Transcript 03-13-07-barney-miller-presentation-gr-2007

“CAN GENETIC VARIATION BE USED
TO PREDICT RESPONSE TO
PSYCHOTROPIC DRUGS?”
BARNEY E. MILLER, Ph.D.
Associate Professor and Director of Research,
Department of Psychiatry and Behavioral Sciences
Associate Professor, Department of Anatomy and Cell
Biology, ETSU
yes
But not as well as this fellow.
• Only product on the market (FDA approved 2006) in
the US in the field of pharmacogenetics: Roche’s
AmpliChip® CYP450 Test.
– Identifies patient metabolic phenotype based on their genetic
variability in two cytochrome P450 (CYP450) enzymes.
– Test rates patient as one of 4 classes in terms of speed of
drug metabolism. Used as a guide for dosing, including
psychotropic drugs.
– Uses PCR and Affymetrix high-density microarray
technology.
……more about this later.
Individuals have different
responses to treatment
• Obviously not every member of a species
responds in the same way to a given dose of
a drug.
• Some differences are subtle, eg. Person A
undergoes remarkable improvement while
Person B improves but less well than desired,
Person C - no improvement.
WHY?
Why do individuals have different
responses to treatment?
• Genetic differences
– Linkage has been made between “specific genetic variations
and treatment response” in a few drugs, eg.; P450 2D6 gene
(metabolizes many psychotropic drugs)
– This linkage provides some guidance to the clinician in drug
choice
• In the above case the drug choice is guided by the “type of
metabolizer” identified by polymorphisms in the 2D6 gene
• Environmental or circumstantial differences
SNP
• *SNP = pronounced “snip”, a single nucleotide polymorphism, a
single chemical group (nucleotide) difference in the DNA code of
a gene.
• Although all members of a biological species “share” the same
fundamental DNA there are many differences within the coding
regions for genes.
• Some of these differences involve significant variations in
phenotype; some involve smaller much less obvious changes.
• Some of these differences produce no detectable phenotypic
variation, some produce subtle variations (enzyme activity,
receptor binding) and some produce obvious differences (hair
color, height, etc.)
• The SNP’s that we’re interested in are those changes that lead
to subtle variations in phenotypic response to medicines.
Some examples:
If genetic variation via SNPs can be used
to guide the pharmacological treatment of
depression then….
• Where does one start looking?
• How might such small changes in a
gene be involved?
– Metabolically?
– Via “drug site of action proteins”?
– Via control processes; eg., transport and
activation systems associated with “site of
action proteins”?
Depression
• In 2001 there were 24.5 million visits (~8%
US pop.) to physicians for depression
treatment(1).
• 89% of these cases received medication
• The top 5 medications were: sertraline
(18%), paroxetine (16%), fluoxetine (14%),
citalopram (13%), and bupropion (9%)
• The lifetime prevalence for depression in the
US is estimated at ~16%(2)
(1) Stafford RS et al. Primary Care Companion J Clin Psychiatry 2001; 3(6) p232235
(2) Nestler EJ et al. Neuron 2002,34 p13-25.
Treatment
• Most physician administered cases of
depression are treated with
antidepressant drugs of the following
two categories:
– SSRI; eg., Prozac, Zoloft, Celexa, Paxil
– Non-SSRI (SNRI, SDRI); eg., Wellbutrin,
Effexor, or Duloxetine
Standard of care*:
• A patient is started at a low to mid-range
dosage usually with an SSRI
– Clinical improvement is usually expected at 2-3
weeks
– If no clinical improvement in 4-6 weeks:
•
•
•
•
Dosage may be increased
Drug may be switched
Another drug added
Non-medical augmentation
– The time to clinical improvement (discovery of an
efficacious drug/combination) varies from 1-12
months.
*Mann, JJ. NEJM 2005; 353:1819-1834.
Current Pathway to Finding the Right Drug
Therapy for the Patient
1st
Medication
Adjustment /
Change
4th
Medication
Adjustment /
Change
2nd
Medication
Adjustment /
Change
Initial
Patient
Visit w/ Dr.
3rd
Medication
Adjustment /
Change
Copyright 2006, The Fallon Group, LLC
I think the doctor
has finally found
the right
medication at the
right dose for me.
Primary Challenges for the Physician are…
1) Which therapeutic class will the patient best respond to?
2) Which drug within the class?
So which patient gets which class?
?
?
?
?
SSRI’s
SNRI’s
Other
?
Paxil®
Zoloft®
Prozac®
Luvox®
Copyright 2006, The Fallon Group, LLC
Effexor®
Cymbalta®
Wellbutrin®
Individual Response to Treatment
• 30 – 50% of patients have substantial residual
symptoms after adequate first-line treatment *.
• The choice of starting drug is largely based on the
experience of the clinician with little rational basis.
• All antidepressants do work – they reduce or
eliminate the symptoms of depression in some, but
not all people.
• No genetic differences are currently used to guide
drug choice.
*Mann, JJ. NEJM 2005; 353:1819-1834.
Pharmacogenetics of
Antidepressant Drug Response
• Variation in clinical response is a critical problem in
the management of depression*.
• Polymorphisms in genes encoding neurotransmitter
receptors, particularly serotonin, are prime targets for
pharmacogenetic research.
• STAR*D, a large multi-center study, is currently
evaluating some 768 SNPs associated with 68
genes**.
*Malhotra
AK et al. Am J Psychiatry 2004; 161: 780-796.
**McMahon
FJ et al. Am J Human Genetics 2006; 78:804-814.
The C(-1019)G SNP
• In the promoter region of the serotonin
receptor 1A a polymorphism occurs as a C
(cytosine) to G (guanine) difference. Thus
someone will be CC, CG or GG at this site.
• The GG occurs in 28% of the depressed
group and 11% in the controls(1)
• Thus in the US of the 24.5 million depression
cases/year (2001) 6.8 million might be
expected to be the GG type.
(1) Lemonde S, et al. J Neuroscience, 2003, 23(25) p. 8788-8799.
Serotonin 2A SNP
• In addition to the C(-1029)G
polymorphism in the 1A receptor, we
also sequenced a SNP in the 2A
receptor T(102)C reported to be
associated with SSRI intolerance *.
*Murphy GM, et al. Am J Psychiatry 2003; 160:1830-1835.
How’s it work?
• The serotonin 1A receptor is a sort of flow
control receptor. It is found on the dendritic
field of a neuron (near the cell body) and it
causes the neuron to slow its firing rate when
it is activated by the presence of serotonin. It
is a negative feedback control on the neuron.
• The GG people produce more of this receptor
because of reduced binding for a repressor
factor at the 1A’s gene promoter region.
Too much 1A receptor?
• If a person makes too much 1A receptor their
serotonergic neurons are rendered less
active, excitable or capable of normal
responsiveness in the presence of serotonin.
• This condition directly opposes the action of
SSRI drugs which work to keep more
serotonin available to neurons.
Our finding
•
•
•
•
In an on-going observational study of depressed patients, we have
correlated genotype at the C(-1019)G with patient history and
measures of depression. Blood was obtained by finger prick and cycle
sequenced in both directions using primers designed for this purpose.
Results: A disproportional number of individuals homozygous for G(1019) were found to be currently prescribed a drug that was not a
selective serotonin reuptake inhibitor (SSRI; p<0.025, n=48).
Preliminary data suggest that these individuals showed significantly
less improvement with drug therapy based on two independent
measures (p = 0.0008, PHQ9; p =0.02, CGI).
The improvement of only G/G patients tended to correlate with the
NAT/SERT selectivity of the drug (p = 0.075, n =14) and with the
DAT/SERT selectivity of the drug (p=0.08, n=14).
SERT=serotonin transporter, NAT=norepinephrine transporter, & DAT=dopamine transporter
Genotype Influences Drug Class Prescribed
30
SSRI
Number of Patients
Non-SSRI
20
p = 0.02
10
0
G/G
Non-G/G
Genotype
Genotype Predicts Self-Rated Improvement
20
Improvement on PHQ9
p = 0.0008
15
10
5
0
G/G
Non-G/G
Genotype
Genotype Predicts Clinician-Rated Improvement
4
Improvement on CGI
p = 0.02
3
2
1
0
G/G
Non-G/G
Genotype
Correlation to Drug Potency
• Drug potency (expressed as inhibition
constants in nmoles) ratios were
calculated for each GG subject’s current
medication
• Lower number = greater potency
Self-Rated Improvement by G/G Genotype
vs. NE/5-HT Selectivity of Drug
25
p = 0.0751
Improvement on PHQ9
20
15
10
5
y = -2.727x + 17.743
0
0
1
2
3
Log Selectivity NE/5-HT
Selectivity = (ki NAT / ki SERT)
4
Self-Rated Improvement by G/G Genotype
vs. DA/5-HT Selectivity of Drug
25
p = 0.0832
Improvement on PHQ9
20
15
10
5
y = -1.732x + 14.687
0
-2
-1
0
1
2
3
4
5
Log Selectivity DA/5-HT
Selectivity = (ki DAT / ki SERT)
Self-Rated Improvement by Non G/G Genotype
vs. NE/5-HT Selectivity of Drug
30
Improvement PHQ9
25
20
15
10
p = 0.67
5
y = -0.827x + 18.761
0
0
1
2
3
Log NE/5-HT Selectivity
Selectivity = (ki NAT / ki SERT)
4
Our Findings on the
Serotonin 2A Receptor SNP
• A previous study compared intolerance to paroxetine (an SSRI)
compared to a non-SSRI as a function of genetic markers.
Paroxetine side effect severity was associated with the C/C
genotype of the 2A T(102)C SNP *.
– Since only one SSRI was included, the specificity of this
association with paroxetine could not be addressed.
• Our data suggest that the drug intolerance of the C/C genotype
is selective for paroxetine.
• Due to limited number of subjects this finding needs additional
study.
*Murphy GM, et al. Am J Psychiatry 2003; 160:1830-1835.
Failure Rate on Paroxetine May Be Influenced by
5-HT 2A Receptor Genotype
Failure Rate in Percent
100
75
p = 0.14
50
25
0
C/C
Non-C/C
Genotype
Failure rate = stopped drug due to side effects, based on Subject history
Overall Failure Rate on SSRIs Does Not Differ by
5-HT 2A Receptor Genotype
Failure Rate in Percent
100
75
50
25
0
C/C
Non-C/C
Genotype
Utility
•
Determination of a patient’s genotype at this serotonin receptor loci
may allow the prescribing physician to make a rational decision with
respect to initial antidepressant drug choice.
– These patients are relatively resistant to current pharmacotherapy
especially to the SSRI class
– Should be treated more aggressively and with NE or DA class
antidepressants (eg., Buproprion, Venlafaxine, Duloxetine)
•
Most of the GG patients in our study have been on more than 3 SSRI’s
(at various doses and combinations) prior to starting Non-SSRI type
drugs. This means that their medications were being adjusted for up to
a year.
Need for more subjects
• We need to recruit at least 30 more
subjects for this study.
• Anyone who has a primary diagnosis of
depression and is taking any standard
antidepressant qualifies.
• Contact Chris Newell (439-2126)or
myself (439-2121) for more information.