Attention Deficit Hyperactivity Disorder (ADHD)
Diseases

Guido Bussone
Guido Pastorini

ADHD, and its treatments, remains one of the most controversial area of psychiatry.
In this research, our aim is to highlight the link between Iron deficiency, Zinc deficiency, Magnesium deficiency and ADHD (Attention-Deficit/Hyperactivity disorder) .

IRON DEFICIENCY AND ADHD

Iron is a coenzyme of tyrosine hydroxylase, which is critical in dopamine synthesis. Iron dependent enzymes in the brain.1988.
Iron is also related with monoamine oxidase, which is critically related with degradation of dopamine. Iron is localized with dopaminergic neurons in the brain. D2 and D4 receptor and dopamine transporter densities decrease with decreased brain iron levels Iron status and distribution on iron in the brains of the developing rats.1997.

A proof of this theory is the study of Eric Konofal where he confronted a group of children affected with ADHD with a control group (age- and sex-matched) evaluating the serum ferritin level.
These are studies done in children from the same school district that were referred to an university pediatric hospital for school related problems (between 2002 and 2003).
The results were that the mean serum ferritin levels were lower in the children with ADHD than in the controls . Serum ferritin levels were abnormal (30 ng/mL) in 84% of children with ADHD and 18% of controls.

In addiction, lower ferritin levels were associated with higher behavioral problems Nutritional iron deficiency and dopamine binding sites in the rat brain. 1982.

But the connection between Iron deficiency and neurological disorders was also seen in another study where were made experiment on rats with Iron deficiency.
Here they investigated the possibility that iron-deficiency may affect postsynaptic events at the level of receptor by measuring the specific binding sites of several neurotransmitters in different brain areas. The results clearly show that iron deficiency causes a significant (40–60%) reduction of the dopamine D2 binding sites.
These elements suggest that iron-deficiency is correlated to low dopamine brain level, responsible for the disease.
Postnatal iron deficency.

ZINC AND ADHD

Role of Zinc

1. Zinc is an important cofactor for metabolism relevant to neurotransmitters, prostaglandins, and melatonin
2. Indirectly affects dopamine metabolism.
3. It is necessary for 100 different metalloenzymes and metal-enzyme complexes .
4. It contributes to the structure and function of the brain. One example is a coenzyme with delta-6-desaturase, which is necessary for anabolism from dietary linolenic and linoleic acid of the longchain polyunsaturated fatty acids that make up neuronal membranes .
5. It is needed for cell membrane stabilization
6. Indirect antioxidant functions
7. Proper hormonal metabolism
8. Cellular energy release
9. Zinc is necessary for the conversion of dietary pyridoxine (vitamin B6)to its active form, pyridoxal phosphate. In this form, vitamin B6 is necessary for the conversion of tryptophan to serotonin

In conclusion Zinc is necessary for the production and modulation of melatonin, which helps regulate dopamine function, and for the conversion of dietary pyridoxine to its active form, pyridoxal phosphate, which is necessary for the conversion of tryptophan to serotonin . Both the dopamine and serotonin neurotransmitter systems appear to be involved in ADHD which is widely believed to be a key factor in attention-deficit/hyperactivity disorder(ADHD) Zinc deficiency in attention-deficit/hyperactivity disorder.1990.

The relation to brain and other central nervous system (CNS) functions is also suggested
by the effects of zinc deficiency. Some evidence from both animal and human studies suggests that zinc deficiency may affect cognitive development, though the mechanisms remain unclear.
Zinc deficiency has been identified in children from many parts of the world, especially in newly developing countries.

Numerous controlled studies report cross-sectional evidence of lower zinc tissue
levels (serum, red cells, hair, urine, nails) in children who have ADHD, compared to normal
controls and population norms Zinc in Attention-Deficit/Hyperactivity Disorder. 2005.

The connection between lack of zinc and ADHD was investigated in a study of 1996.
The study involved 43 children aged between 6 and 16 years of (average age 10) who were formally diagnosed with ADHD via a full psychiatric assessment. 90% were male, and 21 were receiving stimulant medication. They were compared with 28 normal children (recruited through a pediatric clinic) who were matched for age and sex.
The study found out that zinc levels in the ADHD group were significantly lower than in the non-ADHD labeled group.
We have to consider that zinc is an essential co-factor in a huge number of different processes in the brain and body.
It seems that zinc deficiencies have been linked to a hyperadrenal syndrome and also with reduced production of melatonin and serotonin. All these factor could contribute to the behavioral disturbances that we can found in ADHD Zinc deficiency in attention-deficit hyperactivity disorder.1996.

These findings lead naturally to hypotheses that improving zinc nutritional status might
improve the response to stimulants or might even have a beneficial effect independent of
stimulants, or at least might lower the stimulant dose needed for benefit.
Several studies have examined the potential treatment effects of zinc on ADHD symptoms in children, with some suggestion that, as in depression, zinc may enhance the treatment effects of traditional treatments for ADHD Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder.2004.

Furthermore zinc deficiency causes the shortage of the complex omega-3 and omega-6 fatty acids Does zinc moderate essential fatty acid and amphetamine treatment of attention-deficit/hyperactivity disorder?.2000.
Zinc is an essential co-factor in the synthesis of HUFA (highly unsaturated fatty acids) from EFA (essential fatty acids).
In fact Omega-3 fatty acids are dietary essentials, and are critical to brain development and function. Both omega-3 and omega-6 fatty acids are essential to human health but must be provided by the diet.

The longer-chain, highly unsaturated fatty acids of each series are the most important for brain development and function, especially in dopaminergic system, notably the omega-6 arachidonic acid (AA) and the omega-3 eicosapentaenoic and docosahexaenoic acids (EPA and DHA).

Increasing evidence suggests that a relative lack of omega-3 may contribute to many psychiatric and neurodevelopmental disorders. Theory and experimental evidence support a role for omega-3 in ADHD, dyslexia, developmental coordination disorder (DCD) and autism. In fact Dietary supplementation with fish oils appears to alleviate ADHD-related symptoms in at least some children Omega-3 fatty acids in ADHD and related neurodevelopmental disorders.2006.

MAGNESIUM AND ADHD

Magnesium is a mineral. It is the 4th most abundant element in our body.
Studies have shown that deficiencies in magnesium can cause a lot of problems, and attention deficit disorder symptoms are among the symptoms that have been linked to nutritional deficiencies of this mineral.

Ionic magnesium (Mg2+) depletion has long been known to cause hyperexcitability with convulsive seizures in rodents, effects that have been reversed by treatment with magnesium (Mg).
A study evalueted the the effects of Mg2+ on the behavior of 52 hyperexcitable children (under 15 years of age) and their families. The results were that in all patients symptoms of hyperexcitability (physical aggressivity, instability, scholar attention, hypertony, spasm, myoclony) were reduced after 1 to 6 months treatment Magnesium VitB6 Intake Reduces Central Nervous System Hyperexcitability in Children.2004.

DEFINITION

Attention deficit hyperactivity disorder (ADHD) is a developmental condition of inattention and distractibility, with or without accompanying hyperactivity. In the past, various terms were used to describe this condition, including hyperactive syndrome and, from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III), "minimal brain dysfunction." In the revised DSM-III, this condition was renamed ADHD. In the DSM-IV-TR, adults or children must have had an onset of symptoms before age 7 years that caused significant social or academic impairment. More recently, attention has focused on adult forms of ADHD, which probably have been underdiagnosed.

ADHD has three subtypes:

• Predominantly hyperactive-impulsive
  • Most symptoms (six or more) are in the hyperactivity-impulsivity categories.
    Fewer than six symptoms of inattention are present, although inattention may still be present to some degree.
• Predominantly inattentive
  • The majority of symptoms (six or more) are in the inattention category and fewer than six symptoms of hyperactivity-impulsivity are present, although hyperactivity-impulsivity may still be present to some degree.
    Children with this subtype are less likely to act out or have difficulties getting along with other children. They may sit quietly, but they are not paying attention to what they are doing. Therefore, the child may be overlooked, and parents and teachers may not notice symptoms of ADHD.
• Combined hyperactive-impulsive and inattentive
  • Six or more symptoms of inattention and six or more symptoms of hyperactivity-impulsivity are present. Most children with ADHD have the combined type.

EPIDEMIOLOGY

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood. However, basic information about how the prevalence of ADHD varies by race/ethnicity, sex, age, and socio-economic status remains poorly described. The diagnosis of ADHD depend heavily on parent and teacher reports;

Its prevalence is in the same range in many countries. Varying rates in the worldwide prevalence of ADHD in school-age children might be attributed to methodologic differences in criteria used to define this disorder.

SEX
In community settings, males were diagnosed at least three times as often as females.

AGE
-In childhood
ADHD estimated to affect 5%-10% of children

-In adult
Follow-up studies have found that 5-66% of children with ADHD persist with this disorder in adulthood and studies revealed that clinical correlates demographic, psychosocial, psychiatric, and cognitive features mirrored well-documented findings among children with ADHD.
So the prevalence of adult ADHD is estimated to be between 3% and 5%.

SYMPTOMS

INATTENTION evidenced by:
-Fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities
-Has difficulty sustaining attention in tasks or play activities
-Does not seem to listen to what is being said
-Does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace
-Has difficulties organizing tasks and activities
-Avoids or strongly dislikes tasks (such as schoolwork or homework) that require sustained mental effort
-Loses things necessary for tasks or activities (school assignments, pencils, books, tools, or toys)
-Is easily distracted by extraneous stimuli
-Forgetful in daily activities

HYPERACTIVITY/IMPULSIVITY evidenced by:
-Fidgeting with hands or feet, squirming in seat
-Leaving seat in classroom or in other situations in which remaining seated is expected
-Running about or climbing excessively in situations where this behavior is inappropriate
-Difficulty playing or engaging in leisure activities quietly
-Blurting out answers to questions before the questions have been completed
-Showing difficulty waiting in lines or awaiting turn in games or group situations
-The disturbance causes clinically significant distress or impairment in social, academic, or occupational functioning.

DIAGNOSIS

LABORATORY TESTING
These tests are useful only for the differential diagnosis and for the assessment of the ADHD therapy. So liver function tests and thyroid function tests should be done before starting therapy and also electrolyte levels and iron should be assessed periodically.

PSYCHOLOGICAL TEST
There are many of these and the ADHD is diagnosed mainly with psychiatric assessment. In North America, the DSM-IV criteria are often the basis for a diagnosis. Instead European countries use the ICD-10. Both of them based on symptoms and behaviours. There are also questionnaire and scale useful for the diagnosis like The Conners Parent-Teacher Rating Scale (link)in the children or the The Wender Utah Rating Scale in adults. Also the Barkley Home Situations Questionnaire may be useful.

NMR
Brain imaging, such as functional MRI or single photon emission computed tomography (SPECT) scans have been useful for research, but no clinical indication exists for these procedures.

HISTOPATHOLOGY
In adults physiologically, there are increased dimensions of the right frontal and left occipital cortical regions. In ADHD there is loss of the prefrontal component of this evolving asymmetry and this is compatible with disruption of prefrontal functions (which are believed to be responsible for the ability to control and focus thinking). In contrast motor cortex in the ADHD patients was seen to mature faster than normal, suggesting that both slower development of behavioral control and advanced motor development might be required for the fidgetiness that characterizes ADHD.
Other studies demonstrate lower bilateral phospholipids precursor levels in the basal ganglia and higher phospholipids precursor levels in the inferior parietal region (primarily right side) in the children with ADHD as compared with healthy control children. These results are suggestive of alterations in parts of the cortico-striato-thalamo-cortical network.
There also meta-analysis studies about anatomic changes in ADHD and these demonstrate that there is gray matter reduction in the right putamen/globus pallidus region. One of the most replicated alteration is a significantly smaller corpus callosum

PATHOGENESIS

The pathophysiology of ADHD is unclear and there are a number of competing theories.
The nature of neurocognitive abnormalities in ADHD can be reconciled within dysfunction of catecholaminergic neurotransmitters, dopamine (DA) and norepinephrine (NE).

Both systems play a modulatory role (NE in regulating arousal, DA in reward processing) and determine the balance between sensory/reactive and control processes.

One locus of pathology in ADHD is posited to be reduced striatal DA because many studies have found higher expression of DA transporters in the caudate in subjects with ADHD.
Reduced striatal activation in subjects with ADHD observed in fMRI studies may relate to reduced DA in that region. Further DA release was also reduced in the hippocampus and the amygdala.

One interpretation of dopamine pathway tracers is that the biochemical "reward" mechanism works for those with ADHD only when the task performed is inherently motivating; low levels of dopamine raise the threshold at which someone can maintain focus on a task which is otherwise boring.
Iron deficency and other risk factors seem to be deeply involved in this pathogenesis

PATIENT RISK FACTORS

Genetic

Many family and adoption studies supported the strong familiar nature of this disorder (heritability 77%). Many different interacting genes (18 at least) contribute to the neurological phenotype, including dopamine receptors D4 and D5 (details), dopamine transporter, serotonin receptor 1B and SNAP-25 (Investigation of variation in SNAP-25 and ADHD and relationship to co-morbid major depressive disorder.). By far, the gene most strongly implicated in ADHD is the 7-repeat allele of the human dopamine receptor D4 gene (DRD4). Recently, also an association between the low level of catechol-omethyl-transferase (COMT) 158 met allele located in this region and ADHD (Variation in the catechol-O-methyltransferase Val 158 Met polymorphism) has been reported.
One specific receptors (alfa4beta2) in the prefrontal cortex likely play an important role in prefrontal executive function, a cognitive domain particularly affected in ADHD.

Attention Deficit Hyperactivity Disorder comorbid oppositional defiant disorder and its predominately inattentive type: evidence for an association with COMT but not MAOA in a Chinese sample.
Genetics of attention deficit hyperactivity disorder.
Candidate gene studies of attention-deficit/hyperactivity disorder.

TISSUE SPECIFIC RISK FACTORS

Anatomical

Prenatal alcohol exposure is known to induce brain structural anomalies especially in the cerebellum. Children exposed prenatally to alcohol can become hyperactive, disruptive, impulsive, and are at an increased risk for a range of psychiatric disorders.

Physiopathological

-Maternal smoking produces a 2.7-fold increased risk for ADHD and a dose-response relationship between maternal smoking during pregnancy and hyperactivity has been reported (Swanson et al, 2006). Indeed post-natal tobacco exposure is not associated with ADHD and paradoxically could be one treatment option.
Central nicotinic cholinergic systems: a role in the cognitive dysfunction in attention-deficit/hyperactivity disorder?

-Environmental lead exposure, measured in blood or dentin, has been associated with
higher rates of inattention and impulsivity. Mechanism of lead’s toxicity is not already known, but is however implicated in dopaminergic and cholinergic system.
Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children.

-Iron deficiency: A decrease in iron concentration is accompanied by changes in the conduction of cortical fibers, changes in serotonergic and dopaminergic systems, as well as in the formation of myelin. In children, there is an association between anemia caused by iron deficiency or iron deficiency without anemia and poor cognitive and motor development, and behavioral problems, indicating that iron plays an important role in normal functioning and neurological development. And also low levels of ferritin have been observed in children with ADHD, correlating with the severity of the symptoms.
Since iron has a role as a cofactor of tyrosine hydroxylase (dopamine synthesis), its decrease limits enzyme involvement in the synthesis of dopamine, and its deficiency may change the dopamine activity. The benefits of iron supplementation show the truthfullness of this theory.

Iron deficiency alters brain development and functioning
Serum ferritin in children with attention-deficit hyperactivity disorder

-Zinc deficiency: Because zinc is necessary in the metabolism of melatonin, and this is linked to dopamine transmission (details), it can be assumed that zinc deficiency is an important factor in the pathogenesis of attention deficit and hyperactivity disorder.

The role of zinc in the treatment of hyperactivity disorder in children

-Fatty acid deficiency: Among the symptoms ADHD children exhibit there are several typical for essential fatty acid deficiency like excessive thirst, dry skin, dry hair ("skin/thirst symptoms"). The level of arachidonic
acid and docosahexaenoic acid in their plasma phospholipids was lower than that of other children without ADHD-type symptoms. The actions of docosahexaenoic acid in the brain interest regulation of gene transcription and cell signaling, expecially dopamine system.

Effect of docosahexaenoic acid and other dietary constituents on synapses formation.
Roles of docosahexaenoic acid in the prenatal brain
Omega-3 fatty acid status in attention-deficit/hyperactivity disorder.

THERAPY

-Methylphenidate (Ritalin): Methylphenidate is a norepinephrine and dopamine reuptake inhibitor, which means that it increases the level of the dopamine neurotransmitter in the brain by partially blocking the dopamine transporter (DAT) that removes dopamine from the synapses. It also stimulates the release of dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus.

-Atomoxetine (Strattera): classified as a noradrenaline reuptake inhibitor, has become a second-line and, in some cases, first-line treatment in children and adults with ADHD because of its efficacy and classification as a nonstimulant.

-Clonidine and guanfacine have been used with mixed reports of efficacy. Sudden deaths have been reported in children taking clonidine with methylphenidate at bedtime. Again, the etiology of these deaths is unclear, and this remains a controversial topic.

-Other: Antidepressant like Imipramine, Desipramine, Bupropion. Many variant of Ritalin are in commerce.

Only 70% of patients will achieve a therapeutic response to a psychostimulant and the effects of long term of stimulant treatment during child development are only now being explored with some results suggestive of long-lasting negative effects. One recent study indicates that stimulants increase smoking behavior by increasing the relative reinforcing effects of cigarette smoking.

-Cholinergic agents: with the advent of well tolerated, orally available cholinergic agents, the potential for utilizing cholinergic treatment as either a primary or secondary approach to treating ADHD has become a more realistic possibility.

-Psychosocial Interventions is also usefull in therapy.

Many Authors describes evidence on supplementation, including single ingredients (e.g., minerals, vitamins, amino acids and essential fatty acids), botanicals and multi-ingredient formulas in the treatment of ADHD symptoms.
The best results were obtained with iron and zinc supplementation.

Effects of iron supplementation on attention deficit hyperactivity disorder in children.

The role of zinc in the treatment of hyperactivity disorder in children

Obesity and ADHD

Recent studies suggest a possible comorbidity between Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity.
The first hypothesis is that obesity or factors associated with obesity manifest as ADHD in the sense that impulsivity associated with binge eating behaviors manifests as impulsivity of ADHD in these patients (interruptions of their activities in order to get food, disorganization, inattentiveness, etc).
The second hypotesis is that obesity and ADHD are different expressions of common underlying biological mechanisms, explained in the reward deficiency syndrome
The third, and newest, hypotesis is the union of the previous two.

Edoardo Ceraolo
Alessandro Lamorte