Molecular Psychiatry (2005) 10, 598–605
& 2005 Nature Publishing Group All rights reserved 1359-4184/05 $30.00
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ORIGINAL RESEARCH ARTICLE
Association between COMT (Val158Met) functional
polymorphism and early onset in patients with major
depressive disorder in a European multicenter genetic
association study
I Massat1, D Souery1, J Del-Favero2, M Nothen3, D Blackwood4, W Muir4, R Kaneva5, A Serretti6,
C Lorenzi6, M Rietschel7, V Milanova8, GN Papadimitriou9, D Dikeos9, C Van Broekhoven2
and J Mendlewicz1
1
Department of Psychiatry, University Clinics of Brussels, Erasme Hospital, Free University of Brussels, Belgium; 2Department
of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB8), University of Antwerp, Antwerpen, Belgium;
3
Department of Medical Genetics, University of Antwerp, Antwerpen, Belgium; 4Department of Psychiatry, School of Molecular
and Clinical Medicine, University of Edinburgh, UK; 5Laboratory of Molecular Pathology, University Hospital of Obstetrics,
Medical University, Sofia, Bulgaria; 6Department of Psychiatry, Vita-Salute University, San Raffaele Institute, Milan Italy;
7
Central Institute of Mental Health, Mannheim, Germany; 8First Psychiatric Clinic, Department of Psychiatry, Alexander
University Hospital, Sofia, Bulgaria; 9Athens University Medical School, Department of Psychiatry and University Mental Health
Research Institute, Athens, Greece
The available data from preclinical and pharmacological studies on the role of the C-O-methyl
transferase (COMT) support the hypothesis that abnormal catecholamine transmission has
been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of
a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for
four-fold variation in enzyme activity, with ‘early-onset’ (EO) forms (less than or equal to 25
years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients
(EO-BPD), in a European multicenter case–control sample. Our sample includes 378 MDD (120
EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the
high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These
findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in
linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene
may have complex and pleiotropic effects on susceptibility and symptomatology of
neuropsychiatric disorders.
Molecular Psychiatry (2005) 10, 598–605. doi:10.1038/sj.mp.4001615
Published online 7 December 2004
major depressive disorder; bipolar disorder; candidate genes; catecholamine
neurotransmission; COMT gene; age at onset; association study
Keywords:
Mood disorders (MD), including bipolar disorder
(BPD) and major depressive disorder (MDD), are
multifactorial diseases, presumed to have a complex
inheritance, involving the interaction of various genes
in combination with environmental factors. A polygenic origin implies a limited impact of each gene and
a high phenotypic heterogeneity of the disorder, and/
or a large impact in a small number of families.
Association studies are appropriate for searching
susceptibility genes with minor effects involved in
MD,1 but large samples of subjects are necessary to
Correspondence: Dr I Massat, Department of Psychiatry, Unit of
Adolescents, University Clinics of Brussels, Erasme Hospital,
Free University of Brussels, Route de Lennik 808, B-1070,
Brussels, Belgium. E-mail: [email protected]
Received 30 December 2003; revised 14 September 2004; accepted
23 September 2004
obtain sufficient power of detection. Conflicting
results in molecular genetic studies of MD may be
due to the clinical and genetic heterogeneity of the
disorder. Thus, attention is shifting towards clinical
indicators of MD, which may be able to identify more
heritable subforms of the disease. Evidence is accumulating from ascendant and descendant family
studies, that ‘early onset’ (EO) forms of MD may be
associated with greater familial risk to relatives.2–5
Furthermore, a recent study showed the existence of
intrafamilial correlation for age at onset in BPD.4
Finally, EO was reported to be involved in anticipation (increase in disease severity and decrease in age
at onset in succeeding generations), as suggested in
BPDs.6–9
EO of MD could be an important variable in
identifying some forms of MD that are more genetically homogeneous or may carry some degree of
COMT polymorphism and early onset of mood disorders
I Massat et al
relatively increased genetic loading or phenotypic
expression.5 EO, as a specific phenotype, may be
helpful to identify vulnerability genes (ie increase
penetrance). Age at onset (AAO) of the disease has
been found to be a key indicator for a more heritable
form of MD, in delineating disorder subtypes, thus
leading to gene identification (in other neuropsychiatric disorders, as is the case in Alzheimer’s disease).10
A clinical study reported an association of BPD in a
group of subjects with the velocardiofacial syndrome
(VCFS), a congenital disorder that presents with a
constellation of symptoms, such as cleft palate,
cardiac problems, facial abnormalities, and learning
disabilities.11 Within these subjects, 64% met DSMIII-R criteria for a spectrum of BPD with full
syndromal onset in late childhood or early adolescence. These findings support a strong association
between VCFS and early-onset BPD.11 On a molecular
level, the disorder has been linked to a hemizygous
interstitial deletion of chromosome 22q11, which may
involve the gene coding for the catechol O-methyl
transferase (COMT), a methylation enzyme, which
catalyzes endogenous catecholamines (eg, dopamine,
epinephrine, norepinephrine) by O-methylation in
the presence of S-adenosylmethionine and magnesium ions.12 The COMT gene, considered as a
possible ‘candidate gene’ for MD, was characterized
and sequenced.13–15 There are two common variants, a
low- and a high-activity form, due to a G-to-A
transition at codon 158, predicting an amino-acid
change (Val158Met).12,16,17 The enzyme containing Met
is unstable at 371C and has 14 of the activity of the
enzyme containing Val.12 The alleles are codominant,
as heterozygous individuals have enzyme activities
that are midway between that of homozygous individuals. The erythrocyte COMT activity has been
shown to be higher in BPD patients than their
individually matched controls, and to be increased
by 60% in female MDD patients compared to female
controls, with a significantly higher enzyme activity
than in the corresponding male patients.18 Moreover,
the COMT activity was reported to be highest at an
early age (in particular from age 6 to 20) and lowest
after age 50 years.19 A relationship between COMT
Table 1
Met activity and BPD was postulated as a mechanism
for the BPD phenotype in cases of comorbid BPD and
VCFS.20 Some studies have reported a positive
association between the low-activity COMT Met allele
and MDD,21 BPD,22–24 BPD with rapid cycling,25 and
BPD with ultradian rapid cycling (48 h cycles).20
However, several case–control association studies of
COMT alleles have been negative (see Table 2).
Linkage studies have supported a locus for both
schizophrenia26 and BPD27,28 on chromosome 22q,
near the location of VCFS.
In the present study, we examined the relationship
of the functional COMT (Val158Met) polymorphism in
the EO subphenotype of MD, in a European multicenter association study, using a case–control design
in samples of BPD, MDD, and control subjects.
599
Materials and methods
Subjects
The present sample was recruited within the Biomedical European Collaborative Study on Molecular
Genetics in Affective disorders (BIOMED 2, Contract
No. BMH4-CT-97-2307). This network was established and supported within the framework of the
European Commission. The objectives and detailed
methodology of the project were described previously.29 A total of six clinical centers participated
in the present study (Athens, Bonn, Brussels, Edinburgh, Milan, Sofia, see Table 1). All centers used
DSM-III-R and DSM-IV classification systems criteria
for categorical diagnoses (BPD and MDD) based on
specific criteria, assessed by standardized interviews
that have shown reliability. All subjects were interviewed by experienced psychiatrists fluent in English
as well as in the language of the population being
studied, using the Schedule for Affective Disorders
and Schizophrenia-Lifetime Version30 and the Schedule for Clinical Assessment of Neuropsychiatry.31
One of the two diagnostic interviews was used for all
patients and all controls recruited for the project. The
decision to adopt two instruments arose out of
different research experience within individual research teams. Data published by the European
Contribution of each center to the recruitment of patient-control samples
Centers
Brussels
MDD
Males/females
BPD
Males/females
Controls
Males/females
Total
Sofia
89
34
46
55
12
88
34
54
21
21
63
53
58
24
20
65
36
51
17
24
26
19
163
29
Total
51
43
25
60
45
35
278
Edinburgh
60
38
60
86
80
234
Bonn
58
53
118
104
274
Athens
74
34
84
97
39
Milan
31
213
138
75
333
378
26
129
96
44
52
83
38
217
288
628
45
230
249
506
316
312
1512
MDD: major depressive disorder.
BPD: bipolar disorder.
Molecular Psychiatry
COMT polymorphism and early onset of mood disorders
I Massat et al
600
cluded. Local medical and research ethics committees
approved the study and informed consent was
obtained from patients and controls.
30
25
20
15
10
5
0
1-15
16- 20
21- 25
26-30
31- 35
36- 40
41- 45
MDD
46-50
51- 55
56- 60
61-65
66- 95
BPD
Figure 1 AAO distribution between MDD and BPD
patients.
Science Foundation ESF showed good concordance
between the two instruments.32 Other sources such as
hospital case notes were also include to make
diagnoses. A total of 1512 subjects were selected
with DNA and clinical data: 378 MDD subjects (129
males and 249 females), including 120 with early
onset (r25 years, named EO-MDD), 506 BPD subjects
(217 males and 288 females), including 222 with early
onset (r25 years, named EO-BPD), and 628 controls
(316 males and 312 females). To limit ethnogeographic stratification biases, samples were performed
within centers with subjects ethnically homogenous.
The age distribution between MDD and BPD patients
is described in Figure 1. The age cutoff of 25 (r25) for
early onset (EO) was chosen according to a recent
report that showed three age-at-onset subgroups of
BPD patients (mean ages at onset were 17 years, 25
years, including 50% of patients, and 40 years,
respectively), having different familial vulnerability
factors.33 In our sample, 49.2% of BPD and 33.5% of
MDD patients had EO. AAO was defined as the ‘age at
which the patient first met the DSM criteria for major
depressive/(hypo)manic episode’. To test alternative
approaches based on phenotypic traits, we selected
clinical subgroups, characterized by a positive family
history of MD in first-degree relatives (n ¼ 166 BPD;
n ¼ 107 MDD), history of suicidal attempt (SA)
(n ¼ 126 BPD, n ¼ 83 MDD), presence of psychotic
features (delusions or hallucinations, n ¼ 157 BPD,
n ¼ 29 MDD) and presence of rapid cycling (RC) in
BPD (n ¼ 21 RC, 220 without RC). Family data were
assessed using the Family History RDC instrument.34
When available, family data were also collected from
relatives. Positive family history was defined as
having at least one first-degree relative affected with
BPD or MDD. Subjects for whom clinical information
to categorize them into those subgroups was not
available were not included in these analyses. For the
control group, subjects with a positive personal or
familial history of psychiatric disorder were exMolecular Psychiatry
Genotyping
The COMT gene, located at 22q11.2, has six exons
and two promoters. The COMT (Val158Met) polymorphism is due to a G-to-A transition at codon 158
of the COMT gene, resulting in a valine-to-methionine
substitution.16 The two alleles are commonly referred
to as COMT Val and COMT Met. Genomic DNA was
extracted from whole blood by NaCl precipitation.35
PCR was performed with the following primers: 50 ACT GTG GCT ACT CAG CTG TG-30 and 50 -CCT TTT
TCC AGG TCT GAC AA-30 . The PCR was carried out
in a 10-ml volume containing 20 ng of genomic DNA,
10 pmol of each primer, 200 mM of each dNTP, 1 PCR Gold Buffer (Applied Biosystem), and 0.025 U/ml
of Taq Gold Polymerase (Applied Biosystem). After an
initial denaturation step of 5 min at 961C, 35 cycles of
amplification (45 s at 961C, 45 s at 601C, and 45 s at
721C) and a final extension step of 10 min at 721C
were performed. An aliquot of PCR product was
digested using NlaIII (New England BioLabs); fragments were separated in 4% agarose gels. Depending
on the presence or absence of the restriction NlaIII
site, either one fragment (allele COMT Val) or two
fragments (allele COMT Met) were produced (Table 2).
Statistical analysis
The Hardy–Weinberg equilibrium (HWE) was tested
separately in the three groups (MDD, BPD, and
controls), by using the exact HW test and the
GENEPOP, 3.d program-updated version of GENEPOP.36 In order to determine whether there is an
association of COMT and MD, we performed logistic
regression analyses. We evaluated the effect of
genotypes and alleles as predictors of the dependant
variable (the diagnosis status). Results of these
analyses are shown in Table 3. To evaluate the
possible confounding and/or modifying effect of
center and gender, stratified analyses were performed
and odds ratios (OR) and confidence intervals (95%
CI) were calculated. The Mantel–Haenszel test37 was
applied to evaluate the possible confounding effect of
gender/center. The Breslow–Day38 test was applied to
test the homogeneity of the stratum-specific estimates
(center and gender for strata and presence of genotype
COMT Val/Val as exposition).
Results
No significant deviation from HWE was observed in
any of the three groups.
COMT (Val158Met) polymorphism: MDD patients
compared to control subjects
Results were derived from logistic regression analyses
and did not show any significant difference when
comparing the distribution of genotypes and alleles
COMT polymorphism and early onset of mood disorders
I Massat et al
Table 2
601
Case–control association studies for the COMT (Val158Met) polymorphism in MDD and BPD patients
Patients (n)
Controls (n)
MDD
Kunugi45
Ohara21
Frish46
Russ47
Cusin48
62
75
102
51 (suicidal patients)
212
121
135
172
51
663
BPD
Papolos11
Li22
93
98
88
63
107
412
40
30 BPD females
55 BPD (rapid cycling)
113
63
121
368
135
Parents (trios)
110 BPD (nonrapid
cycling)
Gutiérrez49
Lachman50
Kunugi45
Biomed group51
Ohara21
Mynett–Johnson23
Kirov25
Papolos20
Geller52
Cusin48
Rotondo24
19 rapid-cycling and 6
ultradian rapid cycling)
52 EO-BPD (710 years)
338
111BPD (49 with panic
disorder and 62 without
panic disorder)
COMT
COMT Met Allele
Met/Met Genotype
COMT Met Allele
COMT Met allele
COMT Met Allele
COMT Met /Me
Genotype
Trios
663
127
Comt Met allele
Significance
NS
S (OR ¼ 2.19)
NS
NS
NS
NS
S
S
NS
NS
NS
NS
NS
Tendency
S
S with ultradian rapid
cycling BP
NS
NS
S with BPD without
panic disorder
MDD: major depressive disorder.
BPD: bipolar disorder.
S: significant.
NS: non significant.
between MDD cases and control subjects (see Table
3a). No association emerged when considering subphenotypes including MDD patients with history of
SA, presence of psychotic features, and positive
family history (results not shown).
distribution of the COMT Val allele was significantly
increased in EO-MDD than in MDD (57 vs 48% in
MDD; P ¼ 0.031; df ¼ 1; OR ¼ 1.4; CI ¼ [1.03, 1.92];
Table 3c). However, this result did not resist to
Bonferroni correction.
COMT (Val158Met) polymorphism: EO-MDD patients
compared to control subjects
From the logistic regression analyses emerged a
significant difference for genotype distributions between EO-MDD and controls, in favor of the highactivity Val/Val genotype (33% in E0-MDD vs 21% in
controls, P ¼ 0.01; OR ¼ 2.07, CI ¼ [1.18, 3.61]). The
high-activity COMT Val allele was significantly
increased in EO-MDD patients (56.7 vs 47.5% in
controls, P ¼ 0.009; df ¼ 1; OR ¼ 1.44; CI ¼ [1.09, 1.91];
Table 3b). These results resisted to multiple tests
correction (five tests). When comparing the two
groups of patients (EO-MDD and MDD), the difference
of frequencies of the COMT Val/Val genotype was not
significant (overall test P ¼ 0.09) but the COMT Val/
Val genotype was significantly more frequent (33.3%
in EO-MDD vs 23.5% in MDD; P ¼ 0.037; df ¼ 1;
OR ¼ 1.93; CI ¼ [1.04, 3.6]; Table 3c). Moreover, the
COMT (Val158Met) polymorphism: BPD patients and
EO-BPD compared to control subjects
Results did not show any significant difference when
comparing the distribution of genotypes and alleles
between BPD patients, EO-BPD patients and control
subjects (see Table 3d and e). When exploring
subphenotypes, ‘rapid cycling’ BPD, BPD with positive family history, BPD with psychotic features did
not show association (results not shown). However,
when considering BPD with SA, we found a significant association with the COMT Val/Val genotype
when we compared with controls (34.1 vs 20.9%;
overall
w2:
w2WALD ¼ 10.16;
df ¼ 2;
P ¼ 0.006;
2
wWALD ¼ 6.31; df ¼ 1; P ¼ 0.012; OR ¼ 1.98; CI ¼ [1.16,
3.3]; see Table 3f) and in comparison with BPD
patients without history of SA (34.1 vs 20.6%;
w2WALD ¼ 8.9; df ¼ 2; P ¼ 0.012; w2WALD ¼ 8.9; df ¼ 1;
P ¼ 0.003; OR ¼ 2.1; CI ¼ [1.3, 3.5]). The last results
Molecular Psychiatry
COMT polymorphism and early onset of mood disorders
I Massat et al
602
Table 3 Comparison of genotype and allele distributions at the COMT (Val158Met) polymorphism, between affected patients
and controls
Genotypes
B
SE
Wald
df
Sig.
Exp(B)
95%CI for EXP(B) lower
upper
0.078
0.26
0.158
0.18
4.39
0.241
1.96
2
1
1
0.11
0.62
0.16
1.08
0.77
0.79
0.53
1.47
1.11
0.12
0.09
1.78
1
0.18
0.88
0.73
1.59
(a) MDD compared to controls
Met/Val
Val/Val
Alleles
Val
(b) EO-MDD compared to controls
Met/Val
Val/Val
Alleles
Val
0.13
0.72
0.26
0.28
8.9
0.24
6.61
2
1
1
0.012
0.62
0.01
1.13
2.07
0.68
1.18
1.90
3.6
0.37
0.14
6.8
1
0.009
1.48
1.09
1.91
(c) EO-MDD compared to MDD
Met/Val
Val/Val
Alleles
Val
0.26
0.99
0.28
0.23
4.62
0.80
4.35
2
1
1
0.099
0.37
0.037
1.29
1.93
0.73
1.04
2.28
3.6
0.34
0.16
4.66
1
0.031
1.4
1.032
1.927
0.07
0.19
0.14
0.17
1.2
0.26
1.22
2
1
1
0.536
0.61
0.26
0.92
0.82
0.69
0.58
1.23
1.16
0.09
0.085
1.13
1
0.28
0.91
0.77
1.07
(d) BPD compared to controls
Met/Val
Val/Val
Alleles
Val
(e) EO-BPD compared to controls
Met/Val
Val/Val
Alleles
Val
0.102
0.219
0.19
0.22
0.91
0.28
0.91
2
1
1
0.633
0.59
0.339
1.10
1.24
0.76
0.79
1.61
1.94
0.102
0.110
0.85
1
0.356
1.107
0.89
1.37
1.01
1.98
0.61
1.16
1.66
3.37
1.43
1.08
1.87
(f) BPD patients with history of suicidal attempt compared to controls
10.16
2
0.006
Met/Val
0.12
0.25
0.002
1
0.96
Val/Val
0.68
0.27
6.31
1
0.012
Alleles
Val
0.35
0.139
6.6
1
0.01
Logistic regression analyses (Method: enter, Contrast: indicator, Categorical covariates: genotypes/alleles, dependant
variable: diagnosis—presence/absence). MDD: major depressive disorder.
EO-MDD: early onset-major depressive disorder.
BPD: bipolar disorder.
EO-BPD: early onset-bipolar disorder.
did not resist to Bonferroni correction (six tests). The
distribution of the COMT Val allele was significantly
increased in BPD with a history of SA (56.3%)
compared to controls (47.5%), (w2WALD ¼ 6.6; df ¼ 1;
P ¼ 0.01; OR ¼ 1.4; CI ¼ [1.08, 1.87]; see Table 3f).
For each comparison, Mantel–Haenzsel and Breslow–Day tests were carried out to eliminate a
confounding and a modifier effect. Differences between ORcrude and ORMH estimated according to the
Mantel–Haenzsel test never exceed 15%, excluding
confounding effects of gender and center. The
Molecular Psychiatry
Breslow–Day tests were nonsignificant, excluding
gender and center modifier effect.
Discussion
In this multicentric European study, an association
was found in favor of the high-activity Val allele of the
common functional COMT (Val158Met) polymorphism, in EO-MDD patients. These findings indicate
that the COMT Val allele and especially the COMT
Val/Val genotype may represent a modifying gene that
COMT polymorphism and early onset of mood disorders
I Massat et al
predisposes to early onset in MDD patients or reflect
linkage disequilibrium with a different causative
polymorphism in the vicinity. A previous report
showed that homozygosity for the high-activity
COMT Val/Val genotype is associated with a 3–4-fold
increase of COMT enzyme activity compared with
homozygotes for the low-activity variant.12 Individuals with COMT Val/Val genotype would be expected to have lower levels of transynaptic
catecholamines due to an increased COMT degradation of norepinephrine and dopamine. Age-specific
variations in neurotransmitters and other developmental differences may support different phenotypic
manifestations of MDD across the age span. Another
way to substantiate our findings should be to assess
cathecolamine metabolites in the CSF as endophenotype. AAO and the intrafamilial correlation for AAO
may be attributable to different genetic vulnerability
factors/or the same genetic mechanism differently
expressed in various environments at developmental
steps. Other results have shown in genetic association
studies on subgroups of AAO-BPD an association
between a marker of the tyrosine hydroxylase gene
and late onset of BPD, and an association between the
apolipoprotein E gene and early onset of BPD,33,39
while it has been suggested that EO in MD is the most
severe form (particularly for BPD), associated with
higher rate of comorbidity, poor response to antidepressants and poor prognosis. The COMT Val
variant, as a risk factor of EO-MDD, could help to
differentiate EO-MDD and EO-BPD in young patients
with major depression and better define a therapeutic
strategy. However, it is important to recognize that
this candidate gene variant may also influence
susceptibility to other psychiatric conditions. This
gene variant may give rise to multiple physiological
abnormalities that separately contribute to other
diseases, or it may produce a single deficit that is
common to these disorders. The same polymorphism
has been shown to affect executive function and the
physiology of the prefrontal cortex in humans,
probably by affecting prefrontal dopamine signalling.
The COMT Val allele, associated with relatively poor
prefrontal function, may increase the risk for schizophrenia.40 COMT resides on chromosome 22q, which
showed significant genome-wide linkage for both
schizophrenia and BPD in a recent meta-analysis,
further supporting a common effect of this polymorphism in both disorders.41 COMT may have
complex and pleiotropic effects on the susceptibility
and symptomatology of neuropsychiatric disorders.
We could also hypothesize an indirect effect of COMT
polymorphism on EO-MDD if we consider the
personality trait of neuroticism, a normally distributed quantitative trait, highly genetically correlated
with anxiety and depression, that may be a vulnerability to either type of disorder: A recent study
reported a weak evidence for association with the
same functional COMT polymorphism.42
Our results are not in line with some previous
association studies (see Table 2). Conflicting results
may be explained by multiple reasons: type one and
two errors, recruitment bias, and phenotypic and
genetic heterogeneity. Samples used in previous
studies did not have a sufficient statistical power for
detecting association, if we consider a minor or
moderate effect of genetic variant at this polymorphism. There are also limitations of our study: Assessment of AAO was retrospective and thus subject to
recall error. Several confounding factors may have
influenced the evaluation of AAO (retrospective data:
common bias in patients who are interviewed at a
later age and have no living parents who can provide
valid information on AAO). As reported in a the
recent meta-analysis of case–control and family-based
studies,43 the frequency of the COMT Val allele varies
widely across European populations, ranging from 42
to 60%. In spite of the fact that we did not detect
center effect in genotype distributions, a stratification
bias due to ethnic differences cannot be excluded, as
it was reported for this polymorphism.43 Though the
association between the COMT Val allele and BPD
with history of SA did not resist to multiple test
correction, these findings have to be taken into
consideration, according to a recent study supporting
the hypothesis that the same COMT polymorphism
may modify the phenotype of suicide attempts and
anger-related traits.44 So, it should warrant further
investigation to clarify this issue. Consequently, we
suggest to further investigate COMT in other populations, using family-based association methods (less
susceptible than case–control association design to
inferential errors based on ethnic stratification bias),
to further explore the genetics of EO-MDD and history
of SA.
603
Acknowledgements
This work was supported by the Association for
Mental Health Research (AESM), the European Community Biomed Grant (Grant No CT 92-1217), the
National Fund for Scientific Research (NFSR), the
Fund for Scientific Research Flanders (FWO) and a
concerted action grant of the Special Research Fund
of the University of Antwerp, Belgium.
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