Newer developments in the management of Attention Deficit Hyperactivity Disorder
seen in children
INTRODUCTION:
Attention-deficit hyperactivity disorder (ADHD) is a common, early-onset
neuropsychiatric disorder that affects an estimated 3% to 7% of school-aged children and 1%
to 4% of adults worldwide. Behavioral features such as inattention, easy distractibility, too
much activity, and impulsivity constitute the disorder of ADHD. DSM-IV-TR recognizes
three subtypes of ADHD:
- i) a combined type
- ii) a predominantly inattentive type
- iii) a predominantly hyperactive-impulsive type.
International Statistical Classification of Diseases and Related Health Conditions ICD-10
requires both inattentive and hyperactive-impulsive behavior to make a diagnosis.
MANAGEMENT:
A quarter-century of published treatment studies and clinical experience attest to the
short-term effectiveness of both behavioral and pharmacologic strategies and the optimal
approach to treatment of ADHD combines pharmacological and behavioral intervention.
PHARMACOLOGICAL INTERVENTION
Studies of medication treatment in children with ADHD have shown that the agents
that are most effective target dopamine and/or norepinephrine receptors.
Stimulants are the mainstay of treatment. Stimulants taken orally, such as methylphenidate
(MPH), dextroamphetamine, and the combination of amphetamine (AMP) and
dextroamphetamine, are considered first-line treatment for ADHD. The mechanism of action
involves pre-synaptic inhibition of the reuptake through stimulation of inhibitory auto-
receptors and alteration in the functional activity levels of catecholamines. This action is
observed at both dopamine transporter (DAT) and the norepinephrine transporter (NET).
• Amphetamines. These include dextroamphetamine, dextroamphetamine-amphetamine
and lisdexamfetamine.
• Methylphenidates. These include methylphenidate and dexmethylphenidate.
Stimulant drugs are available in short-acting and long-acting forms. A long-acting patch of
methylphenidate (Daytrana) is available that can be worn on the hip.
Current thinking in ADHD therapy focuses on assessing duration of action and determining
which delivery system is appropriate for the patient. All the delayed delivery systems
decrease the abuse potential of the stimulant agents.
DRUG THERAPY OF ADHD:
METHYLPHENIDATE:
MPH is a psychostimulant drug approved for ADHD. It increases norepinephrine and
dopamine levels by inhibiting their reuptake and facilitating their release especially in the
dorsolateral prefrontal cortex that improves attention, concentration, executive function and
maintains wakefulness. Enhancement of dopamine actions in basal ganglia may explain the
improvement seen in hyperactivity symptom of ADHD with MPH.
MPH - IMMEDIATE RELEASE (MPH-IR):
Immediate release MPH (MPH-IR) has a short half-life of approximately 2 to 3 hours
MPH - EXTENDED RELEASE (MPH-ER):
MPH extended release formulation provides the benefit of a lasting effect that is maintained
even about 12 hours after dosing and is equivalent to twice- or thrice-daily dosing of plain
MPH.
MPH - OSMOTIC RELEASE ORAL SYSTEM (MPH-OROS):
This is a preparation of MPH with a novel drug delivery system using the osmotic pump
process as a release mechanism. It consists of a 50:50 racemic mixture of D, l-threo MPH. It
has a 12-hour coverage period per dose and, the release system being gradual, prevents any
form of tachyphylaxis.
MPH - MODIFIED RELEASE (MPH - MR):
This is a form of MPH that uses a release system made up of two types of coated beads
consisting of MPH-IR and MPH-ER in a 30:70 ratio.
METHYLPHENIDATE-EXTENDED RELEASE CAPSULES (ERC):
This is a preparation of MPH that uses the spheroidal oral drug absorption system (SODAS).
It has bimodal release profile with 50% of the drug i.e. d,l-threo MPH releasing initially and
the other 50% releasing after 3-5 hours. It thus provides 8-hour coverage.
D-THREO-METHYLPHENIDATE, D - METHYLPHENIDATE (D-MPH):
As originally formulated, MPH was produced as an equal mixture of D,l-threo-MPH and D,l-
erythro-MPH. It was later recognised that the erythro form of MPH was responsible for the
cardiovascular side effects of MPH, and thus MPH has been manufactured as an equal
mixture of D and L-threo MPH. Studies have revealed that the D form is the primary active
form of MPH.
MPH TRANSDERMAL PATCH:
MPH has been investigated for use as a transdermal patch in sizes of
- 6.25cm 2 (0.45mg/hour),
- 12.5cm 2 (0.9mg/hour)
- 25cm 2 (1.8mg/hour).
Such innovative yet investigational methods of drug delivery may pave the way for easy
drug administration in a regular manner throughout the day in children with ADHD.
MIXED AMPHETAMINE SALTS:
In recent years, both immediate and extended release preparations of MAS have been
studied in clinical trials. MAS tablets contain equal proportions of
- D-amphetamine saccharate,
D,l-amphetamine asparate,
- D-amphetamine sulfate
- D,l-amphetamine sulfate.
The two isomers have different properties and some children may respond better to one
isomer than the other.
MAS - EXTENDED RELEASE (MAS-ER):
The MAS-ER preparation contains a 50:50 ratio of immediate release beads designed
to release MAS in a fashion similar to MAS tablets and delayed release beads designed to
release MAS 4 to 6 hours after the dosing.
PEMOLINE:
Pemoline is a central nervous system stimulant structurally different from amphetamine and
MPH, and acts via enhancing central dopaminergic transmission.
LISDEXAMPHETAMINE (LDX):
Lisdexamfetamine dimesylate is an AMP prodrug that is inactive until metabolized.
LDX converts to dextroamphetamine in the blood stream due to the action of a peptidase
enzyme and provides a longer duration of effect that is consistent throughout the day. The
prodrug attenuates the onset and intensity of AMP-like effects and is less reinforcing than
equivalent doses of d-AMP, contributing to a lower abuse potential..
ATOMOXETINE:
Although stimulants have been proven safe and effective for the treatment of ADHD,
Atomoxetine is the only non-stimulant medication approved by the FDA for the treatment of
ADHD in children, adolescents, and adults. Atomoxetine inhibits the presynaptic
norepinephrine transporter, which is believed to improve efficiency in the norepinephrine
system and is associated with improved ADHD symptoms.
CLONIDINE AND GUANFACINE:
Alpha-adrenergic agonists have been recommended in patients with a suboptimal
response to psychostimulants, or in whom they cannot be tried. Studies have shown that
guanfacine extended release can be safely administered with MPH or amphetamine and gives
good clinical results in ADHD. The rationale for combining α-adrenergic agonists with
stimulants is the complementary mechanisms of action of the two classes of drugs involving
different neurotransmitter systems that together modulate prefrontal cortex functioning. An
alpha-2-adrenergic agonist, guanfacine may work in ADHD by affecting norepinephrine
discharge rates in the locus ceruleus, and this action may indirectly affect dopamine firing
rates.
BUPROPION:
Bupropion has been used in certain cases of ADHD. It is found to be useful in some cases of
ADHD coupled with nicotine dependence because of its primary effect on smoking cessation
MODAFINIL:
A novel stimulant distinct from amphetamine, modafinil has been FDA approved for
the treatment of narcolepsy and is easily available in Indian markets. It acts by activating
specific hypothalamic regions and is being reviewed for its effectiveness in ADHD. It is a
wake promoting agent and appears to selectively activate the cortex without generalized
effects on the central nervous system. Modafinil film-coated tablets may provide a novel
therapeutic option for the management of ADHD in pediatric and adolescent patients.
OTHER DRUGS WITH ANECDOTAL EVIDENCE:
Certain studies have shown the benefits of selective norepinephrine reuptake inhibitor
drug Reboxetine in the management of ADHD. Similar reports exist for Venlafaxine, a drug
from the same family . Selegiline, another drug, is an irreversible type B monoamine oxidase
inhibitor that is metabolised into amphetamine and methampetamine. Medications used to
slow the decline in Alzheimer's disease have also generated interest in enhancing
cognition in the treatment of ADHD.
Based on the high rates of cigarette smoking in adolescents in ADHD and the
cognitive enhancing properties of nicotine, transdermal nicotine has been tried in isolated
studies to improve the fronto-striatal attention networks in ADHD. At this point though,
nicotine is not a viable or recommended treatment, but remains a potential target for the
development of novel treatments. Theophylline, an adenosine receptor antagonist, is a
psychostimulant widely used as a bronchodilator. Adenosine antagonism may have an effect
on central dopaminergic and noradrenergic neurotransmission and may benefit in conditions
like ADHD. Other agents such as polyunsaturated fatty acids (PUFA), acetyl-L-carnitine, and
iron supplements have been shown to improve ADHD.
The cognition enhancing effects of methylphenidate and amphetamine involve
indirect stimulation of αlpha-2 adrenoceptors and D-1 dopamine receptors in the PFC.
Options for second-line agents include antidepressants such as tricyclic antidepressants,
particularly desipramine and imipramine, or venlafaxine.
NON-PHARMACOLOGICAL THERAPIES FOR ADHD:
Type of intervention Components Age group
Behavioral intervention a)Positive reinforcement; For children 4-6 years of age as
b)Time-out; primary therapy and
c)Response cost (withdrawing rewards/privileges Children >6 years of age and
adolescents, as therapy in
when problem behavior occurs) and
addition
d)Token economy (combination of positive reinforcement to medication
and response cost)
Educational
The classroom modifications and accommodations include Children 5 years and above;
intervention
1. Having assignments written on the board depends on the child’s capacity
2. Sitting near the teacher
3. Having extended time to complete tasks
4. Being allowed to take tests in a less distracting
environment
5. Receiving a private signal from the teacher when the
child
is ‘off-task’
6.Being assigned a ‘Study Buddy’
7.Being assigned a ‘Shadow Teacher’
INTERVENTION
All children with ADHD require psychosocial intervention to improve self-
observation or coping skills, and to enhance skills, which are often compromised by their
ADHD. Improvement in the core symptoms of ADHD, in academic performance, social
skills, defiant and aggressive behavior have been seen with the use of behavioral intervention
such as response cost for unwanted behavior and positive reinforcement.
Among psychosocial treatments, parent behavior management training has been the
most widely researched treatment option for school age children, and also those with co-
morbid oppositional defiant disorder or conduct disorder and has been shown to substantially
impact behavior and compliance. Parent behavior management training involves training
parents to implement behavior therapy programs in the home, to target both home and school
behavior, generally using contingency management approaches.
Parents are taught the principles of positive reinforcement, and a functional behavior
analysis is applied to the negative behaviors, and specific behaviors are pinpointed and their
frequencies tracked. It requires frequent manipulation of behavioral targets and reinforcers.
Cognitive behavioral therapy emphasizes problem solving, as well as anticipation and
consequences of action. One type of cognitive behavioral intervention targets social skills
directly, and is referred to as social skills training.
NEW MEDICAL DEVICE- MONARCH EXTERNAL TRIGEMINAL NERVE
STIMULATION (ETNS) SYSTEM :
The FDA approved a new medical device to treat children with ADHD who are 7 to
12 years old and not taking ADHD prescription medicine. Only available by prescription, it's
called the Monarch external Trigeminal Nerve Stimulation (eTNS) System. About the size of
a cell phone, the eTNS device can be used at home under parental supervision, when the child
is sleeping. The device generates low-level electrical stimulation which moves through a wire
to a small patch placed on the child's forehead, sending signals to areas of the brain related to
attention, emotion and behavior.
THE NEW FOREST PARENTING PACKAGE (NFPP):
The NFPP is a specialized ADHD psychosocial intervention that builds on the
approaches used in preschool by combining behavior management techniques with a novel
therapeutic component targeted directly at those parent-child processes thought to play a
mediating role in the development of attentional and self-organizing skills. This model is
based on the developmental literature relating to the important role played by constructive
and reciprocal parent child interactions during the preschool years in the psychological
development of attention and impulse control. In particular, children of parents who engage
in reciprocal, sensitive, and positive interactions, and effectively scaffold and motivate their
child’s attention and self-organization, display a developmental advantage over children of
parents who do not . Specifically, parents need to be supportive, aware of the child’s
developmental level, and set appropriate and challenging goals .
Key treatment goals in NFPP include
(i) Reduction of parental negative reactions
(ii) Promotion of appropriate limit setting as a basis for authoritative parenting
(iii) Increase in both the quality and quantity of positive and constructive interaction between
the parent and the child
(iv) Tailored motivation and scaffolding of attention and self-organizational competencies.
The Figure presents a schematic description of the structure of the NFPP as it is currently
formulated in terms of its goals and specific treatment targets and the week-byweek setting
for training.
ALTERNATIVE THERAPY:
Unsubstantiated approaches include electroencephalography, biofeedback training,
megavitamin therapy, herbal treatments, body and craniosacral manipulation, sensory
integrative training, and specific supplements. Use of integrative treatment model is
recommended for management of ADHD.
CONCLUSION:
The availability of extended release, delayed release, prodrug, and transdermal
stimulant formulations, as well as alternative non-stimulant agents, offers new options for the
pharmacotherapy of ADHD.
