Attention Deficit Hyperactivity Disorder

What is ADHD?

ADHD affects about 5% of children worldwide, regardless of culture. It is more than 2-fold more
common in boys and over half of children with ADHD continue to suffer from this disorder as adults.
Diagnosis of ADHD is based on ‘hyperactivity’ (e.g. inability to sit still, lack of organisation),
‘inattentiveness’ (forgetful, poor concentration, abandoning tasks before completion) and
‘impulsivity’ (acting without considering the risks, interrupting). These three features must be
evident before the age of seven; they must be present in at least two settings (e.g., school,
workplace or home); and they must last for at least 6 months. The expression of ADHD by patients is
described as either: Predominantly Inattentive (more common in girls), Predominantly Hyperactive /
Impulsive (more common in boys) or Combined type (Inattentive and hyperactivity/impulsive), but
these are not fixed subtypes and they can change with time in individual patients. For instance,
hyperactivity usually disappears as children approach adulthood, although a feeling of ‘restlessness’
persists.

Diagnosing ADHD can be difficult because all these behaviours are often evident in healthy
people to some extent. In ADHD, the chaotic behaviour is so intrusive that it undermines people’s
ability to cope with the demands of daily life. Another factor that can obstruct a definitive diagnosis
is that nearly half of children with ADHD have behavioural problems that overlap with other
disorders. These include Conduct Disorder and Oppositional Defiant Disorder in which antisocial
behaviours are prominent: e.g., aggression, harm to other people and environment, dishonesty,
disobedience.

ADHD is not primarily a learning disorder and the IQ range of patients is normal. Nevertheless,
inattentiveness, hyperactivity and impulsivity can impair performance and so children with ADHD
are often under-achievers, academically. They also tend to have difficulty in making friends, they
alienate their peers and have poor control of their emotions. All these problems can exacerbate
anger, frustration and isolation of children with ADHD and lead to complex social problems in
adulthood.

Other problems experienced in ADHD

The difficulties experienced by ADHD patients are not limited to performance at school or at work.
Social and other psychiatric (‘co-morbid’) problems are also common in ADHD. These include:
inability to sleep normally, aggression, anxiety, obsessive-compulsive behavior, depression, suicidal
thoughts, drug misuse (particularly opiates and alcohol) and criminal behaviour. ADHD patients also
have an increased incidence of physical ill-health (e.g., asthma, headaches and obesity). The extent
to which these co-morbid problems develop because patients find it difficult to cope with adult life,
or whether there are direct biological causal links, is not known.

What are the causes of ADHD

There is some unconfirmed evidence that this disorder is more common in the children of mothers
who smoke, or drink alcohol, while they are pregnant. Otherwise, there seems to be no single cause
of ADHD. Instead, findings from clinical studies tell us that many different biological and
environmental factors could each slightly increase the risk of developing this disorder and that
genetic inheritance accounts for about 75% of all cases.

Many different gene variants seem to be associated with ADHD, but none actually causes
this disorder. Gene variants that have been found most frequently are those that modify the
function of neurones in the brain that release the neurotransmitters, norepinephrine, serotonin or
dopamine. These findings are particularly interesting because these neurones are the target for all
the medicines that are currently used to treat ADHD. Two genes, in particular, show a fairly
consistent association with ADHD. One of these, DRD5 (the gene for the D5 dopamine receptor
subtype) affects the intensity of the response to dopamine after it has been released from neurones.
The other, DAT (the gene for the dopamine transporter), regulates the duration of this dopamine
signal.

publicinfo-adhd

Another gene of interest is tacr1 (also known as NK1R), which encodes a receptor for the
neurotransmitter, substance P, is being investigated by our research group at University College
London. Mutant mice, which lack this gene, are inattentive, hyperactive and impulsive (Yan et al.,
2011). Regulation of dopamine-, norepinephrine- and serotonin-releasing neurones in their brain is
also disrupted (Yan et al., 2010). Our studies with these mice led to the discovery of an association
between specific variants in the tacr1 gene and ADHD (Yan et al., 2010; Sharp et al., 2009). There is
also overlap between mutations in the tacr1 gene of ADHD patients and those found in alcoholism
and bipolar disorder. This is interesting because alcoholism is common in ADHD and the incidence of ADHD is increased in children of parents with bipolar disorder.

It has even been suggested that some
children with ADHD could be expressing a childhood form of bipolar disorder.
Recently, rare genetic abnormalities have been found that are more common in patients
than people without ADHD. These comprise repeated deletions of genetic information from single
chromosomes: so-called copy number variants (‘CNVs’). CNVs in ADHD patients point to functional
disruption of another neurotransmitter, glutamate. Current research is investigating whether or not
these CNVs are associated with subtypes of ADHD and whether they are associated with other
psychiatric illnesses, such as autism, schizophrenia and learning disorders, which have some features
in common with ADHD.

What is going wrong in the brain?
Both clinical and pre-clinical research into the causes of ADHD point to three brain regions: the
prefrontal cortex, the striatum and cerebellum. The prefrontal cortex deals with the processes
needed to plan ahead, solve puzzles and to learn ‘rules’ (so-called executive function) whereas the
striatum looks after pre-programmed sequences of movements (such as riding a bicycle or driving a
car). Both these regions are recruited in the brain’s response to environmental stimuli that are either
pleasurable or stressful. The cerebellum has an important role in learning and co-ordinating
movement. It is thought that ADHD arises from disruption of neuronal circuits that connect the
prefrontal cortex with striatum and cerebellum. The prominence of brain regions concerned with
movement in these circuits may help explain the high incidence of dyspraxia (clumsiness) in ADHD
patients and well as their hyperactivity and impulsivity.

Magnetic resonance imaging (MRI) has been used to look for abnormalities in the brain of
AHDH patients. The details of findings vary markedly from study to study, possibly because of
differences treatment status and patients’ co-morbidity. Nevertheless, most studies find that the
volumes of the frontal cortex, striatum and cerebellum are smaller in children with ADHD suggesting
that their brain matures more slowly than in healthy children of the same age. Patterns of
asymmetry in the volumes of brain regions on the two sides of the brain (suggesting functional
dominance) seems to be disrupted in ADHD as well, although details are still unclear. We have
found similar abnormalities in the brains of NK1-/- mice, also.

Drug treatments and their side-effects

In the UK, only three medicines are licensed to treat AHDH. The two leading treatments are
dexamfetamine (Dexedrine®) and methylphenidate (Ritalin®, Concerta® XL, Equasym XL®,
Medikinet XL®). In high doses both of these drugs increase arousal but when given to children with
ADHD, they are used in low doses that reduce arousal. Moreover, there is convincing evidence that
early treatment with these drugs reduces the incidence of drug misuse by adult ADHD patients.

Both dexamfetamine and methylphenidate augment the signal from neurones that release
monoamine transmitters in the brain, particularly dopamine. At low doses, both drugs prolong the
dopamine signal by blunting its removal from the synapse. At higher doses, dexamfetamine directly
increases release of dopamine from the nerve terminals and so intensifies the dopamine signal. The
third drug used to treat AHDH in the UK is atomoxetine (Strattera®). This drug also slows down the
clearance of neurotransmitters from the synapse and so prolongs the signal but, unlike
methylphenidate, atomoxetine mainly targets the norepinephrine transporter. When used to treat
ADHD, all these drugs are used in low doses that are unlikely to have any harmful effects.
Nevertheless, some caution is indicated, particularly with patients who have cardiovascular
problems (e.g. high blood pressure), glaucoma, or a history of epilepsy.

Lisdexamfetamine and guanfacine are licensed to treat ADHD in the USA, but not the UK.
After ingestion, lisdexamfetamine is metabolised to d-amphetamine, which augments neuronal
signals in the brain (see above). Guanfacine mimics the effects of norepinephrine by binding to, and
activating, (?2) receptors in the brain. This activation improves mental concentration, which is
helpful in ADHD. However, activation of ?2-adrenoceptors also reduces blood pressure and induces
sedation. As a consequence, the potential side-effects of guanfacine are quite different from those
of other ADHD treatments: namely, fatigue and a fall in blood pressure, which can make people feel
giddy or faint.

Buproprion and modafanil have also been tried in ADHD. Both compounds block reuptake of
dopamine to some extent but, in the case of modafanil, it is not at all certain that inhibition of
dopamine uptake is its main mechanism of action. In fact, it has not been established that either of
these drugs has any beneficial effect in ADHD and neither is licensed for this purpose. In any case, a
potentially harmful side-effect of modafanil means that this drug is not approved for treatment of
any clinical condition in children under the age of 17.

The treatment of adults with ADHD presents particular problems, partly because options are
so limited and partly because of the reluctance to prolong treatment with psychostimulants. The
therapeutic challenges, unanswered questions and evidence-based views of the best treatment
strategies are discussed in Guidelines published by the British Association for Psychopharmacology
(Nutt et al., 2007).

Finally, a striking limitation of established drug treatments is that they are ineffective in about
25% of ADHD cases. There is a clear unmet need for developing new approaches to drug treatment
of ADHD, based on a strong scientific rationale, that could help these patients too. Our group is
working on the possibility that NK1 receptors and their downstream targets offer such an
opportunity for drug discovery and development.

References

Nutt DJ, Fone K, Asherson P, Bramble D, Hill P, Matthews K, Morris KA, Santosh P, Sonuga-Barke E, Taylor E, Weiss M, Young S; British Association for Psychopharmacology. (2007) Evidence-based guidelines for
management of attention-deficit/hyperactivity disorder in adolescents in transition to adult services and
in adults: recommendations from the British Association for Psychopharmacology. J Psychopharmacol.
21:10-41. Epub 2006 Nov 8.

Yan TC, Hunt SP, Stanford SC. (2009) Behavioural and neurochemical abnormalities in mice lacking functional
tachykinin-1 (NK1) receptors: a model of attention deficit hyperactivity disorder.
Neuropharmacology.57:627-35.

Yan TC, McQuillin A, Thapar A, Asherson P, Hunt SP, Stanford SC, Gurling H (2010) NK1 (TACR1) receptor gene
‘knockout’ mouse phenotype predicts genetic association with ADHD. J Psychopharmacol. 24:27-38.

Yan TC, Dudley JA, Weir RK, Grabowska EM, Peña-Oliver Y, Ripley TL, Hunt SP, Stephens DN, Stanford SC.
(2011) Performance deficits of NK1 receptor knockout mice in the 5-choice serial reaction-time task:
effects of d-amphetamine, stress and time of day. PLoS One. 2011 Mar 7;6(3):e17586.

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