Management of attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD/ADD) is a neurobehavioral disorder of childhood onset characterized by severe, developmentally inappropriate motor hyperactivity, inattention, and impulsiveness that result in impairment in more than one setting. It affects the home, school, and community life of 39% of school-going children worldwide. There is increasing recognition that ADHD symptoms and clinically defined disorder can persist into adult life and are associated with later drug and alcohol misuse and social and work difficulties. Added to that is the extreme variability of the disorder over time, within the same individual, between individuals, and across different circumstances. Treatment with stimulants and nonstimulants has proven effective in different subgroups, with the effectiveness of specific agents most likely related to the primary neurotransmitter involved. However, stimulants with a short duration of action have been problematic for some patients. Parent training and cognitive behavioral therapies represent the most widely adjunct psychosocial interventions to pharmacotherapy.

Introduction

Attention-deficit hyperactivity disorder (ADHD) is a common, early-onset neuropsychiatric disorder that affects an estimated 3% to 7% of school-aged children[1] and 1% to 4% of adults worldwide.[23] A cross-sectional epidemiological study from Bangalore reported the prevalence of ADHD at 1.6% among children aged 4-16 years. The prevalence was higher (3.7%) in urban setting as compared to the rural setting (0.5%).[4] However, another chart review of the child and adolescent clinic from north India reported the prevalence of 8.3%-17.9% for hyperkinetic and conduct disorders over a 26 year period.[5]

Behavioral features such as inattention, easy distractibility, too much activity, and impulsivity constitute the disorder of ADHD. Diagnosis of ADHD requires an assessment of the severity of the symptoms, and the impairment in functioning resulting from it. As children with ADHD mature, academic failures may lead to demoralization and poor self-esteem. Other risks include high rates of injuries, substance abuse, and delinquency.

Like all other psychiatric disorders, ADHD is a disorder for which there is no objective test. However, as causes and course of ADHD are better understood, newer and more selective medications are being developed for the disorder.

Nosology and Diagnosis

DSM-IV-TR recognizes three subtypes of ADHD: i) a combined type, ii) a predominantly inattentive type, iii) a predominantly hyperactive-impulsive type. International Statistical Classification of Diseases and Related Health Conditions ICD-10 requires both inattentive and hyperactive-impulsive behavior to make a diagnosis. Both recognize the fact that these problems are chronic and are likely to significantly impair the development and functioning of the affected child. In ICD-10, there is a facility to subcategorize hyperkinetic disorders including an entity called hyperkinetic conduct disorder, which includes subjects meeting criteria for hyperkinetic disorders and conduct disorders.

While evaluating these children one must keep in mind the issues of parental denial and minimization. Information may be sought from multiple sources like school, parents, academic records, objective observation of the child after building rapport with him and at times neuropsychological batteries too. Physical and medical history along with educational assessment constitutes an essential part of whole evaluation. Use of rating scales has been recommended as this may add to the validity of the diagnosis.[6]

Management

The diagnostic process for determining the presence of ADHD in a given child depends upon careful history taking and observation. Both the parent and teacher, if possible, should be interviewed. Because the level of impairment may shift between home and school, where tasks and demands on the child are very different, reports may not correlate. Standardized parent and teacher rating scales for ADHD might be used. These scales may be broad (checklists covering the symptoms of many disorders) or narrow range (focused on the symptoms of ADHD). These scales are useful for estimating symptom severity and are used to measure treatment response in controlled drug trials.[7] The best approach remains a mix of a structured interview based on diagnostic criteria and behavior rating scales.[8]

During the initial visit, the clinician should observe the parent and child to evaluate the symptoms of ADHD or co-morbid condition; obtain family history; observe the child's attention and activity level with the parent present and alone with the clinician.[9] In addition, the first visit should be used to assess the child's physical and neurologic status.

During the later visits, the clinician could contact the child's teacher to obtain school information or could have a detailed teacher report and the teacher rating scale filled out.[10] The need for psycho educational, speech, and language tests becomes clear as the evaluation proceeds. For example, the clinician may order a Wechsler Intelligence Scale for Children to determine IQ. For determining mental processing, the Wide Range Achievement Test–Revised can estimate grade level[11] and the Wechsler Individual Achievement Test (WIAT) can be used to yield a more detailed estimate of academic skills.[12] These tests are not diagnostic of ADHD, although they can help plan treatment. Child Behavior Checklist (CBCL), Childhood Psychopathology Measurement Schedule (an Indian adaptation of CBCL) have been used in Indian setting to screen children for presence of behavioral problems including ADHD.[45] Task-switching, attention network, and choice delay tests have been recommended to assess the cognitive deficits in children with ADHD.[13]

After this information gathering, the clinician should present and discuss the findings with the parents and make recommendations. A quarter-century of published treatment studies and clinical experience attest to the short-term effectiveness of both behavioral and pharmacologic strategies and the optimal approach to treatment of ADHD combines pharmacological and behavioral intervention.[14]

Pharmacological Intervention

For most patients, pharmacotherapy has beneficial effects on attention, hyperactivity, and impulsiveness and on social and classroom behaviors. Studies of medication treatment in children with ADHD have shown that the agents that are most effective target dopamine and/or norepinephrine receptors.[15]

Stimulants are the mainstay of treatment. Careful physical examination and medical history must reveal no medical contraindication to treatment. The patient should be 6 years or older. The medication administration must be supervised by an adult. The parents must be reminded that the stimulant drugs are classified as drugs of abuse and educated on this issue. The physician should ascertain that no relative living with the patient is currently abusing stimulants. School personnel must be willing to supervise medication administration if the pill is taken midday. Guidelines for titrating stimulant medication generally endorse a “start low and go slow” approach. Moreover, the current scheduling of the stimulants requires a triplicate prescription for their dispensing.

Stimulants taken orally, such as methylphenidate (MPH), dextroamphetamine, and the combination of amphetamine (AMP) and dextroamphetamine, are considered first-line treatment for ADHD. The mechanism of action involves pre-synaptic inhibition of the reuptake through stimulation of inhibitory auto-receptors and alteration in the functional activity levels of catecholamines.[16] This action is observed at both dopamine transporter (DAT) and the norepinephrine transporter (NET).[1718]

Current thinking in ADHD therapy focuses on assessing duration of action and determining which delivery system is appropriate for the patient. Further help to individualize treatment is by delayed delivery systems, like Diffucaps MPH system, spheroidal oral drug absorption system (SODAS) for MPH, osmotically controlled-release oral delivery system (OROS) for MPH, and mixed amphetamine salts extended-release.[19] All the delayed delivery systems decrease the abuse potential of the stimulant agents. Transdermal MPH system has been FDA approved since 2006 for use in children aged 6 to 12 years and has the advantage of flexible dosing.[20]

Lisdexamfetamine dimesylate is an AMP prodrug that is inactive until metabolized.[2122] The prodrug attenuates the onset and intensity of AMP-like effects and is less reinforcing than equivalent doses of d-AMP, contributing to a lower abuse potential.[23]

Use of stimulants is associated with improvement in hyperactivity, impulsivity, attention, academic productivity, task completion, family interactions, aggression, school disruption, peer interactions, antisocial behaviors. The cognition enhancing effects of methylphenidate and amphetamine involve indirect stimulation of αlpha-2 adrenoceptors and D-1 dopamine receptors in the PFC.[24]

Although stimulants have been proven safe and effective for the treatment of ADHD, an estimated 30% to 50% of all children and adults with ADHD either do not respond to or do not tolerate treatment with stimulants.[25] Frequent unwanted short term effects of medication may be physiological, such as insomnia, dizziness, daytime drowsiness, headaches, stomachaches, and loss of appetite; motor, such as tics, and affective such as mood lability, sudden crying, sadness, social withdrawal, and aggression.[26] Although concerns have been raised about deceleration in growth and reduction of weight with prolonged use of these medicines, but the literature to substantiate these beliefs is negligible.[27]

Despite the commonly held notion that psychostimulant treatment increases risk for developing substance use disorders (SUD), recently, a meta-analysis of published studies led to the conclusion that treating ADHD during childhood reduces the incidence of SUD by half, while failure to treat doubles the risk for SUD.[15]

Atomoxetine is the only non-stimulant medication approved by the FDA for the treatment of ADHD in children, adolescents, and adults.[28] Atomoxetine inhibits the presynaptic norepinephrine transporter, which is believed to improve efficiency in the norepinephrine system and is associated with improved ADHD symptoms.[15] However, the product carries a black box warning regarding suicidal ideation and has been associated with rare cases of severe liver injury from postmarketing reports.[19]

Additional or adjunctive therapy with non-stimulants (other than atomoxetine) is recommended if the patient fails to respond to trials of two different stimulants (MPH and AMP), has intolerable side effects with stimulants, or fails to respond to a trial of atomoxetine.[29] Options for second-line agents include antidepressants such as bupropion, tricyclic antidepressants, particularly desipramine and imipramine, or venlafaxine. Some data show positive neuropsychological effects of nicotinic modulators.[15] Other potentially useful agents include cholinesterase inhibitors, noradrenergic/dopaminergic agonists, and alpha-2-adrenoreceptor agonists such as clonidine and guanfacine.[30]

An alpha-2-adrenergic agonist, guanfacine may work in ADHD by affecting norepinephrine discharge rates in the locus ceruleus, and this action may indirectly affect dopamine firing rates.[19] Weakened prefrontal cortex (PFC) functioning has been implicated in ADHD. Deficits in PFC functioning lead to poor impulse control, distractibility, hyperactivity, forgetfulness, and poor organization and planning.[31] Also, it is implicated in the cognitive deficits seen among these patients.[32] These actions are mediated through the alpha adrenergic receptors in the brain.

Another agent that is being reviewed for its effectiveness in ADHD is the wake promoting agent modafinil. Modafinil appears to selectively activate the cortex without generalized effects on the central nervous system.[15] The pharmacologic profile and structure of modafinil is notably different from the stimulants, and there is no demonstrated abuse potential. Modafinil film-coated tablets may provide a novel therapeutic option for the management of ADHD in pediatric and adolescent patients.[33] Approval of modafinil in pediatric ADHD has been held back by FDA for the fear of development of Stevens- Johnson syndrome.[31]

The NIMH-sponsored Preschool ADHD Treatment Study (PATS) reported a marked decrease in ADHD symptoms in patients aged 3 to 5 years with symptoms of severe ADHD.[32] Similar to 1999 results found in MTA study, and other studies on school-aged children, the medication did appear to slow the preschoolers’ growth rates. Eleven percent, i.e., about 1 in 10 children had to drop out of the study as a result of intolerable side effects like weight loss.[32]

Psychosocial Intervention

Although medication treatment can lead to improvements in behavior for many children with ADHD, few may not show favorable response or may have intolerable adverse effects. In addition, some parents may have a preference not to use medication. Thus, behavioral intervention has an added significance. Also, it could be argued that all children with ADHD require psychosocial intervention to improve self-observation or coping skills, and to enhance skills, which are often compromised by their ADHD.[33]

Studies related to the impact of behavioral intervention in ADHD are far and few in number as compared to those on stimulant treatment in ADHD.[34] Improvement in the core symptoms of ADHD, in academic performance, social skills, defiant and aggressive behavior have been seen with the use of behavioral intervention such as response cost for unwanted behavior and positive reinforcement. However, this improvement has been short term in nature.

Among psychosocial treatments, parent behavior management training has been the most widely researched treatment option for school age children, and also those with co-morbid oppositional defiant disorder or conduct disorder and has been shown to substantially impact behavior and compliance. Parent behavior management training involves training parents to implement behavior therapy programs in the home, to target both home and school behavior, generally using contingency management approaches.[35]

Parents are taught the principles of positive reinforcement, and a functional behavior analysis is applied to the negative behaviors, and specific behaviors are pinpointed and their frequencies tracked. It requires frequent manipulation of behavioral targets and reinforcers. Because this treatment relies on parents as the agent of change for child behavior, it is best suited to pre-school and school age children.

Cognitive behavioral therapy emphasizes problem solving, as well as anticipation and consequences of action. Cognitive behavioral therapy is well suited for adolescents and adults with ADHD, who have a need to develop increased self monitoring capacities, and who have the verbal and self observational skills that are required for treatment implementation.

One type of cognitive behavioral intervention targets social skills directly, and is referred to as social skills training.[36] Although social skills training have considerable face validity, treatment effects have not been robust.

For adolescents, success has been reported with behavior techniques, academic interventions, family therapy, and integrating or coordinating various aspects of care. Individual therapy is successful with co morbidities. However, contingency management has shown limited role in this regard.

A small but growing body of literature is validating the efficacy of psychosocial interventions in ADHD therapy. Some issues, such as the optimal duration of therapy, remain to be determined. For most patients, psychosocial treatment plus medication is optimal, but ultimately an individualized treatment plan is needed for each patient.

Parents of children with ADHD need accurate information about the disease state, treatment options, how treatment is optimized, and myths associated with ADHD. Caregiver resources and support can be made available in group settings using consumer and family facilitators and through reliable internet sources. Appropriate follow-up, adequate contact, and additional support all help to maintain treatment adherence and increase the chance of success.[37]

Parental behavior training has been researched in greater details.[38] Some of the techniques used for this purpose include training parents in general contingency management tactics, such as contingent application of reinforcement or punishment following appropriate and inappropriate behaviors. A parent training model developed by Barkley (1997) has shown high success rate with around 64% of families experiencing clinically significant change of their child's disruptive behavior.[39]

The Multimodal Treatment Study of ADHD (MTA) established that combination behavioral therapy and pharmacotherapy improves overall outcomes in children with ADHD.[40] This multisite study included 579 children aged 7 to 9.9 years who were assigned to four treatment groups: (1) state-of-the-art medication; (2) intensive behavioral intervention; (3) combination medication and behavioral intervention; and (4) community treatment (usual care).

Pharmacogenomic research has started coming out with some preliminary findings on patient-treatment matching. In a work by Polanczyk et al (2007), significant interaction effect between the presence of the G allele and treatment with methylphenidate over time on inattentive scores was detected during the three months of treatment.[41] Similarly, it has been seen that individuals with T allele as one of the alleles (A/T or T/T genotypes) at the -3081(A/T) polymorphism show a better response to methylphenidate treatment than those with the A/A genotype.[42]

Alternative Therapy

Data are still lacking to support a notable benefit of most alternative approaches in ADHD. Such unsubstantiated approaches include electroencephalography, biofeedback training, megavitamin therapy, herbal treatments, body and craniosacral manipulation, sensory integrative training, and specific supplements.[43]

Use of integrative treatment model is recommended for management of ADHD. It involves the concerted effort of the therapist, parents and the child. Additionally, the interventions are likely to follow a chronic care model. A strong therapeutic alliance should be developed with both the patient and parents. ADHD treatment requires frequent monitoring. Adherence to treatment is of considerable importance. Appropriate evidence-based psychosocial modalities must be used in combination with medications.[44] The Texas Children's Medication Algorithm Project guidelines provide suggestions for drug choice as it applies to ADHD treatment.[45] Similarly, the consensus guidelines of the Global ADHD Working Group could be used to make treatment decisions while managing the condition.[46]

Conclusion

ADHD may be best understood as a neuropsychologically heterogeneous condition. Developmentally sensitive, age-appropriate criteria would help clinicians to more accurately diagnose ADHD in both children and adults. The availability of extended release, delayed release, prodrug, and transdermal stimulant formulations, as well as alternative non-stimulant agents, offers new options for the pharmacotherapy of ADHD.

Expanded medication options will help clinicians to choose the most effective and safest treatment for their patients with ADHD, thereby increasing effective therapy and reducing the wide range of ADHD-associated impairments. ADHD management must be multimodal, with best treatment outcome achieved by appropriate dosing and titration of medications as well as by a combination of pharmacotherapy and psychosocial intervention. A long-term therapeutic alliance will prove to be invaluable to patients and their families in improving their quality of life.