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P.7.d.004 Efficacy and safety of fluoxetine in the treatment of posttraumatic stress disorder in children and adolescents
P.7.d. Child and adolescent disorders and treatment − Treatment (clinical) P.7.d.003 Effects of glutamatergic agents in the treatment of compulsivity and impulsivity in child and adolescent psychiatry: a systematic review K. Mechler1 ° , A. H¨age1 , N. Schweinfurth2 , J. Buitelaar3 , J. Glennon3 , T. Banaschewski4 , R. Dittmann1 1 Central Institute of Mental Health, Paediatric Psychopharmacology − Child and Adolescent Psychiatry and Psychotherapy, Mannheim, Germany; 2 Central Institute of Mental Health, Paediatric Psychopharmacology − Child and Adolescent Psychiatry and Psychotherapy − Mannheim, Department of Psychiatry − University Psychiatric Centre Basel UPK − University of Basel − Basel − Switzerland, Germany; 3 Donders Institute for Brain − Cognition and Behavior − RUNMC Radboud University Nijmegen Medical Center − and Karakter Child and Adolescent Psychiatry University Centre, Department of Cognitive Neuroscience, Nijmegen, The Netherlands; 4 Central Institute of Mental Health, Child and Adolescent Psychiatry and Psychotherapy, Mannheim, Germany Introduction: Compulsivity − as a symptom domain − is observed in several psychiatric disorders with onset in childhood or adolescence, particularly in Obsessive-Compulsive Disorder (OCD), Autism Spectrum Disorders (ASD), and Attention Deficit/ Hyperactivity Disorder (ADHD). It represents a serious burden to affected patients and their families and is closely linked to impulsivity and addictive behaviour [1]. Research has implicated glutamatergic projections to and from the various frontal subregions in the pathogenesis of compulsivity [2]. Reducing striatal glutamate release or antagonising the action of glutamate may therefore lead to viable treatment strategies [3]. This review evaluates available literature concerning the effects of glutamatergic agents in the treatment of compulsivity and impulsivity in psychiatric disorders of paediatric patients. Methods: PubMed was searched for studies of glutamatergic agents in ADHD, ASD, Pervasive developmental disorder (PDD), Fragile X Syndrome (FXS) or OCD. We also included studies of related disorders (e.g. Trichotillomania (TTM) or nail-biting), articles from reference lists and abstracts from recent international research conferences. In order to explore efficacy in paediatric patients, only randomized, placebo-controlled, double-blind trials were considered for further analysis. Relevant information such as outcome measures, pre-post-treatment differences, effect sizes etc. were collected from the publications, if available. Number-neededto-treat (NNT) was calculated wherever responder definitions and rates had been provided. Results: Forty-nine publications examining six glutamatergic substances (d-cycloserine, memantine, minocycline, modafinil, n-acetylcysteine, riluzole) in patients with OCD, ASD/PDD/FXS, or ADHD were identified. Of these, 21 included paediatric patients, 25 adult patients, and three trials both groups. Twelve paediatric studies were designed as randomized, placebo-controlled, double-blind, including one withdrawal trial. One publication comprised a pooled analysis of three studies of modafinil in ADHD. It also reflected the only study investigating monotherapeutic drug use. All other trials investigated augmentation therapies. Sample sizes ranged from N = 17 to N = 638. Six of 11 trials reported statistically significant differences in favour of the drug investigated. Effect sizes were reported in 8 of 11 trials, ranging from 0.053 to 1.504. We could calculate NNT for 5 of 11 trials, ranging from 3.6 to 50. Effect sizes were generally small, only
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memantine and riluzole in ASD and modafinil in ADHD showed moderate to large effect sizes in single trials. Heterogeneity in study design and outcome measures as well as small sample sizes did not allow for a meta-analytical approach. Generally, drugs were well tolerated, most adverse events were mild. One case of pancreatitis and several cases of transient elevated liver function tests were reported for riluzole. Conclusions: Available data support the hypothesis that glutamatergic agents are of potential value in the treatment of compulsivity/impulsivity in children and adolescents with OCD, ASD/PDD/FXS or ADHD. Especially memantine, riluzole and modafinil appear to stand out as candidates for further investigation in larger clinical trials. In addition, good risk-benefit profiles have so far been shown for these compounds. Therefore, further formal clinical trials are warranted to substantiate findings on short- and long-term efficacy, tolerability, and safety of these medications in paediatric populations. Clinical research of this nature is a core element of the EU-funded TACTICS project. References [1] Chamberlain S.R., Fineberg N.A., Blackwell A.D., Robbins T.W., Sahakian B.J., 2006. Motor inhibition and cognitive flexibility in obsessive-compulsive disorder and trichotillomania. Am J Psych 163: 1282–1284. [2] Lewin, A.B., Storch, E.A., Geffken, G.R., Goodman, W.K., Murphy, T.K., 2006. A neuropsychiatric review of pediatric obsessivecompulsive disorder: etiology and efficacious treatments. Neuropsychiatr Dis Treat 2: 21−31. [3] Javitt, D.C., 2004. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 9: 984–997, 979. Disclosure statement: The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement nº 278948 (TACTICS project). This abstract reflects only the authors’ views and the European Union is not liable for any use that may be made of the information contained therein.
P.7.d.004 Efficacy and safety of fluoxetine in the treatment of posttraumatic stress disorder in children and adolescents D. Martsenkovskyi1 °
1 TMA
“Psychiatry”, Kyiv, Ukraine
Introduction: Military action in Ukraine has led to more than a million displaced persons, many of them children and adolescents. In these children and adolescents there is an increased diagnosis of PTSD. In addition to PTSD, these children and adolescents often fulfill the diagnostic criteria for Attention Deficit Hyperactivity Disorder, Depressive and Anxiety disorders, and Disruptive, Impulse-Control and Conduct Disorders. Open-label studies have demonstrated the efficacy of SSRIs for the treatment of PTSD, primarily paroxetine. The feasibility of using these drugs in children and adolescents is controversial [1−2]. Objective: To evaluate the short- and long-term efficacy and tolerability of fluoxetine in the treatment of PTSD in children. Methods: A double-blind, placebo-controlled 12-week study with a fixed dose of fluoxetine (20−40 mg) was conducted. The trial design consisted of a 1-week, single-blind, placebo run-in period, followed by a 12-week treatment period and a 2-week taper phase. We randomized 110 children aged from 12 to 18 years (median 14.2 years), who were evacuated from the combat zone in eastern Ukraine and who met the DSM-5 criteria for PTSD. Drug efficacy was assessed weekly using the Clinician-Administered PTSD Scale Part 2 (CAPS-2) in clusters (re-experiencing, avoidance/numbing and hyperarousal), and the Clinical Global Impression Improvement/Severity (CGI-I/CGI-S) scales. Presence of
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P.7.d. Child and adolescent disorders and treatment − Treatment (clinical)
baseline depression was determined using the M.I.N.I. Safety measures: Adverse event (AE) recording, clinical laboratory measures, vital signs parameters, electrocardiograms (ECGs), suicidality assessment, and physical examination. Result: The reduction in CAPS-2 score was significantly different between children randomized to fluoxetine treatment and children receiving placebo in a week-12 endpoint (treatment difference −11.10; 95% CI −13.4, −7.38; p < 0.001). A significantly greater proportion of fluoxetine-treated patients (52%) than placebo-treated patients (43%) were treatment responders according to the CGI scale (adjusted odds ratio = 2.28; 95% CI 1.75, 2.93; p < 0.001). The most common adverse effects in the fluoxetine group were somnolence, headache and irritability, each occurring in <20% of patients. The effect of fluoxetine in the treatment of PTSD is not solely due to its effect on comorbid depressive symptoms. Fluoxetine is statistically significantly effective in treating PTSD in children and adolescents with and without comorbid depression or depressive symptoms (p < 0.001). Fluoxetine is effective in treating all three symptom clusters of PTSD, including the re-experiencing cluster which can be considered to be the most specific for PTSD. Fluoxetine is also effective in patients with PTSD alone and in patients with PTSD and a comorbid condition. There were no significant differences in therapeutic response in these patients. Conclusion: Fluoxetine at a dose of 20−40 mg/day is more effective than placebo, well-tolerated and can be recommended in pediatric practice. More research is needed on the efficacy of combination therapies of fluoxetine and psychological methods of treatment, primarily Trauma Focused CBT and EMDR − desensitization and processing of eye movement and psychoeducational work with primary support group of child. References [1] Smith P, Perrin S, Dalgleish T, et al. Treatment of posttraumatic stress disorder in children and adolescents. Wolters Kluwer Health 2013; 26: 66−72. [2] NICE (2005) Post-traumatic stress disorder (PTSD): The management of PTSD in adults and children in primary and secondary care. NICE clinical guideline. Available at http://www.nice.org.uk/guidance/cg26 [NICE guideline].
P.7.d.005 Effects of methylphenidate on height in ADHD children. The monitoring of bone age within the ADDUCE project S. Carucci1 ° , M. Caddeo2 , R. Romaniello1 , A. Carta1 , A. Lampis3 , A. Zuddas1 1 Center for Pharmacological Therapies in Child and Adolescent Neuropsychiatry, Department of Biomedical Science − University of Cagliari, Cagliari, Italy; 2 Pediatric Clinic, Dept Pediatric Science and Clinical Medicine − P.O. Pediatrico − Microcitemico − University of Cagliari, Cagliari, Italy; 3 Pediatric Clinic, P.O. Pediatrico − Microcitemico, Cagliari, Italy Background: CNS stimulants represent the most effective medication in improving the core symptoms of ADHD, however in the last 30 years, there has been increasing concern about the risks associated with these medications in particular with respect possible growth deficits [1]. Although poor growth is a common concern, especially with children already on the lower growth percentiles, the impact of medication on growth and pubertal maturation has remained somehow unclear and stimulants effects
at different ages have not been extensively investigated. Many unanswered questions remain about the biological mechanism underlying the growth deficit in medicated ADHD subjects, some of the hypothesis considering that the condition of ADHD per se is associated to an impaired growth condition [2]. Objectives: To evaluate, within the prospective, longitudinal, pharmacovigilance, EU funded project ADDUCE, whether ADHD children exhibit an abnormal pattern of growth per se before starting stimulant medication, whether methylphenidate (MPH) interferes with growth in medicated ADHD children and finally to explore the application of monitoring of bone age as a helpful tool in order to study adverse developmental effects of MPH. Methods: Height, Weight, BMI, Target Height, pubertal stage and X-ray of left wrist were collected from 36 drug na¨ıve ADHD children, aged 6−12, at three time points of the ADDUCE longitudinal protocol: baseline visit and after 12 and 24 months. Results: Baseline data analysis revealed normal growth parameters for the ADHD population: height Z-score was 0.33±1.19, weight Z-score 0.52±1.97, BMI Z-score 1.57±2.68 and the Target Height Z-score −0.82±0.88, resulting even slightly taller than expected. The bone age calculated by comparing each of 20 bones of an X-ray of the left hand with the Tanner and Whitehouse II method showed no significant differences between the bone age (8.11±2.19) and the chronological age (8.85±1.77) although about the 61% of subjects reported a slightly lower bone age than expected (7.23±1.61). Same results have been evidenced by the analysis of carpal bone (CB 8.51±2.10) and radio ulna and short bones (RUS 7.67±2.29). Only one subject has presented a Tanner pubertal stage G4 with a testicular volume of 12 cc, with no significant abnormalities of the bone age. No significant differences have been found by further dividing the sample for gender, age (6−10 vs 10−12 years old) or bone age (normal, low or increased). Analysis of the growth parameters and bone age collected at the follow up visits are in due course and will be presented during the conference. Discussion: Results from the present sample reveal that ADHD children presents with a normal growth pattern before starting medication confirming that a possible impact on growth, in particular with respect to height, could be related more to stimulant medication than to the ADHD condition per se. The study of bone age and pubertal stage at follow up will allow to get more information about the growth outcome helping to clarify the effect of MPH with regards to height and pubertal maturation. References [1] Faraone SV, Biederman J, Morley CP, Spencer TJ, 2008. Effect of Stimulants on Height and Weight: A Review of the Literature. J. Am. Acad. Child Adolesc. Psychiatry, 47(9):994–1009. [2] Spencer TJ, Biederman J, Harding M, et al. 1996. Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays? J Am Acad Child Adolesc Psychiatry 35: 1460–1469.
P.7.d.008 The impact of sleep on inattention, impulsiveness and cognitive failures B.I. Voinescu1 ° 1 Babes Bolyai University, Clinical Psychology, Cluj-Napoca, Romania Purpose: To evaluate the impact of several sleep related variables, such as subjective sleep quality, total sleep duration, stress-induced sleep reactivity and daytime fatigue on inattention, impulsiveness
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memantine and riluzole in ASD and modafinil in ADHD showed moderate to large effect sizes in single trials. Heterogeneity in study design and outcome measures as well as small sample sizes did not allow for a meta-analytical approach. Generally, drugs were well tolerated, most adverse events were mild. One case of pancreatitis and several cases of transient elevated liver function tests were reported for riluzole. Conclusions: Available data support the hypothesis that glutamatergic agents are of potential value in the treatment of compulsivity/impulsivity in children and adolescents with OCD, ASD/PDD/FXS or ADHD. Especially memantine, riluzole and modafinil appear to stand out as candidates for further investigation in larger clinical trials. In addition, good risk-benefit profiles have so far been shown for these compounds. Therefore, further formal clinical trials are warranted to substantiate findings on short- and long-term efficacy, tolerability, and safety of these medications in paediatric populations. Clinical research of this nature is a core element of the EU-funded TACTICS project. References [1] Chamberlain S.R., Fineberg N.A., Blackwell A.D., Robbins T.W., Sahakian B.J., 2006. Motor inhibition and cognitive flexibility in obsessive-compulsive disorder and trichotillomania. Am J Psych 163: 1282–1284. [2] Lewin, A.B., Storch, E.A., Geffken, G.R., Goodman, W.K., Murphy, T.K., 2006. A neuropsychiatric review of pediatric obsessivecompulsive disorder: etiology and efficacious treatments. Neuropsychiatr Dis Treat 2: 21−31. [3] Javitt, D.C., 2004. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 9: 984–997, 979. Disclosure statement: The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement nº 278948 (TACTICS project). This abstract reflects only the authors’ views and the European Union is not liable for any use that may be made of the information contained therein.
P.7.d.004 Efficacy and safety of fluoxetine in the treatment of posttraumatic stress disorder in children and adolescents D. Martsenkovskyi1 °
1 TMA
“Psychiatry”, Kyiv, Ukraine
Introduction: Military action in Ukraine has led to more than a million displaced persons, many of them children and adolescents. In these children and adolescents there is an increased diagnosis of PTSD. In addition to PTSD, these children and adolescents often fulfill the diagnostic criteria for Attention Deficit Hyperactivity Disorder, Depressive and Anxiety disorders, and Disruptive, Impulse-Control and Conduct Disorders. Open-label studies have demonstrated the efficacy of SSRIs for the treatment of PTSD, primarily paroxetine. The feasibility of using these drugs in children and adolescents is controversial [1−2]. Objective: To evaluate the short- and long-term efficacy and tolerability of fluoxetine in the treatment of PTSD in children. Methods: A double-blind, placebo-controlled 12-week study with a fixed dose of fluoxetine (20−40 mg) was conducted. The trial design consisted of a 1-week, single-blind, placebo run-in period, followed by a 12-week treatment period and a 2-week taper phase. We randomized 110 children aged from 12 to 18 years (median 14.2 years), who were evacuated from the combat zone in eastern Ukraine and who met the DSM-5 criteria for PTSD. Drug efficacy was assessed weekly using the Clinician-Administered PTSD Scale Part 2 (CAPS-2) in clusters (re-experiencing, avoidance/numbing and hyperarousal), and the Clinical Global Impression Improvement/Severity (CGI-I/CGI-S) scales. Presence of
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P.7.d. Child and adolescent disorders and treatment − Treatment (clinical)
baseline depression was determined using the M.I.N.I. Safety measures: Adverse event (AE) recording, clinical laboratory measures, vital signs parameters, electrocardiograms (ECGs), suicidality assessment, and physical examination. Result: The reduction in CAPS-2 score was significantly different between children randomized to fluoxetine treatment and children receiving placebo in a week-12 endpoint (treatment difference −11.10; 95% CI −13.4, −7.38; p < 0.001). A significantly greater proportion of fluoxetine-treated patients (52%) than placebo-treated patients (43%) were treatment responders according to the CGI scale (adjusted odds ratio = 2.28; 95% CI 1.75, 2.93; p < 0.001). The most common adverse effects in the fluoxetine group were somnolence, headache and irritability, each occurring in <20% of patients. The effect of fluoxetine in the treatment of PTSD is not solely due to its effect on comorbid depressive symptoms. Fluoxetine is statistically significantly effective in treating PTSD in children and adolescents with and without comorbid depression or depressive symptoms (p < 0.001). Fluoxetine is effective in treating all three symptom clusters of PTSD, including the re-experiencing cluster which can be considered to be the most specific for PTSD. Fluoxetine is also effective in patients with PTSD alone and in patients with PTSD and a comorbid condition. There were no significant differences in therapeutic response in these patients. Conclusion: Fluoxetine at a dose of 20−40 mg/day is more effective than placebo, well-tolerated and can be recommended in pediatric practice. More research is needed on the efficacy of combination therapies of fluoxetine and psychological methods of treatment, primarily Trauma Focused CBT and EMDR − desensitization and processing of eye movement and psychoeducational work with primary support group of child. References [1] Smith P, Perrin S, Dalgleish T, et al. Treatment of posttraumatic stress disorder in children and adolescents. Wolters Kluwer Health 2013; 26: 66−72. [2] NICE (2005) Post-traumatic stress disorder (PTSD): The management of PTSD in adults and children in primary and secondary care. NICE clinical guideline. Available at http://www.nice.org.uk/guidance/cg26 [NICE guideline].
P.7.d.005 Effects of methylphenidate on height in ADHD children. The monitoring of bone age within the ADDUCE project S. Carucci1 ° , M. Caddeo2 , R. Romaniello1 , A. Carta1 , A. Lampis3 , A. Zuddas1 1 Center for Pharmacological Therapies in Child and Adolescent Neuropsychiatry, Department of Biomedical Science − University of Cagliari, Cagliari, Italy; 2 Pediatric Clinic, Dept Pediatric Science and Clinical Medicine − P.O. Pediatrico − Microcitemico − University of Cagliari, Cagliari, Italy; 3 Pediatric Clinic, P.O. Pediatrico − Microcitemico, Cagliari, Italy Background: CNS stimulants represent the most effective medication in improving the core symptoms of ADHD, however in the last 30 years, there has been increasing concern about the risks associated with these medications in particular with respect possible growth deficits [1]. Although poor growth is a common concern, especially with children already on the lower growth percentiles, the impact of medication on growth and pubertal maturation has remained somehow unclear and stimulants effects
at different ages have not been extensively investigated. Many unanswered questions remain about the biological mechanism underlying the growth deficit in medicated ADHD subjects, some of the hypothesis considering that the condition of ADHD per se is associated to an impaired growth condition [2]. Objectives: To evaluate, within the prospective, longitudinal, pharmacovigilance, EU funded project ADDUCE, whether ADHD children exhibit an abnormal pattern of growth per se before starting stimulant medication, whether methylphenidate (MPH) interferes with growth in medicated ADHD children and finally to explore the application of monitoring of bone age as a helpful tool in order to study adverse developmental effects of MPH. Methods: Height, Weight, BMI, Target Height, pubertal stage and X-ray of left wrist were collected from 36 drug na¨ıve ADHD children, aged 6−12, at three time points of the ADDUCE longitudinal protocol: baseline visit and after 12 and 24 months. Results: Baseline data analysis revealed normal growth parameters for the ADHD population: height Z-score was 0.33±1.19, weight Z-score 0.52±1.97, BMI Z-score 1.57±2.68 and the Target Height Z-score −0.82±0.88, resulting even slightly taller than expected. The bone age calculated by comparing each of 20 bones of an X-ray of the left hand with the Tanner and Whitehouse II method showed no significant differences between the bone age (8.11±2.19) and the chronological age (8.85±1.77) although about the 61% of subjects reported a slightly lower bone age than expected (7.23±1.61). Same results have been evidenced by the analysis of carpal bone (CB 8.51±2.10) and radio ulna and short bones (RUS 7.67±2.29). Only one subject has presented a Tanner pubertal stage G4 with a testicular volume of 12 cc, with no significant abnormalities of the bone age. No significant differences have been found by further dividing the sample for gender, age (6−10 vs 10−12 years old) or bone age (normal, low or increased). Analysis of the growth parameters and bone age collected at the follow up visits are in due course and will be presented during the conference. Discussion: Results from the present sample reveal that ADHD children presents with a normal growth pattern before starting medication confirming that a possible impact on growth, in particular with respect to height, could be related more to stimulant medication than to the ADHD condition per se. The study of bone age and pubertal stage at follow up will allow to get more information about the growth outcome helping to clarify the effect of MPH with regards to height and pubertal maturation. References [1] Faraone SV, Biederman J, Morley CP, Spencer TJ, 2008. Effect of Stimulants on Height and Weight: A Review of the Literature. J. Am. Acad. Child Adolesc. Psychiatry, 47(9):994–1009. [2] Spencer TJ, Biederman J, Harding M, et al. 1996. Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays? J Am Acad Child Adolesc Psychiatry 35: 1460–1469.
P.7.d.008 The impact of sleep on inattention, impulsiveness and cognitive failures B.I. Voinescu1 ° 1 Babes Bolyai University, Clinical Psychology, Cluj-Napoca, Romania Purpose: To evaluate the impact of several sleep related variables, such as subjective sleep quality, total sleep duration, stress-induced sleep reactivity and daytime fatigue on inattention, impulsiveness