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Concept: Methylphenidate

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Brain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated.

Concepts: Dopamine receptor, Attention-deficit hyperactivity disorder, Hyperactivity, Stimulant, Dopamine, Methylphenidate, Amphetamine, Dopaminergic

192

Amphetamine was discovered over 100 years ago. Since then, it has transformed from a drug that was freely available without prescription as a panacea for a broad range of disorders into a highly restricted Controlled Drug with therapeutic applications restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy. This review describes the relationship between chemical structure and pharmacology of amphetamine and its congeners. Amphetamine’s diverse pharmacological actions translate not only into therapeutic efficacy, but also into the production of adverse events and liability for recreational abuse. Accordingly, the balance of benefit/risk is the key challenge for its clinical use. The review charts advances in pharmaceutical development from the introduction of once-daily formulations of amphetamine through to lisdexamfetamine, which is the first d-amphetamine prodrug approved for the management of ADHD in children, adolescents and adults. The unusual metabolic route for lisdexamfetamine to deliver d-amphetamine makes an important contribution to its pharmacology. How lisdexamfetamine’s distinctive pharmacokinetic/pharmacodynamic profile translates into sustained efficacy as a treatment for ADHD and its reduced potential for recreational abuse is also discussed.

Concepts: Pharmacology, Attention, Attention-deficit hyperactivity disorder, Hyperactivity, Methylphenidate, Amphetamine, Lisdexamfetamine, Dextroamphetamine

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Hyperactivity is one of the core symptoms in attention deficit hyperactivity disorder (ADHD). However, it remains unclear in which way the motor system itself and its development are affected by the disorder. Movement-related potentials (MRP) can separate different stages of movement execution, from the programming of a movement to motor post-processing and memory traces. Pre-movement MRP are absent or positive during early childhood and display a developmental increase of negativity.

Concepts: Attention, Educational psychology, Attention-deficit hyperactivity disorder, Hyperactivity, ADHD predominantly inattentive, Stimulant, Dopamine, Methylphenidate

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INTRODUCTION: The aetiology of attention deficit hyperactivity disorder (ADHD) is attributed to different factors: genetic, environmental, and biological (neurotransmitters: dopaminergic system). Iron is essential for the correct functioning of the dopaminergic system. Iron deficiency is common in patients with ADHD, and its correction may be useful in the treatment. OBJECTIVES: To analyse a possible relationship between iron deficiency and symptoms of inattention, hyperactivity and impulsivity in ADHD patients, and the potential benefit of iron therapy. PATIENTS AND METHODS: A prospective study was conducted on non-anaemic and cognitively normal children, newly diagnosed with ADHD, according to DSM-IV criteria. Specific scales were used (SNAP-IV, ADHS) and serum ferritin was determined. Those with ferritin ≤ 30ng/ml were treated with ferrous sulphate (4mg/kg/day) for 3 months, with its effect quantified being subsequently quantified. RESULTS: A total of 60 patients, with a mean age of 9.02 years (range: 6-14), were analysed. The inattentive subtype was the most frequent one (53.3%). Almost two-thirds (63.3%) had iron deficiency, which was more frequent among the inattentive group (38 vs 22, P<.02). The iron treatment was completed by 17 patients. The treatment was not effective in 7 of the 8 non-inattentive subtypes, with a partial response in the remaining one. Of the 9 inattentive subtypes: the treatment was successful in the total control of symptoms in 5 of them, partially effective in other 3, and ineffective in one patient. The probability of complete response after treatment with iron was higher in inattentive patients with ADHD (P=.02). CONCLUSIONS: Treatment with iron supplements can be an effective alternative to treat patients with ADHD and iron deficiency, especially the inattentive subtype.

Concepts: Attention, Dopamine receptor, Attention-deficit hyperactivity disorder, Hyperactivity, Dopamine, Methylphenidate, Amphetamine, Dopaminergic

169

BACKGROUND: Methylphenidate (MPH), a psycho-stimulant, is the most widely administered drug for the pharmacological management of patients with attention deficit hyperactivity disorder (ADHD). This study attempts to determine whether sustainable improvements occur in neurocognitive function among ADHD patients following 12-month treatment with MPH, at drug-free status. Whether age groups, gender or ADHD subtypes differ in neurocognitive performance during MPH treatment is also examined. METHODS: Study participants consisted of 103 ADHD patients (mean age: 9.1 +/- 1.9 years old) who were drug naive or drug free for at least 6 months. The patients were prescribed oral short-acting MPH at each dose range of 0.3–1.0 mg/kg daily. During 12 months of the study, the patients underwent the test of variables of attention (TOVA) at the baseline, month 6 and month12. Patients were instructed to not intake MPH for one week before the second and the third TOVA. RESULTS: Seventy five patients completed the study. Results of this study indicated that although commission errors and response sensitivity (d') significantly improved during MPH treatment for 12 months, omission errors, response time, response time variability and ADHD score did not. While younger ADHD patients (<9y/o) performed better in response time, response time variability, d' and ADHD score than older ones (>=9y/o), the latter more significantly improved in response time than the former during 12 months of treatment. Additionally, boys improved more than girls in omission error and d'. Moreover, although ADHD subtypes significantly differed in ADHD score during the treatment, MPH treatment and ADHD subtypes did not interact with each other for all TOVA indices. CONCLUSIONS: ADHD patients significantly improved in impulsivity and perceptual sensitivity, determined as TOVA, during MPH treatment for 12 months. Age and gender, yet not ADHD subtypes, appear to influence the MPH treatment effects in some indices of TOVA. A future study containing a comparison group is suggested to confirm whether the neurocognitive improvements are attributed to long-term effects of MPH or natural maturation of patients.

Concepts: Attention, Attention-deficit hyperactivity disorder, Hyperactivity, ADHD predominantly inattentive, Dopamine, Methylphenidate, Amphetamine

165

In previous studies, we found a strong reduction in contrast perception and retinal contrast gain in patients with major depression, which normalized after remission of depression. We also identified a possible role of the dopaminergic system in this effect, because visual contrast perception depends on dopaminergic neurotransmission. Dopamine is also known to play an important role in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Therefore, in order to explore the specificity of retinal contrast gain as a marker of depression in comparison with other psychiatric diseases, we recorded the pattern electroretinogram (PERG) in patients with ADHD. Twenty patients diagnosed with ADHD and 20 matched healthy subjects were studied. Visual pattern electroretinograms were recorded from both eyes. The contrast gain of the patients with attention deficit disorder (ADD) did not differ from the control group, nor did the contrast gain of any ADHD subgroup (predominantly inattentive or combined patients). In the healthy subjects, a significant correlation between depression score and contrast gain was found. As the contrast gain in an earlier study clearly separated the patients with depression from the controls, we assume that retinal contrast gain might be a specific marker in depression.

Concepts: Attention-deficit hyperactivity disorder, Hyperactivity, ADHD predominantly inattentive, Major depressive disorder, Dopamine, Methylphenidate, Amphetamine, Dopaminergic

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Lisdexamfetamine dimesylate (LDX) is a long-acting d-amphetamine prodrug used to treat attention-deficit/hyperactivity disorder (ADHD) in children, adolescents and adults. LDX is hydrolysed in the blood to yield d-amphetamine, and the pharmacokinetic profile of d-amphetamine following oral administration of LDX has a lower maximum plasma concentration (C max), extended time to C max (T max) and lower inter- and intra-individual variability in exposure compared with the pharmacokinetic profile of an equivalent dose of immediate-release (IR) d-amphetamine. The therapeutic action of LDX extends to at least 13 h post-dose in children and 14 h post-dose in adults, longer than that reported for any other long-acting formulation. Drug-liking scores for LDX are lower than for an equivalent dose of IR d-amphetamine, which may result from the reduced euphorigenic potential associated with its pharmacokinetic profile. These pharmacokinetic and pharmacodynamic characteristics of LDX may be beneficial in the management of symptoms in children, adolescents and adults with ADHD.

Concepts: Pharmacology, Attention-deficit hyperactivity disorder, Methylphenidate, Amphetamine, Lisdexamfetamine, Prodrug, Dextroamphetamine, Amphetamines

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 To determine whether treatment with methylphenidate in children and young people with attention-deficit/hyperactivity disorder (ADHD) was associated with cardiovascular events.

Concepts: Attention-deficit hyperactivity disorder, Methylphenidate

64

In addition to causing distress and disability to the individual, neuropsychiatric disorders are also extremely expensive to society and governments. These disorders are both common and debilitating and impact on cognition, functionality and wellbeing. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used to treat cognitive dysfunction in Alzheimer’s disease and attention deficit hyperactivity disorder, respectively. Other cognitive enhancers include specific computerized cognitive training and devices. An example of a novel form of cognitive enhancement using the technological advancement of a game on an iPad that also acts to increase motivation is presented. Cognitive enhancing drugs, such as methylphenidate and modafinil, which were developed as treatments, are increasingly being used by healthy people. Modafinil not only affects ‘cold’ cognition, but also improves ‘hot’ cognition, such as emotion recognition and task-related motivation. The lifestyle use of ‘smart drugs’ raises both safety concerns as well as ethical issues, including coercion and increasing disparity in society. As a society, we need to consider which forms of cognitive enhancement (e.g. pharmacological, exercise, lifelong learning) are acceptable and for which groups (e.g. military, doctors) under what conditions (e.g. war, shift work) and by what methods we would wish to improve and flourish.

Concepts: Attention, Educational psychology, Attention-deficit hyperactivity disorder, Hyperactivity, Methylphenidate, Modafinil, Nootropic, Nootropics

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