Contents

1 Long-term studies

methylphenidate (MPH)-elicited dopamine (DA) increases in ventral striatum are associated with long-term symptom improvement in adults with attention-deficit/hyperactivity disorder (ADHD) [5]. Adult ADHD subjects who were treated with a titrated regimen of MPH for one year showed significant improvement on the Conners’ Adult ADHD Rating Scale, and the improvement in clinical symptoms (before treatment vs. after long-term treatment) was correlated to the DA increase elicited by i.v. MPH (quantified as a reduction in D2/D3 receptor availability in striatal regions, and in frontal and temporal cortical regions) [5]. Individual subjects with the largest increases in DA also had the greatest reduction in symptoms with long-term MPH treatment. Decreases in D2/D3 receptor availability with i.v. MPH in prefrontal and temporal cortices were associated with decreased ratings of inattention when subjects were clinically treated, which suggests that enhancement of DA signaling in these cortical regions may contribute to the therapeutic actions of oral MPH [5]. Volkow et al. [5] also saw an attenuation of MPH-induced DA increases in striatum and a trend toward lower baseline levels of D2/D3 receptor availability in striatum after long-term treatment with oral MPH. MPH could ameliorate inattention by both enhancing saliency (through effects on the ventral striatum) and enhancing the executive components of attention that are mediated through prefrontal regions (including cingulate gyrus) [3–5].

Long-term treatment with MPH decreased MPH-induced DA increases in striatum but not in cortex. Because MPH blood levels are associated with the level of dopamine transporter (DAT) blockade [2] and the concentration of MPH in plasma after i.v. MPH did not differ for treatment-naïve and long-term treatment conditions [5], the lower DA increases in striatum over the year of treatment suggest changes that decrease DA release. These reductions are likely to reflect neuroplasticity effects of chronic MPH treatment. Because the attenuation was in striatum and not in cortical regions, this suggests that they reflect changes in DA autoreceptor sensitivity and/or DAT upregulation because cortical DA projections are much less sensitive to regulation by DA autoreceptors or DAT [1]. Indeed, Wang et al. [6] recently showed that 12 month treatment with oral MPH resulted in upregulation of DAT in striatum.

Acronyms

ADHD

attention-deficit/hyperactivity disorder

DAT

dopamine transporter

DA

dopamine

MPH

methylphenidate

References

Contents

1 Use of Methylphenidate in the Treatment of
Attention-Deficit/Hyperactivity Disorder

For near 50 years, the most widely used pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD) is the racemic (50:50) mixture of d-threo-(R,R)-methylphenidate and l-threo-(S,S)-methylphenidate isomers. The clinical effectiveness of racemic methylphenidate (MPH) appears to reside primarily in the d-isomer, the l-MPH isomer of racemic MPH formulations has long been regarded as an inactive component [11]; because of stereospecific pre-systemic metabolism of oral MPH, l-MPH does not reach effective levels in plasma. However, more direct administration of the l-MPH isomer has been shown to inhibit the locomotor stimulation by d-MPH and other stimulants in rats in a dose-dependent fashion [1].

Stimulants have been prescribed to treat restlessness and ADHD symptoms in children since the 1930s, mostly mixed amphetamine (AMPH) salts until the synthesis of MPH in 1944, and the marketing of MPH as Ritalin^®; in 1954 [2, 10]. Although newer drugs have been developed, including pure d-MPH, a transdermal patch, osmotic and slow release formulatins, racemic-MPH immediate release is still one of the most highly prescribed drugs for the treatment of ADHD [3]. Non-stimulant drugs have also been used to treat ADHD, however the average effect size for stimulants is greater than for non-stimulants, so non-stimulants are primarily used after stimulants have induced unwanted side-effects in individuals [6].

Though it was once assumed that the beneficial effects of stimulant medications on individuals with ADHD were paradoxical, studies have demonstrated that the direction of response is often the same in healthy individuals without ADHD [15]. Stimulant medications elicit a biphasic action in humans; low doses reduce locomotor activity and distractibility; high doses lead to nervousness, sleeplessness, and anorexia; overdoses show signs of excessive central nervous system stimulation including excessive agitation and anxiety as well as dizziness, nausea, palpitations, increased heart rate, and psychosis [16]. At some doses and on some tasks [5], stimulant drugs may have the same direction of effect (cognitive enhancement) in some individuals without ADHD [4] as well as in those with ADHD.

In Europe, where the prescription of stimulants has been restricted by custom and by law, clinical guidelines recommend an initial rigorous trial of multiple psychosocial interventions such as behaviour modification, cognitive therapy, family therapy and teacher consultation. In North America, where the prescription of stimulants has been accepted for decades and some restrictions have been relaxed, clinical guidelines recommend an initial rigorous pharmacological trial [20]. Over the past decade, the prescriptions for these stimulants (MPH and AMPH) have increased from less that 2 million in 1991 to over 10 million in 2001, and now it is estimated that approximately 6 % of school-age children are identified and treated with these drugs (about 3 million/year in the US) [21].

In the The Multimodal Treatment Study of Children with ADHD Cooperative Group (MTA) [14], the largest and longest study of children with ADHD combined type, aged 7 years to 9.9 years, were randomly assigned to 14 months of treatment in four groups: rigorous medication management; intensive behavioral treatment; the two combined; or standard community care (2∕3 treated with medication). All groups in the study showed reduction of symptoms over time [14]. However, the children in the combined treatment and the medication management groups showed further reduction in core ADHD symptoms than those in behavioral alone, or community care groups [14]. This validates the clinical experience that children who largely adhere to a well-titrated regimen of stimulants continue to benefit significantly for at least 14 months [9]. After the MTA study completed, the caregivers/children determined their continued treatment. Interestingly, most children who were treated with stimulants did not continue this treatment. After 8 years, only 32.5 % of ADHD cases were being treated with stimulant medications [19]. By the 3 year follow-up assessment point, the initial relative benefits of assignment to the medication conditions and of current medication use were no longer significant [8, 12, 17]. In an 8 year follow-up [13], treatment-related improvements during the study were generally maintained, but differential treatment efficacy was lost. There were no differences between the four initially assigned treatment groups on repeated measures of psychiatric symptoms, academic function, and social functioning [13]. There was also no difference between groups for long-term outcomes, e.g. substance use or delinquency [12, 13]. This suggests that the relative benefits of childhood treatment with stimulant medication, compared with non-pharmacological treatments—improvement in cognitive deficits as well as reductions in symptom severity—may dissipate after a 2 year to 3 year period, whether or not the medication component of treatment is continued or withdrawn [13, 17, 18].

In a different long-term study, where subjects had self-selected medication status for 9 years, groups separated into medicated > 1 year (average 5.3 years) or no treatment/short-term treatment, differed on 3 measures of academic achievement and on grade point average, with the medicated group outperforming the non-medicated group regardless of current medication status [19]. Compared with non-ADHD controls, the subgroup of ADHD adolescents not taking medication at follow-up had a more pervasive pattern of significant deficits than the subgroup of ADHD adolescents taking medication. The ADHD subgroup on medication had better performance on sustained attention and verbal learning tests [19].

1.0.1 Failures of Stimulant Drugs

A meta-analysis found that stimulants have a three-fold greater benefit on behaviour ratings than on attention as measured by performance on academic tests [20].

The effect of stimulant drugs can sometimes fade over time. This return of symptoms is usually attributed to drug tachyphylaxis or placebo relapse, and in the case of MPH and other reuptake inhibitors, Hinz et al. [7] suggests that this reduction of drug effect is due to systemic depletion of monoamines and a moderate relative nutritional deficit. When the diet was adjusted to include more of the monoamine precursors l-tryptophan and l-tyrosine and monoamine levels had returned to the normal reference range of the population the problem was corrected and the drug effects returned to previous levels. 97 % of subjects who experienced waning of initial drug effects were suffering from monoamine depletion and monoamine electrical dysfunction secondary to developing a relative nutritional deficit [7].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

AMPH

amphetamine

MPH

methylphenidate

MTA

The Multimodal Treatment Study of Children with ADHD Cooperative Group

References

Contents

1 Psychological vs Pharmalogical Treatment

In Europe, where the prescription of stimulants has been restricted by custom and by law, clinical guidelines recommend an initial rigorous trial of multiple psychosocial interventions such as behaviour modification, cognitive therapy, family therapy and teacher consultation. In North America, where the prescription of stimulants has been accepted for decades and some restrictions have been relaxed, clinical guidelines recommend an initial rigorous pharmacological trial [9]. Over the past decade, the prescriptions for these stimulants (methylphenidate (MPH) and amphetamine (AMPH)) have increased from less that 2 million in 1991 to over 10 million in 2001, and now it is estimated that approximately 6 % of school-age children are identified and treated with these drugs (about 3 million/year in the US) [10].

2 Treatment Study of Children with ADHD

In the The Multimodal Treatment Study of Children with ADHD Cooperative Group (MTA) [5], the largest and longest study of children with attention-deficit/hyperactivity disorder (ADHD) combined type, aged 7 years to 9.9 years, were randomly assigned to 14 months of treatment in four groups: rigorous medication management; intensive behavioral treatment; the two combined; or standard community care (2∕3 treated with medication). All groups in the study showed reduction of symptoms over time [5]. However, the children in the combined treatment and the medication management groups showed further reduction in core ADHD symptoms than those in behavioral alone, or community care groups [5].

This validates the clinical experience that children who largely adhere to a well-titrated regimen of stimulants continue to benefit significantly for at least 14 months [2]. After the MTA study completed, the caregivers/children determined their continued treatment. Interestingly, most children who were treated with stimulants did not continue this treatment. After 8 years, only 32.5 % of ADHD cases were being treated with stimulant medications [8].

2.1 Follow-ups

By the 3 year follow-up assessment point, the initial relative benefits of assignment to the medication conditions and of current medication use were no longer significant [1, 3, 6]. In an 8 year follow-up [4], treatment-related improvements during the study were generally maintained, but differential treatment efficacy was lost. There were no differences between the four initially assigned treatment groups on repeated measures of psychiatric symptoms, academic function, and social functioning [4]. There was also no difference between groups for long-term outcomes, e.g. substance use or delinquency [3, 4].

This suggests that the relative benefits of childhood treatment with stimulant medication, compared with non-pharmacological treatments—improvement in cognitive deficits as well as reductions in symptom severity—may dissipate after a 2 year to 3 year period, whether or not the medication component of treatment is continued or withdrawn [4, 6, 7].

3 Following Academic Acheivement

In a different long-term study, where subjects had self-selected medication status for 9 years, groups separated into medicated > 1 year (average 5.3 years) or no treatment/short-term treatment, differed on 3 measures of academic achievement and on grade point average, with the medicated group outperforming the non-medicated group regardless of current medication status [8]. Compared with non-ADHD controls, the subgroup of ADHD adolescents not taking medication at follow-up had a more pervasive pattern of significant deficits than the subgroup of ADHD adolescents taking medication. The ADHD subgroup on medication had better performance on sustained attention and verbal learning tests [8].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

AMPH

amphetamine

MPH

methylphenidate

MTA

The Multimodal Treatment Study of Children with ADHD Cooperative Group

References

Contents

1 Early Diagnosis

A Swedish group, Wichstrøm et al. [6], wrote up a study looking at symptoms of attention-deficit/hyperactivity disorder (ADHD) in preschoolers. In their study, they cited several objections to assigning Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnoses to preschoolers:

∙ Preschool children change so rapidly that symptoms will not cluster in any meaningful way

∙ Normal developmental variation will be wrongly interpreted as psychiatric symptomatology.

∙ Diagnosing young children will stigmatize them in ways that will negatively affect their development.

However, they continue that there are several reasons why research on the epidemiology of preschoolers should be pursued further [6]:

∙ Emerging empirical evidence from a variety of longitudinal studies supports the notion that there is continuity between preschool symptoms and disorders and later problems.

∙ If undetected child problems and relationships with caregivers and peers may deteriorate and with time become more resistant to change.

Early detection and intervention are therefore called for.

In the study, Wichstrøm et al. [6] reported 1.9 % of preschoolers in Scandinavia had ADHD symptoms, and that ADHD syptoms were often comorbid with other disorders in preschool children they observed.

2 The Preschool ADHD Treatment Study

A short-term efficacy and safety trial of methylphenidate (MPH) use in preschoolers diagnosed with moderate-to-severe ADHD was undertaken in the USA with long-term logitudinal followup [2]. Although effect sizes were smaller than those seen in school-age children, MPH did decrease ADHD symptoms in these preschoolers [1]. However, treatment with MPH hardly increases remission of ADHD symptoms over placebo, with only 21 % MPH treated children, and 13 percent of placebo treated children reaching criterion for remission [1]. While MPH is generally well tolerated, 30 % of parents reported moderate to severe adverse events during the trial [7]. These included emotional outbursts, difficulty falling asleep, repetitive behaviors/thoughts, appetite decrease, and irritability. This, along with reductions in growth rate (in both height and weight) reported by the study [4] highlight the importance of balancing the expected benefits in ADHD symptom reduction against a risk of reduced growth rates and possibly exagerated sensitivity to side effects in preschool-aged children.

2.1 Longitudinal followup

At followups 3 and 6 years later (mean age 7.4 years and 10.4 years respectively), most children were still on some sort of pharmacotherapy (65 % to 71 %), stimulant therapy being the most popular [5]. Though there was a slight reduction is symptoms over the 6 year followups, almost 80 % of the preschoolers enrolled in the study continued to be diagnosed with ADHD into mid-to-late childhood [3]. Interestingly, parent and teacher ratings of ADHD symptom severity were not significantly different between children on medication versus those off medication during followup [3].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

DSM-IV

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

MPH

methylphenidate

References

Contents

1 Neuropsychological Theories of ADHD

No single neuropsychological theory can explain all attention-deficit/hyperactivity disorder (ADHD) features, neuropsychological impairments may be heterogeneous, which probably corresponds to causal heterogeneity [15, 30]. There is considerable clinical and neuropsychological heterogeneity among individuals who meet the criteria for ADHD [4]. Rather than attempting to identify a single neurpsychological weakness that is necessary and sufficient to cause ADHD, more recent theoretical models explicitly hypothesize that complex disorders are heterogeneous conditions that arise from the combined effects of weaknesses in multiple cognitive domains [16, 17, 30].

1.1 Executive dysfunction

A prominent neuropsychological theory of ADHD suggests that ADHD symptoms arise from a primary deficit in executive functions: the cognitive processes that perform appropriate problem-solving in order to attain a future goal [18]. Every day, we continuously evaluate potential actions and select the options that are most appropriate for the current, specific set of circumstances. This task is extremely complex because some potential choices can be directed toward achieving a positive outcome in the future, whereas alternative actions may maximize initial gains but eliminate the chance for larger long-term benefits. Executive functions my be more accurately described as a collection of related but separable abilities: the ability to inhibit maladaptive behaviors (“response inhibition/inhibitory control”); hold and manipulate information in memory (“working memory”); shift back and forth between two simultaneous tasks (“set shifting”); and suppress attention to extraneous information in the environment to increase focus on a target (“interference control”) [4].

Candidates for core neuropsychological deficits in executive function that might cause both ADHD symptoms and the constellation of neuropsychological impairments that accompany ADHD include failure of inhibitory control [2], dysregulation of brain systems mediating reward and response cost [11, 29], and deficits in arousal, activation, and effortful control [23–25]. Deficits in arousal and effort lead to state-dependent cognitive deficits, and therefore, ADHD may cause problems in regulating cognitive functions in general. This pattern of neuropsychological deficit in ADHD patients has been interpreted as being caused by dysregulation of frontal–subcortical circuits [5]. Frontal–subcortical circuits control executive functions, including inhibition, working memory, set-shifting, interference control, planning, and sustained attention [7, 39]. One problem with these overarching theories is that executive dysfunction is common, but not universal in ADHD patients [22, 28].

1.2 Dysfunctional reward sensitivity

Motivation and reward may represent another core deficit of ADHD [31, 36]. Explanations of ADHD related to reward sensitivity suggest that ADHD is attributable to a dysfunctional response to reward and punishment contingencies. Johansen et al. [11] and Sonuga-Barke [28] propose theories that ADHD children have a steeper than normal delay-of-reinforcement gradient, and aversion to delay of reinforcement. Delay aversion is a special variant of the dysfunctional reward sensitivity model that suggests that children with ADHD have a motivational style that leads them to find delay extremely aversive [27, 29]. Tripp and Wickens [35] also proposed the dopamine (DA) transfer deficit theory and suggested that children with ADHD have diminished cellular responses of DA cells to cues that precede reinforcement.

A neural circuit that includes ventromedial prefrontal cortex, the amygdala, and other limbic structures plays an essential role in coordinating the interface between motivation and cognition during decision-making processes [3, 20]. Damage to this network often leads to difficulty learning from mistakes, delaying gratification, and monitoring subtle shifts in reward and punishment probabilities to maximize the short-and long-term benefits of a choice.

1.3 Intelligence and academic achievement

More global cognitive aspects like intelligence, academic achievement, and social cognition are of particular importance to the clinical impact of ADHD, and these broad domains are likely impacted by the individual cognitive processes described above [4]. Individual differences in intelligence and academic achievement may correlate better with neuropsychological deficits associated with ADHD rather than categorical placement [13], however, ADHD symptoms may directly cause an individual to perform poorly on standardized tests of intelligence or reading [2]. Also, while patients with ADHD suffer from a range of social and interpersonal problems, it is unclear whether these difficulties arise from true deficits in social cognition or can be better explained by the behavioral symptoms like lapses in attention and impulsivity [4].

2 Laboratory experiments attempt to capture and quantify ADHD

Spatial working memory tasks show the largest performance difference between children with ADHD and those without [16]. Key domains in which deficits are manifested across cases are vigilance/attention, cognitive control, response suppression, working memory, and motivation. These key domains (cognitive control and motivation) highlight principles of DA reinforcement (as discussed in the Dopamine in the Dentate Gyrus section) and its disruption in this disorder [32]. Historically, the core feature of ADHD has been characterized as one of an attention deficit, but increasing evidence suggests that a reward and motivation deficit may be of equal importance [6, 19, 29, 35–37].

2.1 Response variability

The reaction times of children, adolescents, and adults with ADHD are significantly more variable than the reaction times of individuals without ADHD across a wide range of cognitive tasks [8]. Response variability is one of the ubiquitous findings in ADHD research across a variety of speeded-reaction-time tasks, laboratories, and cultures [7]. Increased response variability seems to be due to a relatively small number of trials with extremely long response times rather than systematically greater response variability across all trials [9]. These slow trials may reflect attentional lapses due to chronic underarousal, or inconsistent regulation of arousal during lengthy tasks. These attentional lapses may be caused by problems in the functional connectivity between anterior cingulate and precuneal regions of the brain [6]. Another theory suggests that greater response variability could result from dysfunction in short-duration timing mechanisms mediated by cerebellar circuits [7, 33].

2.2 Processing speed

Although no neuropsychological theoretical models of ADHD explicitly propose slow cognitive processing speed as the primary neuropsychological weakness in ADHD, deficits in processing speed are among the most robust predictors of ADHD symptoms [4, 21, 39]. Slow processing speed has been reported in groups with ADHD on a range of measures that require both verbal and nonverbal responses [26], and is a consistant finding in studies of both children and adults with ADHD [40]. The neurophysiology of slow processing speed is not well understood, but generalized low cortical arousal provides one potential explanation [4].

3 Effects of stimulant medications

Other, non-stimulant medications used to treat ADHD¹ test superior to placebo, but most head-to-head trials compared to stimulant medications (methylphenidate (MPH) and amphetamine (AMPH)) show greater efficacy for stimulant medications [4].

Across well-controlled studies of individuals with ADHD, stimulant-related cognitive enhancements were more prominent on tasks without an executive function component than on tasks with an executive function component [31]. Dose-response studies of stimulant medications suggest that the optimal dose varies across individuals and depends somewhat on the domain of function, with high doses tending to produce greater enhancement on some (e.g. attention, vigilance, memory, and working memory) but not others (e.g. planning, cognitive flexibility, inhibitory control, naming, and motor speed) [4, 31].

In terms of academic achievement, evidence suggests that stimulants improve acute academic performance of children with ADHD, but that long-term effects have not been supported. For example, the The Multimodal Treatment Study of Children with ADHD Cooperative Group demonstrated that treatment with stimulant medications over the 14-month trial resulted in significant improvement of achievement scores in math and reading on the Wechsler Individual Achievement Test (WIAT) immediately post-treatment. However, these improvements were no longer significant at the 3-year follow up assessment, suggesting that any relative cognitive enhancement may not be sustained [10].

Extensive work examining the effects of stimulants on attentional and executive processes has not found consistent evidence that stimulants enhance or ameliorate these ADHD-related deficits. Although reaction times are significantly reduced, performance on tasks with increased attentional or executive demands is not consistently improved by stimulants [4]. Further, while short-term improvements in academic achievement scores have been demonstrated with stimulant treatment, stimulant medications do not completely normalize academic achievement in children with ADHD.

In contrast to the extensive work on the effects of stimulants on attention, executive function, and achievement, the potential influence of stimulants on other types of cognition implicated in ADHD (e.g. social cognition and reward sensitivity) is comparably unknown. In one study by Williams [41], several abnormalities during emotional processing could be observed prior to treatment, which were ameliorated with methylphenidate. In addition, medication significantly improved baseline deficits in the recognition of anger- and fear-related facial expressions. However, the performance of ADHD patients remained impaired relative to healthy controls. Thus, although methylphenidate normalized neural activity, it was associated with only minimal improvement on emotion recognition. This finding is in line with studies that suggest medication results in improvements of inattention and disruptive behavior in children with ADHD, whereas positive social behavior and peer status remain unchanged [38].

3.1 Non-pharmacological interventions to improve cognition in ADHD

Computer-based working memory training has demonstrated improvements on trained and untrained measures of working memory, and also showed improved response inhibition and reductions in parent-rated inattentive symptoms of ADHD that were durable at follow-up assessments [12]. This training protocol was shown to produce increases in brain activation and changes in the density of prefrontal and parietal dopamine D1 receptor binding potential, indicating neural plasticity that arises as a result of the training [14].

A number of studies have been published examining the effects of neurofeedback on a range of outcome measures in individuals with ADHD. These studies have, in general, produced large effects on parent and teacher-rated ADHD symptoms [34]. However, neurofeedback has shown more variable effects with respect to cognitive outcomes.

4 Relevance of cognition-related endpoints in clinical syndrome of ADHD

In one early review of the literature, Barkley [1] concluded that the ecological validity of laboratory tasks to measure clinically relevant feature of inattention, impulsivity, and overactivity was low to moderate. Other studies have shown that performance on laboratory tasks was not predictive of the clinical response in ADHD patients to different medications. To the extent that specific cognitive endpoints are strongly associated with the clinical features that define the disorder (e.g. link between inhibitory control and DSM-IV impulsivity symptoms), assessing the effects of interventions on these endpoints may be useful. However, as many studies have shown, the acute effects of a range of interventions on cognitive endpoints that are less strongly correlated with ADHD clinical features may be less meaningful from a clinical perspective.

Acronyms

ADHD

attention-deficit/hyperactivity disorder

AMPH

amphetamine

DAT

dopamine transporter

DA

dopamine

MPH

methylphenidate

MTA

The Multimodal Treatment Study of Children with ADHD Cooperative Group

NE

norepinephrine

WIAT

Wechsler Individual Achievement Test

References