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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    • "Positron emission tomography (PET) scanning in humans showed that hallucinogens as psilocybin produced a marked activation of the prefrontal cortex caused by serotonergic [Arora and Meltzer, 1991; Joyce et al., 1993; Volleinweider et al., 1997]. The evidence that clozapine is particularly efficacious in treatment resistant schizophrenia provoked further interest because of the 5-HT2 receptor antagonism induced by this and other atypical antipsychotics [Lieberman et al., 1998; Meltzer, 1999; Tamminga and Holcomb, 2005]. "
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    ABSTRACT: When drug-induced psychoses were first identified in the mid-20th century, schizophrenia was considered a discrete disease with a likely genetic cause. Consequently, drug-induced psychoses were not considered central to understanding schizophrenia as they were thought to be phenocopies rather than examples of the illness secondary to a particular known cause. However, now that we know that schizophrenia is a clinical syndrome with multiple component causes, then it is clear that the drug-induced psychoses have much to teach us. This article shows how the major neuropharmacological theories of schizophrenia have their origins in studies of the effects of drugs of abuse. Research into the effects of LSD initiated the serotonergic model; amphetamines the dopamine hypothesis, PCP and ketamine the glutamatergic hypothesis, while most recently the effects of cannabis have provoked interest in the role of endocannabinoids in schizophrenia. None of these models account for the complete picture of schizophrenia; rather the various drug models mimic different aspects of the illness. Determining the different molecular effects of those drugs whose pharmacological effects do and do not mimic the various aspects of schizophrenia has much to teach us concerning the pathogenesis of the illness. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2013; 162(7):661-70. DOI:10.1002/ajmg.b.32177 · 3.42 Impact Factor
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