- Email: [email protected]
hyperactivity disorder (ADHD) treatment with controlled- release methylphenidate
P.7.a Child and adolescent disorders and treatment – Disorders (clinical) [3] Stahl SM, 1977, The human platelet. A diagnostic and research tool for the study of biogenic amines in psychiatric and neurologic disorders. Arch. Gen. Psychiatry 34(5), 509−16.
P.7.a Child and adolescent disorders and treatment – Disorders (clinical) P.7.a.001 Agomelatine efficacy on major sleep disturbances in Smith-Magenis syndrome: an exploratory, open study in children A. Fabiano1 ° , H. de Leersnyder2 . 1 Institut de recherches internationales Servier, Neuropsychiatrie, Courbevoie, France; 2 Hˆ opital Necker, Syst`eme nerveux EEG, Paris, France Introduction: Smith-Magenis syndrome (SMS) is a mental retardation disease with distinctive behavioural characteristics, dysmorphic features and congenital anomalies ascribed to a deletion of chromosome 17p11.2. Severe sleep disturbances and maladaptive daytime behavior have been linked to an abnormal circadian pattern of melatonin, with a diurnal instead of a nocturnal secretion of this hormone. This is the first biologic model of sleep and behavioral disorders in a genetic disease. During the night, early sleep onset, frequent awakenings and early sleep offset are consistent features of the disease and are highly specific diagnostic criteria in SMS. During the day patients are tired in the morning and tantrums appears when melatonin rise. Naps and sleep attacks occur when melatonin peaks at midday and in the evening, respectively. Elucidating pathophysiological mechanisms of behavioral phenotypes is particularly relevant to therapeutic approach in genetic diseases Because the circadian rhythm of melatonin is controlled by the sympathetic nervous system, SMS patients were given acebutolol, as B1-adrenergic antagonists reduce the production of melatonin. After a morning B1-adrenergic antagonists administration, plasma melatonin levels rapidly decreased in all SMS patients. An open clinical trial was designed to assess the potential efficacy of agomelatine, a melatonin agonist and 5-HT2C antagonist [1], on the sleep disturbances in children suffering from SMS. Methods: Open phase II study with direct individual benefit without randomisation. All patients were treated during 6-month with agomelatine (1 or 5 mg o.d., as evening dose). Acebutolol (B1 antagonist, 10 mg/kg o.d., as morning dose) was coadministered to block endogeneous melatonin secretion. The primary efficacy criteria were the actigraphy parameters. Results: Seven male and three female SMS patients, aged from 6 to 17 years, were included. Nine patients completed the 6-month study whereas one patient withdrew from the study, before having taken any dose of agomelatine, due to non medical reason. The results from actigraphy were consistent with those obtained with the sleep diary and the children’s sleep questionnaire, all of which showed less frequent and shorter nocturnal waking up than at baseline, and indicated also a decreased mean duration of daytime naps over the 6-month study period. According to the investigator, clinical improvement in the children was notable and the benefit of the treatment was also confirmed by the parents of every child. The medication allowed children to sleep deeply and to be quiet whereas in the past it used not to be. Sleep was no more fragmented by prolonged nocturnal awakenings and waking-up in the morning was delayed. Conclusion: Data from this exploratory, open trial indicate that 1 or 5 mg agomelatine, when co-administred with acebutolol
S567
(10 mg/kg), was an effective and well-tolerated treatment of disturbed sleep in SMS. On the family request, eight patients are still on treatment and receive now agomelatine since November 2002. Additional trials are needed to confirm the therapeutic potential of agomelatine in SMS. References [1] Millan MJ, Gobert A, Lejeune F, et al, 2003, The novel melatonin agonist Valdoxan (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. JPET 306, 954–964.
P.7.a.002 Adolescent attention deficit/hyperactivity disorder (ADHD) treatment with controlledrelease methylphenidate E. Oh1 ° , J.H. Yoo2 . 1 Dr. Oh’s Psychiatric Clinic, Psychiatry, Suwon, South-Korea; 2 Miclinic skin and LASER center, Dermatology, Seoul, South-Korea Purpose of the study: ADHD is one of the most prevalent childhood and adolescent psychiatric disorders. This disorder significantly affects the patient’s behavior and performance at school and at home and disrupts relationships with family, teachers, and peers. Multiple studies found that this disorder persists into adolescence and adulthood in a substantial proportion of patients, and show higher rates of conduct disorder, antisocial behavior, substance misuse, violence, poor social adjustment, mood instability and academic problems. Stimulant medications are among the first-line agents in the pharmacotherapy of ADHD. Of the stimulant medications, methylphenidate(MPH) is the most studied. However, immediate-release MPH has a short duration of action requiring multiple daily dosing. Such dosing creates significant problems for schools, parents, and patients and may result in poor adherence. OROS MPH is a once-daily, osmotic, controlledrelease formulation of MPH. Each daily dose is behaviorally effective through 12 hours. It is known that OROS MPH have continued effectiveness in treating ADHD children. The purpose of this study is to assess the effectiveness of OROS MPH treatment by comparing the ADS (Attention Diagnosis System; Korean version of TOVA) score prior and post OROS MPH treatment in adolescent ADHD patients and to find out optimal treatment dose. Methods: A 4-week open trial of OROS MPH was conducted in 345 adolescent ADHD patients(age mean±SD = 13.51±2.24). Of them 294 patients were drug-naive and 51 patients were drug-switching to OROS MPH. The drug dose was titrated to control patient’s symptom at each visit. The ADS tests were done at baseline and 4th week after medication. To compare the differences the statistical analyses such as T-test and ANOVA were done. Summary of results and Statistical assessments: Male patients are more prevalent (M:F = 225:120 [65.2%:34.8%]). The positive family history of ADHD was 166/345 (48.1%). The reasons for switching medication are low efficacy (6/52, 12%) and low compliance (44/52, 85%). The comorbid diseases are anxiety disorder (30/345=9%) and tic disorder (20/345, 5.8%). The dose of OROS MPH were increased according to treatment period (repeated measure ANOVA, p < 0.001), such as baseline 22.96±13.34 mg, 2nd week 33.22±13.59 mg and 4th week 37.58±13.76 mg. Only 1.0% (3/330) of patients reported that drug effects sustained until evening, so in order to control symptoms
S568
P.7.a Child and adolescent disorders and treatment – Disorders (clinical)
in late evening most of patients need one more administration of short-acting methylphenidate at early evening. At the baseline ADS test no difference was found on according to gender and age. After treatment the inattention was improved objectively (2.67±0.49 vs. 2.48±0.58). The mental energy changes were significant (2.59±0.52 vs. 2.38±0.63). The mood stability and executive function showed no significant changes. The average dose of OROS MPH was 1.1 mg/kg. Conclusion: The adolescent ADHD symptoms were wellcontrolled by OROS MPH. The initial optimal treatment dose is 1.1 mg/kg of OROS MPH.
P.7.a.003 Efficacy of aripiprazole in the treatment of adolescents with schizophrenia M. Nyilas1 ° , A. Forbes2 , R. McQuade2 , R. Owen3 , K. Cox4 , W.H. Carson1 . 1 Otsuka Pharmaceutical Development and Commercialization, Global Clinical, Princeton, USA; 2 Otsuka Pharmaceutical Development and Commercialization, Global Medical Affairs, Princeton, USA; 3 Bristol Myers Squibb, Clinical, Wallingford, USA; 4 I3 Research, Clinical Research, Princeton, USA Introduction: Although child-onset schizophrenia appears to be a rare condition, adolescent-onset schizophrenia appears to be a relatively common phenomenon, with up to 39% of males who suffer from schizophrenia experiencing their first psychotic episode before their twentieth birthday. Unfortunately, there is a paucity of double-blind and placebo controlled treatment studies that have been performed in adolescents suffering from schizophrenia. Aripiprazole is a first-in-class, dopamine partial agonist approved in adults for treatment of schizophrenia and bipolar disorder. Aripiprazole is a potent partial agonist at dopamine D2 receptors; it is also a partial agonist at serotonin 5-HT1A receptors, and an antagonist at 5-HT2A receptors. Aripiprazole doses of 10 to 30 mg/day have been shown to be efficacious in the treatment of positive and negative symptoms in short- and long-term treatment of schizophrenia or schizoaffective disorder in adults. The overall pharmacological profile of aripiprazole, including a relatively low affinity for H1 histamine receptors, and D2 partial agonism, may account for the relatively low propensity for induction of weight gain, EPS, sedation, and hyperprolactinemia reported in adult patients. The purpose of this randomized, double-blind, placebocontrolled clinical trial was to assess the efficacy and tolerability of aripiprazole in the acute treatment of adolescents with schizophrenia. The a priori hypotheses were that aripiprazole would be superior to placebo in ameliorating symptoms of psychosis and that aripiprazole would be generally well-tolerated in this patient group. Methods: This 6-week, double-blind, randomized placebocontrolled trial was conducted at 101 centers in 13 countries, with an independent safety monitoring board. After a 3-day antipsychotic washout period, 13−17 year-old (mean age 15.5) patients with a DSM-IV diagnosis of schizophrenia confirmed by the K-SADS-PL and with a PANSS total score 70, were randomized 1:1:1 to placebo, or a fixed dose of 10 mg or 30 mg of aripiprazole reached after a 5 or 11 day titration, respectively, and maintained for a minimum of 2 weeks. The primary endpoint was mean change from baseline to endpoint (week 6 LOCF) on the
PANSS total score. Key secondary endpoints included the PANSS positive and negative subscales, and CGI Improvement score. Results: Over 85% of 302 randomized patients completed the 6-week study. The mean baseline PANSS score for patients was 94.5. By week 1, patients randomized to 30 mg had PANSS scores that were statistically significantly different from placebo. At end of study, both the 10 mg and 30 mg doses showed significant differences from placebo (−26.7 and −28.6, respectively; placebo −21.2). Both doses showed statistically significant improvement on the PANSS positive and CGI-I scales compared to placebo and 10 mg dose was superior to placebo on PANSS negative score. Approximately 5% of aripiprazole patients discontinued due to adverse events. Weight gain and changes in prolactin were minimal. Conclusions: • Both 10 mg and 30 mg doses of aripiprazole were superior to placebo at week 6 on PANSS-total score. • Both doses showed statistically significant improvement relative to placebo on the PANSS positive and CGI-I scales, and the 10 mg dose was superior to placebo on PANSS negative score. References [1] Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB, 2002 Jul, Aripiprazole, a novel antipsychotic, is a highaffinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302(1), 381−9.
P.7.a.004 The extent of pupillary fluctuations in the dark correlates with anxiety, depressive and autistic symptoms in ADHD K. Szab´o1 ° , K. Nagyov´a2 , Z. Szele2 , A. Vetr´o1 , Z. Tokaji2 . 1 University of Szeged, Department of Child and Adolescent Psychiatry, Szeged, Hungary; 2 Biological Research Center, Institute of Biophysics, Szeged, Hungary Diagnostic symptoms of attention deficit hyperactivity disorder (ADHD) are grouped into hyperactive/impulsive and inattentive ones. Besides these, other kind of symptoms characteristic for different psychiatric disorders are also frequently present in ADHD children. Recently we have shown in video-pupillographic sleepiness tests that darkness containing only a weakly illuminating fixation point have a beneficial effect by improving alertness of children with ADHD (Tokaji et al., 2006). Since several studies have found that alertness is decreased in children with ADHD, a possibly interesting question is whether inattentive, hyperactive/impulsive, and some possible comorbid disorder symptoms correlate quantitatively with sleepiness test results. Twenty-seven methylphenidate-treated ADHD children (10.8±2 years) were studied before and 1 hour after taking their regular school-day first methylphenidate (MPH) dose by standard videopupillographic sleepiness test (11 minute long recording of their left eyes in complete darkness) (see L¨udtke et al., 1998). The accompanying parents or attendants were asked to characterize their children by filling out a symptom questionnaire (“Stony Brook”) asking for scaling symptoms of attention deficit, hyperactivity/impulsivity, explosiveness/opposition, antisocial behavior, anxiety, depression, phobia, hallucinations, autism, and separation anxiety. Twenty-four subjects were able to complete the videopupillographic measurement without MPH, thus we performed our analyses on this population by correlating average pupil diameters and the extent of pupillary fluctuations using pupillary
P.7.a Child and adolescent disorders and treatment – Disorders (clinical) P.7.a.001 Agomelatine efficacy on major sleep disturbances in Smith-Magenis syndrome: an exploratory, open study in children A. Fabiano1 ° , H. de Leersnyder2 . 1 Institut de recherches internationales Servier, Neuropsychiatrie, Courbevoie, France; 2 Hˆ opital Necker, Syst`eme nerveux EEG, Paris, France Introduction: Smith-Magenis syndrome (SMS) is a mental retardation disease with distinctive behavioural characteristics, dysmorphic features and congenital anomalies ascribed to a deletion of chromosome 17p11.2. Severe sleep disturbances and maladaptive daytime behavior have been linked to an abnormal circadian pattern of melatonin, with a diurnal instead of a nocturnal secretion of this hormone. This is the first biologic model of sleep and behavioral disorders in a genetic disease. During the night, early sleep onset, frequent awakenings and early sleep offset are consistent features of the disease and are highly specific diagnostic criteria in SMS. During the day patients are tired in the morning and tantrums appears when melatonin rise. Naps and sleep attacks occur when melatonin peaks at midday and in the evening, respectively. Elucidating pathophysiological mechanisms of behavioral phenotypes is particularly relevant to therapeutic approach in genetic diseases Because the circadian rhythm of melatonin is controlled by the sympathetic nervous system, SMS patients were given acebutolol, as B1-adrenergic antagonists reduce the production of melatonin. After a morning B1-adrenergic antagonists administration, plasma melatonin levels rapidly decreased in all SMS patients. An open clinical trial was designed to assess the potential efficacy of agomelatine, a melatonin agonist and 5-HT2C antagonist [1], on the sleep disturbances in children suffering from SMS. Methods: Open phase II study with direct individual benefit without randomisation. All patients were treated during 6-month with agomelatine (1 or 5 mg o.d., as evening dose). Acebutolol (B1 antagonist, 10 mg/kg o.d., as morning dose) was coadministered to block endogeneous melatonin secretion. The primary efficacy criteria were the actigraphy parameters. Results: Seven male and three female SMS patients, aged from 6 to 17 years, were included. Nine patients completed the 6-month study whereas one patient withdrew from the study, before having taken any dose of agomelatine, due to non medical reason. The results from actigraphy were consistent with those obtained with the sleep diary and the children’s sleep questionnaire, all of which showed less frequent and shorter nocturnal waking up than at baseline, and indicated also a decreased mean duration of daytime naps over the 6-month study period. According to the investigator, clinical improvement in the children was notable and the benefit of the treatment was also confirmed by the parents of every child. The medication allowed children to sleep deeply and to be quiet whereas in the past it used not to be. Sleep was no more fragmented by prolonged nocturnal awakenings and waking-up in the morning was delayed. Conclusion: Data from this exploratory, open trial indicate that 1 or 5 mg agomelatine, when co-administred with acebutolol
S567
(10 mg/kg), was an effective and well-tolerated treatment of disturbed sleep in SMS. On the family request, eight patients are still on treatment and receive now agomelatine since November 2002. Additional trials are needed to confirm the therapeutic potential of agomelatine in SMS. References [1] Millan MJ, Gobert A, Lejeune F, et al, 2003, The novel melatonin agonist Valdoxan (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. JPET 306, 954–964.
P.7.a.002 Adolescent attention deficit/hyperactivity disorder (ADHD) treatment with controlledrelease methylphenidate E. Oh1 ° , J.H. Yoo2 . 1 Dr. Oh’s Psychiatric Clinic, Psychiatry, Suwon, South-Korea; 2 Miclinic skin and LASER center, Dermatology, Seoul, South-Korea Purpose of the study: ADHD is one of the most prevalent childhood and adolescent psychiatric disorders. This disorder significantly affects the patient’s behavior and performance at school and at home and disrupts relationships with family, teachers, and peers. Multiple studies found that this disorder persists into adolescence and adulthood in a substantial proportion of patients, and show higher rates of conduct disorder, antisocial behavior, substance misuse, violence, poor social adjustment, mood instability and academic problems. Stimulant medications are among the first-line agents in the pharmacotherapy of ADHD. Of the stimulant medications, methylphenidate(MPH) is the most studied. However, immediate-release MPH has a short duration of action requiring multiple daily dosing. Such dosing creates significant problems for schools, parents, and patients and may result in poor adherence. OROS MPH is a once-daily, osmotic, controlledrelease formulation of MPH. Each daily dose is behaviorally effective through 12 hours. It is known that OROS MPH have continued effectiveness in treating ADHD children. The purpose of this study is to assess the effectiveness of OROS MPH treatment by comparing the ADS (Attention Diagnosis System; Korean version of TOVA) score prior and post OROS MPH treatment in adolescent ADHD patients and to find out optimal treatment dose. Methods: A 4-week open trial of OROS MPH was conducted in 345 adolescent ADHD patients(age mean±SD = 13.51±2.24). Of them 294 patients were drug-naive and 51 patients were drug-switching to OROS MPH. The drug dose was titrated to control patient’s symptom at each visit. The ADS tests were done at baseline and 4th week after medication. To compare the differences the statistical analyses such as T-test and ANOVA were done. Summary of results and Statistical assessments: Male patients are more prevalent (M:F = 225:120 [65.2%:34.8%]). The positive family history of ADHD was 166/345 (48.1%). The reasons for switching medication are low efficacy (6/52, 12%) and low compliance (44/52, 85%). The comorbid diseases are anxiety disorder (30/345=9%) and tic disorder (20/345, 5.8%). The dose of OROS MPH were increased according to treatment period (repeated measure ANOVA, p < 0.001), such as baseline 22.96±13.34 mg, 2nd week 33.22±13.59 mg and 4th week 37.58±13.76 mg. Only 1.0% (3/330) of patients reported that drug effects sustained until evening, so in order to control symptoms
S568
P.7.a Child and adolescent disorders and treatment – Disorders (clinical)
in late evening most of patients need one more administration of short-acting methylphenidate at early evening. At the baseline ADS test no difference was found on according to gender and age. After treatment the inattention was improved objectively (2.67±0.49 vs. 2.48±0.58). The mental energy changes were significant (2.59±0.52 vs. 2.38±0.63). The mood stability and executive function showed no significant changes. The average dose of OROS MPH was 1.1 mg/kg. Conclusion: The adolescent ADHD symptoms were wellcontrolled by OROS MPH. The initial optimal treatment dose is 1.1 mg/kg of OROS MPH.
P.7.a.003 Efficacy of aripiprazole in the treatment of adolescents with schizophrenia M. Nyilas1 ° , A. Forbes2 , R. McQuade2 , R. Owen3 , K. Cox4 , W.H. Carson1 . 1 Otsuka Pharmaceutical Development and Commercialization, Global Clinical, Princeton, USA; 2 Otsuka Pharmaceutical Development and Commercialization, Global Medical Affairs, Princeton, USA; 3 Bristol Myers Squibb, Clinical, Wallingford, USA; 4 I3 Research, Clinical Research, Princeton, USA Introduction: Although child-onset schizophrenia appears to be a rare condition, adolescent-onset schizophrenia appears to be a relatively common phenomenon, with up to 39% of males who suffer from schizophrenia experiencing their first psychotic episode before their twentieth birthday. Unfortunately, there is a paucity of double-blind and placebo controlled treatment studies that have been performed in adolescents suffering from schizophrenia. Aripiprazole is a first-in-class, dopamine partial agonist approved in adults for treatment of schizophrenia and bipolar disorder. Aripiprazole is a potent partial agonist at dopamine D2 receptors; it is also a partial agonist at serotonin 5-HT1A receptors, and an antagonist at 5-HT2A receptors. Aripiprazole doses of 10 to 30 mg/day have been shown to be efficacious in the treatment of positive and negative symptoms in short- and long-term treatment of schizophrenia or schizoaffective disorder in adults. The overall pharmacological profile of aripiprazole, including a relatively low affinity for H1 histamine receptors, and D2 partial agonism, may account for the relatively low propensity for induction of weight gain, EPS, sedation, and hyperprolactinemia reported in adult patients. The purpose of this randomized, double-blind, placebocontrolled clinical trial was to assess the efficacy and tolerability of aripiprazole in the acute treatment of adolescents with schizophrenia. The a priori hypotheses were that aripiprazole would be superior to placebo in ameliorating symptoms of psychosis and that aripiprazole would be generally well-tolerated in this patient group. Methods: This 6-week, double-blind, randomized placebocontrolled trial was conducted at 101 centers in 13 countries, with an independent safety monitoring board. After a 3-day antipsychotic washout period, 13−17 year-old (mean age 15.5) patients with a DSM-IV diagnosis of schizophrenia confirmed by the K-SADS-PL and with a PANSS total score 70, were randomized 1:1:1 to placebo, or a fixed dose of 10 mg or 30 mg of aripiprazole reached after a 5 or 11 day titration, respectively, and maintained for a minimum of 2 weeks. The primary endpoint was mean change from baseline to endpoint (week 6 LOCF) on the
PANSS total score. Key secondary endpoints included the PANSS positive and negative subscales, and CGI Improvement score. Results: Over 85% of 302 randomized patients completed the 6-week study. The mean baseline PANSS score for patients was 94.5. By week 1, patients randomized to 30 mg had PANSS scores that were statistically significantly different from placebo. At end of study, both the 10 mg and 30 mg doses showed significant differences from placebo (−26.7 and −28.6, respectively; placebo −21.2). Both doses showed statistically significant improvement on the PANSS positive and CGI-I scales compared to placebo and 10 mg dose was superior to placebo on PANSS negative score. Approximately 5% of aripiprazole patients discontinued due to adverse events. Weight gain and changes in prolactin were minimal. Conclusions: • Both 10 mg and 30 mg doses of aripiprazole were superior to placebo at week 6 on PANSS-total score. • Both doses showed statistically significant improvement relative to placebo on the PANSS positive and CGI-I scales, and the 10 mg dose was superior to placebo on PANSS negative score. References [1] Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB, 2002 Jul, Aripiprazole, a novel antipsychotic, is a highaffinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302(1), 381−9.
P.7.a.004 The extent of pupillary fluctuations in the dark correlates with anxiety, depressive and autistic symptoms in ADHD K. Szab´o1 ° , K. Nagyov´a2 , Z. Szele2 , A. Vetr´o1 , Z. Tokaji2 . 1 University of Szeged, Department of Child and Adolescent Psychiatry, Szeged, Hungary; 2 Biological Research Center, Institute of Biophysics, Szeged, Hungary Diagnostic symptoms of attention deficit hyperactivity disorder (ADHD) are grouped into hyperactive/impulsive and inattentive ones. Besides these, other kind of symptoms characteristic for different psychiatric disorders are also frequently present in ADHD children. Recently we have shown in video-pupillographic sleepiness tests that darkness containing only a weakly illuminating fixation point have a beneficial effect by improving alertness of children with ADHD (Tokaji et al., 2006). Since several studies have found that alertness is decreased in children with ADHD, a possibly interesting question is whether inattentive, hyperactive/impulsive, and some possible comorbid disorder symptoms correlate quantitatively with sleepiness test results. Twenty-seven methylphenidate-treated ADHD children (10.8±2 years) were studied before and 1 hour after taking their regular school-day first methylphenidate (MPH) dose by standard videopupillographic sleepiness test (11 minute long recording of their left eyes in complete darkness) (see L¨udtke et al., 1998). The accompanying parents or attendants were asked to characterize their children by filling out a symptom questionnaire (“Stony Brook”) asking for scaling symptoms of attention deficit, hyperactivity/impulsivity, explosiveness/opposition, antisocial behavior, anxiety, depression, phobia, hallucinations, autism, and separation anxiety. Twenty-four subjects were able to complete the videopupillographic measurement without MPH, thus we performed our analyses on this population by correlating average pupil diameters and the extent of pupillary fluctuations using pupillary