Attention deficit hyperactivity disorder management
Attention deficit hyperactivity disorder management are the treatment options available to people with attention-deficit/hyperactivity disorder (ADHD).
There are several effective and evidence-based options to treat people with ADHD. Multimodal treatment, that is, combined pharmacological and behavioral treatment, is the most effective ADHD management strategy, followed by medication alone, and then behavioral treatment. However, these results have been questioned because the study from the multimodal treatment group phased out the behavioral procedure 3 months prior to the last evaluation point but continued the medication group. Indeed, after 14 months the medication group lost its advantage to the long discontinued behavior modification group. By year eight socioeconomic status and family structure were the only predictive variables for ADHD treatment A separate study highlighted the influence that nonclinical factors such as family size may have in mediating the use of pharmacologic therapies for children with ADHD.
The most common stimulant medications are methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and mixed amphetamine salts (Adderall). Atomoxetine (Strattera), guanfacine (Intuniv) and clonidine (Kapvay) are non-stimulant drugs approved for the treatment of ADHD. Other medications which may be prescribed off-label include certain antidepressants such as tricyclic antidepressants, SNRIs or MAOIs. The presence of comorbid (co-occurring) disorders make finding the right treatment and diagnosis much more costly and time-consuming. Having a comorbid disorder makes the treatment and diagnosis of ADHD more complicated, so it is recommended to assess and treat any comorbid disorders simultaneously.
A variety of psychotherapeutic and behavior modification approaches to managing ADHD including psychotherapy and working memory training may be used. Improving the surrounding home and school environment with Parent Management Training and classroom management can improve the behavior of children with ADHD. Specialized ADHD coaches provide services and strategies to improve functioning, like time management or organizational suggestions. Self-control training programs have been shown to have limited effectiveness. Behaviorally based self-control does better than cognitive self-control training. A meta-analysis found that the use of behavior modification for ADHD are effective.
As of 2006 there was a shortage of data regarding ADHD drugs' potential adverse effects, with very few studies assessing the safety or efficacy of treatments beyond four months, and no randomized controlled trials assessing for periods of usage longer than two years. Treatment of preschool children is not recommended. The U.S. Food and Drug Administration (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.
- 1 Psychosocial
- 2 Medications
- 3 Comparative efficacy, tolerability and regulatory status of ADHD medications
- 4 Concerns regarding stimulants
- 4.1 Increase in use
- 4.2 Stimulant misuse
- 4.3 Medication in preschoolers
- 4.4 Side effects
- 4.5 Issues with long-term use of stimulant medication
- 4.6 Stimulant withdrawal and rebound effects
- 4.7 Cancer
- 5 Cost-effectiveness
- 6 History
- 7 Alternative medicine
- 8 Comorbid disorders
- 9 Legal status of medications
- 10 Notes
- 11 References
There are a variety of psychotherapeutic 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.
Psychotherapy is another option, with or without medication, that has been shown to be effective.
Parent education and classroom management
Improving the surrounding home and school environment can improve the behavior of children with ADHD. 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. Improving the parents' understanding of the child's behavior and teaching them strategies to improve functioning and communication and discourage unwanted behavior has measurable effect on the children with ADHD. 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 of privileges for failing to meet goals or poor behavior. 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.
Working memory training
Many of the problems shown by children with ADHD are linked with deficits in working memory (or short-term memory). Training this memory may diminish some of symptoms of ADHD. In a study by Klingberg et al., children with ADHD who completed a computerized training program for working memory reported a decrease in ADHD symptoms and performed better on working memory tests than the control group. Some researchers attribute this to an improvement in working memory generally, while others believe it is merely the natural effect of practice.
Timers have been found to be effective for allowing people with ADHD to concentrate more effectively on the task at hand. When a target is set, one method is to only turn the timer on whilst working on the given task. A physical stopwatch or an online timer may be used.
Stimulants are the most commonly prescribed medications for ADHD. The most common stimulant medications are methylphenidate (Ritalin, Metadate, Concerta), dexmethylphenidate (Focalin), dextroamphetamine (Dexedrine), mixed amphetamine salts (Adderall), dextromethamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). According to several studies, use of stimulants (e.g. methylphenidate) can lead to development of drug tolerance to therapeutic doses; tolerance also occurs among high dose abusers of methylphenidate. Controlled-release pharmaceuticals may allow once or twice daily administration of medication in the morning. 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.
Stimulants used to treat ADHD raise the extracellular concentrations of the neurotransmitters dopamine and norepinephrine which causes an increase in neurotransmission. The therapeutic benefits are due to noradrenergic effects at the locus coeruleus and the prefrontal cortex and dopaminergic effects at the nucleus accumbens.
About 70 percent of children improve after being treated with stimulants in the short term, but this conclusion may be biased due to the high number of low quality clinical trials in the literature. The long-term effectiveness of methylphenidate has not been scientifically demonstrated. Serious concerns of publication bias regarding the use of methylphenidate for ADHD has also been noted.
Although "under medical supervision, stimulant medications are considered safe", the use of stimulant medications for the treatment of ADHD has generated controversy because of undesirable side effects and uncertain long-term effects and social and ethical issues regarding their use and dispensation. The U.S. FDA has added black-box warnings to some ADHD medications, while the American Heart Association and the American Academy of Pediatrics feel that it is prudent to carefully assess children for heart conditions before treating them with stimulant medications.
Stimulants are the most effective medications available for the treatment of ADHD. Five different formulations of stimulants have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD: three derived from amphetamine and two derived from methylphenidate. Atomoxetine, guanfacine and clonidine are the only non-controlled, non-stimulant FDA-approved drugs for the treatment of ADHD. There are no differences in effectiveness between medications used for ADHD.
Short-term clinical trials have shown medications to be effective for treating ADHD, but the trials usually use exclusion criteria, meaning knowledge of medications for ADHD is based on a small subset of the typical patients seen in clinical practice. They have not been found to improve school performance and data is lacking on long-term effectiveness and the severity of side effects. 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. The behavioural response to stimulants in children is similar regardless of whether they have ADHD or not.
Stimulant medication is an effective treatment for adult attention-deficit hyperactivity disorder although the response rate may be lower for adults than children. Some physicians may recommend antidepressant drugs as the first line treatment instead of stimulants although antidepressants have lower treatment effect sizes than stimulant medication.
|Summary of Evidence on Amphetamine and ADHD|
|Amphetamine (Adderall, Adderall XR)||
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). The differences in these two amphetamine-based medications is the enantiomeric mixture ratio, which results in slightly different effects between the medications. Another medication containing a similar but distinct compound, Desoxyn (pure dextromethamphetamine), is also used, although infrequently.
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. Levoamphetamine also provides Adderall with a longer clinical effect than dextroamphetamine. Some children with ADHD and comorbid disorders respond well to levoamphetamine.
The body metabolizes dextromethamphetamine into dextroamphetamine (in addition to less active metabolites). 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 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.
There are two different medicines derived from methylphenidate: Ritalin, which is half dextrothreomethylphenidate and half levothreomethylphenidate, that is, a mixture of the "chemical mirror images" of methylphenidate, 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 (methylphenidate 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. Methylphenidate has high potential for abuse and addiction due to its pharmacological similarity to cocaine and amphetamines.
Atomoxetine (Strattera), guanfacine (Intuniv) and clonidine (Kapvay) are non-stimulant drugs approved for the treatment of ADHD. Other medications which may be prescribed off-label include certain antidepressants such as tricyclic antidepressants, SNRIs, SSRIs or MAOIs.
Atomoxetine (Strattera) is less effective than stimulants for ADHD, is associated with individual cases of liver damage, and carries a U.S. FDA black box warning regarding suicidal idealization. Controlled studies show increases in heart rate, decreases of body weight, decreased appetite and treatment-emergent nausea.
Intuniv is an extended release form of guanfacine. Intuniv has been approved by the FDA for the treatment of attention-deficit hyperactivity disorder (ADHD) in children as an alternative to stimulant medications. Its beneficial actions are likely due to its ability to strengthen prefrontal cortical regulation of attention and behavior.
Clonidine (Kapvay), an α2A adrenergic receptor agonist has also been approved in the US. Clonidine was 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.
Some medications used to treat ADHD are prescribed off-label, outside the scope of their FDA-approved indications for various reasons. The U.S. FDA requires two 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.
- 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.
- Milnacipran, an anti-depressant drug, is currently being investigated for potential to alleviate the symptoms of ADHD in adults.
- Modafinil (Provigil/Alertec/Sparlon) — Double-blind randomized controlled trials have demonstrated the efficacy and tolerability of modafinil, however there are risks of serious side effects such as skin reactions and modafinil is not recommended for use in children. In the U.S., it is 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.
- Reboxetine (Edronax) — is a selective norepinephrine reuptake inhibitor which is mainly used as an antidepressant. Studies outside the U.S. 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 U.S. FDA.
- Antipsychotic medication
The use of atypical antipsychotic medication as an off-label treatment has been rising. Antipsychotics work by blocking dopamine, whereas stimulants trigger its release. Atypical antipsychotics have been approved for use in children and teenagers with schizophrenia spectrum disorders and autistic spectrum disorders by the U.S. FDA.
Non-ADHD children do not respond differently than ADHD children when prescribed antipsychotic drugs, which are also increasingly prescribed off-label for children with aggression or defiant behavior. Social pressure to control a child's difficult and disruptive behavior, both at home and at school, may inadvertently change focus from what is in the best interest of the child's wellbeing; to how to render the child more compliant and easier to manage.
Comparative efficacy, tolerability and regulatory status of ADHD medications
|Generic name (INN)||Brand name(s)||TGA-labelled for ADHD?||MHRA-labelled for ADHD?||FDA-labelled for ADHD?||Pharmacologic class||Level of support||Notes on adverse effects[note 1]||Efficacy and miscellany[note 2]|
|Adderall[note 3]||Adderall||No||No||Yes (children ≥3 years; adults)||Monoamine reuptake inhibitor and releasing agent||Approved||Transient growth stunting, hypertension or hypotension, dependence and tolerance, rare stimulant psychosis, and insomnia. Elimination is urinary pH-dependent||Highly efficacious, therapeutic effects are usually seen within an hour of oral administration.|
|Yes (children ≥6 years & adults)||Yes (children ≥6 years & adults)||Yes (children ≥3 years; adults)||Monoamine reuptake inhibitor and releasing agent||Approved||Transient growth stunting, hypertension or hypotension, dependence and tolerance, rare stimulant psychosis, and insomnia. Elimination is urinary pH-dependent||Highly efficacious, therapeutic effects are usually seen within an hour of oral administration|
|Yes (children ≥12 years and adults)||Yes (children ≥6 years and adults)||Yes (children ≥6 years and adults)||Monoamine reuptake inhibitor and releasing agent||Approved||Transient growth stunting, hypertension or hypotension, dependence and tolerance, rare stimulant psychosis, and insomnia. Elimination of active metabolite, dexamfetamine, is pH-dependent||Highly efficacious with rapid onset of action.|
|Metamfetamine||Desoxyn||No||No||Yes (children ≥6 years & adults)||Monoamine reuptake inhibitor and releasing agent||Approved||Transient growth stunting, hypertension or hypotension, dependence and tolerance, direct neurotoxicity to dopamine and serotonin neurons, rare stimulant psychosis, and insomnia. Elimination is urinary pH-dependent||Highly efficacious, therapeutic effects are usually seen within an hour of oral administration|
|Dexmethylphenidate||Focalin||No||No||Yes (children ≥6 years and adults)||Norepinephrine-dopamine reuptake inhibitor||Approved||Transient growth stunting, dependence and tolerance, rare stimulant psychosis, hypertension, and insomnia.||Highly efficacious, therapeutic effects are usually seen within 12 hours of oral administration (sustained release formulation)|
|Yes (children ≥6 years and adults)||Yes (children ≥6 years and adults)||Yes (children ≥6 years and adults)||Norepinephrine-dopamine reuptake inhibitor||Approved||Transient growth stunting, dependence and tolerance, rare stimulant psychosis, and insomnia.||Highly efficacious, therapeutic effects are usually seen within 2–7 hours of oral administration (depending on formulation)|
|Atomoxetine||Strattera||Yes (children ≥6 years & adults)||Yes (children ≥6 years & adults)||Yes (children ≥6 years & adults)||Norepinephrine reuptake inhibitor||Approved||Suicidal ideation, insomnia, anorexia, hypertension||Less efficacious than classical stimulants and slower onset of action (usually takes at least a couple weeks)|
|Modafinil||Modavigil, Provigil||No||No||No||Eugeroic||Very high||Stevens-Johnson syndrome, toxic epidermal necrolysis, suicidal ideation||Rapid onset of action (matter of a few hours). May be less efficacious than atomoxetine and classical stimulants in paediatric ADHD, although in adult ADHD it seems as efficacious as classical stimulant medications.|
|α2 adrenoceptor agonists|
|Clonidine||Catapres, Dixarit, Kapvay||No||No||Yes (children ≥6 years)||Alpha-2 adrenoceptor agonism||Approved||Sedation, hypotension, depression. Sedation tends to be more prominent with immediate-release formulations than with extended-release formulations.||Delayed onset of action (1 week). Insufficient data to judge its relative efficacy. Only the more sedating, immediate-release formulations are available in some countries, including Australia.|
|Guanfacine||Intuniv, Tenex||No||No||Yes (children ≥6 years)||Alpha-2 adrenoceptor agonism||Approved||Sedation, hypotension, depression||Delayed onset of action (1 week). May be slightly less efficacious than stimulant medications. Not available in many countries including Australia and the UK.|
|Amitriptyline||Elavil, Endep||No||No||No||Tricyclic antidepressant||Low||Sedation, anticholinergic effects, hypotension, suicidal ideation, urinary retention, angle-closure glaucoma, headache, dizziness, etc. Highly dangerous in overdose.||Delayed onset of action|
|No||No||No||Norepinephrine-dopamine reuptake inhibitor & nAChR antagonist||High||Seizures, memory problems, concentration difficulties. Fairly dangerous in overdose.||Delayed onset of action. Probably less efficacious than atomoxetine and classical stimulant medications in children. May be slightly more effective than atomoxetine in adults, however.|
|Buspirone||Buspar||No||No||No||5-HT1A partial agonist||Low||Memory problems, dizziness, diarrhoea, nausea||Delayed onset of action. Being a 5-HT1A receptor partial agonist may afford it the ability to increase dopamine release in the prefrontal cortex.|
|Desipramine||Norpramin||No||No||No||Tricyclic antidepressant||High||Seizures, hypotension, anticholinergic effects, sedation, weight gain, cardiovascular effects and sexual dysfunction||Delayed onset of action.|
|Duloxetine||Cymbalta||No||No||No||Serotonin-norepinephrine reuptake inhibitor||Moderate||Hypertensive crises, liver failure, myocardial infarction (heart attack), suicidal thoughts, Stevens-Johnson syndrome, sexual dysfunction||Delayed onset of action.|
|Imipramine||Tofranil||No||No||No||Tricyclic antidepressant||Low||Drowsiness, cardiovascular side effects, sexual dysfunction, weight gain, hypotension, seizures and anticholinergic effects. Dangerous in overdose.||Delayed onset of action.|
|Milnacipran||Ixel, Savella||No||No||No||Serotonin-norepinephrine reuptake inhibitor||Negligible||Hypertension, sexual dysfunction||Delayed onset of action.|
|No||No||No||Tricyclic antidepressant||Low||Drowsiness, cardiovascular side effects, sexual dysfunction, weight gain, hypotension, seizures and anticholinergic effects. Dangerous in overdose.||Delayed onset of action.|
|Reboxetine||Edronax||No||No||No||Norepinephrine reuptake inhibitor||Moderate||May be comparatively poorly-tolerated compared to other second-generation antidepressants. Fairly safe in overdose.||Delayed onset of action.|
|No||No||No||Serotonin-norepinephrine reuptake inhibitor||Moderate||Gastrointestinal effects (nausea, vomiting, diarrhoea), weight loss, sexual dysfunction, hypertension, abnormal bleeding, hyponatraemia, suicidal ideation and seizures. Higher risk of provoking mania/hypomania in bipolar individuals than bupropion. Can prolong the QT interval. Less dangerous than bupropion and tricyclic antidepressants in overdose but more dangerous than reboxetine, duloxetine and milnacipran.||Delayed onset of action.|
|No||No||No||NMDA antagonist and dopamine agonist||Low||Anxiety, anorexia, confusion, ataxia, hallucinations, dream abnormality, GI effects||?|
|Carbamazepine||Equetrol, Tegretol, Teril||No||No||No||Sodium channel blocker||High||Ataxia, myocardial infarction, Stevens-Johnson syndrome, hepatic failure, syndrome of inappropriate antidiuretic hormone secretion (SIADH), toxic epidermal necrolysis, pancreatitis, hyponatraemia, renal failure, congestive heart failure, eosinophilic myocarditis, blood dyscrasias (agranulocytosis, aplastic anaemia, leucopaenia, thrombocytopaenia, etc.)||?|
|Memantine||Namenda||No||No||No||NMDA antagonist||Low||Anxiety, anorexia, confusion, ataxia, hallucinations, dream abnormality, GI effects||?|
Levels of support
- Approved indicates that the level of evidence to support the use of the drug in the treatment of ADHD is sufficient for at least one regulatory agency to have already approved it.
- Very high indicates at least ten randomised double-blind placebo-controlled trial support the use of the drug in the treatment of ADHD.
- High indicates that at least three positive randomised double blind placebo-controlled trials have been performed evaluating the efficacy of the drug.
- Moderate indicates that at least one moderately/large-sized (≥30 people) positive randomised double-blind placebo-controlled clinical trial has been performed to evaluate the efficacy of the drug.
- Low indicates that at least one positive open-label or double-blind non-placebo-controlled clinical trial has been performed to evaluate the efficacy of the drug, or a controlled trial that was inadequately sized (<30 participants) or poorly designed.
- Very low. At least two case reports have documented the successful use of the drug in the treatment of ADHD.
- Negligible. One positive case report and additional theoretical (e.g. based on the mechanism of action of the drug in question) support.
Concerns regarding stimulants
The National Institute of Mental Health states that, "one-size-fits-all approach does not apply for all children with ADHD." Some parents and professionals have raised questions about the side effects of drugs and their long-term use. 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."
The American Heart Association feel that it is prudent to carefully assess children for heart conditions before treating them with stimulant medications. Recent extremely large-scale studies by the FDA indicate that, in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, myocardial infarction, and stroke) and the medical use of amphetamine, methylphenidate, or other ADHD stimulants.
Several studies have found growth and weight suppression for stimulants. Compared to the behavior modification group at 8 years of the government-funded MTA study, the stimulant group had higher level of reported substance abuse.
Increase in use
Outpatient treatment rates have held steady in the U.S. recently. Prior to this, outpatient treatment for ADHD in the U.S. grew from 0.9 children per 100 in 1987 to 3.4 per 100 in 1997. A survey conducted by the Centers of Disease Control and Prevention in 2011-2012 found 6.4 million children between the ages of 4 and 17 have been diagnosed with ADHD at some point, a 16% increase since 2007 and a 41% increase over the last decade. There is concern about the rising use of methylphenidate (Ritalin), mainly to treat ADHD and similar disorders, in the UK. The American Psychiatric Association estimates the incidence of ADHD at three to seven percent of the population, but current diagnoses rates in the U.S. are 15% for boys and 7% for girls. Approximately two-thirds of children with current diagnoses are prescribed stimulants.
There is non-medical prescription stimulant use. A 2003 study found that non prescription use by college students in the U.S. was 6.9%, with 4.1% using them within the last year. 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.
Both children with and without ADHD abuse stimulants, with ADHD individuals being at the highest risk of abusing or diverting their stimulant prescriptions. Between 16 and 29 percent of students who are prescribed stimulants report diverting their prescriptions. The National Survey on Drug Use and Health reported that 15% of college students admitted to having used a psychotherapeutic drug for a purpose other than that for which it was prescribed. It also reported that 7% of the 15% said they used Adderall to party or to improve their attention span or grades.
One review indicates that long-term use of methylphenidate has potential for abuse and addiction due to its similarity pharmacologically to cocaine and amphetamines. However, other doctors argue that use of stimulant therapy for ADHD does not increase the risk of subsequent substance abuse and may be protective against it when treatment is started in childhood.[who?] However, when stimulant therapy is started during adolescence or adulthood, there is an increased risk of subsequent substance abuse.
Medication in preschoolers
Parents of children with ADHD note that they usually display their symptoms at an early age. There have been few longitudinal studies on the long-term effects psychostimulants have on children. The use of stimulant medication has not been approved by the FDA for children under the age of six. 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. 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. 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. "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."
Growth delay and 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. A considerable amount of growth hormones (20-40%) are released during the 60-90 minute period after falling asleep. This part of the sleep cycle is suppressed by stimulants, causing a deficit of growth hormones in the body. 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. One notion is that psychostimulant medication can decrease appetite which may result in loss of weight and may be a factor in stunted growth.
Neurological side effects
Long-term exposure to amphetamine throughout adolescence in non-human primates has been observed in two studies. One of these studies found no discernible adverse effect on their physiology, behavior, or dopamine system development, while the other observed large lasting reductions to striatal dopamine and dopamine-associated proteins and metabolites. In contrast for humans, according to Millichap on the use of ADHD stimulants, "[research] has confirmed the effectiveness and safety of the long-term use of [stimulant] medication." Moreover, he emphasized one notable study, stating "a multicenter, placebo-controlled trial of amphetamine treatment for ADHD in Sweden found significant improvements in attention, hyperactivity, and disruptive behaviors and a mean change in IQ of +4.5 after more than 9 months of amphetamine [use];" however, he also noted that the population in the study had a remarkably high incidence of comorbid disorders associated with ADHD. Consequently, the author asserted that other long-term trials of stimulants in ADHD with less comorbidity would be expected to show greater functional improvements and fewer side effects.
Cardiovascular side effects
There is concern that stimulants and Atomoxetine, which increase the heart rate and blood pressure, might cause serious cardiovascular problems. The current US FDA position on ADHD stimulants is that they are not likely to induce serious adverse cardiovascular events, unless there is already a pre-existing cardiovascular condition.
Psychiatric side effects
Many of these drugs are associated with physical and psychological dependence.
Increased rates of psychosis and/or mania are associated with many stimulants used to treat ADHD, including Concerta, Ritalin LA, d-MPH, Atomoxetine, Adderall XR, Modafinil, MTS, and Metadate. A 2009 FDA review of 49 clinical trials found that one to two percent of children taking stimulants for ADHD experienced hallucinations or other psychotic episodes. Nearly half of these were under the age of eleven, and approximately 90% had no history of similar psychiatric events. Hallucinations involving snakes, worms or insects were the most commonly reported. This incidence of psychosis is higher than the 0.1% reported by previous short-term clinical trials. Even this new incidence rate may be low, however, since the clinical trials often excluded children with previous, adverse reactions to ADHD medication.
On occasion, treatment-emergent psychosis can emerge during long-term therapy with methylphenidate. Stimulants such as methylphenidate should be avoided in people who have a vulnerability to schizophrenia or addiction, but psychotic symptoms may emerge even in individuals without these risk factors. Regular psychiatric monitoring of people who are taking methylphenidate for adverse effects such as psychotic symptomatology (with regard to the need for dose adjustment or discontinuation of medication) has been recommended.
Higher rates of schizophrenia and bipolar disorder as well as increased severity of these disorders occur in individuals with a past history of stimulant use for ADHD in childhood. The long-term effects on mental health disorders in later life of chronic use of methylphenidate is unknown.
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 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." A long-term study by Swanson et al. treated nearly 600 children in the 1990s for fourteen months to compare methylphenidate (the active ingredient in Ritalin) versus behavioral treatment. The study consisted of three groups: medication only, behavioral treatment only, and a combination of both. Although it was found that medication was more effective in reducing symptoms, 54% of the medication-alone group required a dose increase of on average 19% per unit of body weight. In a follow-up to the study, the children in the medication-only group reported having lost half of the benefit of medication by the end of two-years, and all of it by the end of three years. Similar results were found in a two-year study in 2005 of 200 children taking Concerta, a delay-release form of methylphenidate. Medication was effective through the second year, but only if the dosage was increased 15% on averaged per unit of body weight.
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 in drug addiction, withdrawal reactions, psychosis, depression, and 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.
Stimulant withdrawal and rebound effects
Tolerance to the therapeutic effects of stimulants can occur, with rebound of symptoms occurring when the dose wears off. Due to the risk of discontinuation and rebound effects doses should be gradually decreased rather than the medication being stopped abruptly. Rebound effects are often the result of the stimulant dosage being too high or the individual not being able to tolerate stimulant medication. Signs that the stimulant dose is too high include irritability, feeling stimulated or blunting of affect and personality.
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. 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. 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. Up to a third of ADHD children experience a rebound effect in ADHD symptoms when the methylphenidate dose wears off.
Concerns about chromosomal aberrations and possible cancer later in life was raised by a small-scale study on the use of methylphenidate, though a review by the Food and Drug Administration (FDA) found significant methodological problems with the study. A follow-up study performed with improved methodology 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."
Combined medical management and behavioral treatment is the most effective ADHD management strategy, followed by medication alone, and then behavioral treatment. In terms of cost-effectiveness, management with medication has been shown to be the most cost-effective, followed by behavioral treatment, and combined treatment. 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. Comorbid (relating to two diseases that occur together, e.g. depression and ADHD) disorders makes finding the right treatment and diagnosis much more costly than when comorbid disorders are absent.
The first reported evidence of stimulant medication used to treat children with concentration and hyperactivity problems came in 1937. Dr. Charles Bradley in Providence, Rhode Island reported that a group of children with behavioral problems improved after being treated with the stimulant Benzedrine. In 1954, the stimulant methylphenidate (Ritalin, which was first produced in 1944) became available; 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.
In 1975, pemoline (Cylert) was approved by the U.S. 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).
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. This was especially good for the behavior modification group, since the behavioral protocols were faded 3 months prior to the last evaluation and the stimulant group continued to receive medication right up to the last evaluation point.
Some proponents of alternative medicine advocate that alternative therapies may be tried before ADHD medications, although not all ADHD children will have any effective response.
Neurofeedback (NF) or EEG biofeedback is a treatment strategy used for children, adolescents and adults with ADHD. The human brain emits electrical energy which is measured with electrodes. Neurofeedback alerts the patient when beta waves are present. This theory believes that those with ADHD can train themselves to decrease ADHD symptoms.
No serious adverse side effects from neurofeedback have been reported. Research into neurofeedback has been limited and of low quality. While there is some indication on the effectiveness of biofeedback it is not conclusive: several studies have yielded positive results, however the best designed ones have either shown reduced effects or non-existing ones.
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. One study suggests that athletic performance in boys with ADHD may increase peer acceptance when accompanied by fewer negative behaviors.
Art is thought by some to be an effective therapy for some of the symptoms of ADHD.
Preliminary studies have supported the idea that playing video games is a form of neurofeedback, which helps those with ADHD self-regulate and improve learning. On the other hand ADHD may experience great difficulty disengaging from the game, which may in turn negate any benefits gained from these activities, and time management skills may be negatively impacted as well.
Children who spend time outdoors in natural settings, such as parks, seem to display fewer symptoms of ADHD, which has been dubbed "Green Therapy".
Dietary supplements and specialized diets are sometimes used by people with ADHD with the intent to mitigate some or all of the symptoms. For example, Omega-3 supplementation (seal, fish or krill oil) may reduce ADHD symptoms for a subgroup of children and adolescents with ADHD "characterized by inattention and associated neurodevelopmental disorders." Although vitamin or mineral supplements (micronutrients) may help children diagnosed with particular deficiencies, there is no evidence that they are helpful for all children with ADHD. Furthermore, megadoses of vitamins, which can be toxic, must be avoided. In the United States, no dietary supplement has been approved for the treatment for ADHD by the FDA. There is however a pilot study done which shows that phosphatidyl serine (PS) can help against ADHD.
Some popular supplements used to manage ADHD symptoms:
- Zinc - Although the role of zinc in ADHD has not been 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 CSIRO, Australia's national science agency, showed polyunsaturated fatty acids to provide "medium to strong positive treatment effects" in ADHD. 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." A 2008 study 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.
- 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.
- 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 - Caffeine intake in moderate amounts may have benefits in ADHD due to caffeine's positive effects on cognition. Anxiety is the main side effect of caffeine, especially at high dosage. Nicotine may improve the symptoms of ADHD in some people.
- Melatonin as well as careful daily sleep practices and light therapy, are sometimes used to treat the sleep disorders such as delayed sleep often associated with ADHD. ADHD itself has genetic commonality with the genes responsible for the human body clock (or circadian rhythm) and poor sleep and ADHD each increase the severity of the other; melatonin itself is a natural neurohormone responsible partly and in tiny amounts for the human body clock.
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 effect of the Feingold diet on the behavior of children with ADHD.
Results of studies regarding the effect of eliminating artificial food coloring from the diet of children with ADHD have been very varied. It has been found that it might be effective in some children but as the published studies have been of low quality results can be more related to research problems such as publication bias. The UK Food Standards Agency (FSA) has called for a ban on the use of six artificial food colorings 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." Nevertheless existing evidence neither refutes nor supports the association between ADHD and food colouring.
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.
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 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).
Legal status of medications
Stimulants legal status was recently reviewed by several international organizations:
- Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.
- In the United States, methylphenidate and amphetamines are classified as Schedule II controlled substances, the designation used for substances that have a recognized medical value but present a high likelihood for abuse because of their addictive potential.
- In the United Kingdom, methylphenidate is a controlled 'Class B' substance, and possession without prescription is illegal, with a sentence up to 14 years and/or an unlimited fine.
- In Australia, stimulants such as methylphenidate and dexamphetamine are Schedule 8 controlled poisons, and as a result have strict prescribing rules due to their potential for abuse.
- Unlike most drugs, Adderall has no generic (USAN, INN, or BAN) name. Also known as mixed amfetamine salts
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