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. The American Academy of Pediatrics recommends different treatment paradigms depending on the age of the person being treated. For those aged 4–5, the Academy recommends evidence-based parent- and/or teacher-administered behavior therapy, with the addition of methylphenidate only if there is continuing moderate-to-severe functional disturbances. For those aged 6–11, the use of medication in combination with behavior therapy is recommended, with the evidence for stimulant medications being stronger than that for other classes. For those aged 12–18, medication should be prescribed with the consent of the treated adolescent, preferably in combination with behavioral therapy. The evidence for the utility of behavioral interventions in this aged group was rated only "C" quality, however.
The most common stimulant medications are amphetamine mixed (Adderall) or dextroamphetamine (Dexedrine), and methylphenidate (Ritalin). Less common are non-stimulants, also approved for the treatment of ADHD, are Atomoxetine (Strattera), guanfacine (Intuniv), and clonidine (Kapvay). 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.
- 1 Psychosocial
- 2 Medications
- 3 Comparative efficacy, tolerability and regulatory status of ADHD medications
- 4 Concerns regarding stimulants
- 5 Cost-effectiveness
- 6 History
- 7 Alternative medicine
- 8 Comorbid disorders
- 9 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.
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.
A 2013 paper published by two researchers from the University of Oslo concluded that working memory training provides short term improvements, but that there was limited evidence that these improvements were sustained or that they were generalized to improved verbal ability, mathematical skills, attention, or word decoding. A 2014 paper published by a group of researchers from the University of Southampton presented the result of meta analysis study of 14 recently published randomized controlled trials (RCTs). The authors concluded that "more evidence from well-blinded studies is required before cognitive training can be supported as a frontline treatment of core ADHD symptoms".
Timers have been found to be effective for allowing people with ADHD to concentrate more effectively on the task at hand.[better source needed] 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), amphetamine (Adderall), methamphetamine (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 increases cellular communication between neurons that utilize these compounds. The therapeutic benefits are due to noradrenergic effects at the locus coeruleus and the prefrontal cortex and dopaminergic effects at the ventral tegmental area, nucleus accumbens, and prefrontal cortex.
Stimulant medications are considered safe when used under medical supervision. Nonetheless, there are concerns that the long term safety of these drugs has not been adequately documented. and social and ethical issues regarding their use and dispensation. The U.S. FDA has added black-box warnings to some ADHD medications, warning that abuse can lead to psychotic episodes, psychological dependence, and that severe depression may occur during withdrawal from abusive use.
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, less-stimulant FDA approved drugs for the treatment of 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.
Amphetamine is a chiral compound which is composed of two isomers: 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. Three different amphetamine-based pharmaceuticals are currently used in ADHD treatment: Adderall, dextroamphetamine, and lisdexamfetamine. Lisfexamfetamine is an inactive prodrug of dextroamphetamine (i.e., lisdexamfetamine itself doesn't do anything in the body, but it metabolizes into dextroamphetamine). Adderall is a proprietary mixture of (75%) dextroamphetamine and (25%) levoamphetamine salts, which results in very mild differences between their effects. 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.[better source needed]
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 less-stimulant drugs approved for the treatment of ADHD. Other medications which may be prescribed off-label include certain antidepressants such as tricyclic antidepressants (TCAs), SNRIs, SSRIs or MAOIs.
Atomoxetine (Strattera) is less effective than stimulants for ADHD, is associated with rare cases of liver damage,:5 and carries a U.S. FDA black box warning regarding suicidal ideation. 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.
Certain antidepressants such as tricyclic antidepressants, SNRIs or MAOIs are sometimes prescribed and appear effective in the treatment some of the symptoms ADHD. With concerns of side effects TCAs overall usefulness is not clear.
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.
- A 2012 systematic review found evidence for the utility of amantadine inconclusive.
- 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.:7 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.
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 from 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 1–1.5 hours 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||Provigil, Modavigil||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.:248||Delayed onset of action|
|No||No||No||Norepinephrine-dopamine reuptake inhibitor & nAChR antagonist||High||Seizures,:247 memory problems, concentration difficulties. Fairly dangerous in overdose.:248||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||Savella, Ixel||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.:588–589||Delayed onset of action.|
|No||No||No||Serotonin-norepinephrine reuptake inhibitor||Moderate||Gastrointestinal effects (nausea, vomiting,:247 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.:117 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||Equetro, 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.
Concerns regarding stimulants
The National Institute of Mental Health states that, "a 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 2008 review stated 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.[when?] 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 for 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. The CDC notes that community samples suggest the incidence of ADHD in American children is higher than the five percent stated by the American Psychiatric Association in DSM-5. Using data from the 2011–2012 survey, CDC estimates that 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. Likewise, there is concern about the rising use of methylphenidate (Ritalin), mainly to treat ADHD and similar disorders, in the UK.
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.
Cardiovascular side effects
There is concern that stimulants and Atomoxetine, which increase the heart rate and blood pressure, might cause serious cardiovascular problems.[better source needed] 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
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. Even this 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.
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
Long-term methylphenidate or amphetamine exposure in some species is known to produce abnormal dopamine system development or nerve damage, but humans experience normal development and nerve growth. Magnetic resonance imaging studies suggest that long-term treatment with amphetamine or methylphenidate decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function of the right caudate nucleus.
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. Controlled trials spanning two years have demonstrated continuous treatment effectiveness and safety. One review highlighted a 9 month randomized controlled trial of amphetamine in children that found an average increase of 4.5 IQ points and continued improvements in attention, disruptive behaviors, and hyperactivity.
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. 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.
Most alternative therapies do not have enough supporting evidence to recommend them. Moreover, when only the best conducted studies are taken into account results tend to be similar to placebo. Some proponents of alternative medicine advocate that alternative therapies may be tried before ADHD medications.
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 mostly 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. In general no effects have been found in the most blinded ADHD measures, which could be indicating that positive results are due to the placebo effect.
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.
Dietary supplements and specialized diets are sometimes used by people with ADHD with the intent to mitigate some or all of the symptoms. However 2009 article in the Harvard Mental Health Letter states, "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.
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 – A 2012 Cochrane review found little evidence that supplementation with omega-3 or other polyunsaturated fatty acids provide any improvement in the symptoms of ADHD in children or adolescents. A 2011 meta analysis found a modest benefit relative to stimulant medications, but concluded that supplementation should be considered based on its benign side effect profile.
- 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.
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).
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New, palatable foods cause dopamine release from VTA neurons of the midbrain that project to the nucleus accumbens, prefrontal cortex, and other limbic structures that regulate emotion. Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward. ... It acts in the orbital prefrontal cortex to set a value on rewards ...
Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the dorsolateral prefrontal cortex and posterior parietal cortex while improving performance of a spacial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. ... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors.
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DA has multiple actions in the prefrontal cortex. It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals. Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions. Cognitive control is impaired in several disorders, including attention deficit hyperactivity disorder. ... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control. ... it has not been shown that 5HT makes a therapeutic contribution to treatment of ADHD.
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