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Politte L.C.,Massachusetts General Hospital | McDougle C.J.,Lurie Center for Autism
Expert Opinion on Orphan Drugs | Year: 2013

Introduction: Fragile X syndrome (FXS), the most common inherited form of intellectual disability and autism, is caused by expansion of CGG trinucleotide repeats in FMR1 and marked reduction or absence of the gene product, FMRP. FMRP suppresses synaptic protein synthesis resulting from group 1 metabotropic glutamate receptor (mGluR) activation, a process critical to normal synaptic plasticity. FXS can be characterized as a disorder of synaptic plasticity with physical, cognitive and behavioral manifestations attributable to, at least in part, excessive mGluR activity and downstream effects. Areas covered: This paper reviews the 'mGluR theory' of FXS and the targeted drugs investigated in Phase II and III trials based on this theory of pathogenesis. A literature review was conducted using the PubMed database with search terms 'fragile X syndrome', 'mGluRs', 'pharmacotherapy' and specific drug-related terms. Other resources were identified by review of relevant reference lists and consultation with experts in the field. Expert opinion: While preclinical trials of targeted drugs in animal models of FXS have been encouraging, more studies are needed to determine clinical efficacy in humans. Challenges to clinical trial design and direction for future drug studies, including consideration of NMDA receptor partial agonists and mGluR2/3 agonists, are discussed. © Informa UK, Ltd. Source


Adler B.A.,Seattle Childrens Hospital | Wink L.K.,Cincinnati Childrens Hospital Medical Center | Early M.,Riley Childrens Hospital | Early M.,Indiana University | And 6 more authors.
Autism | Year: 2015

Aggression, self-injurious behavior, and severe tantrums are impairing symptoms frequently experienced by individuals with autism spectrum disorders. Despite US Food and Drug Administration approval of two atypical antipsychotics targeting these symptoms in youth with autistic disorder, they remain frequently drug refractory. We define drugrefractory aggression, self-injurious behavior, and severe tantrums in people with autism spectrum disorders as behavioral symptoms requiring medication adjustment despite previous trials of risperidone and aripiprazole or previous trials of three psychotropic drugs targeting the symptom cluster, one of which was risperidone or aripiprazole. We reviewed the medical records of individuals of all ages referred to our clinic for autism spectrum disorder diagnostic evaluation, as well as pharmacotherapy follow-up notes for all people meeting autism spectrum disorder criteria, for drug-refractory symptoms. Among 250 consecutively referred individuals, 135 met autism spectrum disorder and enrollment criteria, and 53 of these individuals met drug-refractory symptom criteria. Factors associated with drug-refractory symptoms included age 12 years or older (p < 0.0001), diagnosis of autistic disorder (p = 0.0139), and presence of intellectual disability (p = 0.0273). This pilot report underscores the significance of drug-refractory aggression, self-injurious behavior, and severe tantrums; suggests the need for future study clarifying factors related to symptom development; and identifies the need for focused treatment study of this impairing symptom domain. © The Author(s) 2014. Source


Zurcher N.R.,Massachusetts General Hospital | Zurcher N.R.,Harvard University | Bhanot A.,Massachusetts General Hospital | McDougle C.J.,Lurie Center for Autism | And 3 more authors.
Neuroscience and Biobehavioral Reviews | Year: 2015

Non-invasive positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are techniques used to quantify molecular interactions, biological processes and protein concentration and distribution. In the central nervous system, these molecular imaging techniques can provide critical insights into neurotransmitter receptors and their occupancy by neurotransmitters or drugs. In recent years, there has been an increase in the number of studies that have investigated neurotransmitters in autism spectrum disorder (ASD), while earlier studies mostly focused on cerebral blood flow and glucose metabolism. The underlying and contributing mechanisms of ASD are largely undetermined and ASD diagnosis relies on the behavioral phenotype. Discovery of biochemical endophenotypes would represent a milestone in autism research that could potentially lead to ASD subtype stratification and the development of novel therapeutic drugs. This review characterizes the prior use of molecular imaging by PET and SPECT in ASD, addresses methodological challenges and highlights areas of future opportunity for contributions from molecular imaging to understand ASD pathophysiology. © 2015 Elsevier Ltd. Source


Doyle C.A.,Indiana University | Doyle C.A.,Christian Sarkine Autism Treatment Center | McDougle C.J.,Harvard University | McDougle C.J.,Lurie Center for Autism
Expert Opinion on Pharmacotherapy | Year: 2012

Introduction: Autistic disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS) are pervasive developmental disorders (PDDs) frequently associated with behavioral symptoms that may require pharmacotherapy to manage. Areas covered: Behavioral symptoms in children with autism include interfering repetitive behaviors, irritability, and hyperactivity and inattention, among others. The psychotropic medications examined in this review include: serotonin reuptake inhibitors, typical and atypical antipsychotics, medications used to treat attention-deficit/ hyperactivity disorder, naltrexone, buspirone, divalproex sodium, lamotrigine, levetiracetam, memantine, mirtazapine, riluzole, pioglitazone, and topiramate. Expert opinion: For the treatment of interfering repetitive behaviors, serotonin reuptake inhibitors demonstrate less efficacy and are more poorly tolerated in children with autism compared to adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in children with autism and other PDDs. For the treatment of hyperactivity and inattention, psychostimulants demonstrate some benefit. However, they are overall less efficacious and cause more side effects in children with PDDs compared to typically developing children with attention-deficit/hyperactivity disorder. Results from double-blind, placebo-controlled trials of these agents and others for the treatment of the behavioral symptom domains described above will be discussed in this review. © 2012 Informa UK, Ltd. Source


Hulvershorn L.A.,Indiana University | Schroeder K.M.,Indiana University | Wink L.K.,Cincinnati Childrens Hospital Medical Center | Erickson C.A.,Cincinnati Childrens Hospital Medical Center | McDougle C.J.,Lurie Center for Autism
Human Psychopharmacology | Year: 2015

Objective This pilot study compared the pharmacologic treatment history and clinical outcomes observed in pediatric outpatients with psychiatric disorders exposed to drugs of abuse in utero to those of an age-matched, sex-matched and psychiatric disorder-matched, non-drug-exposed group. Methods In this matched cohort study, medical records of children treated at an academic, child and adolescent psychiatry outpatient clinic were reviewed. Children with caregiver-reported history of prenatal drug exposure were compared with a non-drug-exposed control group being cared for by the same providers. Patients were rated with the Clinical Global Impressions - Severity scale (CGI-S) throughout treatment. The changes in pre-treatment and post-treatment CGI-S scores and the total number of medication trials were determined between groups. Results The drug-exposed group (n=30) had a higher total number of lifetime medication trials compared with the non-drug-exposed group (n=28) and were taking significantly more total medications, at their final assessment. Unlike the non-drug-exposed group, the drug-exposed group demonstrated a lack of clinical improvement. Conclusions These results suggest that in utero drug-exposed children may be more treatment-refractory to or experience greater side effects from the pharmacologic treatment of psychiatric disorders than controls, although we cannot determine if early environment or drugs exposure drives these findings. © 2015 John Wiley & Sons, Ltd. Source

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