ADHD

PHARMACOGENETICS

Mara H. Hutz

ATTENTION DEFICIT HYPERACTIVITY

DISORDER

• Attention-deficit/hyperactivity disorder (ADHD) is

a common, complex and highly heritable disorder,

•ADHD is one of the most common childhood

behavioral disorders , affecting around 5% of

school-aged children worldwide

• Main Symptoms :

inattention

hyperactivity

Impulsivity

•CLINICAL DIAGNOSIS.

• DSM-IV

INATTENTION (9 symptoms)HYPERACTIVITY

IMPULSIVITY

(9 symptoms)

•THREE CLINICAL ADHD SUBTYPES

•primarily inattentive,

•primarily hyperactive/impulsive

• combined

ADHD IS CARACHTERIZED BY :

six or more symptoms in at least one group

Symptom permanence for at least six

months

symptoms occur in more than one

environment

age at onset before 7 years

high prevalence of comorbities .

Persistence to adulthood occurs in 60% of

cases.

FUNCTIONAL DEFICIT

ADHD NEUROBIOLOGY

Cathecolamines

(Dopamine e noradrenaline)

(Solanto, 1998; Biederman, 2005)

METHYLPHENIDATE

inhibits dopamine reuptake

(Solanto, 1998; Berridge et al., 2006)

ADHD

Response to Stimulants

About 70% of patients

respond to methylphenidate,

70% respond to amfetamine

and overall 95% respond to

one or the otherBut around 20 – 25% wont

tolerate a stimulant due to

adverse effects

In Brazil only MPH is used.

Taylor (1987)

Methylphenidate responders were:

• Younger• Had greater pretreatment attentional impairment and hyperactivity• Had lower IQ scores•After controlling for age and IQ, only hyperactivity ratings showed a positive relationship to magnitude of drug-related improvement

Buitellar (1995)

Methylphenidate responders were:

• Younger• Less severely impaired• Less anxious at home • Had higher intelligence test scores • When clinical response was defined less stringently (e.g., cross-setting improvement without normalization), these predictors failed to generalize.

Coghill (2007)

Methylphenidate responders had:

• Greater pretreatment hyperactivity•Higher verbal IQ•Poor performance on a non-executive memory task•Better neuropsychological response on go/no go task•Clinical response was not predicted either by baseline performance on a wide range of executive functioning tasks or by neuropsychological response on tasks

Are there reliable predictors of response to

medication?

•VERY mixed

results

Current Pharmacogenomic studies

with MPH

Kieling et al.

Pharmacogenomics 11:407–

419, 2010

MPH

PHARMACOGENOMICS

IN BRAZILIAN YOUTHS

The Porto Alegre Study

Methods

• Evaluation and Diagnosis:

• Child and Adolescent

Psychiatric Division,

Hospital de Clinicas de

Porto Alegre, Federal

University of Rio Grande

do Sul, Brazil

The diagnosis of mental

disorders for each child or

adolescent was confirmed

through a three – stage process:

semi–structured interview (K-SADS-

E) modified to assess DSM-IV

criteria

discussion of each diagnoses in a

clinical committee;

clinical interviews with the child /

adolescent and the parents conducted

by a child psychiatrist

Inclusion criteria:

1. ADHD diagnosis according

to DSM-IV;

2. Age between 4 and 17 years;

3. drug-naïve for MPH

4. prescribed MPH doses of at

least 0.3 mg/Kg/day .

Symptom Evaluation:

Swanson, Nolan e Pelham Scale

version IV (SNAP-IV)

Before treatment - baseline;

One and three months after

treatment

251 PATIENTS

Methods

Zeni e cols, 2007- American J. Med

Genet B

Pharmacogenetics Analyses with dopaminergic

and serotonergic genes

RESULTS

The action of MPH on the noradrenergic system has

received much less attention.

It was demonstrated that the activation of this system

modulating attentional processes improves PFC function

in humans and animals.

MPH blocks norepinephrine (NE) transporters and low,

oral doses of this medication have more effect on NE than

on DA in subcortical areas.

Adrenergic 2A receptor is a key component of the

noradrenergic system with a putative role on MPH action

demonstrated in studies with animal models.

NORADRENERGIC SYSTEM

Copyright restrictions may apply.

Polanczyk, G. et al. Arch Gen Psychiatry 2007;64:218-224.

ADRA2A –1291 C>G

Demographic and Clinical Characteristics of the Sample According to the Presence of the G Allele*

Copyright restrictions may apply.

Polanczyk, G. et al. Arch Gen Psychiatry 2007;64:218-224.

Mean Swanson, Nolan, and Pelham Scale version IV (SNAP-IV) inattentive scores during methylphenidate hydrochloride treatment according to the presence of the G allele in a mixed-

effects model (n = 106)

Mixed Effect Model:

a) treatment over

time: d.f.=2;

F=79.37; P<0.001;

b) presence of G

allele: d.f.=1;

F=0.67; P=0.41;

c) treatment over

time *presence of

G allele: d.f.=2;

F=4.30; P=0.015.

Copyright restrictions may apply.

Polanczyk, G. et al. Arch Gen Psychiatry 2007;64:218-224.

Effect of the presence of the G allele on mean reductions in Swanson, Nolan, and Pelham Scale version IV (SNAP-IV) inattentive scores from baseline in a mixed-effects model (n = 106)

From baseline to the first and third months of treatment, individuals with the G allele achieved greater reduction of inattentive scores than individuals

without this allele.

Presence of the G allele: F1,101.9=6.6; P = .01.

We have demonstrated the positive effect of the

presence of G allele at the ADRA2A –1291 C>G

polymorphism in promoting a greater reduction of

inattentive symptoms during MPH treatment.

Findings from neurobiological and

pharmacological studies documented the

importance of the noradrenergic system for

methylphenidate’s action.

Corroborating this hypothesis, we were able to

demonstrate the role of a polymorphism at

ADRA2A in the reduction of inattentive scores

associated with MPH use in subjects with ADHD.

ADRA2A –1291 C>G

da Silva et al. 2008 [J. Neural. Transm. 115: 341–345]

assessed a sample comprising of 59 individuals

with ADHD inattentive subtype identified in a

nonreferred sample of children treated with

MPH.

They also investigated the association

between the ADRA2A -1291C>G polymorphism

and the inattentive scores of the SNAP-IV scale

at baseline and after 3 months of treatment.

The presence of the G-allele was associated

with significantly lower inattentive scores after

treatment with MPH

NORADRENERGIC SYSTEM

Monoamine oxidase A (MAOA) is one of the main

enzymes responsible for the metabolism of

catecholamines and is a possible target of MPH.

The functionality of the enzyme is related to a VNTR at

the promoter region of the gene, which presents two

common alleles (3- and 4-repeat). The 3-repeat allele is

related to low enzymatic function, while the 4-repeat

allele is related to a high enzymatic activity.

Given that MPH improves not only the cardinal

symptoms of ADHD but also symptoms such as

aggressiveness found in oppositional defiant disorder

we evaluated the effect of MAOA on MPH response

MAOA

Demographic and clinical characteristics of the sample according to the

presence of MAOA uVNTR alleles

MAOA uVNTR

Guimarães et al. International J. Neuropsychopharmacology 12:709-714, 2009

Mean Swanson, Nolan and Pelham scale – version IV

(SNAP-IV) oppositional scores during methylphenidate

treatment according to the presence of uVNTR MAOA

high-activity alleles

Mixed Effect Model: a)

treatment over time:

d.f.=2; F=22.94; P<0.001;

b) presence of high

activity alleles: d.f.=1;

F=0.33; P=0.57;

c) treatment over time

*presence of high activity

alleles: d.f.=2; F=4.83;

P=0.009.

Guimarães e cols, 2009 Intern J.

Neuropsychopharmacol.

In this investigation, we documented for the first time

that a higher improvement on oppositional symptoms

with MPH treatment was associated with MAOA-uVNTR

high activity genotypes

The biological mechanisms to explain our results is

yet to be determined, even considering the emergent

literature documenting the association between the

uVNTR at MAOA genotype and impulsivity and

aggression the role of this polymorphism in ADHD is

controversial, since findings have suggested an

association between ADHD and either the low and high

transcriptional alleles

MAOA

The Catechol-O-methyltransferase (COMT) enzyme

plays a key role in prefrontal cortical functioning

accounting for most of the degradation of dopamine in

the prefrontal cortex (PFC).

Val158Met (rs4680). This polymorphism is a functional

genetic variant determined by a valine-to-methionine

COMT membrane-bound form, which is primarily

expressed in the brain. The Methionine (Met) allele

results in a 3-4-fold reduction in enzyme activity.

objective of this study was to evaluate the association

between the COMT Val158Met and clinical improvement

of oppositional symptoms with MPH treatment in boys

with ADHD.

COMT

Resultados

Age 9.03 ± 2.93 9.88 ± 2.90 0.13

IQ 95.29 ± 16.38 94.09 ± 13.28 0.69

Inattentive 2 5.71% 11 14.48%

Hyperactive 6 17.14% 6 7.89%

Combined 25 71.43% 55 71.05%

Subthreshold 2 5.71% 5 6.58%

CD 9 25.7% 18 23.4% 0.81

ODD 20 57.1% 38 49.4% 0.54

Mood disorder 5 14.3% 12 15.6% >0.99

Anxiety disorder 10 28.6% 22 28.6% >0.99

Total 1.93 ± 0.46 1.87 ± 0.45 0.55

Inattentive 2.02 ± 0.60 1.98 ± 0.56 0.70

Hyperactivity/Impulsivity 1.98 ± 0.61 1.90 ± 0.62 0.54

Oppositional 1.75 ± 0.55 1.71 ± 0.57 0.69

0.54 ± 0.19 0.49 ± 0.14 0.18

3 8.6% 6 7.8% >0.99

2 5.7% 10 13.2% 0.33

ADHD subtype

Comorbid condictions

Demographic and clinical characteristics

Val homozygous Met carriers

P value(n = 35) (n = 77)

SNAP-IV baseline scores

Methylphenidate dose prescribed at baseline (mg/kg.d)

Concomitant prescription of another medication

Previous use of medication

Abbreviations: ADHD, Attention deficit hyperactivity disorder; CD, conduct disorder; ODD, oppositional defiant disorder; SNAP-IV, Swanson, Nolan and

Pelham Scale – version IV; Val, valine; Met, methionine.aData are given as number (percentage) or mean (± standard deviations).bCalculated by t test (quantitative variables with normal distribution), Mann-Whitney U test (quantitative variables without normal distribution), and 2 test

or Fisher exact test (categorical variables).

Table 1: Demographic and clinical characteristics of the sample according to the presence of COMT VAL158MET polymorphism

generalized

estimating

equations (GEE)

model :

a) treatment over

time: P<0.001;

b) presence Met

allele: P=0.027

c) treatment over

time *presence of

Met allele: P=0.01

Mean Swanson, Nolan and Pelham scale – version IV (SNAP-

IV) oppositional scores during methylphenidate treatment

according to the presence of COMT Val158Met polymorphism

From baseline to the first and third months of treatment, individuals with the Met allele achieved greater reduction of oppositional scores than individuals

without this allele.

Presence of the Met allele: p = 0.018

Effect of the presence of the Met allele on mean reductions in Swanson, Nolan,

and Pelham Scale version IV (SNAP-IV) oppositional scores from baseline in a

GEE model

This investigation suggested that ADHD

boys with at least one Met allele have a higher

improvement on oppositional symptoms than

Val homozygotes when they are treated with

MPH. We are unaware of any previous

studies investigating the effect of COMT gene

specifically in oppositional symptoms in

response to methylphenidate treatment.

COMT

There is an impressive heterogeneity between the

methodological strategies employed by different

studies.

The differences encompass the design of the study,

the definition of “response to treatment”, the dosing

scheme, the duration of treatment, evaluation or not of

compliance identification and control for relevant

confounding factors.

These differences constitute a significant barrier to

interpret convergent findings as replications and non-

convergent findings as failure to replicate.

HOW THE RESULTS PRESENTED

COULD BE COMPARED TO OTHER

STUDIES?

ADHD PROGRAM

Prof. Luiz A Rohde

Guilherme Polanczyk

Cristian Zeni

Ana Paula M. Guimarães

Angelica Salatino-Oliveira

Julia P. Genro

SPONSORS: CNPq, FINEP