseline pHVA values were good responders. However, more than one-half of the good responders had baseline pHVA values of < 15 ng/ml(26/47). Using a pHVA level of 12 ng/ml as a demarcation point (Mazure et al., 1991) 72% of patients (34/47) who had pHVA 3 12 responded whereas 65% (31/48) who had < 12 did not respond (Chi-Square= 13.02, df = 1, p < 0.000 1) (Table 2).

Data on pHVA and clinical response grouped according to fixed-dose and variable-dose sched- ules are presented in Table 3. Although haloperidol dosages and plasma levels in poor responders were significantly higher than those in good responders (0.48 + 0.13 mg/kg/day versus 0.32 f 0.15 mg/kg/ day, t = 2.932, p < 0.01 and 25.9 + 13.5 ng/ml versus 16.4 k 10.9 ng/ml, t = 2.627, p< 0.05) in the vari- able-dose group, higher baseline pHVA levels in

TABLE 1

tt I 1 I

1

-20 0 a 40 EC 80 100

CLINICAL IMPROVEMENT IN SPRS (o/o)

Fig. 1. Correlation between baseline pHVA levels and clinical improvements after 6 weeks of antipsychotic treatment.

good responders and lower levels in poor respond- ers were found in both fixed and variable dose groups: 17.4+ 8.8 ng/ml versus 11.4 ng/ml (~~0.05) and 14.0f7.8 ng/ml versus 9.3k3.0 ng/ml (p < 0.005).

DISCUSSION

Ninety-five schizophrenic patients were divided into two groups on the basis of their clinical outcome following 6 weeks of antipsychotic treat- ment. Patients who responded had higher pretreat- ment pHVA levels than non-responders. A higher than 15 ng/ml pretreatment pHVA level was associ- ated with a more consistent clinical response to

Data on schizophrenic patients grouped according to clinical response to neuroleptic treatment (mean k SD)

Good responders Poor responders

(n=47) (n = 48) Age (years) 29.6 * 8.3 30.9k9.1 Sex (M/F) 28/19 31/17 Baseline BPRS 36.5+9.8 36.8k9.8 BPRS improvement (%) 74.42 14.8 14.5* 19.4 Baseline pHVA (ng/ml) 15.7k8.4 9.9*3.7

BPRS, brief psychiatric rating scale; pHVA, plasma homovanillic acid.

D$erence NS NS NS p<o.o001 p~o.0001

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TABLE 2

Comparison of plasma homovanillic acid and clinical response between two studies

Study Baseline plasma homovanillic acid

> 12 ng/ml Responder Nonresponder < I2 nglml Responder Nonresponder Mazure et al. (1991) 14 (75%) 6 (25%) 5 (29%) 12 (71%) This study 34 (72%) 13 (28%) 17 (35%) 31 (65%) TABLE 3

Data on schizophrenic patients grouped according toJi.xed-dose and variable-dose schedules and clinical response to neuroleptic treatment (mean k SD)

Variable Fixed-dose (n = 33) Variable-dose In = 62)

Good Poor responders responders in = 22) (n=ll) Good responders (n=26) Poor responders in = 36) Baseline pHVA (ng/ml) Age (years) Sex (M/F) Baseline BPRS Dose (mg/kg/day) 17.4k8.8 11.4*5.0” 14.0+7.8 9.3+3.0c 29.4 k 9.1 29.3i 8.7 29.7 k 7.6 31.4k9.3 14/8 615 IS/l1 24112 36.4 k 8.9 43.0* 8.3 36.7+ 10.4 34.9k9.5 Haloperidol Flupenthixol Plasma level (ng/ml) Haloperidol Flupenthixol Improvement BPRS (%) 0.36+0.06 0.37+0.13 0.32kO.15 0.48fO.13” (n= 19) (n = 26) 0.26 x 0. I 1 0.29 k 0.08 (n = 8) (n= II) 18.7k7.0 16.Oi6.7 16.4& 10.9 25.9* 13.5” (n= 19) (n = 26) 3.8+ 1.7 4.8+ 1.3 (n = 8) (n=6) 73.2& 14.0 25.6* 13.9d 75.4+ 15.6 11.2+ 19.7d

Fixed-dose: haloperidol 20 mg/day.

Variable-dose: haloperidol lo-30 mg/day; flupenthixol 6624 mg/day. pHVA: plasma homovanillic acid; BPRS: brief psychiatric rating scale. ap<0.05; bp<O.Ol; ‘p<O.O05; ~p<0.0001.

antipsychotic treatment. This is in accord with the findings of several previous investigations (Bowers,

1991; Bowers et al. 1984, 1987; Chang et al., 1990; Davidson et al., 1991; Mazure et al., 1991). Data obtained from a group of 37 psychotic patients including schizophrenics and nonschizophrenics have been recently reported by Mazure et al. (1991). Using a pHVA level of 12 ng/ml as a demarcation point, these investigators found that 75% of patients (14 of 20) who had pHVA 2 12 responded whereas two-thirds (12 of 17) who had pHVA < 12 did not respond. Our results are

remarkably consistent with these earlier results: 72% of patients (34 of 47) who had higher pHVA levels (2 12 ng/ml) responded while 65% of patients (31 of 48) who had lower pHVA levels (< 12 ng/ml) did not (Table 2).

A study of Pickar et al. (1984) found that schizophrenic patients who responded to fluphe- nazine treatment had higher pretreatment pHVA levels than normal subjects. In a study from another center, Davidson and Davis (1988) reported that treatment-resistant patients had lower pHVA levels than controls. Although we did

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not have a matched group of normal controls, our results are generally consistent with these combined findings. Taken together, studies support the notion that higher pretreatment pHVA levels in schizophrenic patients are associated with good clinical response to neuroleptics, whereas lower pHVA may be related to poor response.

In other respects, our results differ from those reported by the two just cited research groups. Significant positive correlations between baseline pHVA levels and symptom severity have been reported by Pickar et al. (1984) Davis et al. (1985), and Davidson and Davis (1988). We did not find a significant relationship between pretreatment pHVA and BPRS score (data not shown). In this respect, our findings are more consistent with two other reports (Javaid et al., 1990; Mazure et al., 1991). This discrepancy among studies may be attributable to differences in patient populations and methods of symptom assessment. However, if baseline pHVA is generally correlated to symptom severity, it is hard to understand how mean base- line pHVA level in subgroups of schizophrenic patients who appear equally severely ill prior to treatment can be both higher and lower than in normal controls as reported by Pickar et al. (1984) and Davidson and Davis (1988) respectively.

There is far less discrepancy regarding the corre- lation between pHVA change and clinical response following antipsychotic treatment reported by a number of groups (Bowers et al., 1984; Pickar et al., 1984, 1986; Davidson et al., 1987, 1991; Chang et al., 1988, 1990; Davila et al., 1988; Mazure et al., 1991). Most investigators find that a time-dependent decrease in concentrations of pHVA is correlated with clinical improvement in response to antipsychotics, while no decrease in pHVA is associated with poor clinical response (Bowers et al., 1984; Pickar et al., 1984, 1986; Chang et al., 1988, 1990; Davila et al., 1988; Davidson et al., 1991; Mazure et al., 1991).

Combined, the various results suggest that a high pretreatment pHVA concentration followed by a relatively large decrease on antipsychotics reflect biochemical processes that play an impor- tant role in determining therapeutic response. A possible explanation of the differences in baseline pHVA level and pHVA change during long-term antipsychotic treatment between good and poor

responders might be that the syndrome of schizo- phrenia is biochemically heterogeneous.

On the basis of the differential pretreatment pHVA levels and pHVA changes during chronic administration of antipsychotics as well as the different clinical responses to neuroleptic treat- ment, we suggest that at least two biologically distinct subtypes can be differentiated among schiz- ophrenic patients: the first would be related to some forms of increased DA activity, and the second one would not. The two subtypes would be in accord with those identified by clinical symp- toms (positive and negative), responses to antipsy- chotic treatment (good and poor), and brain structures determined by computed tomography (without and with brain atrophy) (Crow, 1980, 1985) with the additional characteristics of func- tional activities in dopaminergic neurons and/or DA synthesizing cells as manifested by pretreat- ment pHVA levels (high and low), and pHVA changes during long-term antipsychotic treatment (decrease and no decrease). Our results could be interpreted as in accord with the suggestion of Friedhoff (1986, 1988) and Davila (1989) that there may be a DA-dependent restitutive or buffer system for the maintenance of mental stability that reduces dopaminergic activity in the face of men- tally destabilizing biological or psychological insults. Patients with evidence of high pretreatment dopaminergic activity (if this produces high pHVA) respond well to neuroleptics correlated with pHVA decrease, because antipsychotic medication is believed to exercise its therapeutic effect by decreasing dopaminergic activity. In contrast, those with low pretreatment DA function (thus low pHVA) have a poor therapeutic response associated with no decrease in dopaminergic activ- ity, as it has already been downregulated by the stabilizing or restitutive system. Our hypothesis also is not inconsistent with the dopamine- serotonin hypothesis as suggested by Meltzer (1989). Treatment-resistent patients who have low baseline pHVA may response to atypical antipsy- chotics (e.g., clozapine). Measurement of pHVA may be a useful tool for drug choice in the treatment of schizophrenia. Patients with high pHVA can be treated with classical antipsychotics, while those with low pHVA may be need an atypical antipsychotic treatment.

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gathered over a long period of time (5 years) is subject to potential errors. Some investigators have found that seasonal variations in HVA in cerebro- spinal fluid and post-mortem brain may exist in humans (Karson et al., 1984; Losonczy et al., 1984). The possibility of a seasonal fluctuation in pHVA levels should be considered (Chang et al., 1993). Moreover, several studies have reported that pHVA and plasma 3-methoxy-4-hydroxyphe- nyl glycol, a metabolite of norepinephrine, are correlated (Bowers et al., 1984, 1897; Chang et al., 1990). These phenomena suggest the possibility that observed variations in pHVA are contributed by peripheral sources (Amin et al., 1992). For instance, the stress induced by admission might cause an elevation in plasma catecholamine metab- olites in some subsets of subjects. Future studies should include efforts to cross these other possible sources of variance in pHVA.

ACKNOWLEDGEMENTS

The authors acknowledge Huey-Fang Chang, Huey-Jen Chang, Ho-Sheng Wu, Shu-Swei Jaw, and Dong-Juiing Juang for technical collaboration; Yuen-Lih Yeh for statistical analysis; and William Z. Potter for his comments on the eirlier version of this manuscript. This work was supprorted by grants NSC 81-0412-B109-501 from the National Science Council and the Taipei City Government.

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數據

Fig.  1.  Correlation  between  baseline  pHVA  levels  and  clinical  improvements  after  6  weeks  of  antipsychotic  treatment

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