The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders—including schizophrenia, drug abuse and addiction, autism, and depression—that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration–approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine–sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development.

Translating Glutamate: From Pathophysiology to Treatment

Genetic and cytogenetic screening of autistic spectrum disorder: Genotype-phenotype profiles

We examined to what extent increased parent reports of autistic traits in some children with Attention Deficit Hyperactivity Disorder (ADHD) are the result of ADHD-related symptoms or qualitatively similar to the core characteristics of autism spectrum disorders (ASD). Results confirm the presence of a subgroup of children with ADHD and elevated ratings of core ASD traits (ADHD+) not accounted for by ADHD or behavioral symptoms. Further, analyses revealed greater oppositional behaviors, but not greater ADHD severity or anxiety, in the ADHD+ subgroup compared to those with ADHD only. These results highlight the importance of specifically examining autistic traits in children with ADHD for better characterization in studies of the underlying physiopathology and treatment.

Examining Autistic Traits in Children with ADHD: Does the Autism Spectrum Extend to ADHD?

Three levels of investigation underlie all biologically based attempts at classification of behaviorally defined developmental and psychiatric disorders: Level A, pseudo-categorical classification of mostly dimensional descriptions of behaviors and their disorders included in the 2013 American Psychiatric Association’s Fifth Edition of the Diagnostic and Statistical Manual (DSM-5); Level C, mostly categorical classification of genetic and environmental causes (etiologies) of Level A disorders; and Level B, the pathophysiologic—both categorical and dimensional—biologic mechanisms underlying Level A “diagnoses” which comprise hierarchically interacting molecular, cellular, and neural networks and major brain pathways orchestrated by Level C etiologies. Besides modest numbers of effective psychotropic medications and their derivatives, major advances in treatment have addressed the behavioral symptoms of Level A-defined developmental and psychiatric disorders. The National Institute of Mental Health proposes support for a new biologically based Research Domain Criteria (RDoC) classification; its goal is to apply to behaviorally defined Level A developmental and psychiatric disorders the biologically based Level C and Level B research strategies that have greatly accelerated treatment and prevention of medical disorders. It plans to supplement effective educational and behavioral symptom-based interventions with faster, more potent and specific biologic therapies and, hopefully, to discover how effective behavioral interventions alter brain function. This commentary raises the question of whether a hybrid nosology that maps biology onto behavior is attainable. At a minimum, such a nosologic effort requires greater in-depth and better informed dialog between investigators of behavior and biology than occurs typically, and more realistic communication of the implications of research results to the public.

Classification of behaviorally defined disorders: biology versus the DSM.

New information continuously alters scientific classifications and their applications. A revision in progress of the DSMâÂÂIVâÂÂTR, which concerns classification of disorders, predominantly of behavioral symptoms, suggests reconsideration of overlaps and differences between two broad families of developmental disorders: autisms and schizophrenias. Developmental disorders are classified within two independent domains: behavioral/descriptive (level A) and biologic/etiologic (level C). Level A classification is syndromic and based on aggregates of mostly continuous, dimensional features with indistinct margins. Etiologic level C classification is based largely on categorical interacting genetic and environmental factors responsible for level A syndromes. Level B encompasses biologic mechanisms (pathogenesis) linking etiology (level C) to behavior (level A). Many level B hierarchical molecular and cellular networks contribute to the structure and function of the many brain networks responsible for level A behaviors. Autism and schizophrenia share some behavioral and cognitive characteristics, pathogenic mechanisms and etiologies, but major clinical disparities (level A) separate them.

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Classification issues in the developmental disorders: the case of autism and schizophrenia

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Classification issues in the developmental disorders: the case of autism and schizophrenia