Article

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

ABSTRACT

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.

Download full-text

Full-text

Available from: Pablo Moya, Nov 21, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Organic cation transporters (OCTs) are polyspecific facilitated diffusion transporters that contribute to the absorption and clearance of various physiological compounds and xenobiotics in mammals, by mediating their vectorial transport in kidney, liver or placenta cells. Unexpectedly, a corpus of studies within the last decade has revealed that these transporters also fulfill important functions within the brain. The high-affinity monoamine reuptake transporters (SERT, NET and DAT) exert a crucial role in the control of aminergic transmission by ensuring the rapid clearance of the released transmitters from the synaptic cleft and their recycling into the nerve endings. Substantiated evidence indicate that OCTs may serve in the brain as a compensatory clearance systems in case of monoamine spillover after high-affinity transporter blockade by antidepressants or psychostimulants, and in areas of lower high-affinity transporter density at distance from the aminergic varicosities. In spite of similar anatomical profiles, the two brain OCTs, OCT2 and OCT3, show subtle differences in their distribution in the brain and their functional properties. These transporters contribute to shape a variety of central functions related to mood such as anxiety, response to stress and antidepressant efficacy, but are also implicated in other processes like osmoregulation and neurotoxicity. In this review, we discuss the recent knowledge and emerging concepts on the role of OCTs in the uptake of aminergic neurotransmitters in the brain and in these various physiological functions, focusing on the implications for mental health.
    Full-text · Article · Sep 2014 · Pharmacology [?] Therapeutics
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent discoveries highlight rare genetic variation as an important class of autism spectrum disorder (ASD) risk factors, and that such variants can implicate biological networks for further investigation. Altered serotonin (5-HT) signaling has been implicated in ASD for over 50 years, and we and others have identified multiple, rare, ASD-associated variants in the 5-HT transporter (SERT, SLC6A4) gene that lead to elevated 5-HT re-uptake and perturbed regulation. We hypothesized that loci encoding SERT regulatory proteins harbor genetic variants that impact SERT function and/or regulation and therefore could contribute to ASD risk. The adenosine A3 receptor (A3AR) regulates SERT via protein kinase G (PKG) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways leading to enhanced SERT surface expression and catalytic activity, respectively. To test our SERT network hypothesis, we asked whether a relative increase of rare functional variants in the A3AR gene (ADORA3) was present in cases vs. controls. Discovery Sanger sequencing of ADORA3 exons and flanking DNA in a case-control sample, and subsequent analysis of a comparison sample using whole exome sequence data were conducted to test for increased functional variants in cases. We evaluated the functional impact of two variants from the discovery sample on A3AR signaling and SERT activity. Sequencing discovery showed an overall increase in rare coding variants in cases vs. controls (P=0.013). While a comparison sample from exome sequence did not show a significant enrichment (P=0.071), combined analysis strengthened evidence for association of rare, functional variants in ASD (P=0.0025). Two variants discovered in ASD cases (Leu90Val and Val171Ile) lie in or near the ligand-binding pocket, and Leu90Val was enriched individually in cases (P=0.040). In vitro analysis of cells expressing Val90 A3AR revealed elevated basal cGMP levels compared with cells expressing the wildtype receptor. Additionally, the specific A3AR agonist N6-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (IB-MECA) induced increased cGMP levels across the full time course studied in Val90 A3AR cells, as compared with the wildtype receptor expressing cells. In Val90 A3AR/SERT co-transfected cells, IB-MECA stimulation elevated SERT activity over that seen with the wildtype receptor, with a delayed recovery of 5-HT uptake activity to baseline levels. By comparison, the Ile171 A3AR variant was unable to support IB-MECA stimulation of SERT. Although both Val90 and Ile171 were present in greater numbers in these ASD cases, segregation analysis in carrier families showed incomplete penetrance, consistent with other documented rare ASD risk alleles. Our results validate the hypothesis that the SERT regulatory network harbors rare, functional variants that impact SERT activity and regulation in ASD, and encourages further investigation of this network as a site for additional functional variation that may impact ASD risk.
    Full-text · Article · Aug 2013 · Molecular Autism
Show more