Advances & Considerations in Pharmacotherapy of Attention-deficit/hyperactivity disorder (ADHD)

ABOUT AUHTORS
Noorul Hasan*, Mohd. Mujahid, Badruddeen, Nesar Ahmad, Shahla Parveen, Shaikh Zohrameena, Zafar Khan
Faculty of Pharmacy,
Integral University, Lucknow, U.P. (India)
*noorulkhan999@gmail.com

ABSTRACT
Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral condition primarily affecting children but regularly persisting into adolescence and adulthood. The symptoms must present in multiple settings ie home, school, work, be inappropriate for developmental level and interfere with the individual’s level of functioning, social development, learning processes, and quality of life. There are three presentations of ADHD i.e. inattentive, hyperactive and combined. There is a substantial pharmacopoeia available for safe and effective treatment of ADHD. CNS stimulants like methylphenidate, amphetamine are recommended as first-line medication therapy for children. It includes various class of drugs like centrally acting sympathomimetic, anti-psychotic, anti-depressant (SSRI), alph2 agonist and some newer agent like atomoxetine in the treatment of ADHD. ADHD remains the only highly prevalent, nondegenerative neuropsychiatric disorder for which effective medications remediate the principal cognitive disturbances in concert with clinical efficacy. Therefore, deeper insight into the neural mechanisms of cognitive remediation may serve to advance treatment development not only in ADHD, but across a wide range of neuropsychiatric disorders in which cognitive dysfunction is a cardinal feature and a strong predictor of clinical outcome. All effective medications for ADHD act on one or both of the major catecholamine neurotransmitter systems in the brain. These 2 systems, which arise from subcortical nuclei and use of norepinephrine (NE) or dopamine (DA) as transmitters exert strong modulatory effects on widely distributed cortical–subcortical neural circuits, with important effects on cognition, mood and behavior in both health and illness

INTRODUCTION
Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in childhood and adolescence and has an estimated worldwide prevalence of approximately 3.4% to 7.2% [1-2]. ADHD is a consistent pattern of behaviors causing the inability to maintain sustained attention and focus and increased impulsivity that affects an individual in multiple settings [3]. There has been a 42% increase in the diagnosis of childhood ADHD from the years 2004 to 2012 [4].This places a financial and social burden on society as the cost of health care continues to rise and mental health care becomes more limited [5].The Diagnostic and Statistical Manual of Mental Disorders (DSM), sets guidelines for the diagnosis of mental health disorders. The 5th edition, released in May 2013, was its first major revision since 1994 [6]. Primary care providers (PCPs) are on the front-line for the screening and diagnosis of ADHD, diagnosing nearly 53.1% of cases [7]. It is one of the most common psychiatric conditions estimated to affect 5-10% of all children and predisposes them to impaired academic, familial, social, vocational, and emotional functioning if untreated [8-9]. ADHD is characterized along two symptom domains, inattention-disorganization and hyperactivityimpulsivity. Individuals with ADHD have significant difficulty in the areas of attention, response inhibition, and self-regulation. The effects of ADHD are life encompassing and are not limited to the 8-hour school day. Usually, some symptoms that cause impairment are present before age seven. Classification of whatconstitutes ADHD has changed dramatically over the last two decade, with successive revisions of the Diagnostic and Statistical Manual four (DSM) [10]. Current DSM IV classification for combined type ADHD requires a minimum of six out of nine symptoms of inattention and a minimum of six out of nine symptoms of hyperactivity/impulsivity. In addition some impairment from the symptoms is present in two or more settings (e.g., at home and at school) and clear evidence of significant impairment in social, school, or work functioning. The DSM IV also allows the classification of two subtype disorders: (i) predominantly inattentive where the child only meets criteria for inattention; and (ii) predominantly hyperactive–impulsive where only the hyperactive– impulsive criteria are met [11-12]. Effective treatment depends on appropriate diagnosis of ADHD. A comprehensive medical evaluation of the child must be conducted to establish a correct diagnosis of ADHD and to rule out other potential causes of the symptoms. ADHD can be reliably diagnosed when appropriate guidelines are used [13-17].

 

EPIDEMIOLOGY
The worldwide prevalence of ADHD continues to increase [18]. The US prevalence of children diagnosed with ADHD was 7.8%, 9.5%, and 11% in 2003, 2007, and 2011 respectively, representing nearly 6.4 million children. Compared with 2003, in 2011 there were nearly 2 million more children diagnosed with ADHD and 1 million more children prescribed medication for ADHD. The number of visits to ambulatory care centers for evaluation and management of ADHD is increasing, according to analyses of insurance claims filed between 2001 and 2010, although this may not represent the uninsured [19]. Teachers identify fewer girls than boys with ADHD symptoms. The prevalence of ADHD is higher in boys with an estimated male/female ratio between 4:1 and 9:1 [20]. The median age for diagnosis is 7 years old, with one-third of total children being diagnosed before age 6 years [21]. The inattentive type is the most common presentation [22]. The prevalence is increasing for several reasons. Increased awareness and social acceptance of the disorder give parents and teachers confidence to request behavioral evaluations for their children or students. Improved screening tools and PCP knowledge increase diagnosis rates. More sophisticated health care has improved the survival of infants who are at increased risk for neurobehavioral disorders. This increased prevalence greatens the societal need for mental health, education, and social services and demands PCPs assume the responsibility of assessment and management of this chronic disorder [23].

ETIOLOGY
The causes of ADHD are unknown. Most children with ADHD have no evidence of gross structural damage in the central nervous system. ADHD does appear to run in families with approximately one-third of affected children having a first degree relative with a history of ADHD [24]. Recent functional MRI brain studies indicate that the disorder may be caused by atypical functioning in the frontal lobes, basal ganglia, corpus callosum, and cerebellar vermis. Pharmacological studies have also implicated dysregulation of frontal-subcortical-cerebellar catecholaminergic circuits in the pathophysiology of the disorder. Central catecholaminergic neurotransmission systems appear to be involved in the pathophysiology of ADHD. Effective medication treatments for ADHD appear to modulate dopaminergic and noradrenergic neurotransmission in the prefrontal cortex. Children with ADHD as a group show differences from unaffected children in the volumes of specific brain regions in imaging studies (i.e., frontal lobes, temporal gray matter, caudate nucleus, and cerebellum) [25]. The cause of such differences is unknown and brain imaging is not useful as a diagnostic tool if used to differentiate youth with ADHD from those without. Traumatic brain injury has been associated with ADHD but probably accounts for ADHD in only a small percentage of affected children [26]. Environmental factors may also be relevant. Exposure to maternal tobacco or alcohol use in utero may increase the risk of ADHD in offspring. Exposure to lead early in life has also been associated with ADHD. Though up to 5% of children with ADHD may respond to dietary manipulations for food allergies, there is little evidence that exposure to refined sugar or food additives are responsible for ADHD in most affected children [27-29].

PATHOPHYSIOLOGY
The idea that dysregulation of dopamine and norepinephrine circuits triggers ADHD was primarily proposed by the action of drugs for the disorder, which upsurge the synaptic availability of these neurotransmitters and by animals showing that abrasions in dopamine pathways create animal models of ADHD [30]. As one of the most enthralling animal models of ADHD, the spontaneously hypertensive rat [31] shows dopamine release anomalies in subcortical structures [32]. Because executive dysfunction is common. Executive functions, which are controlled by frontal subcortical circuits, include inhibition, working memory, set-shifting, interference control, planning, and sustained attention [33–34]. This pattern of dysfunction has led to much debate about what core neuropsychological deficit might cause both ADHD symptoms and neuropsychological deficiencies. Candidates for core arrears include failure of inhibitory control [35], dysregulation of brain systems facilitating reward and response cost[36-37] and arrears in arousal, activation, and effortful control [38-39]. Arrears in arousal and effort lead to state-dependent cognitive arrears and a view of ADHD that emphasize  in regulating cognitive functions rather than core arrears in any single function. But, because no single neuropsychological theory can explain all ADHD features, neuropsychological deficiencies of the disorder could be heterogeneous and this heterogeneity probably resembles to causal heterogeneity [40]. One study has reported extensive, albeit small volume reductions throughout the brain, another has shown extensive cortical abnormalities [41] and others have involved structures such as cerebellum and corpus callosum, which are outside the frontal-sub cortical circuits [42]. Functional neuroimaging studies have considered the degree of brain activation linked with neuropsychological tasks of attention and disinhibition. Because tasks are assembled so that ADHD and control individuals do similarly well, activation differences specify group differences in the neural systems used to achieve the tasks. These studies are unfailing with the structural studies locating abnormalities of brain activation in patients with ADHD in fronto-subcorticalcerebellar circuits [43]. In the subcortical structures allied with ADHD,the striatum has been of specific interest because it is ironic in dopaminergic synapses [44], is weak to the perinatal hypoxic complications associated in the disorder, and if not intact, it produces hyperactivity and deprived inhibitory control [45].

DIAGNOSIS AND ASSESSMENT
Diagnosis and assessment for ADHD varies from clinicians, teachers, and parents. Usually assessment involves a medical examination, a clinical interview, parent and teacher ratings of behavior regarding attention, direct observation, or a combination of all of the above. Clinicians are usually interested to see if a child meets certain diagnostic criteria (DSM criteria) and teachers are typically more interested in developing a behavior management plan for use in the classroom. On the other hand, parents are usually concerned with why their child behaves inappropriately and how they should respond to this behavior [46-47]

TREATMENTS
  Many treatments are currently available for ADHD. These treatments consist of three general approaches; pharmacological therapy, behavioural treatment and a combined approach. Over the past decade, numerous scientific studies have examined each treatment to establish which are most effective. Pharmacological treatment has a greater effect on behaviour than counselling, however counselling results in better educational outcomes [48]. Results from a large scale study showed that both the pharmacological and combined approaches show a significantly greater improvement in ADHD symptoms than behavioural treatment alone [49]. There is still an ongoing debate as to which drug is the most effective for general ADHD treatment. Since each approach has its strengths and weaknesses, it is prudent for healthcare specialists to decide treatments on a case-by-case basis. The American Academy of Pediatrics (AAP) issued modern clinical practice guidelines for the treatment of school-aged children (six to 12 years) with ADHD in 2001. Clinical guidelines are also being developed by the National Institute of Clinical Excellence (NICE) in the UK for treatment of ADHD [50]

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