Le Journal of Child and Adolescent Psychopharmacology consacre intégralement son numéro de novembre 2016 au traitement pharmacologique de l’autisme.

1. Koplewicz HS. From the Editor-in-Chief’s Desk. Journal of Child and Adolescent Psychopharmacology ;2016 (2016/11/01) ;26(9):773-773.

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2. Hendren RL, James SJ, Widjaja F, Lawton B, Rosenblatt A, Bent S. Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism. Journal of Child and Adolescent Psychopharmacology ;2016 (2016/11/01) ;26(9):774-783.

Abstract Objective : Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress. We sought to determine if methyl B12, a key metabolic cofactor for cellular methylation reactions and antioxidant defense, could improve symptoms of ASD. Methods : A total of 57 children with ASD were randomly assigned to 8 weeks of treatment with methyl B12 (75 ??g/kg) or saline placebo every 3 days in a subcutaneous injection. The primary outcome measure was overall improvement in symptoms of ASD as measured by the Clinical Global Impressions-Improvement (CGI-I) score. Secondary outcome measures included changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). Laboratory measures of methionine methylation and antioxidant glutathione metabolism were assessed at baseline and 8 weeks. Results : A total of 50 children (mean age 5.3 years, 79% male) completed the study. The primary outcome measure ? the clinician rated CGI-I score ? was statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2 ?0.2, p ?= ?0.005). Clinical improvement among children treated with methyl B12 was positively correlated with increases in plasma methionine (p ?= ?0.05), decreases in S-adenosyl-l-homocysteine (SAH) (p ?= ?0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH (p ?= ?0.007), indicating an improvement in cellular methylation capacity. No improvements were observed in the parent-rated ABC or SRS. Conclusions : Methyl B12 treatment improved clinician-rated symptoms of ASD that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity. Clinical Trial Registry : Efficacy Study of Subcutaneous Methyl B12 in Children with Autism : NCT01039792 (clinicaltrials.gov1).

Objective : Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress. We sought to determine if methyl B12, a key metabolic cofactor for cellular methylation reactions and antioxidant defense, could improve symptoms of ASD. Methods : A total of 57 children with ASD were randomly assigned to 8 weeks of treatment with methyl B12 (75 ??g/kg) or saline placebo every 3 days in a subcutaneous injection. The primary outcome measure was overall improvement in symptoms of ASD as measured by the Clinical Global Impressions-Improvement (CGI-I) score. Secondary outcome measures included changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). Laboratory measures of methionine methylation and antioxidant glutathione metabolism were assessed at baseline and 8 weeks. Results : A total of 50 children (mean age 5.3 years, 79% male) completed the study. The primary outcome measure ? the clinician rated CGI-I score ? was statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2 ?0.2, p ?= ?0.005). Clinical improvement among children treated with methyl B12 was positively correlated with increases in plasma methionine (p ?= ?0.05), decreases in S-adenosyl-l-homocysteine (SAH) (p ?= ?0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH (p ?= ?0.007), indicating an improvement in cellular methylation capacity. No improvements were observed in the parent-rated ABC or SRS. Conclusions : Methyl B12 treatment improved clinician-rated symptoms of ASD that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity. Clinical Trial Registry : Efficacy Study of Subcutaneous Methyl B12 in Children with Autism : NCT01039792 (clinicaltrials.gov1).

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3. Ghaleiha A, Alikhani R, Kazemi M-R, Mohammadi M-R, Mohammadinejad P, Zeinoddini A, Hamedi M, Shahriari M, Keshavarzi Z, Akhondzadeh S. Minocycline as Adjunctive Treatment to Risperidone in Children with Autistic Disorder : A Randomized, Double-Blind Placebo-Controlled Trial. Journal of Child and Adolescent Psychopharmacology ;2016 (2016/11/01) ;26(9):784-791.

Abstract Objective : This is an investigation of minocycline efficacy and safety as an adjuvant to risperidone in management of children with autism. Methods : Forty-six children with diagnosis of autistic disorder, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria and a score of ≥12 on the Aberrant Behavior Checklist-Community (ABC-C) irritability subscale, who were already drug-free for at least 6 months participated in a randomized controlled trial and underwent 10 weeks of treatment with either minocycline (50 ?mg twice per day) or placebo in addition to risperidone titrated up to 2 ?mg/day (based on bodyweight). Patients were evaluated using ABC-C at baseline and at weeks 5 and 10. Results : General linear model repeated measures showed significant effect for time ? treatment interaction on the irritability [F(2, 88) ?= ?3.94, p ?= ?0.02] and hyperactivity/noncompliance [F(1.50, 66.05) ?= ?7.92, p ?= ?0.002], but not for lethargy/social withdrawal [F(1.61, 71.02) ?= ?0.98, p ?= ?0.36], stereotypic behavior [F(1.34, 58.80) ?= ?1.55, p ?= ?0.22], and inappropriate speech subscale scores [F(1.52, 66.88) ?= ?1.15, p ?= ?0.31]. By week 10, 21 (91.3%) patients in the minocycline group and 15 (65.5%) patients in the placebo group achieved at least partial response (p ?= ?0.03). Frequencies of adverse events were not significantly different between groups. Conclusions : Minocycline seems to be a safe and effective adjuvant in management of patients with autistic disorder. Future studies with larger sample sizes, longer follow-ups, and inflammatory cytokine measurements are warranted to confirm these findings and provide insight into minocycline mechanism of action in autistic disorder.

Objective : This is an investigation of minocycline efficacy and safety as an adjuvant to risperidone in management of children with autism. Methods : Forty-six children with diagnosis of autistic disorder, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria and a score of ≥12 on the Aberrant Behavior Checklist-Community (ABC-C) irritability subscale, who were already drug-free for at least 6 months participated in a randomized controlled trial and underwent 10 weeks of treatment with either minocycline (50 ?mg twice per day) or placebo in addition to risperidone titrated up to 2 ?mg/day (based on bodyweight). Patients were evaluated using ABC-C at baseline and at weeks 5 and 10. Results : General linear model repeated measures showed significant effect for time ? treatment interaction on the irritability [F(2, 88) ?= ?3.94, p ?= ?0.02] and hyperactivity/noncompliance [F(1.50, 66.05) ?= ?7.92, p ?= ?0.002], but not for lethargy/social withdrawal [F(1.61, 71.02) ?= ?0.98, p ?= ?0.36], stereotypic behavior [F(1.34, 58.80) ?= ?1.55, p ?= ?0.22], and inappropriate speech subscale scores [F(1.52, 66.88) ?= ?1.15, p ?= ?0.31]. By week 10, 21 (91.3%) patients in the minocycline group and 15 (65.5%) patients in the placebo group achieved at least partial response (p ?= ?0.03). Frequencies of adverse events were not significantly different between groups. Conclusions : Minocycline seems to be a safe and effective adjuvant in management of patients with autistic disorder. Future studies with larger sample sizes, longer follow-ups, and inflammatory cytokine measurements are warranted to confirm these findings and provide insight into minocycline mechanism of action in autistic disorder.

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4. Mostafavi M, Hardy P, Arnold LE. Varenicline in Autism : Theory and Case Report of Clinical and Biochemical Changes. Journal of Child and Adolescent Psychopharmacology ;2016 (2016/11/01) ;26(9):792-797.

Abstract Objective : To explore the potential benefits of varenicline (CHANTIX ?), a highly specific partial agonist of neuronal α4 ?2 nicotinic acetylcholine receptors (nAChR), for autistic symptoms, and present resulting biochemical changes in light of dopamine-related genotype. Methods : The clinical and biochemical changes exhibited by a 19-year-old severely autistic man following the use of low-dose varenicline in an ABA experiment of nature, and his genotype, were extracted from chart review. Clinical outcome was measured by the Ohio Autism Clinical Impression Scale and 12 relevant urine and saliva metabolites were measured by Neuroscience Laboratory. Results : With varenicline, this patient improved clinically and autonomic biochemical indicators in saliva and urine normalized, including dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), epinephrine, norepinephrine, taurine, and histamine levels. In addition, with varenicline, the dopamine D1 receptor (DRD1) antibody titer as well as the percent of baseline calmodulin-dependent protein kinase II (CaM KII) activity dropped significantly. When varenicline stopped, he deteriorated ; when it was resumed, he again improved. Doses of 0.5, 1, and 2 ?mg daily were tried before settling on a dose of 1.5 ?mg daily. He has remained on varenicline for over a year with no noticeable side effects. Conclusion : This report is, to the best of our knowledge, only the second to demonstrate positive effects of varenicline in autism, the first to show it in a severe case, and the first to show normalization of biochemical parameters related to genotype. As with the previous report, these encouraging results warrant further controlled research before clinical recommendations can be made.

Objective : To explore the potential benefits of varenicline (CHANTIX ?), a highly specific partial agonist of neuronal α4 ?2 nicotinic acetylcholine receptors (nAChR), for autistic symptoms, and present resulting biochemical changes in light of dopamine-related genotype. Methods : The clinical and biochemical changes exhibited by a 19-year-old severely autistic man following the use of low-dose varenicline in an ABA experiment of nature, and his genotype, were extracted from chart review. Clinical outcome was measured by the Ohio Autism Clinical Impression Scale and 12 relevant urine and saliva metabolites were measured by Neuroscience Laboratory. Results : With varenicline, this patient improved clinically and autonomic biochemical indicators in saliva and urine normalized, including dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), epinephrine, norepinephrine, taurine, and histamine levels. In addition, with varenicline, the dopamine D1 receptor (DRD1) antibody titer as well as the percent of baseline calmodulin-dependent protein kinase II (CaM KII) activity dropped significantly. When varenicline stopped, he deteriorated ; when it was resumed, he again improved. Doses of 0.5, 1, and 2 ?mg daily were tried before settling on a dose of 1.5 ?mg daily. He has remained on varenicline for over a year with no noticeable side effects. Conclusion : This report is, to the best of our knowledge, only the second to demonstrate positive effects of varenicline in autism, the first to show it in a severe case, and the first to show normalization of biochemical parameters related to genotype. As with the previous report, these encouraging results warrant further controlled research before clinical recommendations can be made.

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5. Kilincaslan A, Mutluer TD, Pasabeyoglu B, Tutkunkardas MD, Mukaddes NM. Effects of Atomoxetine in Individuals with Attention-Deficit/Hyperactivity Disorder and Low-Functioning Autism Spectrum Disorder. Journal of Child and Adolescent Psychopharmacology ;2016 (2016/11/01) ;26(9):798-806.

Abstract Objectives : This naturalistic, retrospective study investigated the effects of atomoxetine (ATX) on attention-deficit/hyperactivity disorder (ADHD) symptoms and autistic features in children with autism spectrum disorders (ASDs) and intellectual disability (ID). Methods : Participants (n ?= ?37, age range 6 ?17 years, mean : 10.16 ?± ?3.60) were assessed at baseline, 4th and 12th weeks using Clinical Global Impressions (CGI) scales, DSM-IV-based ADHD-rating scale (ADHD-RS), and amended Turkish version of Aberrant Behavior Checklist (ABC). The primary outcome measure was a treatment response defined by a CGI-improvement score of 1 or 2 together with a decrease of at least 25% in the parent-rated ADHD-RS total score at the end of 12th week. Results : Five patients (13.5%) stopped medication at 4 weeks due to ineffectivity (2) and intolerable side effects (increased motor activity and talkativeness [n ?= ?1], irritability [n ?= ?2], temper outbursts [n ?= ?2], and increased blood pressure [n ?= ?1]). Sixteen patients (43.2%) were judged to be responders according to primary outcome measure. Improvement rate on CGI scale was 48.8%. On ADHD-RS, there were significant reductions between baseline and 4th week and between baseline and 12th week in both hyperactivity and inattention, and between baseline and 12th week in impulsivity scores. Decrease was significant in hyperactivity and social withdrawal subscales of the parent-reported ABC. Responders based on primary outcome measure were not significantly different from nonresponders in terms of sociodemographic features or clinical parameters, including intellectual, language, autism symptom, and ADHD symptom levels. Conclusion : In this chart review, ATX appears to be safe and effective for social withdrawal and ADHD symptoms in children with ASD and ID.

Objectives : This naturalistic, retrospective study investigated the effects of atomoxetine (ATX) on attention-deficit/hyperactivity disorder (ADHD) symptoms and autistic features in children with autism spectrum disorders (ASDs) and intellectual disability (ID). Methods : Participants (n ?= ?37, age range 6 ?17 years, mean : 10.16 ?± ?3.60) were assessed at baseline, 4th and 12th weeks using Clinical Global Impressions (CGI) scales, DSM-IV-based ADHD-rating scale (ADHD-RS), and amended Turkish version of Aberrant Behavior Checklist (ABC). The primary outcome measure was a treatment response defined by a CGI-improvement score of 1 or 2 together with a decrease of at least 25% in the parent-rated ADHD-RS total score at the end of 12th week. Results : Five patients (13.5%) stopped medication at 4 weeks due to ineffectivity (2) and intolerable side effects (increased motor activity and talkativeness [n ?= ?1], irritability [n ?= ?2], temper outbursts [n ?= ?2], and increased blood pressure [n ?= ?1]). Sixteen patients (43.2%) were judged to be responders according to primary outcome measure. Improvement rate on CGI scale was 48.8%. On ADHD-RS, there were significant reductions between baseline and 4th week and between baseline and 12th week in both hyperactivity and inattention, and between baseline and 12th week in impulsivity scores. Decrease was significant in hyperactivity and social withdrawal subscales of the parent-reported ABC. Responders based on primary outcome measure were not significantly different from nonresponders in terms of sociodemographic features or clinical parameters, including intellectual, language, autism symptom, and ADHD symptom levels. Conclusion : In this chart review, ATX appears to be safe and effective for social withdrawal and ADHD symptoms in children with ASD and ID.

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6. Hollway JA, Aman MG, Mendoza-Burcham MI, Silverman L, Arnold LE, Tumuluru R, Handen BL, Lecavalier L, Page K, Sayre P, Smith T. Caregiver Satisfaction with a Multisite Trial of Atomoxetine and Parent Training for Attention-Deficit/Hyperactivity Disorder and Behavioral Noncompliance in Children with Autism Spectrum Disorder. Journal of Child and Adolescent Psychopharmacology ;2016 (2016/11/01) ;26(9):807-814.

Abstract Objective : The purpose of this study was to examine caregiver satisfaction with the research experience in a randomized clinical trial of atomoxetine (ATX) and parent training (PT) for attention-deficit/hyperactivity disorder (ADHD) and behavioral noncompliance co-occurring with autism. Methods : The Children with Hyperactivity and Autism Research Treatment Study (CHARTS) randomly assigned 128 children 5.00 ?14.11 years of age to four treatment groups (ATX + PT, ATX alone, PT + placebo[PBO], and PBO). Caregivers completed an 18 item questionnaire about their satisfaction with the research experience. We summarized caregiver responses with descriptive statistics and examined whether the responses were associated with demographic variables, treatment assignment, or the child’s response to treatment (positive or negative). Results : Ninety-three percent of caregivers (119) completed the questionnaire. When asked if they would join the study again if given the chance, 87% (103) responded ?yes, ? 13% (15) responded ?maybe, ? and 1% (1) responded ?no.? When asked if they would recommend the study to other caregivers of children with similar problems, 92% (109) responded ?yes ? and 8% responded (10) ?maybe.? Of the 59 Parent Satisfaction Questionnaire (PSQ) respondents who received PT, 75% (44) felt more confident in managing current child behaviors, 24% (14) felt that their level of confidence was unchanged, and 2% (1) felt less confident. Most caregivers expressed satisfaction with the study procedures, including the number of visits and the safety monitoring protocols. Conclusions : In general, caregivers were highly satisfied with their research experience. These findings may be useful for informing human subject committees and for designing study protocols that are appealing to families.

Objective : The purpose of this study was to examine caregiver satisfaction with the research experience in a randomized clinical trial of atomoxetine (ATX) and parent training (PT) for attention-deficit/hyperactivity disorder (ADHD) and behavioral noncompliance co-occurring with autism. Methods : The Children with Hyperactivity and Autism Research Treatment Study (CHARTS) randomly assigned 128 children 5.00 ?14.11 years of age to four treatment groups (ATX + PT, ATX alone, PT + placebo[PBO], and PBO). Caregivers completed an 18 item questionnaire about their satisfaction with the research experience. We summarized caregiver responses with descriptive statistics and examined whether the responses were associated with demographic variables, treatment assignment, or the child’s response to treatment (positive or negative). Results : Ninety-three percent of caregivers (119) completed the questionnaire. When asked if they would join the study again if given the chance, 87% (103) responded ?yes, ? 13% (15) responded ?maybe, ? and 1% (1) responded ?no.? When asked if they would recommend the study to other caregivers of children with similar problems, 92% (109) responded ?yes ? and 8% responded (10) ?maybe.? Of the 59 Parent Satisfaction Questionnaire (PSQ) respondents who received PT, 75% (44) felt more confident in managing current child behaviors, 24% (14) felt that their level of confidence was unchanged, and 2% (1) felt less confident. Most caregivers expressed satisfaction with the study procedures, including the number of visits and the safety monitoring protocols. Conclusions : In general, caregivers were highly satisfied with their research experience. These findings may be useful for informing human subject committees and for designing study protocols that are appealing to families.

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7. Yalcin O, Kaymak G, Erdogan A, Tanidir C, Karacetin G, Kilicoglu AG, Mutlu C, Adaletli H, Gunes H, Bahali K, Ayik B, Uneri OS. A Retrospective Investigation of Clozapine Treatment in Autistic and Nonautistic Children and Adolescents in an Inpatient Clinic in Turkey. Journal of Child and Adolescent Psychopharmacology ;2016 (2016/11/01) ;26(9):815-821.

Abstract Objective : The aim of this retrospective study is to examine the clinical outcomes and safety of clozapine in children and adolescents with schizophrenia or other psychotic disorders/autism spectrum disorder (ASD) or affective disorders. Methods : The inpatient and outpatient files of all children and adolescents treated with clozapine over a period of 34 months (from October 2011 to July 2014) were reviewed. Demographic and clinical data were examined to describe clinical and metabolic findings, dosing, and tolerability of clozapine treatment in youth with schizophrenia, other psychotic disorders, ASD, or bipolar disorder. Results : The 37 pediatric patients included 26 patients with schizophrenia or other psychotic disorders, 7 patients with ASD complicated by schizophrenia or other psychotic disorders or affective disorders, and 4 patients with ASD only. In all groups (n ?= ?37) there was a significant reduction (p ?
30% symptom reduction on BPRS). In patients with ASD complicated by schizophrenia or other psychotic disorders or bipolar disorders (n?=?7), there was a significant reduction (p?=?0.017) in BPRS scores after clozapine treatment. The discontinuation rate for clozapine was 10.8%, and the most frequently observed side effect was hypersalivation (54.1%). Neutropenia associated with clozapine was observed in only one patient (2.7%). Conclusions: Clozapine seems to be effective and safe in children and adolescents with schizophrenia or other psychotic disorders co-occuring with ASD or not. There is a need for further studies for determining the efficacy of clozapine in children and adolescents with bipolar affective disorder or ASD.

Objective: The aim of this retrospective study is to examine the clinical outcomes and safety of clozapine in children and adolescents with schizophrenia or other psychotic disorders/autism spectrum disorder (ASD) or affective disorders. Methods: The inpatient and outpatient files of all children and adolescents treated with clozapine over a period of 34 months (from October 2011 to July 2014) were reviewed. Demographic and clinical data were examined to describe clinical and metabolic findings, dosing, and tolerability of clozapine treatment in youth with schizophrenia, other psychotic disorders, ASD, or bipolar disorder. Results: The 37 pediatric patients included 26 patients with schizophrenia or other psychotic disorders, 7 patients with ASD complicated by schizophrenia or other psychotic disorders or affective disorders, and 4 patients with ASD only. In all groups (n?=?37) there was a significant reduction (p?30% symptom reduction on BPRS). In patients with ASD complicated by schizophrenia or other psychotic disorders or bipolar disorders (n?=?7), there was a significant reduction (p?=?0.017) in BPRS scores after clozapine treatment. The discontinuation rate for clozapine was 10.8%, and the most frequently observed side effect was hypersalivation (54.1%). Neutropenia associated with clozapine was observed in only one patient (2.7%). Conclusions: Clozapine seems to be effective and safe in children and adolescents with schizophrenia or other psychotic disorders co-occuring with ASD or not. There is a need for further studies for determining the efficacy of clozapine in children and adolescents with bipolar affective disorder or ASD.

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