Practices with established treatment efficacy for ADHD
Attention deficit hyperactivity disorder management options are evidence-based practices with established treatment efficacy for ADHD.
The American Academy of Pediatrics (AAP) recommends different treatment paradigms depending on the age of the person being treated. For those aged 4–5, the AAP recommends evidence-based parent- and/or teacher-administered behavioral interventions as first-line treatment, with the addition of methylphenidate if there is continuing moderate-to-severe functional disturbances. For those aged 6–11, the use of medication in combination with behavioral therapy is recommended, with the evidence for stimulant medications being stronger than that for other classes. For adolescents aged 12–17, use of medication along with psychosocial interventions are recommended.[1] Clinical picture of ADHD can be corrected if rehabilitation interventions are started from the early preschool age, when the compensatory capabilities of the brain are great and a persistent pathological stereotype has not yet formed. If symptoms persist at a later age, as the child grows, defects in the development of higher brain functions and behavioral problems worsen, which subsequently lead to difficulties in schooling.[2]
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. In a 2019 review the effectiveness of social skills training was evaluated in children aged 5 to 18 years. At the time there was little evidence to support or refute this type of training for the treatment of ADHD in this age group.[10]
Parents and classroom
Improving the surrounding home and school environment can improve the behavior of children with ADHD.[7] Parents of children with ADHD often show similar deficits themselves, and thus may not be able to sufficiently help the child with his or her difficulties.[11] 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.[7] The different educational interventions for the parents are jointly called Parent Management Training. Techniques include operant conditioning: a consistent application of rewards for meeting goals and good behavior (positive reinforcement) and punishments such as time-outs or revocation of privileges for failing to meet goals or poor behavior.[7] Classroom management is similar to parent management training; educators learn about ADHD and techniques to improve behavior applied to a classroom setting. Strategies utilized include increased structuring of classroom activities,[12] daily feedback, and token economy.[7] In order for Token Economy to benefit students with ADHD, all staff must be consistent in rewarding the same behaviors. Additionally, establishing classroom routines will help to ensure that students with ADHD remain focused throughout the day.[13]
Cognitive training
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.[14] 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".[15]
Stimulants used to treat ADHD raise the extracellular concentrations of the neurotransmittersdopamine and norepinephrine, which increases cellular communication between neurons that utilize these compounds. Stimulants increase the availability of synaptic dopamine, reduce the overactivity, impulsivity, and inattention characteristics of patients with ADHD, and improve associated behaviors, including on-task behavior, academic performance, and social functioning.[21]
Stimulant medications are considered safe when used under medical supervision.[7] Nonetheless, there are concerns that the long term safety of these drugs has not been adequately documented,[24][25][26][27] as well as 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.[28] Stimulants may be a little harder to be prescribed because they are controlled substances and can be abused easily, an example of this would be Adderall. Studies consistently show that most students report using stimulant medications, legally or illegally to improve academic performance, specifically to increase concentration, organization, and the ability to stay up longer and study.[29] The abuse of this drug has made prescribing it much more meticulous.
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.[31] They have not been found to improve school performance and data is lacking on long-term effectiveness and the severity of side effects. Stimulants, however, may reduce the risk of unintentional injuries in children with ADHD.[32][33]
This class of medicines is generally regarded as one unit; however, they affect the brain differently.[34] Some investigations are dedicated to finding the similarities of children who respond to a specific medicine.[34] The behavioral response to stimulants in children is similar regardless of whether they have ADHD or not.[35]
Stimulant medication is an effective treatment[36] for adult attention-deficit hyperactivity disorder[37][38] although the response rate may be lower for adults than children.[39]
Some physicians may recommend antidepressant drugs as the first line treatment instead of stimulants[40] although antidepressants have much lower treatment effect sizes than stimulant medication.[41]
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 produce a small difference in their pharmacological properties; levoamphetamine has a slightly longer half-life than dextroamphetamine, but dextroamphetamine is a more potent central nervous system stimulant. Although it is effective in reducing primary ADHD symptoms such as hyperactivity and inattention, multiple adverse side effects presented. Included in these were headaches, anxiety, nausea and insomnia.[53]
Five different amphetamine-based pharmaceuticals are currently used in ADHD treatment: racemic amphetamine, dextroamphetamine, lisdexamfetamine, and two mixed enantiomer products (Adderall and Dyanavel XR).[42][47][49] Lisdexamfetamine is an inactive prodrug of dextroamphetamine (i.e., lisdexamfetamine itself does not do anything in the body, but it metabolizes into dextroamphetamine).[42] Adderall is a proprietary mixture of (75%) dextroamphetamine and (25%) levoamphetamine salts, which results in very mild differences between their effects.[42] Dyanavel XR contains a similar mixture.[47] Adderall begins to work before dextroamphetamine because of levoamphetamine.[54] Levoamphetamine also provides Adderall with a longer clinical effect than dextroamphetamine. Some children with ADHD and comorbid disorders respond well to levoamphetamine.[34] Amphetamines are modestly more effective than methylphenidate but also potentiate more side effects.[55][56][57]
The body metabolizes methamphetamine into amphetamine (in addition to less active metabolites). A quarter of methamphetamine will ultimately become amphetamine.[58] After comparing only the common ground between dextroamphetamine and dextromethamphetamine, the latter is said to be the stronger stimulant.[59]
^US generics manufactured by County Line Pharmaceuticals and Abhai; CA generic manufactured by Apotex.
Like amphetamine, methylphenidate (MPH) is a chiral compound which is composed of two isomers: d-threo-methylphenidate (also known as dexmethylphenidate, d-methylphenidate, or d-MPH) and l-threo-methylphenidate (also known as l-methylphenidate or l-MPH). Both isomers 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. Unlike amphetamine, the difference in pharmacological properties between d-MPH and l-MPH is significant, as l-MPH is markedly inferior to d-MPH in its effects, which is due to a number of major differences between the isomers.[71][72]
There are two major medications derived from methylphenidate's isomers: a racemic mixture of half d-threo-methylphenidate and half l-threo-methylphenidate called methylphenidate (Ritalin, Concerta), and an enantiopure formulation containing just d-threo-methylphenidate called dexmethylphenidate (Focalin).[citation needed]
Atomoxetine is a selectivenorepinephrine reuptake inhibitor.[78] It has comparable efficacy, tolerability and response rate to methylphenidate in children and adolescents; efficacy and discontinuation rate is equivalent in adults.[79][80][81][82] It carries a U.S. FDA black box warning regarding suicidal ideation and is associated with rare cases of liver damage.[83][84]: 5 Controlled studies show increases in heart rate, decreases of body weight, decreased appetite and treatment-emergent nausea.[85]
The extended release form 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.[88]
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.[89] It may be more useful for comorbid Tourette syndrome.
Other
Some medications used to treat ADHD are prescribed off-label,[90] outside the scope of their US government 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) and proper dosage and usage instructions are not as well characterized.[citation needed]
Bupropion is classified as an atypical antidepressant. It is the most common off-label prescription for ADHD.[91] It inhibits the reuptake of norepinephrine, and to a lesser extent dopamine, in neuronal synapses,[92] and has little or no effect on serotonergic reuptake.[93] Bupropion is not a controlled substance. It is commonly prescribed as a timed release formulation to decrease the risk of side effects.[94]
A wakefulness-promoting agent that operates primarily as a selective, relatively weak, and atypical dopamine reuptake inhibitor. Double-blind randomized controlled trials have demonstrated the efficacy and tolerability of modafinil in pediatric ADHD.[95][96] There are risks of serious side effects such as skin reactions, however these are rare and modafinil is not recommended for use in children.[97]: 7 In the United States, it was originally pending marketing on-label as Sparlon, but approval was denied by the FDA due to major concerns over the occurrence of Stevens–Johnson syndrome in clinical trials.[98]
Atypical antipsychotic medications, which are approved for the treatment of certain behavioral disorders, are sometimes prescribed off-label as a combination therapy with stimulants for the treatment of comorbid (i.e., co-occurring diseases) ADHD and disruptive behavioral disorders.[101][102] Canadian clinical practice guidelines only support the use of dopaminergic antipsychotics with selectivity for D2-type dopamine receptors, particularly risperidone, as a third-line treatment for both disorders following the failure of stimulant monotherapy and psychosocial interventions.[101][103] Combined use of D2-type receptor antagonists and ADHD stimulants for the treatment of ADHD with comorbidbehavioral disorders does not appear to have significantly worse adverse effects than ADHD stimulant or antipsychotic monotherapy.[101][104] Research suggests, but has not yet confirmed, the treatment efficacy of antipsychotic and stimulant combination treatment for both disorders;[101] it is unclear if the combination therapy for both disorders is superior to stimulant or antipsychotic monotherapy.[101] There is no evidence to support the use of any subclass of antipsychotics for the treatment of the core symptoms of ADHD (i.e., inattention and hyperactivity) without comorbid behavioral disorders.[105]
Dopaminergic antipsychotics affect dopamine neurons by binding to postsynaptic dopamine receptors, where they function as receptor antagonists.[104] In contrast, ADHD stimulants are indirect agonists of postsynaptic dopamine receptors;[104] in other words, these stimulants increase levels of synaptic dopamine, which then binds to postsynaptic receptors.[104] Stimulants increase the concentration of synaptic dopamine by activating certain presynaptic receptors (i.e., TAAR1) or by blocking or altering the function of reuptake transporters (e.g., DAT, VMAT2) in the presynaptic neuron.[citation needed]
Highly efficacious,[117] comparable to atomoxetine[121][122][123][124] but modestly lower than amphetamines.[125][126][127] Therapeutic effects are usually seen within 0.5–1.5 hours of oral administration (depending on formulation).
Highly efficacious,[117] therapeutic effects are usually seen within 0.5–1.5 hours of oral administration (depending on formulation). No significant advantages over methylphenidate at equipotent dosages.
Highly efficacious; comparable to methylphenidate in children and adolescents and equivalent in adults.[130][131][132][133] It yields a slower onset of action (usually takes at least a couple weeks) but has a lower risk of abuse and dependence than stimulants.
Rapid onset of action (several hours). Level of support enough to potentially gain approval for pediatric ADHD, however the FDA rejected approval due to concerns over serious skin reactions.[98] Poorly evaluated for adult ADHD as most published research trials focus on pediatric ADHD.[98]
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.[136]
Delayed onset of action. Being a 5-HT1A receptor partial agonist may afford it the ability to increase dopamine release in the prefrontal cortex.[148][149]
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 six randomised double-blind placebo-controlled trials 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.
Some parents and professionals have raised questions about the side effects of drugs and their long-term use.[90]
Increasing use
Outpatient treatment rates held steady in the U.S. from the late 1990s to early 2000s. 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.[174] A survey conducted by the Centers for Disease Control and Prevention in 2011–2012 found 11% of children between the ages of 4 and 17 were reported to have ever received a health care provider diagnosis of ADHD at some point (15% of boys and 7% of girls),[175] a 16% increase since 2007 and a 41% increase over the last decade.[176] 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, with 8.8% of U.S. children having a current diagnosis in the 2011 survey.[176][177] However, only 6.1% of children in the 2011 survey were taking ADHD medication, suggesting as many as 17.5% of children with current ADHD were not receiving treatment.[176]
Use 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 of stimulant use in children.[178] The use of stimulant medication has not been approved by the FDA for children under the age of six.[179] 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.[180][181] Research on this issue has indicated that stimulant medication can help younger children with "severe ADHD symptoms" but typically at a lower dose than older children. It was also found that children at this age are more sensitive to side effects and should be closely monitored.[179] Evidence suggests that careful assessment and highly individualized behavioural interventions significantly improve both social and academic skills,[182] 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."[183]
Side effects
Constipation and gastrointestinal pain
Central nervous system stimulants such as lisdexamfetamine may be associated with occurrences of constipation, diarrhea, nausea, and stomach pain.[184]
Growth delay and weight loss
There is some evidence of mild reductions in growth rate with prolonged stimulant treatment in children, but no causal relationship has been established and reductions do not appear to persist long-term.[185] Weight loss almost always corresponds with loss of appetite, which may result from the medication. Severe weight loss is very uncommon though. Loss of appetite is very temporary and typically comes back as daily effects of stimulants wear off. Nausea, dizziness, and headaches, other side effect, can also indirectly affect appetite and result in weight loss.[186]
Cardiovascular
There is concern that stimulants and atomoxetine, which increase the heart rate and blood pressure, might cause serious cardiovascular problems.[187][188] 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.[189][190][191][192]
Psychiatric
Many of these drugs are associated with physical and psychological dependence.[193][page needed] Sleep problems may occur.[194]
Methylphenidate can worsen psychosis in psychotic patients, and in very rare cases it has been associated with the emergence of new psychotic symptoms.[195] It should be used with extreme caution in patients with bipolar disorder due to the potential induction of mania or hypomania.[196] There have been very rare reports of suicidal ideation, but evidence does not support a link.[185] The long-term effects on mental health disorders in later life of chronic use of methylphenidate is unknown.[197]
A 2009 FDA review of 49 clinical trials found that approximately 1.5% of children in clinical trials of medications for ADHD had experienced signs or symptoms of psychosis or mania. Postmarketing reports were also analyzed, with nearly half of them involving children under the age of eleven. Approximately 90% of cases had no reported previous history of similar psychiatric events. Hallucinations involving snakes, worms or insects were the most commonly reported symptoms.[198]
Long-term use
Long-term methylphenidate or amphetamine exposure in some species is known to produce abnormal dopamine system development or nerve damage,[199][200] but humans experience normal development and nerve growth.[201][202][203]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.[201][202][203]
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[204][205] Controlled trials spanning two years have demonstrated continuous treatment effectiveness and safety.[205][206] One review highlighted a nine-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.[206]
There is some evidence that ADHD itself may protect the brain against the natural aging process later in life,[207] perhaps by exercising the brain, and helping maintain volume. It is unknown how long term medication treatment effects the trajectory of brain volume decline in the aging ADHD brain.[207]
Withdrawal and rebound
Tolerance to the therapeutic effects of stimulants can occur,[208] and rebound of symptoms may occur when the dose wears off.[209] 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.[210]
Stimulant withdrawal or rebound reactions can occur and can be minimised in intensity via a gradual tapering off of medication over a period of weeks or months.[211] A small study of abrupt withdrawal of stimulants did suggest that withdrawal reactions are not typical, and may only occur in susceptible individuals.[212]
Cancer
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.[213] 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."[214]
History
The first reported evidence of stimulant medication used to treat children with concentration and hyperactivity problems came in 1937.[215]Charles Bradley in Providence, Rhode Island, reported that a group of children with behavioral problems improved after being treated with the stimulant Benzedrine.[215][216] 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.[215]
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).[citation needed]
In 2003, atomoxetine (Strattera) received the first FDA approval for a nonstimulant drug to be used specifically for ADHD.[217] In 2007, lisdexamfetamine (Vyvanse) became the first prodrug[218] for ADHD to receive FDA approval.[219] In March 2019, a Purdue Pharma subsidiary received approval from the FDA for Adhansia XR, a methylphenidate medication to treat ADHD.[220]
Cost-effectiveness
Combined medical management and behavioral treatment is the most effective ADHD management strategy, followed by medication alone, and then behavioral treatment.[30] In terms of cost-effectiveness, management with medication has been shown to be the most cost-effective, followed by behavioral treatment, and combined treatment.[30] 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.[221]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.[citation needed]
Alternative medicine
Caffeine is sometimes used to manage ADHD symptoms.
Most alternative therapies do not have enough supporting evidence to recommend them.[222][223] Moreover, when only the best conducted studies are taken into account results tend to be similar to placebo.[223]
Neurofeedback
Neurofeedback (NF) or EEG biofeedback is a treatment strategy used for children, adolescents and adults with ADHD.[224] 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.[citation needed]
No serious adverse side effects from neurofeedback have been reported.[225] Research into neurofeedback has been mostly limited and of low quality.[225] 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.[failed verification][225][226] 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.[227]
Media
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.[228][229] Memory, multitasking, fluid intelligence, and other cognitive talents may be improved by certain computer programmes and video games.[230] On the other hand, ADHD may experience great difficulty disengaging from the game, which may in turn negate any benefits gained from these activities,[231] and time management skills may be negatively impacted as well.[232]
Nature
Children who spend time outdoors in natural settings, such as parks, seem to display fewer symptoms of ADHD, which has been dubbed "Green Therapy".[233] But it may be due to reverse causation.[clarification needed]
There is insufficient evidence to support dietary changes in ADHD and thus they are not recommended by the American Academy of Pediatrics as of 2019.[234] 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.[235] However, studies have shown little if any effect of the Feingold diet on the behavior of children with ADHD.[236]
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.[237]
The UK Food Standards Agency (FSA) has called for a ban on the use of six artificial food colorings[238] 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."[239] Nevertheless, existing evidence neither refutes nor supports the association between ADHD and food colouring.[240]
Dietary supplements, self-medication,[241] and specialized diets are sometimes used by people with ADHD with the intent to mitigate some or all of the symptoms. However a 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."[242] In the United States, no dietary supplement has been approved for the treatment for ADHD by the FDA.[243]
Some popular supplements used to manage ADHD symptoms:
Caffeine – ADHD is associated with increased caffeine consumption, and caffeine's stimulant effects on cognition may have some benefits for ADHD.[244] Limited evidence suggests a small therapeutic effect that is markedly inferior to standard treatments like methylphenidate and dextroamphetamine while still producing similar or greater side effects.[244][245]
Nicotine – The association between ADHD and nicotine intake is well known, and limited evidence suggests that nicotine may help improve some of the symptoms of ADHD, although the effect is generally small.[246][247][248]
Omega-3 fatty acids – There is no evidence that supplementation with omega-3 or other polyunsaturated fatty acids provides any improvement in the symptoms of ADHD in children or adolescents.[249] A 2011 meta analysis found a "small but significant benefit", with benefits being "modest compared to the efficacy of currently available pharmacological treatments for ADHD".[250] The review concluded that supplementation may be worth consideration as an augmentative treatment in combination with medication due to its "relatively benign side-effect profile", but not as a primary treatment.[250] Most research on omega-3 fatty acids is considered to be of very poor quality with widespread methodological weaknesses.[249][250]
Zinc – Although the role of zinc in ADHD has not been elucidated, there is a small amount of limited evidence that lower tissue zinc levels may be associated with ADHD.[251] In the absence of a demonstrated zinc deficiency (which is rare outside of developing countries), zinc supplementation is not recommended as a treatment option for ADHD.[252]
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.[253]
Exercise
Regular physical exercise, particularly aerobic exercise, is an effective add-on treatment for ADHD in children and adults, particularly when combined with stimulant medication (although the best intensity and type of aerobic exercise for improving symptoms are not currently known).[254][255][256] The long-term effects of regular aerobic exercise in ADHD individuals include better behavior and motor abilities, improved executive functions (including attention, inhibitory control, and planning, among other cognitive domains), faster information processing speed, and better memory.[254][255][256] Parent-teacher ratings of behavioral and socio-emotional outcomes in response to regular aerobic exercise include: better overall function, reduced ADHD symptoms, better self-esteem, reduced levels of anxiety and depression, fewer somatic complaints, better academic and classroom behavior, and improved social behavior.[254] Exercising while on stimulant medication augments the effect of stimulant medication on executive function.[254] It is believed that these short-term effects of exercise are mediated by an increased abundance of synaptic dopamine and norepinephrine in the brain.[254]
Comorbid disorders
Because ADHD comorbidities are diverse and the rate of comorbidity is high, special care must dedicated to certain comorbidities. The FDA is not set up to address this issue, and does not approve medications for comorbidities, nonetheless certain such topics have been extensively researched.
Tic disorders
Patients with Tourette syndrome who are referred to specialty clinics have a high rate of comorbid ADHD. Patients who have ADHD along with tics or tic disorders may also have problems with disruptive behaviors, overall functioning, and cognitive function, accounted for by the comorbid ADHD.[257]
The treatment of ADHD in the presence of tic disorders has long been a controversial topic. Past medical practice held that stimulants could not be used in the presence of tics, due to concern that their use might worsen tics;[258] however, multiple lines of research have shown that stimulants can be cautiously used in the presence of tic disorders.[259][212] Several studies have shown that stimulants do not exacerbate tics any more than placebo does, and suggest that stimulants may even reduce tic severity.[260] A 2011 Cochrane Collaboration review concluded that most major ADHD medications were effective in children with tics, and that stimulants did not generally worsen tics outside of individual cases.[261]Methylphenidate, guanfacine, clonidine, and desipramine were associated with improvement of tic symptoms.[261] 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.[258][262]
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.[263] Current prescribed stimulant medications include: methylphenidate, dextroamphetamine, 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. There is good empirical evidence for short-term safety and efficacy for the use of desipramine, bupropion and atomoxetine.[263]
^ abHazell, P (October 2005). "Do adrenergically active drugs have a role in the first-line treatment of attention-deficit/hyperactivity disorder?". Expert Opinion on Pharmacotherapy. 6 (12): 1989–98. doi:10.1517/14656566.6.12.1989. PMID16197353. S2CID13346726.
^Waxmonsky, James (October 2003). "Assessment and treatment of attention deficit hyperactivity disorder in children with comorbid psychiatric illness". Current Opinion in Pediatrics. 15 (5): 476–482. doi:10.1097/00008480-200310000-00006. PMID14508296. S2CID36186879.
^Kazdin, Alan E. Parent management training: treatment for oppositional, aggressive, and antisocial behavior in children and adolescents. Oxford University Press, 2005
^Sonuga-Barke, E; Brandeis, D; Holtmann, M; Cortese, S (October 2014). "Computer-based Cognitive Training for ADHD: A Review of Current Evidence". Child and Adolescent Psychiatric Clinics of North America. 23 (4): 807–824. doi:10.1016/j.chc.2014.05.009. PMID25220088.
^Howland RH (August 2008). "Lisdexamfetamine: a prodrug stimulant for ADHD". Journal of Psychosocial Nursing and Mental Health Services. 46 (8): 19–22. doi:10.3928/02793695-20080801-05. PMID18777964.
^National Toxicology Program (July 2005). "NTP-CERHR monograph on the potential human reproductive and developmental effects of amphetamines". NTP Cerhr Mon (16): vii–III1. PMID16130031.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapters 10 and 13". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 266, 318–323. ISBN978-0-07-148127-4.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 148, 154–157. ISBN978-0-07-148127-4.
^Stern HP, Stern TP (September 2002). "When children with attention-deficit/hyperactivity disorder become adults". South. Med. J. 95 (9): 985–91. doi:10.1097/00007611-200209000-00011. PMID12356139.
^Lerner M, Wigal T (January 2008). "Long-term safety of stimulant medications used to treat children with ADHD". Pediatric Annals. 37 (1): 37–45. doi:10.3928/00904481-20080101-11. PMID18240852.
^ abcJensen; Garcia, JA; Glied, S; Crowe, M; Foster, M; Schlander, M; Hinshaw, S; Vitiello, B; Arnold, LE (2005). "Cost-Effectiveness of ADHD Treatments: Findings from the Multimodal Treatment Study of Children With ADHD". American Journal of Psychiatry. 162 (9): 1628–1636. doi:10.1176/appi.ajp.162.9.1628. hdl:1811/51178. PMID16135621. S2CID18620849.
^Dalsgaard, Søren; Leckman, James F.; Mortensen, Preben Bo; Nielsen, Helena Skyt; Simonsen, Marianne (1 August 2015). "Effect of drugs on the risk of injuries in children with attention deficit hyperactivity disorder: a prospective cohort study". The Lancet. Psychiatry. 2 (8): 702–709. doi:10.1016/S2215-0366(15)00271-0. ISSN2215-0374. PMID26249301.
^Higgins ES (January 1999). "A comparative analysis of antidepressants and stimulants for the treatment of adults with attention-deficit hyperactivity disorder". J Fam Pract. 48 (1): 15–20. PMID9934377.
^Verbeeck W, Tuinier S, Bekkering GE (February 2009). "Antidepressants in the treatment of adult attention-deficit hyperactivity disorder: a systematic review". Adv Ther. 26 (2): 170–184. doi:10.1007/s12325-009-0008-7. PMID19238340. S2CID5975939.
^"Mydayis Prescribing Information"(PDF). United States Food and Drug Administration. Shire US Inc. June 2017. pp. 1–21. Retrieved 8 August 2017.
^"Adzenys XR-ODT Prescribing Information"(PDF). United States Food and Drug Administration. Neos Therapeutics, Inc. January 2017. p. 16. Retrieved 10 August 2017. ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.
^"Adzenys XR-ODT". United States Food and Drug Administration. Retrieved 7 March 2016.
^ abc"Dyanavel XR Prescribing Information"(PDF). United States Food and Drug Administration. Tris Pharma, Inc. May 2017. pp. 1–14. Retrieved 4 August 2017. DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1 ... DOSAGE FORMS AND STRENGTHS Extended-release oral suspension contains 2.5 mg amphetamine base per mL.
^"Dyanavel XR". United States Food and Drug Administration. Retrieved 1 January 2016.
^ ab"Evekeo". United States Food and Drug Administration. Retrieved 11 August 2015.
^"Vyvanse Prescribing Information"(PDF). United States Food and Drug Administration. Shire US Inc. January 2017. pp. 18–21. Retrieved 16 February 2017.
^Glaser; Thomas, TC; Joyce, BM; Castellanos, FX; Gerhardt, GA; et al. (2005). "Differential Effects of Amphetamine Isomers on Dopamine in the Rat Striatum and Nucleus Accumbens Core". Psychopharmacology. 178 (2–3): 250–258 (Page: 255). doi:10.1007/s00213-004-2012-6. PMID15719230. S2CID3116771.
^ abStuhec, Matej; Lukić, Petar; Locatelli, Igor (February 2019). "Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis". Annals of Pharmacotherapy. 53 (2): 121–133. doi:10.1177/1060028018795703. PMID30117329. S2CID52019992.
^ abFaraone, Stephen V.; Biederman, Joseph; Roe, Christine (October 2002). "Comparative Efficacy of Adderall and Methylphenidate in Attention-deficit/Hyperactivity Disorder: A Meta-Analysis". Journal of Clinical Psychopharmacology. 22 (5): 468–473. doi:10.1097/00004714-200210000-00005. PMID12352269. S2CID19726926.
^ abFaraone, Stephen V.; Buitelaar, Jan (April 2010). "Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis". European Child & Adolescent Psychiatry. 19 (4): 353–364. doi:10.1007/s00787-009-0054-3. PMID19763664. S2CID9447892.
^Shoblock; Sullivan, EB; Maisonneuve, IM; Glick, SD; et al. (2003). "Neurochemical and Behavioral Differences Between D-Methamphetamine and D-Amphetamine in Rats". Psychopharmacology. 165 (4): 359–369 (Page:366). doi:10.1007/s00213-002-1288-7. PMID12491026. S2CID1933979.
^"Education/Training » Clinical Resources". Illinois DocAssist website. University of Illinois at Chicago. Archived from the original on 1 January 2013. Retrieved 26 July 2012. Ritalin‑SR, methylphenidate SR, Methylin ER, and Metadate ER are the same formulation and have the same drug delivery system
^Markowitz, JS; Patrick, KS (June 2008). "Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?". Journal of Clinical Psychopharmacology. 28 (3 Suppl 2): S54–61. doi:10.1097/JCP.0b013e3181733560. PMID18480678.
^Heal DJ, Pierce DM (2006). "Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system". CNS Drugs. 20 (9): 713–738 (Page:730). doi:10.2165/00023210-200620090-00002. PMID16953648. S2CID39535277.
^Bushe, Chris; Day, Kathleen; Reed, Victoria; Karlsdotter, Kristina; Berggren, Lovisa; Pitcher, Ashley; Televantou, Foula; Haynes, Virginia (May 2016). "A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients". Journal of Psychopharmacology. 30 (5): 444–458. doi:10.1177/0269881116636105. PMID27005307. S2CID104938.
^Hazell, Philip L.; Kohn, Michael R.; Dickson, Ruth; Walton, Richard J.; Granger, Renee E.; van Wyk, Gregory W. (November 2011). "Core ADHD Symptom Improvement With Atomoxetine Versus Methylphenidate: A Direct Comparison Meta-Analysis". Journal of Attention Disorders. 15 (8): 674–683. doi:10.1177/1087054710379737. PMID20837981. S2CID43503227.
^Bushe, Chris; Day, Kathleen; Reed, Victoria; Karlsdotter, Kristina; Berggren, Lovisa; Pitcher, Ashley; Televantou, Foula; Haynes, Virginia (May 2016). "A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients". Journal of Psychopharmacology. 30 (5): 444–458. doi:10.1177/0269881116636105. PMID27005307. S2CID104938.
^Hazell, Philip L.; Kohn, Michael R.; Dickson, Ruth; Walton, Richard J.; Granger, Renee E.; van Wyk, Gregory W. (November 2011). "Core ADHD Symptom Improvement With Atomoxetine Versus Methylphenidate: A Direct Comparison Meta-Analysis". Journal of Attention Disorders. 15 (8): 674–683. doi:10.1177/1087054710379737. PMID20837981. S2CID43503227.
^Allen AJ, Kurlan RM, Gilbert DL, Coffey BJ, Linder SL, Lewis DW, Winner PK, Dunn DW, et al. (December 2005). "Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders". Neurology. 65 (12): 1941–9. doi:10.1212/01.wnl.0000188869.58300.a7. PMID16380617. S2CID878719.
^Biederman J, Swanson JM, Wigal SB, Boellner SW, Earl CQ, Lopez FA (May 2006). "A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study". The Journal of Clinical Psychiatry. 67 (5): 727–35. doi:10.4088/JCP.v67n0506. PMID16841622.
^Greenhill LL, Biederman J, Boellner SW (May 2006). "A randomized, double-blind, placebo-controlled study of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder". Journal of the American Academy of Child and Adolescent Psychiatry. 45 (5): 503–11. doi:10.1097/01.chi.0000205709.63571.c9. PMID16601402.
^Cephalon, Inc. (21 December 2007). "Modavigil Product Information". healthlinks.net. healthlinks.net Pty. Ltd. Archived from the original(PDF) on 21 July 2008. Retrieved 2 July 2008.
^Moore JJ, Saadabadi A (January 2020). "Selegiline". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID30252350.
^Rubinstein, S.; Malone, M. A.; Roberts, W.; Logan, W. J. (2006). "Placebo-controlled study examining effects of selegiline in children with attention-deficit/hyperactivity disorder". Journal of Child and Adolescent Psychopharmacology. 16 (4): 404–415. doi:10.1089/cap.2006.16.404. PMID16958566.
^ abcdeLinton, D; Barr, AM; Honer, WG; Procyshyn, RM (May 2013). "Antipsychotic and psychostimulant drug combination therapy in attention deficit/hyperactivity and disruptive behavior disorders: a systematic review of efficacy and tolerability". Current Psychiatry Reports. 15 (5): 355. doi:10.1007/s11920-013-0355-6. PMID23539465. S2CID45484062.
^Birnbaum ML, Saito E, Gerhard T, Winterstein A, Olfson M, Kane JM, Correll CU (2013). "Pharmacoepidemiology of antipsychotic use in youth with ADHD: trends and clinical implications". Curr Psychiatry Rep. 15 (8): 382. doi:10.1007/s11920-013-0382-3. PMC4010184. PMID23881713. Most importantly, antipsychotics are not approved for the treatment of symptoms of ADHD and limited, if any, evidence exists to suggest their utility for the core symptoms of inattention and hyperactivity. Although, aripiprazole and risperidone are approved for irritability and aggression associated with autistic disorder (age 5 or 6–17 years), and data exist for their utility in disruptive behavior disorders and aggression, antipsychotics should be the last resort for the treatment of impulsivity, oppositionality and aggression.
^Santosh, PJ; Sattar, S; Canagaratnam, M (September 2011). "Efficacy and Tolerability of Pharmacotherapies for Attention-Deficit Hyperactivity Disorder in Adults". CNS Drugs. 25 (9): 737–763. doi:10.2165/11593070-000000000-00000. PMID21870887. S2CID207300617. (subscription required)
^Faraone, SV; Glatt, SJ (June 2010). "A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes". Journal of Clinical Psychiatry. 71 (6): 754–763. doi:10.4088/JCP.08m04902pur. PMID20051220. S2CID41977828. (subscription required)
^Stuhec, Matej; Lukić, Petar; Locatelli, Igor (February 2019). "Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis". Annals of Pharmacotherapy. 53 (2): 121–133. doi:10.1177/1060028018795703. PMID30117329. S2CID52019992.
^Faraone, Stephen V.; Pliszka, Steven R.; Olvera, Rene L.; Skolnik, Rebecca; Biederman, Joseph (June 2001). "Efficacy of Adderall and Methylphenidate in Attention Deficit Hyperactivity Disorder: A Reanalysis Using Drug–Placebo and Drug–Drug Response Curve Methodology". Journal of Child and Adolescent Psychopharmacology. 11 (2): 171–180. doi:10.1089/104454601750284081. PMID11436957. ProQuest204600452.
^Faraone, Stephen V.; Biederman, Joseph; Roe, Christine (October 2002). "Comparative Efficacy of Adderall and Methylphenidate in Attention-deficit/Hyperactivity Disorder: A Meta-Analysis". Journal of Clinical Psychopharmacology. 22 (5): 468–473. doi:10.1097/00004714-200210000-00005. PMID12352269. S2CID19726926.
^Faraone, Stephen V.; Buitelaar, Jan (April 2010). "Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis". European Child & Adolescent Psychiatry. 19 (4): 353–364. doi:10.1007/s00787-009-0054-3. PMID19763664. S2CID9447892.
^Bushe, Chris; Day, Kathleen; Reed, Victoria; Karlsdotter, Kristina; Berggren, Lovisa; Pitcher, Ashley; Televantou, Foula; Haynes, Virginia (May 2016). "A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients". Journal of Psychopharmacology. 30 (5): 444–458. doi:10.1177/0269881116636105. PMID27005307. S2CID104938.
^Hazell, Philip L.; Kohn, Michael R.; Dickson, Ruth; Walton, Richard J.; Granger, Renee E.; van Wyk, Gregory W. (November 2011). "Core ADHD Symptom Improvement With Atomoxetine Versus Methylphenidate: A Direct Comparison Meta-Analysis". Journal of Attention Disorders. 15 (8): 674–683. doi:10.1177/1087054710379737. PMID20837981. S2CID43503227.
^Stuhec, Matej; Lukić, Petar; Locatelli, Igor (February 2019). "Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis". Annals of Pharmacotherapy. 53 (2): 121–133. doi:10.1177/1060028018795703. PMID30117329. S2CID52019992.
^Faraone, Stephen V.; Biederman, Joseph; Roe, Christine (October 2002). "Comparative Efficacy of Adderall and Methylphenidate in Attention-deficit/Hyperactivity Disorder: A Meta-Analysis". Journal of Clinical Psychopharmacology. 22 (5): 468–473. doi:10.1097/00004714-200210000-00005. PMID12352269. S2CID19726926.
^Faraone, Stephen V.; Buitelaar, Jan (April 2010). "Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis". European Child & Adolescent Psychiatry. 19 (4): 353–364. doi:10.1007/s00787-009-0054-3. PMID19763664. S2CID9447892.
^Bushe, Chris; Day, Kathleen; Reed, Victoria; Karlsdotter, Kristina; Berggren, Lovisa; Pitcher, Ashley; Televantou, Foula; Haynes, Virginia (May 2016). "A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients". Journal of Psychopharmacology. 30 (5): 444–458. doi:10.1177/0269881116636105. PMID27005307. S2CID104938.
^Hazell, Philip L.; Kohn, Michael R.; Dickson, Ruth; Walton, Richard J.; Granger, Renee E.; van Wyk, Gregory W. (November 2011). "Core ADHD Symptom Improvement With Atomoxetine Versus Methylphenidate: A Direct Comparison Meta-Analysis". Journal of Attention Disorders. 15 (8): 674–683. doi:10.1177/1087054710379737. PMID20837981. S2CID43503227.
^Malhotra, S; Santosh, PJ (April 1998). "An open clinical trial of buspirone in children with attention-deficit/hyperactivity disorder". Journal of the American Academy of Child and Adolescent Psychiatry. 37 (4): 364–371. doi:10.1097/00004583-199804000-00013. PMID9549956.
^Mohammadi, MR; Hafezi, P; Galeiha, A; Hajiaghaee, R; Akhondzadeh, S (November 2012). "Buspirone versus Methylphenidate in the Treatment of Children with Attention- Deficit/ Hyperactivity Disorder: Randomized Double-Blind Study". Acta Medica Iranica. 50 (11): 723–728. PMID23292622.
^Sutherland, SM; Adler, LA; Chen, C; Smith, MD; Feltner, DE (2012). "An 8-Week, Randomized Controlled Trial of Atomoxetine, Atomoxetine Plus Buspirone, or Placebo in Adults With ADHD". The Journal of Clinical Psychiatry. 73 (4): 445–450. doi:10.4088/JCP.10m06788. PMID22313788.
^Davari-Ashtiani, R; Shahrbabaki, ME; Razjouyan, K; Amini, H; Mazhabdar, H (2010). "Buspirone Versus Methylphenidate in the Treatment of Attention Deficit Hyperactivity Disorder: A Double-Blind and Randomized Trial". Child Psychiatry and Human Development. 41 (6): 641–648. doi:10.1007/s10578-010-0193-2. PMID20517641. S2CID8423643.
^Garfinkel, BD; Wender, PH; Sloman, L; O'Neill, I (July 1983). "Tricyclic antidepressant and methylphenidate treatment of attention deficit disorder in children". Journal of the American Academy of Child Psychiatry. 22 (4): 343–8. doi:10.1016/s0002-7138(09)60669-5. PMID6875128.
^Kako, Y; Niwa, Y; Toyomaki, A; Yamanaka, H; Kitagawa, N; Denda, K; Koyama, T (April 2007). "A case of adult attention-deficit/hyperactivity disorder alleviated by milnacipran". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 31 (3): 772–775. doi:10.1016/j.pnpbp.2006.12.017. PMID17300859. S2CID45319497.
^Priest, R. G.; Gimbrett, R.; Roberts, M.; Steinert, J. (April 1995). "Reversible and selective inhibitors of monoamine oxidase A in mental and other disorders". Acta Psychiatrica Scandinavica. 91: 40–43. doi:10.1111/j.1600-0447.1995.tb05923.x. PMID7717094. S2CID25115362.
^Wilens, TE; Biederman, J; Geist, DE; Steingard, R; Spencer, T (March 1993). "Nortriptyline in the treatment of ADHD: a chart review of 58 cases". Journal of the American Academy of Child and Adolescent Psychiatry. 32 (2): 343–349. doi:10.1097/00004583-199303000-00015. PMID8444763.
^Spencer, T; Biederman, J; Wilens, T; Steingard, R; Geist, D (January 1993). "Nortriptyline treatment of children with attention-deficit hyperactivity disorder and tic disorder or Tourette's syndrome". Journal of the American Academy of Child and Adolescent Psychiatry. 32 (1): 205–210. doi:10.1097/00004583-199301000-00029. PMID8428873.
^Ghanizadeh, A (May 2015). "A systematic review of reboxetine for treating patients with attention deficit hyperactivity disorder". Nordic Journal of Psychiatry. 69 (4): 241–8. doi:10.3109/08039488.2014.972975. PMID25415763. S2CID6406537.
^Rubinstein, S; Malone, MA; Roberts, W; Logan, WJ (August 2006). "Placebo-controlled study examining effects of selegiline in children with attention-deficit/hyperactivity disorder". Journal of Child and Adolescent Psychopharmacology. 16 (4): 404–15. doi:10.1089/cap.2006.16.404. PMID16958566.
^Ahmad Ghanizadeh; Roger D. Freeman; Michael Berk (March 2013). "Efficacy and adverse effects of venlafaxine in children and adolescents with ADHD: a systematic review of non-controlled and controlled trials". Reviews on Recent Clinical Trials. 8 (1): 2–8. doi:10.2174/1574887111308010002. PMID23157376.
^Mohammadi, MR; Kazemi, MR; Zia, E; Rezazadeh, SA; Tabrizi, M; Akhondzadeh, S (2010). "Amantadine versus methylphenidate in children and adolescents with attention deficit/hyperactivity disorder: a randomized, double-blind trial". Human Psychopharmacology. 25 (7–8): 560–565. doi:10.1002/hup.1154. PMID21312290. S2CID30677758.
^Popper, CW (July 2000). "Pharmacologic alternatives to psychostimulants for the treatment of attention-deficit/hyperactivity disorder". Child and Adolescent Psychiatric Clinics of North America. 9 (3): 605–46, viii. doi:10.1016/S1056-4993(18)30109-3. PMID10944659.
^Surman, CB; Hammerness, PG; Petty, C; Spencer, T; Doyle, R; Napolean, S; Chu, N; Yorks, D; Biederman, J (May 2013). "A pilot open label prospective study of memantine monotherapy in adults with ADHD". The World Journal of Biological Psychiatry. 14 (4): 291–298. doi:10.3109/15622975.2011.623716. PMID22436083. S2CID45700232.
^Name, LM; Gameroff, M; Marcus, MJ; Jensen, SC; Jensen, PS (2003). "National trends in the treatment of attention deficit hyperactivity disorder". American Journal of Psychiatry. 160 (6): 1071–1077. doi:10.1176/appi.ajp.160.6.1071. PMID12777264. S2CID17985245.
^ abCortese, S; Holtmann, M; Banaschewski, T; Buitelaar, J; Coghill, D; Danckaerts, M; Dittmann, RW; Graham, J; Taylor, E; Sergeant, J; European ADHD Guidelines, Group (March 2013). "Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 54 (3): 227–46. doi:10.1111/jcpp.12036. PMID23294014. S2CID20052221.
^Kraemer M, Uekermann J, Wiltfang J, Kis B (July 2010). "Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature". Clin Neuropharmacol. 33 (4): 204–6. doi:10.1097/WNF.0b013e3181e29174. PMID20571380. S2CID34956456.
^Wingo, AP; Ghaemi, SN (2008). "Frequency of stimulant treatment and of stimulant-associated mania/hypomania in bipolar disorder patients". Psychopharmacology Bulletin. 41 (4): 37–47. PMID19015628.
^Millichap JG (2010). "Chapter 3: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York: Springer. pp. 111–113. ISBN978-1-4419-1396-8.
^Bader, A; Adesman, A (December 2012). "Complementary and alternative therapies for children and adolescents with ADHD". Current Opinion in Pediatrics. 24 (6): 760–9. doi:10.1097/mop.0b013e32835a1a5f. PMID23111680. S2CID41643161.
^ abSonuga-Barke, EJ; Brandeis, D; Cortese, S; Daley, D; Ferrin, M; Holtmann, M; Stevenson, J; Danckaerts, M; van der Oord, S; Döpfner, M; Dittmann, RW; Simonoff, E; Zuddas, A; Banaschewski, T; Buitelaar, J; Coghill, D; Hollis, C; Konofal, E; Lecendreux, M; Wong, IC; Sergeant, J; European ADHD Guidelines, Group (1 March 2013). "Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments". The American Journal of Psychiatry. 170 (3): 275–89. doi:10.1176/appi.ajp.2012.12070991. PMID23360949. S2CID434310.
^Greydanus, DE; Pratt, HD; Patel, DR (February 2007). "Attention deficit hyperactivity disorder across the lifespan: the child, adolescent, and adult". Disease-a-Month. 53 (2): 70–131. doi:10.1016/j.disamonth.2007.01.001. PMID17386306.
^Lofthouse N, Arnold LE, Hurt E (October 2012). "Current status of neurofeedback for attention-deficit/hyperactivity disorder". Curr Psychiatry Rep. 14 (5): 536–42. doi:10.1007/s11920-012-0301-z. PMID22890816. S2CID37075142.
^Shaw R.; Grayson A.; Lewis V. (2000). "Inhibition, ADHD, and computer games: The inhibitory performance of children and ADHD on computerized tasks and games". Journal of Attention Disorders. 8 (4): 160–168. doi:10.1177/1087054705278771. PMID16110046. S2CID21265539.
^Tolchinsky A.; Jefferson, S.D. (2011). "Problematic video game play in a college sample and its relationship to time management skills and Attention-Deficit/Hyperactivity disorder symptomology". Cyberpsychology, Behavior, and Social Networking. 14 (9): 489–496. doi:10.1089/cyber.2010.0315. PMID21288135.
^Rojas, NL; Chan, E (2005). "Old and new controversies in the alternative treatment of attention-deficit hyperactivity disorder". Mental Retardation and Developmental Disabilities Research Reviews. 11 (2): 116–30. doi:10.1002/mrdd.20064. PMID15977318.
^Schnoll R, Burshteyn D, Cea-Aravena J (March 2003). "Nutrition in the treatment of attention-deficit hyperactivity disorder: a neglected but important aspect". Applied Psychophysiology and Biofeedback. 28 (1): 63–75. doi:10.1023/A:1022321017467. PMID12737097. S2CID7783422.
^ abIoannidis, K; Chamberlain, SR; Müller, U (September 2014). "Ostracising caffeine from the pharmacological arsenal for attention-deficit hyperactivity disorder—was this a correct decision? A literature review". Journal of Psychopharmacology. 28 (9): 830–6. doi:10.1177/0269881114541014. PMID24989644. S2CID13465319.
^Toledano A, Alvarez MI, Toledano-Díaz A (September 2010). "Diversity and variability of the effects of nicotine on different cortical regions of the brain – therapeutic and toxicological implications". Central Nervous System Agents in Medicinal Chemistry. 10 (3): 180–206. doi:10.2174/1871524911006030180. hdl:10261/61750. PMID20528766.
^Arnold LE, DiSilvestro RA (2005). "Zinc in attention-deficit/hyperactivity disorder". Journal of Child and Adolescent Psychopharmacology. 15 (4): 619–27. doi:10.1089/cap.2005.15.619. hdl:1811/51593. PMID16190793.
^Haslam RH, Dalby JT, Rademaker AW (1984). "Effects of megavitamin therapy on children with attention deficit disorders". Pediatrics. 74 (1): 103–111. doi:10.1542/peds.74.1.103. PMID6234505. S2CID24645872.
^Sukhodolsky DG, Scahill L, Zhang H, et al. (January 2003). "Disruptive behavior in children with Tourette's syndrome: association with ADHD comorbidity, tic severity, and functional impairment". J Am Acad Child Adolesc Psychiatry. 42 (1): 98–105. doi:10.1097/00004583-200301000-00016. PMID12500082. S2CID24550481.
Hoekstra PJ, Steenhuis MP, Troost PW, et al. (August 2004). "Relative contribution of attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and tic severity to social and behavioral problems in tic disorders". J Dev Behav Pediatr. 25 (4): 272–9. doi:10.1097/00004703-200408000-00007. PMID15308928. S2CID22578353.
Carter AS, O'Donnell DA, Schultz RT, et al. (February 2000). "Social and emotional adjustment in children affected with Gilles de la Tourette's syndrome: associations with ADHD and family functioning. Attention Deficit Hyperactivity Disorder". J Child Psychol Psychiatry. 41 (2): 215–23. doi:10.1111/1469-7610.00602. PMID10750547.
Spencer T, Biederman J, Harding M, O'Donnell D, Wilens T, Faraone S, Coffey B, Geller D (October 1998). "Disentangling the overlap between Tourette's disorder and ADHD". J Child Psychol Psychiatry. 39 (7): 1037–44. doi:10.1111/1469-7610.00406. PMID9804036.
^Palumbo D, Spencer T, Lynch J, Co-Chien H, Faraone SV (Summer 2004). "Emergence of tics in children with ADHD: impact of once-daily OROS methylphenidate therapy". Journal of Child and Adolescent Psychopharmacology. 14 (2): 185–94. doi:10.1089/1044546041649138. PMID15319016.
Kurlan R (July 2003). "Tourette's syndrome: are stimulants safe?". Current Neurology and Neuroscience Reports. 3 (4): 285–8. doi:10.1007/s11910-003-0004-2. PMID12930697. S2CID35508887.
Law SF, Schachar RJ (August 1999). "Do typical clinical doses of methylphenidate cause tics in children treated for attention-deficit hyperactivity disorder?". Journal of the American Academy of Child and Adolescent Psychiatry. 38 (8): 944–51. doi:10.1097/00004583-199908000-00009. PMID10434485.
^Tourette's Syndrome Study Group (February 2002). "Treatment of ADHD in children with tics: a randomized controlled trial". Neurology. 58 (4): 527–36. doi:10.1212/WNL.58.4.527. PMID11865128. S2CID224482.
