ArticleLiterature Review

A review of the use of modafinil for attention-deficit hyperactivity disorder

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Abstract

Modafinil (Provigil) is a novel wakefulness-promoting agent that has been shown to have greater efficacy than placebo in the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adults. In particular, three large, drug-company sponsored trials of a film-coated formulation of modafinil (modafinil-ADHD; Sparlon) in children and adolescents with ADHD demonstrated consistent improvements in ADHD symptoms compared with placebo. Mean reductions in symptom ratings (measured using the ADHD-Rating Scale-IV school version questionnaire) ranged from 15.0 to 19.7 (7.3 to 10.1 for placebo). The most common adverse events were insomnia, headache and decreased appetite. Modafinil was generally well tolerated with most side effects considered mild to moderate in severity. Modafinil may have advantages over current therapies for ADHD in that it can be administered once daily and has fewer reinforcing properties than traditional stimulants. Modafinil could potentially be a valuable new treatment option for patients with ADHD. However, rigorous comparative studies with current first-line treatments for ADHD and longer-term independent studies are necessary before modafinil's role in the treatment of ADHD can be fully established.

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... In addition, modafinil has also been prescribed for off-label uses in a variety of conditions including neuropsychiatric disorders (Peñaloza et al. 2013). Of note, modafinil has been reported to be effective in improving attention in patients with attentional disturbance, including ADHD (Turner 2006) and schizophrenia (Turner et al. 2004) for off-label uses. The mechanism of action of modafinil is unique and complex, and is distinct from that of traditional psychostimulants such as amphetamine (Mereu et al. 2013;. ...
... These patients also demonstrated behavioral deficits in alerting when the ANT task was applied (Johnson et al. 2008;Backes et al. 2011). Although modafinil has been reported to be effective in improving attention in patients with ADHD (Turner 2006) and schizophrenia (Turner et al. 2004), the underlying mechanism has not been clarified. The present result may provide insight into the clinical availability of modafinil and the pathogenesis of attentional impairment in neuropsychiatric disorders. ...
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RationaleModafinil is a wake-promoting agent and has been reported to be effective in improving attention in patients with attentional disturbance. However, neural substrates underlying the modafinil effects on attention are not fully understood. Objectives We employed a functional magnetic resonance imaging (fMRI) study with the attention network test (ANT) task in healthy adults and examined which networks of attention are mainly affected by modafinil and which neural substrates are responsible for the drug effects. Methods We used a randomized placebo-controlled within-subjects cross-over design. Twenty-three healthy adults participated in two series of an fMRI study, taking either a placebo or modafinil. The participants performed the ANT task, which is designed to measure three distinct attentional networks, alerting, orienting, and executive control, during the fMRI scanning. The effects of modafinil on behavioral performance and regional brain activity were analyzed. ResultsWe found that modafinil enhanced alerting performance and showed greater alerting network activity in the left middle and inferior occipital gyri as compared with the placebo. The brain activations in the occipital regions were positively correlated with alerting performance. Conclusions Modafinil enhanced alerting performance and increased activation in the occipital lobe in the alerting network possibly relevant to noradrenergic activity during the ANT task. The present study may provide a rationale for the treatment of patients with distinct symptoms of impaired attention.
... The time required to stop a response in this way, the stop-signal reaction time (SSRT), is used extensively as a clinical index of inhibitory control, primarily in the study of attention deficit/hyperactivity disorder (ADHD), where impulsive subjects have slower SSRTs. Disruption of executive functions leading to impaired stopping may be the core deficit in ADHD (Barkley 1997; Turner 2006), although recently, a more integrative model of ADHD has been proposed, which includes stopping as one of several key executive function deficits within ADHD (Castellanos et al. 2006). Methylphenidate (Ritalin™) is the most commonly prescribed drug in the treatment of ADHD. ...
... erers may be due to a general improvement in vigilance and attention. However, this has yet to be supported by controlled studies in experimental animals; for example, Waters et al. (2005) found no improvement in rat performance with modafinil on the five-choice serial reaction time test, a welldocumented test of attentional control (Robbins 2002). Turner (2006) concluded that modafinil did not appear to act through a direct dopaminergic mechanism like conventional stimulants (e.g. Lin et al. 1992; Taylor and Russo 2000), although it may activate the locus coeruleus by potentiating tonic DA excitation (Szabadi 2006 ). Furthermore , the orexin/hypocretin system may be activated via this mechanis ...
Data
Rationale The stop-signal reaction time (SSRT) task mea-sures inhibition of a response that has already been initiated, i.e. the ability to stop. 'Impulsive' human subjects, e.g. with attention deficit and hyperactivity disorder (ADHD), have longer SSRTs. Both SSRT and go-trial reaction time (GoRT) may be sensitive to drugs such as d-amphetamine, methylphenidate and modafinil, both in normal subjects and those with ADHD. Objectives To investigate the effects of modafinil (3, 10, 30 and 100 mg/kg) and methylphenidate (0.3, 1.0 and 3.0 mg/kg) on SSRT task performance in the rat. To investigate the possible contribution of dopamine receptors in the action of these drugs using the mixed D1/D2 dopamine receptor antagonist cis-flupenthixol. Results Modafinil significantly decreased SSRT with little effect on GoRT but only in rats with slow baseline SSRTs. Fast SSRTs were not changed by modafinil. Methylpheni-date decreased GoRTs of all rats. However, methylpheni-date had baseline-dependent effects on SSRT, decreasing SSRT in slow responders but increasing SSRT in fast responders. Cis-flupenthixol (0.01, 0.04 and 0.125 mg/kg) had no effects on SSRT but increased GoRT at higher doses. At the lowest dose (0.01 mg/kg), cis-flupenthixol failed to disrupt the SSRT-decreasing effects of either modafinil or methylphenidate, whereas at 0.04 mg/kg, the cis-flupenthixol-dependent increase in GoRT was antago-nised by methylphenidate but not by modafinil. Conclusions This evidence supports a hypothesis that stop and go processes are under control of distinct neurochem-ical mechanisms.
... The time required to stop a response in this way, the stop-signal reaction time (SSRT), is used extensively as a clinical index of inhibitory control, primarily in the study of attention deficit/hyperactivity disorder (ADHD), where impulsive subjects have slower SSRTs. Disruption of executive functions leading to impaired stopping may be the core deficit in ADHD (Barkley 1997;Turner 2006), although recently, a more integrative model of ADHD has been proposed, which includes stopping as one of several key executive function deficits within ADHD (Castellanos et al. 2006). ...
... However, this has yet to be supported by controlled studies in experimental animals; for example, Waters et al. (2005) found no improvement in rat performance with modafinil on the five-choice serial reaction time test, a welldocumented test of attentional control (Robbins 2002). Turner (2006) concluded that modafinil did not appear to act through a direct dopaminergic mechanism like conventional stimulants (e.g. Lin et al. 1992;Taylor and Russo 2000), although it may activate the locus coeruleus by potentiating tonic DA excitation (Szabadi 2006). ...
Article
Full-text available
The stop-signal reaction time (SSRT) task measures inhibition of a response that has already been initiated, i.e. the ability to stop. 'Impulsive' human subjects, e.g. with attention deficit and hyperactivity disorder (ADHD), have longer SSRTs. Both SSRT and go-trial reaction time (GoRT) may be sensitive to drugs such as d-amphetamine, methylphenidate and modafinil, both in normal subjects and those with ADHD. To investigate the effects of modafinil (3, 10, 30 and 100 mg/kg) and methylphenidate (0.3, 1.0 and 3.0 mg/kg) on SSRT task performance in the rat. To investigate the possible contribution of dopamine receptors in the action of these drugs using the mixed D1/D2 dopamine receptor antagonist cis-flupenthixol. Modafinil significantly decreased SSRT with little effect on GoRT but only in rats with slow baseline SSRTs. Fast SSRTs were not changed by modafinil. Methylphenidate decreased GoRTs of all rats. However, methylphenidate had baseline-dependent effects on SSRT, decreasing SSRT in slow responders but increasing SSRT in fast responders. Cis-flupenthixol (0.01, 0.04 and 0.125 mg/kg) had no effects on SSRT but increased GoRT at higher doses. At the lowest dose (0.01 mg/kg), cis-flupenthixol failed to disrupt the SSRT-decreasing effects of either modafinil or methylphenidate, whereas at 0.04 mg/kg, the cis-flupenthixol-dependent increase in GoRT was antagonised by methylphenidate but not by modafinil. This evidence supports a hypothesis that stop and go processes are under control of distinct neurochemical mechanisms.
... The time required to stop a response in this way, the stop-signal reaction time (SSRT), is used extensively as a clinical index of inhibitory control, primarily in the study of attention deficit/hyperactivity disorder (ADHD), where impulsive subjects have slower SSRTs. Disruption of executive functions leading to impaired stopping may be the core deficit in ADHD (Barkley 1997; Turner 2006), although recently, a more integrative model of ADHD has been proposed, which includes stopping as one of several key executive function deficits within ADHD (Castellanos et al. 2006). Methylphenidate (Ritalin™) is the most commonly prescribed drug in the treatment of ADHD. ...
... erers may be due to a general improvement in vigilance and attention. However, this has yet to be supported by controlled studies in experimental animals; for example, Waters et al. (2005) found no improvement in rat performance with modafinil on the five-choice serial reaction time test, a welldocumented test of attentional control (Robbins 2002). Turner (2006) concluded that modafinil did not appear to act through a direct dopaminergic mechanism like conventional stimulants (e.g. Lin et al. 1992; Taylor and Russo 2000), although it may activate the locus coeruleus by potentiating tonic DA excitation (Szabadi 2006 ). Furthermore , the orexin/hypocretin system may be activated via this mechanis ...
Article
Full-text available
Rationale The stop-signal reaction time (SSRT) task mea-sures inhibition of a response that has already been initiated, i.e. the ability to stop. 'Impulsive' human subjects, e.g. with attention deficit and hyperactivity disorder (ADHD), have longer SSRTs. Both SSRT and go-trial reaction time (GoRT) may be sensitive to drugs such as d-amphetamine, methylphenidate and modafinil, both in normal subjects and those with ADHD. Objectives To investigate the effects of modafinil (3, 10, 30 and 100 mg/kg) and methylphenidate (0.3, 1.0 and 3.0 mg/kg) on SSRT task performance in the rat. To investigate the possible contribution of dopamine receptors in the action of these drugs using the mixed D1/D2 dopamine receptor antagonist cis-flupenthixol. Results Modafinil significantly decreased SSRT with little effect on GoRT but only in rats with slow baseline SSRTs. Fast SSRTs were not changed by modafinil. Methylpheni-date decreased GoRTs of all rats. However, methylpheni-date had baseline-dependent effects on SSRT, decreasing SSRT in slow responders but increasing SSRT in fast responders. Cis-flupenthixol (0.01, 0.04 and 0.125 mg/kg) had no effects on SSRT but increased GoRT at higher doses. At the lowest dose (0.01 mg/kg), cis-flupenthixol failed to disrupt the SSRT-decreasing effects of either modafinil or methylphenidate, whereas at 0.04 mg/kg, the cis-flupenthixol-dependent increase in GoRT was antago-nised by methylphenidate but not by modafinil. Conclusions This evidence supports a hypothesis that stop and go processes are under control of distinct neurochem-ical mechanisms.
... Modafinil has no effects on either the go process (GoRT) or the no-delay, action-restraint component of the stopsignal task (Eagle et al. 2007; Turner et al. 2004), unlike conventional psychostimulants which often speed GoRT and SSRT (Bedard et al. 2003; Lijffijt et al. 2006; Tannock et al. 1989). From a translational perspective, modafinil similarly improves SSRT in rats and humans (Eagle et al. 2007; Turner 2006; Turner et al. 2003 Turner et al. , 2004), effects that are directly comparable with the effects of conventional psychostimulants. Modafinil is conventionally used to treat narcolepsy and idiopathic hypersomnia by stimulating wakefulness and vigilance (Bastuji and Jouvet 1988; Billiard et al. 1994), leading to suggestions that the therapeutic benefits conferred to ADHD sufferers resulted from generally improved vigilance and attention. ...
Data
Background and rationale The term 'action inhibition' encapsulates the ability to prevent any form of planned physical response. Growing evidence suggests that different 'stages' or even subtypes of action inhibition activate subtly different neuropharmacological and neuroanatomical processes. Objectives In this review, we present evidence from two commonly used and apparently similar behavioural tests, the stop-signal task and the go/no-go task, to determine if these have similar neuroanatomical and neurochemical modulation. Results Whilst performance of the stop-signal and go/no-go tasks is modulated across only subtly different anatomical networks, serotonin (5-HT) is strongly implicated in inhibitory control on the go/no-go but not the stop-signal task, whereas the stop-signal reaction time appears more sensitive to the action of noradrenaline. Conclusions There is clear neuropharmacological and neuroanatomical evidence that stop-signal and go/no-go tasks represent different forms of action inhibition. This evidence translates with remarkable consistency across species. We discuss the possible implications of this evidence with respect to the development of novel therapeutic treatments for disorders in which inhibitory deficits are prominent and debilitating.
... Modafinil has no effects on either the go process (GoRT) or the no-delay, action-restraint component of the stopsignal task (Eagle et al. 2007;Turner et al. 2004), unlike conventional psychostimulants which often speed GoRT and SSRT (Bedard et al. 2003;Lijffijt et al. 2006;Tannock et al. 1989). From a translational perspective, modafinil similarly improves SSRT in rats and humans (Eagle et al. 2007;Turner 2006;Turner et al. 2003Turner et al. , 2004, effects that are directly comparable with the effects of conventional psychostimulants. ...
Article
The term 'action inhibition' encapsulates the ability to prevent any form of planned physical response. Growing evidence suggests that different 'stages' or even subtypes of action inhibition activate subtly different neuropharmacological and neuroanatomical processes. In this review, we present evidence from two commonly used and apparently similar behavioural tests, the stop-signal task and the go/no-go task, to determine if these have similar neuroanatomical and neurochemical modulation. Whilst performance of the stop-signal and go/no-go tasks is modulated across only subtly different anatomical networks, serotonin (5-HT) is strongly implicated in inhibitory control on the go/no-go but not the stop-signal task, whereas the stop-signal reaction time appears more sensitive to the action of noradrenaline. There is clear neuropharmacological and neuroanatomical evidence that stop-signal and go/no-go tasks represent different forms of action inhibition. This evidence translates with remarkable consistency across species. We discuss the possible implications of this evidence with respect to the development of novel therapeutic treatments for disorders in which inhibitory deficits are prominent and debilitating.
... Further, amphetamines, which have clinical utility in ADHD, are good ligands at trace amine receptors [2]. Of possible relevance in this aspect is modafanil, which has shown beneficial effects in ADHD patients [101] and has been reported to enhance the activity of PE at TAAR1 [102]. Conversely, methylphenidate, which is also clinically useful in ADHD, showed poor efficacy at the TAAR1 receptor [2]. ...
Article
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Mining of the human genome has revealed approximately 7000 novel proteins, which could serve as potential targets for the development of novel therapeutics. Of these, approximately 2000 are predicted to be G-protein coupled receptors. Within this group of proteins, a family of 18 mammalian receptors has recently been identified that appear to exhibit selectivity toward the so-called trace amines. The trace amines are a family of endogenous compounds with strong structural similarity to classical monoamine neurotransmitters, consisting primarily of 2-phenylethylamine, m- and p-tyramine, tryptamine, m- and p-octopamine and the synephrines. The endogenous levels of these compounds are at least two orders of magnitude below those of neurotransmitters such as dopamine, noradrenaline and 5-HT. The effects of these low physiological concentrations have been difficult to demonstrate but it has been suggested that they may serve to maintain the neuronal activity of monoamine neurotransmitters within defined physiological limits. Such an effect of trace amines would make them ideal candidates for the development of novel therapeutics for a wide range of human disorders. Although the demonstration of a trace amine family of receptors has seen a resurgence of interest in these endogenous compounds, with recent articles reviewing trace amine pharmacological and physiological responses, the potential clinical utility of the trace amine receptors has not been specifically addressed. Historically, trace amines have been implicated in a diverse array of human pathologies ranging from schizophrenia to affective disorders to migraine. Recent studies have strengthened some of this historical data by linking trace amine receptor polymorphisms and mutations to distinct clinical conditions. The aim of the current article is to review the previous studies linking trace amines to human pathology in the context of the recently discovered trace amine receptors and evidence of the existence of trace amine receptor polymorphisms and mutations associated with such disorders. In addition, recent evidence linking trace amines to the development of drug dependence will be discussed.
... Of note, this change of formulation should protect the new indication from generic competition [49]. While its mechanism of action is not fully understood, modafinil is classified as nonstimulant555657. Similar to atomoxetine [58], a selective norepinephrine reuptake inhibitor, improvement of core symptoms had an effect size on core symptoms (school version of ADHD-RS) of 0.69 [59] to 0.76 [60]. ...
Article
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During the last decade, pharmaceutical spending for patients with attention-deficit-hyperactivity disorder (ADHD) has been escalating internationally. First, to estimate future trends of ADHD-related drug expenditures from the perspectives of the statutory health insurance (SHI; Gesetzliche Krankenversicherung, GKV) in Germany and the National Health Service (NHS) in England, respectively, for children and adolescents age 6 to 18 years. Second, to evaluate the budgetary impact on individual prescribers (child and adolescent psychiatrists and pediatricians treating patients with ADHD) in Germany. A model was developed to predict plausible scenarios of future pharmaceutical expenditures for treatment of ADHD. Model inputs were derived from demographic and epidemiological data, a literature review of past spending trends, and an analysis of new pharmaceutical products in development for ADHD. Only products in clinical development phase III or later were considered. Uncertainty was addressed by way of scenario analysis. For each jurisdiction, five scenarios used different assumptions of future diagnosis prevalence, treatment prevalence, rates of adoption and unit costs of novel drugs, and treatment intensity. Annual ADHD pharmacotherapy expenditures for children and adolescents will further increase and may exceed euro 310 m (D; E: 78 m) in 2012 (2002: approximately euro 21.8 m; approximately 7.0 m). During this period, overall drug spending by individual physicians may increase 2.3- to 9.5-fold, resulting from the multiplicative effects of four variables: increased number of diagnosed cases, growing acceptance and intensity of pharmacotherapy, and higher unit costs of novel medications. Even for an extreme low case scenario, a more than six-fold increase of pharmaceutical spending for children and adolescents is predicted over the decade from 2002 to 2012, from the perspectives of both the NHS in England and the GKV in Germany. This budgetary impact projection represents a partial analysis only because other expenditures are likely to rise as well, for instance those associated with physician services, including diagnosis and psychosocial treatment. Further to this, by definition budgetary impact analyses have little to nothing to say about clinical appropriateness and about value of money. Providers of care for children and adolescents with ADHD should anticipate serious challenges related to the cost-effectiveness of interventions.
... In such instances or when families are unwilling to consider a stimulant, non-stimulant medications can be appealing (Mohammadi and Akhondzadeh, 2007). It has been reported that modafinil causes fewer adverse effects and less dependency potential than methylphenidate and the amphetamines (Ballon and Feifel, 2006; Turner, 2006). In this double blind, randomized, controlled study of children with ADHD, the authors detected a statistically significant effect of modafinil and methylphenidate on ADHD. ...
Article
Attention-Deficit/Hyperactivity Disorder (ADHD) is the most prevalent psychiatric disorder currently afflicting children and is among the most common chronic conditions affecting school-age children. Modafinil is structurally different from the psychostimulants that are typically used to treat ADHD and has been reported to be effective in improving the symptoms of ADHD. The aim of the present study was to further evaluate, under double blind and controlled conditions, the efficacy of modafinil for ADHD in children and adolescents as compared to methylphenidate. Patients included 60 outpatients, children (47 boys and 13 girls) between the ages of 6-15 who clearly met the DSM-IV-TR diagnostic criteria for ADHD. Subjects were recruited from an outpatient child and adolescent clinic for a 6 week double blind, randomized clinical trial. All study subjects were randomly assigned to receive either treatment with modafinil film coated tablet (in doses of 200-300 mg/day) depending on weight (200 mg/day for <30 kg and 300 mg/day for >30 kg) (group 1) or methylphenidate (in doses of 20-30 mg/day) depending on weight (20 mg/day for <30 kg and 30 mg/day for >30 kg) (group 2). The principal measure of outcome was the Teacher and Parent ADHD Rating Scale-IV. Patients were assessed at baseline and at 21 and 42 days after the medication started. No significant differences were observed between the two groups on the Parent and Teacher Rating Scale scores. Side effects of decreased appetite and difficulty falling asleep were observed more in the methylphenidate group. The results of this study indicate that modafinil significantly improved symptoms of ADHD and was well tolerated and it is beneficial in the treatment of children with ADHD.
... Most common side effects are insomnia, headache and decreased appetite. Modafi nil can be administered once daily (Turner 2006). Modafi nil fi lm-coated tablets present a new formulation that is administered once daily. ...
Article
This review focuses on the treatment of attention deficit hyperactivity disorder (ADHD) in adults. It briefly addresses prevalence, diagnostic and differential diagnostic issues specific to adults. Stimulant medication, non-stimulant medication, and psychosocial treatments are thoroughly reviewed. For each class of medication possible mechanism of action, efficacy and side effects are summarized. Special attention is given to the pharmacological treatment for patients with adult ADHD and various comorbidities. In summary, stimulant medications are most effective and combined medication and psychosocial treatment is the most beneficial treatment option for most adult patients with ADHD.
... In such instances or when families are unwilling to consider a stimulant, non-stimulant medications can be appealing (Mohammadi and Akhondzadeh, 2007). It has been reported that modafinil causes fewer adverse effects and less dependency potential than methylphenidate and the amphetamines (Ballon and Feifel, 2006;Turner, 2006). ...
Article
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Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood, with an estimated prevalence worldwide of 7%-17% among school-aged children. Modafinil is a centrally acting agent that is structurally and pharmacologically different from stimulants such as amphetamine and methylphenidate. It has been reported that modafinil is effective in diminishing the symptoms of ADHD. The aim of the present study was to further evaluate, under double-blind and placebo-controlled conditions, the efficacy of modafinil for ADHD in children and adolescents. Patients were 46 outpatients, children (35 boys and 11 girls) between the ages of 6 and 15 who clearly met the DSM-IV-TR diagnostic criteria for ADHD. All study subjects were randomly assigned to receive treatment with modafinil in a film-coated tablet, 200-300 mg/day, depending on weight (200 mg/day for <30 kg and 300 mg/day for >30 kg) (group 1) or placebo (group 2) for a 6-week double-blind, randomized clinical trial. The principal outcome measure was the Teacher and Parent ADHD Rating Scale-IV. Patients were assessed by a psychiatrist at baseline, 14, 28 and 42 days after the medication started. At 6 weeks, modafinil produced a significantly better outcome on the Parent and Teacher Rating Scale scores than placebo. Decreased appetite was observed more often in the modafinil group. The results of this study indicate that modafinil significantly improved symptoms of ADHD, was well tolerated, and may open a new window in the treatment of children with ADHD.
... However, the demonstrable pro-cognitive properties and high-tolerability of modafinil make it a promising candidate for the treatment of cognitive dysfunction associated with a range of neuropsychiatric disorders. Indeed, modafinil has recently demonstrated efficacy in the treatment of attentiondeficit hyperactivity disorder (ADHD), a condition often characterized by impairments in 'executive functions', which include planning, working memory and inhibitory control (Chamberlain, et al., 2007;Taylor and Russo, 2000;Turner, 2006). ...
Article
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Previous research has demonstrated cognitive-enhancing effects of modafinil in humans and generated evidence for its therapeutic potential in psychiatric disorders. The neurochemical basis of these effects remains unresolved although a role for α1-adrenoceptors has been hypothesised. In this within-subject, double-blind, placebo-controlled study, 12 healthy male adults received modafinil (300 mg), the α1-adrenoceptor antagonist prazosin (3 mg), both together and placebo on separate occasions at least 5 days apart. Cognitive effects were assessed using a well-validated testing battery focusing on executive and working memory functions. Blood pressure, heart rate and salivary α-amylase (sAA) were measured at hourly intervals. Cognitive effects of modafinil and prazosin were identified at the difficult levels of the One-Touch Stockings of Cambridge (OTSOC) planning task. Prazosin antagonized the error-reducing effect of modafinil when the agents were given together. In contrast, the combined agents acted synergistically to increase time taken to complete OTSOC problems compared with placebo. The tachycardic and sAA-elevating effects of prazosin were also potentiated by concurrent modafinil administration. The current data suggest that the cognitive effects of modafinil on performance accuracy and latency are dissociable in terms of their neurochemical mechanisms. Our findings support the hypothesised involvement of α1-adrenoceptors in some of the cognitive-enhancing effects of modafinil and warrant further investigation.
... Stimulants (methylphenidate and dexamphetamine) are first choice medication treatments for ADHD in children and adults, based on an extensive and still growing body of data concerning efficacy and safety [32,260]. Atomoxetine is usually considered the second line treatment, followed by other non-stimulants like bupropion, guanfacine, modafinil and tricyclic antidepressents, based on efficacy outcomes in controlled studies in different age groups [239,[261][262][263][264]. ...
Article
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Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe. The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated. Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated? ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group.
... An additional hypothesis is that modafinil can act as a hypocretin/orexin agonist with excitatory influences on locus coeruleus adrenergic system ( Morein-Zamir et al. 2007). Given that modafinil had good efficacy as a cognitive enhancer in sleepdeprived and even healthy individuals, as well as positive evidence for cognitive enhancement with modafinil in a number of psychiatric disorders (Turner 2006; Turner et al. 2003 Turner et al. , 2004a), a number studies have examined its effects on cognitive and brain function in schizophrenia (seeTable 8). Early studies using a single-dose design provided evidence for improvement in either cognition (Turner et al. 2004b) or brain function (Hunter et al. 2006; Spence et al. 2005) and a 4-week open-label study also showed evidence for some cognitive improvement among individuals with schizophrenia (Rosenthal and Bryant 2004). ...
Article
Researchers have long recognized that individuals with schizophrenia experience challenges in a wide range of cognitive domains, and research on cognitive impairment in schizophrenia is not a recent phenomena. However, the past 10-20 years have seen an increasing recognition of the central importance of cognition to understanding function and outcome in this illness (Green et al. in Schizophr Bull 26:119-136, 2000), an awareness that has shifted the emphasis of at least some work on schizophrenia. More specifically, there has been a rapidly growing body of work on methods of enhancing cognition in schizophrenia, as a means to potentially facilitate improved outcome and quality of life for individuals with this debilitating illness. The current chapter reviews the results of a range of studies examining adjunctive pharmacological treatments to enhance cognition in schizophrenia using a range of designs, including single-dose studies, open-label repeated dosing studies, and double-blind parallel group and crossover designs with repeated dosing. Although many of the single-dose and open-label studies have suggested positive cognitive effects from a range of agents, few of the larger-scale double-blind studies have generated positive results. The current state of results may reflect the need to identify alternative molecular mechanisms for enhancing cognition in schizophrenia or the need to reconceptualize the ways in which pharmacological agents may improve cognition in this illness, with a concomitant change in the traditional clinical trial study design used in prior studies of cognitive enhancement in schizophrenia.
... Modafinil (Provigil, 1997) is a wake promoting agent of largely unknown mechanism with demonstrable efficacy in the treatment of daytime sleepiness associated with narcolepsy (Benerjee et al., 2004) and shift-work (Czeisler et al., 2005). Modafinil has been shown to significantly improve performance on tests of executive cognition such as working memory, cognitive flexibility and planning in non sleep-deprived healthy volunteers (Turner et al., 2003; Müller et al., 2004; Finke et al., 2010; Repantis et al., 2010; Mohamed and Sahakian, 2012) and in patients with neuropsychiatric disorders (Turner et al., 2004; Turner, 2006;). These pro-cognitive effects of modafinil are of possible therapeutic importance given its low liability for abuse (Deroche-Gamonet et al., 2002), lower risk of adverse effects on the cardiovascular system (Makris et al., 2004; Lynch et al., 2009) and lack of anxiogenic effects that may occur with typical stimulant drugs such as dexamphetamine (Simon et al., 1994). ...
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Modafinil, a putative cognitive enhancing drug, has previously been shown to improve performance of healthy volunteers as well as patients with attention deficit disorder and schizophrenia, mainly in tests of executive functions. The aim of this study was to investigate the effects of modafinil on non-verbal cognitive functions in healthy volunteers, with a particular focus on variations of cognitive load, measures of motivational factors and the effects on creative problem-solving. A double-blind placebo-controlled parallel design study evaluated the effect of 200 mg of modafinil (N = 32) or placebo (N = 32) in non-sleep deprived healthy volunteers. Non-verbal tests of divergent and convergent thinking were used to measure creativity. A new measure of task motivation was used, together with more levels of difficulty on neuropsychological tests from the CANTAB battery. Improvements under modafinil were seen on spatial working memory, planning and decision making at the most difficult levels, as well as visual pattern recognition memory following delay. Subjective ratings of enjoyment of task performance were significantly greater under modafinil compared with placebo, but mood ratings overall were not affected. The effects of modafinil on creativity were inconsistent and did not reach statistical significance. Modafinil reliably enhanced task enjoyment and performance on several cognitive tests of planning and working memory, but did not improve paired associates learning. The findings confirm that modafinil can enhance aspects of highly demanding cognitive performance in non-sleep deprived individuals. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
... In humans a baseline dependent action of modafinil on impulsivity was also observed in pathological gamblers 35 : increase in patients with low impulsivity and decrease in patients with high impulsivity. The symptom improvement by modafinil in ADHD children 5,36 , who have high baseline impulsivity, also fits this profile, however, modafinil decreased impulsivity in healthy volunteers 1 , sleep-deprived doctors 4 , and first episode schizophrenics 27 as well. As far as CE-123 is concerned, further, more specific experiments are needed to fully characterize its effect on impulsivity but based on the results obtained so far, we predict actions in humans similar to those of modafinil. ...
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The lack of novel cognitive enhancer drugs in the clinic highlights the prediction problems of animal assays. The objective of the current study was to test a putative cognitive enhancer in a rodent cognitive test system with improved translational validity and clinical predictivity. Cognitive profiling was complemented with post mortem proteomic analysis. Twenty-seven male Lister Hooded rats (26 months old) having learned several cognitive tasks were subchronically treated with S-CE-123 (CE-123) in a randomized blind experiment. Rats were sacrificed after the last behavioural procedure and plasma and brains were collected. A label-free quantification approach was used to characterize proteomic changes in the synaptosomal fraction of the prefrontal cortex. CE-123 markedly enhanced motivation which resulted in superior performance in a new-to-learn operant discrimination task and in a cooperation assay of social cognition, and mildly increased impulsivity. The compound did not affect attention, spatial and motor learning. Proteomic quantification revealed 182 protein groups significantly different between treatment groups containing several proteins associated with aging and neurodegeneration. Bioinformatic analysis showed the most relevant clusters delineating synaptic vesicle recycling, synapse organisation and antioxidant activity. The cognitive profile of CE-123 mapped by the test system resembles that of modafinil in the clinic showing the translational validity of the test system. The findings of modulated synaptic systems are paralleling behavioral results and are in line with previous evidence for the role of altered synaptosomal protein groups in mechanisms of cognitive function.
... An example of prenatal stress in children is attention deficit hyperactivity disorder (ADHD) [73]. Although results are mixed [74,75], ADHD patients are commonly treated with the DAT inhibitor, methylphenidate [76], although other DAT inhibitors, such as modafinil [77], were also clinically tested in ADHD. ...
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Maternal separation (MS) is a key contributor to neurodevelopmental disorders, including learning disabilities. To test the hypothesis that dopamine signaling is a major factor in this, an atypical new dopamine transporter (DAT) inhibitor, CE-123, was assessed for its potential to counteract the MS-induced spatial learning and memory deficit in male and female rats. Hence, neonatal rats (postnatal day (PND)1 to 21) were exposed to MS (180 min/day). Next, the acquisition of spatial learning and memory (Barnes maze task) and the expression of dopamine D1 receptor, dopamine transporter (DAT), and the neuronal GTPase, RIT2, which binds DAT in the vehicle-treated rats were evaluated in the prefrontal cortex and hippocampus in the adolescent animals. The results show that MS impairs the acquisition of spatial learning and memory in rats, with a more severe effect in females. Moreover, the MS induced upregulation of DAT and dopamine D1 receptors expression in the prefrontal cortex and hippocampus in adolescent rats. Regarding RIT2, the expression was decreased in the hippocampus for both the males and females, however, in the prefrontal cortex, reduction was found only in the females, suggesting that there are region-specific differences in DAT endocytic trafficking. CE-123 ameliorated the behavioral deficits associated with MS. Furthermore, it decreased the MS-induced upregulation of D1 receptor expression level in the hippocampus. These effects were more noted in females. Overall, CE-123, an atypical DAT inhibitor, is able to restore cognitive impairment and dopamine signaling in adolescent rats exposed to MS—with more evident effect in females than males.
... Modafinil has no effects on either the go process (GoRT) or the no-delay, action-restraint component of the stopsignal task ( Eagle et al. 2007;Turner et al. 2004), unlike conventional psychostimulants which often speed GoRT and SSRT ( Bedard et al. 2003;Lijffijt et al. 2006;Tannock et al. 1989). From a translational perspective, modafinil similarly improves SSRT in rats and humans (Eagle et al. 2007;Turner 2006;Turner et al. 2003Turner et al. , 2004), effects that are directly comparable with the effects of conventional psychostimulants. ...
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Background and rationale The term 'action inhibition' encapsulates the ability to prevent any form of planned physical response. Growing evidence suggests that different 'stages' or even subtypes of action inhibition activate subtly different neuropharmacological and neuroanatomical processes. Objectives In this review, we present evidence from two commonly used and apparently similar behavioural tests, the stop-signal task and the go/no-go task, to determine if these have similar neuroanatomical and neurochemical modulation. Results Whilst performance of the stop-signal and go/no-go tasks is modulated across only subtly different anatomical networks, serotonin (5-HT) is strongly implicated in inhibitory control on the go/no-go but not the stop-signal task, whereas the stop-signal reaction time appears more sensitive to the action of noradrenaline. Conclusions There is clear neuropharmacological and neuroanatomical evidence that stop-signal and go/no-go tasks represent different forms of action inhibition. This evidence translates with remarkable consistency across species. We discuss the possible implications of this evidence with respect to the development of novel therapeutic treatments for disorders in which inhibitory deficits are prominent and debilitating.
... Most common side effects are insomnia, headache and decreased appetite. Modafi nil can be administered once daily (Turner 2006). Modafi nil fi lm-coated tablets present a new formulation that is administered once daily. ...
Article
This review focuses on the treatment of attention deficit hyperactivity disorder (ADHD) in adults. It briefly addresses prevalence, diagnostic and differential diagnostic issues specific to adults. Stimulant medication, non-stimulant medication, and psychosocial treatments are thoroughly reviewed. For each class of medication possible mechanism of action, efficacy and side effects are summarized. Special attention is given to the pharmacological treatment for patients with adult ADHD and various comorbidities. In summary, stimulant medications are most effective and combined medication and psychosocial treatment is the most beneficial treatment option for most adult patients with ADHD.
... It improves memory [31], executive function [32], and increases alertness and response accuracy in healthy subjects [25]. Importantly, the cognitive enhancer effect of modafinil has also been reported in a number of different neurological conditions including schizophrenia [33,34] and attention deficit hyperactivity disorder [35]. Modafinil has also been shown to be effective when given as an adjunct to standard treatment for treating mood disorders [36,37]. ...
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Huntington’s disease (HD) is characterised by progressive symptoms including cognitive deficits and sleep/wake disturbances reflected in an abnormal electroencephalography (EEG). Modafinil, a wake-promoting and cognitive-enhancing drug, has been considered as a treatment for HD. We used HD (R6/2) mice to investigate the potential for using modafinil to treat sleep-wake disturbance in HD. R6/2 mice show sleep-wake and EEG changes similar to those seen in HD patients, with increased rapid eye movement sleep (REMS), decreased wakefulness/increased non-REMS (NREMS), and pathological changes in EEG spectra, particularly an increase in gamma power. We recorded EEG from R6/2 and wild-type mice treated with modafinil acutely (with single doses between 25 and 100 mg/kg; at 12 and 16 weeks of age), or chronically (64 mg/kg modafinil/day from 6 to 15 weeks). Acutely, modafinil increased wakefulness in R6/2 mice and restored NREMS to wild-type levels at 12 weeks. It also suppressed the pathologically increased REMS. This was accompanied by decreased delta power, increased peak frequency of theta, and increased gamma power. At 16 weeks, acute modafinil also restored wakefulness and NREMS to wild-type levels. However, whilst REMS decreased, it did not return to normal levels. By contrast, in the chronic treatment group, modafinil-induced wakefulness was maintained at 15 weeks (after 9 weeks of treatment). Interestingly, chronic modafinil also caused widespread suppression of power across the EEG spectra, including a reduction in gamma that increases pathologically in R6/2 mice. The complex EEG effects of modafinil in R6/2 mice should provide a baseline for further studies to investigate the translatability of these result to clinical practice.
... In such instances or when families are unwilling to consider a stimulant, non-stimulant medications can be appealing (Mohammadi and Akhondzadeh, 2007). It has been reported that modafinil causes fewer adverse effects and has less dependency potential than methylphenidate and the amphetamines (Ballon and Feifel, 2006;Turner, 2006). ...
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Objective: Recent studies have focused on the role of inflammatory cascades as one of the possible etiologic factors of bipolar disorder. We hypothesize that celecoxib, through its anti-inflammatory properties, may have a therapeutic role in acute bipolar mania. Patients and methods: Forty-two adolescent inpatients with the diagnosis of acute bipolar mania participated in a parallel, randomized, double-blind controlled trial, and 40 patients underwent an 8-week treatment with either celecoxib (100 mg twice daily) or placebo as an adjunctive treatment to lithium and risperidone. Patients were evaluated using Young Mania Rating Scale (YMRS) at baseline and weeks 2, 4, and 8. The primary outcome measure was to assess the efficacy of celecoxib compared with placebo in improving mania symptoms. Result: General linear model repeated measures showed significant effect for time × treatment interaction on YMRS scores [F (2.54, 96.56) = 3.21, p = 0.03]. Significantly greater improvement was observed in YMRS scores in the celecoxib group compared with the placebo group from baseline YMRS score at week 8 (p = 0.04). Although a 35% greater response to treatment (considering a Clinical Global Impressions-Improvement score of ≤2, very much/much improved) was observed in the celecoxib group compared with the placebo group, the difference did not reach the statistical significance level (p = 0.09). No serious adverse event was reported. Conclusions: Celecoxib may be an effective adjuvant therapy in treatment of manic episodes (without psychotic features) of adolescents with bipolar mood disorder. The mood-stabilizing role of this drug might be mediated through its action on inflammatory cascades.
... 116 Amphetamines, which are good ligands at TAAR, also possess clinical utility for the treatment of ADHD. 23 The wake-promoting drug, modafanil, which is beneficial in ADHD patients, 117 has been reported to enhance the activity of PEA at TAAR1. 118 Several studies have reported decreased urinary PEA levels in ADHD patients in comparison with controls. ...
Chapter
Trace amines (TAs) are biogenic amines located in mammalian brains and peripheral nervous tissues in low concentrations. Examples of TAs include phenylethylamine, tyramine, tryptamine, and octopamine, all of which are closely related to dopamine, norepinephrine, and serotonin neurotransmitter systems metabolically. Understanding the role of TAs in the progression of neuropsychiatric disorders is important for elucidating the pathway(s) and mechanism(s) leading up to the management of such disorders. Recently, TAs have been implicated in various neuropsychiatric disorders such as, depression, schizophrenia, attention deficit hyperactivity disorder, Parkinson disease, Alzheimer disease, Reye syndrome, Tourette syndrome, epilepsy, and migraines. The neuropsychiatric disorders and the associated psychotropic drugs, coupled with the possibility of the elucidation of the newer pathways have been explored in this chapter along with highlighting the recent advances in the area of TAs chemistry and synaptic physiology and their interrelationships.
... For example, modafinil, an atypical DAT inhibitor, is suggested to have relatively little potential for abuse because it interacts with DAT in a different manner compared with drugs such as MPD (i.e., modafinil stabilizes the closed conformation; see Schmitt and Reith, 2011). Furthermore, modafinil has been demonstrated to be clinically effective and a viable alternative compared with traditional stimulant medication (e.g., Adderall; Shire, Lexington, MA) for the treatment of ADHD (Taylor and Russo, 2000;Turner, 2006). These studies highlight the notion that understanding atypical ligands and their interactions with DAT might lead to improved medications for other disorders linked to perturbations in dopaminergic systems, such as substance abuse (Tanda et al., 2009b;Loland et al., 2012). ...
Article
Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders.
... Only a limited number of studies have directly assessed modafinilrelated effects on food intake, although several investigators have documented decreased appetite as a common side effect of the medication (e.g., Turner, 2006;Wigal et al., 2006). Nicolaidis and De Saint Hilaire (1993) examined feeding behavior of rats following modafinil treatment and found that the drug produced a U-shaped dose-response curve: feeding was decreased by the 20 and 40 mg/kg doses but was unaffected by the 10 and 80 mg/kg doses. ...
Article
In a limited number of studies modafinil has been shown to decrease food intake by laboratory animals and humans. The present study represents a secondary data analysis, in which the effects of modafinil on several measures of food intake were determined in humans living in a residential laboratory during simulated shift work. During this 23-day study, a wide selection of food items and beverages were freely available. During this double-blind, within-participant study, volunteers (N = 11) received oral modafinil dose (0, 200, or 400 mg) 1 h after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an "off" day. Modafinil (200, 400 mg) dose-dependently decreased total caloric intake by approximately 18% and approximately 38%, respectively, regardless of shift condition, without selectively altering the proportion of total calories derived from carbohydrate, fat and protein. Ratings of "Hungry" were also significantly decreased by both active doses, but only immediately before the lunch break period. In addition, tolerance to the anorexic effects of modafinil was not apparent, as these effects remained stable across the three days of modafinil dosing. These findings show that modafinil produced clear reductions in food intake and suggest that future prospective studies should examine the drug in obese participants.
... Most common side effects are insomnia, headache and decreased appetite. Modafi nil can be administered once daily (Turner 2006). Modafi nil fi lm-coated tablets present a new formulation that is administered once daily. ...
... The authors conclude that these results support MOD as a reasonable alternative to the more addictive psychostimulants for the treatment of ADHD. Several other reports and meta-analyses show mostly positive effects and efficacy of MOD as a treatment for ADHD (Faraone and Glatt 2010;Lindsay et al. 2006;Mann and Bitsios 2009;Turner 2006; but see Wilens et al. 2011), thus making it a potentially safer candidate for this therapeutic application. ...
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Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off-label, as cognitive enhancers in populations of patients with mental disorders, including substance abusers that demonstrate impaired cognitive function. A debated nonmedical use of MOD in healthy individuals to improve intellectual performance is raising questions about its potential abuse liability in this population. MOD has low micromolar affinity for the dopamine transporter (DAT). Inhibition of dopamine (DA) reuptake via the DAT explains the enhancement of DA levels in several brain areas, an effect shared with psychostimulants like cocaine, methylphenidate, and the amphetamines. However, its neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory. At variance with typical psychostimulants, MOD shows very low, if any, abuse liability, in spite of its use as a cognitive enhancer by otherwise healthy individuals. Finally, recent clinical studies have focused on the potential use of MOD as a medication for treatment of drug abuse, but have not shown consistent outcomes. However, positive trends in several result measures suggest that medications that improve cognitive function, like MOD or R-MOD, may be beneficial for the treatment of substance use disorders in certain patient populations.
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Noradrenergic (NE) neurotransmission and particularly α-adrenergic receptor function has been identified as a critical component of the sleep/wake regulation in animals and humans. This work (i) provides an update on the impact of NE neurotransmission on the sleep/wake regulation, (ii) summarizes the effects of α-receptor agonists and antagonists on arousal and sleep in animals and healthy humans, and (iii) reviews the current body of evidence for the effectiveness and safety of these compounds in the treatment of clinical conditions characterized by alterations of arousal or sleep, including attention deficit and hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), borderline personality disorder and primary sleep disorders. This systematic evaluation of the potential and limitations of the effects of α-adrenergic compounds might promote novel inroads for the treatment of these highly prevalent clinical conditions.
Article
To evaluate sleep macrostructure, sleep disorders incidence and daytime sleepiness in attention-deficit/hyperactivity disorder (ADHD) affected children compared with controls. Thirty-one patients (26 boys, 5 girls, mean age 9.3±1.7, age range 6-12 years) with ADHD diagnosed according to DSM-IV criteria, without comorbid psychiatric or other disorders, as never before pharmacologically treated for ADHD. The controls were 26 age- and sex-matched children (22 boys, 4 girls, age range 6-12 years, mean age 9.2±1.5). Nocturnal polysomnography (PSG) was performed for two nights followed by the multiple sleep latency test (MSLT). No differences between the two groups comparing both nights were found in the basic sleep macrostructure parameters or in the time (duration) of sleep onset. A first-night effect on sleep variables was apparent in the ADHD group. Occurrence of sleep disorders (sleep-disordered breathing [SDB], periodic limb movements in sleep [PLMS], parasomnias) did not show any significant differences between the investigated groups. A statistically significant difference (p=0.015) was found in the trend of the periodic limb movement index (PLMI) between two nights (a decrease of PLMI in the ADHD group and an increase of PLMI in the control group during the second night). While the mean sleep latency in the MSLT was comparable in both groups, children with ADHD showed significant (sleep latency) inter-test differences (between tests 1 and 2, 1 and 4, 1 and 5, p<0.01). After the inclusion of adaptation night and exclusion of psychiatric comorbidities, PSG showed no changes in basic sleep parameters or sleep timing, or in the frequency of sleep disorders (SDB, PLMS) in children with ADHD compared with controls, thus not supporting the hypothesis that specific changes in the sleep macrostructure and sleep disturbances are connected with ADHD. A first-night effect on sleep variables was apparent only in the ADHD group. Though we found no proof of increased daytime sleepiness in children with ADHD against the controls, we did find significant vigilance variability during MSLT in the ADHD group, possibly a sign of dysregulated arousal.
Article
Objective: Enhanced reactivity to substance related cues is a central characteristic of addiction and has been associated with increased activity in motivation, attention, and memory related brain circuits and with a higher probability of relapse. Modafinil was promising in the first clinical trials in cocaine dependence, and was able to reduce craving in addictive disorders. However, its mechanism of action remains to be elucidated. In this functional magnetic resonance imaging (fMRI) study therefore, cue reactivity in cocaine dependent patients was compared to cue reactivity in healthy controls (HCs) under modafinil and placebo conditions. Methods: An fMRI cue reactivity study, with a double-blind, placebo-controlled cross-over challenge with a single dose of modafinil (200mg) was employed in 13 treatment seeking cocaine dependent patients and 16 HCs. Results: In the placebo condition, watching cocaine-related pictures (versus neutral pictures) resulted in higher brain activation in the medial frontal cortex, anterior cingulate cortex, angular gyrus, left orbitofrontal cortex, and ventral tegmental area (VTA) in the cocaine dependent group compared to HCs. However, in the modafinil condition, no differences in brain activation patterns were found between cocaine dependent patients and HCs. Group interactions revealed decreased activity in the VTA and increased activity in the right ACC and putamen in the modafinil condition relative to the placebo condition in cocaine dependent patients, whereas such changes were not present in healthy controls. Decreases in self-reported craving when watching cocaine-related cues after modafinil administration compared to the placebo condition were associated with modafinil-induced increases in ACC and putamen activation. Conclusions: Enhanced cue reactivity in the cocaine dependent group compared to healthy controls was found in brain circuitries related to reward, motivation, and autobiographical memory processes. In cocaine dependent patients, these enhanced brain responses were attenuated by modafinil, mainly due to decreases in cue- reactivity in reward-related brain areas (VTA) and increases in cue reactivity in cognitive control areas (ACC). These modafinil-induced changes in brain activation in response to cocaine-related visual stimuli were associated with diminished self-reported craving. These findings imply that in cocaine dependent patients, modafinil, although mainly known as a cognitive enhancer, acts on both the motivational and the cognitive brain circuitry.
Article
Attention-deficit hyperactivity disorder (ADHD) in adults is a common disorder which results in a lot of secondary problems. Pharmacological treatment is essential in the management of ADHD. Stimulant treatment has for decades been proven to be effective and safe. Amphetamine was the first drug for this indication; most studies have been carried out with methylphenidate, which has been shown to be very effective and well tolerated. Newer extended-release methylphenidate preparations have considerable advantages. Because of hepatic side effects, pemoline no longer plays a role. Modafinil seems to have comparable effects like amphetamine. Atomoxetine is a potent norepinephrine-specific reuptake inhibitor which is approved for the treatment of ADHD in children, adolescents and adults. Tricyclic antidepressants may be third-line agents. Bupropion targets both ADHD and depressive symptoms which are frequent comorbid conditions. Clonidine and guanfacine have positive effects in patients with ADHD and comorbid tics. Several other compounds may be beneficial in ADHD treatment.Copyright © 2010 S. Karger AG, Basel
Chapter
This chapter guides the reader through the first part of the treatment of ADHD in adults. Treatment always starts with psychoeducation, and the special attitude of the therapist treating patients with ADHD is first discussed. Frequent asked questions and answers about ADHD and the treatment are addressed, as well as different forms of psychoeducation to patients and to the public, and at different phases of the treatment. Psychoeducation is regarded as a continuous process to empower patients to make their own well-informed decisions during treatment. The part on medication treatment gives an overview of the available medications for ADHD. The effect of medication on the brain and on addiction is discussed. The order of treatment in case of comorbidity, how to deal with alcohol and cannabis use while on medication, contraindications, the physical exam before starting, measures to evaluate efficacy, dosing, and duration of action of different short- and long-acting stimulant preparations are all reviewed, as well as how to deal with pregnancy and driving issues while using medication for ADHD. The combination of stimulants with other psychopharmacotherapeutical treatments and finally treatment with melatonin for the delayed sleep phase in ADHD are described in a practical way for everyday clinical practice. Finally, the place of complementary and alternative treatments is shortly reviewed.
Article
Non classical bioisosters of modafinil featuring interesting biological profile have been easily produced through replacement of the sulfoxide function with a carbonyl group and modification of the carboxylic acid amide functionality.
Chapter
Die Aufmerksamkeitsdefizit-/ Hyperaktivitätsstö-rung (ADHS), die ursprünglich als eine ausschließ-lich im Kindesalter auftretende psychiatrische Er-krankung eingeordnet wurde, wird inzwischen als lebenslange chronische Störung verstanden, da mehrere, voneinander unabhängige Langzeitunter-suchungen nachwiesen, dass sich bei bis zu 6o% der ursprünglich erkrankten Kinder die Symptomatik bis ins Erwachsenenalter fortsetzt (Barkley, Fischer et al, 2004; Rasmussen & Gillberg, 2000) und epi-demiologische Untersuchungen unter Zugrunde-legung von DSM-IV-Kriterien eine Prävalenz von ADHS zwischen 3,3% und 4,4% im Erwachsenen-alter zeigten (Kessler, Adler, Barkley, Biederman, Gönners, Demier et al., 2006; Fayyad, DeGraaf, Kessler, Alonso et al., 2007).
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The optically active Ir(III) complex Λ-[Ir(ppy)2(MeCN)2](PF6) (ppy is 2-phenylpyridine) with a chiral-at-metal was first demonstrated to preferentially react with (R)-configuration sulfoxides 2-(alkylsulfinyl)phenol (HLO-R, R = Me, Et, (i)Pr, and Bn) rather than (S)-configuration sulfoxides under thermodynamic equilibrium due to the hydrogen-bonding interaction and the differences in the steric interference, and thus act as a highly efficient enantioreceptor for resolution of sulfoxide enatiomers. Treatment of Λ-[Ir(ppy)2(MeCN)2](PF6) with 2 equiv of rac-HLO-R offered (S)-HLO-R in yields of 46-47% with 97-99% enantiomeric excess (ee) values and Λ-[Ir(ppy)2{(S)-LO-R}] complex in yields of 89-93% with 98% diastereomeric excess (de). The (R)-HLO-R chiral sulfoxides were obtained by the acidolysis of Λ-[Ir(ppy)2{(S)-LO-R}] complexes with trifluoroacetic acid (TFA) in the presence of coordinated solvent MeCN in yields of 45-47% with 98-99% ee values. Moreover, the enantioreceptor Λ-[Ir(ppy)2(MeCN)2](PF6) can be recycled in a yield of 86-91% with complete retention of the configuration at metal center and can be reused in a next reaction cycle without loss of reaction activity and enantioselectivity. The absolute configurations at the metal centers and sulfur atoms were determined by X-ray crystallography.
Article
Attention-deficit/hyperactivity disorder (ADHD) has been commonly thought of as a childhood disorder that diminished over time. It is one of the most common developmental disorders and it is estimated that ADHD affects 5-10% of children. Two-thirds of children with ADHD will continue to have symptoms of ADHD that persist throughout adolescence. Longitudinal studies have demonstrated that symptoms of ADHD can also remain in adulthood, affecting 4.4% of the adult population. However, diagnosing adults with ADHD can prove difficult because they often find that their symptoms are egosyntonic. In addition, the development of comorbid conditions, such as anxiety, depression, personality disorders or substance abuse, can often overshadow underlying ADHD symptoms. Nonetheless, treatments such as stimulant and nonstimulant medication (e.g., atomoxetine), and cognitive-behavior therapy have been effective in treating adults with ADHD. This article reviews the prevalence of adults with ADHD, followed by a discussion of the neurobiological and genetic underpinnings of the disorder. Issues regarding the diagnosis and treatment of ADHD are also addressed.
Chapter
Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by core symptoms of inattention, impulsivity, and hyperactivity. ADHD has been considered for a long time as a childhood condition, fading as children grew up. Instead, ADHD changes its clinical presentation over the lifespan, but persists in most cases in adulthood with its associated impairment. It is only since 2013, with the release of DSM-5, that it is possible to diagnose ADHD in the presence of ASD. This change was based on studies performed in children, adolescents, and adults that found high comorbidity rates between ASD and ADHD. Studies investigating the co-occurrence of such disorders at a genetic, at structural and functional neuroimaging levels indicate that they share common genetic risk factors, involve similar biological mechanisms, and affect the same brain regions. The co-existence of both disorders causes a significant burden. Individuals with ASD presenting ADHD symptomatology exhibit a more severe phenotype, with more autistic traits, greater impairment in adaptive behavior, and increased risk for developing additional psychiatric conditions. Pharmacotherapeutic treatments for ADHD, such as methylphenidate and atomoxetine, have been studied in individuals with ADHD+ASD, demonstrating efficacy in decreasing the severity of ADHD symptoms, although with lower effect sizes than in people with only ADHD. The diagnosis of ADHD is established clinically and requires the use of rating scales as well as clinical interviews for avoiding the risk of misdiagnosis. The stigma surrounding individuals with ADHD is huge, therefore it is necessary to increase awareness about this disorder among both the public and healthcare professionals, in order to reduce the barriers that patients face to get access to proper diagnosis and treatment.
Article
Main observation and conclusion Chiral‐at‐metal strategy was developed to resolve the essential sulfoxide pharmaceutical intermediates R‐modafinil acid and its analogues with high yields and ee values. The efficient resolution process was achieved based on the diastereoselective discrimination caused by hydrogen bond and intramolecular π‐π interaction between chiral‐at‐metal center and the coordinated chiral sulfoxide ligands. Moreover, the chiral Ir(III) receptor can be reused with complete retention of their configurations and without the loss of reaction activity and enantioselectivity. This work provides a new access to synthesize R‐modafinil acid as well as its analogues and develops the application of chiral‐at‐metal strategy in chiral resolution.
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Background PharmacologyPharmacokinetics and Drug MetabolismEfficacy and SafetySynthesis
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A film-coated tablet formulation of modafinil (ProvigilR) was used to treat a total of 246 patients, ages 6 to 17 years, with attention deficit hyperactivity disorder (ADHD) at the Massachusetts General Hospital, Boston, MA, and other centers.
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Much experimental and clinical data suggest that the pharmacological profile of modafinil, a newly discovered waking substance, differs from those of amphetamine and methylphenidate, two classical psychostimulants. The brain targets on which modafinil acts to induce wakefulness, however, remain unknown. A double-blind study using the protooncogene c-fos as experimental marker in the cat was, therefore, carried out to identify the potential target neurons of modafinil and compare them with those for amphetamine and methylphenidate. Cats were sacrificed after a single oral administration of amphetamine, methylphenidate, or modafinil at equivalent doses for wake induction (1, 2.5, or 5 mgykg, respectively) and brain sections examined for Fos by immunocytochemistry. Administration of either amphetamine or methylphenidate evoked Fos-like immunoreactivity in a large number of neurons in the striatum and whole cortex, especially in the caudate nucleus and mediofrontal cortex, which are known to be dopaminergic targets. In contrast, administration of modafinil resulted in the labeling of few cells in these structures, but did induce marked Fos labeling in neurons of the anterior hypothalamic nucleus and adjacent areas. These results provide evidence for the potential brain targets of modafinil, which differ from those of amphetamine or methylphenidate, and suggest that modafinil induces wakefulness by mechanisms distinct from those of the two stimulants.
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Seventeen adult cats were chronically implanted with electrodes for polygraphic recordings in order to assess the role of catecholamines in the arousal effects of oral administrations of modafinil, a presumed noradrenergic agonist, and amphetamine, a well-known catecholamine-releasing agent. Whereas both modafinil (1, 2.5 and 5 mg/kg) and amphetamine (0.25, 0.5 and 1 mg/kg) caused a significant and dose-dependent increase in wakefulness and brain temperature, amphetamine, but not modafinil, elicited marked signs of behavioral excitation. Pretreatments with alpha-methyl-DL-p-tyrosine methyl ester (50 mg/kg, i.p.), an inhibitor of catecholamine synthesis, almost completely prevented the effects of amphetamine (0.25 and 1 mg/kg), but only slightly reduced the duration of the waking effect of modafinil (2.5 and 5 mg/kg). Pretreatments with phentolamine (10 mg/kg, i.p.), prazosin (1.5 mg/kg, per os) and propranolol (5 mg/kg, i.p.), an alpha-, alpha 1- and beta-receptor antagonist, respectively, attenuated significantly the arousal effect of modafinil (1 mg/kg, the same as below) but not of amphetamine (0.25 mg/kg, the same as below). Intraperitoneal injections of haloperidol (0.5 mg/kg), a dopamine-receptor antagonist, blocked significantly the arousal of amphetamine but not of modafinil. The effects of both modafinil and amphetamine were enhanced by a pretreatment with yohimbine (1 mg/kg, i.p.), an alpha 2-receptor antagonist. These results suggest that the arousal effect of modafinil does not depend on the availability of the endogenous catecholamines but results from an enhancement of alpha 1- and beta-receptor activity and that the waking and behavioral effects of amphetamine may be mainly due to an increase in dopamine release.
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Modafinil is a unique wake-promoting agent. Preclinical studies indicate a mechanism of action which is distinct from that of amphetamine or methylphenidate. To compare the pharmacodynamic profiles of modafinil, methylphenidate, and placebo in humans, a double-blind Latin square crossover study was conducted in 24 male volunteers with a history of polysubstance abuse that included the stimulant cocaine. Each subject was given single oral doses of methylphenidate (45 mg or 90 mg), modafinil (200 mg, 400 mg or 800 mg) and placebo. Measures of subjective, behavioural, and physiological responses were evaluated at fixed intervals during 72 h after each dosing occasion. Subjects discriminated both modafinil and methylphenidate from placebo. Subjects liked the effects of both drugs. However, modafinil differed from methylphenidate in its lack of a significant response on the Amphetamine Scale of the Addiction Research Center Inventory. The profile of physiological effects for modafinil differed from methylphenidate in that it showed greater inhibition of observed and reported sleep, less facilitation of orthostatic tachycardia and less reduction of caloric intake. These findings are consistent with preclinical pharmacological data suggesting that modafinil is not an amphetamine-like agent.
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Modafinil, a novel wake-promoting agent, has been shown to have a similar clinical profile to that of conventional stimulants such as methylphenidate. We were therefore interested in assessing whether modafinil, with its unique pharmacological mode of action, might offer similar potential as a cognitive enhancer, without the side effects commonly experienced with amphetamine-like drugs. The main aim of this study was to evaluate the cognitive enhancing potential of this novel agent using a comprehensive battery of neuropsychological tests. Sixty healthy young adult male volunteers received either a single oral dose of placebo, or 100 mg or 200 mg modafinil prior to performing a variety of tasks designed to test memory and attention. A randomised double-blind, between-subjects design was used. Modafinil significantly enhanced performance on tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time. These performance improvements were complemented by a slowing in latency on three tests: delayed matching to sample, a decision-making task and the spatial planning task. Subjects reported feeling more alert, attentive and energetic on drug. The effects were not clearly dose dependent, except for those seen with the stop-signal paradigm. In contrast to previous findings with methylphenidate, there were no significant effects of drug on spatial memory span, spatial working memory, rapid visual information processing or attentional set-shifting. Additionally, no effects on paired associates learning were identified. These data indicate that modafinil selectively improves neuropsychological task performance. This improvement may be attributable to an enhanced ability to inhibit pre-potent responses. This effect appears to reduce impulsive responding, suggesting that modafinil may be of benefit in the treatment of attention deficit hyperactivity disorder.
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To assess the therapeutic efficacy of modafinil in the treatment of increased daytime sleepiness in patients with Parkinson's disease (PD). Double-blind, randomized, placebo-controlled crossover study with two 2-week treatment blocks, separated by a 2-week washout phase. Tertiary Parkinson's disease care center and sleep laboratory at university hospital neurology department. Fifteen patients with idiopathic PD and daytime sleepiness (Epworth sleepiness score (ESS) 10 or more). Administration of placebo or modafinil as a single morning dose in a randomized crossover order. The modafinil dose was 100 mg in the first, and 200 mg in the second treatment week. At baseline and at the end of each treatment block, sleepiness was evaluated using subjective (perceived sleepiness with the ESS) and objective measures (maintenance of wakefulness test). Twelve patients completed the study (9 male, 3 female; mean age 65.0 +/- 7.6 years, mean disease duration 6.8 +/- 4.1 years). Epworth scores were significantly improved with modafinil (3.42 +/- 3.90) compared to placebo (0.83 +/- 1.99; p = 0.011). Latency to sleep in the maintenance of wakefulness test was not significantly altered by modafinil treatment: 10.9 (3-40)/15.1 (2.5-40) minutes before/after placebo and 12 (2.6-40)/17.8 (4.2-40) minutes before/after modafinil (p = 0.139) [data given as mean +/- standard deviation or median (range)]. The results of this study suggest that modafinil improves daytime sleepiness in PD patients, at least on a subjective or behavioral level. Modafinil treatment may be considered for EDS in PD patients, in whom otherwise treatable causes of Excessive Daytime Sleepiness (EDS) are absent.
Conference Paper
Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by inattention, hyperactivity, and impulsivity. ADHD is commonly treated with behavioral therapy and noradrenergic and dopaminergic pharmacotherapy with psychostimulants such as methylphenidate and dextroamphetamine. Stimulants primarily have dopaminergic and noradrenergic mechanisms of action, with blockade at the dopamine transporter reducing reuptake, resulting in an increase in these neurotransmitters at the synapse. Theoretically, inattention, hyperactivity, and impulsivity in ADHD may be due to underlying executive functioning, alerting, and orienting deficits, and the nonstimulant modafinil could be beneficial in managing symptoms of ADHD by improving these components of attention that accompany wakefulness. Although modafinil exhibits a small degree of dopaminergic action by blocking the dopamine transporter, the major effect of modafinil may be attributable to neuronal activity in the hypothalamus, particularly pertaining to the recently discovered peptides hypocretin I and 2 (also known as orexin A and 13). However, further placebo-controlled and flexible-dose studies are needed to determine the efficacy of modafinil in treating the symptoms of ADHD in children and adults.
Conference Paper
Attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance abuse in adults. Additional psychiatric comorbidity increases this risk. ADHD is associated with different characteristics of substance abuse: substance abuse transitions more rapidly to dependence, and lasts longer in adults with ADHD than those without ADHD. Self-medication may be a factor in the high rate of substance abuse in adults with ADHD. While previous concerns arose whether stimulant therapy would increase the ultimate risk for substance abuse, recent studies have indicated that pharmacologic treatment appears to reduce the risk of substance abuse in individuals with ADHD. When treating adults with ADHD and substance abuse, clinicians should assess the relative severity of the substance abuse, the symptoms of ADHD, and any other comorbid disorders. Generally, stabilizing or addressing the substance abuse should be the first priority when treating an adult with substance abuse and ADHD. Treatment for adults with ADHD and substance abuse should include a combination of addiction treatment/psychotherapy and pharmacotherapy. The clinician should begin pharmacotherapy with medications that have little likelihood of diversion or low liability, such as bupropion and atomoxetine, and, if necessary, progress to the stimulants. Careful monitoring of patients during treatment is necessary to ensure compliance with the treatment plan.
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Seventeen adult cats were chronically implanted with electrodes for polygraphic recordings in order to assess the role of catecholamines in the arousal effects of oral administrations of modafinil, a presumed noradrenergic agonist, and amphetamine, a well-known catecholamine-releasing agent. Whereas both modafinil (1, 2.5 and 5 mg/kg) and amphetamine (0.25, 0.5 and 1 mg/kg) caused a significant and dose-dependent increase in wakefulness and brain temperature, amphetamine, but not modafinil, elicited marked signs of behavioral excitation. Pretreatments with a-methyI-DL-p-tyrosine methyl ester (50 mg/kg, i.p.), an inhibitor of catecholamine synthesis, almost completely prevented the effects of amphetamine (0.25 and 1 mg/kg), but only slightly reduced the duration of the waking effect of modafinil (2.5 and 5 mg/kg). Pretreatments with phentolamine (10 mg/kg, i.p.), prazosin (1.5 mg/kg, per os) and propranolol (5 mg/kg, i.p.), an a-, a I- and/3-receptor antagonist, respectively, attenuated signifcantly the arousal effect of modafinil (1 mg/kg, the same as below) but not of amphetamine (0.25 mg/kg, the same as below). Intraperitoneal injections of haloperidol (0,5 mg/kg), a dopamine-receptor antagonist, blocked significantly the arousal of amphetamine but not of modafinil. The effects of both modafinil and amphetamine were enhanced by a pretreatment with yohimbine (! mg/kg, i.p.), an a2-rece~tor antagonist. These results suggest that the arousal effect of modafinil does not depend on the availability of the endogenous catecholamines bu! results from an enhancement of al- and/.t-receptor activity and that the waking and behavioral effects of amphetamine may be mainly due to an increase in dopamine release.
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Objective: The objective of this fixed-dose study was to determine the efficacy and safety of a new formulation of modafinil (modafinil film-coated tablets) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). In addition, the effect of abrupt discontinuation of modafinil was evaluated in a 2-week observation period. Method: Patients aged 6 to 17 years with DSM-IV-TR-defined ADHD were randomly assigned to 7 weeks of double-blind treatment with modafinil or placebo in a 2:1 ratio, followed by abrupt discontinuation of modafinil and a 2-week, double-blind observation period in which 46% of patients receiving modafinil were switched to placebo without tapering and half continued to receive modafinil. Study drug was administered once daily and titrated over the first 7 to 9 days to daily doses of 340 mg for patients < 30 kg or 425 mg for patients > = 30 kg. Assessment instruments included the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impressions-Improvement scale (CGI-I). The study was conducted from November 2003 to June 2004. Results: A total of 190 patients were randomly assigned to receive modafinil (340 mg, N = 44; 425 mg, N = 82) or placebo (N = 64). 189 patients were evaluated for safety. Modafinil significantly improved symptoms of ADHD as shown by reductions in ADHD-RS-IV School Version total scores compared with placebo at all visits (p < =.009), including the final visit of the double-blind phase (p < .0001). With modafinil, ADHD-RS-IV School Version mean total scores changed from 37.8 at baseline to 29.3 at week 1 and 20.7 at final visit; corresponding placebo values were 36.6, 32.8, and 28.4, respectively; effect size at final visit was 0.76 (95% CI = 0.63 to 0.88). Total scores on the ADHD-RS-IV Home Version were also significantly reduced at all visits (p < = .022) and final visit (p = .001) in patients receiving modafinil compared with those receiving placebo. Significantly higher proportions of patients receiving modafinil were rated "much improved" or "very much improved" in overall clinical condition (CGI-I) at all visits compared with patients receiving placebo (p < .001). No withdrawal symptoms were observed when modafinil was abruptly discontinued at the beginning of the final 2-week observation period. Modafinil was generally well tolerated. Insomnia, headache, and decreased appetite were the most commonly reported adverse events. Sixty-three percent of patients who received modafinil completed the study; 13% discontinued because of lack of efficacy; 10%, because of adverse events; and 13%, for other reasons (e.g., consent withdrawn, lost to follow-up). Conclusion: Modafinil significantly improved symptoms of ADHD both at school and at home and was well tolerated by children and adolescents. Abrupt discontinuation of modafinil was not associated with symptoms of withdrawal or with rebound of symptoms of ADHD.
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Modafinil is a new drug used in the treatment of narcolepsy. Its administration in mice induced a dose-dependent increase in locomotor activity. The effects of modafinil were compared with those of dexamphetamine on three tests that assessed the anxiety level (drugs were used at doses which induced a roughly similar stimulation of locomotor activity). Dexamphetamine increased the latency of exploration of a white compartment, increased thigmotaxis in an open-field and decreased the time spent in the open arms of an elevated plus-maze. None of these responses was significantly modified by modafinil. We conclude that modafinil does not share the anxiogenic effects of dexamphetamine.
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The purpose of this manual is to describe two behavior questionnaires (the ADHD Rating Scale—IV: Home Version and the ADHD Rating Scale—IV: School Version) that are based on the diagnostic criteria for attention deficit hyperactivity disorder (ADHD) as described in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. Information is presented about the development and standardization of these scales, collection of normative data, factor structure, psychometric properties (i.e., reliability and validity), as well as the interpretive uses of these scales in clinical and school settings. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
The acute or chronic administration of modafinil, (diphenyl-methyl-sulfinyl-2-acetamide, 30 mg/kg s.c.) decreased γ-aminobutyric acid (GABA) outflow from the cerebral cortex of freely moving guinea pigs and rats. In 5,7-dihydroxytryptamine intracerebroventricularly pretreated guinea pigs, the effect of modafinil on GABA outflow was reversed and the noradrenaline cortical levels increased. Prazosin (35,8 ng/kg i.p.) blocked the drug-induced increase in GABA efflux. In vitro experiments, performed in rat cortical slices, showed that modafinil failed to affect [3H]GABA release and uptake as well as glutamic acid decarboxylase activity. In conclusion, our results suggest that the balance between central noradrenaline and 5-hydroxytryptamine transmission is important for the regulation by modafinil of the GABAergic release in the cerebral cortex.
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We have studied the effect of modafinil and amphetamine, two waking drugs, on the electrical activity of central dopaminergic and noradrenergic neurons in the rat. Modafinil (128 mg/kg, i.p.) was unable to modify the firing pattern of these neurons, while amphetamine (2 or 5 mg/kg, i.p.) consistently inhibited their activity. A pretreatment with modafinil did not change thereafter the effect of amphetamine. Contrary to amphetamine, the waking effect of modafinil does not seem to be mediated by the catecholaminergic neuron activity per se.
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1. In a double-blind study forty abstinent hospitalized male patients with an alcoholic organic brain syndrome (OBS) were treated for 6 weeks with either 200 mg modafinil or placebo. 2. Modafinil (CRL 40476) is a putative central alpha-1 adrenergic agonist. It's pharmacological profile is quite different from that of amphetamine, which can be seen by the lack of peripheral sympathomimetic effects. The vigilance promoting effect of modafinil has been shown previously in pharmaco-EEG and psychometric studies as well as in clinical studies involving treatment of daytime sleepiness in idiopathic hypersomniacs and narcoleptics. 3. The present clinical investigations demonstrated that the spontaneous restitution of the alcoholic OBS was significantly augmented and accelerated by modafinil. 4. Psychometric tests did not show significant intergroup differences. Modafinil- and placebo-treated patients improved continously over the 6-week period. 5. Psychophysiological and autonomous nervous system parameters were affected neither by placebo nor by modafinil. 6. Neurophysiological investigations by means of quantitative pharmaco-EEG showed partly inconsistent findings. However, superimposed dosages of modafinil (on the top of 6 weeks chronic administration) induced a decrease of slow activity and an increase of alpha activity suggesting an improvement of vigilance after the daily drug intake. 7. Considering the beneficial effects of modafinil in abstinent chronic alcoholic patients, it may be said that activation and improvement of adaptive behaviour by an alpha-adrenergic agonist could be regarded as a therapeutic principle in the treatment of the OBS, eventually due to noradrenergic deficits.
Article
Single administration of the new drug modafinil was followed by an increase in locomotor activity in mice and in nocturnal activity in monkeys. Stereotyped behaviour in mice and rats, and potentiation of amphetamine-induced stereotyped behaviour were not observed; however, at the highest dose used, a slight potentiation of apomorphine-induced stereotyped behaviour was observed in rats. The modafinil-induced increase in locomotor activity in mice was prevented by the centrally acting alpha 1-adrenoceptor antagonists, prazosin and phenoxybenzamine, and by reserpine but not by the mixed dopamine D-1/D-2 antagonist, haloperidol, the dopamine D-2 antagonist, sulpiride, the peripherally acting alpha 1-adrenoceptor antagonist, phentolamine, the alpha 2-adrenoceptor antagonist, yohimbine, the beta-adrenoceptor antagonist, propranolol, or by the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine. Likewise, the modafinil-induced increase in nocturnal activity in monkeys was prevented by prazosin. Interestingly, modafinil did not produce obvious peripheral sympathetic effects in mice and rats (no salivation, no contraction of the pilomotor muscles, slight mydriasis only at high doses). Therefore, modafinil appears to produce a strong stimulating effect in rodents and in primates. These effects could be linked to modulation (stimulation) of central alpha 1-adrenoceptors unaccompanied by peripheral sympathetic effects, which is unexpected.
Article
Modafinil is a new drug used in the treatment of narcolepsy. Its administration in mice induced a dose-dependent increase in locomotor activity. The effects of modafinil were compared with those of dexamphetamine on three tests that assessed the anxiety level (drugs were used at doses which induced a roughly similar stimulation of locomotor activity). Dexamphetamine increased the latency of exploration of a white compartment, increased thigmotaxis in an open-field and decreased the time spent in the open arms of an elevated plus-maze. None of these responses was significantly modified by modafinil. We conclude that modafinil does not share the anxiogenic effects of dexamphetamine.
Article
To evaluate the predictors of persistence and the timing of remission of attention-deficit hyperactivity disorder (ADHD). Subjects were 6- to 17-year old Caucasian, non-Hispanic boys with and without ADHD. DSM-III-R structured diagnostic interviews and blind raters were used to examine psychiatric diagnoses, cognitive achievement, social, school, and family functioning at a 4-year follow-up assessment. At the 4-year follow-up assessment, 85% of children with ADHD continued to have the disorder and 15% remitted. Of those who remitted, half did so in childhood and the other half in adolescence. Predictors of persistence were familiality of ADHD, psychosocial adversity, and comorbidity with conduct, mood, and anxiety disorders. The findings prospectively confirm that the majority of children with ADHD will continue to express the disorder 4 years later. For a minority of children, ADHD was a transient disorder that remits early in development. In addition, we have shown that persistence of ADHD is predictable. Familiality, adversity, and psychiatric comorbidity may be clinically useful predictors of which children with ADHD are at risk for a persistent disorder.
Article
The effects of modafinil and amphetamine on daytime sleep (polysomnographic recordings) and cataplexy (the food-elicited cataplexy test) were compared using the narcoleptic canine model. Results indicate that both modafinil (5 and 10 mg/kg body weight i.v.) and amphetamine (100 and 200 micrograms/kg i.v.) increase wakefulness and reduce slow-wave sleep in control and narcoleptic dogs. In contrast, the results of cataplexy testing demonstrate that amphetamine (2.5-160 micrograms/kg i.v.), but not modafinil (0.125-8.0 mg/kg i.v.) significantly suppresses canine cataplexy. These results suggest that the pharmacological property of modafinil is distinct from amphetamine. Results of polysomnographic recordings also demonstrate that narcoleptic dogs slept significantly more during the daytime than control dogs and required very high doses (10 mg/kg i.v. modafinil; 200 micrograms/kg i.v. amphetamine) of stimulants to reduce their level of sleepiness to that of control dogs. This finding is consistent with the data collected in human narcolepsy and validates the use of this canine model for the screening of stimulant compounds.
Article
A randomized, double-blind, placebo-controlled, ascending-dose study was conducted to evaluate the pharmacokinetic and safety profiles of increasing modafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7-day period in normal healthy male volunteers. Eight subjects (six modafinil; two placebo) were randomized to each of the four dose groups. Modafinil or a placebo was administered once daily for 7 days. Serial blood samples were obtained following administration of the day 1 and day 7 doses for characterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. Pharmacokinetic parameters were calculated using noncompartmental methods. Modafinil steady state was reached after three daily doses. Modafinil pharmacokinetics were dose and time independent over the range of 200 mg to 800 mg. Steady-state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of approximately 50 mL/min, a volume of distribution of approximately 0.8 L/kg, and a long half-life of approximately 15 hr. Modafinil was primarily eliminated by metabolism. Modafinil acid was the major urinary metabolite. Stereospecific pharmacokinetics of modafinil were demonstrated. The d-modafinil enantiomer was eliminated at a threefold faster rate than 1-modafinil. Modafinil 200 mg, 400 mg, and 600 mg doses were generally well tolerated. The modafinil 800 mg dose panel was discontinued after 3 days of treatment due to the observation of increased blood pressure and pulse rate. The safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg.
Article
An open-label, single-center, single-dose, parallel-group study was performed in healthy young males and females as well as healthy elderly males to examine the influence of age and gender on the pharmacokinetics of modafinil following administration of a single 200 mg oral dose. Twelve subjects were enrolled in each of the following three groups: young males, young females, and elderly males. Each fasted (overnight) subject received 2 x 100 mg modafinil tablets. Blood and urine samples were collected at various times up to 72 hours postdose for the determination of plasma and urine levels of modafinil as well as the acid and sulfone metabolites. The plasma concentrations of the individual isomers, d- and l-modafinil, were also determined. Pharmacokinetic parameters were determined by noncompartmental methods. Modafinil was well tolerated at a single oral dose of 200 mg. The most commonly reported adverse events were headache, fever, pharyngitis, and asthenia. There were no clinically meaningful differences with respect to the incidence rate of treatment-emergent adverse events among the young female, young male, and old male groups. Modafinil was rapidly absorbed after oral dosing and slowly cleared (t1/2 approximately 11-14 hr) from the body. Modafinil acid was the major urinary metabolite, which accounted for 35% to 60% of the dose. Results from this study indicated that there were age and gender effects on modafinil clearance processes. In this regard, the clearance rate of modafinil in males decreased with age while young females cleared modafinil at a faster rate than young males. Stereospecific pharmacokinetics of modafinil were also demonstrated. The d-modafinil was eliminated three times faster than the l-modafinil.
Article
The scientific literature about attention-deficit hyperactivity disorder (ADHD) is based almost exclusively on male subjects, and girls with ADHD may be underidentified and undertreated. The aim of this study was to examine clinical correlates of ADHD in females using comprehensive assessments in multiple domains of functioning. Subjects were 140 girls with ADHD and 122 comparison girls without ADHD ascertained from pediatric and psychiatric referral sources of the same age and social class. Subjects were assessed with structured diagnostic interviews, psychometric tests assessing intellectual functioning and academic achievement, as well as standardized assessments of interpersonal, school, and family functioning by raters who were blind to clinical diagnosis. Compared with female controls, girls with ADHD were more likely to have conduct, mood, and anxiety disorders; lower IQ and achievement scores; and more impairment on measures of social, school, and family functioning. These results extend to girls previous findings in boys indicating that ADHD is characterized by prototypical core symptoms of the disorder, high levels of comorbid psychopathology, and dysfunction in multiple domains. These results not only support findings documenting phenotypic similarities between the genders but also stress the severity of the disorder in females.
Article
The neuropsychological functioning of adults with Attention Deficit Hyperactivity Disorder (ADHD) was compared to that of healthy controls and individuals with mild psychiatric disorders including attentional complaints. Thirty adults in each group were examined on the Conners' Continuous Performance Test (CPT) and measures of attention, executive function, psychomotor speed, and arithmetic skills. The ADHD group performed lower than healthy controls on most measures. However when compared to the psychiatric group, the performances of the ADHD group were not significantly lower on any of the measures. The predictive power of the tests was poor in discriminating ADHD from psychiatric disorder. Implications for the clinical diagnosis of ADHD are discussed.
Article
Psychostimulants have been used routinely for the treatment of the disabling daytime sleepiness associated with narcolepsy. However, the perceived and real potential for abuse of amphetamine and amphetaminelike stimulants prompted a search for new wake-promoting compounds with lower dependency and abuse liabilities. Modafinil is a novel wake-promoting agent with a mechanism of action that differs markedly from that of amphetamine and amphetamine-like stimulants. In controlled clinical trials, modafinil has been shown to be an effective and well-tolerated treatment for excessive daytime sleepiness (EDS) in patients with narcolepsy. With a benzhydrylsulfinylacetamide structure, modafinil has a low level of solubility in water (< 1 mg/mL) and is unstable at temperatures > or = 180 degrees C, physicochemical properties that reduce the potential for its abuse via intravenous injection and smoking, respectively. Available preclinical and clinical data on the abuse liability of modafinil suggest a much lower potential for abuse and dependency than amphetaminelike stimulants commonly used for treating EDS in patients with narcolepsy. Therefore, modafinil represents a valuable therapeutic option for the treatment of EDS associated with narcolepsy.
Article
To assess the validity of adult attention-deficit/hyperactivity disorder (ADHD), we reviewed clinical, family, psychopharmacologic, neurobiological, and outcome studies. We found multiple reports describing adults with clinical features highly reminiscent of the childhood ADHD. These adults, who are impulsive, inattentive, and restless, have the clinical "look and feel" of ADHD children. As with their childhood counterparts, many adults with ADHD suffer from antisocial, depressive, and anxiety disorders. They also show clinically significant impairments--histories of school failure, occupational problems, and traffic accidents. Studies of biological features show correspondences between child and adult cases of ADHD. Both show familial aggregation and a characteristic profile of neuropsychologic deficits; an emerging neuroimaging literature suggests that abnormalities in the same brain regions underlie both the child and adult forms of the disorder. Although these converging lines of evidence support the validity of ADHD in adults, follow-up studies of ADHD children have yielded ambiguous results. This ambiguity is in part due to differences in how researchers define the persistence of ADHD, a problem that suggests future research focus on how best to diagnose ADHD in adulthood.
Article
Modafinil is an increasingly popular wake-promoting drug used for the treatment of narcolepsy, but its precise mechanism of action is unknown. To determine potential pathways via which modafinil acts, we administered a range of doses of modafinil to rats, recorded sleep/wake activity, and studied the pattern of neuronal activation using Fos immunohistochemistry. To contrast modafinil-induced wakefulness with spontaneous wakefulness, we administered modafinil at midnight, during the normal waking period of rats. To determine the influence of circadian phase or ambient light, we also injected modafinil at noon on a normal light/dark cycle or in constant darkness. We found that 75 mg/kg modafinil increased Fos immunoreactivity in the tuberomammillary nucleus (TMN) and in orexin (hypocretin) neurons of the perifornical area, two cell groups implicated in the regulation of wakefulness. This low dose of modafinil also increased the number of Fos-immunoreactive (Fos-IR) neurons in the lateral subdivision of the central nucleus of the amygdala. Higher doses increased the number of Fos-IR neurons in the striatum and cingulate cortex. In contrast to previous studies, modafinil did not produce statistically significant increases in Fos expression in either the suprachiasmatic nucleus or the anterior hypothalamic area. These observations suggest that modafinil may promote waking via activation of TMN and orexin neurons, two regions implicated in the promotion of normal wakefulness. Selective pharmacological activation of these hypothalamic regions may represent a novel approach to inducing wakefulness.
Article
Our objective was to compare the efficacy of the new wake-promoting drug modafinil to that of dextroamphetamine for the treatment of attention deficit hyperactivity disorder (ADHD) in adults. Twenty-two adults who met DSM-IV criteria for ADHD participated in a randomized, double-blind, placebo-controlled, three-phase crossover study comparing placebo, modafinil, and dextroamphetamine for the treatment of ADHD. The twice-daily study medications were titrated to doses of optimum efficacy over 4-7 days and then held constant during the rest of each 2-week treatment phase. Measures of improvement included the DSM-IV ADHD Behavior Checklist for Adults, the Controlled Oral Word Association Test (COWAT, using the letters C, F, and L version), Stroop, and Digit Span (Wechsler Adult Intelligence Scale version). For the 21 (96%) completers, the mean (+/- SD) optimum doses of modafinil and dextroamphetamine were 206.8 mg/day +/- 84.9 and 21.8 mg/day +/- 8.9, respectively. Scores on the DSM-IV ADHD Checklist (p < 0.001) were significantly improved over the placebo condition following treatment with both active medications. Performance on the COWAT (p < 0.05) reached trend levels of significance. Both medications were generally well tolerated. This preliminary study suggests that modafinil may be a viable alternative to conventional stimulants for the treatment of adults with ADHD.
Article
To examine the effect of once-daily dosing of modafinil, a stimulant that has a long duration of action, on clinical features of attention-deficit/hyperactivity disorder (ADHD) in children. An open-label design was used to compare the Conners Parent and Teacher Rating Scale-Revised (L) (CPRS, CTRS), the ADHD Rating Scale-IV, and the Test of Variables of Attention (TOVA), without and with medication, in children with ADHD. Eleven children with ADHD, ranging in age from 5 to 15 years, took modafinil for an average of 4.6 weeks. Average TOVA ADHD scores improved by 2.43 SD (p = .0009). CTRS and CPRS ADHD index T scores improved by an average of 14.1 (p = .0009) and 17.7 points (p = .001), respectively. The mean ADHD Rating Scale-IV scores improved from the 88th percentile to the 75th percentile (p = .047). One subject withdrew from the study because of an adverse event that was resolved completely with medication withdrawal. Other side effects were mild and responded to dose adjustment. No subjects required more than one dose per day. Modafinil may be a useful once-daily treatment for children with ADHD. Further study using a double-blind, placebo-controlled design is needed.
Article
The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is controversial. In this study, polygraphic recordings and caudate microdialysate dopamine measurements in narcoleptic dogs revealed that the wake-promoting antinarcoleptic compounds modafinil and amphetamine increase extracellular dopamine in a hypocretin receptor 2-independent manner. In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil.
Article
Amphetamine-like stimulants are commonly used to treat sleepiness in narcolepsy. These compounds have little effect on rapid eye movement (REM) sleep-related symptoms such as cataplexy, and antidepressants (monoamine uptake inhibitors) are usually required to treat these symptoms. Although amphetamine-like stimulants and antidepressants enhance monoaminergic transmission, these compounds are non-selective for each monoamine, and the exact mechanisms mediating how these compounds induce wakefulness and modulate REM sleep are not known. In order to evaluate the relative importance of dopaminergic and noradrenergic transmission in the mediation of these effects, five dopamine (DA) uptake inhibitors (mazindol, GBR-12909, bupropion, nomifensine and amineptine), two norepinephrine (NE) uptake inhibitors (nisoxetine and desipramine), d-amphetamine, and modafinil, a non-amphetamine stimulant, were tested in control and narcoleptic canines. All stimulants and dopaminergic uptake inhibitors were found to dose-dependently increase wakefulness in control and narcoleptic animals. The in vivo potencies of DA uptake inhibitors and modafinil on wake significantly correlated with their in vitro affinities to the DA and not the NE transporter. DA uptake inhibitors also moderately reduced REM sleep, but this effect was most likely secondary to slow wave sleep (SWS) suppression, since selective DA uptake inhibitors reduced both REM sleep and SWS proportionally. In contrast, selective NE uptake inhibitors had little effect on wakefulness, but potently reduced REM sleep. These results suggest that presynaptic activation of DA transmission is critical for the pharmacological control of wakefulness, while that of the NE system is critical for REM sleep regulation. Our results also suggest that presynaptic activation of DA transmission is a key pharmacological property mediating the wake-promoting effects of currently available CNS stimulants.
Article
We compared the neuropsychological test performance of adult ADHD patients to the neurocognitive profiles of control subjects recruited from the general population. We administered a neuropsychological test battery consisting of measures considered sensitive to either orbitofrontal or dorsolateral-prefrontal (DLPF) dysfunction. Orbitofrontal hypoarousal is associated with behavioral disinhibition and a relative indifference to punishment. The DLPF region may function as a central executive system. Indeed, DLPF dysfunction may underlie many of the cardinal symptoms associated with ADHD. We tested the following hypotheses: (1) adult subjects meeting DSM-IV criteria for ADHD, predominantly hyperactive-impulsive type, would display neuropsychological deficits on tasks sensitive to orbitofrontal dysfunction; (2) adult subjects meeting DSM-IV criteria for ADHD, predominantly inattentive type, would perform poorly on measures sensitive to DLPF dysfunction; and (3) adult subjects meeting DSM-IV criteria for ADHD, combined type, would exhibit performance deficits on orbitofrontal measures and on DLPF tasks. Results partially confirmed our hypotheses. Subtyping ADHD patients revealed important group differences. Distinct neurocognitive and clinical profiles were observed.
The frequency of occurrence of attention-deficit/hyperactivity disorder (AD/HD) is in dispute. This uncertainty has contributed to the concern that too many children in the United States are being treated with stimulant medication. To determine the cumulative incidence of AD/HD in a population-based birth cohort and to estimate the prevalence of pharmacologic treatment for children who fulfill research criteria for AD/HD. Population-based birth cohort study. All children born between 1976 and 1982 in Rochester, Minn, who remained in the community after age 5 years (N = 5718). Medical and school records were reviewed for clinical diagnoses of AD/HD and supporting documentation (symptoms consistent with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and positive results for AD/HD-related questionnaires). Research-identified cases were defined as: (1) "definite" AD/HD (clinical diagnosis and at least one type of supporting documentation); (2) "probable" AD/HD (clinical diagnosis but no supporting documentation or no clinical diagnosis but both types of supporting documentation); (3) "questionable" AD/HD (no clinical diagnosis, but at least one type of supporting documentation); and (4) "not AD/HD" (all other subjects). Information about pharmacologic treatment for AD/HD was abstracted for all subjects. The highest estimate of the cumulative incidence at age 19 years (with 95% confidence interval) of AD/HD (definite plus probable plus questionable AD/HD) was 16.0% (14.7-17.3). The lowest estimate (definite AD/HD only) was 7.4% (6.5-8.4). Prevalence of treatment with stimulant medication was 86.5% for definite AD/HD, 40.0% for probable AD/HD, 6.6% for questionable AD/HD, and 0.2% for not AD/HD. These results provide insight into the apparent discrepancies in estimates of the occurrence of AD/HD, with less stringent criteria resulting in higher cumulative incidence. Children who met the most stringent criteria for AD/HD were most likely to receive pharmacologic treatment.
Article
Children with Attention-Deficit/Hyperactivity Disorder (ADHD) appear to be deficient in executive control. The purpose of this study was to determine if adults with ADHD are also deficient in executive control. The performance of 18 adults with ADHD and 18 control subjects was compared on two tests of executive control, and two control tasks. The executive control tasks used in the study were the Trail Making Test (B), and the Tower of Hanoi. The control tasks used were the Trail Making Test (A), and the Benton Facial Recognition Test. The subjects with ADHD performed more poorly than did the normal controls on the executive control tasks. The subjects with ADHD, however, also performed more poorly on the Trail Making Test (A). The ADHD subjects showed a deficit in executive control, but this deficit was not confined to the executive control domain.
Article
After an initial patient with cerebral palsy had an apparent dramatic reduction in spasticity when placed on modafinil, a pilot study was undertaken in 10 pediatric patients to confirm or refute the benefit of modafinil in cerebral palsy. Nine of 10 patients completed the 1-month treatment period. The study patients were treated with 50 or 100 mg of modafinil once daily in the morning. An assessment was made at baseline and at 1 month on treatment. All patients had a clinical examination, Modified Ashworth Scale scores (spasticity) determined by a physical therapist, and videotaping of ambulation. In comparing visit 1 (baseline) and visit 2 (on treatment), statistically significant improvement in the modified Ashworth Scale scores was noted in seven of the nine patients completing the study (P = .0080). A blinded review of the videotapes did not show statistically significant differences in ambulation, but the speed (ft/sec) of gait improved in six of the nine patients (P = .0192). In this study, modafinil, a newly released central stimulant for narcolepsy, showed benefit in treating spasticity in patients with cerebral palsy. A second larger, placebo-controlled, double-blinded trial is planned to confirm these initial results and observations. Modafinil appears to benefit spastic cerebral palsy by a yet to be determined mechanism; however, a primary effect of modafinil on brainstem structures is hypothesized to reduce spasticity of central origin.
Article
Exciting new developments in the psychopharmacology of wakefulness are clarifying the neurotransmitters, pathways, and drugs that impact this important physiologic state. Selectively inducing normal wakefulness without stimulating external vigilance may lead to therapeutic benefits not only in sleep disorders but also in cognitive disorders and conditions associated with fatigue.
Article
Issue: The neuroanatomical substrate of wakefulness involves 2 parallel pathways that activate the cortex, one arising from neurons in the brainstem and another arising from neurons that make up a hypothalamic sleep-wake switch. Multiple neurotransmitters regulate wakefulness as do several drugs, including the novel wake-promoting agent modafinil.
Article
Modafinil is a unique wake-promoting agent for oral administration. Its pharmacological properties are distinct from those of other CNS agents, and it selectively targets neuronal pathways in the sleep/wake centres of the brain. Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine. Less than 10% of the dose is excreted as unchanged drug. Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways. In patients who are renally or hepatically compromised, the elimination processes can be slowed, and in a similar manner (although to a lesser extent), elimination in the elderly may be reduced due to normal effects of aging. Because modafinil is administered concomitantly with other medications, the potential for metabolic drug-drug interactions has been examined both in vitro and in vivo. In vitro, modafinil was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small, but concentration-dependent, induction of CYP1A2, CYP2B6 and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes. Clinical studies have been conducted to examine the potential for interactions with methylphenidate, dexamfetamine, warfarin, ethinylestradiol and triazolam. The only substantive interactions observed were with ethinylestradiol and triazolam, apparently through induction of CYP3A4, primarily in the gastrointestinal system. Overall, the results of the interaction studies suggest that modafinil has potential to affect the pharmacokinetics of drugs that are metabolised by certain CYP enzymes. Compounds that induce or inhibit CYP activity are unlikely to have major effects on the pharmacokinetics of modafinil. In summary, the results show that modafinil is a moderately long-lived drug that is well absorbed and extensively metabolised.
Article
Although historically conceptualized as a disorder that was limited to males during middle childhood, ADHD is currently conceptualized as a chronic disorder that persists into adolescence and adulthood for both sexes. Nonetheless, the veracity of adult ADHD continues to be the source of debate. In order to frame this debate, research leading to the conceptualization of ADHD as a chronic disorder is reviewed. A distinction is made between the developmental outcomes versus the developmental course of ADHD. It is concluded that although childhood ADHD is associated with negative developmental outcomes in adolescence and adulthood, questions about the developmental course of ADHD remain. Although it appears that ADHD diminishes with advancing age, a number of methodological limitations prohibit firm conclusions. Recommendations for future studies are made with an emphasis on 1) overcoming extant methodological limitations in the literature and 2) the need for theoretically derived hypotheses regarding continuity and change in ADHD symptomatology over time.
Article
Up to 30% of patients with major depression fail to respond to an antidepressant trial, with most taking a selective serotonin reuptake inhibitor (SSRI) as initial treatment. While the tricyclic antidepressants might be effective for SSRI nonresponders, they have been relegated to third- and fourth-line treatment. This study assesses the efficacy of nortriptyline for patients with treatment-resistant major depression. 92 patients with treatment-resistant DSM-III-R major depression, with resistance defined by at least 1, but no more than 5, well-documented adequate trials of antidepressants during the current episode, were treated openly with nortriptyline for 6 weeks. Patients were titrated up to full target doses of nortriptyline within 1 week, with target blood levels of 100 ng/mL. Response was defined as a 50% or greater decrease of baseline 17-item Hamilton Rating Scale for Depression score. We performed an intent-to-treat analysis with the last observation carried forward. Approximately 40% of patients were responders (N = 39) and 12% were remitters (N = 11) after 6 weeks of nortriptyline. Over a third of patients were unable to complete the trial. Nortriptyline was effective for over a third of patients with treatment-resistant depression, and nortriptyline should be considered as potential treatment if patients fail to respond to other antidepressants.
Article
Modafinil, (RS)-2-(Diphenylmethylsulfinyl)acetamide, is a well known wake promoting drug used for the treatment of narcolepsy. We investigated the effect of modafinil on the hypothalamic histamine release in the anesthetized rat using in vivo microdialysis. Modafinil (150 mg/kg, i.p.) increased histamine release by 150% of the basal release. The intracerebroventricular (i.c.v.) injection of modafinil (1 nmol) also increased histamine release, however, when modafinil (1 nmol) was injected directly into the tuberomammillary nucleus, a limited region where cell bodies of the histaminergic neurons are located, histamine release was not altered. These observations suggest that modafinil may promote waking via the activation of the histaminergic system, although it does not appear to be a direct pharmacological target of modafinil.