Attention-deficit hyperactivity disorder management

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Attention-deficit/hyperactivity disorder management refers to the treatment options available to people with attention-deficit/hyperactivity disorder (ADHD).

There are several effective and clinically proven options to treat people with ADHD. Combined medical management and behavioral treatment is the most effective ADHD management strategy, followed by medication alone, and then behavioral treatment.^[1] The individually most effective and cost efficient way is with stimulant medication. The most common stimulant medications are methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and mixed amphetamine salts (Adderall).^[2] Atomoxetine (Strattera) is currently the only non-stimulant drug approved for the treatment of ADHD.^[3] Other medications which may be prescribed off-label include certain antidepressants such as tricyclic antidepressants, SNRIs or MAOIs.^[4][5][6] The presence of comorbid (relating to two diseases that occur together, e.g. depression and ADHD) disorders make finding the right treatment and diagnosis much more costly and time consuming.

A variety of psychotherapeutic and behavioral approaches to managing ADHD are employed by psychologists and psychiatrists. These include psychotherapy and working memory therapy. Improving the surrounding home and school environment with parent management training and classroom management can improve the behavior of children with ADHD.^[7] Specialized ADHD coaches provide services and strategies to improve functioning, like time management or organizational suggestions.

Experimental and alternative treatments include nutritional supplements, specialized diets, and biofeedback.

A 2006 meta-analysis of ADHD research concluded that there was a shortage of data regarding ADHD drugs' potential adverse effects,^[8] with very few studies assessing the safety or efficacy of treatments beyond four months,^[9] and no randomized controlled trials assessing for periods of usage longer than two years.^[10][11] Treatment of preschool children is not recommended.^[12] The FDA found that a large number of the controlled trials required subjects who were known to respond to stimulants or who had no history of intolerance to stimulants, and this limits assumed generalizability of the trials' results.^[13]

Contents 1 Attention-deficit/hyperactivity disorder 2 Cost effectiveness 3 Psychotherapeutic approaches 3.1 Psychotherapy 3.2 Parent Education and Classroom Management 3.3 Working Memory Training 3.4 Coaching 4 Medications 4.1 FDA-approved medicines 4.1.1 Amphetamine based medications 4.1.1.1 Levoamphetamine and dextroamphetamine 4.1.1.2 Dextromethamphetamine 4.1.2 Methylphenidate based medications 4.1.3 Controlled release of drugs 4.1.3.1 Multiple beads 4.1.3.2 Osmosis 4.1.3.3 Transdermal 4.1.3.4 Prodrug 4.1.4 Non stimulants 4.2 Non FDA approved medications 4.2.1 Off-label medications 5 Experimental and alternative medicine treatments 5.1 Aerobic fitness 5.2 Biofeedback 5.3 Dietary supplements 5.4 Diets 6 Treatment of ADHD with Comorbid disorders 6.1 Tic disorders 7 Concerns about the use of stimulant medication 7.1 Increase in use of stimulant medication in children 7.2 Stimulant misuse 7.3 Use of medication in preschoolers 7.4 Adverse side effects 7.4.1 Tics 7.4.2 Weight Loss 7.4.3 Cardiovascular side effects 7.4.4 Psychiatric side effects 7.5 Issues with long-term use of stimulant medication 7.6 Long term use and schizophrenia and drug induced psychosis 7.7 Stimulant withdrawal and rebound effects 7.8 Questions about the possibility of stimulant medication causing cancer 8 History 8.1 Medication use 9 References

Attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioural developmental disorder^[14] characterized by a persistent pattern of inattention and/or hyperactivity, as well as forgetfulness, poor impulse control or impulsivity, and distractibility.^[15][16] The most common symptoms of ADHD include, but are not limited to, distractibility, difficulty with concentration and focus, short term memory slippage, procrastination, problems organizing ideas and belongings, tardiness, impulsivity, and weak planning and execution.^[17] ADHD has three subtypes: predominantly inattentive, predominantly hyperactive, and combined.^[18]

ADHD 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.^[19] 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.^[20]

ADHD has a high rate of comorbidity^[21] (relating to two diseases that occur together, i.e. ADHD and depression).^[22] 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.^[23]

In the USA these critera the usual criteria for diagnosis are those of the American Psychiatric Association in their Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 4th edition.

Cost effectiveness

Combined medical management and behavioral treatment is the most effective ADHD management strategy, followed by medication alone, and then behavioral treatment.^[1] In terms of cost-effectiveness, management with medication has been shown to be the most cost-effective, followed by behavioral treatment, and combined treatment.^[1] The individually most effective and cost efficient way is with stimulant medication. Additionally, long-acting medications for ADHD, in comparison to short-acting varieties, generally seem to be cost effective.^[24] Comorbid (relating to two diseases that occur together, e.g. depression and ADHD) disorders make finding the right treatment and diagnosis much more costly than when comorbid disorders are absent.

Psychotherapeutic approaches

There are a variety of psychotherapy approaches employed by psychologists and psychiatrists, the one used depends on the patient and the patient's symptoms. The approaches include psychotherapy, cognitive-behavior therapy, support groups, parent training, meditation, and social skills training. If psychotherapy fails to bring improvement medications can be considered as an add-on or alternative.^[25][26][27]

Psychotherapy

Psychotherapy is another option, with or without medication, that has been shown to be effective.^[28]

Parent Education and Classroom Management

Improving the surrounding home and school environment can improve the behavior of children with ADHD.^[7] 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.^[29] Improving the parents' understanding of the child's behavior and teaching them strategies to improve functioning and communication and discourage unwanted behavior has measurable affect on the children with ADHD.^[7] The different educational interventions for the parents are jointly called Parent Management Training. Techniques include operant conditioning: a consistent application of rewards for meeting goals and good behavior (positive reinforcement) and punishments such as time-outs or revocation or privileges for failing to meet goals or poor behavior.^[7] Classroom management is similar to parent management training; educators learn about ADHD and techniques to improve behavior applied to a classroom setting. Strategies utilized include increased structuring of classroom activities, daily feedback, and token economy.^[7]

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 training program has shown good results in working memory, even if the generalized effect to behavioural symptoms was not as clear.^[30]

Coaching

ADHD Coaching is a specialized type of life coaching that uses specific techniques geared toward working with the unique brain wiring of individuals with attention-deficit/hyperactivity disorder. Professional coaching is not a substitute for traditional, multimodal treatment for ADHD such as medication, diet, exercise, and therapy.

Medications

FDA-approved medicines

Stimulants are the most effective medications available for the treatment of ADHD.^[1] 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, non-stimulant Food and Drug Administration (FDA) approved drug for the treatment of ADHD. There are no differences in effectiveness between medications used for ADHD.^[31]

Short term clinical trials have shown medications to be effective for ADHD but the trials usually use exclusion criteria means knowledge on medications for ADHD is limited to a small subset of typical patients seen in clinical practice.^[32] They have not been found to improve school performance and data is lacking on long term effectiveness and the severity of side effects.^[33] This class of medicines is generally regarded as one unit;^[34] however, they affect the brain differently.^[35] Some investigations are dedicated to finding the similarities of children who respond to a specific medicine.^[35] The behavioural response to stimulants in children is similar regardless of whether they have ADHD or not.^[36]

Stimulant medication is an effective treatment^[37] for Adult Attention-deficit hyperactivity disorder^[38][39] although the response rate may be lower for adults than children.^[40] Some physicians may recommend antidepressant drugs as the first line treatment instead of stimulants^[41] although antidepressants have lower treatment effect sizes than stimulant medication.^[42]

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).^[43] 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 dextroamphetamine because of levoamphetamine.^[44] Levoamphetamine also provides Adderall with a longer clinical effect than dextroamphetamine. However, the brain’s preference for dextroamphetamine over levoamphetamine shows that the clinical value of Adderall is, for the most part, due to dextroamphetamine.^[44] A few children with ADHD and comorbid disorders have helpful responses to levoamphetamine.^[35]

Dextromethamphetamine

The body metabolizes dextromethamphetamine into dextroamphetamine (in addition to less important chemicals). A quarter of dextromethamphetamine will ultimately become dextroamphetamine.^[45] After comparing only the common ground between dextroamphetamine and dextromethamphetamine, the latter is said to be the stronger stimulant.^[46] In theory—and in practice—a larger dose of dextroamphetamine is needed to achieve dextromethamphetamine’s clinical potency. In fact, when dextroamphetamine and methylphenidate are unhelpful, some doctors may prescribe dextromethamphetamine. Although more rarely prescribed, anecdotal reports suggest dextromethamphetamine is very helpful in cases where the other two are ineffective, or cause limiting side effects.^[47]

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 pharmacological activity than its mirror levo-form or enantiomer. Levothreomethylphenidate has much weaker activity than the dextro isomer, and so for instance if Daytrana (Ritalin in transdermal patch form) is used, then the levothreomethylphenidate comprising half of the administered dose, accounts for only around one thirteenth of the total clinical effect.^[48]

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 the methylphenidate 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 gelatin capsule that quickly dissolves once swallowed releasing lisdexamfetamine dimesylate.

Non stimulants

Atomoxetine (Strattera) is a non-stimulant drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is less effective than stimulants for ADHD, is associated with individual cases of liver damage, carries an FDA black box warning regarding suicidal idealization, and controlled studies show increases in heart rate, decreases of body weight, decreased appetite and treatment-emergent nausea.^[49]

Certain antidepressants such as tricyclic antidepressants, SNRIs or MAOIs are sometimes prescribed and are also effective in the treatment of ADHD.^{[4][5][6][50]}

Non FDA approved medications

Off-label medications

Some medications used to treat ADHD are prescribed off-label,^[51] 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 licensed 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) — an antiviral drug and dopamine agonist. There have been reports of low-dose amantadine having been successfully used off-label to treat ADHD.^[52]
• Amineptine (Survector/Maneon) — 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) — 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,^[53] and has little or no effect on serotonergic re-uptake.^[54] 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 — 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.^[55] It may be more useful for comorbid Tourette syndrome.
• Milnacipran, an anti-depressant drug, is currently being investigated for potential to alleviate the symptoms of ADHD in adults.^[56]
• Modafinil (Provigil/Alertec/Sparlon) — In the U.S., it is currently off-label pending decision by the FDA on August 22, 2006. It was originally pending marketing on-label as Alertec but denied for a reported incidence of Stevens-Johnson Syndrome.^[57]
• Pemoline (Cylert) — 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) — 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,^[58] 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 — an MAOI currently being investigated for ADHD.
  • Emsam is a version of Selegiline delivered via transdermal patch.

Tricyclic anti-depressants are also occasionally prescribed,^[4] 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.

Experimental and alternative medicine treatments

Alternative therapies are often sought out due to conerns of the long term effects of stimulants on children. Parents, children, consumer advocacy organizations and some physicians are increasingly looking for alternatives to stimulant drugs. There is a large body of evidence of effectiveness of some alternative therapies including supplementation with certain nutrients, elimination diets, avoidance of food additives or dyes, allergy treatment, family counseling and behavior therapy. Some advocate that alternative therapies should be tried before ADHD medications although not all ADHD children will have an effective response.^[59]

Aerobic fitness

Aerobic fitness may improve cognitive functioning and neural organization related to executive control during pre-adolescent development, though more studies are needed in this area.^[60] One study suggests that athletic performance in boys with ADHD may increase peer acceptance when accompanied by fewer negative behaviors.^[61]

Biofeedback

EEG biofeedback also sometimes referred to as neurofeedback is effective in treating attention, impulsivity and hyperactivity. There are no known side effects from biofeedback therapy although research into biofeedback has been limited and further research has been recommended.^[62]

Dietary supplements

There are indications that children with ADHD are metabolically different from others.^[63][64][65]

• Zinc- Although the role of zinc in ADHD has not be elucidated, "numerous controlled studies report cross-sectional evidence of lower zinc tissue levels."^[66]
• Omega-3 fatty acids - Some studies suggest that a lack of omega-3 fatty acids is associated with certain ADHD symptoms.^[67] 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.^[68][69] 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.^[70] Researchers from Australia's national science agency showed polyunsaturated fatty acids to provide "medium to strong positive treatment effects" in ADHD.^[69] Another double blind study conducted by the University of Oxford, where children were given omega 3 fatty acids concluded that "significant improvements for active treatment versus placebo were found in reading, spelling, and behavior over 3 months of treatment in parallel groups."^[71] A 2008 study^[72] also concludes that Omega-3/Omega-6 supplementation reduces ADHD-symptoms for some. Thus it increasingly is documented in clinical studies that omega 3 fatty acids provide a safe way to treat hyperactivity.
• 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.^[73]
• 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.^[74]
• 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.^{[citation needed]}
• Medical cannabis - Medical cannabis is used by many people with ADHD, most often self-medicated, or occasionally, supervised by a doctor.[2][3][4]
• 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.^[75]
• Mild stimulants such as caffeine, theobromine, and nicotine may improve the function of some children suffering from ADHD.^[76][77][78]

Diets

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.^[79] However, studies have shown little if any effect of the Feingold diet on the behavior of children with ADHD.^[80]

A meta-analysis has found that dietary elimination of artificial food coloring and preservatives provides a statistically significant benefit in children with ADHD.^[81] Other more recent studies agree with these conclusions.^[82][83] The UK Food Standards Agency (FSA) has called for a ban on the use of six artificial food colorings^[84] and the European Union (EU) has ruled that some food dyes must be labeled with the relevant E number as well as this warning: "may have an adverse effect on activity and attention in children."^[85]

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.^[86]

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;^[87] however, multiple lines of research have shown that stimulants can be cautiously used in the presence of tic disorders.^[88] Several studies have shown that stimulants do not exacerbate tics any more than placebo does, and suggest that stimulants may even reduce tic severity.^[89] 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.^[87][90]

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.^[91] 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 and venlafaxine. There have been case reports of tics worsening with bupropion (brand name Wellbutrin). There is good empirical evidence for short-term safety and efficacy for the use of desipramine, bupropion and atomoxetine (Strattera).^[91]

Concerns about the use of stimulant medication

The National Institute of Mental Health states that, "stimulant drugs, when used with medical supervision, are usually considered quite safe."^[92] Still, some parents and professionals have raised questions about the side effects of drugs and their long term use.^[93] A recent review states that ADHD studies "have major methodological deficiencies which are compounded by their restriction to school-age children, relatively short follow-up, and few data on adverse effects."^[10]

The American Heart Association feel that it is prudent to carefully assess children for heart conditions before treating them with stimulant medications.^[94]

Increase in use of stimulant medication in children

Outpatient treatment rates have held steady in the US recently.^[95] Prior to this, outpatient treatment for ADHD in the US grew from 0.9 children per 100 in 1987 to 3.4 per 100 in 1997.^[96] There is concern about the rising use of methylphenidate (Ritalin), mainly to treat ADHD and similar disorders, in the UK.^[97] The incidence of ADHD is estimated at three to five percent of the population, while the number of children in the United States taking Ritalin is estimated at one to two percent.^[98] In a small study of four American communities, the reported incidence of ADHD varied from 1.6% to 9.4%. The study also found that only 12.5% of the children reportedly meeting the DSM-III-R ADHD criteria for ADHD had been treated with stimulants during the past year.^[99]

Stimulant misuse

There is non-medical prescription stimulant use. A 2003 study found that non prescription use by college students in the US was 6.9% with 4.1% using them within the last year.^[100]. A 2006 study with teens in Grades 7 to Grade 12 found that 2% reported non-medical use of prescription stimulant medication in the past 12 months, with 2% also reporting non-medical use of prescribed sedatives/and or anxiety medications, 3% using sleeping medications, and 12% reporting non-medical use of prescribed pain medications.^[101].

Use of medication in preschoolers

It is believed that ADHD affects seven percent of the preschool-aged population.^{[citation needed]} Michael J. Manos of the Cleveland hospital for Children states, "Severe ADHD in children 2–4 years of age is especially problematic. Young children do not have the ability to use or respond to language to moderate behavior that older children have."^{[citation needed]} Evidence indicates that forty percent of children who show signs of ADHD are suspended from preschool, while approximately sixteen percent are eventually expelled. The disorder, which makes it difficult for children to control their behavior and pay attention, affects about 7 percent of the school-aged population. Parents of children with ADHD note that they usually display their symptoms at an early age. Dr. John Van Brakle has stated, "pediatricians have long questioned whether such children can accurately be identified, given the overlap with normal behaviors in young children."^[102] The use of stimulant medication has not been approved by the FDA for children under the age of six.^[103] A growing trend is the diagnosis of younger children with ADHD. Prescriptions for children under the age of 5 rose nearly 50 percent from 2000 to 2003.^[104] Research on this issue has indicated that stimulant medication can help younger children with "severe ADHD symptoms" but typically at a lower dose then older children. It was also found that children at this age are more sensitive to side effects and should be closely monitored.^[103] Manos states, "it is prudent for physicians to be cautious," with medications. Evidence suggests that careful assessment and highly individualized behavioural interventions significantly improve both social and academic skills while medication only treats the symptoms of the disorder.^[102] Manos suggests that, "one of the primary reasons cited for the growing use of psychotropic interventions was that many physicians realize that psychological interventions are costly and difficult to sustain."^[105]

A study published in the November 2006 Journal of the American Academy of Child and Adolescent Psychiatry followed 300 three- to five-year-olds with severe ADHD (hyperactive/impulsive, inattentive, or combined type). One-third of those children experienced reduced ADHD symptoms after engaging in 10 weeks of behavior modification techniques wherein parents offered consistent praise, ignored negative behavior, and used time-outs. The remaining two-thirds showed improvement with a combination of behavior therapy and low doses of Ritalin. 11% of the children stopped treatment due to side effects including appetite reduction, insomnia, and anxiety.^[106]

Adverse side effects

A number of possible side effects are of concern with respect to ADHD medications.

Tics

The emergence or worsening of tics have been thought to occur. Despite belief to the contrary, no significant effects have been observed on the emergence of tics.^[107]

Weight Loss

The stunting of growth in children has been a concern. Past studies suggested that "long-term use of the drugs could stunt children's growth."^[108] However, more recent studies suggest that children eventually do reach normal height and weight. According to Wilens (2004), treated children with ADHD tend to grow at a slower rate but catch up during adolescence and adulthood.^[109] One notion is that psychostimulant medication can decrease appetite which may result in loss of weight and may be a factor in stunted growth.

Cardiovascular side effects

There is concern that stimulants and Atomoxetine, which increase the heart rate and blood pressure, might cause serious cardiovascular problems.^[110]

In 2007 the FDA requires all ADHD drug manufacturers to notify patients about serious cardiovascular side effects. This was due to reports of sudden death in children taking these medications who had underlying heart problems and of high risk adults who suffered heart attacks and strokes.^[111]

Studies indicated that, "the rate of sudden death of children taking ADHD medications do not appear to exceed the base rate of sudden death in the general population". Matthew Smith is purported to have died at age 14 after long-term use of Ritalin. The medical examiner determined that Smith died from Ritalin usage, but medical experts dispute this. The examiner also argued that it was likely that diabetic children were at higher risk for cardiac problems.^[112]

Psychiatric side effects

In 2006 the FDA examined the occurrence of psychiatric side effects in ADHD medication. They found increased rates of psychosis and or mania with all drug treatments examined, including: Concerta, Ritalin LA, d-MPH, Atomoxetine, Adderall XR, Modafinil, MTS, and Metadate.^[13]

Sleep problems may occur.^[113]

Many of these drug are associated with physical and psychological dependence.^[114]

Issues with long-term use of stimulant medication

The short term use of stimulant medication has been shown to be effective yet its long term effects are yet to be determined. The Multimodal Treatment Study of Children with ADHD study concluded that while drugs such as Ritalin and Concerta (a delayed release form of Ritalin) worked in the short term, there was no demonstrable improvement in children's behavior after three years of medication."^[115]

Wilens and other professionals have shown that the controlled use of medication can reduce the likelihood of substance abuse later on.^{[citation needed]} Biederman and colleagues reported on a longitudinal study in which it was found that unmedicated children with ADHD were at greater risk of later substance use. Children who received medication for their ADHD were less likely to later use substances ^[116]. A 2007 study from the Mayo clinic found that, "treatment with stimulant medication during childhood was associated with more favorable long-term school outcomes."^[117]

Long term use and schizophrenia and drug induced psychosis

Although the safety profile of short-term methylphenidate therapy in clinical trials has been well established, repeated use of psychostimulants such as methylphenidate is less clear. The long term effects of methylphenidate such as drug addiction, withdrawal reactions, psychosis and depression and effects in pregnancy has received very little research and thus the long term effects of using stimulants for ADHD are largely unknown. There are no well defined withdrawal schedules for discontinuing long term use of stimulants.^[118] Short term clinical trials have shown an incidence of psychosis of 0.1%.^[119] Psychosis occurs more commonly as a result of chronic use effecting about 6% of children on long term methylphenidate.^[120] The long term effects on mental health disorders in later life of chronic use of methylphenidate is unknown.^[121] Concerns have been raised that long-term therapy might cause drug dependence, paranoia, schizophrenia and behavioral sensitisation, similar to other stimulants.^[122] Psychotic symptoms from methylphenidate can include, hearing voices, visual hallucinations, urges to harm oneself, severe anxiety, euphoria, grandiosity, paranoid delusions, confusion, increased aggression and irritability. Methylphenidate psychosis is unpredictable in who it will occur. Family history of mental illness does not predict the incidence of stimulant toxicosis in ADHD children. High rates of childhood stimulant use are found in ADHD patients who will eventually be diagnosed with comorbid schizophrenia and bipolar disorder. Individuals with a diagnosis of bipolar or schizophrenia who were prescribed stimulants during childhood typically have a significantly earlier onset of the psychotic disorder and suffer a more severe clinical course of psychotic disorder.^{[123][124][125]}

Stimulant withdrawal and rebound effects

Stimulant withdrawal or rebound reactions can occur and should be minimised in intensity, i.e. via a gradual tapering off of medication over a period of weeks or months.^{[126][127][128]} A very small study of abrupt withdrawal of stimulants did suggest that withdrawal reactions are not typical. Nonetheless withdrawal reactions may still occur in susceptible individuals.^[129] The withdrawal or rebound symptoms of methylphenidate can include psychosis, irritability and depression and a return of ADHD symptoms in an exaggerated form. Methylphenidate may be worse for causing rebound and withdrawal effects due to its very short half life. Amphetamine may cause less severe rebound or withdrawal effects due to its somewhat longer half life.^{[59][130][131]} Up to a third of ADHD children experience a rebound effect in ADHD symptoms when the methylphenidate dose wears off.^[132]

Questions about the possibility of stimulant medication causing cancer

A small-scale 2005 Texas study indicated that methylphenidate might cause chromosome aberrations.^[133] At the time this study caused concern because of the link between chromosome aberrations and cancer. The authors of the study stated that all the children in this study showed suspicious DNA changes within a very short time and suggested that further research was warranted. A team from the Food and Drug Administration (FDA), the National Institutes of Health (NIH) and the Environmental Protection Agency (EPA) went to Texas in 2005 to evaluate the methodology of the study. Dr. David Jacobson-Kram of the FDA said that the study had flaws in its methods but that its results could not be dismissed. Flaws cited are (1) that the study did not include a control group on placebo, and (2) that it is too small. A follow up study led by a team of six scientists from the Department of Child and Adolescent Psychiatry and Psychotherapy and the Department of Toxicology, University of Würzburg, Würzburg, Germany looked at this issue with an in-depth study. They sought to respond to the challenge noted above to attempt to replicate the results of El-Zein et al. in a larger study. Their paper was completed in 2006 and published in 2007 in Environmental Health Perspectives (EHP), the peer-reviewed journal of the United States' National Institute of Environmental Health Sciences. This study used a larger cohort and a longer period of follow-up and included a small group of long-term users, but otherwise used what researchers believed to be an identical methodology to that used by El-Zein et al. (They note that El-Zein et al. published a short study report and did not publish detailed descriptions of methodology.) After follow-ups at six months, the researchers found no evidence that methylphenidate might cause cancer, stating "the concern regarding a potential increase in the risk of developing cancer later in life after long-term MPH treatment is not supported."^[134]

History

Medication use

The first reported evidence of stimulant medication used to treat children with concentration and hyperactivity problems came in 1937.^[135] Dr. Charles Bradley in Providence, RI reported that a group of children with behavioral problems improved after being treated with the stimulant Benzedrine.^[136] In 1957, the stimulant methylphenidate (Ritalin, which was first produced in 1950) became available under various names (including Focalin, Concerta, Metadate, and Methylin); it remains one of the most widely prescribed medications for ADHD. Initially the drug was used to treat narcolepsy, chronic fatigue, depression, and to counter the sedating effects of other medications. The drug began to be used for ADHD in the 1960s and steadily rose in use.^{[citation needed]}

In 1975, pemoline (Cylert) was approved by the FDA for use in the treatment of ADHD. While an effective agent for managing the symptoms, the development of liver failure in 14 cases over the next 27 years would result in the manufacturer withdrawing this medication from the market. New delivery systems for medications were invented in 1999 that eliminated the need for multiple doses across the day or taking medication at school. These new systems include pellets of medication coated with various time-release substances to permit medications to dissolve hourly across an 8–12 hour period (Metadate CD, Adderall XR, Focalin XR) and an osmotic pump that extrudes a liquid methylphenidate sludge across an 8–12 hour period after ingestion (Concerta).^{[citation needed]}

In 2003, atomoxetine (Strattera) received the first FDA approval for a nonstimulant drug to be used specifically for ADHD. In 2007, lisdexamfetamine (Vyvanse) becomes the first prodrug to receive FDA approval for ADHD.

In 1999 the largest study of treatment for ADHD was published in the American Journal of Psychiatry. Known as the Multimodal Treatment Study of ADHD (MTA Study), it involved more than 570 children with ADHD at 6 sites in the United States and Canada randomly assigned to 4 treatment groups. All 4 treatment groups showed marked improvement from the time of baseline measurements to completion of the study 14 months later. Behavioral treatment was as effective as medication alone on 16 of 19 outcome measures.^[11]

References

v • d • e Attention-deficit hyperactivity disorder Main articles History of ADHD · ADHD in adults · ADHD controversies · ADHD management · List of ADHD organizations · Social construct theory of ADHD · ADHD coaching Major characteristics: Attention · Hyperactivity · Impulsivity Sub-types ADHD predominantly inattentive (ADHD-I, formerly ADD) · ADHD predominantly hyperactive (ADHD-H, formerly ADHD) · ADHD combined type (ADHD-C) Notable Publications Driven to Distraction (1994) · Delivered from Distraction (2005) Notable Experts Russell Barkley · Stephen Faraone · Edward Hallowell · John Ratey · Joseph Biederman · 19th Century: Alexander Crichton Relevant Drugs methylphenidate (Ritalin) · dextroamphetamine (Dexedrine) · mixed amphetamine salts (Adderall) · Non-stimulant: Atomoxetine (Strattera) · More... See also: Low arousal theory · Sluggish cognitive tempo · Sensory integration dysfunction · Hypokalemic sensory overstimulation · Deficits in Attention, Motor control and Perception