Attention-deficit hyperactivity disorder treatments

Background
There are several effective and clinically proven options to treat people with attention-deficit hyperactivity disorder (ADHD). The most popular and best (both effectively, and cost efficiently) way to treat ADHD has been with stimulant medication. The most common stimulant medications are methylphenidate, dextroamphetamine, and mixed amphetamine salts. . Treatment costs vary greatly depending on the severity of ADHD. Medication management is the least expensive, followed by behavioral treatment, and combined treatment. Medical management was more effective, yet more costly than community care, and more cost effective than combination treatment alone and behavioral treatment alone. Comorbid (relating to two diseases that occur together, i.e. depression and ADHD) disorders make finding the right treatment and diagnosis much more costly and time consuming than a non comorbid disorder. Having a comorbid disorder complicates the treatment and diagnosis of ADHD so it is better to treat a comorbid disorder as soon as possible. Some cases of comorbidities, including depression or an anxiety disorder, are best treated with the combined treatment of psychosocial therapies and medication and are better then when only present is ADHD (2).

Attention-Deficit Hyperactivity Disorder
Attention-Deficit Hyperactivity Disorder (ADHD) is a neurobehavioural developmental disorder characterized by a persistent pattern of inattention and/or hyperactivity, as well as forgetfulness, poor impulse control or impulsivity, and distractibility. The most common symptoms of ADHD include, but are not limited to, are distractibility, difficulty with concentration and focus, short term memory slippage, procrastination, problems organizing ideas and belongings, tardiness, impulsivity, and weak planning and execution. . ADHD has three subtypes: predominantly inattentive, predominantly hyperactive, and combined.

The ADD is most likely a heterogeneous disorder caused by a combination of both genetics and environmental conditions. Researchers believe that a large majority of ADHD arises from a combination of various genes, many of which affect dopamine transporters. It appears to be highly heritable. The estimated contribution of non genetic factors in 20 percent, the majority of which are trauma or toxic exposure.

ADHD has a high rate of comorbidity (relating to two diseases that occur together, i.e. ADHD and depression). Oppositional defiant disorder, conduct disorder, anxiety, depression, bipolar disorder, and substance abuse can be comorbid conditions. Treating ADHD is much more difficult when comorbidities are present.

The formal diagnosis of ADHD is made by a qualified professional in the field based on a set number of criteria. In the USA these critera are laid down by the American Psychiatric Association in their Diagnostic and Statistical Manual of Mental Disorders (DSM-IV ), 4th edition.

Treatment choices for AD/HD
ADHD can be treated by any physician MD or DO (usually family practice or pediatrician), psychiatrists, psychiatric/mental health nurse practitioners, and neurologists; some practitioners of this type specialize in treating children with ADHD and others specialize in the treatment of adults with ADHD. Children's hospitals that have psychiatric units with programs dedicated to treating ADHD are often a good place to receive treatment, but a psychiatrist's or neurologist's office will generally have staff who can understand and treat ADHD effectively.

The treatment provider can provide the child’s school with a written ADHD diagnosis that informs the school of accommodations that may aid the student in academic endeavors. In the United States, an educational institution must make accommodations for a child with ADHD which now requires a full psychological evaluation including a battery of tests and observational studies repeated every three years. These tests often pick up added learning diabilities which help qualify for even more benefits. If these test concure with the diagnosis, the school will enact a 504 or Individualize Educational Plan (IEP) for the student

Accommodations may include:
 * Extended time for taking exams
 * Extended due dates for homework
 * A distraction-free environment during examination
 * Permission to record lectures
 * Copies of lecture notes

FDA-approved medicines
Stimulants are the most effective medications available for the treatment of ADHD. This class of medicines is generally regarded as one unit; however, they affect the brain differently. Some investigations are dedicated to finding the similarities of children who respond to a specific medicine.

Five different formulations of stimulants have been approved by the FDA for the treatment of ADHD: three derived from amphetamine and two derived from methylphenidate. Atomoxetine is the only non-controlled Food and Drug Administration (FDA) approved drug for the treatment of ADHD, but is less effective than stimulants for ADHD, is associated with individual cases of liver damage, carries an FDA black box warning regarding suicidal ideation, and controlled studies show increases in heart rate, decreases of body weight, decreased appetite and treatment-emergent nausea.

Amphetamine based medications
Three different medicines derived from amphetamine are used in ADHD treatment. Their trade names are Adderall (a mixture of 72% dextroamphetamine and 28% levoamphetamine), Dexedrine (pure dextroamphetamine), and Desoxyn (pure dextromethamphetamine). The differences in these three Amphetamine based medications' active compounds and mixture ratios results in each medications' slightly different activities.

Levoamphetamine and dextroamphetamine
Levoamphetamine and dextroamphetamine have the same chemical formula but are mirror images of each other, the same way that a person's hands are the same but are mirror images of each other. This mirror difference is enough to cause the two compounds to be metabolized differently. Adderall begins to work before Dexedrine because of levoamphetamine. Levoamphetamine also provides Adderall with a longer clinical effect than Dexedrine. However, the brain’s preference for dextroamphetamine over levoamphetamine shows that the clinical value of Adderall is, for the most part, due to dextroamphetamine. A few children with ADHD and comorbid disorders have helpful responses to levoamphetamine.

Dextromethamphetamine
The body metabolizes dextromethamphetamine into dextroamphetamine (in addition to less important chemicals). A quarter of dextromethamphetamine will ultimately become dextroamphetamine. After comparing only the common ground between dextroamphetamine and dextromethamphetamine, the latter is said to be the stronger stimulant. In theory—and in practice—a larger dose of dextroamphetamine is needed to achieve dextromethamphetamine’s clinical potency. In fact, when Dexedrine and Ritalin are unhelpful, some doctors may prescribe Desoxyn. Although more rarely prescribed, anecdotal reports suggest Desoxyn is very helpful in cases where the other two are ineffective, or cause limiting side effects.

Methylphenidate based medications
There are two different medicines derived from methylphenidate: Ritalin, which is half dextrothreomethylphenidate and half levothreomethylphenidate, and Focalin, which is pure dextrothreomethylphenidate. Dextrothreomethylphenidate has a higher pharmocological activity than its mirror handed levo-form. The levothreomethylphenidate in orally taken Ritalin has no useful activity and therefore does not improve child’s symptoms; however, if Daytrana (Ritalin in transdermal patch form) is used, then levothreomethylphenidate accounts for about a thirteenth of the total clinical value. Since children with ADHD do not seem to be able to identify when they are on the drug or placebo, this suggests a low liability for the development of any "addiction" to stimulants.

Controlled release of drugs
Doctors may prescribe a controlled release pharmaceutical so that patients only have to take medication in the morning, or at a time more convenient for the patient. This is especially helpful for children who do not like taking their medication in the middle of the school day. Several controlled release methods are used in the FDA approved medications for ADHD. Each way provides makes the FDA drugs pharmaceutically different.

Multiple beads
Adderall and Dexedrine Spansules are examples of pharmaceuticals that use a system of two beads to achieve a controlled release. The beads are contained in a gelatin capsule that quickly dissolves in water, thus releasing the beads. The two different types of beads dissolve at different rates, thus extending the effects of the amphetamines. The company that markets Adderall is developing a new version of Adderall with three different kinds of beads that would be effective for up to 16 hours.

Osmosis
The only ADHD medication that currently utilizes osmotic pressure to achieve a controlled release of medicine is Concerta. A tablet of Concerta is actually a coated capsule. The coating is a mix of methylphenidate hydrochloride and binders such as lactose, povidone, and carnauba wax. Under that coating is a hollow filled capsule made of a semipermeable rigid membrane. The actual capsule is insoluble in water, but some of the ingredients that fill the capsule are water-soluble and others react in special ways with water. At one end of the capsule there is a laser drilled small hole, big enough for methylphenidate particles to pass through. The capsule's volume is partitioned into three sections. At the end closest to the hole is the first partition, which is a mixture containing a small concentration of methylphenidate. In the middle is the second partition is a different mixture that contains a higher concentration of methylphenidate. Occupying the third of the capsules volume that is furthest away from the small hole is triacetin, cellulose acetate, hypromellose, polyethylene glycol and polyethylene oxides.

Once swallowed, the capsule's shell quickly disintegrates and the methylphenidate that was contained in the shell is released. When water sweeps through the semipermeable membrane, the third partition that is furthest away from the capsule's hole will grow because the hypromellose absorbs water and swells up and the polyethylene glycol will increase the osmotic pressure. This partition will slowly push the contents of the other two partitions out the small hole, starting with the lower concentrations of methylphenidate, once the lower concentration of methylphenidate has mostly left the capsule the higher concentration of methylphenidate will begin to be pushed out of the capsule's hole. The capsule will be pharmacologically inactive once all the methylphenidate is expelled.

Transdermal
This is a patch applied to the skin that allows the drug to diffuse through the skin layers and enter the bloodstream. Unlike oral drugs, it may be removed and replaced conveniently, so it is flexible around the patient's schedule. Daytrana is the brand name of a transdermal patch which is essentially the same formulation as Ritalin. Daytrana is applied to the skin in the morning and the drug is evenly absorbed throughout the day, the patient should expect to feel the effects of Daytrana until two hours after the patch was removed, so patients should expect to take the patch off a few hours before bedtime. The collaborators that developed Daytrana are developing a transdermal patch version of dextroamphetamine and have completed phase 1 FDA human studies. This medicinal patch is code named SPD483 (a.k.a., ATS; Amphetamine Transdermal System; Amphetamine patch).

Prodrug
A prodrug is a compound which is itself inactive, but when metabolized becomes pharmacologically active. Prodrugs are usually designed to improve oral bioavailability as the chemical properties of the active compound may cause it to be poorly absorbed from the gastrointestinal tract. Lisdexamfetamine (Sold as Vyvanse) is a prodrug of dextroamphetamine. Vyvanse is a geltin capsule that quickly dissolves once swollowed releasing lisdexamfetamine dimesylate.

Off-label medications
Some medications used to treat ADHD are prescribed off-label, outside the scope of their FDA-approved indications for various reasons. The Food and Drug Administration (FDA) requires numerous clinical trials to prove a potential drug's safety and efficacy in treating ADHD. The drugs below have not been through these tests, so the efficacy is unproven (however these drugs have been licesnsed for other indications, so have been proven to be safe in those populations), however proper dosage and usage instructions are not as well characterized.


 * Amantadine (Symmetrel) &mdash; an antiviral drug and dopamine agonist. There have been reports of low-dose amantadine having been successfully used off-label to treat ADHD.
 * Amineptine (Survector/Maneon) &mdash; a tricyclic antidepressant now illegal in many countries for being thought to have a small potential for abuse. It is still legal in some parts of the EU, such as Spain and Italy; it is no longer available in the U.S., Canada, France or the UK.
 * Benzphetamine (Didrex) &mdash; a less powerful stimulant. It has little psychoactive effects until the liver metabolizes it into amphetamine and methamphetamine. Since this acts as a sustained release mechanism, it has lower abuse potential and is schedule 3.
 * Bupropion (Wellbutrin) is classified as an antidepressant. It is the most common of off-label prescription for ADHD. It inhibits the reuptake of norepinephrine, and to a lesser extent, dopamine, in neuronal synapses, and has little or no effect on serotonergic re-uptake. Bupropion is not a controlled substance. It is commonly prescribed as a timed release formulation to decrease the risk of side effects. Bupropion is not particularly known for its stimulant properties because at high doses it tends to cause seizures in a large portion of the population.
 * Clonidine &mdash; Initially developed as a treatment for high blood pressure, low doses in evenings and/or afternoons are sometimes used in conjunction with stimulants to help with sleep and because Clonidine sometimes helps moderate impulsive and oppositional behavior and may reduce tics. It may be more useful for comorbid Tourette syndrome.
 * Modafinil (Provigil/Alertec/Sparlon) &mdash; In the U.S., it is currently off-label pending decision by the FDA on August 22, 2006. Was originally pending marketing on-label as Alertec but denied for a reported incidence of Stevens-Johnson Syndrome.
 * Pemoline (Cylert) &mdash; a stimulant used with great success until the late 1980s when it was discovered that this medication could cause liver damage. In March 2005, the makers of Cylert announced that it would discontinue the medication's production.  It is no longer available in the United States.
 * Reboxetine (Edronax) &mdash; is a selective norepinephrine reuptake inhibitor which is mainly used as an antidepressant. Studies outside the USA have found it to be an effective treatment for ADHD, and it is prescribed off-label for this purpose in Israel and some European countries, however reboxetine has never been approved by the FDA in the United States.
 * Selegiline &mdash; an MAOI currently being investigated for ADHD.
 * Emsam is a version of Selegiline delivered via transdermal patch.

Tricyclic anti-depressants are also occasionally prescribed, but they seem to only treat the hyperactive part of the condition. There is research on the selective serotonin reuptake enhancer class of medications (SSREs); currently, the only one available is tianeptine (trade name Stablon); this is an atypical tricyclic anti-depressant which is inconclusive in its efficacy and hence not approved. Tianeptine is not available in North America.

Alternative medicine treatments
Many alternative treatments have been proposed for ADHD. However, none of the treatments has widespread acceptance in the mainstream medical community, and none of the alternative treatments has proven to cause significant reduction of ADHD symptoms. Evening Primrose Oil, St.John's Wort, and Ginkgo biloba are used as herbal remedies.

Experimental treatments
There are indications that children with ADHD are metabolically different from others.
 * Zinc- Although the role of zinc in ADHD has not be elucidated, "numerous controlled studies report cross-sectional evidence of lower zinc tissue levels".
 * Omega-3 fatty acids - Some studies suggest that a lack of omega-3 fatty acids is associated with certain ADHD symptoms. and it has therefore been suggested that diet modification may play a role in the management of ADHD. People with ADHD were found to have significantly lower plasma phospholipids and erythrocytes omega-3 fatty acids. Their intake of saturated fat was found to be 30% higher than in controls, while the intake of many other nutrients was not different.  In support of the idea that it is not the intake of essential fatty acids that causes low tissue levels, a preliminary study showed that exhaled ethane, a marker of omega-3 fatty acids peroxidation, was higher in children with ADHD relative to controls. Researchers from Australia's national science agency showed polyunsaturated fatty acids to provide "medium to strong positive treatment effects" in ADHD.
 * Magnesium and vitamin B6 (pyridoxine) - In 2006, a study demonstrated that children with autism had significantly lower magnesium than controls, and that the correction of this deficit was therapeutic: Mousain-Bosc et al showed that children with ADHD (n = 46) had significantly lower red blood cell magnesium levels than controls (n = 30). Intervention with magnesium and vitamin B6 reduced hyperactivity, hyperemotivity/aggressiveness and improved school attention.
 * Iron supplements - In 2005, the official journal of the American Academy of Pediatrics, Pediatrics, published the case report of a child with ADHD with low ferritin who showed "considerable behavioral improvement" after his ferritin was normalized by iron supplementation. Based on earlier studies on iron deficiency and attentional function (notably the dopamine synthesis aspect), the screening of ferritin levels in children with ADHD was suggested.
 * Potassium - In 2007, Harvard-associated researchers described a form of ADHD that was well treated with over-the-counter potassium supplements. The molecular mechanism suggested by the authors was one producing sensory overstimulation, often triggered by ingesting carbohydrates, suggesting that people with ADHD who have sensitivity to sugar may be particularly likely to have this variant.
 * Feingold diet - Perhaps the best known of the dietary alternatives is the Feingold diet which involves removing salicylates, artificial colors and flavors, and certain synthetic preservatives from children's diets. However, studies have shown little if any affect of the Feingold diet on the behavior of children with ADHD.
 * Medical cannabis - Medical cannabis is used by many people with ADHD, often self-medicated, or supervised by a doctor.
 * In the 1980s vitamin B6 was promoted as a helpful remedy for children with learning difficulties including inattentiveness, however, a study of large doses of vitamins with ADHD children showed that they were ineffective in changing behavior.
 * Mild stimulants such as caffeine, theobromine, and nicotine may improve the function of some children suffering from ADHD.  However, since ADHD is thought to be related to deficiencies of dopamine and/or norepinephrine, such treatments are not medically recognized, as opposed to amphetamine-like drugs which have significant dopaminergic and norepinephrinergic action.
 * Milnacipran, an anti-depressant drug, is currently being investigated for potential to alleviate the symptoms of ADHD in adults.

Treatment of ADHD with Comorbid disorders
Because ADHD comorbidities are diverse and the rate of comorbidity is high, special care must dedicated to certain comorbidities. The FDA is not set up to address this issue, and does not approve medications for comorbidities, nonetheless certain such topics have been extensively researched.

Tic disorders
Patients with Tourette syndrome who are referred to specialty clinics have a high rate of comorbid ADHD. Patients who have ADHD along with tics or tic disorders may also have problems with disruptive behaviors, overall functioning, and cognitive function, accounted for by the comorbid ADHD.

The treatment of ADHD in the presence of tic disorders has long been a controversial topic. Past medical practice held that stimulants (such as Ritalin) could not be used in the presence of tics, due to concern that their use might worsen tics; however, multiple lines of research have shown that stimulants can be cautiously used in the presence of tic disorders. Several studies have shown that stimulants do not exacerbate tics any more than placebo does, and suggest that stimulants may even reduce tic severity. Controversy remains, and the PDR continues to carry a warning that stimulants should not be used in the presence of tic disorders, so physicians may be reluctant to use them. Others are comfortable using them and even advocate for a stimulant trial when ADHD co-occurs with tics, because the symptoms of ADHD can be more impairing than tics.

The stimulants are the first line of treatment for ADHD, with proven efficacy, but they do fail in up to 20% of cases, even in patients without tic disorders. Current prescribed stimulant medications include: methylphenidate (brand names Ritalin, Metadate, Concerta), dextroamphetamine (Dexedrine), and mixed amphetamine salts (Adderall). Other medications can be used when stimulants are not an option. These include the alpha-2 agonists (clonidine and guanfacine), tricyclic antidepressants (desipramine and nortriptyline), and newer antidepressants (bupropion, venlafaxine and atomoxetine). There have been case reports of tics worsening with bupropion (brand name Wellbutrin). There is good empirical support for the use of desipramine, bupropion and atomoxetine (brand name Strattera).

Psychotherapeutic approaches
There are a variety of psychotherapy approaches employed by psychiatrists, the one used depends on the patient and the patient's symptoms.

Psychotherapy
Psychotherapy is another option, with or without medication, that has been shown to be effective.

Parent Education
Parents of children with ADHD often show similar deficits themselves, and thus may not be able to sufficiently help the child with his or her difficulties. Educating parents in the management of the disorder can be helpful. The different educational interventions for the parents are jointly called Parent Management Training.

Working Memory Training
Many of the problems shown by children with ADHD can be traced back to deficits in working memory (or short-term memory). By training and improving this memory some of the other symptoms may diminish as well. In a study by Klingberg et al, a computerized such training program has shown good results in working memory, even if the generalized effect to behavioural symptoms was not as clear.

Coaching
ADHD Coaching is a program where coaches work with ADHD individuals to help them prioritize, organize, and develop life skills. Coaching is aimed at helping clients to be more realistic in setting goals for themselves by learning about their individual challenges and gifts, and emphasizes spending more time in areas of strength, while minimizing time spent dealing with areas of difficulty.

Only recently, studies on the cost-effectiveness of ADHD treatment have begun to appear. To date valid information is limited, although a review presented identified 11 health technology assessments and cost-effectiveness analyses, all of which compared the economic merits of at least two treatment alternatives.