Cross-sectional study of 24-hours blood pressure measures and left ventricular mass using echocardiograms in late adolescents and adults with ADHD.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common
behavioural disorders of childhood, characterized by the early onset of
age-inappropriate hyperactivity, impulsivity and inattentiveness, and a
world-wide pooled population-prevalence of 5.3 % (Polanczyk et al. 2007). The
current psychiatric disease classification system, DSM-IV, distinguishes three
subtypes: a mainly inattentive, a mainly hyperactive-impulsive and a combined
subtype (American Psychiatric Association (APA), 2000).
ADHD is strongly persistent over time. Approximately 15% of the patients still
meet full ADHD criteria according to the DSM-IV in adulthood, whereas 40-60%
remits only partially and has increased symptom counts as adults (Faraone et
al. 2006). Given the high burden of ADHD and associated problems on the
patient, the family environment and on society as a whole, the need for
effective treatment is eminent. Clinical guidelines and practice parameters
describe the pivotal role of medication in the clinical management of ADHD
(National Institute for Health& Clinical Excellence (NICE), 2009; Scottish
Intercollegial Network Guidelines (SIGN), 2009; Pliszka, 2007; Taylor et al.
2004; Banaschewski et al. 2006). These recommendations are based on numerous
clinical trials that have shown both psychostimulant and non-stimulant
medication to be highly efficacious in treating ADHD with a percentage of
clinical responders around 70% or higher. Therapeutic effects of medication
include a reduction of the hyperactivity, impulsivity, and inattention
characteristic of patients with ADHD, and improvement of associated behaviors,
including on-task behavior, academic performance, and social functioning
(Greenhill et al. 2002).

The most commonly prescribed medications are the psychostimulants
methylphenidate and other amphetamines. Methylphenidate and dexamfetamine
belong to a group of drugs known as central nervous system stimulants. The
mechanism by which stimulants act in reducing symptoms in ADHD is not
completely clear, however it is believed that they inhibit the reuptake of
dopamine and noradrenaline into the presynaptic neuron and increase their
release into extraneuronal space thus increasing intrasynaptic concentrations
(Faraone & Biederman, 1998).

However, as ADHD is a rather chronic condition, medication treatment typically
will be extended over a long period of time, up to several years. The main goal
of this protocol is to examine the long-term effects of methylphenidate on the
cardiovascular system and in particular on blood pressure and on left
ventricular mass. We focus on methylphenidate because it is the most often
prescribed psychostimulant. Before we develop our research question in somewhat
greater detail, we briefly review what is known about cardiovascular effects of
methylphenidate.

Stimulants and heart rate and blood pressure

Stimulant medication is recognised to result in a small increase in heart rate
averaging 1 - 2 beats per minute (Vetter et al 2008). Taking the average value
in clinical studies hides a small proportion where the increment is larger; an
increase of up to 50 beats per minute has been observed on rare occasions.
Unfortunately, clinical trial data are rarely reported in a format that allows
the incidence of clinically significant tachycardia to be quantified. In
addition there is a lack of data on the longer term impact of methylphenidate
on heart rate and the lack of appropriate controls in such studies.
Methylphenidate, like other stimulant drugs, is also well known to have small,
short term effects on blood pressure. In clinical trials, children treated with
methylphenidate showed increases in systolic and diastolic blood pressure of
1-4 mmHg on average compared to those treated with placebo. A more relevant
measure of risk, however, would be whether increases resulted in children
entered the category of hypertension i.e. when blood pressure exceeds the 95th
percentile, and if so how many children/young people are affected in this way.
For this categorical measure, controlled trial data are not available for
methylphenidate but data for atomoxetine (which has a comparable effect on mean
blood pressure) suggested that elevations above the 95th percentile are seen in
6.8 % of patients (systolic) and 2.8% (diastolic) in comparison to 3% and 0.5%
respectively in patients treated with placebo (Wernicke et al 2003). There are
inadequate data at any stage of therapy, not just in the longterm and it
remains to be established whether similar figures apply for methylphenidate.
Because of the association between hypertension and socioeconomic status,
studies will require socioeconomic status matched controls in addition to
untreated ADHD controls.

Primary Objective:
To determine whether the long*term use of methylphenidate (> 3 years) increases
the blood pressure and causes left ventricular hypertrophy (LVH) identified by
echocardiography in late adolescent (>=15 years) and young adults with ADHD.

Secondary Objectives:
1) To explore the role of potential mediators, moderators and confounders e.g.
age, sex, socioeconomic status, family functioning, comedication, negative
lifestyle factors, weight and familial cardiovascular risk, in the relationship
between methylphenidate treatment and the effects on blood pressure and
echocardiogram.
2) To describe the dose*response relationship (dosage, duration of treatment,
discontinuation vs. continued use) between methylphenidate exposure and the
effects on blood pressure and echocardiogram.

This is an observational study, conducted within The European Network for
Hyperkinetic Disorders (EUNETHYDIS) a well established network of child and
adolescent mental health researchers all of whom are experts in researching
ADHD and many of whom are experts in paediatric psychopharmacology and
pharmacovigalence. EUNETHYDIS has been recognized by the European Network of
Paediatric Research at the European Medicines Agency (EnprEMA) and/or within
the framework of IMpACT (International Multi-site persistent ADHD). IMpACT is a
network of academic sites with strong clinical and research interest in adult
ADHD in Europe (Nijmegen, Barcelona, London, Dundee, Budapest), Brasil and the
USA (Boston). We will also recruit patients with ADHD from child and adolescent
psychiatry clinics, in close collaboration with sites participating in
observational studies in children and adolescents with ADHD in the framework of
the ADDUCE grant.

This study will use a cross-sectional design to compare two groups of patient
with ADHD: a group of late adolescent and young adult subjects with ADHD,
treated with methylphenidate for > 3 years, and a matched group of late
adolescent and adult subjects with ADHD who have never been treated with
methylphenidate.

This is an observational study, and all procedures are very standard, and
without increased risks. Benefits are formed by a systematic and thorough
monitoring of adverse events.