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Association between CYP2C19 polymorphism and depressive symptoms.

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RESEARCH ARTICLE
Neuropsychiatric Genetics
Association Between CYP2C19 Polymorphism
and Depressive Symptoms
Sarah C. Sim,1* Linn Nordin,1 Therese M.-L. Andersson,2 Susanne Virding,1 Marita Olsson,2,3
and Nancy L. Pedersen2
1
Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
2
3
Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
Received 20 May 2009; Accepted 10 February 2010
Cytochrome P450 2C19 (CYP2C19) is a polymorphic enzyme
active in the metabolism of for example diazepam and the
antidepressants sertraline, citalopram, and escitalopram, whereby allelic variants cause increased (CYP2C19*17) or abolished
(mainly CYP2C19*2) enzymatic activity in drug metabolism. In
light of the importance of CYP2C19 in the metabolism of
psychoactive substances we considered it of interest to investigate the relationship between CYP2C19 polymorphisms and
depressive symptoms in 1,472 subjects of European ancestry
(45–98 years old) from the Swedish Twin Registry. Depressive
symptoms were assessed using the Center of Epidemiologic
Studies Depression (CES-D) scale. We found that poor metabolizers lacking CYP2C19 activity (PMs, CYP2C19*2/*2) had
significantly lower levels of depressive symptoms than extensive
metabolizers (EMs, CYP2C19*1/*1) (P ¼ 0.0018). The size of
this difference was in the same range as that between subjects
reported taking antidepressants (n ¼ 104) and those without
antidepressant treatment (P < 0.0001). Our results suggest for
the first time that the CYP2C19 polymorphism might be of
importance for depressive symptoms, as here shown for older
European adults. 2010 Wiley-Liss, Inc.
Key words: neurosteroids; serotonin; depressed mood
INTRODUCTION
Cytochrome P450s (CYPs) compose a large family of phase I
metabolizing enzymes active in the metabolism of clinically used
drugs, other xenobiotics and endogenous substances. Most of these
P450s are polymorphic, giving rise to a wide spectrum of metabolizing phenotypes ranging from ultra-rapid metabolizers (UMs),
through extensive metabolizers (EMs) to poor metabolizers (PMs),
who lack enzymatic activity. Due to the polymorphisms, there are
large interindividual as well as interethnic differences in the metabolism of different cytochrome P450 substrates [Ingelman-Sundberg et al., 2007].
CYP2C19 is active in the metabolism of clinically used drugs,
several of which are psychoactive such as the antidepressants sertraline
[Rudberg et al., 2008a], escitalopram [Rudberg et al., 2008b] and
citalopram [Yin et al., 2006], as well as diazepam [Fukasawa et al.,
2010 Wiley-Liss, Inc.
How to Cite this Article:
Sim SC, Nordin L, Andersson TM-L, Virding
S, Olsson M, Pedersen NL, IngelmanSundberg M. 2010. Association Between
CYP2C19 Polymorphism and Depressive
Symptoms.
Am J Med Genet Part B 153B:1160–1166.
2007]. There is a large interethnic variation in the frequency of the
different CYP2C19 phenotypes: the PM phenotype encompasses
3–5% of Swedes, 20% in Japanese and is as high as 79% on the
island of Vanuatu in the Pacific Ocean [Desta et al., 2002]. In
Europeans and Asians, the defective CYP2C19*2 allele is responsible
for the majority of the PM phenotypes, whereas in Asia, the defective
CYP2C19*3 allele also contributes [Desta et al., 2002]. The
CYP2C19*17 allele is associated with a rapid metabolizer (RM)
phenotype in vivo for drugs such as omeprazole and escitalopram
and has an allele frequency of 18–27% in different European populations [Kurzawski et al., 2006; Sim et al., 2006; Schroth et al., 2007;
Baldwin et al., 2008; Ohlsson Rosenborg et al., 2008; Rudberg et al.,
2008b], thus giving rise to a homozygous RM genotype frequency of
3–7%.
Recently, the relationship between CYP2C19 polymorphism and
personality traits, as measured by the Temperament and Character
Inventory (TCI), has been investigated in Japanese healthy volunteers [Ishii et al., 2007; Yasui-Furukori et al., 2007]. Ishii et al. [2007]
Additional Supporting Information may be found in the online version of
this article.
Sarah C. Sim and Linn Nordin contributed equally to this study.
*Correspondence to:
Dr. Sarah C. Sim, Ph.D., Section of Pharmacogenetics, Department of
Physiology and Pharmacology, Karolinska Institutet, SE-171 77
Stockholm, Sweden. E-mail: sarah.sim@ki.se
Published online 7 April 2010 in Wiley Online Library
(wileyonlinelibrary.com).
DOI 10.1002/ajmg.b.31081
1160
SIM ET AL.
found a significant difference in three of the seven dimensions of the
TCI between female genotypic CYP2C19 EMs and PMs, but no
significant difference when comparing males. Specifically, the
female PMs had significantly lower scores on reward dependence,
cooperativeness and self-transcendence as compared to the EMs.
Yasui-Furukori et al. [2007] found a statistically significant higher
score in harm avoidance in genotypic PMs as compared to EMs
without stratifying for sex. Thus, these data might possibly indicate
an endogenous psychoactive function for CYP2C19, although these
studies need to be reproduced in other Asian populations and
investigated in Europeans.
Because of the involvement of CYP2C19 in the metabolism of
psychoactive drugs and in personality phenotypes, we investigated
the relationship between CYP2C19 genotypes resulting in
CYP2C19 RMs, EMs, and PMs and depressive symptoms using a
large subset of elderly Swedish subjects from the Swedish Twin
Registry (STR). As measured by CES-D, we found a significantly
lower level of depressive symptoms in PMs (CYP2C19*2/*2) as
compared to EMs (CYP2C19*1/*1), with a stronger relationship in
men and in the younger age group. Thus, our results might suggest
that CYP2C19 polymorphism influences the level of depressive
symptoms in European adults.
MATERIALS AND METHODS
Subjects
In total, 1,555 subjects (nmen ¼ 653, nwomen ¼ 902) from the STR
were included in the study. The participants originated from
three different longitudinal studies of aging, which have all
been described elsewhere: Origins of Variance in the Oldest
Old/Octogenarian Twins (OCTO-Twin) [McClearn et al.,
1997], Swedish Adoption/Twin Study of Aging (SATSA)
[Pedersen et al., 1991; Finkel and Pedersen, 2004], and Gender
[Gold et al., 2002]. At the time of blood sampling, the age
distribution of our study population was 45–98 years with a
mean age of 73 years (71 for men and 74 for women). Subjects
taking antidepressant drugs were identified at the time of filling in
questionnaires (SATSA, 1/3 of the material) or through review of
medical records covering the last approximately 15 years (OCTOTwin and Gender, 2/3) [Jansson et al., 2003]. All drugs with the
Anatomical Therapeutic Chemical (ATC) code N06A were classified as antidepressants. All participants were of European
ancestry and born in Sweden.
The study was approved by the Ethics Committee at Karolinska
Institutet and the Swedish Data Inspection Board. All participants
provided informed consent.
Genotyping
DNA samples were genotyped using the TaqMan Drug Metabolism Genotyping Assays for the CYP2C19*2 (C__25986767_70)
and the CYP2C19*17 allele (C__469857_10) (Applied Biosystems,
CA, Foster City). One microliter of genomic DNA (undetermined
concentration) was included in a 5 ml reaction volume with PCR
conditions as recommended by the manufacturer. The samples
were run on a 7500 Real Time PCR System (Applied Biosystems)
and the data were analyzed using the Sequence Detection Software
1161
version 1.3.1 (Applied Biosystems). Subjects with undetermined
CYP2C19 alleles either from the CYP2C19*2 or CYP2C19*17
genotyping assays were excluded. Subjects were divided into the
following genotype categories: PMs, CYP2C19*2/*2 (n ¼ 35); heterozygous EMs, CYP2C19*1/*2 (n ¼ 290); homozygous EMs, CYP2C19*1/*1 (n ¼ 637); heterozygous RMs, CYP2C19*1/*17
(n ¼ 380); homozygous RMs, CYP2C19*17/*17 (n ¼ 45); and CYP2C19*2/*17 (n ¼ 85).
Assessment of Depressive Symptoms
Depressive symptoms were self-reported using the Swedish
translation of the Center of Epidemiologic Studies Depression
Scale (CES-D) [Gatz et al., 1993]. This 20-item scale assesses the
level of depressive symptom during the past week, but the CES-D
scores are relatively stable over time [Fiske et al., 2003]. The CESD scale consists of four sub-scales that together sum to a total
score (T1): depressed mood, psychomotor retardation and somatic complaints, well-being, and interpersonal difficulties. Each
sub-scale is assessed by a number of questions with scores ranging
from 0 to 3 with a maximal total score of 60 where higher total
scores indicate higher levels of depressive symptoms [Radloff,
1977]. For the present analyses, only the total scale and the subscales ‘‘psychomotor retardation and somatic complaints,’’
and ‘‘depressed mood’’ were evaluated. Average CES-D scores
were used for the 84% of the participants who had answered
the test more than once at 2- to 4-year intervals [Jansson et al.,
2003].
Information on antidepressant use came from two sources:
medical records and self-report of the trade name of all medications
taken during the last month which were then coded into the ATC
system. All drugs with the ATC code N06A were classified as
antidepressive (antidep). Use of antidepressants was included as
a covariate, in order to be able to evaluate the effect of genotype on
depressive symptoms independent of any confounding effect of the
antidep variable.
Statistics
The association between the CES-D scores and the genotypic
information was analyzed using linear regression. To account for
dependence within the data due to including related individuals
(twin pairs), we used a Generalized Estimating Equation (GEE)
approach with an exchangeable correlation structure. Estimated
effects of covariates are expressed as change in mean score. The
main models, including males and females of all ages, were
adjusted for sex and antidepressant drug intake as binary variables and age as a linear variable. The age and sex stratified models
were adjusted for the same variables as the main models, except
for age and sex, respectively. In the statistical analyses, everyone
with missing genotype information or the outcome variable for
that specific model was excluded. The study population used for
statistical analyses included both members of a twin pair
(monozygotic (MZ) females n ¼ 158, MZ males n ¼ 104, dizygotic (DZ) females n ¼ 362, DZ males n ¼ 702) as well as singletons (MZ females n ¼ 46, MZ males n ¼ 33, DZ females n ¼ 102,
and DZ males n ¼ 48). All statistical analyses were performed in
1162
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
SAS 9.1 using the GENMOD procedure (SAS Institute, Cary,
NC).
RESULTS
Out of 1,555 DNA samples, 1,472 (nmen ¼ 622, nwomen ¼ 850) were
successfully genotyped for both CYP2C19*2 and CYP2C19*17. The
genotype frequencies were in Hardy–Weinberg equilibrium.
Due to missing information on some items, the final numbers of
participants were 1,416 for the total CES-D score (T1), 1,426 for
psychomotor retardation and somatic complaints (SA), and 1,425
for depressed mood (DA).
Individuals on antidepressants (antidep, n ¼ 104) had significantly higher T1, SA and DA scores compared to subjects that had
no antidepressant record (P < 0.0001, Table I, Fig. 1). Increasing
age was associated with decreased T1 scores (P < 0.0001, Table I),
and males had significantly lower levels of depressive symptoms
than females (P ¼ 0.0009, Table I). The same results were found in
the SA and DA sub-scales, but the magnitude of the differences were
smaller (Table I).
In the entire study population, the CYP2C19*2/*2 genotype,
which confers a PM phenotype, had significantly lower T1 scores,
and thus a lower level of depressive symptoms, as compared to the
reference genotype CYP2C19*1/*1 with an EM phenotype
(P ¼ 0.0018, Table I, Fig. 1). The SA and DA sub-scales displayed
similar patterns of differences between genotypes as the T1 scale
(Table I). The study population used for the analyses in Table I (as
well as Tables II and III) included both members of a twin pair
(monozygotic (MZ) n ¼ 262, dizygotic (DZ) n ¼ 1,064) as well as
singletons, only one twin in a pair (MZ ¼ 79, DZ ¼ 150, see the
Materials and Methods Section for further information on sex
distribution). We performed the same analyses with only one
member of a pair selected at random (i.e., n ¼ 815–820 depending
on the scale tested) and the results were analogous: the magnitudes
of the parameters were very similar, and because of the smaller
sample, the P-values were somewhat increased but remained
significant (the only exceptions being lack of significance for the
DA sub-scale with CYP2C19*2/*2 and age with P-values of 0.07 and
0.19, respectively).
After stratifying for sex, the same pattern of difference in the T1
scores between CYP2C19 genotype groups was found in the males
(Table II), but not in the females (data not shown). Thus, in the
males, the CYP2C19*2/*2 genotype group showed significantly
lower T1 values compared to the CYP2C19*1/*1 genotype group
(Table II, Fig. 1). Noteworthy, the size of the difference in T1 scores
between the antidep group and subjects not treated with antidepressant drugs was higher in the male study population (Table II) as
compared to the mixed study population (Table I). The results from
analyses of the sub-scales SA and DA were similar to that of the T1
total score but with smaller differences (Table II).
Furthermore, we stratified the study population for age,
dividing the data set into two age groups, a younger (mean age
(range) ¼ 65 (45–72) years, nmen ¼ 344, nwomen ¼ 348) and an
older group (mean age (range) ¼ 80 years (73–98), nmen ¼ 264,
nwomen ¼ 460). The CES-D scores differed by genotype in the
younger subgroup (Table III, Fig. 1) but not the older subgroup
(data not shown). The magnitude of difference in T1 scores between
CYP2C19*2/*2 and CYP2C19*1/*1 was greater in the younger
subgroup as compared to the entire study population. As was also
observed in the entire study population, males in the younger age
group displayed a lower level of depressive symptoms than females,
and subjects on antidepressant medication scored higher than those
without (Table III). Again, the difference in T1 scores between
genotype groups in the younger age group was also observed for the
sub-scales SA and DA (Table III).
DISCUSSION
The present study investigated the relationship of CYP2C19 polymorphism with depressive symptoms in 1,472 subjects with Euro-
TABLE I. CES-D Scores for the Entire Study Population
CES-D total score: T1
Category
CYP2C19*2/*2
CYP2C19*1/*2
CYP2C19*2/*17
CYP2C19*1/*1
CYP2C19*1/*17
CYP2C19*17/*17
Antidep
Age
Male
Female
n
33
277
84
613
365
44
91
—
608
808
Estimate
2.9743
0.2155
0.0639
(Ref)
0.1550
1.5395
4.2803
0.1071
1.2497
(Ref)
Standard
error
P-value
n
0.9529
0.0018 33
0.4904
0.6603 279
0.8520
0.9402 84
(Ref)
(Ref)
617
0.4733
0.7433 369
1.0720
0.1510 44
1.0964 <0.0001 95
0.0219 <0.0001 —
0.3754
0.0009 611
(Ref)
(Ref)
815
CES-D sub-scale:
SA (somatic complaints)
Estimate
1.0069
0.1129
0.1416
(Ref)
0.2697
0.4742
1.8159
0.0203
0.5496
(Ref)
Standard
error
P-value
n
0.3372
0.0028 33
0.1759
0.5208 279
0.2924
0.6281 84
(Ref)
(Ref)
617
0.1638
0.0996 368
0.2988
0.1126 44
0.3764 <0.0001 95
0.0071
0.0043 —
0.1312 <0.0001 611
(Ref)
(Ref)
814
CES-D sub-scale:
DA (depressed mood)
Estimate
0.7057
0.0561
0.2146
(Ref)
0.0491
0.3908
1.3534
0.0193
0.7551
(Ref)
Standard
error
P-value
0.2858
0.0135
0.1610
0.7275
0.2795
0.4426
(Ref)
(Ref)
0.1584
0.7564
0.3335
0.2412
0.3260 <0.0001
0.0073
0.0084
0.1241 <0.0001
(Ref)
(Ref)
Estimates are deviations from the intercept (reference group). The CYP2C19 genotype categories were analyzed with CYP2C19*1/*1 as the reference group. The antidep line compares subjects reported to
take antidepressant medication with subjects not taking antidepressant drugs (the reference group). Age is presented as unit difference per extra year of age, and males were compared with females.
Since the statistical models contained several variables (CYP2C19 genotype, antidep, age, and sex), each variable analyzed was adjusted for the other variables. P-values in bold refer to values below 0.05
and are considered statistically significant.
SIM ET AL.
1163
TABLE II. CES-D Scores for Males, All Ages
CES-D sub-scale:
DA (somatic complaints)
CES-D total score: T1
Category
CYP2C19*2/*2
CYP2C19*1/*2
CYP2C19*2/*17
CYP2C19*1/*1
CYP2C19*1/*17
CYP2C19*17/*17
Antidep
Age
n
17
123
31
260
160
17
30
—
Estimate Standard error
4.6120
1.0378
0.3330
0.6810
0.8579
1.2719
(Ref)
(Ref)
0.1994
0.6259
2.1727
1.2971
6.0744
1.9360
0.0553
0.0298
P-value
<0.0001
0.6249
0.5000
(Ref)
0.7500
0.0939
0.0017
0.0636
n
17
124
31
261
161
17
31
—
Estimate Standard error
1.3509
0.4047
0.0563
0.2518
0.2328
0.3974
(Ref)
(Ref)
0.0961
0.2326
0.3379
0.4000
2.3364
0.7024
0.0044
0.0102
CES-D sub-scale:
SA (depressed mood)
P-value
0.0008
0.8231
0.5580
(Ref)
0.6795
0.3983
0.0009
0.6659
n
17
124
31
261
161
17
31
—
Estimate Standard error
0.9433
0.3138
0.1506
0.1940
0.4362
0.4299
(Ref)
(Ref)
0.1564
0.1959
0.5931
0.3268
1.5282
0.5746
0.0037
0.009
P-value
0.0026
0.4377
0.3103
(Ref)
0.4246
0.0696
0.0078
0.6784
Estimates are deviations from the intercept (reference group). The CYP2C19 genotype categories were analyzed with CYP2C19*1/*1 as the reference group. For other details, see Table I. P-values in bold
refer to values below 0.05 and are considered statistically significant.
pean ancestry from the Swedish Twin Registry. CYP2C19 PMs had a
significantly lower level of depressive symptoms than homozygous
EMs both when analyzing the total CES-D score (T1) and when
analyzing the sub-scales of psychomotor retardation and somatic
complaints (SA) and depressed mood (DA). This difference was
even more prominent in men and in the younger age group
(summarized in Fig. 1). The other genotype groups (including
subjects homozygous or heterozygous for CYP2C19*17) did not
differ from the reference group (EMs, CYP2C19*1/*1).
Interestingly, the differences in depressive symptoms between
genotypically classified PMs and EMs were accentuated in males
and in the younger group of twins. This might be due to differences
in the etiology of depressive symptom as indicated by previous
studies demonstrating different etiologies for clinical depression in
younger people as compared to older [Kendler et al., 2007], and in
males as compared to females [Kendler et al., 2006]. It is thus
possible that the consequences of poor metabolism of CYP2C19
activity (CYP2C19*2/*2) has differential effects in different depressive phenotypes.
Our study suggests a link between depressive symptoms and
CYP2C19 genetic polymorphism, yet the mechanism is not clear.
Today, medical treatment for depression is directed towards manipulating the monoaminergic neurotransmission in the brain,
such as that of serotonin. The commonly prescribed selective
serotonin reuptake inhibitors (SSRIs) function by increasing the
levels of serotonin (5-hydroxytryptamine, 5-HT) in the postsynaptic space. The increased level of 5-HT is associated with relief of
the depressive symptoms, although the exact mechanisms are not
clear. Thus far, a possible link between CYP2C19 and 5-HT has only
been described in vitro, suggesting that CYP2C19 participates in the
biotransformation of 5-HT [Fradette et al., 2004]. However, the
affinity of CYP2C19 for 5-HT was shown to be very low and the
transformation by no means specific for CYP2C19 since both
CYP2B6 and CYP2C9 had identical capacities in this reaction.
TABLE III. CES-D Scores for Both Sexes, Younger Age Group
CES-D sub-scale:
DA (somatic complaints)
CES-D total score: T1
Category
*2/*2
*1/*2
*2/*17
*1/*1
*1/*17
*17/*17
Antidep
Male
Female
n
15
132
36
317
166
26
21
344
348
Estimate
5.6424
0.3557
0.2359
(Ref)
0.4726
0.3660
7.6179
1.5526
(Ref)
Standard
error
1.2314
0.6622
1.1338
(Ref)
0.7235
1.0768
2.1366
0.5120
(Ref)
P-value
<0.0001
0.5912
0.8352
(Ref)
0.5136
0.7340
0.0004
0.0024
(Ref)
n
15
133
36
318
167
26
21
346
349
Estimate
1.9557
0.2521
0.2712
(Ref)
0.0487
0.3687
2.7555
0.6281
(Ref)
Standard
error
0.3877
0.2290
0.3728
(Ref)
0.2468
0.3694
0.7242
0.1785
(Ref)
P-value
<0.0001
0.2708
0.4670
(Ref)
0.8434
0.3182
0.0001
0.0004
(Ref)
CES-D sub-scale:
SA (depressed mood)
n
15
133
36
318
167
26
21
346
349
Estimate
1.3826
0.0495
0.0007
(Ref)
0.2856
0.4654
2.1718
0.8651
(Ref)
Standard
error
0.3795
0.2243
0.4244
(Ref)
0.2469
0.3140
0.6679
0.1777
(Ref)
P-value
0.0003
0.8254
0.9986
(Ref)
0.2474
0.1382
0.0011
<0.0001
(Ref)
Estimates are deviations from the intercept (reference group). The CYP2C19 genotype categories were analyzed with CYP2C19*1/*1 as the reference group. For other details, see Table I. P-values in bold
refer to values below 0.05 and are considered statistically significant.
1164
FIG. 1. The CES-D total scores (T1) represent deviations from the
intercept (reference group). The value of the antidep group
(subjects having taken antidepressant treatment) is shown as
the deviation from subjects reported not to take antidepressant
drugs as the reference group. The CYP2C19*2/*2 subjects are
compared with the CYP2C19*1/*1 genotype as the reference
group. The graph displays results from analyses using all
subjects, the males, and the younger age group, respectively. All
differences were statistically significant with *P < 0.01,
**P < 0.001, ***P < 0.0001.
Furthermore, the proposed enzymatic conversion did not follow
true Michaelis–Menten kinetics but most probably merely reflected
oxidation as a result of auto-oxidation by cytochrome P450-generated oxyradicals [Ingelman-Sundberg and Johansson, 1984; Butura et al., 2009]. In addition, there was no selectivity in the action of
different inhibitors like ketoconazole and omeprazole in inhibiting
the different CYP-mediated 5-HT conversions, indicating that 5HT merely acted as a radical scavenger.
However, it is possible that CYP2C19 metabolizes other endogenous compounds that could be of importance for depressive
symptoms. In support of this finding is CYP2C19’s importance
for clearance of escitalopram and other antidepressants, whereby a
structure–function relationship might hold true for endogenous
substrates with similar actions. In vitro studies suggest CYP2C19 is
involved in the metabolism of steroid hormone structures such as
progesterone, testosterone [Yamazaki and Shimada, 1997], estrone
[Cribb et al., 2006], and estradiol [Cheng et al., 2001], thus raising
the possibility of a mechanism involving neurosteroids [Pinna et al.,
2009].
Today, the presence of CYP2C19 in the human brain remains
controversial although presence in the brain may not be necessary
for an impact on depressive symptoms. Hepatic CYP2C19 could
potentially regulate levels of circulating neuroactive substances
such as steroids, which in turn indirectly affect brain function.
Furthermore, a genetic element that is associated with depressive
symptoms may be in linkage disequilibrium with CYP2C19 (on
chromosome 10q24), and thus CYP2C19 per se may not influence
depressive symptoms. Apparently, the molecular link between the
CYP2C19 genotype and depressive symptoms has to await further
investigation.
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
As could be expected, subjects on antidepressant treatment (the
antidep group) identified either at the time of CES-D testing or
through review of medical records had significantly higher CES-D
scores than subjects not on this type of medication, both when
analyzing the total T1 score and the SA and DA sub-scales. The
results are thus consistent with the assumption that subjects who
receive antidepressant treatment would presumably show higher
levels of depressive symptoms than healthy subjects despite their
treatment. This expectation is supported by findings in elderly
depressed in-patients receiving escitalopram for 4 weeks who
improved from a Geriatric Depression Scale score of on average
9.4 to an average of 4.7, which however does not match the score of
that of healthy controls (average 1.2) [Savaskan et al., 2008]. Further
support comes from the observation that the hippocampal volume
reduction that occurs in male in-patients with depression can be
partially reversed with a ‘‘successful’’ antidepressant treatment, but
will still not reach the volume of healthy controls [Kronmuller et al.,
2008]. It is noteworthy that the magnitude of difference in CES-D
scoring between subjects homozygous for the CYP2C19*2 (PMs) or
the CYP2C19*1 allele (EMs) was in the same range as the difference
between subjects who had been treated with antidepressants and
those who had not.
Recently, Rudberg et al. [2008b] found a strong gene dose effect
on the steady state plasma level of escitalopram in relation to the
CYP2C19 genotype in 166 psychiatric patients. The authors
found a 15-fold difference in escitalopram concentration between subjects homozygous for CYP2C19*17 (RMs) and subjects
homozygous for defect CYP2C19 alleles (PMs). When comparing
the different CYP2C19 genotype groups, it is evident that the
genotype with highest relative impact on the escitalopram level is
that conferring a PM phenotype, whereas the RM phenotype
(homozygous for CYP2C19*17) has a comparatively lower yet
significant effect. With EMs (CYP2C19*1/*1) as the reference,
PMs had almost six times higher escitalopram levels (P < 0.001),
whereas RM subjects only had 58% of the levels (P < 0.01)
[Rudberg et al., 2008b]. In analogy, we observed an effect of the
CYP2C19 PM genotype on the level of depressive symptoms, but
no significant effect of the RM genotype. Thus, the magnitude of
difference in escitalopram plasma levels between genotypic PMs
and RMs in relation to EMs as reported by Rudberg et al. [2008b]
is compatible with the relative impact of the CYP2C19 genotype
groups on the level of depressive symptoms shown here. Specifically, genotypic PMs were shown to have a lower level of depressive symptoms, whereas there was no significant difference
between EMs and RMs.
Although the current study focuses on depressive symptoms
rather than clinical depression, a cut-off value of 16 on the 20-item
CES-D has a sensitivity of 100%, a specificity of 88%, and a positive
predictive value of 13% for detecting major depression in the past
year [Beekman et al., 1997]. Furthermore, Suthers et al. [2004]
found that the more stringent syndromal criteria of the CIDI-SF
actually results in fewer detected cases of depression than a cut-off
score on the short form of CES-D with 11 items. It should be
emphasized that the CES-D scores from 84% of the subjects in the
current study were based on an average of multiple tests with 2- to 4year intervals. Hence, the scores reflect more the ‘‘trait’’ of depressive symptoms rather than a transient state. Nevertheless, of all
SIM ET AL.
subjects in this study, 16% had a CES-D score of 16 or higher,
indicative of a major depression.
In conclusion, the present study based on 1,472 Swedes suggests
that CYP2C19 polymorphism is associated with depressive symptoms as assessed by the CES-D scale. For the first time, we have
demonstrated that subjects of European ancestry with a CYP2C19
PM genotype have a significantly lower level of depressive symptoms than EMs. The fact that CYP2C19 metabolizes psychoactive
drugs implies a potential affinity for substances active in the central
nervous system. Further studies are needed however in order to
investigate the functional link between CYP2C19 and depressive
symptoms.
ACKNOWLEDGMENTS
This work was supported by grants from The Swedish Brain
Foundation (Hj€arnfonden), Torsten och Ragnar S€
oderbergs Stiftelser and by the Swedish Research Council. The twin data were
collected with support of NIH grants AG 04563, AG 10175,
AG08861, the MacArthur Foundation Research Network on
Successful Aging, and The Axel and Margaret Ax:son Johnson’s
Foundation.
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