Modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: Results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by abrupt discontinuation
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.
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 > or = 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.
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 < or = .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 < or = .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).
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.
"In the past decade, there has been a marked increase in offlabel use of modafinil for a variety of indications (Peñaloza et al. 2013). As a nonamphetamine stimulant with low abuse liability, modafinil may be a safe alternative for treatment of fatigue syndrome and psychiatric disorders such as treatmentresistant depression and attention deficit/hyperactivity disorder (Minzenberg and Carter 2008; Swanson et al. 2006). Despite the widespread clinical use of modafinil, the precise mechanisms underlying its therapeutic efficacy are complex and not well understood (for review, see Ballon and Feifel 2006; Minzenberg and Carter 2008). "
[Show abstract][Hide abstract] ABSTRACT: Seizures occur when the excitability of brain circuits is not sufficiently restrained by inhibitory mechanisms. Although modafinil is reported to reduce GABA-activated currents and extracellular GABA levels in the brain, the drug exerts anticonvulsant effects in animal studies.
The aim of this study was to determine the effects of modafinil and its metabolites (sulfone and carboxylic acid) on the anticonvulsant action of four classical antiepileptic drugs (AEDs)-carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA).
Anticonvulsant activity was assessed with the maximal electroshock seizure threshold (MEST) test and MES test in mice. Brain concentrations of AEDs were measured to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects.
Intraperitoneal injection of 75 mg kg(-1) of modafinil or its metabolites significantly elevated the threshold for electroconvulsions in mice, whereas 50 mg kg(-1) of each compound enhanced the anticonvulsant activity of CBZ, PHT, and VPA, but not that of PB. A 25-mg kg(-1) dose of modafinil or its sulfone metabolite enhanced anticonvulsant activity of VPA. Modafinil and its metabolites (50 mg kg(-1)) did not alter total brain concentrations of PB and VPA but did elevate CBZ and PHT.
Enhancement of anticonvulsant actions of VPA by modafinil in the mouse MES model is a pharmacodynamic effect. Collectively, our data suggest that modafinil may be a safe and beneficial adjunct to the therapeutic effects of AEDs in human patients.
"In addition, modafinil has been proposed to improve concentration (Minzenberg and Carter, 2008) and to lessen the symptoms of attention-deficit hyperactivity disorder (ADHD) (Turner et al., 2004; Swanson et al., 2006). It has been also used to treat cocaine/ methamphetamine abuse and depression (for a review see Ballon and Feifel, 2006). "
[Show abstract][Hide abstract] ABSTRACT: Although the wake-promoting drug modafinil has been shown to bind quite exclusively to the dopamine transporter (DAT), its action in the brain has been thought to be partially independent from the facilitation of the dopaminergic signals. Here we used electrophysiological and amperometric techniques to investigate the effects of modafinil on the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and on the synaptic overflow of dopamine in the dorsal striatum from sliced tissue of wild-type and cocaine-insensitive genetically modified mice (DAT-CI). Moreover, we examined the consequences of modafinil administration on the locomotor behavior of wild-type and DAT-CI mice. In in vitro experiments, modafinil inhibited the spontaneous firing discharge of the dopaminergic neurons. More consistently, it potentiated firing inhibition and the membrane responses caused by exogenously applied dopamine on these cells. Furthermore, it augmented the stimulus-evoked outflow of DA in the striatum. Noteworthy, modafinil caused locomotor activation in wild-type mice. On the other hand, neither the electrophysiological nor the behavioral effects of modafinil were detected in DAT-CI animals. These results demonstrate that modafinil potentiates brain dopaminergic signals via DAT inhibition by acting at the same binding site of cocaine. Therefore, this mechanism of action explains most of the pharmacological properties of this compound in the clinical setting.
"82 1 52 n n n n 1 089 Geller et al. 2001 103 21 13 n n n n 2 090 Anderson et al. 2007 101 5 8 n n n n 2 091 RUPP Autism Network 2005 63 5 8 y y None reported y 7 092 Sporn et al. 2007 54 Not reported 6 n n n n 1 093 Armenteros et al. 2007 25 Not reported 4 n n n n 2 094 Armour et al. 2008 40 1 2 n y n n 1 095 Clarke et al. 2005 152 1 52 n n n n 0 096 Zepf et al. 2009 17 1 2 days n n n n 1 097 Greenhill et al. 2002 321 32 154 1 4 n n n n 1 100 Arnold et al. 2006 16 Not reported 13 n n n n 2 101 Biederman et al. 2005 248 24 9 n n n n 1 102 Biederman et al. 2007 290 40 4 n n n n 2 103 Greenhill et al. 2006 97 12 7 n n n n 1 104 Hollander et al. 2010 27 Not reported 12 n n n n 2 105 King et al. 2001 39 6 4 n n n n 1 106 McCracken et al. 2003 51 4 5 n n n n 1 107 McGough et al. 2006 80 Not reported 2 n n n n 2 108 Palumbo et al. 2008 122 4 16 y y None reported none reported 4 109 Pelham et al. 2001 68 1 3 n n n n 2 110 Pelham et al. 2005 36 3 1 n n n n 2 111 Scahill et al. 2001 34 1 8 n n n n 3 112 Scheffer et al. 2005 40 1 12 n n n n 2 113 March et al. 2004 439 13 12 y None reported None reported None reported 1 114 Wagner et al. 2003 376 53 10 n n n n 1 115 Wasserman et al. 2006 20 1 10 n n n n 0 116 Swanson et al. 2006 190 17 "
[Show abstract][Hide abstract] ABSTRACT: Abstract In recent years, there has been an increase in pediatric clinical trials as the result of an identified need for greater research with this population. Given the potential risks, and the vulnerability of the population, there has also been an identified need for greater safety elicitation and monitoring in pediatric psychopharmacology trials, for example, through the use of a data and safety monitoring board (DSMB). However, research indicates that pediatric trials and psychiatric trials are less likely to use a DSMB. The rationale for the current study was to determine what safety methodologies have been reported in pediatric psychopharmacology trials over the past 10 years. A literature review was conducted of all pediatric psychopharmacology trials published since 2001. Results indicated that the most common elicitation method was collecting laboratory information and vital signs. Six percent of trials solely relied on spontaneous reporting of adverse events, and only 11.8% reported using a DSMB. These results suggest that elicitation methods and use of DSMBs are still low. Practical considerations, affected stakeholders, and barriers are discussed. Recommendations for moving forward include the use of multiple elicitation methods and automatic requirement of a DSMB for pediatric psychopharmacology trials, required completion of a standardized safety reporting form, and engaging multiple interested parties in these processes.
Journal of child and adolescent psychopharmacology 04/2013; 23(3):148-62. DOI:10.1089/cap.2011.0142 · 2.93 Impact Factor
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