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A Pilot Open-Label Trial of Use of the Glycine Transporter I Inhibitor

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A Pilot Open-Label Trial of Use of the Glycine Transporter I Inhibitor nal atio Me sl d n ic a in r e T Yang, et al., Transl Med (Sunnyvale) 2014, 4:2 Translational Medicine DOI: 10.4172/2161-1025.1000127 ISSN: 2161-1025 Research Article Open Access A Pilot Open-Label Trial of Use of the Glycine Transporter I Inhibitor, Sarcosine, in High-Functioning Children with Autistic Disorder Pinchen Yang1, Hsien-Yuan Lane2, Cheng-Fang Yen1, Chen-Lin Chang 3,4* 1Department of Psychiatry, College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 2Institute of Clinical Medical Science & Departments of Psychiatry, China Medical University and Hospital, Taichung, Taiwan 3Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 4Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan *Corresponding author: Chen-Lin Chang, 100, Shin Chuan 1 st Rd, Kaohsiung 807, Taiwan, Graduate Institute of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital & Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan, Tel:+886-9-36360220; Fax: +886-7-3134761; E-mail: [email protected] Rec date: Apr 01, 2014; Acc date: Apr 17, 2014; Pub date: Apr 22, 2014 Copyright: © 2014 Yang P et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract This open-label trial examined the efficacy and safety of a glycine transporter I inhibitor, sarcosine, in the 24-week treatment of high-functioning children with autistic disorder. Four children (three boys, one girl, 9-11 years of age; average intelligence quotient 80.5) completed the 24 weeks of study. Sarcosine administration was at 30 mg/kg/day in the form of a capsule in two divided doses. The outcome measures were. Autism Diagnostic Observation Schedule (Module 3), parent and teacher-reported Adaptive Behavior Assessment System-II, parenting stress index, Conners’ Continuous Performance Test, Wisconsin Card Sorting Test, child behavior checklist and Swanson, Nolan and Pelham IV hyperactivity attention scales. Safety assessments included monthly recorded vital signs, body weight, body height and adverse events. Statistical analysis found no significant treatment effect on all the outcome measures using the Wilcoxon Signed Rank test and generalized estimating equations analysis. However, an activation effect was reported by caregivers, and was corroborated by clinician’s observation. Details were reported as a case-series in the text. We concluded that sarcosine was well tolerated. Though the data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, and worthy of a double-blind placebo-controlled study with a focus on a certain subgroup of children with autism spectrum disorders. Keywords: Glutamate; Autism; Clinical trial; Sarcosine; Glycine It has been suggested that direct stimulation of NMDA receptors can cause neuronal injury through excessive excitotoxicity. An indirect Introduction approach to enhancing the NMDA neurotransmission is through increasing the availability of synaptic glycine, the “co-transmitter” of Autism Spectrum Disorders (ASDs), including autistic disorder, glutamate, by the attenuation of the glycine reuptake through glycine Asperger’s syndrome, and pervasive developmental disorder not transporter 1 (GlyT-1) [7]. Sarcosine, also known as N-methylglycine otherwise specified, are developmental disorders characterized by with the chemical formula CH3NHCH2COOH, is a potent dysfunction in several core behavioral dimensions: social endogenous inhibitor of GlyT-1 and can enhance NMDA communication/interaction deficits and specific behavior neurotransmission [8-10]. Sarcosine was firstly isolated and named by characteristics. The social deficit dimension involves deficits in German chemist Justus von Liebig in 1847. It is a non-proteinogenic reciprocal social interactions, lack of eye contact, diminished ability to amino acid that occurs as an intermediate product in the synthesis and carry on conversation, and impaired daily interaction skills. The degradation of the amino acid glycine. This molecule has been shown communication domain can include problems ranging from lack of to be effective in clinical trials involving the negative and cognitive verbal language to fluent but odd speech with little comprehension of symptoms of chronic patients with schizophrenia [11], in acutely ill pragmatics. The behavioral domain involves compulsive behaviors, persons with schizophrenia [12,13], in patients with obsessive– unusual attachments to objects, rigid adherence to routines or rituals, compulsive disorders[14], to temporarily relieve the depressive and repetitive motor mannerisms and unusual reactions to sensory stimuli neuropsychiatric symptoms of patients with Parkinson-related [1]. Genetic studies and human pathological and model system studies dementia [15] and to improve depressive-like behavior in a rodent have all led to the hypothesis that molecular pathways involved in model and inhuman depression [16]. To the authors’ knowledge, there brain synaptic growth, development, and stability are perturbed in is currently no report on using sarcosine for the treatment of patients ASDs [2-4]. Molecules targeting brain cell dendritic spine regulation with ASD. In the present study, we hypothesized that sarcosine is a for the purpose of promoting its maturation and restoring spine therapeutic agent for children with ASD due to its activity as an stability are thus proposed to be of therapeutic potential in ASD. NMDA receptor and glutamate transmission enhancement. Because glutamate and its ionotropic N-methyl-D-Aspartate (NMDA) receptors have long been known to be associated with synaptic Methods plasticity, glutamate and NMDA receptors-mediated signaling have become targets of interest in exploring the pharmacological treatment This study was a pilot 24-week open label trial with the aim of of ASDs [5,6]. gaining preliminary experience with sarcosine for the treatment of Transl Med (Sunnyvale) Volume 4 • Issue 2 • 1000127 ISSN:2161-1025 TM, an open access Journal Citation: Yang P, Lane HY, Yen CF, Chang CL (2014) A Pilot Open-Label Trial of Use of the Glycine Transporter I Inhibitor, Sarcosine, in High- Functioning Children with Autistic Disorder. Transl Med (Sunnyvale) 4: 127. doi:10.4172/2161-1025.1000127 Page 2 of 4 children with autistic disorders. The participants were a convenient Data analysis sample of outpatients children aged between 9 to 12 years old and of both genders. They were recruited from the Department of Psychiatry, Statistical analysis found no significant treatment effect for all the Kaohsiung Medical University Hospital and Kaohsiung Armed Forces outcome measures using the Wilcoxon Signed Rank test for baseline General, which are major medical centers in Taiwan. and final state comparison and generalized estimating equations analysis for some of the outcome measures. Nevertheless, observation The diagnosis of autistic disorder was made using DSM-IV-TR of subjects by parents and clinicians noted that sarcosine criteria [17] with clear documentation of each criterion in the history administration seemed to have an activating effect. Details were record or current interview. All the interviews were conducted by an reported as the case-series as below. Please see Table 1 for the expert child and adolescent psychiatrist (P.Y). Assessments were summary of the characteristics and primary outcome measures of the performed by a child psychologist trained to use the Autism four subjects. Diagnostic Observation Schedule [18]. Each participant’s mother and a designated teacher were responsible for filling out the required A B C D questionnaires. The level of intelligence was considered as an Gender M M F M exclusion criterion, in that for each participant the Full Scale Intelligent Quotient (FSIQ) or the subscale of the Perceptual Age 9Y9M 10Y9M 9Y10M 11Y2M Reasoning Index (PRI) as ascertained by the Wechsler Intelligence Scale for Children Fourth Edition-Chinese version [19] had to be Highest subscale IQ 83 103 83 101 above 70. For children receiving other medication treatments, the Sarcosine mg/day 1000 1000 900 900 drugs had to be at a stable dose for at least 2 months before entering the study and remained unaltered throughout the clinical trial. Other mg/day Concerta 54 Concerta54 X X Concomitant educational, occupational, physical, communicational or ADOS-1 11 22 20 14 behavioral treatment was permitted, but no new treatment was allowed to be added. Special care was taken to exclude children with ADOS-2 19 21 22 13 seizure disorders or known genetic syndromes. The research protocol was approved by the Institutional Review Boards (Registration GCS-P-1 70 77 87 72 number: 101-023) of the hospital mentioned above. Sarcosine is GCS-P-2 70 81 91 87 regulated as a food supplement in Taiwan and an Investigational New Drug (IND) application was not required. After a description of the GCS-T-1 75 89 78 88 study, informed consent was obtained from parents and the children GCS-T-2 67 86 84 76 themselves gave their assents. This trial was performed in 2012 and 2013. ADOS-1: Social interaction & communication score from Autism Diagnostic Observation Schedule (ADOS) at the baseline; ADOS-2: ADOS at the
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