Phenotype of schizophrenia: A review and formulation

Department of Psychiatry, UT Southwestern Medical School, Dallas, TX 75390, USA.
Molecular Psychiatry (Impact Factor: 14.5). 02/2005; 10(1):27-39. DOI: 10.1038/
Source: PubMed


The discovery of the pathophysiology(ies) for schizophrenia is necessary to direct rational treatment directions for this brain disorder. Firm knowledge about this illness is limited to areas of phenomenology, clinical electrophysiology, and genetic risk; some aspects of dopamine pharmacology, cognitive symptoms, and risk genes are known. Basic questions remain about diagnostic heterogeneity, tissue neurochemistry, and in vivo brain function. It is an illness ripe for molecular characterization using a rational approach with a confirmatory strategy; drug discovery based on knowledge is the only way to advance fully effective treatments. This paper reviews the status of general knowledge in this area and proposes an approach to discovery, including identifying brain regions of dysfunction and subsequent localized, hypothesis-driven molecular screening.

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Available from: Carol Tamminga, Aug 29, 2015
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    • "The identification of endophenotypes aids the classification of heterogeneous phenotypes into biologically distinct subtypes of individuals and facilitates understanding of the genetic underpinning and early detection of the disease [Greenwood et al., 2007; Leboyer et al., 1998]. Schizophrenia is a syndrome that is characterized by complex symptomatic manifestations and cognitive dysfunctions in multiple domains [Dickson et al., 2012; Glahn et al., 2007; Tamminga and Holcomb, 2005]. These features have been attributed to the disruption of the underlying structures of neural networks [Ellison-Wright and Bullmore , 2009; Kubicki et al., 2007]. "
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    ABSTRACT: Trait markers of schizophrenia aid the dissection of the heterogeneous phenotypes into distinct subtypes and facilitate the genetic underpinning of the disease. The microstructural integrity of the white matter tracts could serve as a trait marker of schizophrenia, and tractography-based analysis (TBA) is the current method of choice. Manual tractography is time-consuming and limits the analysis to preselected fiber tracts. Here, we sought to identify a trait marker of schizophrenia from among 74 fiber tracts across the whole brain using a novel automatic TBA method. Thirty-one patients with schizophrenia, 31 unaffected siblings and 31 healthy controls were recruited to undergo diffusion spectrum magnetic resonance imaging at 3T. Generalized fractional anisotropy (GFA), an index reflecting tract integrity, was computed for each tract and compared among the three groups. Ten tracts were found to exhibit significant differences between the groups with a linear, stepwise order from controls to siblings to patients; they included the right arcuate fasciculus, bilateral fornices, bilateral auditory tracts, left optic radiation, the genu of the corpus callosum, and the corpus callosum to the bilateral dorsolateral prefrontal cortices, bilateral temporal poles, and bilateral hippocampi. Posthoc between-group analyses revealed that the GFA of the right arcuate fasciculus was significantly decreased in both the patients and unaffected siblings compared to the controls. Furthermore, the GFA of the right arcuate fasciculus exhibited a trend toward positive symptom scores. In conclusion, the right arcuate fasciculus may be a candidate trait marker and deserves further study to verify any genetic association. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 11/2014; 36(3). DOI:10.1002/hbm.22686 · 5.97 Impact Factor
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    • "The clinical symptoms of schizophrenia generally do not emerge until late adolescence and adulthood (Tamminga & Holcomb 2005), although severe forms of schizophrenia have been diagnosed in children (Rapoport et al. 2012). "
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    ABSTRACT: NMDA receptor deficient mice can be used to understand the role that NMDA receptors (NMDAR) play in the pathophysiology of neurodevelopmental disorders like schizophrenia. Genetically modified mice with low levels of NR1 subunit (NR1 knockdown mice) have reduced receptor levels throughout development, and have robust abnormalities in behaviours that are relevant to schizophrenia. We traced the onset and severity of these behaviours at three developmental stages to understand when in development the underlying circuits depend on intact NMDAR function. We examined social behaviour, working memory, executive function, locomotor activity, and stereotypy at 3, 6, and 12 weeks of age in NR1 knockdown mice and their wildtype littermates. We discovered that each of these behaviours had a unique developmental trajectory in mutant mice, and males showed an earlier onset and severity than females in several behaviours. Hyperlocomotion was most substantial in juvenile mice and plateaued in adult mice, whereas stereotypy progressively worsened with age. Impairments in working memory and sociability were sexually dimorphic, with deficits first detected in peri-adolescent males but only detected in adult females. Interestingly, executive function was most impaired in peri-adolescent mice of either sex. Furthermore, while juvenile mutant mice had some ability to problem solve in the puzzle box test, the same mice lost this ability when tested four weeks later. Our studies highlight key developmental periods for males and females in the expression of behaviours that are relevant to psychiatric disorders.
    Genes Brain and Behavior 10/2014; 13(8). DOI:10.1111/gbb.12183 · 3.66 Impact Factor
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    • "Schizophrenia is a complex psychotic disorder that affects approximately 1% of the population worldwide (Tamminga and Holcomb, 2005). Its aetiology remains unclear but it is now well accepted that this neurodevelopmental disorder arises from the combination of genetic and environmental factors (for review see Brown, 2011). "
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    ABSTRACT: Stress exposure during adolescence/early adulthood has been shown to increase the risk for psychiatric disorders such as schizophrenia. Reelin plays an essential role in brain development and its levels are decreased in schizophrenia. However, the relationship between stress exposure and reelin expression remains unclear. We therefore treated adolescent reelin heteroyzogous mice (HRM) and wild-type (WT) littermates with the stress hormone, corticosterone (CORT) in their drinking water (25 mg/l) for 3 wk. In adulthood, we measured levels of full-length (FL) reelin and the N-R6 and N-R2 cleavage fragments in the frontal cortex (FC) and dorsal (DH) and ventral (VH) hippocampus. As expected, levels of all reelin forms were approximately 50% lower in HRMs compared to WT. In male mice, CORT treatment significantly decreased FL and N-R2 expression in the FC and N-R2 and N-R6 levels in the DH. This reelin down-regulation was accompanied by significant reductions in downstream N-methyl-D-aspartate (NMDA) GluN2C subunit levels. There were no effects of CORT treatment in the VH of either of the sexes and only subtle changes in female DH. CORT-induced reelin and GluN2C down-regulation in males was not associated with changes in two GABAergic neuron markers, GAD67 and parvalbumin, or glucocorticoids receptors (GR). These results show that CORT treatment causes long-lasting and selective reductions of reelin form levels in male FC and DH accompanied by changes in NMDAR subunit composition. This sex-specific reelin down-regulation in regions implicated in schizophrenia could be involved in the effects of stress in this disease.
    The International Journal of Neuropsychopharmacology 02/2014; 17(08):1-12. DOI:10.1017/S1461145714000121 · 4.01 Impact Factor
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