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The current construct of schizophrenia as a unitary disease is far from satisfactory, and is in need of reconceptualization. The first five papers in our "facts" series reviewed what is known about schizophrenia to date, and a limited number of key facts appear to stand out. Schizophrenia is characterized by persistent cognitive deficits, positive and negative symptoms typically beginning in youth, substantive heritability, and brain structural, functional and neurochemical alterations including dopaminergic dysregulation. Several pathophysiological models have been proposed with differing interpretations of the illness, like the fabled six blind Indian men groping different parts of an elephant coming up with different conclusions. However, accumulating knowledge is integrating the several extant models of schizophrenia etiopathogenesis into unifying constructs; we discuss an example, involving a neurodevelopmental imbalance in excitatory/inhibitory neural systems leading to impaired neural plasticity. This imbalance, which may be proximal to clinical manifestations, could result from a variety of genetic, epigenetic and environmental causes, as well as pathophysiological processes such as inflammation and oxidative stress. Such efforts to "connect the dots" (and visualizing the elephant) are still limited by the substantial clinical, pathological, and etiological heterogeneity of schizophrenia and its blurred boundaries with several other psychiatric disorders leading to a "fuzzy cluster" of overlapping syndromes, thereby reducing the content, discriminant and predictive validity of a unitary construct of this illness. The way ahead involves several key directions: a) choosing valid phenotype definitions increasingly derived from translational neuroscience; b) addressing clinical heterogeneity by a cross-diagnostic dimensional and a staging approach to psychopathology; c) addressing pathophysiological heterogeneity by elucidating independent families of "extended" intermediate phenotypes and pathophysiological processes (e.g. altered excitatory/inhibitory, salience or executive circuitries, oxidative stress systems) that traverse structural, functional, neurochemical and molecular domains; d) resolving etiologic heterogeneity by mapping genomic and environmental factors and their interactions to syndromal and specific pathophysiological signatures; e) separating causal factors from consequences and compensatory phenomena; and f) formulating or reformulating hypotheses that can be refuted/tested, perhaps in the mouse or other experimental models. These steps will likely lead to the current entity of schizophrenia being usefully deconstructed and reconfigured into phenotypically overlapping, but etiopathologically unique and empirically testable component entities (similar to mental retardation, epilepsy or cancer syndromes). The mouse may be the way to rescue the trapped elephant! [ABSTRACT FROM AUTHOR]

In vivo proton ((1)H) Magnetic Resonance spectroscopy ((1)H MRS) has shown abnormalities in young first-episode patients with schizophrenia. It is unclear whether these abnormalities reflect trait related vs. state related alterations in schizophrenia. We compared young first-degree relatives of schizophrenia patients and healthy controls using (1)H MRS. We hypothesized alterations in the (1)H MRS metabolites N-acetyl aspartate (NAA) and glutamate in corticostriatal and thalamic brain regions. We obtained multi-voxel, short-TE (1)H MRS measurements at 1.5 Tesla in 40 consenting adolescent offspring at risk for schizophrenia (HR), and 48 age matched healthy controls (HC). Absolute levels of NAA, phosphocreatine plus creatine (PCr+Cr), choline-containing compounds (GPC+PC), myo-inositol and glutamate plus glutamine (Glu+Gln) were obtained from the seven different anatomical brain areas (nominal voxel size of 4.5cm(3) each) and corrected for tissue voxel composition. HR subjects showed NAA (p=.0049), PCr+Cr (p=0.028) and GPC+PC (p=0.0086) reductions in the caudate compared with HC subjects. Male HR subjects had significant Glu+Gln reductions compared to male HC subjects (p=.0022). HR subjects had increased NAA in prefrontal white matter. NAA levels in the prefrontal white matter and Glu+Gln levels in the inferior parietal/occipital region were both increased in HR without psychopathology compared with HC subjects. Lower NAA, PCr+Cr and GPC+PC levels may reflect an overall reduction in cellular processes in the caudate of HC subjects, perhaps related to decreases in cell density, or synaptic overpruning. Further studies are needed to examine the pathophysiologic significance of these observations, and their potential predictive value for schizophrenia related psychopathology that may emerge in these at risk relatives during adolescence and early adulthood. [ABSTRACT FROM AUTHOR]

Investigating the neurobiological basis of schizophrenia is a critical step toward establishing its diagnostic validity, predicting outcome, delineating causative mechanisms and identifying objective targets for treatment research. Over the past two decades, there have been several advances in this field, principally related to developments in neuroimaging, electrophysiological and neuropathological approaches. Several neurobiological alterations in domains of brain structure, physiology and neurochemistry have been documented that may reflect diverse pathophysiological pathways from the "genome to the phenome". While none of the observed abnormalities are likely to qualify as diagnostic markers at this time, many can serve as potential intermediate phenotypes for elucidating etiological factors including susceptibility genes, and as therapeutic targets for novel drug discovery. Despite several challenges including the substantial phenotypic, pathophysiologic and etiological heterogeneity of schizophrenia, technological limitations, and the less than ideal animal models, considerable progress has been made in characterizing the neurobiological substrate of schizophrenia. The accumulating fact-base on the neurobiology of schizophrenia calls for novel integrative model(s) that may generate new, testable predictions. [ABSTRACT FROM AUTHOR]

Converging data from multiple lines of research provide growing understanding of the pharmacological basis of the efficacy and tolerability of antipsychotic agents. This review highlights some of the drawbacks of the current practice of classifying antipsychotic agents into first- and second-generation agents, and argues that much of what is known about an antipsychotic agent in terms of its efficacy and tolerability can be predicted from its binding affinity at different receptors. This makes a case for a new system of classification that reflects the receptor binding affinity profiles of individual antipsychotic agents. In its quest to make a compelling case, the review provides detailed explanations for the pharmacological basis of antipsychotic efficacy, antipsychotic-induced weight gain and diabetes mellitus, cognitive effects and other adverse effects. [ABSTRACT FROM AUTHOR]

Although we have studied schizophrenia as a major disease entity over the past century, its causes and pathogenesis remain obscure. In this article, we critically review genetic and other epidemiological findings and discuss the insights they provide into the causes of schizophrenia. The annual incidence of schizophrenia averages 15 per 100,000, the point prevalence averages approximately 4.5 per population of 1000, and the risk of developing the illness over one's lifetime averages 0.7%. Schizophrenia runs in families and there are significant variations in the incidence of schizophrenia, with urbanicity, male gender, and a history of migration being associated with a higher risk for developing the illness. Genetic factors and gene-environment interactions together contribute over 80% of the liability for developing schizophrenia and a number of chromosomal regions and genes have been "linked" to the risk for developing the disease. Despite intensive research and spectacular advances in molecular biology, however, no single gene variation has been consistently associated with a greater likelihood of developing the illness and the precise nature of the genetic contribution remains obscure at this time. Environmental factors linked to a higher likelihood of developing schizophrenia include cannabis use, prenatal infection or malnutrition, perinatal complications, and a history of winter birth; the exact relevance or nature of these contributions is, however, unclear. How various genetic and environmental factors interact to cause schizophrenia and via which precise neurobiological mechanisms they mediate this effect is not understood. Etiological heterogeneity, complex patterns of gene-gene and gene-environment interaction, and inadequately elucidated schizophrenia pathophysiology are among the explanations invoked to explain our inadequate understanding of the etio-pathogenesis of schizophrenia. The ability to question some of our basic assumptions about the etiology and nature of schizophrenia and greater rigor in its study appear critical to improving our understanding about its causation. [ABSTRACT FROM AUTHOR]

For every disorder, there is a set of established findings and accepted constructs upon which further understanding is built. The concept of schizophrenia as a disease entity has been with us for a little more than a century, although descriptions resembling this condition predate this conceptualization. In 1988, for the inaugural issue of Schizophrenia Research, at the invitation of the founding editors, a senior researcher, since deceased (RJ Wyatt) published a summary of generally accepted ideas about the disorder, which he termed "the facts" of schizophrenia. Ten years later, in conjunction with two of the authors (MSK, RT), he compiled a more extensive set of "facts" for the purpose of evaluating conceptual models or theoretical constructs developed to understand the nature of schizophrenia. On the 20th anniversary of this journal, we update and substantially expand our effort to periodically summarize the current body of information about schizophrenia. We compile a body of seventy-seven representative major findings and group them in terms of their specific relevance to schizophrenia -- etiologies, pathophysiology, clinical manifestations, and treatments. We rate each such "fact" on a 0-3 scale for measures of reproducibility, whether primary to schizophrenia, and durability over time. We also pose one or more critical questions with reference to each "fact", answers to which might help better elucidate the meaning of that finding for our understanding of schizophrenia. We intend to follow this paper with the submission to the journal of a series of topic-specific articles, critically reviewing the evidence. [ABSTRACT FROM AUTHOR]

The introduction of second-generation antipsychotics and cognitive therapies for schizophrenia over the past two decades generated considerable optimism about possibilities for recovery. To what extent have these developments resulted in better outcomes for affected individuals? What is the current state of our science and how might we address the many unmet needs in the prevention and treatment of schizophrenia? We trace the evolution of various treatments for schizophrenia and summarize current knowledge about available pharmacological and psychosocial treatments. We consider the widely prevalent efficacy-effectiveness gap in the application of available treatments and note the significant variability in individual treatment response and outcome. We outline an individualized treatment approach which emphasizes careful monitoring and collaborative decision-making in the context of ongoing benefit-risk assessment. We note that the evolution of both pharmacological and psychosocial treatments thus far has been based principally on serendipity and intuition. In view of our improved understanding of the etiology and pathophysiology of schizophrenia, there is an opportunity to develop prevention strategies and treatments based on this enhanced knowledge. In this context, we discuss potential psychopathological treatment targets and enumerate current pharmacological and psychosocial development efforts directed at them. Considering the stages of schizophrenic illness, we review approaches to prevent progression from the pre-symptomatic high-risk to the prodrome to the initial psychotic phase to chronicity. In view of the heterogeneity of risk factors, we summarize approaches towards targeted prevention. We evaluate the potential contribution of pharmacogenomics and other biological markers in optimizing individual treatment and outcome in the future. [ABSTRACT FROM AUTHOR]

Although dementia praecox or schizophrenia has been considered a unique disease entity for the past century, its definitions and boundaries have continued to vary over this period. At any given time, the changing concept of schizophrenia has been influenced by available diagnostic tools and treatments, related conditions from which it most needs to be distinguished, extant knowledge and scientific paradigms. There is significant heterogeneity in the etiopathology, symptomatology, and course of schizophrenia. It is characterized by an admixture of positive, negative, cognitive, mood, and motor symptoms whose severity varies across patients and through the course of the illness. Positive symptoms usually first begin in adolescence or early adulthood, but are often preceded by varying degrees of negative and cognitive symptomatology. Schizophrenia tends to be a chronic and relapsing disorder with generally incomplete remissions, variable degrees of functional impairment and social disability, frequent comorbid substance abuse, and decreased longevity. Although schizophrenia may not represent a single disease with a unitary etiology or pathogenetic process, alternative approaches have thus far been unsuccessful in better defining this syndrome or its component entities. The symptomatologic, course, and etio-pathological heterogeneity can usefully be addressed by a dimensional approach to psychopathology, a clinical staging approach to illness course, and by elucidating endophenotypes and markers of illness progression, respectively. This will allow an approach to the deconstruction of schizophrenia into its multiple component parts and strategies to reconfigure these components in a more meaningful manner. Possible implications for DSM-V and ICD-11 definitions of schizophrenia are discussed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Prefrontal cortical dysfunctions, including disturbances in adaptive context-specific behavior, have been reported in neuropsychological and brain imaging studies of schizophrenia. Some data suggest that treatment with antipsychotic medications may ameliorate these deficits. METHOD: We investigated antisaccade performance in 39 antipsychotic-naive, first-episode schizophrenia patients who were re-evaluated 6 weeks after treatment initiation. A group of matched healthy subjects were examined at similar time-points. Patients and healthy individuals available for longer-term testing were re-assessed 26 and 52 weeks after initial testing. RESULTS: Before treatment, patients showed elevated rates of response suppression errors and prolonged latencies of correct antisaccades. Increased rates of antisaccade errors were associated with faster response latencies during a separate, visually guided saccade task, but only prior to treatment. Throughout the 1-year follow-up, patients progressively improved in their ability to voluntarily suppress context-inappropriate behavior. Although treatment assignment was by clinician choice, results of exploratory analyses revealed that patients treated with risperidone progressively planned and initiated correct antisaccades more quickly than patients receiving haloperidol. CONCLUSIONS: Deficits in the voluntary control of spatial attention are exaggerated during acute episodes of illness, but remain an enduring aspect of prefrontal dysfunction in schizophrenia even after treatment. During acute illness, speeded sensorimotor transformations may compound these deficits and contribute to the heightened distractibility associated with acute psychosis. Continued improvement in task performance throughout the 1-year follow-up suggests that partial normalization of prefrontal cognitive functions resulting from antipsychotic treatment may have a longer and more gradual time course than the reduction of acute psychotic symptoms. [ABSTRACT FROM AUTHOR]

Objective: Brain-derived neurotrophic factor (BDNF) is a key factor known to mediate neuronal proliferation, differentiation, survival and response to stress. Decreases in BDNF levels have been reported in schizophrenia, but studies in treatment naïve patients are few. Herein we report on serum BDNF levels in a series of patients with first-episode treatment naïve psychoses in comparison to age matched healthy controls.Method: Fasting serum BDNF levels were measured in 41 patients with treatment naive first episode psychosis (24 with schizophrenia, schizoaffective disorder or schizophreniform disorder, and 17 with non-schizophrenia psychotic disorders) and 41 age-matched healthy controls.Results: A three group analyses of covariance (ANCOVA) showed a diagnosis effect (p=.038) in which patients with schizophrenia had lesser serum BDNF levels than patient with non-schizophrenia psychosis, who in turn had lesser BDNF levels than matched healthy controls. Planned two-group ANCOVAs suggested that patients with schizophrenia had lower serum BDNF level than matched controls (p=.016), whereas patients with non-schizophrenia psychosis did not differ from controls. There were no age effects on BDNF, but there was a trend (p=.08) for a gender by group interaction with greater reductions in female patients with schizophrenia. The BDNF levels did not correlate with magnitude of smoking, body mass index, severity of positive and negative symptoms or overall functioning.Conclusions: Serum BDNF may be reduced at the onset of psychosis but its role in the pathogenesis of schizophrenia remains unclear. Elucidating the role of BDNF in schizophrenia and related psychotic disorders may provide an important therapeutic target. Further studies are also needed to examine if patients with schizophrenia have more pronounced reductions in BDNF than those with affective psychosis. [ABSTRACT FROM AUTHOR]

The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) is a key measure of social cognition recommended by the MATRICS committee. While the psychometric properties of the MSCEIT appear strong, previous evidence suggested its factor structure may have shifted when applied to schizophrenia patients, posing important implications for cross-group comparisons. Using multi-group confirmatory factor analysis, we explicitly tested the factorial invariance of the MSCEIT across schizophrenia (n=64) and two normative samples (n=2099 and 451). Results indicated that the factor structure of the MSCEIT was significantly different between the schizophrenia and normative samples. Implications for future research are discussed. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the relationship between thalamic volume and brain size in individuals with Asperger's disorder (ASP). Volumetric measurements of the thalamus were performed on MRI scans obtained from 12 individuals with ASP (age range: 10-35 years) and 12 healthy controls (age range: 9-33 years). A positive correlation was found between total brain volume and thalamic size in controls, but not in ASP subjects. This occurred in the absence of differences in mean thalamic volumes between the study groups. Findings from this investigation point to an abnormal relationship between the thalamus and its projection areas in ASP and are consistent with similar studies in autism, supporting that these disorders are qualitatively similar and possibly quantitatively different. [ABSTRACT FROM AUTHOR]