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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    • "Improvements in both obsessivecompulsive and affective symptoms by a single treatment suggest an underlying connection between affective dysregulation and OCD, strengthening the idea that emotional dysregulation is critical to promoting OCD symptoms. This is supported by epidemiological evidence showing that anxiety disorders, particularly social anxiety, panic disorder, and generalized anxiety disorder, have higher than chance levels of comorbidity in patients with OCD (Black et al., 1992; Nestadt et al., 2001; Bartz and Hollander, 2006; Murphy et al., 2013). Taken as a whole, these findings support the presence of convergent neuropathologies in anxiety and OCD (Nestadt et al., 2003), and suggest that it is critical to model both components of the disorder for a more accurate understanding of OCD pathophysiology. "
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    ABSTRACT: Significant interest in the mechanistic underpinnings of obsessive-compulsive disorder (OCD) has fueled research on the neural origins of compulsive behaviors. Converging clinical and preclinical evidence suggests that abnormal repetitive behaviors are driven by dysfunction in cortico-striatal-thalamic-cortical (CSTC) circuits. These findings suggest that compulsive behaviors arise, in part, from aberrant communication between lateral orbitofrontal cortex (OFC) and dorsal striatum. An important body of work focused on the role of this network in OCD has been instrumental to progress in the field. Disease models focused primarily on these regions, however, fail to capture an important aspect of the disorder: affective dysregulation. High levels of anxiety are extremely prevalent in OCD, as is comorbidity with major depressive disorder. Furthermore, deficits in processing rewards and abnormalities in processing emotional stimuli are suggestive of aberrant encoding of affective information. Accordingly, OCD can be partially characterized as a disease in which behavioral selection is corrupted by exaggerated or dysregulated emotional states. This suggests that the networks producing OCD symptoms likely expand beyond traditional lateral OFC and dorsal striatum circuit models, and highlights the need to cast a wider net in our investigation of the circuits involved in generating and sustaining OCD symptoms. Here, we address the emerging role of medial OFC, amygdala, and ventral tegmental area projections to the ventral striatum (VS) in OCD pathophysiology. The VS receives strong innervation from these affect and reward processing regions, and is therefore poised to integrate information crucial to the generation of compulsive behaviors. Though it complements functions of dorsal striatum and lateral OFC, this corticolimbic-VS network is less commonly explored as a potential source of the pathology underlying OCD. In this review, we discuss this network's potential role as a locus of OCD pathology and effective treatment.
    Preview · Article · Jan 2016 · Frontiers in Systems Neuroscience
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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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