Pipeline ADHD Attention Deficit Hyperactivity Disorder.

A.D.H.D. (Attention Deficit Hyperactivity Disorder).

What is ADHD?

Attention Deficit Hyperactivity Disorder (ADHD, an acronym for Attention Deficit Hyperactivity Disorder) is a neurodevelopmental disorder in children and adolescents, characterized, according to the criteria of the Diagnostic and Statistical Manual Of Mental Disorders (DSM-III; DSM-IIIR; DSM-IV), by inattention and impulsivity/hyperactivity.
Specifically, DSM-IV distinguishes three clinical forms: inattentive, hyperactive, and combined.

In the course of development, the same individual may evolve from one category to another, manifesting the three different psychopathological dimensions in varying ways at different age stages.
All these symptoms are not caused by cognitive impairment (mental retardation), but by objective difficulties in self-control and planning ability, are persistent in all contexts and situations of the child’s life causing significant limitation of daily activities.
Inattention or easy distractibility tends to present itself particularly as poor attention to detail and inability to complete tasks or games undertaken. Impairment of focal attention (the ability to pay attention to a given stimulus, neglecting irrelevant details that are not useful to the task at hand) and sustained attention, i.e., the ability to maintain active attention over time while performing schoolwork, homework, play, or simple daily activities, is present. Impulsivity manifests as an inability to procrastinate in time in response to an external or internal stimulus. Typically, children with ADHD always respond without thinking, they almost never manage to wait their turn in daily activities or games; they often get involved in dangerous activities without adequately assessing the consequences (sometimes causing physical harm to themselves or others). Impulsivity is generally associated with hyperactivity: these children are described as “like being moved by a moped,” they cannot sit still, if seated they move with their hands or feet, they frequently have the urge to get up and move without a specific purpose or goal. This is accompanied by a subjective internal feeling of tension, pressure, and instability that must be discharged (this subjective feeling often becomes prevalent in adolescence or adulthood, when motor hyperactivity is reduced).
Children with ADHD show, especially in the absence of an adult supervisor, a rapid attainment of a high level of “fatigue” and boredom that is evidenced by frequent shifts from one activity, not completed, to another, loss of concentration and inability to complete any task or game protracted over time. In most situations, these children have difficulty controlling their impulses and postponing a gratification: they fail to think before they act, to wait their turn, to work for a prize far away in time even if it is substantial. When compared with peers, these children show excessive motor activity (such as constantly moving their legs even while sitting, fiddling or throwing objects, moving from one position to another).
Hyperactivity at these levels impairs adequate performance of required tasks. The inability to remain attentive and control impulses means that, often, children with ADHD perform less well in school and develop their cognitive skills with greater difficulty: they frequently show poor skills in the use of social norms of living together, particularly in those skills of grasping those nonverbal social indices that modulate interpersonal relationships.
This results in significant interference in the quality of relationships between these children and the world around them. Normal hyperactivity, impulsivity, and attentional instability do not result in significant functional consequences; true Attentional Deficit Disorder with Hyperactivity results in negative short- and long-term consequences.

DIAGNOSIS OF A.D.H.D.

According to the Diagnostic Manual of Major Psychological Disorders (DSM-IV 2002), which is generally referred to internationally, a whole set of characteristics below must be present in order to make a diagnosis of ADHD:

To diagnoseADHD, there must be six (or more) of the following symptoms that are persistent for at least 6 months with an intensity that causes maladjustment and contrasts with developmental level, specifically:

For the Inattention criterion, the symptoms are:

• Often fails to pay attention to details or makes distracting errors in schoolwork, work, or other activities
• Often has difficulty maintaining attention on homework or play activities
• often does not seem to listen when spoken to directly
• Often fails to follow instructions and complete school assignments, tasks, or duties in the workplace (not because of oppositional behavior or inability to understand instructions)
• Often has difficulty organizing himself in tasks and activities
• Often avoids, feels aversion to, or is reluctant to engage in tasks that require protracted mental effort (such as schoolwork or homework)
• often loses items needed for homework or activities (e.g., toys, schoolwork, pencils, books or tools)
• Is often easily distracted by extraneous stimuli

For the Hyperactivity criterion, the symptoms are:

• Often restlessly moves hands or feet or fidgets in the chair
• Often leaves his or her seat in class or other situations where he or she is expected to remain seated
• often scurry and jump everywhere excessively in situations where this is inappropriate (in adolescents or adults, this may be limited to subjective feelings of restlessness)
• Often has difficulty playing or engaging in leisurely entertainment
• Is often “under pressure” or acts as if it were “motorized”

For the impulsivity criterion, the symptoms are:

• Often “shoots out” answers before questions have been completed
• Often has difficulty waiting his turn
• Often interrupts others or is intrusive toward them (e.g., intrudes into conversations or games)

What are the causes of ADHD?

ADHD is a complex disorder that is determined by several components:

Organic component.

Research indicates that children with ADHD have some areas of the brain smaller than children who do not have this disorder; in particular, a neuroimaging study published in The American Journal of Psychiatry (AJP) demonstrates for the first time morphological abnormalities in the brains of children with ADHD (A. Qiu, D. Crocetti, M. Adler, , E. M. Mahone, M. B. Denckla, M. I. Miller, S. H. Mostofsky, Basal Ganglia Volume and Shape in Children With Attention Deficit Hyperactivity Disorder, Am J Psychiatry, Nov. 18, 2008). Specifically, researchers from the Kennedy Krieger Institute in Baltimore and the Johns Hopkins Center for Imaging Sciences found in male children with ADHD, in addition to overall volumetric reductions in the brain, already demonstrated in previous studies, significant morphological abnormalities of the basal ganglia (caudate nucleus, putamen, and globus pallidum) are evident compared to a reference sample.

There would seem to be, therefore, a recurrent and particular organic feature, so it is quite likely that this neurobiological difference is related in some way to the disorder.

In an experiment carried out through MRI (functional magnetic resonance imaging), significant differences were observed between the brains of a child who does not have ADHD and a child who has ADHD.

In this experiment, both children were asked to perform an attention task, such as reading, writing or summarizing something. In the MRI image, it was noticed that in the brain of the child who does not have ADHD, the area of the frontal lobes, which are in charge of, among other things, regulating attention, is activated; in fact, it is shown to be colored red, while in the other image, that of the child with ADHD, this area is not activated at all, and it is noticed that instead a whole series of other areas are activated, as if the brain is trying to compensate for the deficit.

Genetic component

Genetic factors also seem to come into play. In fact, research on homozygotic twins suggests that a child with ADHD has an 80 percent chance of having a homozygotic twin who has the same disorder. While dizygotic twins, that is, those who do not have the same genetic makeup, have a 30 percent chance of developing the disorder. This information suggests that the heredity factor plays an absolutely important role. Another aspect is that the disorder is more prevalent in males than in females in a ratio of 8 to 1. So in most cases these are male children, and this also points us back to a genetic component.

Environmental component

The environmental component concerns everything that surrounds and/or is subjected to a child with A.D.H.D., namely:

• behavior of people around him (parents, family members, teachers),
• Physical organization of the surrounding furnishings and objects
• Setting up the rutinary activities that are proposed to them

The environmental components described above play a very important role in the progression or regression of ADHD. The more appropriate the above environmental components surrounding the child, the better the response in terms of improving ADHD symptoms.

Current possible treatments for ADHD

Individuals with ADHD may undergo the following therapies:

– pharmacological

– psycho-behavioral

– combined (psycho-behavioral and pharmacological)

The medications currently in use for the treatment of ADHD

Psychostimulants are considered the most effective therapy for ADHD, and methylphenidate is the drug for which, to date, the most experience has been gathered. Psychostimulants act on transporters for monoamines: methylphenidate mainly modulates the amount of dopamine, and norepinephrine, present in the intersynaptic space. It potentiates a deficient dopaminergic transmission and attenuates a state of dopaminergic overactivity. It can improve response inhibition, working memory and stimulus discrimination processes.

Methylphenidate

Methylphenidate (Ritalin®) is the drug of choice for the treatment in drug therapy of ADHD. Methylphenidate is administered according to body weight, averaging 0.3-0.6 mg/kg/dose in two” three doses per day. Methylphenidate gastrointestinal absorption is rapid and nearly complete. Oral administration of methylphenidate induces a plasma peak after one to two hours with elimination half-life of 3-6 hours: the drug begins to show clinical activity about half an hour after oral administration, reaches peak activity after one hour, for a therapeutic duration of about 2-5 hours. Therefore, methylphenidate is usually administered 2-3 times a day. However, there is considerable variability in clinical response among individuals, and efficacy does not appear to correlate with plasma levels of the drug.

Methylphenidate is used in most European Union countries and many other states: U.S., Australia, India, Canada, Chile, Hong Kong, England, Iran, Israel, Malaysia, Mexico, the Netherlands, New Zealand, South Africa, Singapore, and Venezuela.

The benefits

The results of some controlled clinical trials have shown that methylphenidate is effective in about 70% of children with ADHD. The therapeutic effect is rapid. One week of treatment is usually sufficient to achieve assessable benefits in the school setting as well: increased attention, ability to complete assigned tasks, as well as a reduction in impulsivity, distraction, and conflicting interpersonal interactions. In studies to date, it has been noted that the same dose of methylphenidate can nevertheless produce positive, negative or no changes in children with ADHD, depending on the assessment method used. This paradox highlights the heterogeneity of assessment methods used in clinical trials to date, ranging from subjective parental perception of improvement, to outpatient clinical assessments, to analysis of the child’s school performance. About 30% of children with ADHD do not respond to methylphenidate. Factors that appear to limit the drug’s efficacy include: the predominance of anxiety and depression in the symptom picture (symptoms that in children with ADHD methylphenidate ameliorates), the concomitance of organic and neurodevelopmental lesions, and the presence of unfavorable socioeconomic and environmental conditions. All of which also lead back to the difficulty and heterogeneity of the diagnostic definition of this syndrome. While efficacy in the short term is well documented, few studies to date have examined the long-term effects of methylphenidate. The results obtained did not show improved social integration or attainment of higher levels of schooling in treated patients compared with controls. It follows that the evidence to date supports the use of the drug only for a short period of time and as part of non-drug therapy.

A meta-analysis of the literature data available to date indicates that, regardless of whether methylphenidate sensitization is present, early exposure to drug treatment of children with ADHD, rather than promoting, prevents psychotropic substance abuse in adolescence or young adulthood (Odd Ratio 1.9; Wilens et al. 2003). Possible mechanisms of such a protective effect include: reduction of ADHD symptoms, especially impulsivity; improvement in school performance and relationships with peers and key adults; possible reduction of progression to conduct disorder and later to antisocial personality disorder (Taylor et al. 2004).

The FDA recently asked manufacturers of stimulant drugs used in the treatment of ADHD to add a new warning about adverse effects to the cardiovascular system.

Atomoxetine

Atomoxetine is a selective norepinephrine reuptake inhibitor for the treatment of ADHD in children over 6 years of age, adolescents and adults. It is not known how the drug reduces symptoms in attention deficit hyperactivity disorder, however, norepinephrine is believed to play an important role in regulating attention, impulsivity, and activity levels. Atomoxetine was first introduced to the market in the US in November 2002 and then later in the UK in May 2004; it is already on the market in the states of Singapore, Hong Kong and Canada. In all European Union countries (except France), following mutual recognition, procedures for marketing the drug are currently under way. During the first week of therapy, Atomoxetine is administered in daily doses of 0.5mg/kg, with gradual increase to the intermediate maintenance dosage of 0.8mg/kg die. Administration is once a day: in case of tolerability difficulties it can be divided into two times.

The benefits

The efficacy of atomoxetine was evaluated through 8 placebo-controlled studies conducted in about 1,500 patients, of whom more than 1,000 were children and adolescents. Some of the patients, both pediatric and adult, were followed in open-label studies for several years (time period of more than 3 years) to obtain data on the efficacy and safety of long-term treatment. To date, there is no clear evidence about long-term efficacy and the actual need for prolonged treatment beyond 3-6 months. Regarding the safety of the drug, it should be noted that during 2005, both the EMEA and the Food and Drug Administration (FDA) alerted medical personnel and patients about the increased risk of suicidal thoughts in children and adolescents on atomoxetine therapy. The increased suicide risk was identified in a meta-analysis of several trials lasting from six to eighteen weeks.

The study showed that 0.4 percent of children treated with atomoxetine manifested suicidal thoughts while no such cases were reported in those treated with placebo. A similar analysis was performed among adults with ADHD or depression: there was no increase in self-injurious behaviors in these subjects. Regulatory authorities have decided to have updated warnings about the risk of suicidal ideation and behavior included in the product data sheet to call attention to the fact that teens who are starting atomoxetine therapy should be monitored closely for abnormal behavioral manifestations, suicidal thoughts, or worsening psychiatric clinical picture. Special attention should also be paid to cardiovascular effects that may be induced by the drug.

The FDA recently asked manufacturers of stimulant drugs used in the treatment of ADHD to add a new warning about adverse effects to the cardiovascular system while rejecting recommendations reported by a pro-black box panel regarding the possible risk of sudden death-this information was included in the drug’s general warnings. The FDA had sent a letter in May 2006 directly to sponsors to reinforce precautions for use.

A new warning about the risks of cardiovascular and psychiatric events produced by atomoxetine in the treatment of ADHD has been produced and added by a well-known manufacturer. It is possible that the risk reported for this drug reflects differences in the mechanism of action of atomoxetine.

New drug product under study for the treatment of ADHD

Given the manifestation of significant side effects referred to the traditional drugs innately indicated for the treatment of ADHD, Nevia Biotech’s research team has identified the possible use of a molecule endogenous to the human body capable of developing therapeutic actions similar to that of methylphenidate and atomoxetine, but without the evidence of the severe side effects inherent in these drugs.

Currently, ongoing studies are focused on the preclinical phase of drug development.