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Cocaine addiction continues to be an important public health problem with over 1.7 million users in the US alone. Although there are no approved pharmacotherapies for cocaine addiction, a number of medications have been tested with some promising results. In this review, we summarise some of the emerging targets for cocaine pharmacotherapy including dopaminergic and GABA medications, adrenoceptor antagonists, vasodilators and immunotherapies. The brain dopamine system plays a significant role in mediating the rewarding effects of cocaine. Among dopaminergic agents tested for cocaine pharmacotherapy, disulfiram has decreased cocaine use in a number of studies. Amantadine, another medication with dopaminergic effects, may also be effective in cocaine users with high withdrawal severity. GABA is the main inhibitory neurotransmitter in the brain, and accumulating evidence suggests that the GABA system modulates the dopaminergic system and cocaine effects. Two anticonvulsant medications with GABAergic effects, tiagabine and topiramate, have yielded positive findings in clinical trials. Baclofen, a GABAB receptor agonist, is also promising, especially in those with more severe cocaine use. Some of the physiological and behavioural effects of cocaine are mediated by activation of the adrenergic system. In cocaine users, propranolol, a β-adrenoceptor antagonist, had promising effects in individuals with more severe cocaine withdrawal symptoms. Cerebral vasodilators are another potential target for cocaine pharmacotherapy. Cocaine users have reduced cerebral blood flow and cortical perfusion deficits. Treatment with the vasodilators amiloride or isradipine has reduced perfusion abnormalities found in cocaine users. The functional significance of these improvements needs to be further investigated. All these proposed pharmacotherapies for cocaine addiction act on neural pathways. In contrast, immunotherapies for cocaine addiction are based on the blockade of cocaine effects peripherally, and as a result, prevent or at least slow the entry of cocaine into the brain. A cocaine vaccine is another promising treatment for cocaine addiction. The efficacy of this vaccine for relapse prevention is under investigation. Many initial promising findings need to be replicated in larger, controlled clinical trials. [ABSTRACT FROM AUTHOR]

The symptoms of attention-deficit hyperactivity disorder (ADHD) can have an early onset, beginning before the age of 6 years. Despite the significant number of preschool-aged children that can be diagnosed with ADHD, there are limited controlled data available on the pharmacological interventions being increasingly used in this population. A 1990 review showed that 34% of paediatricians and 15% of family physicians had prescribed psychostimulant medications to preschoolers with ADHD, and pharmacoepidemiological studies indicate growing use of stimulants in preschoolers during the 1990s. Unfortunately, only six controlled trials, with a total enrollment of less than 200 children, have been conducted using these drugs in preschoolers. While these small studies provide some evidence of benefit from the use of methylphenidate in preschoolers with ADHD, more data are critically needed. Practice parameters developed by the American Academy of Child & Adolescent Psychiatry and the American Academy of Pediatrics provide some guidance regarding the diagnosis and treatment of young children with ADHD, but are mainly based upon research in children of primary-school age. The ongoing PATS (Preschool ADHD Treatment Study), funded by the National Institute of Mental Health, will provide important clinical guidance for diagnostic considerations and intervention strategies for children with ADHD aged 3-5 years. Pending the release of data from the PATS study, clinicians must rely on developmental assessment skills, available standardised rating instruments, reports about the child from multiple informants, and knowledge of the risks and benefits of available pharmacological and behavioural treatments, in order to treat preschool children with ADHD effectively. [ABSTRACT FROM AUTHOR]

New formulations of stimulant medications for the treatment of attention-deficit hyperactivity disorder (ADHD) have been an important focus for pharmaceutical industry research and development over the past decade. In this article, we review and assess the therapeutic potential of five new stimulant formulations (one immediate release and four longer-acting preparations) that have recently become available for the treatment of ADHD. While the therapeutic potential of immediate-release enantiomers of methylphenidate has not yet been clinically realised, new long-acting formulations of stimulants have changed the standard of care for children, adolescents and adults with ADHD. The longer duration of action of these once-daily compounds, and the consequent expansion of the duration of daily ADHD coverage afforded by them, has introduced the realistic possibility of reducing the overall daily burden of ADHD on affected individuals. Although more expensive, these new stimulant formulations are easier for patients to use than older stimulants, more resistant to abuse and misuse, and allow for increased privacy of ADHD treatment at school or work. [ABSTRACT FROM AUTHOR]

Pervasive developmental disorders (PDDs) are severe psychiatric disorders characterised by impaired social interaction, reduced verbal and nonverbal communication, and restricted and stereotyped patterns of interest and behaviour, with onset in the first 3 years of life. As part of a multimodal approach that includes educational and behavioural interventions, appropriate use of pharmacotherapy in patients with PDDs can improve some symptoms and behaviours and increase the patient’s response to nonpharmacological interventions. Pharmacotherapy is aimed at stabilising the dysregulated systems that are thought to underlie the abnormal behaviours, namely the serotonergic and dopaminergic systems. This paper critically reviews the available literature on the pharmacotherapy of PDDs in children and adolescents. Pharmacological, efficacy and safety data on drugs acting on serotonin (serotonergic agents such as clomipramine, fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine), on both serotonin and norepinephrine (venlafaxine and mirtazapine), dopamine (dopamine-blocking antipsychotics such as haloperidol and pimozide), and on both serotonin and dopamine (atypical antipsychotics such as clozapine, risperidone, olanzapine, quetiapine and ziprasidone) are presented. The paper concludes with a brief discussion of other psychotropic medications, such as the opioid antagonists, α-adrenoceptor agonists (clonidine and guanfacine), psychostimulants, mood stabilisers, glutamatergic compounds (lamotrigine, amantadine), buspirone, and secretin. Available evidence suggests that atypical antipsychotics (mainly risperidone and olanzapine) are particularly indicated when more serious behavioural symptoms, such as aggression, self-injurious behaviours and hyperactivity, are prominent. Serotonergic agents may be effective in children with repetitive phenomena or affective symptoms. Social relatedness is more frequently refractory to both atypical antipsychotics and serotonergic agents. Further research into the drug treatment of PDDs, including placebo-controlled trials and long-term, naturalistic follow-up studies of large samples of patients of different age ranges, is warranted. [ABSTRACT FROM AUTHOR]

Up to 12% of the general population experience excessive daytime sleepiness (EDS), with increasing prevalence in the elderly. EDS may lead to cognitive impairment, resulting in inattentiveness, poor memory, mood disorders and an increased risk of accidents. As a result, quality of life is reduced in most patients with EDS as well as in their caregiving spouses. There are a variety of causes leading to EDS, including CNS pathology, neurological dysfunction, associated sleep disorders with insufficient or fragmented sleep, and drug therapy. Since EDS accompanies many neurological disorders, such as neurodegenerative and neuromuscular diseases, neurologists should be familiar with the diagnosis, its major causes and with treatment options. The main focus of this article is on movement disorders, neuromuscular diseases, multiple sclerosis, dementia, cerebrovascular diseases, head and brain trauma, pain and epilepsy. General managment strategies for EDS in all these neurological diseases include sleep hygiene aspects such as extensions of noctural time in bed and frequent naps during the day. Pharmacological treatment is generally achieved with stimulants such as amphetamine, methylphenidate and pemoline, or newer compounds such as modafinil. [ABSTRACT FROM AUTHOR]

The purpose of this review is to summarize existing data on the long-term safety and efficacy of stimulant treatment, and how long-term stimulant treatment of children with attention deficit hyperactivity disorder (ADHD) affects their outcome. Existing controlled studies of children with ADHD treated and untreated with stimulants, as well as long-term prospective follow-up studies, are reviewed. Children with ADHD treated with stimulants for as long as 2 years continue to benefit from the treatment, with improvements observed in ADHD symptoms, comorbid oppositional defiant disorder, and academic and social functioning, with no significant problems of tolerance or adverse effects. Long-term, prospective follow-up studies into adulthood show that stimulant treatment in childhood has slight benefits regarding social skills and self-esteem. Long-term adverse effects from stimulant treatment in childhood regarding adult height or future substance abuse have not been supported by existing studies. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety and efficacy of extended-release methylphenidate with a bimodal profile using SODAS™ technology (Ritalin[sup ®] LA™) compared with placebo in children aged 6–14 years with attention deficit hyperactivity disorder (ADHD). Method: This was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study in children meeting Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for ADHD. Following titration and a 1-week placebo washout period, patients were randomized to 2 weeks of double-blind treatment with either Ritalin[sup ®] LA™ (10–40 mg/day) or placebo. The efficacy assessments used were the Conners' ADHD/DSM-IV Scales for teachers (CADS-T) and for parents (CADS-P), and the Clinical Global Impression-Improvement Scale (CGI-I) completed by the investigator. The primary efficacy variable was the change from baseline (end of placebo washout) to the final rating (end of 2-week double-blind treatment) in the CADS-T Total subscale score. Results: One-hundred-and-sixty-one children were treated and 134 responders were included in the intent-to-treat analysis. Ritalin[sup ®] LA™ achieved a mean change from baseline (± SD) on the CADS-T Total subscale of -10.7 (±15.68) compared with 2.8 (±10.59) for placebo (p < 0.0001); the effect size on the CADS-T Total score with Ritalin[sup ®] LA™ was 0.90. Additionally, 69.8% of patients in the Ritalin[sup ®] LA™ group were rated as much or very much improved on the CGI-I at final assessment compared with 40% of patients in the placebo group (p = 0.0009). The adverse events reported were generally mild or moderate, and were similar in both groups. Conclusion: The results demonstrate that Ritalin[sup ®] LA™ administered once daily for up to 2 weeks achieved outcomes statistically superior to placebo in children with ADHD. [ABSTRACT FROM AUTHOR]

Practitioners are increasingly called upon to diagnose and treat attention deficit hyperactivity disorder (ADHD) in adults. Although the use of pharmacotherapy in children with ADHD is well studied, the use of drugs for the treatment of adults with ADHD remains less well established. A systematic review of the literature identified 15 studies (n = 482 patients) of stimulants, and 27 studies of nonstimulant medications (n = 1179 subjects) including antidepressants, norepinephrine reuptake inhibitors, antihypertensive agents, amino acids and wake-promoting agents for the treatment of ADHD in adults. Controlled clinical trials in adults showed that stimulants, antidepressants and norepinephrine reuptake inhibitors demonstrated significant short-term improvements in ADHD symptoms compared with placebo. The two longer term trials with methylphenidate in adults confirmed the ongoing effectiveness and tolerability of stimulants. The response to amphetamine and methylphenidate appears to be dose-dependent. Methylphenidate and amphetamine had an immediate onset of action, whereas responses to pemoline, antidepressants and norepinephrine reuptake inhibitors appeared delayed. Controlled data on nicotinic/cholinergic compounds appear promising. Considerable variability was found in the diagnostic criteria for ADHD in adults, drug dosages and response rates between the various studies. Under controlled conditions, the aggregate literature comprised mainly of short-term studies, shows that stimulants, norepinephrine reuptake inhibitors and specific antidepressants had clinically and statistically significant beneficial effects in the treatment of ADHD in adults. Cholinergic agents appear promising. Further studies are necessary to evaluate the long-term effectiveness and tolerability of various agents, functional and neuropsychological outcomes, and the use of various agents in specific subgroups of adults with ADHD. [ABSTRACT FROM AUTHOR]

Objectives: The primary objective was to compare the differences in clinical efficacy of the starting dose of Ritalin[sup ®] LA™ (20mg) to the starting dose of Concerta[sup ®] (18mg), in a laboratory school setting for the duration of an entire school day. Secondary objectives were to compare Ritalin[sup ®] LA™ 20mg with Concerta[sup ®] 36mg, and Ritalin[sup ®] LA™ and both Concerta[sup ®] doses versus placebo across the school day. Methods: Thirty-six children (29 males, 7 females), aged 6–12 years, with attention deficit hyperactivity disorder, previously stabilized on methylphenidate (MPH), completed this four-way, randomized, single-blind crossover, analog classroom study. Patients were evaluated on day 0 and randomized to receive treatment on days 7, 14, 21, and 28 (Ritalin[sup ®] LA™ 20mg, Concerta[sup ®] 18mg, Concerta[sup ®] 36mg, or placebo). Results: Swanson, Kotkin, Agler, M-Flynn and Pelham Rating Scale (SKAMP)-attention: The effect of Ritalin[sup ®] LA™ 20mg across the morning was statistically different from that of Concerta 18mg and 36mg, as demonstrated by the change in the area under the curve (AUC) during the first 4 hours (0–4) from pre-dose. AUC[sub (0–4)] for Ritalin[sup ®]LA™ was -2.48 versus -1.36 for Concerta[sup ®] 18mg (p = 0.015), and -1.55 for Concerta[sup ®] 36mg (p = 0.043). AUC[sub (0–8)] change from pre-dose for Ritalin[sup ®] LA™ was -4.48 versus -2.72 for Concerta[sup ®] 18mg (p = 0.074), and -3.24 for Concerta[sup ®] 36mg (p = 0.208). SKAMP-deportment: AUC[sub (0–4)] for Ritalin[sup ®] LA™ was -1.67 compared with -0.28 for Concerta[sup ®] 18mg (p < 0.001), and -0.55 for Concerta[sup ®] 36mg (p = 0.004). AUC[sub (0–8)] change from pre-dose for Ritalin[sup ®] LA™ was -2.81 compared with -0.82 for Concerta[sup ®] 18mg (p = 0.018), and -1.34 for Concerta[sup ®] 36mg (p = 0.078). Combined: Mean AUC[sub (0–4)] change from pre-dose for Ritalin[sup ®] LA™ was -2.05 compared with -0.78 for Concerta[sup ®] 18mg (p < 0.001), -1.01 for Concerta[sup ®] 36mg (p = 0.003). The mean AUC[sub (0–8)] change from pre-dose for Ritalin[sup ®] LA™ was -3.58 compared with -1.70 for Concerta[sup ®] 18mg (p = 0.010), -2.22 for Concerta[sup ®] 36mg (p = 0.061). Math test-attempted: Mean pre-dose score for Ritalin[sup ®] LA™ was about 73 compared with 74, 90, and 81 for Concerta[sup ®] 18mg, 36mg, and placebo, respectively. Mean AUC[sub (0–8)] change from pre-dose for Ritalin[sup ®] LA™ was 202 compared with 115 for Concerta[sup ®] 18mg (p = 0.135), 137 for Concerta[sup ®] 36mg (p = 0.265). Math test-correct: Mean pre-dose score for Ritalin[sup ®] LA™ was 68 compared with 64, 78, and 76 for Concerta[sup ®] 18mg, 36mg, and placebo, respectively. Mean AUC[sub (0–8)] change from pre-dose for Ritalin[sup ®] LA™ was 183 compared with 100 for Concerta[sup ®] 18mg (p = 0.144), and 117 for Concerta[sup ®] 36mg (p = 0.245). Safety: One patient from each treatment group experienced a single mild adverse event that included abdominal pain, nausea, and dyspnea. Conclusion: While both Ritalin[sup ®] LA™ and Concerta[sup ®] were shown to be effective, the different release profiles of each formulation can result in distinct differences between the effects on measures of attention and deportment. [ABSTRACT FROM AUTHOR]

Attention-deficit/hyperactivity disorder (ADHD) affects approximately 8-10% of school-aged children in the US and for many individuals persists into adolescence and adulthood. Both pharmacological and nonpharmacological (behavioural) therapies are used to treat individuals with ADHD. Treatment with stimulant medications, which include methylphenidate and amphetamine, typically requires multiple daily doses to maintain efficacy. The frequency of treatment, coupled with the importance of timing of doses and the long-term nature of treatment, make noncompliance a particular issue in the treatment of ADHD. Studies report noncompliance rates of 20-65% with stimulant treatment, although there are only limited published studies and these show considerable individual variation. Noncompliance can arise through inadequate supervision of those receiving medication, leading to delayed or missed doses, or through the reluctance of individuals to take medication, which is influenced by a number of factors (e.g. social attitudes, pressures or worries surrounding medication use and the inconvenience of multiple daily doses). Two approaches are likely to increase compliance with stimulant treatment: effective once-daily formulations of medication and improved treatment information. The development of effective once-daily formulations for stimulant treatments removes the need for multiple daily doses, with the associated problems of ensuring adequate treatment supervision and personal privacy. Improved provision of education and information for individuals with ADHD, as well as their families and teachers, should help them address the issues surrounding stimulant medication and allow full participation in the treatment process. Together, these strategies should improve treatment compliance for individuals with ADHD. [ABSTRACT FROM AUTHOR]

Objective: To use a single national data source to discern trends in the prevalence of office-based visits resulting in a diagnosis of attention deficit hyperactivity disorder (ADHD) among girls, and trends in the prescribing of stimulant pharmacotherapy (including methylphenidate) for its treatment in the US.Methods: Data from the US National Ambulatory Medical Care Survey were utilised for this analysis. The number and rate of office-based physician visits resulting in a diagnosis of ADHD (International Classification of Diseases, 9th Revision, Clinical Modification code 314.00 or 314.01) were discerned from the beginning of 1990 to the end of 1998, for children aged 5 to 18 years. Gender-specific trend analyses were conducted using four time intervals: 1991 to 1992, 1993 to 1994, 1995 to 1996, and 1997 to 1998.Results: The estimated number of office-based visits documenting a diagnosis of ADHD among children increased from 947 208 in 1990 to 3 234 180 in 1998. The rate of office-based visits documenting a diagnosis of ADHD among children increased from 19.4 per 1000 of the US population aged 5 to 18 years in 1990 to 59.0 per 1000 in 1998, a 3-fold increase (p < 0.05). The annualised mean number of office-based visits documenting a diagnosis of ADHD among girls tripled between 1991 to 1992 and 1997 to 1998 (from 296 389 to 886 798), whereas the number for boys increased 2.2-fold (from 1 006 243 to 2 200 021). The US population-adjusted rate of office-based visits documenting a diagnosis of ADHD among girls increased 2.7-fold between 1991 to 1992 and 1997 to 1998 (from 12.3 per 1000 girls to 33.4 per 1000; p < 0.05), whereas the rate among boys doubled (from 39.5 per 1000 boys to 78.7 per 1000; p < 0.05). Documentation of a diagnosis of ADHD and the prescribing of stimulant pharmacotherapy increased 2.8-fold for girls, from 7.5 per 1000 girls in 1991 to 1992 to 21.1 per 1000 in 1997 to 1998 (p < 0.05), as compared with a 2.2-fold increase among boys (from 25.5 per 1000 boys to 57.0 per 1000; p < 0.05).Conclusion: Over the time frame 1990 to 1998, the rate of ADHD as well as the prescribing of stimulant medications for its treatment increased significantly among children aged 5 to 18 years. Between 1991 to 1992 and 1997 to 1998, the increased rate of diagnosis of ADHD among girls contributed to the overall upward trend. The rapidly increasing rate of ADHD among girls, and the prolonged nature of the disorder, represent significant public health problems. There exists a need for additional research examining both the aetiology and treatment of ADHD by gender. [ABSTRACT FROM AUTHOR]

Narcolepsy is a chronic sleep disorder characterised by excessive daytime sleepiness, with or without cataplexy, sleep paralysis and hypnagogic hallucinations, with an estimated prevalence of 0.02 to 0.05% worldwide. The goal of managing narcolepsy is to keep patients as alert as possible during daytime hours and to minimise the incidence of cataplexy. A combination of nonpharmacological (lifestyle and behavioural modifications) and pharmacological treatments may be used to alleviate excessive daytime sleepiness. Stimulants such as amphetamines and methylphenidate have been the mainstay of pharmacological treatment, although a range of different agents have been used over several decades. Modafinil, a benzohydrylsulfinyl-acetamide derivative, has demonstrated good efficacy in the treatment of excessive daytime sleepiness, but has limited anticataplectic effects. In clinical studies modafinil 200 to 400 mg/day significantly improved subjective and objective measures of sleepiness and alertness compared with placebo. A long term study of up to 10 years' duration showed modafinil to have good to excellent efficacy in 64% of patients. Use of modafinil does not appear to be associated with the development of tolerance or dependence, and it is considered to have limited potential for abuse. Modafinil is generally well tolerated with few adverse effects, the most common being headache, nausea, nervousness and anxiety. It may be coadministered with drugs for treating cataplexy. The efficacy and the cost effectiveness of modafinil in the treatment of narcolepsy have not been compared with other available agents. Conclusions: Modafinil provides a useful alternative to traditional stimulants for the treatment of excessive daytime sleepiness associated with narcolepsy. It is well tolerated, may be taken in combination with medications for cataplexy, and shows long term efficacy without development of tolerance. [ABSTRACT FROM AUTHOR]

Methylphenidate is prescribed for over 90% of children in the US diagnosed as having attention-deficit hyperactivity disorder (ADHD). Although ADHD has been widely studied, the use of methylphenidate in ADHD still poses a number of unresolved questions, including its pharmacodynamic characteristics (drug concentration-effect relationship) and the effect of long term treatment on the patient's psychopathology later in life. The objective of this review is to provide an analysis of the pharmacokinetic-pharmacodynamic properties and therapeutic effectiveness of methylphenidate that may help to answer some of these questions. Methylphenidate has 2 chiral centres, but the drug used in therapy comprises only the threo pair of enantiomers. d-threo-Methylphenidate is more potent than the l-enantiomer. Methylphenidate is administered as a racemic mixture that undergoes stereoselective clearance. Methylphenidate is a short-acting stimulant with a duration of action of 1 to 4 hours and a pharmacokinetic half-life of 2 to 3 hours. Maximum drug concentration after oral administration occurs at about 2 hours. Methylphenidate is absorbed well from the gastrointestinal tract and easily passes to the brain. Methylphenidate is efficacious for short term treatment for children with ADHD. Its mechanism of action is not understood, but may be associated with its influence on multiple neurotransmitters, especially the release and reuptake of dopamine in the striatum. There is marked individual variability in the dose-response relationship for methylphenidate, and therefore dosage must be titrated for optimal effect and avoidance of toxicity in each child. It is unclear whether this variability is predominantly pharmacokinetic or pharmacodynamic. If variable stereoselective metabolism occurs clinically, therapeutic drug monitoring of methylphenidate will require the application of chiral assay methods for the analysis of the active component, d-threo-methylphenidate. It is difficult to predict which children will have a favourable response to methylphenidate. Nonetheless, several studies have been published linking the severity of ADHD in children with improved clinical response to methylphenidate. The use of individual single-blind medication trials may be a practical solution to this problem. Additionally, the targeted condition warrants careful consideration, since different conditions (e.g. misbehaviour or poor academic performance) may require different regimens. Further studies of the relationship between the pharmacokinetic and pharmacodynamic properties of methylphenidate are required to allow the development of optimal dosage regimens. [ABSTRACT FROM AUTHOR]