Download Increased carrier prevalence of deficient CYP2C9, CYP2C19 and

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Increased carrier prevalence of deficient CYP2C9,
CYP2C19 and CYP2D6 alleles in depressed patients
referred to a tertiary psychiatric hospital
Objective: This study compared the types and carrier prevalences of clinically significant DNA polymorphisms
in the cytochrome P450 (CYP450) genes CYP2C9, CYP2C19 and CYP2D6 in major depressive disorder
patients with a control group of nonpsychiatrically ill, medical outpatients. Method: We conducted a
case–control study using 73 psychiatric outpatients diagnosed with depression and referred to a tertiary
center, The Institute of Living (Hartford, CT, USA), for treatment resistance or intolerable side-effects to
psychotropic drugs. The controls were 120 cardiovascular patients from Hartford Hospital being treated
for dyslipidemia but otherwise healthy and not psychiatrically ill. DNA typing to detect polymorphisms in
the genes CYP2C9, CYP2C19 and CYP2D6 was accomplished with the Tag-It™ mutation detection assay and
the Luminex xMAP® system. Results: The percentage of individuals in psychiatric versus control groups
with two wild-type alleles for CYP2C9, CYP2C19 and CYP2D6 genes, were 50 versus 74% (p < 0.001), 71
versus 73% (not statistically significant) and 36 versus 43% (trend, p < 0.2), respectively. Within the
psychiatric population, 57% of individuals were carriers of non-wild-type alleles for 2–3 genes, compared
with 36% in the control population (p < 0.0001). The balance, 43% in the psychiatric population and 64%
in the control, were carriers of non-wild-type alleles for none or one gene. Conclusions: These findings
reveal that clinically relevant CYP2C9 polymorphisms occur more frequently in depressed psychiatric
patients than in nonpsychiatric controls. The same trend was found for polymorphisms in the CYP2D6
gene. We found a significant cumulative metabolic deficiency in the psychiatric population for combinations
of the CYP2C9, CYP2C19 and CYP2D6 genes. The significant enrichment of CYP2C9-deficient alleles in the
psychiatric population validates a previously reported association of this gene with the risk for depression
disorders. The high prevalence of carriers with deficient and null alleles suggests that CYP450 DNA typing
may play a role in the management of psychiatric patients at tertiary care institutions.
KEYWORDS: alleles, CYP2D6, CYP2C9, CYP2C19, drug metabolism, patient safety,
pharmacogenetics, psychotropic drug safety
Major depressive disorder (MDD) is currently
the leading cause of disability in North America
as well as other countries and, according to the
WHO, may become the second leading cause
of disability worldwide (after heart disease) by
the year 2020 [1] . Over the years, the elusive and
highly variable nature of psychiatric disorders
has led to drug therapy treatment that largely
relies on empiricism to ascertain individual
patient differences. This empirical approach has
resulted in a high rate of refractory and adverse
responses to drug therapies, rendering treatment
of MDD one of the most significant challenges
in psychiatry.
Both published literature studies and clinical
experience reveal great variability in an individual’s response to psychotropic drug treatment
with regards to drug metabolism, side effects and
efficacy [2–4] . This variability is in part attributable to genetic differences that result in slowed
or accelerated oxidation of many psychotropic
drugs metabolized by the cytochrome P450
(CYP450) isoenzyme system in the liver [5–7] .
In particular, clinically relevant variants have
been identified for the isoenzymes coded by
the CYP2C9, CYP2C19 and CYP2D6 genes.
While the pharmacogenetic significance of
CYP2C9-deficient alleles is not as prominent
in psychiatry as that of CYP2D6 and CYP2C19,
it is known that the gene represents a minor
metabolic pathway for some antidepressants [5] .
Therefore, polymorphisms in CYP2C9 may be
important in psychiatric patients deficient for
other CYP450 enzymatic activities [8] . Some
of the potential consequences of polymorphic
drug metabolism are extended pharmacological
effect, adverse drug reactions (ADRs), lack of
prodrug activation, drug toxicity, increased or
decreased effective dose, metabolism by alternative deleterious pathways and exacerbated drug–
drug interactions [9,10] . CYP450 isoenzymes are
also involved in the metabolism of endogenous
substrates, including neurotransmitter amines,
and have been implicated in the pathophysiology
10.2217/17410541.5.6.579 © 2008 Future Medicine Ltd
Personalized Medicine (2008) 5(6), 579–587
Gualberto Ruaño1†,
David Villagra1,
Umme Salma Rahim2,
Andreas Windemuth1,
Mohan Kocherla1,
Bruce Bower1,
Bonnie L Szarek2
& John W Goethe 2
†
Author for correspondence:
Genomas, Inc., 67 Jefferson
Street, Hartford, CT 06107 USA;
Tel.: +1 860 545 3773;
Fax: +1 860 545 4575;
[email protected]
2
Institute of Living, Hartford
Hospital, Hartford CT, USA
1
ISSN 1741-0541
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Ruaño, Villagra, Rahim et al.
of mood disorders. CYP2D6 activity has been
associated to personality traits and CYP2C9 to
MDD [11,12] .
The CYP2D6 gene product metabolizes several
antipsychotics (e.g., aripiprazole and risperidone)
and antidepressants (e.g., duloxetine, paroxetine
and venlafaxine) [9] . CYP2D6 is highly polymorphic. More than 60 alleles and more than
130 genetic variations have been described for
this gene, located on chromosome 22q13 [9,101] .
Clinically, the most significant phenotype is the
null metabolizer, which has no CYP2D6 activity because it has two nonfunctional CYP2D6
alleles or is missing the gene altogether. The
prevalence of null metabolizers is approximately
7% in Caucasians and 1–3% in other races [2,9,13] .
Gene duplications of CYP2D6 that may lead to an
ultra-rapid metabolizer (UM) phenotype are also
clinically significant. A recent worldwide study
suggested that up to 40% in some North African
and more than 20% in Australian populations are
CYP2D6 UMs [14] . In a 2006 US survey, the prevalence of CYP2D6 UMs was 1–2% in Caucasians
and African–Americans [2] . CYP2C9 is located
on chromosome 10q24, and its gene product is
involved in the metabolism of several important
psychoactive substances (e.g., fluoxetine, phenytoin, sertraline and tetrahydrocannabinol) [11,15] . It
has been reported that CYP2C9 activity is modulated by endogenous substrates such as adrenaline
and serotonin [16] . CYP2C19 is also located on
chromosome 10q24, but in linkage equilibrium
with CYP2C9. Its gene product is involved in the
metabolism of various antidepressants (e.g., citalopram and escitalopram). For some psychotropics,
a cumulative deficit in drug metabolism resulting from multigene polymorphisms in CYP2D6,
CYP2C9 and CYP2C19 may be clinically significant. For example, gene products for CYP2C19
and CYP2D6 provide joint drug-metabolism
pathways for various tricyclic antidepressants
(e.g., amitriptyline and imipramine) [6] . Given
that CYP2D6, CYP2C9 and CYP2C19 genes
are not linked physically or genetically, their
polymorphisms would be expected to segregate
independently in populations.
Pharmacogenetics is a discipline that attempts
to correlate specific gene variations with responses
to particular drugs. Such DNA-guided pharmacotherapy would be potentially cost effective and
could spare patients from unwanted side effects
by matching each with the most suitable, individualized drug and dosing regimen at initiation
of pharmacotherapy. There have been strategies personalizing dosing for psychiatric drugs
according to algorithms derived from studies of
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Personalized Medicine (2008) 5(6)
blood levels [6] . Beyond pharmacogenetics, it has
become apparent that therapeutic index is a necessary concept in understanding how CYP450
polymorphism may inf luence personalized
prescription [17] .
A 1998 meta-ana lysis of 39 prospective studies in US hospitals estimated that
106,000 Americans die annually from ADRs [18] .
Adverse drug events are also common (50 per
1000 person years) among ambulatory patients,
particularly the elderly on multiple medications.
The 38% of events classified as ‘serious’ are also
the most preventable [19] . It is now clear that
virtually every pathway of drug metabolism,
transport and action is susceptible to gene variation [20] . Within the top 200 selling prescription drugs, 59% of the 27 most frequently cited
in ADR studies are metabolized by at least one
enzyme known to have gene variants that code
for reduced or nonfunctional proteins [21] .
In psychiatry, the high carrier prevalence of
deficient CYP450 alleles has significant implications for healthcare management. Uninformed
prescribing of psychotropics to individuals with
highly compromised biochemical activity for
the CYP450 isoenzymes, may expose 50% of
patients to preventable severe side effects. In this
study, the majority of psychiatric patients (57/73)
were taking two or more psychotropic medications at the time of the study. If these patients
were carriers of gene polymorphisms resulting in
deficient psychotropic metabolism, their risk of
adverse drug effects would substantially increase.
Were DNA typing to be performed upon admission, such information could guide pharmacotherapy during hospitalization and after. The
value of DNA typing for diagnosing severe drug
side effects and treatment resistance has been
documented in various case reports [8,22] .
While it is well known that interindividual
variation in drug metabolism is highly dependent
on inherited gene polymorphisms, the debate
regarding the role of genotyping in clinical practice continues. The aim of the current study was
to compare the carrier prevalence of CYP2C9,
CYP2C19 and CYP2D6 polymorphisms in psychiatric patients and controls in order to support
DNA typing as a clinical tool for antidepressant
management at a tertiary referral center.
Methods
Patient cohorts
The study sample consisted of 73 psychiatric patients (48% male and 52% female, aged
5–86 years with a median age of 22 years) suffering from a MDD and treated with psychotropic
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CYP450 genotyping in psychiatric referrals
medication through the outpatient psychiatric
services at The Institute of Living at Hartford
Hospital (CT, USA). They were referred to the
Laboratory of Personalized Health at Genomas
(CT, USA) for CYP450 diagnostic genotyping
as part of their clinical care because of efficacy
or safety problems related to their medications.
Self-reported ethnicities were 92% Caucasian,
5% African–American, 1.5% Hispanic and
1.5% Asian.
The control sample consisted of 120 medical patients treated with statins at Hartford
Hospital [23] . They were genotyped for CYP2C9,
CYP2C19 and CYP2D6 in a recent survey of the
prevalence of drug-metabolism deficiencies [24] .
The patients provided informed written consent
as approved by the Institutional Review Board
of Hartford Hospital. Ages of patients ranged
between 40 and 80 years; 63% were males and
37% were females. The self-reported ethnicities
were 87% Caucasian, 3% African–American,
9% Hispanic and 1% Asian.
CYP450 DNA typing data were obtained for
all 73 psychiatric patients on CYP2D6, and for
72 patients on CYP2C9 and CYP2C19. Among
controls, genotyping data was obtained for
120 patients on CYP2C9 and CYP2C19, and for
92 patients on CYP2D6, the difference attributable to specific gene assay yields. Data regarding
CYP450 DNA polymorphisms in the control
population have been previously published [24] .
SNP assays
Blood samples were collected into tubes containing either ethylenediamine tetra-acetic acid
(EDTA) or citrate and were extracted from
lymphocytes using the Qiagen (West Sussex,
UK) EZ-1 robotic DNA isolation procedure.
DNA typing was performed at the Genomas
Laboratory of Personalized Health (LPH) at
Hartford Hospital. LPH is a high-complexity
clinical DNA testing center licensed by the
Connecticut Department of Public Health (CL0644) and certified by the Centers for Medicare
and Medicaid Services (ID #07D1036625)
under Clinical Laboratory Improvement
Amendments (CLIA).
The Tag-It™ Mutation Detection assays
(Luminex Corporation, TX, USA) were utilized for DNA typing of 14, 5 and 7 alleles in
genes CYP2C9, CYP2C19 and CYP2D6, respectively, as previously described [25,26] . These assays
employed PCR to amplify selectively the desired
gene without co-amplifying pseudogenes or
other closely related sequences. In addition, the
kit employs a PCR strategy to amplify fragments
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characteristic of unique genomic rearrangements
in order to detect the presence of the deletion
and duplication alleles in these genes. The kits
use multiplexed allele-specific primer extension
(ASPE) to identify small nucleotide variations
including single-base changes and deletions of
one or three bases on the Luminex xMAP® system (Luminex Corporation, TX, USA) [26] .
Allele categorization
We classified the alleles into clinically distinct
categories for each of the three genes examined
as null, deficient, functional or ultra based on
well-defined molecular properties of the altered
gene [24] . Null alleles lack any enzymatic activity because the altered gene does not produce a
functional protein. Such null alleles include gene
deletions, frameshift mutations, stop codons
and splicing defects. Deficient alleles have subfunctional enzymatic activity due to nucleotide
substitutions resulting in amino acid changes
in the protein, and these variants may manifest
subnormal enzymatic activity for some drug substrates. The functional allele refers to the genetic
wild-type, the most common allele in the population with enzymatic activity considered normal.
Ultra alleles exhibit increased enzymatic activity
as a consequence of either gene duplication or a
promoter change. TABLE 1 lists alleles detected in
this study and their functional classification. To
determine the combinatorial non-wild-type carrier prevalence across all three genes examined, we
used the genotype data for each patient in each
population and tallied the number of subjects
who had variant alleles in 3, 2, 1 or no genes.
Conventions for naming the alleles according
to the Human Cytochrome P450 (CYP) Allele
Nomenclature Committee have been followed
in this study [101] . Accordingly, all variant alleles
contain nucleotide changes that have been shown
to affect transcription, splicing, translation, posttranscriptional or post-translational modifications
or result in at least one amino acid change.
Results
Demographic characteristics
The psychiatric and control populations differed slightly in age, and in numbers of men and
women (TABLE 2) . Allele carrier status did not differ between male and female psychiatric patients
(data not shown).
Clinical characteristics
All psychiatric patients were treated, and
those psychotropic medications prescribed for
three patients or more are provided in TABLE 3.
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Ruaño, Villagra, Rahim et al.
Table 1. Allele frequencies in control and psychiatric populations for the CYP2C9, CYP2C19 and CYP2D6 genes.
Marker
Control
Psychiatric
Gene
Allele
Change
Phenotype
Count
Frequency (%)
Count
CYP2C9
WT
*2
*3
*6
WT
*2
*4
*8
Reference
Arg 144 Cys
Ile 359 Leu
Frame shift
Reference
Splicing defect
Start codon
Trp 120 Arg
Normal
Deficient
Deficient
Null
Normal
Null
Null
Null
203
22
15
0
208
30
1
1
84.6
9.2
6.2
–
86.7
12.5
0.4
0.4
104
26
13
1
123
20
1
0
72.2
18.1
9.0
0.7
85.4
13.9
0.7
–
WT
Dup *2a
Dup *4
*2a
*5
*3
*4
*6
*9
*10
*12
*17
Reference
Gene duplication (*2a)
Gene duplication (*4)
Promoter variant
Gene deletion
Frameshift
Splicing defect
Frameshift
Lys 281 del
Pro 34 Ser
Gly 42 Arg
Thr 107 Ile
Normal
Ultra
Null
Ultra
Null
Null
Null
Null
Deficient
Deficient
Null
Deficient
87
2
1
37
5
3
28
0
6
6
1
8
47.3
1.1
0.5
20.1
2.7
1.6
15.2
–
3.3
3.3
0.5
4.4
70
0
2
28
3
1
25
7
7
0
0
3
47.9
–
1.4
19.1
2.1
0.7
17.1
4.8
4.8
–
–
2.1
CYP2C19
CYP2D6
Frequency (%)
The total allele count differs among genes because of assay yields. WT: Wild-type.
These drugs include antipsychotics, antidepressants and anticonvulsants. Most frequently prescribed were aripiprazole, risperidone, fluoxetine and lamotrigine. In addition,
57 patients (78%) concurrently received two
or more psychotropic medications, 12 patients
(16%) received only one medication, while for
four patients (6%), no psychotropic medications
were reported.
In the case of the CYP2D6 gene, the *4 allele
(null, splicing defect) was the most common null
allele within both groups. Frequencies were 15.2
and 17.0% in the control and psychiatric groups,
respectively. The *6 allele (a frameshift mutation) was only seen in the psychiatric group,
appearing at a frequency of 4.8%.
Carrier prevalences
depicts the prevalence of carrier status
for each of the three CYP2 genes. Noncarriers
have two copies of normal alleles. Single carriers
have one copy of a normal allele and one copy
of a deficient or null allele. A double carrier may
have two copies of deficient alleles, two copies of
null alleles, or one copy each of a deficient and a
null allele. Duplication of a functional allele, or
homozygosity for the CYP2D6*2a allele, confers
ultra-rapid metabolizer status [5] .
The top panel of F IGUR E 1 illustrates the
increased prevalence of CYP2C9 carrier status
among the psychiatric group when compared
with the control group, with 50% of the psychiatric group carrying two wild-type alleles
compared with 74% of the control population
(p < 0.001). The middle panel of FIGURE 1 shows
no significant difference between the two populations with regards to the CYP2C19 carrier
prevalence. The bottom panel of FIGURE 1 presents
FIGURE 1
Allele frequencies
lists the alleles of clinical significance
detected in the CYP2C9, CYP2C19 and
CYP2D6 genes and their frequencies for both
study groups.
In the CYP2C9 gene, the observed alleles in
the control sample were all deficient while the
patients from the psychiatric sample possessed
both deficient and null alleles. The deficient *2
and *3 alleles were observed at higher frequencies in the psychiatric sample, 18.1 and 9.0%,
respectively, compared with 9.2 and 6.3%,
respectively, in the control group. The null (*6,
frameshift mutation) allele was found in only
one patient of the psychiatric group.
In the CYP2C19 gene, all commonly observed
alleles were null in both groups, with no significant differences between the control and the
psychiatric populations.
TABLE 1
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Personalized Medicine (2008) 5(6)
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CYP450 genotyping in psychiatric referrals
the CYP2D6 allele carrier prevalence results. Of
particular significance is that 43% of the control
patients versus 36% of the psychiatric ones had
no deficient alleles (p < 0.2). Additionally, in
the psychiatric group 52% of the patients were
single carriers compared with 37% of patients
in the control group (p < 0.1). The prevalence of
double carriers was 7 and 13% in the psychiatric
and control groups, respectively.
FIGURE 2 represents the differences in combinatorial carrier prevalence in CYP2C9, CYP2C19
and CYP2D6 genes between the psychiatric and
control populations. As illustrated by FIGURE 2 ,
there is a much higher prevalence of carriers of
non-wild-type alleles in two or three genes among
the referred psychiatric patients than there is in
the control population (p = 1.2 × 10 –5). Analysis
of the genotype data results for each patient
revealed that 36% of the control population had
two or three genes with variant alleles resulting
in deficient or null metabolism. Of those, 34%
were deficient in two genes and 2% were deficient in three genes. In total, 52% of the control
population had only one null or deficient gene,
while 12% were wild-type for all three genes in
question. In comparison, 57% of the psychiatric
population possessed deficient or null alleles on
more than one gene. A total of 47% had variant alleles in two genes and 10% had variant
alleles in three genes. Only 6% were wild-type
for all three genes and the remaining 36% had
a deficient or null allele in one gene.
Discussion & future perspective
This study demonstrates that a psychiatric
population of patients referred to a tertiary
mental health center could have deficient
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Table 2. Patient characteristics.
Control
Psychiatric
Sample size (n)
121
73
Age range (years)
40–80
5–86
Male
63
48
Female
37
52
Caucasian
African–American
87
3
92
6
Hispanic
Asian
9
1
1
1
Gender (%)
Ethnicity (%)
innate drug metabolism capacity. Compared
with a hyperlipidemic population drawn from
the same medical center, there was a significantly higher prevalence of patient carriers of
subfunctional polymorphisms in the CYP2C9
and CYP2D6 genes, but not for the CYP2C19
gene. Furthermore, the study found a significant combinatorial metabolic deficiency in the
psychiatric population. These genes code for
isoenzymes involved in key metabolic pathways
of numerous psychotropic drugs, including
antidepressants such as fluoxetine and antipsychotics such as risperidone. These medications are associated with many side effects,
which could be exacerbated if a patient is
innately deficient for their metabolism.
In addition to drug metabolism, the CYP450
isoenzymes metabolize endogenous substrates. For example, CYP2D6 is also a 3- and
4-methoxy phenylethylamine O-demethylase
and a tyramine hydroxylase, both of which
are pathways that lead to the endogenous
Table 3. Medications given to three or more study patients.
Brand name
Generic name
Class
Abilify
Risperdal®
Prozac®
Lamictal®
Seroquel®
Aripiprazole
Risperidone
Fluoxetine
Lamotrigine
Quetiapine
Antipsychotic
Antipsychotic
Antidepressant
Anticonvulsant
Antipsychotic
10
8
7
7
6
Wellbutrin®
Bupropion
Venlafaxine
Valproic acid
Methylphenidate
Paroxetine
Oxcarbazepine
Clonazepam
Sertraline
Topiramate
Antidepressant
Antidepressant
Anticonvulsant
Stimulant
Antidepressant
Anticonvulsant
Anticonvulsant
Antidepressant
Anticonvulsant
6
6
6
5
4
4
4
3
3
®
Effexor®
Depakote®
Concerta®
Paxil®
Trileptal®
Klonopin®
Zoloft®
Topamax®
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Patients
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Ruaño, Villagra, Rahim et al.
Control
Psych
5%
6%
*21%
*44%
CYP2C9
*50%
*74%
29%
27%
CYP2C19
73%
71%
7%
5%
7%
13%
‡
‡
43%
36%
CYP2D6
‡
‡
37%
Ultra rapid
52%
Single carrier
Noncarrier
Double carrier
Figure 1. Carrier prevalences of deficient and null alleles for CYP2C9,
CYP2C19 and CYP2D6 between the control and psychiatric populations.
*
p < 0.001; ‡0.05 < p < 0.20.
formation of dopamine [27] . CYP2C9 activity is modulated by endogenous substrates
such as adrenaline, and serotonin and may be
involved in the metabolism of serotonin and its
metabolites in the brain [16] . The involvement
of CYP2C9 in the metabolism of melatonin has
also been suggested [28] . Polymorphisms in the
CYP2C9 gene may interrupt or inhibit these
endogenous pathways and thus contribute to
susceptibility to psychiatric disorders. CYP2C9
is also involved in the metabolism of amitryptyline, fluoxetine and sertraline and its polymorphisms may contribute to altered CYP450
enzymatic activity and metabolism of such
substances important for psychiatric patients
[5,8] . In CYP2C9 we observed a highly significant increase (p < 0.001) in deficient alleles,
specifically the CYP2C9*2 allele. These results
parallel the previous report of CYP2C9*3 allele
association with depression by a Spanish group
[12] . Both *2 and *3 alleles are functionally deficient and are therefore both likely to reduce
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Personalized Medicine (2008) 5(6)
the metabolism of endogeneous and exogenous
substrates processed by the CYP2C9 *2 and *3
gene product. Furthermore, in our study patients
being treated with psychotropic drugs and evidencing treatment resistance or side effects
was the main criteria for entry. In the Llerena
cohort, disease diagnosis without regard to
treatment outcome was the basis for enrolment.
Adverse drug response phenotypes may unmask
innate disease characteristics and allow genetic
associations to otherwise latent phenotypes.
The Institute of Living is a psychiatric tertiary care center that by virtue of its expertise
treats patients with advanced mental illnesses
referred from primary or secondary care centers. Such patients may not have responded
positively to drug therapy or have suffered
from serious side effects. By contrast, the cardiology patients at Hartford Hospital serve as
a control group with regards to their disease
status and ability to metabolize psychotropic
drugs. These patients had been treated with
statins for at least 1 month. Statins are metabolized primarily by the CYP3 family [29] . Hence,
it is unlikely that these patients were selected
for variants in the CYP2 family, although this
possibility cannot be excluded. Considering
this difference in populations, one would
expect to see both a psychopathological and
a pharmacotherapeutic referral bias in psychiatric patients referred to a tertiary center.
The higher carrier prevalence of CYP2C9 and
CYP2D6 gene variants in the psychiatric population could be attributed to either or both
effects. Additionally, strong evidence for such
a referral bias can be found in the data represented by FIGURE 2 , which illustrates the notable
difference between the percentage of patients
with non-wild-type genotypes when considering multiple genes at once. Thus, we note that
patients who have been referred to a tertiary
psychiatric hospital may be experiencing a high
degree of adverse side effects or drug resistance
in part due to a higher prevalence of polymorphisms across three CYP2 genes known
to play an important role in the metabolism
of psychotropic drugs.
The present study has various limitations.
There was no difference in CYP2C19 allele
frequencies in this study between the psychiatric and control populations. CYP2C19 is less
polymorphic than the other two genes, and the
current study size did not provide enough statistical power to detect frequency differences.
Although both populations are predominantly
Caucasian, other patient demographics are
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CYP450 genotyping in psychiatric referrals
different between the psychiatric and control
populations. The age range for the psychiatric
patients is broader because many of the referred
patients were adolescents. Since DNA is inherited and does not change with aging, adults are
not expected to differ from children in the carrier prevalence of certain target SNPs. It is well
known that referral psychiatric populations are
disproportionately female. Reflecting clinical
practice, this study does not attempt to restrict
drug prescriptions or patient selection, and benefits from a naturalistic setting but at the expense
of controlled conditions. Finally, the gamut of
alleles for the CYP450 genes continues to expand
with discovery efforts in various populations
[14,30,31] . Nevertheless, we believe this study documents the prevalence of the most commonly
observed ultra-rapid, deficient and null alleles
for CYP2C9, CYP2C19 and CYP2D6, which
are of immediate clinical relevance. We are also
pursuing targeted recruitment of populations
under-represented in this clinical survey, such
as the Hispanic population.
Recently the Evaluation of Genomic
Applications in Practice and Prevention
(EGAPP) Working Group assessed the use of
CYP2C19 and CYP2D6 genotyping in adult
patients beginning selective serotonin reuptake
inhibitor for nonpsychotic depression [32] . This
CYP2C9 • CYP2C19 • CYP2D6
Control
*36%
*64%
Psych
*43%
*57%
Non-wild-type alleles found in:
0–1 genes
2–3 genes
Figure 2. Combinatorial CYP2C9, CYP2C19
and CYP2D6 deficiencies in control versus
psychiatric populations.
*
p < 0.0001.
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Group concluded that evidence was insufficient
to support a recommendation for or against use
of CYP450 genotyping in patients beginning
selective serotonin reuptake inhibitor treatment.
Notably, EGAPP did not consider CYP2C9 variability, and explicitly excluded from its purview
treatment refractory or hospitalized patients. By
contrast, our study included combinatorial genotyping of CYP2C9, CYP2C19 and CYP2D6, and
applied it to patients referred to a tertiary psychiatry hospital because of repeated poor response
and/or side effects to antidepressant therapy.
Comprehensive, combinatorial genotyping and
targeted applications to populations with the
greatest medical need stand in sharp contrast to
limited genotyping for broad population screening. In assessing the value of genotype-guided
healthcare in psychiatry, it is apparent that the
former scenario may be the most relevant.
We believe the defi nition of a novel drugsensitivity syndrome is warranted in carriers of multiple null and defi cient alleles of
CYP450 genes. We had already presented one
patient in this series as a detailed case study [8] .
Independently segregating alleles have the
property of sporadic, nonfamilial, concurrence
in an individual depending on chance. Such
individuals are multiply deficient in CYP450
metabolic routes, which places them at risk for
adverse reactions with several psychotropics.
That 57% of referred psychiatric patients may
be severely compromised in drug-metabolism
capacity ascertained for two or three genes
among CYP2C9, CYP2C19 and CYP2D6
should serve as a public health imperative for
the wide use of DNA typing as an adjunct of
psychopharmacology. As the field of personalized healthcare advances to clinical practice,
we foresee DNA-guided medicine being used
to prevent ADRs, particularly in high-risk
populations referred to tertiary hospitals.
We conclude that CYP2C9, CYP2C19 and
CYP2D6 combinatorial genotyping could
be useful for patients with histories of drug
resistance and intolerance reactions to multiple psychotropics. As the field of pharmacogenetics advances, significant system and
health economic value may materialize [33] .
Genotype-guided prescription of psychotropics
may prevent drug-induced morbidity in many
psychiatric care settings, including treatment
resistant and drug intolerant patients, as well as
children and adolescents. Physicians and other
healthcare providers should have an understanding of the relevance of drug-metabolism genetic
polymorphisms in psychiatric practice.
www.futuremedicine.com
585
PERSONALIZED MEDICINE IN ACTION
Ruaño, Villagra, Rahim et al.
Financial & competing interests disclosure
Ruaño, Windemuth, Kocherla and Villagra are full-time
employees of Genomas, Inc. Bower is a consultant to the company. Goethe, Szarek, and Rahim have no disclosures. Funds
for this study were provided by Hartford Hospital grant
#122959 and by Genomas internal research funds. The
authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of
this manuscript.
Executive summary
CYP2C9, CYP2C19 and CYP2D6 genes play a role in the metabolism of numerous psychoactive substances. Common variants in these
genes can result in deficient metabolic capacity for many psychotropic drugs and altered endogenous pathways.
From the Institute of Living, a tertiary psychiatric hospital in Hartford, CT, USA, 73 outpatients were genotyped for common variants in
the CYP2C9, CYP2C19 and CYP2D6 genes. The results were compared with 120 control (nonpsychiatric) cardiology patients from the
same medical center genotyped for the same polymorphisms.
Individuals in psychiatric versus control groups were carriers of two wild-type alleles for CYP2C9, CYP2C19 and CYP2D6 genes, as
follows: 50 versus 74%, 71 versus 73%, and 36 versus 43%, respectively.
Combinatorial genotype analysis revealed that 57% of individuals in the psychiatric population were carriers of multiple polymorphisms
on two or three genes compared with 36% of individuals in the control population.
CYP450 genotyping would allow for DNA-guided treatment in tertiary psychiatric centers and could be particularly useful for patients
with treatment resistance and drug intolerance to multiple psychotropics.
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