Download Is genetics useful for MD treatment?

The role of genetics in diagnosis and
treatment of mood disorders
Alessandro Serretti, MD, PhD
Institute of Psychiatry
University of Bologna
Italy
Genetics of mood disorders
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
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Is genetics important for MD?
Is genetics useful for MD diagnosys?
Is genetics important for MD treatment?
Is genetics useful for MD treatment?
Genetics of mood disorders




Is genetics important for MD?
Is genetics useful for MD diagnosys?
Is genetics important for MD treatment?
Is genetics useful for MD treatment?
Morbid Risk in Bipolar Disorder
%
70
62
60
50
40
30
20
8
10
8
2
1
0
MZ
DZ
First degree
Second degree
General Population
Morbid Risk in Major Depressive
Disorder
%
45
40
35
30
25
20
15
10
5
0
40
11
9
5
MZ
DZ
First degree
General Population
Genetics of mood disorders




Is genetics important for MD? Yes
Is genetics useful for MD diagnosys?
Is genetics important for MD treatment?
Is genetics useful for MD treatment?
Genetics of mood disorders




Is genetics important for MD? Yes
Is genetics useful for MD diagnosys?
Is genetics important for MD treatment?
Is genetics useful for MD treatment?
%
70
62
60
50
40
30
20
8
10
8
2
1
0
MZ
DZ
First degree
Second degree
?
General Population
?
Genetics of mood disorders




Is genetics important for MD? Yes
Is genetics useful for MD diagnosys?
Not as we may think! Plasticity
Is genetics important for MD treatment?
Is genetics useful for MD treatment?
Genetics of mood disorders




Is genetics important for MD? Yes
Is genetics useful for MD diagnosys?
Not as we may think! Plasticity
Is genetics important for MD
treatment?
Is genetics useful for MD treatment?
TODAY….
trials and errors
diagnosis
effective treatment
TODAY….
trials and errors
diagnosis
TOMORROW….
tailor made
effective treatment
Genetic Variation
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Unrelated individuals are (only) 99%
genetically similar.
There is about a 7 million bp difference
between any two non-related individuals.
 Plus CNVs, epigenetics, expression controls…

This explains interindividual variability
 Hair color, weight and …. disease liability, drug
response.
Pharmacogenetic studies
(Medline 1992-2008)
1200
1000
800
600
400
200
19
92
19
94
19
96
19
98
20
00
20
02
20
04
20
06
0
Number of studies
VARIATIONS IN DRUG RESPONSE
GENE
DRUG
EFFECT
ß2-ADREN.
ALBUTEROL
Asthma response
CETP
PRAVASTATIN
Atherosclerosis resp.
D2, D3, 5HT2
ANTIPSYCHOTICS
Response-Side eff.
APOE4
TACRINE
Alzheimer resp.
RYANODINE
HALOTHANE
Malignant hyperthermia
PROTHROMBIN
CONTRACEPTIVES
Thrombosis
NET
ATOMOXETINE
Response (Ramoz 2009)
Her2/neu
TRASTUZUMAB
Efficacy/Tolerance
GENETIC
POLYMORPHISMS
Pharmacokinetic
•Transporters
•Plasma protein binding
•Metabolism
Pharmacodynamic
•Receptors
•Ion channels
•Enzymes
•Immune molecules
Genes investigated in the short term
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







HTTLPR
SERT-STin2
5HT1A C-1019G
5-HT1B
5HT2A T102C
5HT2A G1438A
5HT2C
5HT6 C267T
TPH A218C TPH2
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

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
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


NET T-182C
NET G1287A



COMT
MAOA
DRD2 S311C
DRD4 VNTR
ACE I/D polymorphism
G-protein beta3 C825T
ADRB1 G1165C
CRHR1
NOS C276T
IL-1beta C511T
DTNBP1
FKBP5
CLOCK







MDNF
DTNBP1
nNOS
IL-1beta
APOE
MDR1P-gp
A-161T
REGULATORY VARIANT OF 5-HT TRANSPORTER
A functional polymorphism in the transcriptional control region upstream of the
5-HTT coding sequence (5-HTTLPR) has been reported (Heils et al., 1996).
H
A
M
DD
E
C
R
E
A
S
ED
U
R
IN
GFLU
V
O
X
A
M
IN
ETR
E
A
TM
E
N
T
5-H
TTLP
Rvariantsinpsychoticandnonpsychoticsubjects
35
30
25
P
<0.001
HAMDSCORE
20
15
10
5
0
0
1
2
3
4
5
6
H
TT
s/s
H
TT
l/s
H
TT
l/l
TIM
E
5-HTTLPR variants explained 7% of the variance of antidepressant efficacy
HTTLPR - Conclusions
• HTTLPR l variant associated with better outcome
and side effects in caucasians, conflicting in asians
(“flip-flop” Lin, 2007)
• Possibly through a complex and indirect effect
• Multiple effects both in normals and patients (Serretti, 2006)
• Further variants control its effects
HTTLPR - Conclusions
• HTTLPR l variant associated with better outcome in
caucasians
• Possibly through a complex and indirect effect
• Multiple effects both in normals and patients (Serretti,
2006)
• Further variants control its effects
HTTLPR - Conclusions
5-HTTLPR variations……
Broad influence of a single gene
on a range of aspects
Poor serotonin pathway plasticity
Stress reactivity
Anatomical change
Temperament
Response to antidepressants
Mood disorders
Harro J (2009): The brain prepared to become
anxious: predisposing neurobiology
in animals and humans. Eur. Neuropsychopharm.
19:S113.
HTTLPR - Conclusions
• HTTLPR l variant associated with better outcome in
caucasians
• Possibly through a complex and indirect effect
• Multiple effects both in normals and patients (Serretti et al.,
Curr Drug Targ, 2006)
• Further variants control its effects
Types of 16th repeat (*l)
1
2
3
4
5
6
7
8
9
10 11
12 13 14 15 16















 16-A







 16-D
tgcacccccagcatcccccc








tgcacccccggcatcccccc
16-F













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

tgcactcccagcatcccccc
Nakamura, 2000; Goldman, 2004
Studies with at least two independent
replications
FKBP5
(Binder et al., 2004)
(Tsai et al., 2007)
(van Rossum et al., 2006)
(Papiol et al., 2007)
(Lekman et al., 2008)
(Kirchheiner et al., 2008)
FKBP5
FKBP5
NR3Cl ER22/23EK
FKBP5 rs1360780
FKBP5 rs4713916
FKBP5 rs3800373
Assoc. with resp. in 2 indep. samples
No association
Associated with response
trend with response (p=0.09)
Assoc with remission
and rs1360780 associated with response
(venlafaxine and drug combination)
BDNF
Studies with at least two independent replications
Dysbindin
Studies with at least two independent replications
Dysbindin associated with SSRI antidepressant efficacy
Dysbindin associated with SSRI antidepressant efficacy
DTNBP1 haplotype analysis for rs2005976, rs760761 and rs2619522, on final
MADRS covariated for baseline scores (haplotypes frequency>1%) P=0.0073.
DYSBINDIN GENE (DTNBP1) IN mood disorders:
ASSOCIATION WITH CLINICAL RESPONSE TO
SSRIs
Arias, B; Serretti, A; Mandelli, L; Gastó, C; Catalán, R;
Di Ronchi, D; Fañanás, L.
Pharmacogenet Genomics, In Press
Two-way repeated measures ANOVA for rs760761
30
HDRS scores
25
CC
CT
TT
20
15
10
5
0
0
4
8
Weeks
12
Studies with at least two independent replications
P-glycoprotein - MDR1
MDR1
GRIK4
(Paddock, 2007)
GRIK4
rs1954787 assoc. with remiss. p=.001
(Gau, 2007)
p75 NTR
S250L assoc. with response p=.039
Genes investigated in the short term
of SSRI
HTTLPR Different target
 COMT

 SERT-STin2
 MAOA
Different Plasticity 
 5HT1A C-1019G
 DRD2 S311C

 5-HT1B
 DRD4 VNTR


 5HT2A T102C
Different
SSRI availability
inpolymorphism
the brain 

5HT2A G1438A
 ACE I/D
 5HT2C
 G-protein beta3 C825T 
Glutamate
modulation
 5HT6 C267T
 ADRB1 G1165C
 TPH1 A218C TPH2
 CRHR1
 NOS C276T
 NET T-182C
 IL-1beta C511T
 NET G1287A
 FKBP5
 CLOCK

MDNF
DTNBP1
nNOS
IL-1beta
APOE
MDR1P-gp
GRIK4
Some gene variants influence
antidepressant effects
But…
Is antidepressant a unitary
effect?
And…
Do genes influence only one
behavioral feature?
CLOCK 3111T/C
Broad influence of a single gene
on a range of aspects
Insomnia
Diurnal Preference
Response to antidepressants
Temperament
Mood fluctuations
Genetics of mood disorders




Is genetics important for MD? Yes
Is genetics useful for MD diagnosys?
Not as we may think! Plasticity
Is genetics important for MD
treatment? Yes
Is genetics useful for MD treatment?
Genetics of mood disorders




Is genetics important for MD? Yes
Is genetics useful for MD diagnosys?
Not as we may think! Plasticity
Is genetics important for MD treatment?
Yes
Is genetics useful for MD treatment?
Yes, but in a complex way
Some gene variants influence
antidepressant effects
and other features
Can we use them in everyday
clinical practice?
NO
NOT YET
Pharmacogenetics: problematic
issues…and possible solutions
•
•
•
Low variance explained by polymorphisms (HTTLPR=2.8%,
TPH=2.7%, Gß3=1.2%)  Other variables influence drug response:
Life events, social support, temperament, hormons…and should be
included in the model! Neural Network?
Epigenetic factors, CNV, Splicing, Regional expression, gene
interactions…should be controlled with multivariate or neural
network models.
Drug response may differ across episodes…longer follow up
Would be the puzzle the
actual image of reality?
Principal Collaborating Centers
Kansai Medical University, Japan
Athens University, Greece
Prof. Toshihiko Kinoshita
Masaki Kato MD
Prof. Yoannis Liappas
Antonis Politis MD
Petros Malitas MD
The Catholic University of Korea College of
Medicine, South Korea
Prof. Chi-Un Pae
University of Toronto, Canada
Prof. Jim Kennedy
Daniel Muller MD
Universitat de Barcelona, Spain
Ludwig-Maximilians-Universität München, Germany
Prof. Lourdes Fananas
Barbara Arias PhD
Univerza V Ljubljani - University Of
Ljubljana, Slovenia
Prof. Vita Dolzan
Prof. Dan Rujescu
Ina Giegling PsyD
Psychiatric Genetic Unit, Institute of
Psychiatry, University of Bologna,
Italy
Alberto Chiesa MD
Diana De Ronchi MD PhD
Alessandro Serretti MD PhD
Laura Mandelli PsyD
Martina Forlani
Antonio Drago MD
Raffaella Calati
PsyD, PhD
Sara Gibiino