American Journal of Medical Genetics (Neuropsychiatric Genetics) 60:154-156 (1995)

Schizophrenia: Gender, Family Risk, and Plasma Homovanillic Acid

Ricardo Davila, Mercedes Zumarraga, Miguel A. Gonzalez-Torres, Isabel Andia, Maria I. Zamalloa, Edurne Basterreche, Jose Guimon, and Arnold J. Friedhoff Departmento de Investigacibn Neuroquimica, Servicio Vasco de Salud, 4801 6 Zamudio, Vizcaya (R.D., M.Z., I.A., M.I.Z., E.B.), Departamento de Psiquiatria, Hospital de Basurto, 48013 Bilbao (M.A.G.T.), Spain, Institutions Universitaires de Psychiatrie de Geneve, Clinique de Psychiatrie I , Geneva (J.G.), Switzerland; and Department of Psychiatry, Millhauser Laboratories, New York University Medical Center, New York (A.J.F.), New York

Plasma homovanillic acid concentration was assessed in 60 young schizophrenic patients, with and without first-degree rela- tives with schizophrenia, before treatment, and 3 days after starting haloperidol treat- ment. The baseline concentration of ho- movanillic acid in plasma was no different in the two groups before treatment; it was, however, significantly higher in the patients with relatives than in those without rela- tives diagnosed of schizophrenia after 3 days of haloperidol treatment. 0 1995 Wiley-Liss, Inc.

KEY WORDS: homovanillic acid, haloperi- dol, plasma

INTRODUCTION New views have been recently expressed on the rela-

tionship between gender and schizophrenia [Castle and Murray, 1991; Foerster et al., 1991; Goldstein et al., 1990a,bl. One such is the possibility that first degree kin of schizophrenic men have a lower risk of schizo- phrenia than close relatives of schizophrenic women [Goldstein et al., 1990a,b; Pulver et al., 19921; indeed, relatives of schizophrenic women are more a t risk re- gardless of sex.

Angemeyer et al. [1990] have suggested that the clinical outcome of schizophrenia is better in women. Goldstein et al. [1990a,bl have hypothesized that there exists a subgroup of schizophrenia, predominant in men, that has low familial risk for schizophrenia, poor pre- morbid history, deficit symptoms, and poor prognosis; gender differences in brain development and in perina-

Received for publication January 24, 1994; revision received June 27,1994.

Address reprint requests to Ricardo Davila, Departamento de Investigacion Neuroquimica, Servicio Vasco de Salud, B" Arteaga, 107, 48016 Zamudio, Vizcaya, Spain.

0 1995 Wiley-Liss, Inc.

tal injury could explain the different prevalence of this subtype in men. Finally, Lewis [1992] speculates about the advantages and disadvantages of subdividing the patients by gender, and suggests that gender might in- fluence the development and outcome of schizophrenia.

The recent data about the existence of a susceptibil- ity gene for schizophrenia in the sexual chromosomes have not been conclusive. It has been reported the exis- tence of positive linkage [DAmato et al., 19931 and of no linkage [Curtis et al., 19931 in the pseudo-autosomal XY region. The possibility of a gene in the X sex specific region of the X chromosome has also been suggested [Crow et al., 19931.

These considerations are related to our studies whose object has been to analyze the relationship be- tween plasma homovanillic acid concentration (pHVA) and clinical outcome in schizophrenic patients during neuroleptic treatment. In those studies we have found that an initial increase in pHVA during the first days of treatment predicts better clinical outcome [Davila et al., 1988al. In the present study we report variations in pHVA levels during the first days of treatment which may prove interesting in relation to studies of gender, family risk, and schizophrenia.

METHODS Subjects

Thirty-four male and twenty-six female subjects di- agnosed as suffering from having schizophrenia or a schizophreniform disorder (DSM 111) were included in the study; the patients diagnosed as having a schizo- phreniform disorder (n = 3) were later diagnosed as schizophrenics; their mean age was 23.5 years (s.d. = 5.3) (range 18-30). All were in need of treatment and gave informed consent for inclusion in the study. The patients were included in the study following the con- secutive admission method. Duration of illness for the sample was less than 3 years and all subjects had re- ceived medication for less than 9 months, having had no medication for the 3 months prior to the study. No subject suffered from systemic disease or substance abuse.

Plasma HVA and Family Risk in Schizophrenics 155

Procedures Plasma HVA was assessed before treatment (basal)

and 3 days after starting haloperidol treatment (0.25 mg/kg/day). Blood samples were taken routinely at 8.30 A.M. after 13 hours fasting, and just before medication was administered. Plasma HVA was determined by high performance liquid chromatography as previously described [Zumarraga et al., 19871.

The presence of first degree relatives with schizo- phrenia was investigated by interviewing the patient and one relative known to be living in the same house- hold with the patient and his family. The relative inter- viewed was unaware of the patient’s diagnosis and the research hypothesis. The interviewer was also unaware of the research hypothesis.

Data Analysis The fitting of the data with a normal distribution was

checked using the Kolmogorov-Smirnof test. Compari- son of the means was performed using the Student’s t test. Distributions were compared with the Mann- Whitney test.

RESULTS Fifteen of the sixty patients studied had first-degree

relatives diagnosed as schizophrenic. Ten of these fif- teen patients with psychotic family histories were women and only five were men. The proportion of women with schizophrenic relatives (10 out of 26) was notably higher than that of men (5 out of 34). Table I shows concentrations of pHVA before and 3 days after commencement of treatment, both in patients with and without family history of schizophrenia. Basal concen- tration of pHVA was not different in the two groups. The concentration of pHVA increases significantly from day 0 to day 4 of treatment in the group of patients with family history of schizophrenia (estimated Kolmogorof D = 0.126; paired t test: t = 2.20, P = 0.04). Plasma HVA concentrations were also significantly higher in the patients with family history of schizophrenia than in those without such a family history after 3 days’ treatment (estimated Kolmogorov D were 0.183 and 0.125, respectively) (t = 2.31, P = 0.04; Mann-Whitney z = 2.35, P = 0.018). Table I1 shows the concentration of pHVA in the same days of treatment, separating the patients by gender. The concentration of pHVA in-

creases significantly from day 0 to day 4 of treatment in the group of women with family history of schizophre- nia (estimated Kolmogorov D = 0.118, t = 2.68, P = 0.02). The concentration of pHVA was also significantly higher in the group of women with family history of schizophrenia than in the group of women without such a family history after 3 days’ treatment (estimated Kol- mogorov D = 0.177 and 0.125, respectively, t = 2.15, P = 0.04).

DISCUSSION It may be that neuroleptics control aberrant mental

activity by altering the basal firing rate of dopaminer- gic neurons without interferring with the dynamic abil- ity of the system to respond to other stimuli [Friedhoff, 19881. Increase in plasma HVA after administration of neuroleptics reflects an adaptive aspect of the dopamin- ergic system that apparently is related with clinical outcome [Davila et al., 1988b; Duncan et al., 1993; Green et al., 19931.

The small number of male patients with a family his- tory of schizophrenia included in this study counsels caution. The presence of first degree relatives of schiz- ophrenic probands with schizophrenia was invest- igated by means of a very simple method. Since the family structure in the geographic region included in this report is very stable, this method is good enough to obtain a fiable information in this study.

In spite of these reservations some points can be made. If, as it has been suggested [Davila et al., 1988a1, there is a correlation between the initial increase in pHVA concentration and clinical improvement, care must be taken not to obscure or magnify it by not tak- ing into account the presence in the sample of a vari- able proportion of different subtypes of schizophrenic patients. Gender, then, might be important in that it re- lates to a subtype of schizophrenia characterized by good prognosis and greater frequency in women. The hypothesis can be advanced that there is a subgroup of schizophrenic patients characterized by having psy- chotic relatives and a strong dopaminergic response to the initial administration of neuroleptics, and that this predicts a good clinical response. It would be necessary to study a larger number of patients in order to clarify the counfounding overlapping effects of gender and family history of schizophrenia. In respect to these

TABLE I. Concentrations of Plasma HVA, Expressed in ng/ml, in Schizophrenic Patients With Schizophrenic Relatives and Without Schizophrenic Relatives*

pHVA day 0 pHVA day 4

Mean S.D. Mean S.D.

With schizophrenic relatives (n = 15) 14.02 3.98 18.02” 7.64 Without schizophrenic relatives (n = 45) 14.66 5.58 13.16b 4.93

* The measurements were carried out immediately before treatment (day 0 ) and 3 days after the begin- king of treatment with haloperidol (day 4). t = 2.20, P = 0.04 Student’s t test, comparing the values on day 4 with the baseline (day 0) in the

patients with family history of schizophrenia. t = 2.31, P = 0.04 Student’s t test, comparing the values on day 4 for those patients without schizo-

phrenic relatives with the values on day 4 for those with schizophrenic relatives.

156 D a d a et al.

TABLE 11. Concentrations of Plasma HVA, Expressed in ng/ml, in Schizophrenic Men and Women With and Without Schizophrenic Relatives*

pHVA day 4 pHVA day 0

Mean S.D. Mean S.D.

With schizophrenic relatives Menn = 5 13.69 4.66 13.07 4.94 (n = 15) Women n = 10 14.19 3.87 20.50” 7.73

Without schizophrenic relatives Men n = 29 13.53 5.58 12.37 4.01 (n = 45) Womenn = 16 16.71 5.12 14.61b 6.18

* The measurements were carried out immediately before treatment (day 0) and 3 days after the begin- ;ing of treatment with haloperidol (day 4). t = 2.68, P = 0.02 Student’s t test, comparing the values on day 4 with the baseline (day 0) in the women

with family history of Schizophrenia. t = 2.15, P = 0.04 Student’s t test, comparing the values on day 4 for those women with schizophrenic

relatives with the values on day 4 for those women without schizophrenic relatives.

overlapping effects we want to point out that the pres- ence or absence of a family history of schizophrenia does not guarantee the homogeneity of the group so defined. The family history of schizophrenia is not an unequivocal parameter as gender is.

Another hypothesis that could be tested is that a subgroup of schizophrenics, characterized by hav- ing an association of negative symptoms in the probands and their relatives [Tsuang, 19931, would also have a flat response in the concentration of pHVA after the administration of neuroleptics and poor clinical outcome.

Further studies are needed to analyze whether the subgroup that we propose is also characterized by a particular premorbid functioning, brain damage, and the age of onset. Studies are in progress to determine the relationship of this subgroup with the classification of schizophrenic patients using a multisyndromal model.

REFERENCES Angemeyer MC, Kuhn L, Goldstein JM (1990): Gender and the course

of schizophrenia: Differences in treated outcomes. Schizophr Bull

Castle DJ, Murray RM (1991): The neurodevelopmental basis of sex differences in schizophrenia. Psycho1 Med 21:565-575.

Crow TJ, DeLisi LE, Lofthouse R, Poulter M, Lehner T, Bass N, Shah T, Walsh C, Boccio-Smith A, Shields G, Ott J (1993): An examina- tion of linkage of schizophrenia and schizo-affective disorder to the pseudo-autosomal region. Psychiatr Genet 3:125.

Curtis D, Kalsi G, Brynjolfsson J , Read T, Sharma T, Petursson H, Gurling H (1993): Investigation by linkage analysis of the XY chromosomal region in the genetic susceptibility to schizophrenia. Psychiatr Genet 3: 125-126.

16:293-307.

DAmato T, Laurent C, Campion D, Waksman G, Jay M, Gonvood P, Samolyk D, Martinez M, Mallet J (1993): Linkage analysis using RFLP markers within the pseudoautosomal region in schizophre- nia. Psychiatr Genet 3:125.

Davila R, Manero E, Zumarraga M, Andia I, Schweitzer JW, Friedhoff AJ (1988a): Plasma homovanillic acid as a predictor of response to neuroleptics. Arch Gen Psychiatry 45:564-567.

Davila R, Zumarraga M, Friedhoff AJ, Miller JC (198813): Character- istics of the adaptive aspects of the dopaminergic system. Psycho- pharmacol Bull 24:338-340.

Duncan E, Wolkin A, Angrist B, Sanfilipo M, Wieland S, Cooper TB, Rotrosen J (1993): Plasma homovanillic acid in neuroleptic re- sponsive and nonresponsibe schizophrenics. Biol Psychiatry 34:523-528.

Foerster A, Lewis S, Owen M, Murray R (1991): Premorbid personal- ity in psychosis: Effects of sex and diagnosis. Br J Psychiatry 158:171-176.

Friedhoff AJ (1988): Dopamine as a mediator of central stabilizing system. Neuropsychopharmacology 1:189-191.

Goldstein JM, Faraone SV, Chen WJ, Tolomiczencko GT, Tsuang MT (1990a): Sex differences in the familial transmission of schizo- phrenia. Br J Psychiatry 156:819-826.

Goldstein JM, Santangelo SL, Simpson JC, Tsuang MT (1990b): The role of gender in identifying subtypes of schizophrenia: A latent class analytical approach. Schizophr Bull 16:263-275.

Green AI, Alam MY, Sobieraj JT, Pappalardo KM, Waternaux C, Salz- man C, Schatzberg AF, Schildkraut JJ (1993): Clozapine response and plasma catecholamines and their metabolites. Psychiatry Res 46:139-149.

Lewis S (1992): Sex and schizophrenia: vive la difference. Br J Psy- chiatry 161:445-450.

Pulver AE, Liang KY, Brown CH, Wolyniec P, McGrath J , Adler L, Tam D, Carpenter WT, Childs B (1992): Risk factors in schizo- phrenia season of birth, gender and familial risk. Br J Psychiatry

Tsuang MT (1993): Genotypes, phenotypes, and the brain: A search for connections in schizophrenia. Br J Psychiatry 163:299-307.

Zumarraga M, Andia I, Barcena B, Zamalloa MI, Davila R (1987): Liq- uid chromatographic method for the determination of homovanil- lic acid in plasma with electrochemical detection. Clin Chem 33:72-75.

160~65-7 1.