Chamberlain SR, Menzies L. Endophenotypes of obsessive-compulsive disorder: rationale, evidence and future potential. Expert Rev Neurother 9: 1133-1146

Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Expert Review of Neurotherapeutics (Impact Factor: 2.78). 09/2009; 9(8):1133-46. DOI: 10.1586/ern.09.36
Source: PubMed


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.

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Available from: Samuel Robin Chamberlain, Jun 19, 2014
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    • "Thus, it has been stated that a challenge for modern-day neuropsychiatry research is to find common and distinct neurobiological correlates of depression and OCD, i.e. to identify discriminating endophenotypes such as neuropsychological probes for neuroimaging use [6]. A promising neuropsychological paradigm in this context is cognitive flexibility - defined as the ability to rapidly change response strategies upon altering task-relevant information in the environment [11] - that is likely to be impaired in both OCD [12] and MDD [13]. Several ways of operationalizing cognitive flexibility have been introduced in laboratory settings, e.g. "
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    ABSTRACT: Obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) are frequently co-morbid, and dysfunctional frontal-striatal circuits have been implicated in both disorders. Neurobiological distinctions between OCD and MDD are insufficiently clear, and comparative neuroimaging studies are extremely scarce. OCD and MDD may be characterized by cognitive rigidity at the phenotype level, and frontal-striatal brain circuits constitute the neural substrate of intact cognitive flexibility. In the present study, 18 non-medicated MDD-free patients with OCD, 19 non-medicated OCD-free patients with MDD, and 29 matched healthy controls underwent functional magnetic resonance imaging during performance of a self-paced letter/digit task switching paradigm. Results showed that both patient groups responded slower relative to controls during repeat events, but only in OCD patients slowing was associated with decreased error rates. During switching, patients with OCD showed increased activation of the putamen, anterior cingulate and insula, whereas MDD patients recruited inferior parietal cortex and precuneus to a lesser extent. Patients with OCD and MDD commonly failed to reveal anterior prefrontal cortex activation during switching. This study shows subtle behavioral abnormalities on a measure of cognitive flexibility in MDD and OCD, associated with differential frontal-striatal brain dysfunction in both disorders. These findings may add to the development of biological markers that more precisely characterize frequently co-morbid neuropsychiatric disorders such as OCD and MDD.
    PLoS ONE 04/2013; 8(4):e59600. DOI:10.1371/journal.pone.0059600 · 3.23 Impact Factor
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    • "Because these endophenotypes are understood to be heritable traits that serve as risk factors for the disorder, they should be present in both patients and their unaffected relatives (Gottesman & Gould, 2003). For instance, Chamberlain and Menzies (2009) reported that patients with OCD and their unaffected relatives showed impaired inhibitory control, and these deficits were related to brain gray matter structural abnormalities. Possibly, general uncertainty, which runs across the various subtypes of OCD, together with the inclination to respond to uncertainties with perseverative checking also represents an OCD-related endophenotype . "
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    ABSTRACT: Patients with obsessive-compulsive disorder respond to clinical uncertainty with perseverative checking, which, ironically, enhances uncertainty. However, patients also display general subclinical uncertainty, which may tempt vulnerable individuals to seek reassurance by perseveration in response to mild uncertainty that is superimposed on general uncertainty. An experimental eye-tracking paradigm was developed to investigate whether mild uncertainty indeed induces checking behavior in people with high obsessive-compulsive tendencies (OC+, n = 34), compared to people with low obsessive-compulsive tendencies (OC–, n = 31). Participants were presented 50 visual search displays, and they indicated whether a target was “present” or “absent.” Decisions about target presence induced little uncertainty, but decisions about its absence were more ambiguous, because participants relied on not having overlooked the target. Results revealed no differences on target-present trials. However, in target-absent trials, OC+ participants searched longer and used more fixations. Thus, even in mildly uncertain situations, individuals with subclinical obsessive-compulsive disorder respond with more checking behavior, which has implications for treatment.
    04/2013; 1(2):103-109. DOI:10.1177/2167702612472487
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    • "Despite reasonable knowledge of PG, little is known of its cognitive and neurobiological antecedents. Cognitive tests sensitive to cortico-subcortical dysfunction are well placed as candidate vulnerability markers in psychiatry, since they are situated along the chain of pathogenesis between underlying genetic-environmental contributions and the top-level manifestation of symptoms (Gottesman and Gould, 2003; Chamberlain and Menzies, 2009). Dysfunction of neural circuitry thought to underpin aspects of decision-making is central to neurobiological models of PG (Grant et al., 2006, Wilber and Potenza, 2006; Potenza, 2008) and patients with the disorder often manifest impaired decision-making on objective tests (van Holst et al., 2010a). "
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    ABSTRACT: Despite reasonable knowledge of pathological gambling (PG), little is known of its cognitive antecedents. We evaluated decision-making and impulsivity characteristics in people at risk of developing PG using neuropsychological tests. Non-treatment seeking volunteers (18-29 years) who gamble ≥ 5 times/year were recruited from the general community, and split into two groups: those "at risk" of developing PG (n=74) and those social, non-problem gamblers (n=112). Participants undertook the Cambridge Gamble and Stop-signal tasks and were assessed with the Mini-International Neuropsychiatric Interview and the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling. On the Cambridge Gamble task, the at-risk subjects gambled more points overall, were more likely to go bankrupt, and made more irrational decisions under situations of relative risk ambiguity. On the Stop-signal task, at-risk gamblers did not differ from the social, non-problem gamblers in terms of motor impulse control (stop-signal reaction times). Findings suggest that selective cognitive dysfunction may already be present in terms of decision-making in at-risk gamblers, even before psychopathology arises. These findings implicate selective decision-making deficits and dysfunction of orbitofronto-limbic circuitry in the chain of pathogenesis between social, non-problematic and pathological gambling.
    Psychiatry Research 06/2011; 189(1):115-20. DOI:10.1016/j.psychres.2011.05.034 · 2.47 Impact Factor
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