(Author, Department, University,
Corresponding Address and email)
Research Outline
Introduction of ADHD
Diagnostic criteria for ADHD
Causes of the development of ADHD
Changes in brain structure in ADHD
Therapeutic strategies used in ADHD
Stimulant medications for the treatment of ADHD
Non-stimulant medications for the treatment of ADHD
Side effects of the medications
Efficacy and safety of medications in the treatment of ADHD
Stopping the medications
Long-term efficacy and safety of Medications in the treatment of ADHD
Concluding Remarks
Attention deficit hyperactivity disorder (ADHD) is a childhood psychiatric problem that is characterized by behavioural and learning disorders (Riva & Njiokiktjien, 2010). It has a strong genetic and neurobiological as well as neurochemical basis. It has been reported that nearly 4% of the children are affected by this problem. Whereas, further estimates of the prevalence of the problem ranges from 3% to 11%. According to DSM-V (The Diagnostic and Statistical Manual of Mental Disorders-V), symptoms of the disorder include inattention with or without impulsivity and hyperactivity that can significantly affect the behaviour and performance of the child (Singh, Yeh, Verma, & Das, 2015).
Diagnostic criteria for ADHD
The diagnostic criteria for the disorder have changed during the last few decades. According to the present classification, at least six out of nine symptoms of inattention, impulsivity, and hyperactivity have to be present in the patient, and those symptoms have to impair the life of the patient in two or more settings such as school and home, and there must be obvious indication of impairment in social or work functioning, to ensure the presence of combined type ADHD in the patient (Singh et al., 2015). Nine symptoms of inattention include (1) poor attention to details, (2) difficulty in sustaining attention in different activities, (3) disturbed listening , (4) problem in following the instructions, (5) difficulty in organizing and completing tasks, (6) disliking the exertion of mental effort, (7) losing important things, (8) easy distraction as a result of extraneous stimuli, and (9) difficulty in remembering things and activities. Three symptoms of impulsivity include (1) blurting out answers, (2) inability to wait, and (3) interrupting others. Six motor symptoms of hyperactivity include (1) fidgeting, (2) leaving the classroom seat, (3) running here and there, (4) inability to play quietly, (5) remains “on the go”, and (6) excessive talking (Swanson, Baler, & Volkow, 2011).
The DSM has also divided the disorder into two sub-types; (1), predominantly inattentive in which the child is diagnosed with only the symptoms of inattention, and (2), predominantly hyperactive-impulsive in which the child is diagnosed with only the symptoms of hyperactivity and/or impulsivity (Singh et al., 2015).
Causes of the development of ADHD
ADHD is thought to be caused by biological and environmental issues. Biological issues may include genetics and brain structure, and their impact on neuropsychology, whereas environmental issues may include problems at the time of birth and after birth, parenting, diet, and exposure to environmental toxins. Genetic factors are thought to be the cause of ADHD in about 80% of the cases. Genes such as DRD4, CHRNA4, and some other dopaminergic and serotonin transporter genes have been found to be involved in ADHD (Singh et al., 2015).
Changes in brain structure in ADHD
After studying the brain structure, researchers found that brain circuits involved in the connection of the striatum, prefrontal cortex, and cerebellum do not function properly in children facing the problem of ADHD. Researchers are also considering the importance of medial frontal regions in ADHD-related anomalies. These areas are important in the control of voluntary actions. Dopamine activity in the right midbrain region of children having ADHD is also disturbed, and this disturbance in the dopamine activity correlates with the degree of abnormality. Studies have also shown smaller corpus callosum in children with ADHD as compared to normal children. This smaller size has been found especially in the region of genu and splenium. Researchers have also found smaller cerebellar volume in children with ADHD. This finding is important as cerebellum has an important role in executive functioning (Singh et al., 2015).
Therapeutic strategies used in ADHD
Medications are among the most efficacious treatments of ADHD, and most of the children diagnosed with ADHD receive pharmacotherapy (Bourgeois, Kim, & Mandl, 2014). Medications produce calming effects on a child. However, the American Academy of Pediatrics (AAP) gives recommendations of using behavioral therapy along with medication for the treatment of children having the age of 6 years or more (Centers for Disease Control and Protection, 2016).
Stimulant medications for the treatment of ADHD
Psychostimulants are most commonly prescribed pharmacotherapeutic agents in the treatment of problems associated with ADHD. These are fast-acting medications, and from 70% to 80% of children with ADHD start taking these medications while having fewer ADHD symptoms (Centers for Disease Control and Protection, 2016). Psychostimulants may include amphetamine, methylphenidate, and pemoline. Studies have shown the short term efficacy of these medicines in the treatment of symptoms as well as the secondary features of the disease. Researchers have found that children, who use psychostimulants, create fewer interruptions in the class and decrease task-irrelevant activities in the school. Moreover, those children show improved performance in arithmetic skills and spelling tasks. They also show improved sustained attention in playing, and better parent-child interaction (Singh et al., 2015).
Researchers have reported stimulant-medication related improvements in cognitive functions in children with ADHD. Those improvements were more prominent in activities without any executive functioning such as memory reaction time as compared to the activities with some form of executive functioning such as planning and strategy formation. Moreover, cognitive functioning was also dependent on the doses of medications, i.e. greater doses result in greater improvement in some cognitive abilities such as vigilance, and no or less improvement in other abilities such as planning. It has also been found that dose response to the improvement changes from one individual to other (Swanson et al., 2011).
On the other hand, studies on the long-term effects of stimulant medication on cognitive abilities are showing mixed results, i.e. some studies are showing long-term benefits of the medication on cognition, while other studies are showing that there are no benefits of childhood treatment with stimulant medications (Swanson et al., 2011).
Non-stimulant medications for the treatment of ADHD
Some children with ADHD are unable to respond to stimulants or stimulants may start showing side effects such as loss of appetite. Therefore, some non-stimulant medications can be prescribed to those children. Reboxetine and modafinil have shown promising results in the treatment of ADHD. Moreover, atomoxetine has also been approved by FDA for the treatment of ADHD (Antshel et al., 2011). On broader scale, non-stimulant medications can be classified into tricyclic antidepressants including imipramine and desipramine; non-tricyclic antidepressants including bupropion; specific norepinephrine re-uptake inhibitors; alpha-2 adrenergic agonists including clonidine and guanfacine; non-schedule stimulants including modafinil, and others including beta-blockers such as propanolol. Use of the non-stimulants for the treatment of ADHD is supported by many studies, and the trend in the use of non-stimulants in the disease is increasing with the passage of time, especially, if the patient is unable to respond to stimulant medications or in the presence of adverse effects or contraindications. However, many of these drugs such as clonidine and beta-blockers are unable to show any effect on cognitive abilities (Budur, Mathews, Adetunji, Mathews, & Mahmud, 2005).
Side effects of the medications for the treatment of ADHD
Different drugs may show different adverse effects. Those adverse effects may include growth retardation, insomnia, decreased appetite, and cardiovascular effects (Bourgeois et al., 2014).
Efficacy and safety of medications in the treatment of ADHD
Most of the studies of ADHD medications deal with the short-term therapeutic response of the drugs. Therefore, they are unable to give information about the long-term safety and/or efficacy of drugs, and rare adverse events that may develop as a result of long-term use of ADHD medications. In this case, “International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use” (ICH) provides guidelines and recommendations for the safety as well as efficacy studies of drugs and their uses. Those guidelines also help the U.S. Food and Drug Administration (FDA) in clinical trial practices. According to the guideline, most of the adverse events related to the drug develop during the first few months of the drug use, and studies for the efficacy and safety of the drug have to include 300 to 600 patients, who have to be treated for a minimum of 6 months before the availability of the drug to the general public. Some adverse events may appear after many months of treatment, and sometimes adverse events may increase in severity or frequency. Therefore, a minimum of 100 patients have to be exposed to the drugs for a minimum of 12 months. Moreover, nearly 1500 patients have to be treated with the medicine before its approval (Bourgeois et al., 2014).
Considering these guidelines, researchers worked on the FDA approved drugs for ADHD, and evaluated the efficacy and safety trials submitted to the FDA. Active ingredients used in the medicines include methylphenidate hydrochloride, methamphetamine hydrochloride, pemoline, dextroamphetamine sulphate, amphetamine + dextroamphetamine mixed salts, dexmethylphenidate hydrochloride, lisdexamphetamine dimesylate, atomoxetine hydrochloride, guanfacine hydrochloride, and clonidine hydrochloride. Last three of these were non-stimulants (Bourgeois et al., 2014).
In the study, researchers reported that Ritalin (methylphenidate) was the oldest drug in the study that was approved for the treatment of ADHD, but the approval was based on the prior clinical experience. Moreover, Methylin (methylphenidate) went through the process of New Drug Approval (NDA) but paediatric efficacy trials were not conducted. Desoxyn (methamphetamine) was initially approved in the year 1943 for obesity, but no clinical trials to assess the safety and efficacy of the drug in children were found in the approval package. Dexedrine (dextroamphetamine) was initially approved to treat obesity, narcolepsy, and ADHD, but the approval package was without any information about the trials on children or efficacy of the drug in ADHD. In the same way, the approval package of Biphetamine (amphetamine + dextroamphetamine) does not show safety assessments in children (Bourgeois et al., 2014).
Researchers noted that after studying 13 drugs having clinical trials for ADHD, 31% of drugs (4 drugs) were approved in spite of the involvement of less than 100 participants in the trials and 54% of drugs (7 drugs) were approved after studying less than 300 participants. In the studies, efficacy trials were in the range of 1 week to 10 weeks, while safety trials were in the range of 6 months to 12 months. They also noted that none of the clinical trials on drugs met the ICH recommendation of the inclusion of 1500 participants before the approval of the drug. Three drugs, Daytrana (methylphenidate), Focalin (dexmethylphenidate), and Concerta (methylphenidate) met the requirements of minimum 300 participants exposed to the drugs before their marketing, and Daytrana (methylphenidate) and Focalin (dexmethylphenidate) also met the requirement of studying minimum 100 participants for a minimum of 12 months (Bourgeois et al., 2014). These outcomes show that Daytrana, Concerta, and Focalin are the medicines that are fulfilling the ICH recommendations.
Stopping the medications
Consistent use of ADHD medication is helpful for children with the disease, but sometimes, drug vacations may come as, for example, doctors may prescribe a drug vacation to know the progress of the child. However, it is important to talk with the physician before stopping the medication as it can result in decreasing the efficacy of the pharmacological intervention (Woo & Keatinge, 2016). Moreover, some problems such as the quick development of side effects on restarting the medication (Collins-Bride & Saxe, 2011), social alienation, and impulsive behaviour can also develop on restarting the medication, i.e. optimal treatment is affected (Bope & Kellerman, 2011).
Long-term efficacy and safety of Medications in the treatment of ADHD
ADHD is a chronic condition, so it is important to study the long-term efficacy and safety of medicines. In a prospective study with 8 year follow-up of children with ADHD, who were treated with the medications for a minimum of 14 months, it was found that medications were unable to show any added advantage in social functioning or academic performance as compared to behavioural interventions (Molina et al., 2009).
In a study published by the Government of Western Australia, it has been reported that the long-term use of stimulant medication does not have significant connection to the depression, poorer self-perception, and social functioning in children with ADHD. It has also been noted that the long-term effect of the stimulant medication in academic outcomes need further studies as some studies show long-term benefit of those medications, whereas other studies show no significant affects. It has also been noted that teacher-rated academic performance can be decreased as a result of long-term use of medication. This decreased performance of children has also been reported in a study published in the Journal of Health Economics (Currie, Stabile, & Jones, 2014). However, researchers have found that the emotional outcomes were not deteriorated in children, who were using stimulant medication for a long time, i.e. from eight years up until 14 years. Experts have also stated that the use of stimulant medication is unable to significantly affect children’s enjoyment at school or their absenteeism (Government of Western Australia, 2010). Considering these findings, it can be noted that further long-term follow-up studies on large number of subjects are required to know the efficacy, safety, and adverse events of the medications in the children with ADHD.
Researchers have found that the use of stimulant medications such as dexamphetamine and methylphenidate can result in “less than expected” growth. Studies show that the medication-use can result in significant affect on growth trajectory within first few years of the use. Previous studies show that the normal growth resumes after this starting use of medication, but the height and weight of the children remain at a significantly lower level as compared to the children, who have never taken stimulant medication. However, the report by the Government of Western Australia shows that the stimulant medication may not have significant affect of growth measure (Government of Western Australia, 2010). Another study published in the journal International Clinical Psychopharmacology shows that maturation of children is not affected as a result of stimulant medication, though the growth can be slightly affected (Poulton, Bui, Melzer, & Evans, 2015).
Researchers have reported that the prolonged use of stimulant medication can result in significantly increased blood pressure (Vitiello et al., 2012), i.e. increase of 10.8 mmHg, in the patients as compared to the normal subjects, who have never used the stimulant medication. Moreover, consistent use of stimulant medication can increase the blood pressure by about 7.05 mmHg as compared to the situation when the medication use has just been started. However, researchers noted that further studies are required to know the long-term effects of stimulant medication on diastolic pressure. On the other hand, they have not found any significant affect of stimulant medication on resting heart rate or systolic blood pressure (Government of Western Australia, 2010).
Research also shows that the use of stimulant medication is unable to provide significant improvement in the key symptoms of ADHD (Roberts & Steele, 2010) such as long-term improvement in attention problems or externalizing behaviour (Government of Western Australia, 2010).
Concluding Remarks
ADHD is one of the childhood psychiatric problems that have been studied extensively in the last few years. Due to extensive research on the disease, several treatment options have been developed. Among those options, pharmacological therapeutic approach consisting of the use of stimulant and non-stimulant medications has been used widely. Research has also helped in not only improving therapeutic strategies for the treatment of the disease but also helped in reducing the side-effects that may develop as a result of the treatment. Studies show that stimulant medications are very safe for the treatment of ADHD, and in right amount of doses, they have very few side effects. Most often, a child with ADHD may also develop tolerance to side effects (Passmore, 2015). Studies have also made it clear that in case of side effects as a result of one medicine or a class of medicine, patients can move to the other medicine or class of medicine having little or no side effects, thereby helping in improving the condition of the patient. Another option of reducing the side effects is that the dose of the medicine can be reduced without losing any beneficial effects. Medications for ADHD are also beneficial in many cases of long-term use without producing any serious kind of life-threatening outcomes. However, further are still required on long-term uses and adverse effects of ADHD medications.
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