Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: Obsessive-compulsive disorder as an example of overlapping clinical and genetic heterogeneity

Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, , Bethesda, MD 20892, USA.
Philosophical Transactions of The Royal Society B Biological Sciences (Impact Factor: 7.06). 02/2013; 368(1615):20120435. DOI: 10.1098/rstb.2012.0435
Source: PubMed


Individuals with obsessive-compulsive disorder (OCD) have also been shown to have comorbid lifetime diagnoses of major depressive disorder (MDD; rates greater than 70%), bipolar disorder (rates greater than 10%) and other anxiety disorders (e.g. panic disorder, post-traumatic stress disorder (PTSD)). In addition, overlap exists in some common genetic variants (e.g. the serotonin transporter gene (SLC6A4), the brain-derived neurotrophic factor (BDNF) gene), and rare variants in genes/chromosomal abnormalities (e.g. the 22q11 microdeletion syndrome) found across the affective/anxiety disorder spectrums. OCD has been proposed as a possible independent entity for DSM-5, but by others thought best retained as an anxiety disorder subtype (its current designation in DSM-IV), and yet by others considered best in the affective disorder spectrum. This review focuses on OCD, a well-studied but still puzzling heterogeneous disorder, regarding alterations in serotonergic, dopaminergic and glutamatergic neurotransmission in addition to other systems involved, and how related genes may be involved in the comorbidity of anxiety and affective disorders. OCD resembles disorders such as depression, in which gene × gene interactions, gene × environment interactions and stress elements coalesce to yield OC symptoms and, in some individuals, full-blown OCD with multiple comorbid disorders.

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Available from: Pablo Moya, Nov 21, 2014
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    • "The results of these studies should also be appreciated in the light of the potential up-or down-regulation of other monoamine transporters, a parameter which was not compared in these two mice lines. The principal component responsible for 5-HT uptake, SERT, is for instance significantly implicated in anxiety-related behaviors and disease (Murphy et al., 2013). Still, in spite of these limitations , an interesting link can be drawn between these findings in rodents and the identification of an OCT3 variant with decreased NE transport capacity in patients with obsessive–compulsive disorder (Lazar et al., 2008), an anxiety disorder which can affect up to 2% of the general population (Fontenelle, Mendlowicz, & Versiani, 2006). "
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    • "Following observations of significant genetic linkage at 17q11.2 (harboring SLC6A4) in multiplex ASD families [17-19], we screened exons of SLC6A4 specifically in families contributing to the observed linkage and found multiple, novel coding variants (Ile425Leu, Phe465Leu, and Leu550Val) and an elevated frequency of a previously documented coding variant (Gly56Ala) to a degree that profoundly deviated from expectations under Hardy-Weinberg equilibrium [17]. Further support for a role of these variants in ASD comes from studies reporting an Ile425Val variant that segregated in pedigrees harboring multiple psychiatric phenotypes, with Asperger syndrome (an ASD), OCD, and other anxiety disorders being the most prominent [20-22]. Functional characterization of these SERT variants revealed that each elevated 5-HT transport function, as well as altered protein kinase G (PKG) and p38 mitogen activated protein kinase (MAPK) regulation [23,24]. "
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