The genetics of schizophrenia spectrum disorders have come a long way since the early demonstration of a substantial genetic component by family, twin and adoption studies. After over a decade of intensive molecular genetic studies, initially by linkage scans and candidate gene association studies, and more recently genome-wide association studies, a picture is now emerging that susceptibility to schizophrenia spectrum disorders is determined by many genetic variants of different types, ranging from single nucleotide polymorphisms to copy number variants, including rare and de novo variants, of pleiotropic effects on multiple diagnoses and traits. Further large-scale genome-wide association studies, and the forthcoming availability of affordable whole-genome sequencing technology, will further characterise the genetic variants involved, which in turn will be translated to improved clinical practice.
Gene Dosage ; Genetic Linkage ; Genome-Wide Association Study ; Humans ; Polymorphism, Single Nucleotide ; Schizophrenia ; genetics

Neuroimaging in psychiatry, and in schizophrenia in particular, moves ahead at a rapid pace delivering new insights into the nature of the illness and its intriguing symptoms via technologies such as MRI, fMRI, PET, and SPET scanning. How do these impact on understanding the patient in front of us? What do they mean for the busy clinician in clinic? We outline some of the recent findings in neuroimaging research of schizophrenia and consider their potential application in clinical practice.
Brain ; diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Schizophrenia ; diagnostic imaging ; physiopathology

Humans ; Nervous System ; physiopathology ; Schizophrenia ; physiopathology

Animal models of schizophrenia are important for research aimed at developing improved pharmacotherapies. In particular, the cognitive deficits of schizophrenia remain largely refractory to current medications and there is a need for improved medications. We discuss the pathophysiology of schizophrenia and in particular the possible mechanisms underlying the cognitive deficits. We review the current animal models of schizophrenia and discuss the extent to which they meet the need for models reflecting the various domains of the symptomatology of schizophrenia, including positive symptoms, negative symptoms and cognitive symptoms.
Animals ; Drug Therapy ; Humans ; Models, Animal ; Schizophrenia ; drug therapy ; physiopathology

Schizophrenia is a brain disease with differing symptomatic presentations, outcomes, and complex genetic mechanisms. A selection of recent work integrating clinical observations, human brain imaging and genetics will be reviewed. While the mechanics of brain dysfunction in schizophrenia remains to be well understood, the emerging evidence suggests that a number of interacting genetic mechanisms in dopaminergic and glutamatergic systems affect fundamental disease-related cognitive brain processes and may do so early in disease neurodevelopment. The availability of new imaging and genetic technologies, and institutional support for research in the translational neurosciences, extends the hope that increased understanding of these brain processes could yield meaningful clinical applications.
Cognition Disorders ; etiology ; genetics ; Dopamine ; genetics ; Glutamic Acid ; genetics ; Humans ; Magnetic Resonance Imaging ; Neurosciences ; Schizophrenia ; genetics ; physiopathology

The largely consistent columnar circuitry observed throughout the cortex may serve to continuously predict bottom-up activation based on invariant memories. This "memory-prediction" function is essential to efficient and accurate perception. Many of the defined cognitive deficits associated with schizophrenia suggest a breakdown of memory-prediction function. As deficits in memory-prediction function are proposed to lie more proximal to the biological causes of schizophrenia than deficits in standard cognitive constructs, tests that more directly probe memory-prediction function may be especially sensitive predictors of conversion in individuals at high-risk for schizophrenia. In this article, we review the conceptual basis for this hypothesis, and outline how it may be tested with specific cognitive paradigms. The accurate identification of cognitive processes that precede the onset of psychosis will not only be useful for clinicians to predict which young people are at greatest risk for schizophrenia, but will also help determine the neurobiology of psychosis onset, thus leading to new and effective treatments for preventing schizophrenia and other psychoses.
Cognition Disorders ; Humans ; Memory ; Neuropsychological Tests ; Predictive Value of Tests ; Risk Assessment ; Schizophrenia ; etiology ; physiopathology ; Schizophrenic Psychology

INTRODUCTIONNeurological soft signs (NSS) are suggested as a candidate endophenotype for schizophrenia. This article aims to review relevant literature and discuss the role of NSS in understanding schizophrenia.

METHODSThis is an update on a review article published in 2003. Articles from 2003 onwards were specifically reviewed and discussed with relevance to the role of NSS as endophenotype for schizophrenia.

RESULTSConsistent data suggest an excess of NSS in schizophrenic patients. NSS appear to be related to schizophrenic symptoms, in particular negative symptoms and disorganisation. Information on NSS and demographic correlates is scarce, and the confounding effects between age, education and intelligence on NSS constitute an important gap in current knowledge. Longitudinal data suggest NSS as both a trait and state variable in the course of disease. NSS are not specific with regard to diagnosis, although there are claims that individual sub-components may be more specific. The weight of evidence raises question on the specificity of NSS for schizophrenia.

CONCLUSIONSThe usefulness and feasibility of NSS as a specific endophenotype target for schizophrenia is unclear. However, NSS remain an important feature and symptom correlate of schizophrenia. Future research should focus on delineating the effects of NSS from those of confounding demographic variables, and the stability of NSS over the course of illness to elucidate its role in schizophrenia.

Humans ; Mental Disorders ; Neurologic Examination ; Phenotype ; Risk Factors ; Schizophrenia ; diagnosis ; genetics ; Sensitivity and Specificity

AIMVarious forms of social adversity have been implicated in the development and emergence of psychosis. However, how and when these events exert their influences are not clear. In this paper, we attempt to examine these putative psychosocial factors and place them in a temporal context and propose a neurobiological mechanism linking these factors.

METHODSMedline databases were searched between 1966 and 2007 followed by the cross-checking of references using the following keywords: psychosocial, stress, stressors, life events, psychological, combined with psychosis and schizophrenia.

RESULTSWhile some findings are conflicting, there are a number of positive studies which suggest that factors like prenatal stress, urban birth and childhood trauma accentuate the vulnerability for schizophrenia and other psychoses while other factors like life events, migration particularly being a minority group, and high expressed emotions, which occur later in the vulnerable individual may move the individual towards the tipping point for psychosis.

CONCLUSIONOverall, there is evidence to implicate psychosocial factors in the pathophysiology of schizophrenia. These factors may act via a common pathway, which involves stress-induced dysregulation of the HPA axis and the dopaminergic systems. To establish the causal relationship of the various factors would require prospective studies that are adequately powered.

Humans ; Nervous System ; physiopathology ; Psychology ; Schizophrenia ; physiopathology

Mitochondrial dysfunction and oxidative stress are increasingly implicated in the pathophysiology of schizophrenia. The brain is the body's highest energy consumer, and the glutathione system is the brain's dominant free radical scavenger. In the current paper, we review the evidence of central and peripheral nervous system anomalies in the oxidative defences of individuals with schizophrenia, principally involving the glutathione system. This is reflected by evidence of the manifold consequences of oxidative stress that include lipid peroxidation, protein carboxylation, DNA damage and apoptosis - all potentially part of the process of neuroprogression in the disorder. Importantly, oxidative stress is amenable to intervention. We consider the clinical potential of some possible interventions that help reduce oxidative stress, via augmentation of the glutathione system, particularly N-acetyl cysteine. We argue that a better understanding of the mechanisms and pathways underlying oxidative stress will assist in developing the therapeutic potential of this area.
Acetylcysteine ; Glutathione ; Humans ; Magnetic Resonance Imaging ; Mitochondrial Diseases ; Nervous System ; physiopathology ; Oxidative Stress ; Schizophrenia ; physiopathology

INTRODUCTIONPrevious studies examining brain effects of duration of illness in schizophrenia have focused on either cortical or subcortical structures. Hence this study sought to elucidate the regional grey matter changes (both cortical and subcortical) and neurocognitive correlates with increased duration of illness in a large sample of patients with schizophrenia using voxel-based morphometry.

MATERIALS AND METHODSNinety patients (72 males and 18 females) with DSM-IV diagnosis of schizophrenia were recruited and assessed using magnetic resonance imaging and a battery of neuropsychological tests.

RESULTSA longer duration of illness was associated with smaller grey matter volumes in the left superior frontal gyrus, bilateral putamen, right superior temporal gyrus, right superior occipital gyrus as well as the right thalamus. No region showed increased grey matter volume above threshold with longer duration of illness. Longer duration of illness was correlated with poorer attention.

CONCLUSIONSThe grey matter reductions in different brain regions highlighted that a distributed network of cortical and subcortical regions was associated with duration of illness. This is consistent with neural models that implicate involvement of thalamo-cortical circuitry as the disruption in these neural pathways can result in specific deficits such as poorer attention. The results have implications for the understanding of brain changes in schizophrenia, and with further studies, may guide better tailored and targeted clinical management in terms of reducing the impact of duration of illness on neural substrates in schizophrenia in the future.

Adult ; Age of Onset ; Brain ; pathology ; Cognition ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Neuropsychological Tests ; Schizophrenia ; diagnosis ; physiopathology ; Schizophrenic Psychology ; Young Adult