Journal of Affective Disorders 92 (2006) 277–281www.elsevier.com/locate/jad

Brief report

Influence of the catechol-O-methyltransferase Val108/158Metpolymorphism on the plasma concentration of catecholamine

metabolites and on clinical features in type Ibipolar disorder—A preliminary report

Ricardo Dávila a,⁎, Mercedes Zumárraga a, Nieves Basterreche b, Aurora Arrúe a,M. Isabel Zamalloa a, Juan B. Anguiano c

a Departamento de Investigación Neuroquímica, Hospital Psiquiátrico de Zamudio, Servicio Vasco de Salud (Osakidetza), Arteaga Auzoa No. 45,E-48170 Zamudio, Vizcaya, Spain

b Servicio de Corta Estancia, Hospital Psiquiátrico de Zamudio, Servicio Vasco de Salud (Osakidetza), Arteaga Auzoa No. 45,E-48170 Zamudio, Vizcaya, Spain

c Centro de Salud Mental de Ortuella, Servicio Vasco de Salud (Osakidetza), Avenida Minero No. 1, E-48530 Ortuella, Vizcaya, Spain

Received 20 July 2005; received in revised form 6 February 2006; accepted 6 February 2006Available online 15 March 2006

Abstract

Background: The activity of catechol-O-methyltransferase (COMT) may be related to psychosis susceptibility. The Val108/158Metpolymorphism of the COMT gene influences its enzymatic activity and may result in altered concentrations of monoaminemetabolites and different clinical responses of patients to pharmacological treatments.Methods: We examined in a sample of 42 bipolar patients if the Val108/158Met polymorphism influences: (a) the presence ofpsychosis in type I bipolar patients; (b) the blood plasma concentration of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), which are metabolites of dopamine and noradrenaline respectively and (c) the severity of theclinical characteristics of these patients and their response to pharmacological treatment.Results: No significant associations were found between the studied COMT genotypes and the studied parameters. However, anon-significant aggregation of bipolar patients presenting with psychosis was found in the homozygous Val-Val group. Clinicalimprovement was found to significantly correlate with the levels of plasma MHPG prior to treatment. Moreover, a significantdifference was found between the standard deviations of the concentrations of HVA in the three genotypes, but not in their meanvalues. Significant associations were not detected between COMT polymorphisms and the initial severity of the disorder, or theclinical response to pharmacological treatment.Limitations: The size of the studied sample is somewhat small and comparisons have been made with a previously studied controlgroup.Conclusions: The Val108/158Met polymorphism does not appear to be a crucial determinant in type I bipolar disorder.© 2006 Elsevier B.V. All rights reserved.

Keywords: Bipolar disorder; Catechol-O-methyltransferase; Psychosis; 3-Methoxy-4-hydroxyphenylglycol; Homovanillic acid

⁎ Corresponding author. Tel.: +34 944 006 519; fax: +34 944 006 526.E-mail address: rdavila@hzam.osakidetza.net (R. Dávila).

0165-0327/$ - see front matter © 2006 Elsevier B.V. All rights reserved.doi:10.1016/j.jad.2006.02.009

278 R. Dávila et al. / Journal of Affective Disorders 92 (2006) 277–281

1. Introduction

Bipolar disorder shares certain clinical and geneticcharacteristics with schizophrenia. It can often be difficultto distinguish both conditions, especially when bipolardisorder is accompanied by psychotic symptoms. Differ-ent aspects of monoaminergic dysfunction seem to berelated to the principal psychiatric syndromes. Thus, theclinical response to neuroleptic treatment can be predictedby measuring blood plasma concentrations of homova-nillic acid (HVA), a dopamine metabolite (Davidson andDavis, 1987; Dávila et al., 1988, 1995; Green et al., 1993;Pickar et al., 1986; Sumiyoshi et al., 2004), or 3-methoxy-4-hydroxyphenylglycol (MHPG), a norepinephrine me-tabolite (Bowers et al., 1987; Mazure and Bowers, 1998).

Catechol-O-methyltransferase (COMT) is an enzymewhich participates in the catabolism of certain mono-amine neurotransmitters. The Val108/158 polymor-phism consists of a guanine to adenine substitution inthe corresponding gene, which results in a valine tomethionine amino acid substitution in the correspondingenzyme. The Val-Val homozygote is four times moreactive in metabolizing dopamine (DA) than the Met-Methomozygote (Weinshilboum et al., 1999). Thus, it isconceivable that the COMT genotype may influencephasic and tonic dopaminergic activity and be associatedwith distinct neuropsychiatric phenotypes (reviewed byBilder et al., 2004). Akil et al. (2003) demonstrated thatthe COMT genotype is an inheritable aspect of themechanisms of DA regulation and that it may contributeto explaining the increased susceptibility of somepatients to develop psychosis. It thus seems possiblethat increased or reduced dopaminergic activity, condi-tioned by the presence of one or other allele, wouldfacilitate the emergence of a specific motor or psychiatricpathology, or influence the beneficial response ofpatients to treatments which increase or reduce dopami-nergic neurotransmission (Meltzer et al., 2003).

The objective of the present study was to examine ifthe Val108/158Met genotype of the COMT gene isrelated to: (a) the presence of psychosis in type I bipolarpatients; (b) different plasma levels of HVA and MHPGbefore neuroleptic treatment and (c) the initial severityof psychosis and the clinical response to pharmacolog-ical treatment.

2. Methods

2.1. Patients

Forty-two DSM-IV diagnosed, manic or mixed type Ibipolar patients, ranging between 19 and 50 years of

age, were selected. They did not present a history ofalcoholism or drug addiction, nor any serious organicdisease. They scored more than 20 on the Young scalefor mania and all gave written consent to participate inthe study. Patients were included in the study upon beingadmitted to our hospital. A minimum washout period of1 week without neuroleptic medication or mood sta-bilizers was required. The duration of this washoutperiod was very variable since some patients had alreadybeen without medication for a long period upon beingadmitted to the hospital. The current study was approvedby the relevant Ethics Committee of the Basque HealthService (Osakidetza) and was carried out in accordancewith the Helsinki Declaration.

2.2. Treatment

Patients were treated initially with 10 mg/day Olanza-pine for 4 days and subsequently with 20 mg/day. On the8th day, lithium was included until a concentration of 0.6to 1.2 mEq/l lithium was reached in plasma.

2.3. Clinical assays

The clinical status of each patient was evaluatedbefore treatment, after 4 days of treatment and sub-sequently every week, with the Young scales for mania(Colom et al., 2002) and the Andreasen scale for pos-itive symptoms (Andreasen, 1984). The clinical globalimpression (CGI) (Spearing et al., 1997) was assessedbefore treatment and after 4 weeks of treatment.

2.4. Genetic and neurochemical determinations

Blood samples were obtained before initiatingpharmacological treatment according to proceduresdescribed elsewhere (Dávila, 1989). The Val108/158COMT polymorphism and the plasma concentrations ofHVA and MHPG were evaluated according to previ-ously described methods (Rotondo et al., 2002;Zumárraga et al., 1994; Rizzo and Melxi Devil, 1987).

2.5. Statistical analyses

We examined associations between the distinctCOMT Val108/158Met genotypes and: (a) the presenceof psychotic symptoms using the exact Fisher test;(b) the basal concentrations of HVA and MHPG, (c) theseverity of symptoms and (d) the clinical evolution ofpatients, by means of analysis of variance. Correlationsbetween plasma concentrations of HVA and MHPGprior to treatment, and the initial gravity of symptoms or

Fig. 1. Distribution of patients according to the COMTVal108/158Metgenotype.

Table 2Pearson correlation coefficient for the clinical measurements and thebasal plasma concentrations of MHPG and HVA

Baseline MHPG Baseline HVA

Changes in Young scores r=0.319 ⁎, p=0.04 r=0.255, p=0.11Changes in SAPS scores r=0.328 ⁎, p=0.04 r=0.244, p=0.12

Clinical measurements: variations in the Young and SAPS evaluationscores between the basal value measured before initiating treatmentand that measured on day 28 of treatment.⁎ Significant coefficient of correlation.

279R. Dávila et al. / Journal of Affective Disorders 92 (2006) 277–281

clinical evolution were calculated using the Pearsonproduct moment correlation coefficient.

3. Results

Forty-two type I bipolar patients, 19 women (age 32±8), and 23 men (age 36±10) (mean±S.D.) were an-alyzed. Eighty-one percent of these patients, 19 men and15 women, presented psychotic symptoms.

The distribution of COMT genotypes is illustrated inFig. 1. It is not significantly different to that found forthe normal population of Spanish origin described byGutierrez et al. (1997) (chi squared 0.78; p=0.67), or thenormal population of European Caucasian origindescribed by Kunugi et al. (1997) (chi squared 0.22;p=0.89). The distribution of patients as psychotic ornon-psychotic was as follows: Val-Val: 9 psychotic and1 non-psychotic; Val-Met: 19 psychotic and 4 non-psychotic; Met-Met: 6 psychotic and 3 non-psychotic.Thus, there is apparently no significant associationbetween the Val 108/158Met COMT genotype and thepresence of psychosis (exact Fisher statistic 1.694;p=0.437).

Table 1Basal concentrations of blood plasma HVA andMHPG in patients withdifferent COMT genotypes

Genotype HVA (ng/ml) ⁎ MHPG (ng/ml) N

Mean (S.D.) Mean (S.D.)

Val-Val 15.97 (7.59) 4.05 (2.14) 10Val-Met 13.33 (5.01) 3.66 (1.63) 23Met-Met 11.80 (3.23) 2.85 (0.99) 9ALL 13.63 (5.50) 3.58 (1.67) 42

Metabolite concentrations (ng/ml) are expressed as mean (standarddeviation S.D.) and were obtained from patients before initiatingneuroleptic treatment.⁎ Significant difference between the S.D. of the concentrations ofHVA (Q Cochran 0.618, p=0.01).

Basal values for the concentration of HVA andMHPG for each genotype are presented in Table 1.Significant differences were detected in the standarddeviations of the levels of HVA in the three genotypes(Q Cochran 0.618, p=0.01), but not in the cor-responding mean values (F=1.47; p=0.24). No signif-icant differences were observed between the values ofbasal MHPG (F=1.30; p=0.28) or their standard devi-ations, between the distinct genotypes.

The percentage reduction in symptoms (mean±S.D.)over the 28 days of treatment with respect to the initialvalues was 71.2±18.2% according to the Young scale;71.9±24.5% according to the SAPS scale and 59.5±36% according to the Clinical Global Impression rating.Clinical data was not obtained from one patient on the28th day of this study. No significant relation (ANOVA)was found between the COMT Val108/158Met poly-morphism and initial severity (CGI, F=0.47, p=0.62;Young, F=2.32, p=0.11; and SAPS, F=0.98, p=038,scales before treatment) or the initial response totreatment (variation in the Young F=0.30, p=0.73;and SAPS F=0.09, p=0.91, scales after 1 week oftreatment), or the response to olanzapine plus lithiumafter 4 weeks of treatment (CGI F=0.04, p=0.95; SAPSF=1.26, p=0.29; Young F=1.36, p=0.26). However,clinical improvement as measured by variation in theYoung or SAPS scales was found to correlate signifi-cantly with the levels of MHPG prior to treatment(Table 2). In contrast, no correlation was found betweenthese clinical parameters and the basal concentration ofplasma HVA.

4. Discussion

In the present study, the distribution of the COMTVal108/158Met phenotypes among a population ofbipolar patients was not significantly different to thatof the normal European (Kunugi et al., 1997) or Spanishpopulation (Gutierrez et al., 1997). Moreover, we didnot detect a significant association between this poly-morphism and the presence of psychosis, the severity of

280 R. Dávila et al. / Journal of Affective Disorders 92 (2006) 277–281

bipolar disorder or its response to pharmacologicaltreatment, suggesting that the Val108/158Met polymor-phism is not a crucial determinant in type I bipolardisorder. Our data are consistent with those of Serretti etal. (2002) who reported a lack of association of COMTgenotype and the efficacy of lithium in mood disorders.

A significant association between clinical response inschizophrenic patients and the values of plasma HVA,rather than MHPG, has been reported in other studies(Dávila et al., 1988, 1995; Pickar et al., 1986). Levels ofMHPG have been found to be a good predictor of theclinical response to neuroleptic treatment in manicpsychosis (Mazure and Bowers, 1998). Our findings areconsistent with those of Young et al. (1994) who foundincreased MHPG levels in the cortex of bipolar patients,suggesting that noradrenergic turnover may be animportant component in bipolar disorder symptomatol-ogy. It is possible that the initial levels of HVA weremore affected than those of MHPG by the variableperiod of patient washout. The study of patients whoseillness has a shorter time course and whose washoutperiods are more homogeneous may reveal increasedsignificance of plasma HVA levels (Dávila, 1989;Dávila et al., 1997). On the other hand, the finding oflarger standard deviations in the concentrations ofplasma HVA in the Val-Val genotype may reflect alarger dopaminergic instability of this genotype.

The human organism appears to be well capable ofadapting to different levels of COMT activity, due todifferent genetic constitutions, in order to establish asatisfactory homeostasis, since different ethnic groupspresent large variability in their proportion of COMTalleles (Palmatier et al., 1999). Nevertheless, it will beinteresting to evaluate the association between specificCOMTalleles and other genotypes, since the psychiatricphenotype is likely the result of multiple gene expres-sion patterns, rather than due to that of one gene alone.

The high incidence (90%) of psychotics in the Val-Val group (9:1), together with the results of other au-thors regarding schizophrenic patients (Akil et al., 2003;Weinberger et al., 2001), would seem to support the ideathat the Val-Val genotype may contribute to a largersusceptibility, not to schizophrenia, nor to bipolar dis-order, but rather to the development of psychotic symp-toms. The presence of this genotype would not bestrictly speaking necessary for the appearance of psy-chosis, since there are many psychotic patients withMet-Met or Val-Met genotypes. However, it is possiblethat, as pointed out by Akil et al. (2003), the Val-Valgenotype may be associated with diminished prefrontaldopamine activity and hyper-subcortical dopaminergicfunctioning and may facilitate psychotic destabilization.

Psychotic manifestations often accompany bipolardisorder and schizophrenia, in addition to a variety ofother illnesses (Tsuang et al., 2002). Current concepts ofpsychosis may need to be redefined in order to take intoaccount that psychosis can accompany a disorder as ageneral, temporal symptom, but with no more specific-ity than pain or fever. Thus, in specific cases, it may bemore appropriate to ask, “Does the patient havepsychosis?”, rather than, “Is the patient psychotic?”.Within the context of a patient “having” psychosis,dopaminergic hypersensitivity could be considered asthe final stage which leads to psychotic destabilization.Seeman et al. (2005) have shown that “many types ofbrain impairment cause dopamine behavioral supersen-sitivity”, suggesting that there are many pathways topsychosis.

Overall, our results suggest that there is no directrelationship between the studied genotype and thesymptomatology or clinical evolution of type I bipolarpatients. Nevertheless, the presence of a larger disper-sion in the values of the concentration of HVA inplasma, together with a larger aggregation of patientspresenting psychotic symptoms in the Val-Val genotype,may be indicative of higher dopaminergic lability in thissubgroup, which may influence patient response totreatment.

Acknowledgements

This work was supported in part by Grant 021108from the Fondo de Investigación Sanitaria, Spain andFEDER funding. The authors would like to express theirthanks to the agency ACTS (Academic Consulting andTranslating Services; http://www.euskalnet.net/acts) forhaving corrected the English of this paper.

References

Akil, M., Kolachana, B.S., Rothmond, D.A., Hyde, T.M., Weinberger,D.R., Kleinman, J.E., 2003. Catechol-O-methyltransferase geno-type and dopamine regulation in the human brain. J. Neurosci. 15,2008–2013.

Andreasen, N.C., 1984. The Scale for the Assessment of PositiveSymptoms (SAPS). University of Iowa, Iowa City.

Bilder, R.M., Volavka, J., Lachman, H.M., Grace, A.A., 2004. Thecatechol-O-methyltransferase polymorphism: relations to thetonic-phasic dopamine hypothesis and neuropsychiatric pheno-types. Neuropsychopharmacology 29, 1943–1961.

Bowers Jr., M.B., Swigar, M.E., Jatlow, P.I., Hoffman, F.J.,Goicoechea, N., 1987. Early neuroleptic response: clinical profilesand plasma catecholamine metabolites. J. Clin. Psychopharmacol.7, 83–86.

Colom, F., Vieta, E., Martínez-Arán, A., García-García, A., Rainares,M., Torrent, C., Goikolea, J.M., Banus, S., Salamero, M., 2002.

281R. Dávila et al. / Journal of Affective Disorders 92 (2006) 277–281

Versión española de la escala de evaluación de la manía: validez yfiabilidad de la escala de Young. Med. Clin. (Barc) 119, 366–371.

Davidson, M., Davis, K.L., 1987. A comparison of plasmahomovanillic acid concentrations in schizophrenic patients andnormal controls. Arch. Gen. Psychiatry 20, 307–312.

Dávila, R., 1989. Plasma HVA, neuroleptics, and dopaminergicplasticity. Biol. Psychiatry 25, 1–3.

Dávila, R., Manero, E., Zumárraga, M., Andía, I., Schweitzer, J.W.,Friedhoff, A.J., 1988. Plasma homovanillic acid is a predictor ofresponse to neuroleptics. Arch. Gen. Psychiatry 45, 564–567.

Dávila, R., González-Torres, M.A., Zumárraga, M., Andía, I., Guimón,J., Silva, R.R., Friedhoff, A.J., 1995. Plasma prolactine and plasmahomovanillic acid predictors of clinical response in schizophrenia.Biol. Psychiatry 38, 267–269.

Dávila, R., Zumárraga, M., Andía, I., Almoguera-Abad, A., Friedhoff,A.J., 1997. Early increase of plasma HVA during neuroleptictreatment: a tool for outcome prediction and subtyping ofschizophrenia. In: Friedhoff, A.J., Amin, A. (Eds.), HomovanillicAcid in Schizophrenia. American Psychiatric Press, Washington,DC, pp. 89–102.

Green, A.I., Alam, M.Y., Boshes, R.A., Waternaux, C., Pappalardo,K.M., Fitzgibbon, M.E., Tsuang, M.T., Schildkraut, J.J., 1993.Haloperidol response and plasma catecholamines and theirmetabolites. Schizophr. Res. 10, 33–37.

Gutierrez, B., Bertranpetit, J., Guillamat, R., Valles, V., Arranz, M.J.,Kerwin, R., Fañanas, L., 1997. Association analysis of thecatechol-O-methyltransferase gene and bipolar affective disorder.Am. J. Psychiatry 154, 113–115.

Kunugi, H., Vallada, H.P., Hoda, F., Kirov, G., Gill, M., Aitchison,K.J., Ball, D., Arranz, M.J., Murray, R.M., Collier, D.A., 1997.No evidence for an association of affective disorders with high-or low-activity allele of catechol-O-methyltransferase gene. Biol.Psychiatry 42, 282–285.

Mazure, C.M., Bowers, M.B., 1998. Pretreatment plasma HVApredicts neuroleptic response in manic psychosis. J. Affect.Disord. 48, 83–86.

Meltzer, H.Y., Li, Z., Kaneda, Y., Ichicawa, J., 2003. Serotoninreceptor: their key role in drugs to treat schizophrenia. Prog.Neuropsychopharmacol. Biol. Psychiatry 27, 1159–1172.

Palmatier, M.A., Kang, A.M., Kidd, K.K., 1999. Global variation inthe frequencies of functionally different catechol-O-methyltrans-ferase alleles. Biol. Psychiatry 46, 557–567.

Pickar, D., Labarca, R., Doran, A.R., Wolkowitz, O.M., Roy, A.,Breier, A., Linnoila, M., Paul, S.M., 1986. Longitudinalmeasurement of plasma homovanillic acid levels in schizophrenicpatients: correlation with psychosis and response to clinicaltreatment. Arch. Gen. Psychiatry 43, 669–676.

Rizzo, V., Melxi Devil, G.V., 1987. Determination of free MHPG inplasma and CSF by HPLC. Clin. Chem. 33, 844–845.

Rotondo, A., Mazzanti, C., Dell'Osso, L., Rucci, P., Sullivan, P.,Bouanani, S., Gonnelli, C., Goldman, D., Cassano, G.B., 2002.Catechol-O-methyltransferase, serotonin transporter, and trypto-phan hydroxylase gene polymorphisms in bipolar disorder patientswith and without comorbid panic disorder. Am. J. Psychiatry 159,23–29.

Seeman, P., Weinshenker, D., Quirion, R., Srivastava, L.K.,Bhardwaj, S.K., Grandy, D.K., Premont, R.T., Sotnikova, T.F.,Boksa, P., El-Ghundi, M., O'Dowd, B.F., George, S.R., Perreault,M.L., Männisto, P.T., Robinson, S., Palmiter, R.D., Tallerico, T.,2005. Dopamine supersensitivity correlates with D2 high states,implying many paths to psychosis. Proc. Natl. Acad. Sci. U. S. A.102, 3513–3518.

Serretti, A., Lorenzi, C., Lilli, R., Mandelli, L., Pirovano, A., Smeraldi,E., 2002. Pharmacogenetics of lithium prophylaxis in mooddisorders: analysis of COMT, MAO A, and Gβ3 variants. Am. J.Med. Genet. (Neuropsychiatric Genetics) 114, 370–379.

Spearing, M.K., Post, R.M., Leverich, G.S., Brandt, D., Nolen, W.,1997. Modification of the clinical global impression (CGI) scalefor use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 73,159–171.

Sumiyoshi, T., Roy, A., Kim, C.H., Jayathilake, K., Lee, M.A.,Sumiyoshi, C., Meltzer, H.Y., 2004. Prediction of changes inmemory performance by plasma homovanillic acid levels inclozapine-treated patients with schizophrenia. Psychopharmacol-ogy 177, 79–83.

Tsuang, M.T., Stone, W.S., Tarbox, S.I., Faraone, S.V., 2002. Anintegration of schizophrenia with schizotypy: identification ofschizotaxia and implications for research on treatment andprevention. Schizophr. Res. 54, 169–175.

Weinberger, D.R., Egan, M.F., Beertolino, A., Callicot, J.H., Mattay,V.S., Lipska, B.K., Berman, K.F., Goldberg, T.E., 2001. Prefrontalneurons and the genetics of schizophrenia. Biol. Psychiatry 50,825–844.

Weinshilboum, R.M., Otterness, D.M., Szumlanski, C.L., 1999.Methylation pharmacogenetics: catechol-O-methyltransferase,thiopurine methyltransferase, and histamine N-methyltransfer-ase. Annu. Rev. Pharmacol. Toxicol. 39, 19–52.

Young, L.T., Warsh, J.J., Kish, S.J., Shannak, K., Hornykeiwicz, O.,1994. Reduced brain 5-HT and elevated NE turnover andmetabolites in bipolar affective disorder. Biol. Psychiatry 35,121–127.

Zumárraga, M., Andía, I., Dávila, R., Zamalloa, M.I., 1994.Homovanillic acid in plasma determined by HPLC with directinjection of plasma filtrates. Clin. Chem. 40, 2119–2120.