Article

Endophenotypes of obsessive-compulsive disorder: rationale, evidence and future potential.

Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Expert Review of Neurotherapeutics (Impact Factor: 2.83). 09/2009; 9(8):1133-46. DOI: 10.1586/ern.09.36
Source: PubMed

ABSTRACT Obsessive-compulsive disorder (OCD) is a heritable and debilitating neuropsychiatric condition. Attempts to delineate genetic contributions have met with limited success, and there is an ongoing search for intermediate trait or vulnerability markers rooted in the neurosciences. Such markers would be valuable for detecting people at risk of developing the condition, clarifying etiological factors and targeting novel treatments. This review begins with brief coverage of the epidemiology of OCD, and presents a hierarchical model of the condition. The advantages of neuropsychological assessment and neuroimaging as objective measures of brain integrity and function are discussed. We describe the concept of endophenotypes and examples of their successful use in medicine and psychiatry. Key areas of focus in the search for OCD endophenotypes are identified, such as measures of inhibitory control and probes of the integrity of orbitofrontal and posterior parietal cortices. Finally, we discuss exciting findings in unaffected first-degree relatives of patients with OCD that have led to the identification of several candidate endophenotypes of the disorder, with important implications for neurobiological understanding and treatment of this and related conditions.

Full-text

Available from: Samuel Robin Chamberlain, Jun 19, 2014
1 Follower
 · 
93 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Compulsivity and impulsivity are cross-disorder traits observed in Autism Spectrum Disorders (ASD), Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD). Aberrant fronto-striatal glutamatergic signaling is core to the understanding of compulsive and impulsive disorders. In this review, the glutamate (Glu) neurochemistry of fronto-striatal circuits in paediatric and adult ASD, ADHD and OCD, as described in 59 studies, is outlined from the perspective of proton magnetic resonance spectroscopy ((1)H MRS). Despite the methodological inconsistencies between studies, two observations stand out that form possible hypotheses for future studies. Firstly, a possible increase in Glx (combination of Glu, glutamine and GABA) in the striatum across ADHD, OCD and ASD. Secondly, an increased Glx signal in the anterior cingulate cortex in paediatric ASD and ADHD but a lower Glx signal in adult ASD and ADHD. This suggests neurodevelopmental changes in fronto-striatal glutamatergic circuits across the lifespan. Future studies should incorporate more homogeneous samples, perform MRS at field strengths of at least 3 Tesla and provide much more precise and standardized information on methods to improve our understanding of fronto-striatal glutamatergic transmission in compulsive and impulsive syndromes. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience & Biobehavioral Reviews 02/2015; 52. DOI:10.1016/j.neubiorev.2015.02.009 · 10.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Obsessive-Compulsive Disorder (OCD) is the tenth most disabling illness of any kind. OCD stands as a paradigm for complex neurobehavioral disorders due to its polygenic origin. It presents heterogenic clinical presentation, variable disease onset, progression and treatment responses, what makes its understanding a major neuropsychiatric challenge. Like with other neurobehavioral disorders, animal models are essential tools for decoding OCD genetic complexity, understanding its biological base and discovering novel treatments and diagnostic methods. 20 years of rodent OCD modeling have helped to understand the disease better, but multiple questions remain regarding OCD. Innovative whole genome sequencing (WGS) approaches might provide important answers on OCD risk associated genes. However, exploiting those large data sets through the use of traditional animal models is costly and time consuming. Zebrafish might be an appropriate animal model to streamline the pipeline of gene functional validation. This animal model shows several advantages versus rodent models, such as faster and cheaper genetic manipulation, strong impact on the 3Rs implementation, behavioral phenotypic reproducibility of OCD-like behaviors (obsessions and compulsions) and feasibility to develop high-throughput assays for novel OCD drug therapies discovery. In conclusion, zebrafish could be an innovative and relevant model for understanding OCD. Copyright © 2015 Elsevier B.V. All rights reserved.
    European journal of pharmacology 03/2015; 759. DOI:10.1016/j.ejphar.2015.03.027 · 2.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: ENG, G.K., Sim, K. and Chen, S.H.A. Meta-Analytic Investigations of Structural Grey Matter, Executive Domain-related Functional Activations, and White Matter Diffusivity in Obsessive Compulsive Disorder: An Integrative Review. NEUROSCI BIOBEHAV REV XX(X) XXX-XXX, XXXX. Obsessive-compulsive disorder (OCD) is a debilitating disorder. However, existing neuroimaging findings involving executive function and structural abnormalities in OCD have been mixed. Here we conducted meta-analyses to investigate differences in OCD samples and controls in: Study 1-Grey matter structure; Study 2--Executive function task-related activations during i) response inhibition, ii) interference, and iii) switching tasks; and Study 3-White matter diffusivity. Results showed grey matter differences in the frontal, striatal, thalamus, parietal and cerebellar regions, task domain-specific neural differences in similar regions; and abnormal diffusivity in major white matter regions in OCD samples compared to controls. Our results reported concurrence of abnormal white matter diffusivity with corresponding abnormalities in grey matter and task-related functional activations. Our findings suggested the involvement of other brain regions not included in the cortico-striato-thalamo-cortical network, such as the cerebellum and parietal cortex, and questioned the involvement of the orbitofrontal region in OCD pathophysiology. Future research is needed to clarify the roles of these brain regions in the disorder. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience & Biobehavioral Reviews 03/2015; 52. DOI:10.1016/j.neubiorev.2015.03.002 · 10.28 Impact Factor