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UNIVERSIDADE FEDERAL DO RIO GRANDE DO SUL
FACULDADE DE MEDICINA
PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS MÉDICAS:
PSIQUIATRIA
TESE DE DOUTORADO
ESTUDO DA PREVALÊNCIA DO TRANSTORNO DE DÉFICIT DE
ATENÇÃO/HIPERATIVIDADE NA INFÂNCIA, ADOLESCÊNCIA E IDADE
ADULTA.
GUILHERME VANONI POLANCZYK
ORIENTADOR: PROF. DR. LUIS AUGUSTO PAIM ROHDE
MARÇO DE 2008.
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UNIVERSIDADE FEDERAL DO RIO GRANDE DO SUL
FACULDADE DE MEDICINA
PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS MÉDICAS:
PSIQUIATRIA
TESE DE DOUTORADO
ESTUDO DA PREVALÊNCIA DO TRANSTORNO DE DÉFICIT DE
ATENÇÃO/HIPERATIVIDADE NA INFÂNCIA, ADOLESCÊNCIA E IDADE
ADULTA.
Guilherme Vanoni Polanczyk
Orientador: Prof. Dr. Luis Augusto Paim Rohde
Tese apresentada ao Programa de Pós-
Graduação em Ciências Médicas: Psiquiatria,
Faculdade de Medicina, Universidade Federal
do Rio Grande do Sul, como requisito parcial
para a obtenção do grau de Doutor.
Porto Alegre, março de 2008.
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Catalogação-na-Publicação
P762 Polanczyk, Guilherme Vanoni
Estudo da prevalência do transtorno de déficit de
atenção/hiperatividade na infância, adolescência e idade adulta. —
2008.
159 f.
Tese (doutorado) — Programa de Pós-Graduação em Ciências Médicas:
Psiquiatria. Faculdade de Medicina. Universidade Federal do Rio
Grande do Sul, Porto Alegre, 2008.
Orientador: Prof. Dr. Luis Augusto Paim Rohde.
1. Transtorno da falta de atenção com hiperatividade 2.
Criança 3. Adolescente 4. Adulto I. Rohde, Luis Augusto Paim II.
Título
NLM WS 350.8.A8
(Bibliotecária responsável: Lenise Di Domenico Colpo – CRB-10/1757)
“Dias inteiros de calmaria, noites de ardentia, dedos no leme
e olhos no horizonte, descobri a alegria de transformar
distâncias em tempo. Um tempo em que aprendi a entender
as coisas do mar, a conversar com as grandes ondas e não
discutir com o mau tempo. A transformar o medo em respeito,
o respeito em confiança. Descobri como é bom chegar
quando se tem paciência. E para se chegar, onde quer que
seja, aprendi que não é preciso dominar a força, mas a razão.
É preciso, antes de mais nada, querer.”
Amyr Klink, Cem dias entre céu e mar.
À Mariana,
pela paciência e incentivo,
por compartilhar os sonhos e,
acima de tudo, pelo amor.
Agradecimentos
À Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, pelo incentivo a este
projeto através da bolsa de estudos.
Aos professores da Faculdade de Medicina da UFRGS, especialmente do
Departamento e do Programa de Pós-Graduação em Psiquiatria, que tanto contribuíram
para a minha formação profissional.
Aos colegas do Programa de Déficit de Atenção/Hiperatividade, pelo convívio e
aprendizado.
Aos colegas Maurício Silva de Lima, Bernardo Horta, Ronaldo Laranjeira e Eduardo
Chachamovich, que contribuíram de forma valiosa para a realização dos estudos que
fazem parte desta tese.
Ao Professor Luis Augusto Rohde, pelo exemplo de seriedade, dedicação e
competência, pela disponibilidade e pelo grande estímulo à minha formação e carreira.
Aos meus amigos e ao meu irmão, por suas companhias e pelo incentivo fundamental.
Aos meus pais, pela família que construíram, por estimular e apoiar o meu crescimento.
SUMÁRIO
LISTA DE ABREVIATURAS..............................................................................................8
LISTA DE FIGURAS..........................................................................................................9
LISTA DE TABELAS........................................................................................................10
RESUMO.........................................................................................................................11
ABSTRACT......................................................................................................................13
1 INTRODUÇÃO..............................................................................................................15
2 BASE CONCEITUAL....................................................................................................16
2.1 Os transtornos mentais e a saúde da população...................................................16
2.2 O Transtorno de Déficit de Atenção/Hiperatividade...............................................18
2.3 A prevalência do Transtorno de Déficit de Atenção/Hiperatividade na infância e
adolescência...........................................................................................................19
2.4 Aspectos metodológicos dos estudos de prevalência do Transtorno de Déficit de
Atenção/Hiperatividade na infância e adolescência..............................................27
2.5 A prevalência do Transtorno de Déficit de Atenção/Hiperatividade na idade
adulta......................................................................................................................31
3 REFERÊNCIAS BIBLIOGRÁFICAS.............................................................................36
4 OBJETIVOS..................................................................................................................47
5 JUSTIFICATIVA............................................................................................................48
6 CONSIDERAÇÕES ÉTICAS........................................................................................49
7 ARTIGOS.............................................……...............................…………....................50
7.1 Artigo 1.................................................................................…...………………......50
The worldwide prevalence of attention-deficit/hyperactivity disorder: A systematic
review and metaregression analyses.
Polanczyk G, Lima MS, Horta B, Biederman J, Rohde LA.
American Journal of Psychiatry 2007; 164: 942-948.
7.2 Artigo 2....................................................................…………………......................57
ADHD in a representative sample of the Brazilian population: estimated prevalence
and evaluation of the ASRS Screener according to Item Response Theory.
Polanczyk G, Laranjeira L, Caetano R, Zaleski M, Pinsky I, Rohde LA.
Manuscrito submetido – Journal of Psychiatric Research.
8 CONSIDERAÇÕES FINAIS..........................................................................................76
ANEXOS: Produção científica durante o período de Doutorado (03/2006 - 03/2008)
relacionada à Tese..........................................................................................................80
Anexo 1..........................................…………………………….……..................................80
Epidemiology of Attention-Deficit/Hyperactivity Disorder across the lifespan.
Polanczyk G, Rohde LA.
Current Opinion in Psychiatry 2007; 20:386-92.
Anexo 2...............................................…………………………………..............................87
Epidemiologic Considerations in Attention-Deficit/Hyperactivity Disorder: A Review and
Update.
Polanczyk G, Jensen P.
Child and Adolescent Psychiatric Clinics of North America, 2008; 17(2).
Anexo 3........................................……………..………………….....................................
103
Prevalence Rates of Attention-Deficit/Hyperactivity Disorder in a School Sample of
Venezuelan Children.
Montiel C, Pena JA, Montiel-Barbero I, Polanczyk G.
Child Psychiatry and Human Development 2007. doi10.1007/s10578-007-0090-5
Anexo 4......................................……………………………….........................................
115
ADHD treatment in Latin America and Caribbean.
Polanczyk G, Rohde LA, Szobot C, Schmitz M, Montiel C, Bauermeister J.
Journal of American Academy of Child and Adolescent Psychiatry, no prelo.
Anexo 5................................…………………………………...........................................118
Methodological insights on ADHD Pharmacogenetic Studies.
Polanczyk G, Faraone SV, Bau C, Victor M, Becker K, Pelz R, Buitelaar JK, Franke B,
Kooij S, van der Meulen E, Cheon K, Mick E, Purper-Ouakil D, Stein MA, Cook Jr. EH,
Rohde LA.
Manuscrito a ser submetido - American Journal of Medical Genetics Part B:
Neuropsychiatric Genetics.
Anexo 6......................................……………………………….........................................
133
Lista dos artigos completos revisados no estudo 1.
Anexo 7......................................……………………………….........................................
159
ASRS Screener, versão em português.
LISTA DE ABREVIATURAS
ADHD Attention-Deficit/Hyperactivity Disorder
ASRS Adult ADHD Self-Report Scale
CID Classificação Internacional das Doenças
DALY Disability-Adjusted Life-Years
DAT1 Gene para o Transportador de Dopamina
DF Degrees of Freedom
DIF Differential Item Functioning
DRD4 Gene para o Receptor D4 de Dopamina
DRD5 Gene para o Receptor D5 de Dopamina
DSM-III Diagnostic and Statistical Manual of Mental Disorders, Third
Edition
DSM-III-R Diagnostic and Statistical Manual of Mental Disorders, Third Edition,
Revised
DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
HD Hyperkinetic Disorder
IRB Institutional Review Board
IRT Item Response Theory
NCS-R National Comorbidity Survey Replication
OR Odds Ratio
PPS Probability Proportional to Size
PSI Person Separation Index
PSU Primary Sampling Unit
SD Standard Deviation
TDAH Transtorno de Déficit de Atenção/Hiperatividade
WHO World Health Organization
95% CI 95% Confidence Interval
LISTA DE FIGURAS
Artigo 1
Figure 1. Flow diagram of study selection………………………………….......……..
52
Figure 2. ADHD/HD pooled prevalence according to demographic
characteristics and geographic location…………………………………
….........................53
LISTA DE TABELAS
Base Conceitual
Tabela 1. Estudos de prevalência do TDAH em crianças e adolescentes publicados
entre Janeiro de 1997 a Junho de 2007.. ………………........……......…..21
Artigo 1
Table 1. Methodological characteristics and geographic location of the studies
(N=102)……………………………….......……………………………………51
Table 2. Association between methodological covariates and geographic area with
ADHD/HD prevalence estimates………..................................……………53
Artigo 2
Table 1. Proportion of respondents stratified by age range and scores strata on the
ASRS Screener, weighted to represent the Brazilian population…..…….72
Table 2. Prevalence of positives screeners for ADHD according to socio-
demographic characteristics (n=3007)………………………………………73
Table 3. Fit of the ASRS Screeners to the Rash model………………….………
….75
RESUMO
Introdução
O Transtorno de Déficit de Atenção/Hiperatividade (TDAH) é caracterizado por sintomas
de desatenção, hiperatividade e impulsividade, que têm início na infância e podem
persistir até a idade adulta. Um grande número de estudos investigou a prevalência do
TDAH entre crianças e adolescentes em diversos países, inclusive no Brasil. Os
estudos geraram dados conflitantes, permanecendo dúvidas quanto à influência de
características demográficas e metodológicas sobre a variabilidade das estimativas.
Entre adultos, há dados escassos sobre a prevalência do TDAH em todo o mundo e
inexistem estudos realizados em nosso meio. Este cenário é reforçado por incertezas
sobre a validade dos critérios diagnósticos e instrumentos de avaliação do TDAH nesta
etapa do desenvolvimento.
Objetivos
Buscamos estudar a prevalência do TDAH na infância, adolescência e idade adulta,
abordando as lacunas existentes na literatura.
Métodos
Realizamos uma revisão sistemática da literatura buscando estudos que tenham
avaliado a prevalência do TDAH na infância e adolescência em amostras comunitárias
nos últimos 25 anos. Agregando os estudos encontrados, avaliamos a influência de
características metodológicas e da localização geográfica onde foram conduzidos sobre
a heterogeneidade dos resultados através de uma análise de metaregressão. Entre
adultos, investigamos a prevalência de rastreamento positivo para o TDAH em uma
amostra representativa da população brasileira maior de 14 anos de idade. A seguir,
avaliamos a adequação do instrumento utilizado ao modelo de Rasch da Teoria de
Resposta ao Item.
Resultados
A revisão sistemática realizada localizou 9105 resumos, tendo sido incluídos 102
estudos originais. A prevalência agregada do TDAH entre crianças e adolescentes foi
estimada em 5.29%, estando associada a heterogeneidade significativa. As variáveis
significativamente associadas às taxas de prevalência foram: a) critério diagnóstico
utilizado; b) exigência de prejuízo funcional para o diagnóstico; c) fonte de informação.
A localização geográfica dos estudos esteve associada à heterogeneidade quando
comparadas as estimativas encontradas na África e Oriente Médio em relação àquelas
encontradas na América do Norte e Europa. Estimativas geradas na América do Norte,
Europa, América do Sul, Ásia e Oceania não diferiram entre si. A prevalência de
indivíduos com rastreamento positivo para TDAH na amostra de 3007 indivíduos
avaliados em todo o Brasil foi de 5.8%. A taxa de rastreamento positivo foi de 7.6% para
indivíduos entre 14 e 17 anos, 5.2% para indivíduos entre 18 e 44 anos e 6.1% para
indivíduos maiores de 44 anos. A análise de Rasch revelou a inadequação dos dados
referentes à amostra global às expectativas do modelo. Entretanto, os dados
relacionados apenas aos indivíduos entre 14 e 17 anos de idade se adequaram ao
modelo, o que não ocorreu com os dados dos indivíduos entre 18 e 44 anos e com mais
de 44 anos de idade.
Conclusões
A variabilidade significativa das estimativas de prevalência do TDAH em crianças e
adolescentes em todo o mundo é largamente influenciada pelas características
metodológicas dos estudos. O papel da localização geográfica parece ser limitato, não
havendo diferenças nas estimativas geradas na Europa e América do Norte. As
diferenças encontradas relacionam-se ao Oriente Médio e África, onde poucos estudos
foram realizados, em relação à Europa e América do Norte. Estudos futuros são
necessários para confirmar este achado. Os sintomas de TDAH são comuns na
população brasileira adulta. A falta de adequação dos dados ao modelo de Rasch, no
entanto, limita a possibilidade de realização de testes paramétricos com os resultados
gerados e alerta para a necessidade de que os instrumentos utilizados sejam avaliados
à luz de teorias psicométricas modernas. A diferença de adequação ao modelo de
Rasch entre dados de adolescentes e adultos sugere a necessidade de que seja
agregada uma perspectiva desenvolvimental aos futuros critérios diagnósticos para o
TDAH.
Palavras-chave: Transtorno de Déficit de Atenção/Hiperatividade, crianças,
adolescentes, adultos, prevalência, epidemiologia.
ABSTRACT
Introduction
Attention Deficit/Hyperactivity Disorder (ADHD) is characterized by symptoms of
inattention, hyperactivity, and impulsivity, which begin in childhood and can persist into
adulthood. Several studies have evaluated the prevalence of ADHD among children and
adolescents in different countries, including Brazil. Results are conflicting, remaining
doubts about the potential role of demographic and methodological issues on the
variability of estimates. There are scarce data about the prevalence of ADHD in
adulthood worldwide, and there are no studies conducted in our country. This scenario is
reinforced by uncertainties concerning the validity of current ADHD diagnostic criteria
and available instruments at this developmental stage.
Aims
We aimed to study the ADHD prevalence in childhood, adolescence, and adulthood,
addressing the gaps in the literature.
Methods
We conducted a systematic review of the literature aiming to detect studies that have
evaluated the prevalence of ADHD in childhood and adolescence in community samples
in the last 25 years. Pooling the selected studies, we evaluated the role of demographic
and methodological issues on the heterogeneity of results through a metaregression
analysis. In adults, we evaluated the prevalence of positive screeners for ADHD in a
representative sample of the Brazilian population older than 14 years of age. Afterwards,
we evaluated the fitness of the scale to the Rasch model of Item Response Theory.
Results
The systematic review located 9105 abstracts, and 102 original studies were included.
The ADHD pooled prevalence among children and adolescents was estimated in 5.29%,
which was associated with significant heterogeneity. The methodological variables
significantly associated with the prevalence rates were: a) diagnostic criteria; b)
requirement of impairment for the diagnosis; c) source of information. Geographic
location was associated with significant variability between estimates from North
America and Europe in relation to Africa and the Middle East. No significant differences
were found in prevalence rates between North America, Europe, South America, Asia,
and Oceania. The prevalence of positive screeners in the sample of 3007 individuals
evaluated in Brazil was 5.8%. The rate of positive screening was 7.6% for respondents
younger than 18 years, 5.2% for adults 18 to 44 years old, and 6.1% for respondents
older than 44 years of age. Rash analyses revealed that data for the overall sample
misfitted the model. However, data related to respondents 14 to 17 years old fitted the
model, which was not true for the other age strata.
Conclusion
The significant variability of ADHD prevalence estimates among children and
adolescents worldwide is largely influenced by methodological characteristics of studies.
Geographic location seems to play a limited role, since there are no differences on
prevalence rates detected in Europe and North America. Differences detected are
related to the Middle East and Africa, where few studies were conducted. In this regard,
further studies are necessary to support this finding. ADHD symptoms are common in
adults from the Brazilian population. The absence of fitness of ASRS to the Rasch model
challenges the utilization of parametric analyses of data and calls for the evaluation of
currently employed research methods in light of modern theories of psychometrics. The
difference between adolescents and adults on the fitness to the model suggests the
inclusion of developmental perspective into future ADHD diagnostic criteria.
Key-words: Attention Deficit/Hyperactivity Disorder, children, adolescents, adults,
prevalence, epidemiology.
1 INTRODUÇÃO
Os transtornos mentais freqüentemente têm início na infância e adolescência e
apresentam uma persistência considerável ao longo do tempo. Estes são responsáveis
por prejuízos significativos em diversas áreas da vida dos indivíduos, que podem se
agravar ao longo do tempo. É estimado que aproximadamente 15 a 20% das crianças e
adolescentes apresentem pelo menos um transtorno mental em todo o mundo, o que
representa um número absoluto de 10 milhões de crianças e adolescentes no Brasil.
O Transtorno de Déficit de Atenção/Hiperatividade (TDAH) é uma das causas mais
freqüentes de busca de atendimento em serviços de saúde mental para crianças e
adolescentes. É caracterizado por sintomas persistentes de desatenção, hiperatividade
e impulsividade presentes desde a infância e anormais em relação ao estágio do
desenvolvimento do indíviduo. Atualmente, o TDAH é entendido como um transtorno
crônico, que freqüentemente persiste até a idade adulta, provocando prejuízos
cumulativos ao longo do desenvolvimento dos indivíduos afetados.
A prevalência do TDAH na infância e adolescência vem sendo amplamente
estudada nas últimas décadas em diversos locais do mundo, inclusive no Brasil. Os
estudos realizados empregaram estratégias metodológicas diversas e geraram taxas
bastante variáveis. As evidências atualmente existentes não são suficientes para
responder se a variabilidade das estimativas da prevalência do TDAH encontrada na
literatura é conseqüência da diversidade metodológica dos estudos ou se há uma
distribuição desigual do transtorno em função do país e da cultura.
Em relação ao TDAH na idade adulta, há dados escassos sobre a sua prevalência
em todo o mundo. Apenas quatro inquéritos populacionais avaliaram a prevalência
deste transtorno nesta faixa etária, não existindo dados gerados em amostras
brasileiras até o momento. Contribuem para este cenário as incertezas existentes sobre
a validade dos atuais critérios diagnósticos em adultos, que não captariam a
complexidade da apresentação clínica do TDAH neste etapa do desenvolvimento, e os
dados limitados sobre os instrumentos de avaliação disponíveis.
2 BASE CONCEITUAL
2.1 Os transtornos mentais e a saúde da população
Os transtornos mentais são uma importante causa de incapacidade, dependência
e de sofrimento para os indivíduos afetados e para suas famílias (Prince et al., 2007).
Estima-se que aproximadamente 30% da população mundial sofra de transtornos
psiquiátricos (Kessler et al., 2005), que são responsáveis por elevados custos diretos e
indiretos, relacionados a serviços médicos, incapacidade para o trabalho,
hospitalizações, desenvolvimento de doenças físicas e outras doenças psiquiátricas,
além de morte prematura (Patel et al., 2007; Prince et al., 2007). Os transtornos
neuropsiquiátricos foram responsáveis por aproximadamente 10.5% dos anos de vida
ajustados para incapacidade (disability-adjusted life-years [DALY]) em todo o mundo no
ano de 1990, segundo estudo da Organização Mundial de Saúde (Murray et al., 1997;
Prince et al., 2007). Entende-se que estes dados subestimem a dimensão do problema,
considerando que os transtornos mentais são, ao mesmo tempo, causa e conseqüência
de incapacidade, além de serem fatores de risco para doenças físicas, comunicáveis e
não comunicáveis, bem como para acidentes, violência e pobreza, que também estão
relacionados à incapacidade (Prince et al., 2007).
Um corpo sólido de estudos conduzidos em diferentes países mostra que
aproximadamente 15 a 20% das crianças e adolescentes apresentam pelo menos um
transtorno mental (Fleitlich-Bilyk et al., 2004; Patel et al., 2007; Shaffer et al., 1996).
Assim, aproximadamente 10 milhões de crianças e adolescentes são afetados por
transtornos mentais no Brasil. Além de serem responsáveis por diversos eventos
negativos neste período do desenvolvimento (Patel et al., 2007), grande parte dos
transtornos mentais apresentam um caráter crônico, persistindo ao longo do tempo
(Costello et al., 2006). Por outro lado, os transtornos mentais em adultos
freqüentemente iniciam na infância ou na juventude (Kessler et al., 2005; Kim-Cohen et
al., 2003). Neste sentido, a intervenção precoce sobre os transtornos mentais pode
representar uma redução importante no custo social destas condições ao longo do
desenvolvimento (Remschmidt et al., 2005). Cientistas sociais como James Heckman,
agraciado com o Prêmio Nobel de Economia em 2000, apontam para o investimento na
infância como a maneira mais eficaz para que problemas sociais possam ser resolvidos
no futuro. Heckman estima que, a cada dólar aplicado na infância, os governos poderão
economizar 8 dólares quando o indivíduo estiver na idade adulta (Heckman, 2006).
Apesar da grande significância que as doenças mentais representam para a saúde
das populações, investimentos nesta área são historicamente negligenciados
(Thornicroft, 2007). Nos EUA e Europa, mais de 60% das pessoas afetadas por
transtornos mentais não recebem qualquer tipo de tratamento (Patel et al., 2007; Wang
et al., 2007). Financiamentos para pesquisa e investimentos em estratégias de
prevenção e em serviços de atendimento em todos os níveis são restritos em todo o
mundo (Horton, 2007). Os recursos destinados à área da saúde mental de crianças e
adolescentes são particularmente escassos, principalmente em países em
desenvolvimento, onde políticas públicas de educação, prevenção e tratamento são
praticamente inexistentes (Belfer et al., 2007; Belfer et al., 2006; Berganza, 2005). Há
um número limitado de pesquisas sobre transtornos mentais em crianças e
adolescentes em comparação com outras faixas etárias e as estimativas do seu impacto
são pouco conhecidas (Belfer et al., 2007). Os transtornos mentais que têm início na
infância e adolescência não foram incluídos no primeiro estudo Global Burden of
Disease, um grande projeto colaborativo que gerou estimativas do impacto das
condições médicas sobre a saúde das populações (Murray et al., 1996). Além disso, a
estatística utilizada por este estudo (anos de vida ajustados para incapacidade) atribui
maior valor ao impacto de uma condição médica aos 25 anos de idade, refletindo o
papel social do indivíduo (Lopez et al., 2006). No entanto, desconsidera o potencial
impacto negativo que os transtorno mentais na infância podem assumir ao longo da vida
(Belfer et al., 2007). Ao mesmo tempo em que existem poucos dados a respeito da
relevância dos transtornos mentais com início na infância e adolescência sobre o
indivíduo ao longo do seu desenvolvimento e sobre a sociedade de forma geral,
crianças e adolescentes com transtornos mentais são mais dificilmente diagnosticados e
tratados do que adultos com os mesmos problemas (Patel et al., 2007; Remschmidt et
al., 2005).
2.2 O Transtorno de Déficit de Atenção/Hiperatividade (TDAH)
O Transtorno de Déficit de Atenção/Hiperatividade (TDAH) é caracterizado por
sintomas persistentes de desatenção, hiperatividade e impulsividade, presentes desde a
infância e anormais em relação ao estágio do desenvolvimento do indivíduo (1994). O
TDAH é a categoria diagnóstica mais freqüente em crianças encaminhadas para
serviços de saúde mental (Dulcan, 1997; Goldman et al., 1998). A Associação
Psiquiátrica Americana estima que, na comunidade em geral, 3 a 7% das crianças em
idade escolar sejam afetadas pelo transtorno (DSM-IV, 1994).
O TDAH foi conceitualizado como um transtorno da infância e adolescência, mas
recentemente se tornou foco de atenção clínica em estudos com adultos, bem como
entre clínicos que atendem predominantemente adultos (Asherson et al., 2007; Wilens
et al., 2004). Isto ocorreu devido à observação de que indivíduos com TDAH na infância
seguiam apresentando sintomas ao longo do desenvolvimento, bem como prejuízos
funcionais associados (Hill et al., 1996). Assim, o TDAH é atualmente entendido como
um transtorno crônico, com início na infância mas não restrito à ela (Pliszka, 2007).
O TDAH está associado a importantes prejuízos em diversas áreas da vida dos
sujeitos afetados (Pliszka, 2007), que são agravados ao longo do tempo na ausência de
um tratamento adequado (NIH, 2000). Freqüentemente o prejuízo é ausente ou mínimo
em crianças na idade pré-escolar com predomínio de desatenção, o que não ocorre
com aquelas com sintomas de hiperatividade e impulsividade, que tendem a apresentar
dificuldades nos relacionamentos familiares antes dos 7 anos de idade (Dulcan, 1997).
Com o início do processo de alfabetização, há um progressivo e crescente
reconhecimento do transtorno. No período escolar, o TDAH está relacionado a baixo
rendimento, repetências, suspensões e expulsões (Lahey et al., 2004; Rohde et al.,
1999). Crianças com TDAH também apresentam dificuldades nos relacionamentos com
amigos e colegas (Lahey et al., 2004), maior freqüência de acidentes e injúrias físicas
(Swensen et al., 2004), o que se traduz em piores medidas de qualidade de vida
(Klassen et al., 2004). Estas dificuldades, associadas à percepção de que não
conseguem atender às demandas da escola e da família, freqüentemente provocam
sentimentos de baixa auto-estima e inadequação (Shaw-Zirt et al., 2005). Ao longo do
tempo, as crianças com TDAH apresentam maior chance de desenvolver outros
transtornos psiquiátricos do que as crianças sem TDAH (Biederman et al., 1996).
Entre adolescentes e adultos, as comorbidades são muito freqüentes,
principalmente transtornos de humor, de ansiedade, abuso e dependência de drogas,
transtorno de conduta e transtorno de personalidade anti-social, entre outras (Mannuzza
et al., 1998; Wilens et al., 2004), traduzindo a gravidade do TDAH ao longo do tempo.
Além disso, os adultos com TDAH apresentam elevada freqüência de acidentes
automobilísticos (Barkley et al., 1996), instabilidade nos relacionamentos afetivos e
profissionais, parentalidade mais precoce, maior freqüência de doenças sexualmente
transmissíveis, pior nível educacional e pior colocação no mercado de trabalho do que
indivíduos controles (Barkley et al., 2006; Mannuzza et al., 1993). Em termos de
impacto econômico, foi realizada uma revisão abrangente da literatura que mostrou
dados convergentes de 22 estudos sobre o tema (Matza et al., 2005). Crianças e
adultos com TDAH apresentaram custos médicos anuais maiores do que indivíduos
controles devido ao maior número de hospitalizações, visitas a serviços de atendimento
médico primário e de saúde mental, além de gastos com medicamentos. Os familiares
de crianças com TDAH também utilizaram serviços de saúde de forma mais freqüente
do que familiares de controles, representando gastos mais elevados. Há evidências de
custos adicionais relacionados à criminalidade, ao tratamento das comorbidades, a
acidentes e à perda de dias de trabalho (Matza et al., 2005).
2.3 A prevalência do TDAH na infância e adolescência
Ainda que a Associação Psiquiátrica Americana estime que entre 3 a 7% das
crianças em idade escolar sejam afetadas pelo TDAH (DSM-IV, 1994), taxas de
prevalência bastante variáveis são encontradas na literatura (Scahill et al., 2000;
Szatmari, 1992). Estudos apontam estimativas da prevalência que variam de 0.2% na
Alemanha (Essau et al., 1999), 0.4% na Austrália (McKelvey et al., 2002), 0.7% na Índia
(Hackett et al., 1999) e 0.9% nos Emirados Árabes (Eapen et al., 2003), Escócia (West
et al., 2003) e Coréia (Yoo et al., 2005), a 19.8% na Ucrânia (Gadow et al., 2000),
20.4% na Colômbia (Cornejo et al., 2005), 23.4% nos EUA (Kurlan et al., 2002) e 26.8%
no Brasil (Vasconcelos et al., 2003). Entretanto, estimativas bastante discordantes
também são encontradas em um mesmo país, como no Brasil, com taxas de 0.9%
(Goodman et al., 2005), 13% (Fontana et al., 2007) e 26.8% no Rio de Janeiro
(Vasconcelos et al., 2003), 1.8% em São Paulo (Fleitlich-Bilyk et al., 2004) e 5.8%
(Rohde et al., 1999) e 17.9% em Porto Alegre (Guardiola et al., 2000). Por outro lado,
taxas similares à estimativa da Associação Psiquiátrica Americana são detectadas
mesmo em regiões com diferenças sócio-culturais importantes, como 5.2% na Suíça
(Steinhausen et al., 1998), 5.6% no Congo (Kashala et al., 2005), 7.3% na Itália
(Mugnaini et al., 2006) e 7.5% em Taiwan (Gau et al., 2005). Na Tabela 1 são
apresentados os estudos publicados nos últimos dez anos (Janeiro de 1997 a Junho de
2007) que avaliaram a prevalência do TDAH, suas localizações geográficas, principais
características metodológicas e resultados.
A variabilidade das estimativas da prevalência do TDAH na infância e
adolescência, geradas por um grande número de estudos, conduzidos em diversos
países do mundo, apresenta importantes repercussões. No que se refere ao
planejamento de políticas públicas de saúde mental, gera incertezas quanto ao real
número de crianças afetadas e que devem receber tratamento, bem como quanto à
necessidade de implementação de estratégias de prevenção e educação sobre o
transtorno (Remschmidt et al., 2005). No que se refere ao entendimento do TDAH e da
sua etiologia, impõe questões referentes à importância da localização geográfica na
ocorrência deste transtorno.
Historicamente, o mapeamento geográfico dos casos de uma determinada
condição médica foi uma ferramenta útil para a melhor compreensão da origem de tal
condição, com implicações diretas na sua erradicação (Lilienfeld et al., 1984). Assim,
havendo reais diferenças geográficas na distribuição do TDAH, estudos que avaliem as
particularidades de cada área e as diferenças entre as populações poderiam contribuir
para o entendimento da etiologia deste transtorno. Considerando que o TDAH
apresenta um coeficiente de herdabilidade de aproximadamente 75% (Faraone et al.,
2005), diferenças no perfil genético entre as populações poderiam fornecer novos
indícios quanto aos genes implicados neste transtorno. De fato, diversos estudos foram
realizados acerca do papel de genes do sistema catecolaminérgico na etiologia do
TDAH, sendo evidenciada uma magnitude de risco limitada para o efeito de genes
Tabela 1. Estudos de prevalência do TDAH em crianças e adolescentes publicados entre Janeiro de 1997 a Junho de 2007.
Autor, ano País
Faixa de
Idade
Sistema
Classificatório
Fonte de
informação
Critério de
prejuízo
Estimativa de
prevalência (%)
Almqvist et al., 1999 Finlândia 8 - 9 DSM-III-R pais sim 7.1
Angold et al., 2002 EUA 9 - 17 DSM-IV “regra ou” sim 2.6
Ashenafi et al., 2001 Etiópia 5 - 15 DSM-III-R pais não 1.5
Bener et al., 2006 Qatar 6-12 DSM-IV professores não 9.4
Benjasuwantep et al., 2002 Tailândia 6 - 14 DSM-IV melhor estimativa - 6.5
Breton et al., 1999 Canadá 6 - 14 DSM-III-R pais sim 4.0
Bussing et al., 2002 EUA
Jardim inf. –
5
o
série
DSM-IV pais não 11.8
Canino et al., 2004 Porto Rico 7 - 17 DSM-IV pais e sujeitos sim 3.7
Cardo et al., 2007 Ilha de Majorca 6-11 DSM-IV pais e professores não 4.6
Carlson et al., 1997 EUA séries 1 - 5 DSM-IV professores não 18.9
Cornejo et al., 2005 Colômbia 4 - 17 DSM-IV - - 20.4
Eapen et al., 1998
Emirados
Árabes
6 - 15 DSM-IV melhor estimativa sim 0.5
Eapen et al., 2003
Emirados
Árabes
6 - 18 DSM-IV melhor estimativa sim 0.9
Ersan et al., 2004 Turquia 6 - 15 DSM-IV
pais or
professores
não 8.1
Essau et al., 1999 Alemanha 12 - 17 DSM-IV sujeitos sim 0.2
Fleitlich-Bilyk et al., 2004 Brasil 7 - 14 DSM-IV melhor estimativa sim 1.8
Fontana et al., 2007 Brasil 6 - 12 DSM-IV “regra e” não 13
Ford et al., 2003 Grã-Bretanha 5 - 15 DSM-IV melhor estimativa sim 2.2
Gadow et al., 2000 Ucrânia 10 - 12 DSM-IV pais não 19.8
Gau et al., 2005 Taiwan 13 - 15 DSM-IV melhor estimativa sim 7.5
Gaub et al., 1997 EUA séries 1 - 5 DSM-IV professores não 8.1
Gomez et al., 1999 Austrália 5 - 11 DSM-IV “regra e” não 2.4
Goodman et al., 2000
Inglaterra e
Escócia
5 - 15 DSM-IV melhor estimativa sim 2.4
Goodman et al., 2005 Brasil 5 - 14 DSM-IV melhor estimativa sim 0.9
Goodman et al., 2005 Rússia 7 - 14 ICD-10 melhor estimativa sim 1.3
Graetz et al., 2001 Austrália 6 - 17 DSM-IV pais não 7.5
Guardiola et al., 2000 Brasil 1
o
série DSM-IV professores não 17.9
Hackett et al., 1999 Índia 8 - 12 ICD-10 pais sim 0.7
Hebrani et al., 2007 Irã 5 - 6 DSM-IV pais sim 12.3
Kadesjo et al., 2001 Suécia 7 DSM-III-R melhor estimativa sim 3.7
Kashala et al., 2005 Congo 7 – 9 DSM-IV professores não 5.6
Kroes et al., 2001 Holanda 6 - 8 DSM-IV pais - 3.7
Kuntsi et al., 2004
Inglaterra e País
de Gales
5 DSM-IV “regra ou” não 5.7
Kurlan et al., 2002 EUA 9 - 17 DSM-IV “regra ou” não 23.4
Larsson et al., 2000 Suécia 8 - 9 DSM-III-R pais não 5.4
Levy et al., 1997 Austrália 4 - 12 DSM-III-R pais não 9.9
Loeber et al., 2001 EUA 7, 10, 13 DSM-III-R pais não 15.7
Lynch et al., 2006 Irlanda 12 - 15 DSM-IV melhor estimativa sim 3.7
MacLeod et al., 1999 Canadá 6 - 16 DSM-III “regra e” não 1.6
Malhotra et al., 2002 India 4 - 11 ICD-10 melhor estimativa - 0.9
McArdle et al., 2004 Grã-Bretanha 7 – 8 DSM-III-R pais sim 6.7
McKelvey et al., 2002 Austrália 9 - 17 DSM-III-R pais não 0.4
Merrell et al., 2001 Inglaterra 5 - 6 DSM-IV professores não 11.2
Meyer, 1998 África do Sul 6 - 12 DSM-IV professores não 7.2
Meyer et al., 2004 África do Sul 6 - 15 DSM-IV professores não 19.7
Miller et al., 1999 Faixa de Gaza acima de 5 DSM-III pais não 4.6
Montiel-Nava et al., 2002 Venezuela 6 - 12 DSM-IV “regra ou” não 7.1
Montiel-Nava et al., 2003 Venezuela 3 – 13 DSM-IV pais - 10.1
Mugnaini et al., 2006 Itália 6 - 7 DSM-IV professores sim 7.3
Mullick et al., 2005 Bangladesh 5 - 10 ICD-10 pais sim 2.0
Neuman et al., 2005 EUA 7 - 18 DSM-IV - não 6.2
Owens et al., 2003 EUA 9 - 13 DSM-IV pais não 2.9
Pineda et al., 1999 Colômbia 4 - 17 DSM-IV pais não 16.1
Pino et al., 2001 Espanha 6 - 15 DSM-III-R pais sim 3.1
Puura et al., 1998 Finlândia 8 - 9 DSM-III-R pais sim 6.6
Rohde et al., 1999 Brasil 12 - 14 DSM-IV “regra ou” sim 5.8
Romano et al., 2001 Canadá 14 - 17 DSM-III-R pais sim 3.3
Rowland et al., 2001 EUA séries 1 - 5 DSM-IV “regra ou” sim 16.1
Sherman et al., 1997 EUA 11 - 18 DSM-III-R pais não 5.1
Simonoff et al., 1997 EUA 8 - 16 DSM-III-R “regra ou” sim 1.4
Skounti et al., 2006 Grécia 7 DSM-IV - 6.5
Srinath et al., 2005 India 0 - 16 ICD-10 melhor estimativa não 1.6
Steinhausen et al., 1998 Suíça 6 - 17 DSM-III-R pais não 5.2
Sugawara et al., 1999 Japão 7 - 9 DSM-III-R “regra ou” não 10.5
Tercyak et al., 2002 EUA 14 - 16 DSM-IV sujeitos não 6.3
Vasconcelos et al., 2003 Brasil 6 - 15 DSM-IV professores não 26.8
Verhulst et al., 1997 Holanda 13 - 18 DSM-III-R “regra e” sim 0.4
Wacharasindhu et al., 2002 Tailândia 8 - 11 DSM-IV - não 5.1
West et al., 2003 Escócia 15 DSM-IV sujeitos sim 0.9
Yoo et al., 2005 Coréia 7 - 12 DSM-IV - sim 0.9
Zuddas et al., 2006 Itália 6 - 12 DSM-IV “regra e” não 1.38
Células em branco indica que não foi possível extrair o dado do estudo
isolados (Faraone et al., 2005). Falhas em replicar associações positivas são praticamente a regra, mesmo em relação aos
polimorfismos de genes candidatos mais consistentes, como aqueles nos genes para o transportador de dopamina (DAT1),
para o receptor D4 (DRD4) e D5 de dopamina (DRD5) (Faraone et al., 2005). Diversas hipóteses são levantadas para
explicar a freqüente não replicação dos achados, entre elas a potencial influência de particularidades do perfil genético de
cada amostra, relacionado à etnia específica de cada população, o que vai ao encontro da possível distribuição desigual do
TDAH entre diferentes países (Brookes et al., 2006). Mais ainda, a não mensuração de fatores ambientais que poderiam
estar envolvidos na etiologia do TDAH obscureceria o efeito dos genes (Rutter, 2002; Thapar et al., 2007). Assim, além de
diferenças quanto ao perfil genético, seria também interessante avaliar a freqüência de exposição das populações a fatores
de risco ambientais, como tabaco e álcool durante o período intra-uterino (Langley et al., 2005; Mick et al., 2002; Schmitz et
al., 2006) e complicações no nascimento, como baixo peso (Bhutta et al., 2002).
Além da influência de características genéticas ou ambientais relacionadas a países ou regiões específicas, discute-se
também a influência da cultura sobre a ocorrência de sintomas e sobre a freqüência do diagnóstico de TDAH (Anderson,
1996; Marcovitch, 2004; Timimi et al., 2004). O diagnóstico psiquiátrico, por não ser baseado em medidas objetivas, como
exames laboratoriais ou de imagem, é influenciado pela cultura onde psiquiatras e pacientes estão inseridos (U.S.
Department of Health and Human Services, 1999). Fatores culturais são reconhecidamente moderadores da expressão de
sintomas emocionais e comportamentais. Além disso, moderam também a forma como estes são entendidos no ambiente
onde os indivíduos estão inseridos (Bird, 1996). Assim, o comportamento das crianças é também interpretado à luz do que a
sociedade permite e espera destas. Em relação ao TDAH, este fenômeno pode ser evidenciado por um estudo que
comparou a percepção de sintomas de hiperatividade em psiquiatras de diferentes nacionalidades. Psiquiatras oriundos da
Indonésia e China interpretaram os mesmos sintomas de hiperatividade como mais graves do que psiquiatras provenientes
dos EUA e Japão. Assim, em sociedades ou famílias mais exigentes, onde o desempenho individual, principalmente
intelectual, é altamente valorizado, comportamentos minimamente desviantes podem ser considerados prejudiciais e
anormais. Estes mesmos comportamentos, apresentados por crianças inseridas em sociedades ou famílias menos
exigentes, possivelmente não serão interpretados como desviantes ou anormais com tanta facilidade (U.S. Department of
Health and Human Services, 1999). Evidentemente, questões relacionadas ao acesso ao sistema de saúde também
influenciam no processo de identificação e diagnóstico do TDAH (Angold et al., 1998).
Assumindo uma distribuição verdadeiramente desigual da prevalência do TDAH ao redor do mundo, com maiores taxas
no Ocidente, alguns autores explicam este fenômeno através de uma hipótese bastante controversa. Apontam para o que
chamam de uma “produção de transtornos mentais” em países ocidentais (Timimi et al., 2004; Timimi, 2005). Estes
transtornos, segundo estes autores, seriam criados pelos psiquiatras, motivados por laços financeiros com a indústria
farmacêutica e pela necessidade de gerar demanda para os seus serviços (Timimi, 2005). A sociedade de forma geral
também seria responsável pela criação destes transtornos, entre eles o TDAH, por ser altamente exigente em relação ao
desempenho dos indivíduos e por não tolerar que possam apresentar dificuldades, criando então “rótulos ou doenças” para
que sejam tratados (Marcovitch, 2004; Timimi, 2005; 2005). Esta hipótese é bastante frágil frente às evidências que
amparam a validade do TDAH sob diversos ângulos (2000; Dulcan, 1997; Goldman et al., 1998). No entanto, considerando o
incremento na utilização de medicamentos para o tratamento do TDAH e as evidências relacionadas ao seu freqüente uso
indevido, alerta a sociedade para a possibilidade da exposição desnecessária de crianças e adolescentes a agentes
farmacológicos (Marcovitch, 2004; Timimi, 2003; Faraone et al., 2003).
Por outro lado, importantes autores argumentam que as diferenças metodológicas entre os estudos não permitem uma
comparação adequada das estimativas da prevalência detectadas em diferentes países (Buitelaar et al., 2004; Faraone et
al., 2003). Segundo estes autores, é pouco provável que diferentes características genéticas, ambientais ou culturais sejam
responsáveis por taxas de prevalência variáveis. Além disso, apoiados na extensa literatura que evidencia a validade do
TDAH, desconsideram que este transtorno seja produto de uma “sociedade doente” (Faraone et al., 2003). Os autores
argumentam, baseados em hipóteses conceituais, que a variabilidade das estimativas da prevalência seria secundária a
particularidades metodológicas, como método de seleção da amostra, variabilidade dos critérios diagnósticos e sistemas
classificatórios, entre outras (Faraone et al., 2003; Scahill et al., 2000; Szatmari, 1992). Frente à esta hipótese, torna-se
importante o entendimento das estratégias metodológicas adotadas pelos estudos e o potencial impacto sobre os resultados
gerados.
2.4 Aspectos metodológicos dos estudos de prevalência do TDAH na infância e adolescência
Um aspecto metodológico fundamental de estudos epidemiológicos refere-se a quem está na amostra e como esta foi
recrutada. As estimativas de prevalência detectadas em uma amostra podem ser extrapoladas para a população apenas se
a amostra é representativa desta. Idealmente, a probabilidade de um determinado indivíduo ser selecionado deveria ser
conhecida e determinada pelos pesquisadores. Considerando que é virtualmente impossível ter uma lista completa e
atualizada de toda a população, os estudos epidemiológicos freqüentemente selecionam suas amostras de forma
probabilística a partir de registro de nascimentos (Levy et al., 1997), residências (Breton et al., 1999) ou escolas (Rohde et
al., 1999), denominando estas de lista ou base de amostragem.
Uma vez determinada a lista ou base de amostragem, a estratégia de seleção não pode estar relacionada ao desfecho
do estudo, ou seja, os métodos de recrutamento utilizados para o estudo não devem estar associados de nenhuma forma à
probabilidade do diagnóstico de TDAH. De forma similar, inquéritos de prevalência devem abordar os problemas
relacionados à recusa dos sujeitos em participar do estudo, que pode enviesar os resultados de forma importante.
Considerando que o TDAH é um diagnóstico clínico, os critérios adotados e a validade das medidas utilizadas
desempenham um papel fundamental nos resultados gerados (Offord, 1985). Os sistemas classificatórios apresentam
diferentes critérios diagnósticos, o que poderia influenciar as estimativas de prevalência. O TDAH foi descrito de forma
operacional pela primeira vez no Manual Diagnóstico e Estatístico dos Transtornos Mentais, na sua terceira edição em 1980
(DSM-III, 1980). Após, duas outras versões do DSM foram publicadas, com diferentes conceitualizações do transtorno. Na
primeira classificação, desatenção e hiperatividade eram representadas em dois domínios separados, sendo possível derivar
o diagnóstico de TDAH baseado na presença de sintomas suficientes em apenas uma dimensão. O DSM-III-R (1986)
agrupou estes sintomas em um domínio único, junto à impulsividade. O DSM-IV (1994) listou os sintomas de desatenção e
hiperatividade-impulsividade em domínios separados, sendo possível derivar o diagnóstico baseado na presença dos
sintomas em um ou ambos domínios, resultando em três possíveis subtipos. Os sintomas devem estar associados a prejuízo
funcional em pelo menos dois ambientes e alguns dos sintomas associados ao prejuízo devem estar presentes antes dos 7
anos de idade. Em relação à décima edição da Classificação Internacional das Doenças (CID-10, 1993), o DSM-IV (1994) é
muito semelhante no que se refere à lista dos sintomas e os construtos avaliados, havendo diferenças importantes quanto ao
modo como o diagnóstico é operacionalizado. A CID-10 exige tanto um número mínimo de sintomas em todas as três
dimensões (desatenção, hiperatividade e impulsividade) como a presença de cada sintoma em pelo menos dois locais
distintos. Considera ainda a presença concomitante de transtornos de humor, de ansiedade e do desenvolvimento como
exclusão do diagnóstico de TDAH. Por outro lado, o DSM-IV e o DSM-III-R permitem o diagnóstico de TDAH na presença de
transtornos de humor e ansiedade, mas não na presença de transtornos pervasivos do desenvolvimento. Assim, quando o
TDAH é avaliado através da mesma entrevista diagnóstica e o diagnóstico é gerado a partir de diferentes sistemas
classificatórios, taxas mais altas tendem a ser encontradas de acordo com os critérios da DSM-IV, tanto em amostras
clínicas como em amostras comunitárias (Goodman et al., 2000).
Inúmeras entrevistas diagnósticas estruturadas e semi-estruturadas, baseadas tanto nos critérios do DSM como nos
critérios da CID, foram construídas para avaliar a presença do TDAH. Estas podem ser aplicadas por entrevistadores leigos
ou com formação clínica. Alguns estudos também utilizam listas de sintomas para avaliar a presença destes, o que
comumente resulta em altas estimativas da prevalência, já que estas não avaliam de forma efetiva prejuízo funcional ou
idade de início (Scahill et al., 2000).
Levando em consideração que a atividade motora e a capacidade atencional são expressas em um contínuo na
população e que não existe um ponto de corte natural para categorizar o comportamento em normal ou anormal (Buitelaar et
al., 2004), alguns critérios adicionais são utilizados. O DSM-IV (1994) exige que os sintomas sejam inapropriados do ponto
de vista desenvolvimental e que ocorram freqüentemente, ainda que não defina este termo de forma objetiva. O prejuízo é
outro freqüente indicador de anormalidade e relaciona-se à significância clínica do transtorno. Entende-se que a presença de
prejuízo depende, além dos próprios sintomas, das demandas ambientais e das circunstâncias de vida do indivíduo. O
prejuízo funcional pode ser entendido como relacionado exclusivamente aos sintomas de um determinado transtorno
(prejuízo interno) ou pode ser entendido como o prejuízo global em todas as áreas de funcionamento do indivíduo, sem
referência à causa (prejuízo externo). Muitos estudos que avaliam prejuízo funcional, no entanto, não realizam esta distinção.
Considerando a dificuldade de operacionalizar constructos subjetivos como estes, não é surpreendente que estimativas da
prevalência variem conforme a definição e a presença desta medida. Canino et al. (Canino et al., 2004) avaliaram a
prevalência do TDAH utilizando os critérios do DSM-IV sem a exigência de prejuízo funcional para o diagnóstico e também
de acordo com três diferentes definições de prejuízo. A proporção de crianças com critérios suficientes para o diagnóstico de
TDAH variou de 3.7% a 8.9%, com estimativas mais baixas associadas a critério de prejuízo funcional mais rigoroso.
Ainda, uma importante questão metodológica na determinação das estimativas da prevalência do TDAH se relaciona à
estratégia utilizada pelos investigadores para coletar e combinar as informações necessárias para o diagnóstico. Levando
em conta a natureza estruturada do exame clínico, as crianças freqüentemente não exibem sintomas de TDAH durante a
avaliação (Offord, 1985). Além disso, estas tendem a minimizar comportamentos externalizantes e não apresentam
condições cognitivas suficientes para avaliar sintomas de desatenção (Pliszka, 2007). Os adolescentes tendem a informar
sintomas de desatenção de forma mais acurada do que as crianças, mas ainda persistem com dificuldades de relatar
sintomas comportamentais (Jensen et al., 1999) Assim, os relatos de crianças e adolescentes não são suficientemente
válidos para que sirvam de fonte única de informação para o estabelecimento do diagnóstico de TDAH. Como resultado, o
clínico deve se basear no relato subjetivo dos sintomas pelos pais e professores.
A confiabilidade entre pais e professores quanto ao relato de sintomas do TDAH tende a ser baixa (Zuddas et al.,
2006). Em parte, isto provavelmente ocorre porque a manifestação dos sintomas é dependente do ambiente e da tarefa;
além disso, há evidências de que pais e professores são sensíveis a comportamentos diferentes. Em relação à qualidade
das informações, os pais têm a vantagem de possuir um bom conhecimento sobre o comportamento dos filhos e de terem
acompanhado o seu desenvolvimento ao longo do tempo. Por outro lado, os professores parecem ter condições de observar
as crianças e adolescentes de forma mais objetiva do que os pais, além de terem acesso a inúmeros indivíduos no mesmo
momento do desenvolvimento, facilitando comparações (Offord, 1985; Scahill et al., 2000). Como resultado desta
variabilidade entre fontes de informação, diferentes estimativas de prevalência parecem ser geradas dependendo da forma
como as informações são coletadas. Diferentes estratégias podem ser adotadas, como a utilização de relatos de um único
informante (sujeito, pais ou professores) ou no exame direto do indivíduo, que pode ser muito oneroso em estudos
populacionais. Outra estratégia possível é a combinação de relatos de diferentes informantes, através da “regra do e”
(quando um sintoma é considerado presente apenas se endossado por dois informantes) ou da “regra do ou” (quando um
sintoma é considerado presente se endossado por um entre dois informantes). Muitos estudos adotam o procedimento de
melhor estimativa, integrando relatos objetivos com a avaliação clínica. Este procedimento consiste na revisão, por um
clínico experiente, de todos os dados disponíveis, que concilia discrepâncias e toma uma decisão diagnóstica baseada na
combinação das informações (Scahill et al., 2000; Szatmari, 1992). Estimativas variáveis parecem ser encontradas em
função dos diferentes enfoques adotados. Como exemplo, em uma amostra representativa de 2400 crianças do Canadá, a
prevalência de TDAH conforme o DSM-III-R foi estimada em 3.3% de acordo com o relato das próprias crianças, em 8.9%
conforme o relato dos professores e em 5% conforme o relato dos pais (Breton et al., 1999).
A revisão dos estudos de prevalência do TDAH na infância e adolescência evidencia a grande diversidade de
estratégias metodológicas adotadas e de resultados encontrados. Ainda que a hipótese de uma relação causal entre ambos
os fatores seja bastante provável, sendo apoiada por estudos individuais, esta não foi empriricamente testada até o
momento. Ainda, caso as características metodológicas dos estudos realmente tenham influência sobre as estimativas
geradas, o papel de fatores demográficos não é necessariamente afastado. Assim, seria extremamente interessante testar a
influência de ambos os fatores em conjunto, determinando ainda quais estratégias metodológicas são significativas neste
contexto.
2.5 A prevalência do TDAH na idade adulta
Diversos estudos longitudinais foram realizados com o objetivo de descrever a história natural do TDAH ao longo do
desenvolvimento dos indivíduos afetados. Uma revisão destes estudos, todos referentes a amostras clínicas, aponta para
uma grande variabilidade das estimativas de persistência do diagnóstico ao longo do tempo, de 8 a 72% (Hill et al., 1996).
Através de uma estimativa matemática, os autores estimaram que os sintomas do TDAH praticamente desapareciam no
início da terceira década de vida (Hill et al., 1996). Entretanto, os estudos disponíveis apresentavam limitações relacionadas
ao tempo de seguimento (apenas um estudo avaliou sujeitos com 30 anos) e às alterações históricas dos sistemas
classificatórios, impondo evidentes restrições às conclusões. Assim, foi aventada a hipótese de que a variabilidade das
estimativas seria secundária a artefatos metodológicos, como definição de persistência na idade adulta (sintomática ou
sindrômica) e idade dos indivíduos na reavaliação (Mannuzza et al., 2003).
Neste sentido, Biederman et al. (2000) demonstraram a influência da definição de remissão sobre as taxas de
persistência. Em uma amostra clínica de 128 meninos acompanhados durante 4 anos, a taxa de persistência do diagnóstico
aos 18 anos de idade foi de 40%, enquanto 90% dos indivíduos permaneciam com prejuízo funcional neste momento. Estes
achados indicaram que a redução dos sintomas vista durante o desenvolvimento não necessariamente é acompanhada pelo
desaparecimento do prejuízo clínico, desafiando o critério de pelo menos seis sintomas para o estabelecimento do
diagnóstico em adultos. Mais ainda, os sintomas avaliados foram construídos para crianças e adolescentes, não
contemplando, portanto, as particularidades desenvolvimentais. Assim, adultos podem apresentar outros sintomas que não
aqueles contemplados na lista do DSM-IV, o que de fato é observado clinicamente (McGough et al., 2004).
Com o objetivo de testar a influência da definição de persistência do TDAH sobre a sua estimativa, Faraone et al.
(2006) conduziram uma nova revisão sistemática e uma meta-análise. Os autores encontraram uma taxa de persistência de
15% para o diagnóstico pleno e de 40-60% quando casos de TDAH em remissão parcial eram incluídos. Ainda com o intuito
de definir a taxa de persistência do transtorno ao longo do tempo, Todd et al. (Todd et al., 2008) avaliaram uma amostra
comunitária de crianças e adolescentes ao longo de 5 anos. O TDAH foi definido conforme os critérios do DSM-IV e
conforme “subtipos derivados da população”, através de análise de classes latentes. A estabilidade dos subtipos do TDAH
variou de 11 a 24%, conforme os critérios do DSM-IV, e de 14 a 35%, conforme os subtipos derivados da população.
Biederman et al. (2006) avaliaram uma amostra clínica de indivíduos 10 anos após o diagnóstico inicial de TDAH, com idade
média de 21 anos. Neste intervalo de tempo, 58% dos indivíduos apresentaram critérios para o diagnóstico atual de TDAH
pleno ou sublimiar (4 ou 5 sintomas).
Abordando a validade do diagnóstico de TDAH sublimiar em adultos, Faraone et al. (2006) compararam adultos com
diagnóstico completo de TDAH, com diagnóstico de TDAH de início tardio (presença de todos os critérios exceto idade de
início menor de 7 anos de idade), com diagnóstico de TDAH sublimiar (três ou mais sintomas de desatenção ou
hiperatividade-impulsividade mas menos de 6) e indivíduos controles em relação a diversas medidas de psicopatologia, de
prejuízo funcional e de risco familiar de TDAH. Sujeitos com TDAH sublimiar apresentaram níveis menores de psicopatologia
e de prejuízo do que indivíduos com TDAH de início tardio e completo. Embora o grupo de sujeitos com TDAH sublimiar
apresentasse prejuízo funcional significativo, estes resultados forneceram evidências fracas para a validade do TDAH
sublimiar em adultos, não corroborando hipóteses anteriores.
Neste sentido, persistem dúvidas quanto à história natural do TDAH, que são diretamente relacionadas às incertezas
quanto à adequação dos critérios diagnósticos para adultos. A realização de estudos longitudinais comunitários, que
poderiam responder estas questões, é limitada por dificuldades metodológicas, como necessidade de amostras bastante
grandes, longo tempo de espera até o desfecho e alterações históricas nos critérios diagnósticos do TDAH, implicando em
altos custos. Frente à necessidade de melhor entender a distribuição do TDAH entre adultos e de planejar os serviços de
saúde, levantamentos populacionais avaliaram a prevalência do TDAH nesta faixa etária.
O primeiro inquérito populacional a avaliar o TDAH não o fez de forma direta. Um grande estudo populacional
conduzido pela Organização Mundial de Saúde, o World Mental Health Survey Initiative (Demyttenaere et al., 2004), avaliou
a prevalência de transtornos mentais de acordo com o DSM-IV em 60.463 adultos de 14 países. O TDAH foi incluído na
categoria de transtornos de controle de impulsos (bulimia, transtorno explosivo intermitente, TDAH, transtorno de conduta e
transtorno oposicional desafiante), não sendo relatada a sua prevalência individual. Nos 9 países onde foram avaliados os
transtornos de controle de impulsos, a prevalência destes variou de 0.3% na Itália e Alemanha a 6.8% nos EUA.
Subseqüentemente, em uma amostra comunitária de 1813 adultos pacientes de serviços médicos primários da
Holanda, Kooij et al. (Kooij et al., 2005) avaliaram a presença de sintomas de TDAH, abordando também a adequação dos
critérios diagnósticos e o impacto destes sobre os resultados. A presença de sintomas de desatenção e hiperatividade
esteve associada de forma significativa a prejuízo funcional. Indivíduos com quatro ou mais sintomas apresentaram prejuízo
significativamente maior do que indivíduos com dois, um ou nenhum sintoma de TDAH. A prevalência de TDAH foi estimada
em 1.0% (IC 95%, 0.6-1.6) utilizando um ponto de corte de seis sintomas e em 2.5% (IC 95%, 1.9-3.4) utilizando um ponto
de corte de quatro sintomas, com a exigência dos três sintomas nucleares durante a infância.
Faraone & Biederman (Faraone et al., 2006) avaliaram a prevalência do TDAH durante a idade adulta através de um
rastreamento telefônico em uma amostra comunitária de 966 adultos. Dois critérios foram utilizados: diagnóstico amplo (os
sintomas eram considerado positivos se ocorriam algumas vezes ou freqüentemente) e diagnóstico restrito (os sintomas
eram considerados positivos apenas se o indivíduo relatava a ocorrência destes de forma freqüente). Os resultados
revelaram uma prevalência estimada de 16.4% e 2.9% para os diagnósticos amplo e restrito, respectivamente. No entanto, a
taxa de perda amostral foi superior a 80%, o que impõe restrições importantes à validade interna deste estudo.
A avaliação do TDAH entre adultos foi incluída na replicação de um grande estudo comunitário, que avaliou uma
amostra representativa da população dos EUA, o National Comorbidity Survey Replication (NCS-R). (Kessler et al., 2006).
Partindo de uma amostra inicial de 9282 indivíduos, 5692 foram selecionados por apresentarem critérios para pelo menos
um transtorno ou por terem sido incluídos em uma sub-amostra randômica com rastreamento negativo. Foram selecionados
apenas os participantes entre 18 e 44 anos de idade, totalizando 3199 indivíduos, que foram avaliados retrospectivamente
para TDAH na infância e que responderam uma única questão referente à persistência dos sintomas no momento do estudo.
Os sujeitos foram então divididos nos seguintes grupos, de acordo com a presença de sintomas durante a infância e durante
a idade adulta: a) ausência de sintomas em ambos os períodos; b) sintomas de TDAH na infância sem critérios plenos; c)
diagnóstico de TDAH na infância com critérios plenos e ausência de sintomas na idade adulta; d) diagnóstico de TDAH na
infância com critérios plenos e presença de sintomas na idade adulta. Finalmente, 30 indivíduos de cada um dos três
primeiros grupos e 60 indivíduos do quarto grupo foram contactados e clinicamente avaliados para TDAH na idade adulta. A
partir da prevalência do transtorno em cada um dos quatro grupos, os autores realizaram uma análise de imputação múltipla,
predizendo o diagnóstico em indivíduos que não foram clinicamente avaliados para o diagnóstico atual mas que o foram para
o diagnóstico na infância e que responderam a questão sobre a persistência destes no momento. Assim, a prevalência
estimada de TDAH na vida adulta (entre 18 e 44 anos de idade) foi de 4.4%. Em análises retrospectivas do NCS-R, a taxa de
persistência do TDAH da infância à idade adulta foi estimada em 36.3% (Kessler et al., 2005).
Uma estratégia idêntica àquela utilizada no NCS-R foi empregada no estudo World Health Organization World Mental
Health Survey Initiative para avaliar a prevalência do TDAH entre adultos em dez países (Bélgica, Colômbia, França,
Alemanha, Itália, Líbano, México, Holanda, Espanha e EUA) (Fayyad et al., 2007). Uma amostra de 11.422 indivíduos entre
18 e 44 anos de idade foi avaliada de forma retrospectiva para TDAH na infância, tendo os participantes respondido a uma
questão única a respeito da continuidade dos sintomas na idade adulta. Baseado na calibração clínica com os 154 indivíduos
na amostra proveniente dos EUA, foi utilizada a estratégia de múltipla imputação para estimar a prevalência na amostra
global. O resultado foi de 3.4% para a amostra global, com estimativas significativamente mais altas encontradas na França
(7.3%) e mais baixas na Espanha (1.2%), Líbano (1.8%), México (1.9%) e Colômbia (1.9%). Apesar destas diferenças
intrigantes, a premissa implícita na utilização da imputação múltipla, que não foi testada, levanta dúvidas se diferenças
significativas entre os países seriam encontradas se métodos diagnósticos mais rigorosos fossem utilizados.
A partir das evidências disponíveis até o momento, ficam claras as incertezas quanto à adequação dos critérios
diagnósticos do TDAH em adultos e quanto à validade destes em distintas populações. Como conseqüência, há dados
escassos sobre a prevalência deste transtorno na população adulta, principalmente em países em desenvolvimento.
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4 OBJETIVOS
4.1 Objetivo Geral
Estudar a prevalência do TDAH na infância, adolescência e idade adulta.
4.2 Objetivos Específicos
Selecionar estudos originais que tenham avaliado a prevalência do TDAH na infância e adolescência.
Avaliar a influência de características metodológicas e da localização geográfica dos estudos de prevalência do TDAH na
infância e adolescência sobre a variabilidade das estimativas encontradas.
Estimar a prevalência do TDAH na infância e adolescência agrupando as estimativas disponíveis na literatura.
Estimar a prevalência de sintomas do TDAH em uma amostra representativa de adolescentes e adultos brasileiros.
Avaliar a adeqüação de um instrumento para rastreamento do TDAH em uma amostra representativa de adolescentes e
adultos brasileiros.
5 JUSTIFICATIVA
O estudo das causas da variabilidade das estimativas da prevalência do TDAH na infância e adolescência disponíveis
até o momento pode gerar dados importantes para o planejamento de futuras investigações. Ao serem definidas as
particularidades metodológicas implicadas na variação dos resultados, estas podem ser mantidas constantes em diferentes
estudos, permitindo a comparação adequada dos resultados. Por outro lado, se revelada que a localização geográfica tem
implicação na distribuição do TDAH, estudos futuros, focados neste achado, poderão fornecer novos dados sobre a etiologia
do transtorno.
O estudo da prevalência do TDAH na idade adulta na população brasileira é relevante como forma de testar a sua
validade transcultural. Mais ainda, a avaliação de um instrumento de rastreamento para o TDAH freqüentemente utilizado em
estudos populacionais é fundamental para a interpretação dos resultados gerados. Esforços para melhor entender o TDAH
nesta fase do desenvolvimento são justificados pela demanda crescente de adultos por atendimento psiquiátrico devido a
problemas de desatenção, hiperatividade e impulsividade. Além disto, estes sintomas vêm sendo cada vez mais
reconhecidos na trajetória psicopatológica de indivíduos em tratamento por outros problemas psiquiátricos, somando-se ao
fato de que as crianças diagnosticadas com TDAH no passado, quando este transtorno passou a ser reconhecido, hoje
ultrapassam a terceira década de vida.
Além de considerar as especificidades do estudo da prevalência do TDAH nas diferentes etapas do desenvolvimento,
deve ser destacada a relevância do estudo da prevalência deste transtorno de uma forma geral. O conhecimento acurado da
prevalência de qualquer condição médica, incluindo do TDAH, é fundamental para que seja estimado o impacto desta sobre
a saúde da população a que se refere. Assim, pode ser realizado um planejamento adequado da alocação de recursos para
serviços de saúde, bem como de estratégias amplas de prevenção e educação. Estas medidas têm o potencial de, no futuro,
gerar beneficios significativos para a saude da população.
6 CONSIDERAÇÕES ÉTICAS
Os indivíduos que fizeram parte do estudo I Levantamento sobre Padrões de Consumo de Álcool na População
Brasileira, cuja parte dos resultados são relatados no Artigo 2 desta Tese, assinaram um Termo de Consentimento livre e
esclarecido. Os pais de indivíduos menores de 18 anos de idade forneceram autorização formal para a participação de seus
filhos. O projeto foi aprovado pelo Comitê de Ética em Pesquisa da Universidade Federal de São Paulo, sob protocolo
número 1672/04.
7 ARTIGOS
7.1 Artigo 1
7.2 Artigo 2
ADHD in a representative sample of the Brazilian population: estimated prevalence and evaluation of the ASRS
Screener according to Item Response Theory.
Guilherme Polanczyk
1
, Ronaldo Laranjeira
3
, Raul Caetano
4
, Marcos Zaleski
2
, Ilana Pinsky
3
, Luis Augusto Rohde
1
Manuscrito submetido – Journal of Psychiatric Research
1
ADHD Program, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Brazil.
2
Federal University of
Santa Catarina, Santa Catarina, Brazil.
3
Department of Psychiatry, Federal University of Sao Paulo, UNIAD, Brazil.
4
University of Texas School of Public Health, USA.
Corresponding author: Prof. Luis Augusto Rohde. ADHD Program, Hospital de Clinicas de Porto Alegre. Rua Ramiro
Barcelos, 2350. Porto Alegre, RS , Brazil. 90035-003. Phone/Fax: +55 51 3321 3946. E-mail: [email protected]
Short-title: ADHD in a representative sample of Brazilian population.
Key-words: attention-deficit/hyperactivity disorder, WHO ASRS Screener, adult, prevalence, epidemiology.
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a clinically significant disorder that can persist across the lifespan. However,
current diagnostic systems do not seem to adequately capture the complexity of the disorder in adulthood. Accordingly, there
are limited data on the proportion of adults affect by the disorder, specially in developing countries. We assessed the
proportion of adults with a positive screening of ADHD in a representative household sample of the Brazilian adolescent and
adult population, and evaluated the ASRS Screener according to the Rash model of Item Response Theory. The prevalence
of positive screeners in the overal sample was 5.8% (95% CI, 4.8-7.0), 7.6% (95% CI, 5.4-10.7) for respondents younger than
18 years, 5.2% (95% CI, 4.0-6.8) for adults 18 to 44 years old, and 6.1% (95% CI, 4.5-8.3) for respondents older than 44
years of age. Rash analyses revealed that the instrument for the overall sample misfitted the model. However, data related
only to respondents 14 to 17 years old showed a superior fitness to the model than data related to the two other age strata
(18 to 44 years old and 45 years old or more). The absence of fitness to the model for respondents older than 17 years
challenges the possibility of a linear transformation of the ordinal data into interval measures and the utilization of parametric
analyses of data. This result suggests that diagnostic criteria for ADHD must take into account a developmental perspective.
Moreover, it calls for further evaluation of currently employed research methods in light of modern theories of psychometrics.
Introduction
Attention-deficit/hyperactivity disorder (ADHD) has only been recognized as a disorder that frequently persist beyond
childhood and adolescence and accompanies individuals during their lifetimes in the past two decades (Wilens et al., 2004).
ADHD in adulthood is associated with a substantial cumulative impairment in academic, occupational, and inter-personal
functioning, as well as with accidents and comorbid mental disorders (Barkley et al., 2006; Mannuzza et al., 1998; Wilens et
al., 2004). Adult mental health services are being adapted to adequately treat subjects affected by ADHD, but there is a virtual
absence of mental health policies that address the disorder (Asherson et al., 2007).
Longitudinal studies demonstrated a decline of symptoms with time. The persistence rate varies from 15 to 65% at 25
years of age, depending on the definition of persistence (full diagnosis versus ADHD in partial remission) (Faraone et al.,
2006). Few community surveys have evaluated the prevalence of ADHD in adults, and available studies have used different
diagnostic criteria and measures, which makes data comparisons difficult. Faraone and Biederman (2005) estimated the
prevalence of adult ADHD in 2.9% for a narrow diagnosis (symptoms occurring often) and in 16.4% for a broad diagnosis
(symptoms occurring sometimes or often). In a probabilistic sample of adults from a general practice in The Netherlands,
ADHD was estimated to occur in 1.0% (95% CI, 0.6–1.6) of adults according to the standard DSM-IV cutoff of six symptoms
or in 2.5% (95% CI, 1.9–3.4) when a cutoff of four symptoms was applied (the requirement of presence of all three core
symptoms during childhood was used for both definitions) (Kooij et al., 2005). In the US, ADHD prevalence has been
estimated in a sub-sample of 3199 individuals 18-44 years of age who took part of the National Comorbidity Survey
Replication (NCS-R) (Kessler et al., 2006). The respondents were divided into four groups based on the presence of ADHD
symptoms during childhood and adulthood and 154 subjects of them were clinically evaluated for adult ADHD. According to
the prevalence of the disorder on each group and on multiple imputation to assign predicted diagnoses to respondents who
did not participate in the clinical interviews, the estimated prevalence of current adult ADHD was 4.4% (Kessler et al., 2006).
In a study conducted in 10 different countries by the World Health Organization, adult ADHD was estimated to occur in 3.4%
of the sample (Fayyad et al., 2007). Samples from three developing countries (Colombia, Lebanon and Mexico) were included
in the study, with prevalence rates of 1.9%, 1.8% and 1.9%, respectively (Fayyad et al., 2007). However, the prevalence
imputation for the 10 samples was based on results from a clinical calibration in a US sample, which may have masked
differences between cultures. It is important to note that this is the only data on ADHD prevalence in adults obtained in
community samples from developing countries to date.
Although the validity of ADHD in adulthood is clearly supported by empirical evidence, current diagnostic systems do not
seem to adequately capture the complexity of the disorder at this developmental stage (Brown, 2006; McGough et al., 2004;
Wilens et al., 2004; Willoughby, 2003). Accordingly, the understanding of ADHD distribution in the community have important
limitations (Polanczyk et al., 2007). The current lack of agreement between experts on the definition of the most appropriate
diagnostic criteria for adults, and consequently the lack of a “gold-standard” diagnostic tool, is a pivotal limitation for the
estimation of ADHD prevalence. However, several instruments have been constructed, and the WHO Adult ADHD Self-
Report Scale (ASRS), which was developed by a group of experts and used in the NCS-R, is one of the most promising
scales for community samples. It is composed by 6 items and was derived from a 18-item instrument that reflected all DSM-IV
ADHD symptoms. This short version with 6-questions outperformed the original scale in its diagnostic properties (Kessler et
al., 2005). In a subsequent study, with an independent sample, a superior diagnostic accuracy was achieved with the ASRS
Screener when the intensity of each symptom (never to very often, corresponding to scores from 0 to 4) was taken into
consideration, yielding a score from 0 to 24, which led the authors to propose the use of this scoring method (Kessler et al.,
2007). However, the psychometric properties of this instrument were neither extensively explored in different samples nor
using different methodological approaches.
Thus, there is a strong relevance of both generating data on the prevalence of ADHD in adulthood in other developing
countries, and evaluating the psychometric properties of the most used scale to derive an estimation of adult ADHD
prevalence in community samples according to modern approaches. Item Response Theory (IRT) is a general statistical
theory about the relationship between items (questions or individual criterion) and subjects’ ability (symptom severity), which
has been increasingly used to assess the adequacy of DSM-IV diagnostic criteria for several disorders (Hartman et al., 2008;
Ietsugu et al., 2007). Rasch measurement is an IRT model that assumes that the probability that a person will endorse a
symptom is a logistic function of the difference between a person’s ability (intensity of symptoms) and the difficulty of the item
(severity of the symptom evaluated) (Rash, 1960). Data is compared to the expectations of the model and once it fits it, a
linear transformation of the raw ordinal scale is possible. This makes possible the analysis of data using parametric tests. If
this were true for the ASRS Screener, it would support the adequacy of the scoring method proposed by Kessler et al. (2007).
Moreover, Rasch analyses provides results on the internal consistency of the instrument, assess the way categories of an
item works, and if items are answered in a different way according to specific characteristics of the subjects (Pallant et al.,
2007).
Thus, we aimed to assess the proportion of adults with a positive screening to ADHD in a representative household
sample of the Brazilian adolescent and adult population according to the ASRS Screener, and to evaluate the scale according
to the Rash model of IRT.
Methods
Setting
Brazil constitutes one of biggest countries of the world in territorial extension. With approximately 170 million inhabitants,
it is the most populous country in Latin America and ranks sixth in the world. The country is divided into five geographic
regions, which are highly heterogeneous in terms of socio-economic, ethnic, and cultural characteristics.
Sample and Data Collection
The first Brazilian National Alcohol Survey is a nationally representative survey of 3007 Portuguese-speaking household
residents in urban and rural areas aged 14 or older. The study was conducted between November 2005 and April 2006.
Institutionalized and indigenous people living in tribes were not included. Respondents were selected through a three-stage
cluster sampling procedure.
The first stage involved the selection of 143 counties, the primary sampling unit (PSU), using probability proportional to
size methods (PPS). Stage 2 involved the selection of two census sectors for each county based on the PPS, with an
exception of census sectors in the 14 biggest counties which were included a priori due to the number of inhabitants in these
counties, totaling 325 census sectors. Stage 3 corresponded to the selection of 8 households within each census sector by
simple random sampling, followed by the selection of a household member using the “the closest future birthday” technique. A
total of 2,522 interviews were conducted with respondents 14 years of age or older, and 485 additional interviews were
conducted with respondents 14 to 17 years of age. The survey response rate was 66.4%. All respondents granted their
informed consent. The project was approved by the IRB of the Federal University of São Paulo.
Instrument
The WHO Adult ADHD Self-Report Scale (ASRS) Screener has been developed in the context of the WHO World
Mental Health Survey Initiative and was derived from a 18-item questionnaire which mirrored all 18 DSM-IV ADHD symptoms.
ASRS Screener is composed by 6 questions, with adequate diagnostic properties (sensitivity: 68.7%; specificity: 99.5%; total
classification accuracy: 97.9%) (Kessler et al., 2005). The frequency of each symptom is evaluated in a 4-point scale, from
never to very often. The Portuguese version of the scale is available at http://www.hcp.med.harvard.edu/ncs/ asrs.php
Analysis of data
Based on a previous study in a different population (Kessler et al., 2007), a positive screening in the ASRS Screener
was defined as a score of 14 or higher. Socio-demographic correlates were evaluated by using logistic regression analysis,
conducted on data weighted for correcting to the probability of selection and non-response rates. Post-stratification weights
were calculated to adjust the sample to known Census population distributions of sociodemographic variables. Analyses were
conducted with Taylor linearized variance estimation using STATA 9.2 to account for the complex nature of the sample.
Significance tests of sets of coefficients used Wald χ
2
tests adjusted for the design. Statistical significance was evaluated by
using two-sided design-based tests with an alpha level of 0.05.
The fitness of the ASRS Screener was tested in comparison to the expectations of the Rasch model (Rash, 1960). An
estimate of the internal consistency reliability of the scale is calculated based on the Person Separation Index (PSI). Three
overall fit statistics are considered: two item–person interaction statistics transformed to approximate a z score, and an item–
trait interaction statistic reported as a χ
2
. A significant test indicates that the hierarchical ordering of the items varies across
the trait, thus compromising the required property of invariance. In addition to these overall summary fit statistics, item-fit
statistics is presented (misfit is defined by residual ≥ 2.5 or significant χ
2
test for a p value < 0.05 after Bonferroni correction)
and the category ordering is evaluated (the consistency of categories with the level of the trait evaluated), and item bias, or
differential item functioning (DIF). We evaluated the following characteristics as “person factors” for DIF analysis: gender,
social class, Brazil’s geographic region, and educational level. We used RUMM2020 software to perform theses analyses.
Results
According to the scoring approach proposed by Kessler et al. (2007), 5.8% (CI 95%, 4.8-7.0) of subjects screened
positive for ADHD. The prevalence of positive screeners stratified by age range was 7.6% (95% CI, 5.4-10.7) for respondents
younger than 18 years, 5.2% (95% CI, 4.0-6.8) for respondents 18 to 44 years old and 6.1% (95% CI, 4.5-8.3) for
respondents older than 44 years of age. No significant differences were detected in the rates between the three age groups
(F
1.82,294.7
=1.37, P=0.2). The distributions of respondents according to the score and age strata, weighted to represent the
Brazilian population, are presented in Table 1.
Logistic regression analysis revealed that women presented a higher prevalence of positive screening than men
(OR=2.03, 95% CI, 1.3-3.2). No significant differences on rates of positive versus negative screeners were found concerning
race, occupational, educational, and marital status, social class and geographic region in Brazil (Table 2). Correlates were
also analyzed within each age group (14 to 17, 18 to 44, and older than 44). Among subjects 18-44 years of age, women had
a higher prevalence of screening positive than men (OR=2.04, 95% CI, 1.03-4.05). There was a significant lower rate of
positive screeners among respondents 25 to 34 (OR=0.32, 95% CI, 0.15-0.69) and 35 to 44 (OR=0.29, 95% CI, 0.14-0.61)
years of age in comparison to those aged 18 to 24. Further analyzes on the rates of positive screeners according to race,
occupational, educational, and marital status, social class and geographic region in Brazil, within the three age strata, yielded
non-significant differences (available upon request).
The fitness of the ASRS Screener to the Rasch model was initially assessed in the total sample (483 cases were
excluded from Rash analysis due to extreme scores). It was detected a significant item-trait interaction (χ
2
271.700, df=30;
P<0.001), suggesting that there is some degree of misfit between the data and the model, which could be caused by misfit to
model expectations of respondents or items, or both. The residual mean value for items was 1.01 with a SD of 3.06, much
higher than the expected value of 1, given adequate fit to the model. The residual mean value for persons was -0.25 with a
SD of 1.17, indicating a reasonable fit among the respondents in the sample (Table 1). With respect to reliability, the PSI
statistic was 0.808, which indicates that the ASRS Screener has good person separation reliability. The same pattern of
results was confirmed in a random sample of 1000 subjects.
Subsequently, we stratified the sample in three categories according to age range (14 to 17, 18 to 44, and older than 44)
to test the hypothesis that the misfit of the data to the model was related to age. Data from each age group were tested
against the Rash model in separate. PSI statistic varied from 0.80 to 0.82 for the three groups, indicating that ASRS Screener
has good internal consistency reliability. In the group of adolescents, item-trait interaction showed a borderline significance
(χ
2
=44.6; P=0.04) indicating a slight variability on hierarchical ordering of items across the trait. The residual mean value for
items was 0.53 (SD 0,68) and the residual mean value for persons was -0.29 (SD 1,16). There were no items displaying DIF
or presenting misfit. Items 1, 2, 3 and 4 showed altered thresholds. In the strata composed by individuals age 18 to 44, item-
trait interaction was highly significant (χ
2
=185.3; P<0.001) indicating a lack of hierarchical ordering of items across the trait.
The residual mean value for items was 0.74 (SD 2,44) and the residual mean value for persons was -0.27 (SD 1,14). Items 1,
2, 4 and 6 showed misfit to model expectation and items 4 and 6 showed some degree of uniform DIF regarding social class.
Moreover, item 6 showed DIF regarding demographic region in Brazil. Items 1 and 3 showed altered thresholds. In the group
of subjects older than 44 years of age, item-trait interaction was also highly significant (χ
2
=90,3; P<0.001) indicating an
altered hierarchical ordering of items across the trait. The residual mean value for items was 0.42 (SD 1,79) and the residual
mean value for persons was -0.3 (SD 1,26). Items 1, 2 and 6 showed misfit to model expectation and item 6 showed uniform
DIF regarding social class and educational level. Items 1, 2, 3 and 5 showed altered thresholds. Altered thresholds were
reordered in the three sets of analyses and did not result in a significant improvement of the overall performance of the scale.
Discussion
We have evaluated the prevalence of positive screeners for ADHD in a representative sample of household Brazilian
population. It was estimated that approximately 6% of Brazilian population screens positive for ADHD based on the ASRS
Screener. This is the first representative survey conducted in Brazil that evaluated adult ADHD and the fourth conducted in a
developing country to date.
We found a significant higher prevalence of positive screeners among women, a finding also detected in the subgroup
of 18 to 44 years of age. It is well established the higher prevalence of ADHD among boys, specially in clinical samples
(Pliszka, 2007). However, in community samples, the difference between gender is less prominent (Polanczyk et al., 2007). A
scarcity of data had been published on this matter among adults. Kessler et al. (2006) and Fayyad et al. (2007) found a higher
prevalence of ADHD among men in their sample, with modest odds ratio (1.6 and 1.5, respectively). Kooij et al. (2005)
explored the validity of two different cut-off points (6 and 4 symptoms) for the diagnosis of ADHD and found no gender effect
when applying the cut-off of 6 symptoms but a higher prevalence of females when applying the cut-off of 4 symptoms. The
authors ruled out a confounding effect of comorbidities and hypothesized that women during adulthood may be more sensitive
than men to the identification of symptoms. An alternative explanation is that the stability of ADHD symptoms during the
lifetime might be higher in women. We cannot exclude that the presence of other mental disorders (e.g depression or anxiety)
have a role in the higher prevalence of ADHD among women in our sample. Our results, in conjunction with those from Kooj’s
investigation and from a clinical study in a developing country which also detected a higher prevalence of ADHD among
women (Almeida Montes et al., 2007), points to this intriguing hypothesis, which deserves further study.
These results must to be understood in the context of a main methodological limitation. Subjects were evaluated with
a screening scale and we were not able to determine the diagnostic performance of the instrument in our sample due to the
lack of a “gold-standard” assessment. ASRS Screener have initially presented adequate sensitivity (68.7%), specificity
(99.5%), and total classification accuracy (97.9%) when compared to clinical evaluation (Kessler et al., 2005). A subsequent
study confirmed these results, but documented that an alternative method of scoring (0-24 approach) showed a better
diagnostic accuracy than the original scoring method (0-6 approach) (Kessler et al., 2007). However, it is important to note
that all other epidemiological investigations in the adult ADHD have not assessed the psychometric properties of the
instruments used in light of more recent approaches like IRT. Item Response Theory is a very useful method to assess the
adequacy of constructs and instruments and addresses a number of issues not usually considered in epidemiological studies
(Chachamovich et al., in press; Hartman et al., 2008; Tennant et al., 2004).
Our results from Rash analyses provides several interesting insights to the ADHD and to the epidemiology field in
general. First, we showed that data pertaining the overall sample misfitted the model. Since conceptual assumptions of the
Rash model support its independence of the individuals who answer the itens (i.e., sample free) (Andrich, 1988), this finding
should call attention to the fact that the ADHD field might be employing instruments to disentagle several aspects of the
disorder that do not have the adequate psychometric properties for this purpose. The absence of fitness to the model for
respondents older than 17 years challenges the possibility of a linear transformation of the ordinal data from the ASRS into
interval measures, as proposed by Kessler et al. (2007). This has an important practical implication: since the interval
between two scores may not be the same along the entire continuum, mathematical operations and parametric analysis of
data may not be possible (Andrich, 1988; Pallant et al., 2007). Thus, any epidemiological data based on cutoff scores derived
from models assuming interval properties of the data is questionable without the appropriate testing.
Second, data related to adolescents showed a superior fitness to the model than data related to the two other strata
(18 to 44 years old and 45 years old or more). This is a very interesting result that is in complete agreement to those of Merrel
& Tymms (2005) and Smith & Johnson (2000), who also evaluated the ADHD criteria with Rasch model. Their results
indicated that the same scale could not be used by young children and college students. ASRS Screener items were
constructed adapting ADHD symptoms to adulthood. Even so, data from adults misfitted the model, while data from
adolescents did not. Our results, along with previous studies, may indicate problems in the construct validity of ADHD
diagnostic criteria for adults, since this diagnosis was more extensively validated in children and adolescents (Pliszka, 2007;
Rohde, in press; Wilens et al., 2004).
The results from the first study to assess ADHD symptoms in a representative sample of the Brazilian population
indicated that these are common problems in all age ranges in this country. Furthermore, our results point to the relevance of
evaluating both the validity of constructs which investigators intend to measure, and the properties of the scales used in this
field. The phenomenology of ADHD in adults seem to be specific and a list of symptoms that takes into account this
developmental perspective must be developed and validated in this age group before any effort to integrate adult ADHD
diagnosis in future classificatory systems.
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Table 1. Proportion of respondents stratified by age range and scores strata on the ASRS Screener, weighted to
represent the Brazilian population.
ASRS Screener strata Age range (years)
< 18 18 – 44 >44
0-9 66,5 77.3 82.9
10-13 25.9 17.5 11
14-17 6.8 4.5 5.2
18-24 0.8 0.7 0.9
Table 2. Prevalence of positives screeners for ADHD according to socio-demographic characteristics (n=3007)
Characteristic
% (95% CI) Adjusted Odds Ratio
(95% CI)
Gender*
Male 3.6 (2.6-5.1) 1
Female 7.7 (6.3-9.4) 2.03 (1.3-3.2)
Race
White 5.8 (4.4-7.6) 1
Non-white 5.7 (4.4-7.4) 0.93 (0.6-1.4)
Age, years
14 – 17 7.6 (5.4-10.7) 1
18 – 44 5.2 (4.0-6.8) 0.76 (0.3-1.7)
> 44 6.1 (4.5-8.3) 0.87 (0.3-2.2)
Occupational
status**
Employed 4.9 (3.7-6.4) 1
Unemployed 3.1 (1.4-6.5) 0.58 (0.2-1.4)
Student 8.5 (5.5-13.0) 1.41 (0.5-3.7)
Homemaker 8.6 (6.1-11.9) 1.3 (0.8-2.2)
Retired 6.4 (4.2-9.8) 1.05 (0.5-2.1)
Educational
status (years)
0 - 5 5.9 (4.4-8.0) 1
6 - 8 5.5 (4.0-7.5) 0.88 (0.5-1.5)
9 – 11 6.1 (4.3-8.5) 0.98 (0.6-1.6)
> 12 5.0 (2.2-11.0) 0.94 (0.4-2.4)
Marital status
Single 6.1 (4.4-8.3) 1
Married 5.3 (4.2-6.8) 0.91 (0.5-1.6)
Divorced 6.1 (3.7-10.0) 0.97 (0.5-2.1)
Widow/er 8.0 (4.7-13.1) 1.07 (0.5-2.6)
Social class
A 1.7 (0.4-6.6) 1
B/C 6.2 (4.7-8.2) 4.45 (0.9-20)
D/E 5.5 (4.4-7.0) 3.89 (0.8-18.6)
Geographic region
North 4.5 (2.8-7.2) 1
South 3.5 (2.2-5.5) 0.77 (0.4-1.6)
Southeast 7.0 (5.2-9.3) 1.6 (0.9-2.8)
Northeast 5.0 (3.5-7.2) 1.2 (0.6-2.1)
Central-west 7.3 (3.7-13.9) 1.74 (0.7-4.2)
Univariate analysis, Design-based χ
2
: *F(1, 162)=18.59,
P<0.001; **F(3.73, 603.86)=3.4, P=0.01;
Table 3. Fit of the ASRS Screeners to the Rash model.
Item Location SE Fit
Residual
DF Chi-Sq DF Prob
Item 1 0.471 0.023 -0.76 2099 59.437 5 0.000006
Item 2 0.316 0.022 -1.778 2099 76.276 5 0.000001
Item 3 -0.037 0.02 1.745 2099 11.451 5 0.043139
Item 4 0.107 0.021 -1.573 2099 59.55 5 0.000001
Item 5 -0.463 0.018 2.221 2099 6.437 5 0.266015
Item 6 -0.393 0.018 6.228 2099 58.549 5 0.000001
Misfitting values are in bold (after Bonferroni correction)
8 CONSIDERAÇÕES FINAIS
A avaliação da prevalência do TDAH na infância e adolescência tem sido alvo de esforço considerável por parte de
pesquisadores de diferentes países e culturas nos últimos anos. As taxas de prevalência detectadas por meio de uma
revisão sistemática e agrupadas através de uma meta-análise geraram uma estimativa global da prevalência do TDAH em
crianças e adolescentes de 5.29%. No entanto, a estimativa agrupada demonstrou heterogeneidade significativa,
comprovando a hipótese de que os dados existentes não são consensuais em relação à prevalência do TDAH. Com o
objetivo de entender as causas da heterogeneidade entre as estimativas, realizamos uma análise de metaregressão.
A análise de metaregressão permitiu que investigássemos a influência de características metodológicas dos estudos e
do local onde estes foram conduzidos sobre a heterogeneidade das estimativas encontradas. Os resultados mostraram que
as seguintes estratégias metodológicas influenciam a variabilidade das taxas de prevalência do TDAH: critério diagnóstico
utilizado, exigência de critério de prejuízo para o diagnóstico e fonte de informação para o estabelecimento do diagnóstico.
Não houve diferença entre as estimativas geradas na Europa e na América do Norte e entre estas e aquelas encontradas na
Ásia, Oceania e América do Sul. No entanto, quando comparadas as taxas geradas na Europa e América do Norte com
aquelas detectadas na África e Oriente Médio, foram encontradas diferenças significativas. Entretanto, o número reduzido de
estudos conduzidos nestes dois últimos continentes limita a validade deste achado, que deve ser avaliado por análises
futuras.
Este estudo documentou, de forma inédita na literatura, o papel significativo de estratégias para avaliação e diagnóstico
do TDAH, utilizadas por investigações de prevalência, na variabilidade dos resultados encontrados. Documentamos ainda a
influência limitada da localização geográfica dos estudos sobre as estimativas geradas. Este achado vai de encontro à
hipótese de que o TDAH seria um produto da cultura ocidental, que “fabricaria” novos casos, e corrobora a hipótese de que
este transtorno, quando avaliado de forma similar em diferentes países, tende a apresentar taxas de prevalência similares ao
redor do mundo. Este resultado não exclui a existência de especificidades relacionadas a áreas demográficas, com papéis
ou relevâncias variadas, no complexo processo etiológico do TDAH. No entanto, as evidências disponíveis não demonstram
que tais especificidades sejam relevantes o suficiente para gerar um número maior ou menor de casos em áreas
demográficas circunscritas. Assim, não há evidências que amparem o mapeamento demográfico dos casos de TDAH como
método para melhor entender a sua etiologia.
Ainda que a taxa agrupada da prevalência do TDAH esteja associada à heterogeneidade significativa, considerando o
criterioso processo de revisão da literatura e de inclusão de estudos, esta é a melhor estimativa disponível até o momento.
Assim, assumindo a ausência de diferenças demográficas na distribuição do TDAH, comunidades que não dispõem de tais
estimativas para a sua população podem calcular que aproximadamente 5% das crianças e adolescentes são afetadas por
este transtorno. Neste sentido, escolas e serviços de saúde devem estar preparados para atender tal demanda. Caso esta
demanda não seja identificada, devem ser realizados programas de educação para a comunidade em geral, assim como
para professores e profissionais de saúde, buscando as crianças e adolescentes afetados que, ao receberem o diagnóstico,
podem ser beneficiados pelos tratamentos disponíveis.
A comprovação da influência das características metodológicas dos estudos sobre as diferentes estimativas da
prevalência do TDAH na infância e adolescência alerta para a importância do rigor metodológico na condução de
investigações epidemiológicas. Ao serem realizadas meta-análises, além de determinar a presença ou não de
heterogeneidade dos dados, a determinação de questões relacionadas a esta, através de análises de metaregressão, pode
ser bastante enriquecedora para o desenvolvimento do campo da pesquisa. Neste sentindo, identificando quais técnicas ou
metodologias influenciam os resultados, futuros estudos podem ser planejados com metodologias equivalentes, buscando a
geração de achados comparáveis. Da mesma forma, estudos já realizados e que tenham metodologias similares, não
associadas à heterogeneidade significativa, podem ser agregados, resultando em maior poder para a investigação de
questões ainda não respondidas.
Os dados referentes à primeira amostra representativa de adolescentes e adultos da população brasileira avaliada para
o TDAH, através de um instrumento de rastreamento, indicam que os sintomas deste transtorno são comuns na nossa
população. A utilização de um ponto de corte previamente estabelecido resultou em uma prevalência de indivíduos com
rastreamento positivo de 5.8%. Tendo em vista as incertezas a respeito dos critérios diagnósticos para o TDAH, e a
conseqüente ausência de um padrão ouro para este diagnóstico em relação ao qual o desempenho do instrumento utilizado
poderia ser comparado, investigamos a sua adequação frente ao modelo de Rasch. Com esta estratégia, avaliamos se a
intensidade dos sintomas de TDAH e a gravidade medida por cada item seriam os únicos fatores que influenciariam na forma
como os indivíduos respondem à escala. Os resultados documentaram a inadequação dos dados às expectativas do modelo,
o que impede a interpretação das medidas como sendo intervalares e impõe restrições à atribuição de intensidades
equivalente entre todos os itens, à sua soma e à utilização de testes paramétricos. Estes resultados vão de encontro à
estratégia previamente sugerida pelos autores do instrumento para definir o seu ponto de corte
Buscamos entender se a adequação do instrumento utilizado ao modelo seria dependente da idade do indivíduo
avaliado. Foram encontradas diferenças importantes, que revelaram que o instrumento é adeqüado para a avaliação de
adolescentes, mas não o é para a avaliação de adultos. Tendo sido este instrumento adaptado para o uso em adultos, estes
resultados sugerem que não seria propriamente a escala, mas sim os critérios nos quais ela se baseia, inapropriados para a
avaliação do TDAH na idade adulta. Os resultados deste estudo sugerem que os futuros sistemas classificatórios devam
incluir uma perspectiva desenvolvimental para o diagnóstico de adultos com TDAH.
O modelo de Rasch apresenta uma estratégia útil para a avaliação de fatores culturais na aferição de um construto,
através da análise de differential item functioning. Esta análise permite entender quais fatores influenciam a forma como um
indivíduo responde a um determinado item. Uma vez que avaliamos uma amostra representativa de todas as regiões
brasileiras, que apresentam diferenças culturais relevantes entre si, investigamos a influência destas sobre as respostas ao
instrumento. Para adolescentes e adultos entre 18 e 44 anos de idade, a região não interfere na forma como estes entendem
e respondem à escala; já para indivíduos maiores de 44 anos, a região interfere na forma como respondem a uma única
questão entre as cinco. Estes dados, em conjunto com evidências de ausência de variabilidade consistente das estimativas
da prevalência do TDAH em crianças e adolescentes conforme o continente, são evidências da validade transcultural deste
transtorno. Ainda que provavelmente ocorra variações na interpretação de comportamentos e na manifestação destes em
diferentes culturas, o TDAH não parece ser um transtorno mental restrito a culturas específicas.
A interpretação dos resultados de estudos de prevalência do TDAH, tanto na infância e adolescência como na idade
adulta, deve ser realizada à luz das estratégias metodológicas adotadas por estes. Os resultados deste estudo mostram a
importância de que sejam conduzidas investigações com metodologias apropriadas aos objetivos a que se propõe, e que a
interpretação dos seus achados considere as limitações dos métodos utilizados. Estratégias de análise de dados utilizadas
neste estudo, como a metaregressão e a Teoria de Resposta ao Item, permitem a avaliação cuidadosa de metodologias e
instrumentos de pesquisa. A sua utilização tende a proporcionar dados fidedignos e interpretações acuradas, o que pode
representar economia de investimentos em pesquisa. Neste sentido, investigações futuras devem ser realizadas utilizando
estas técnicas.
Considerando que o TDAH está associado a diversos e importantes eventos negativos na infância, adolescência e
idade adulta, afetando uma proporção significativa da população, é necessária a criação e a implementação de políticas
públicas visando a educação da população a seu respeito e o planejamento dos serviços de saúde para que disponibilizem
tratamentos adeqüados. Ainda, é fundamental que sigam sendo realizados estudos focados na geração de conhecimentos
que, no futuro, possam proporcionar a criação de estratégias de prevenção do TDAH.
ANEXOS - Produção científica durante o período de Doutorado (03/2006 – 03/2008) relacionada à Tese.
Anexo 1
Anexo 2
Anexo 3
Anexo 4
Treatment of ADHD in Latin America and the Caribbean
Guilherme Polanczyk, Luis Augusto Rohde, Claudia Szobot, Marcelo Schmitz, Cecilia Montiel-Nava, José J. Bauermeister.
Journal of the American Academy of Child and Adolescent Psychiatry, in press.
To the Editor:
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent mental disorders of childhood and has
been a major focus of scientific attention in the past decades.
1
A wide range of empirical data support the validity of the
disorder, its associated burden,
1
and its worldwide distribution.
2
However, uncertainties remain about the rate of treatment
around the world. In the USA, it is estimated that approximately 56% of children with a reported diagnosis of ADHD have
been treated with medication.
1
The rate of treatment in developing countries is expected to be much lower than in developed
countries, due to inadequate health care systems, lack of human resources and poor knowledge of the population about the
disorder.
3
Community data on the rate of children with ADHD on treatment around the world have the potential to identify
cultural and/or economic barriers to treatment and to guide efforts and resources to overcome them. Thus, we performed an
electronic review with the goal of identifying studies with non-referred samples from the community that have evaluated the
prevalence of children with ADHD treated with stimulants in Latin America and the Caribbean.
We searched Medline through PubMed with the key-words ADHD and therapy, therapeutics, pharmaceutical
preparations, medication, stimulant, methylphenidate, and Latin America, Caribbean, and each of the 46 countries from Latin
America and the Caribbean according to the Economic Commission for Latin America (ECLA). This review yielded 92
abstracts, and only one study that specifically covered the issue.
4
Furthermore, we were aware of three studies that evaluated
non-referred children and adolescents from the community for ADHD and which, as a secondary measure, assessed the
number of children on stimulants.
5-7
The results of these four studies are reported here.
In Puerto Rico, Bauermeister et al.
4
evaluated a probability household sample of 1897 children aged 4 to 17 years.
Among those children diagnosed with ADHD by the researchers, 7.0% had received stimulants during the previous year, and
only 3.6% were receiving stimulants at the time of the interview. In Venezuela, Montiel-Nava et al.
5
evaluated a probability
school-based sample of 1535 individuals aged 4 to 12 years. The rate of stimulant treatment among children diagnosed with
ADHD was 4.0%. In Brazil, Schmitz et al.
6
ascertained more than 400 non-referred school children aged 6 to 18 years who
screened positive for ADHD, and identified 100 individuals with ADHD inattentive subtype. Among those children with ADHD,
only 3.0% were on stimulant treatment at the time of diagnosis. Szobot et al.,
7
also in Brazil, evaluated 968 male adolescents
aged 15 to 20 years for substance use disorder (SUD) and ADHD. Among those adolescents with ADHD, or even (and
perhaps more relevant) those with ADHD and SUD, none were on, or had ever received stimulants during their lifetime.
The ECLA estimates an overall population of more than 576 000 million people in Latin America and the Caribbean in
2007, and children and adolescents younger than 15 years of age represent approximately 30% of the population. Assuming
that ADHD affects 5.0% of children worldwide,
2
and that no more than 4.0% of children diagnosed with ADHD are treated with
stimulants in Latin America and the Caribbean, we would estimate that more than 8 million children with ADHD are under-
treated and under-diagnosed in this region of the world. It is possible that some of these children receive psychosocial
treatment rather than medication (from 13 to 23% with ADHD in Puerto Rico).
4
However, the type of psychosocial treatment
employed in community settings is frequently not empirically supported and the existing resources for effective behavioral
treatment for ADHD in these countries are scarce.
3
We detected a complete absence of national surveys concerning
children’s mental health in Latin American and Caribbean countries and were able to find studies that generated evidence
pertaining to specific populations in only 3 out of 46 countries. The existing data indicate that children and adolescents with
ADHD are under-treated in Latin America and the Caribbean. There is an urgent need for consistent policies on children’s
mental health, for which the empirical evaluation of clinical practices is a prerequisite.
References
1. Pliszka S. Practice parameter for the assessment and treatment of children and adolescents with attention-
deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007;46(7):894-921.
2. Polanczyk G, Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: A systematic review and
metaregression analysis. Am J Psychiatry 2007;164(6):942-948.
3. Berganza CE. Children's right to mental health. How adults have failed youth worldwide: the Latin America case. World
Psychiatry 2005;4(3):157-158.
4. Bauermeister JJ, Canino G, Bravo M, et al. Stimulant and psychosocial treatment of ADHD in Latino/Hispanic children. J
Am Acad Child Adolesc Psychiatry 2003;42(7):851-855.
5. Montiel-Nava C, Peña J, Montiel-Barbero I, Polanczyk G. Prevalence rates of Attention Deficit/Hyperactivity Disorder in a
school sample of Venezuelan children. Child Psychiatry Hum Dev, in press.
6. Schmitz M, Denardin D, Laufer Silva T, et al. Smoking during pregnancy and attention-deficit/hyperactivity disorder,
predominantly inattentive type: a case-control study. J Am Acad Child Adolesc Psychiatry 2006;45(11):1338-1345.
7. Szobot CM, Rohde LA, Bukstein O, et al. Is attention-deficit/hyperactivity disorder associated with illicit substance use
disorders in male adolescents? A community-based case-control study. Addiction 2007;102(7):1122-1130.
Anexo 5
Methodological insights on ADHD Pharmacogenetic Studies
Guilherme Polanczyk
1
, Stephen V. Faraone
2
, Claiton Bau
3
, Marcelo Victor
3
, Katja Becker
4
, Reta Pelz
4
, Jan K. Buitelaar
5
,
Barbara Franke
5,6
, Sandra Kooij
7
, Emma van der Meulen
8
, Keun-Ah Cheon
9
, Eric Mick
10
, Diane Purper-Ouakil
11
, Mark A.
Stein
12
, Edwin H. Cook Jr.
12
, Luis Augusto Rohde
1
Manuscrito a ser submetido - American Journal of Medical Genetics Part B: Neuropsychiatric Genetics.
1
ADHD Program, Child and Adolescent Psychiatric Division, Hospital de Clinicas de Porto Alegre, Federal University of Rio
Grande do Sul, Brazil.
2
Departments of Psychiatry and Neuroscience & Physiology, SUNY Upstate Medical University,
Syracuse, USA.
3
Adult ADHD Outpatient Clinic, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do
Sul, Brazil.
4
Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health,
Mannheim, Germany.
5
Department of Psychiatry, University Medical Center St Radboud, Nijmegen, Netherlands.
6
Department of Human Genetics, University Medical Center St Radboud, Nijmegen, Netherlands.
7
ADHD Program / Psy-Q,
Center for Mental Health, Den Hague, Netherlands.
8
Bascule, Academic Center for Child and Adolescent Psychiatry,
Amsterdam, Netherlands.
9
Division of Child and Adolescent Psychiatry, Department of Psychiatry, Myong-Ji Hospital,
Kwandong University College of Medicine, Koyang City, Kyunggi, South Korea.
10
Pediatric Psychopharmacology,
Massacusetts General Hospital, Harvard Medical School, Boston, USA.
11
AP/HP Hôpital Robert Debré, Child and Adolescent
Psychopathology Unit, Paris, France.
12
HALP CLinic and ADHD Research Center, Institute for Juvenile Research, The
University of Illinois at Chicago, Chicago, USA.
Conflict of interests:
Drs Polanczyk, Franke, van der Meulen, Bau, Victor, Becker, Pelz, and Cook Jr. do not have any potential conflict of interest.
Dr. Faraone receives research support from, is on the speakers’ bureaus of, and has had an advisory or consulting
relationship with McNeil Pediatrics and Shire Laboratories; he also has had an advisory or consulting relationship with
Novartis and Eli Lilly.
Dr Buitelaar is/has been a speaker for, or is/has been on the advisory board for the following pharmaceutical companies: Eli
Lilly & Company, Shire US Inc, UCB, Medice, Janssen Cilag B.V, and Pfizer.
Dr Sandra Kooij is/has been a speaker for, or is/has been on the advisory board for the following pharmaceutical companies:
Eli Lilly & Company, Shire US Inc, UCB, Medice, Janssen Cilag B.V, and Pfizer.
Dr Cheon received research support from Janssen Korea and is on the speakers’ bureaus of Janssen Korea and Eli Lilly
Korea.
Dr Stein is a consultant for Novartis and serves on their speaker’s bureau. He also speaks for McNeil Pediatrics and receives
research support from McNeil Pediatrics, Eli-Lilly, Novartis and Pfizer. Dr Rohde was on the speakers’ bureau and/or acted as
consultant for Eli-Lilly, Janssen-Cilag, and Novartis in the last three years. Currently, his only industry related activity is take
part of the advisory board for Eli Lilly & Company. The ADHD Outpatient Program receives research support from the
following pharmaceutical companies: Bristol-Myers Squibb, Eli-Lilly, Janssen-Cilag, and Novartis.
Funding sources:
This work was partially supported by research grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq, Brazil) (MCT/CNPq 02/2006 – Universal, Grant 478202/2006-7), FIPE - Hospital de Clinicas de Porto Alegre. Dr
Polanczyk holds a doctoral fellowship, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Ministry of
Education, Brazil. Collaboration among site was facilitated by NIMH conference grant R13MH59126 to S.V. Faraone.
Abstract
Several studies have evaluated the association between individual polymorphisms and response to methylphenidate (MPH) in
subjects with attention-deficit/hyperactivity disorder (ADHD). There are few replication studies for each polymorphism of
interest and the existing replications are sometimes inconsistent. Although data collection from multiple international sites
would allow large sample sizes, this approach has been criticized for introducing sampling variability due to differences in
ethnicity and methodology among studies. To examine these issues, we aggregated nine studies on pharmacogenetics from
four different continents and conducted a two stage analysis: a) we evaluated the role of methodological aspects in the
variability of ADHD symptoms improvement among studies using meta-regression analyses; b) we assessed the role of
individual characteristics of the subjects in the variability of ADHD symptoms improvement using multivariate regression
analyses in the same data sets. At the study level, the design of the study (p=.001) was significantly associated with
heterogeneity of results. At the individual level, age (p<.001) comorbid oppositional defiant disorder (p<.001), and pre-
treatment scores (p<.001) were associated with change of ADHD scores with treatment in the final multivariate model. Our
results suggest that the joint analysis of pharmacogenetic studies is feasible, since no fixed variable, such as the site where
the study was conducted, was related to results. Nevertheless, stratified analyzes according to the design of the study must
be preferentially conducted and the role of individual factors such as demographic data and comorbid profile as confounders
should be assessed.
Key-words: ADHD, Pharmacogenetics, methylphenidate, treatment, meta-analyses.
Introduction
Pharmacogenetics addresses the association between genes and clinical response to pharmacological interventions
(Goldstein et al., 2003). Targeting genes related to the pharmacokinetics or pharmacodynamics of a medication,
pharmacogenetics aims to understand the variability among individuals in the rates of adverse reactions or clinical
improvement associated with medication use. Besides its potential in tailoring interventions to the genetic background of
individuals, pharmacogenetics can illuminate neural pathways of specific disorders (Polanczyk et al., 2007).
Several research groups have evaluated the association of individual polymorphisms and the response to
methylphenidate (MPH) in subjects with attention-deficit/hyperactivity disorder (ADHD) (Polanczyk et al., 2005; Stein et al., in
press). These studies focused mainly on genes believed to be associated with the disease (Faraone et al., 2005),
predominantly from the dopaminergic system (Cheon et al., 2007; Kooij et al., 2007; Mick et al., 2006; Roman et al., 2002;
Stein et al., 2005), but also from the noradrenergic (Polanczyk et al., 2007) and serotoninergic systems (Tharoor et al., 2007;
Zeni et al., 2007). To date, there are few replication studies for each polymorphism of interest and the existing replications
have provided inconsistent results (Roman et al., 2002; Stein et al., 2005). Methodological aspects of the studies, such as
variability in design, diagnostic and outcome measures used, as well as limitations, such as not controlling for confounding
factors, have been hypothesized to be related to these differing results (Polanczyk et al., 2005). Moreover, considering that
the effect of a single gene on the response to medication is expected to be small (Polanczyk et al., 2007), most samples are
probably underpowered to detect existing effects (Goldstein et al., 2003).
Collaborative studies aggregating samples from diverse international centers have the potential to assess the effect of
polymorphisms on methylphenidate’s response with adequate power (Goldstein et al., 2003). Nevertheless, this strategy has
been criticized because it may introduce sampling variability due to different ethnicity and methodological issues among
studies. In other words, if methodological aspects of the studies or ethnicity were related to heterogeneity in the response to
MPH among investigations, the potential gain in power would be offset by the introduction of noise into analyses. In a meta-
analysis of methylphenidate for treating adult ADHD, Faraone et al. (2004) found a significant association between type of
rater, dose and variability in efficacy of methylphenidate in adults with ADHD. In a subsequent meta-analysis of medications
used to treat ADHD in children, Faraone et al. (2006) reported that the design of the trial (parallel versus crossover) and the
conceptualization of outcome (end score versus change of score) were significantly associated with the reported effect size of
methylphenidate. Such issues would likely also add variability to pharmacogenetic studies of ADHD.
Thus, we decided to conduct a two stage analysis: a) we evaluated the role of methodological aspects in the variability
of ADHD symptom improvement among studies using meta-regression analyses in the available data sets on
pharmacogenetics from the ADHD Molecular Genetics Network; and b) we assessed the role of individual characteristics of
the subjects in the variability of ADHD symptoms improvement using multivariate regression analyses in the same data sets.
Methods
This study has been conducted in the context of the Pharmacogenomics Working Group of the ADHD Molecular
Genetics Network, which brings together collaborative research groups for studying the molecular genetics of ADHD
(Faraone, 2003). Participants of the Working Group were invited to collaborate providing data on pharmacogenetic studies of
MPH in subjects with ADHD (published or not) that have been conducted in their centers. Data on each individual were
requested, and these included demographic and clinical variables, as well as variables related to the treatment. Furthermore,
the following study-level were requested: continent, design, symptom-rating scale used, rater who completed the scale, and
sample size.
We computed the effect size of MPH in each study through the standardized mean difference, using change-from-
baseline measure. We calculated the change in total ADHD symptoms from pre- to post-treatment within individuals and used
the pooled standard deviation to generate the effect size. This strategy corrects for the correlation between measures within a
patient (Curtin et al., 2002; Elbourne et al., 2002). Data was corrected for placebo if this group was available.
Analyses were conducted separately for variables at the study and individual levels. Random-effect meta-regression
analysis evaluated the effect of study level variables on the heterogeneity of results across different studies. This strategy has
been previously applied to assess the effect of methodological and demographic variables in ADHD prevalence estimates
(Polanczyk et al., 2007) and in methylphenidate’s effect size (Faraone et al., 2004; Faraone et al., 2006). The study level
variables assessed were: continent where the study was conducted, design of the study (open-label versus randomized
controlled trial [RCT]), sample size, symptom-rating scale used, and rater who completed the scale. Variables associated with
the outcome at a p value <.2 in univariate analyses were included in the multivariate model. Given the results obtained in
univariate analysis, we conducted an additional strategy of analysis, which consisted of a multivariate model comprising all
variables independently of the univariate results.
Individual level variables were analyzed with linear regression analysis. The outcome was defined as the percent of
change from pre- to post-treatment in combined inattention and hyperactivity-impulsive symptoms (negative results indicate
decrease of symptoms). Independent factors assessed were: age, gender, ethnicity, ADHD subtype, presence of conduct
disorder (CD), oppositional defiant disorder (ODD), any mood or anxiety disorder, any other disorder (eating, substance
use/abuse, tic, Tourette disorder, enuresis/encopresis), IQ, pre-treatment score, MPH formulation (immediate release [IR],
long-acting [LA], osmotic release [OROS]), MPH dose (per kilograms per day), number of times MPH was administered a day
if immediate release, concomitant use of another medication, previous use of MPH, time from pre- to post-treatment
evaluations. Initially, all dependent factors were assessed in univariate analysis. Based on a conceptual hypothesis, the
association between the dependent factors and pre-treatment score were investigated, and this factor was included as a
covariate when appropriate. Variables associated with the outcome in univariate analysis at a p value <.2 were included in the
multivariate model. At this stage, a p value <.05 was considered as statistically significant. All analyses were conducted with
STATA version 9.2.
Results
Nine samples (Cheon et al., 2007; Kooij et al., 2007; Mick et al., 2006; Polanczyk et al., 2007; Purper-Ouakil et al.,
submitted; Stein et al., 2005; van der Meulen et al., 2005) from seven centers were included in the study. Characteristics of
the samples are described in Table 1. The pooled random effect size of methylphenidate for the treatment of combined
inattentive and hyperactive-impulsive symptoms was estimated in 1.32 (CI 95% .88-1.76). Findings indicated the presence of
heterogeneity across samples (Q=108.34; df=8, p<.001, tau
2
=.42). Meta-regression univariate analysis revealed that design
of studies (p=.002) was significantly associated to heterogeneity of results, while continent, symptom-rating scale, rater, and
sample size were not. All variables were included in the multivariate model, and again only design of the study was
associated to heterogeneity of results (p=.001).
At a second stage, the samples were aggregated and the effects of individual level factors over the change of ADHD
symptoms from pre- to post-treatment of the 782 individuals were assessed. Pre-treatment score was highly associated with
the outcome (p<.001) and with 8 of 16 independent factors assessed (p<.05). All variables associated to the outcome in
univariate analysis at a p value < .2 were included in the multivariate model (pre-treatment score, age, ADHD subtype, ODD,
mood, other disorders, IQ, previous use of medication, and time of follow-up). Since information on the number of times MPH
was administered was available for only 200 individuals, it was excluded from analyses. In the multivariate model, age (β= –.
45, SE=.08, p<.001), presence of ODD (β=9.58, SE=2.38, p<.001) and pre-treatment score (β= –.41, SE=.06, p<.001) were
associated with the percent of change from pre- to post-treatment in combined ADHD symptoms. This model accounted for
8% in the variance in the change of scores from pre- to post-treatment. To further understand the effect of age on response to
methylphenidate, we calculated the effect size of methylphenidate for preschoolers, school-age children, adolescents and
adults. Results indicated an effect size above 1.2 for all strata, with minor differences between age-ranges related to the
variability of data (data available upon request).
Discussion
This study evaluated the association between study and individual level factors and response to MPH aggregating
pharmacogenetic studies from diverse cultural backgrounds. Design of the study (open-label versus RCTs) was significantly
associated with heterogeneity of results. Furthermore, in the analyses of individual level characteristics, age, comorbid ODD,
and baseline symptoms were associated with change in ADHD symptoms during treatment with MPH.
This is the third study conducted to date that evaluated the association of methodological characteristics and response
to methylphenidate and the first one to access exclusively pharmacogenetic studies. Faraone et al. (2004) assessed six RCTs
of adults with ADHD treated with methylphenidate and detected significant effects for type of rater (self- versus physician
rating) and dose but not for study design (crossover versus parallel). In a subsequent study, Faraone et al. (2006) evaluated
the association between methodological aspects of 29 RCTs and improvement of ADHD symptoms with stimulants and non-
stimulants medications. The authors detected the association between effect sizes of medications and both study design
(crossover versus parallel designs) and type of score (outcome versus change scores). Other characteristics, such as type of
raters, the score categories used to assess efficacy, the use of fixed-dose vs titration for best dose designs, whether or not
subjects with a history of non-response were excluded, exclusion of nonresponders, or use of a placebo lead-in were not
significantly associated with medications’ effect size. In our study, we compared exclusively open-label studies versus RCTs
and we were not able to evaluate differential effects of parallel versus cross-over designs. Even with this limitation, our
analyses underline the importance of the design of the study in the interpretation of its results in ADHD trials as proposed by
Faraone et al (2006). In relation to the type of scores used, we decided to use only change scores based on expert
recommendations (Elbourne et al., 2002). In this regard, we couldn’t assess the effect of the type of outcome on
heterogeneity of results. It is important to emphasize that we evaluated individual level characteristics through appropriate
analytical techniques. The inclusion of a summary statistic (e.g., proportion of male or average age) in the meta-regression
can be difficult to interpret, since the relationship of patient averages or proportion across and within trials may not be the
same, a phenomenon called ecological or aggregation bias (Berlin et al., 2002; Morton et al., 2004; Thompson et al., 2002).
This study aggregated nine samples from four different continents (Europe, North America, South America, and Asia)
and demonstrated that the origin of the sample was not associated with differential pattern of response to methylphenidate in
the meta-regression analysis. The resulted sample size (n=782) allowed the evaluation of ethnicity as an individual level
variable. With this strategy, ethnicity was not significantly associated with the outcome. This is the first study to date that
evaluated the response to methylphenidate aggregating studies from different cultural backgrounds. These findings are in the
same direction of those from the Multimodal Treatment Study with children with ADHD, which detected a substantial and
clinically similar response to MPH between African Americans, Latinos, and Caucasians (Arnold et al., 2003). It is important to
stress that we have not assessed in this study the effect of specific polymorphisms on the outcome. In this way, we are not
hypothesizing that specific polymorphisms implicated in the clinical response or adverse events to methylphenidate are
equally distributed across different ethnic backgrounds. This is a matter for future studies. Demographic and/or cultural
aspects are commonly hypothesized to have a role on studies’ findings (Timimi, 2005). However, we could neither find a role
of the continent where the study was conducted nor of the ethnic background of patients in the individual level analyses of
response to methylphenidate. This finding is in the same direction of a previous study where the site of the study was not
related to variability in ADHD prevalence estimates (Polanczyk et al., 2007). These two studies differ in the sense that the
current one is not a systematic review and our results are related to the set of pharmacogenetic studies here included, which
is not necessarily the same for all methylphenidate trials for ADHD.
Age was significantly associated with improvement in ADHD symptoms in the pooled analysis. However, previous
studies suggest that MPH is equally effective in treating children and adolescents with ADHD (Findling et al., 2001).
Moreover, in a meta-analysis of ADHD trials, Faraone et al. (2004) reported a mean effect size of 0.9 for MPH treatment in
adults with ADHD, which is similar to the avarage effect size of methylphenidate for the treatment of school-age children
(Faraone et al., 2006). Althought differences were detected between different age groups, our results showed a robust clinical
improvement of ADHD symptoms regardless of age. Direct comparisons across age-ranges within the same study would
further illuminate this issue. Furthermore, we detected an association between the presence of ODD and a reduced response
to methylphenidate. Goez et al. (2007) evaluated the response to MPH in 1122 children with ADHD. The authors detected a
large subgroup of patients with comorbid ODD and anxiety disorders that presented significant lower response. On the other
hand, in 165 preschoolers treated with MPH, the presence of three or more comorbid disorders were related to the lack of
response to treatment, while one (primarily ODD) or two comorbidities were not related to a decreased response to treatment
(Ghuman et al., 2007). In the MTA Study, subjects with comorbid ODD and/or CD were similar to those without comorbidities
in terms of response to treatment. However, the comorbid subgroup presented persistent differences at the end-point,
indicating an unfavorable prognosis (Jensen et al., 2001). It is important to note that the evaluation of the role of comorbid
conditions in the treatment of ADHD is usually conducted with underpowered samples due to the prevalence of these
conditions. In this regard, pooled samples allow an adequate evaluation of these factors.
The identification of the study level characteristics of studies related to variability of results is recent, with three studies
conducted in the ADHD field to date (Faraone et al., 2004; Faraone et al., 2006; Polanczyk et al., 2007), although meta-
analysis is a frequently employed statistical technique. It is of interest, apart of detecting or not heterogeneity between results,
to study the influence of methodological characteristics on results variability, even if overall heterogeneity test are non-
significant, which can occur due to their low power (Thompson et al., 2002).
The aggregation of pharmacogenetic studies, in comparison to association studies, imposes an additional
methodological difficulty, since the measurement of the effect of intervention can be biased by a number of variables. This is
not a major problem within studies, since all patients are evaluated in the same manner, irrespectively of their genotype.
However, this can be a source of variability of results between studies. Our results point to the fact that joint analysis of
pharmacogenetic studies are possible, since no fixed variable, as the site where the study was conducted or ethnic
background of individuals, were related to results. Nevertheless, analyzes must be preferentially conducted in stratified
groups by the design of the study. In addition, we recommend, based on experts’ advice (Higgins et al., 2002; Thompson et
al., 2002), that future meta-analysis evaluate the role of study level characteristics on variability of results, independent of
results of heterogeneity tests. This will add to the understanding on what methodological characteristics are related to
variability of results, and for this reason must be kept fixed in replication studies. This may facilitate the planning of future
studies and, ultimately, appropriate data comparison.
References
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Table 1. Characterisitcs of included samples.
Site
Sample
size
Study design
Age
range
Rating Scale Rater
MPH
formulation
ES
(SE)
Boston, USA (Mick et al.,
2006)
104 RCT, parallel 20-62 ASRS clinician IR / OROS 0.62 (0.21)
Chicago, USA (Stein et al.,
2005)
44 RCT, crossover 5-16 ADHD-RS clinician OROS 0.83 (0.22)
Kyunggi, South Korea
(Cheon et al., 2007)
70
open study, no
control
6-12 ADHD-RS parent* IR / OROS 2.41 (0.22)
Manhaimen, Germany 34
open study, no
control
6-13 ADHD-RS parent IR 1.05 (0.26)
Paris, France(Purper-
Ouakil et al., submitted)
135
open study, no
control
6-17 ADHD-RS clinician IR/ LA/ OROS 2.11 (0.15)
Porto Alegre, Brazil
(Polanczyk et al., 2007)
106
open study, no
control
4-17 SNAP-IV parent IR 1.02 (0.15)
Porto Alegre, Brazil 165
open study, no
control
18-61 SNAP-IV subject IR 1.64 (0.13)
Utrecht, The Netherlands
(van der Meulen et al.,
2005)
82
open study, no
control
3-18 SWAN parent IR 1.90 (0.19)
Utrecht, The Netherlands
(Kooij et al., 2007)
42 RCT, crossover 20-56 ADHD-RS clinician IR 0.28 (0.22)
ADHD: Attention Deficit/Hyperactivity Disorder; MPH: methylphenidate; ES: effect size; SE: standard error; RCT: randomized controlled
trial; ASRS: World Health Organization Adult ADHD Self-Report Scale (Kessler et al., 2005); ADHD-RS: ADHD Rating-Scale (DuPaul et
al., 1998); SNAP: Swanson, Nolan, and Pelham Scale version IV (Swanson et al., 2001); SWAN: Strengths and Weakness of ADHD-
symptoms and Normal-behavior scale (Swanson et al., 2005); IR: immediate-release; LA: long-acting; OROS: osmotic release. *Report
from parents and teachers were available.
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Anexo 7
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