Brain structure and function correlates of cognitive subtypes in schizophrenia.

Stable neuropsychological deficits may provide a reliable basis for identifying etiological subtypes of schizophrenia. The aim of this study was to identify clusters of individuals with schizophrenia based on dimensions of neuropsychological performance, and to characterize their neural correlates. We acquired neuropsychological data as well as structural and functional magnetic resonance imaging from 129 patients with schizophrenia and 165 healthy controls. We derived eight cognitive dimensions and subsequently applied a cluster analysis to identify possible schizophrenia subtypes. Analyses suggested the following four cognitive clusters of schizophrenia: (1) Diminished Verbal Fluency, (2) Diminished Verbal Memory and Poor Motor Control, (3) Diminished Face Memory and Slowed Processing, and (4) Diminished Intellectual Function. The clusters were characterized by a specific pattern of structural brain changes in areas such as Wernicke's area, lingual gyrus and occipital face area, and hippocampus as well as differences in working memory-elicited neural activity in several fronto-parietal brain regions. Separable measures of cognitive function appear to provide a method for deriving cognitive subtypes meaningfully related to brain structure and function. Because the present study identified brain-based neural correlates of the cognitive clusters, the proposed groups of individuals with schizophrenia have some external validity.

An exploratory study of the relationship of symptom domains and diagnostic severity to PET scan imaging in borderline personality disorder.

The purpose of this report is to describe the relationship between clinical rating assessments of borderline personality disorder (BPD) and regional brain metabolism as measured by positron emission tomography with fluorodeoxyglucuse-F18 (PET-FDG). Fourteen women with BPD underwent PET-FDG scanning in a medication-free state. Correlations were performed on a voxel-by-voxel basis with Buss-Durkee Hostility Index (BDHI) and the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) which provides a score for BPD severity. There was a significant negative correlation between glucose metabolism in frontal brain areas and the BDHI. Correlations of brain metabolic changes and diagnostic behavioral rating scale scores (ZAN-BPD) were small and seen mostly in posterior areas. The assessment of the statistical relationship of the BDHI to brain regions was substantially more robust than the correlations of the total ZAN-BPD. This exploratory study illustrates regional metabolic values that are highly related to hostile behavior. Our findings replicate some prior studies that have identified a negative relationship between frontal metabolism and aggression in personality disorders. We have also identified a range of other areas that relate to both positive (representing increased drive) and negative (representing impaired control) hostility scores. The substantially greater correlations of the BDHI compared with the ZAN-BPD provide information about the neural underpinnings of BPD.

Efficacy and tolerability of second-generation antipsychotics in children and adolescents with schizophrenia.

Early-onset schizophrenia-spectrum (EOSS) disorders (onset of psychotic symptoms before 18 years of age) represent a severe variant associated with significant chronic functional impairment and poor response to antipsychotic treatment. All drugs with proven antipsychotic effects block dopamine D(2) receptors to some degree. The ongoing development of the dopamine and other neurotransmitter receptor systems during childhood and adolescence may affect clinical response and susceptibility to side effects in youth. A literature search was conducted of clinical trials of antipsychotics in children and adolescents with EOSS disorders between 1980 and 2007 from the Medline database, reference lists, and conference proceedings. Trials were limited to double-blind studies of duration of 4 or more weeks that included 15 or more patients. Ten clinical trials were identified. Antipsychotic medications were consistently found to reduce the severity of psychotic symptoms in children and adolescents when compared with placebo. The superiority of clozapine has been now demonstrated relative to haloperidol, standard-dose olanzapine, and "high-dose" olanzapine for EOSS disorders. However, limited comparative data are available regarding whether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness. The available data from short-term studies suggest that youth might be more sensitive than adults to developing antipsychotic-related adverse side effects (eg, extrapyramidal side effects, sedation, prolactin elevation, weight gain). In addition, preliminary data suggest that SGA use can lead to the development of diabetes in some youth, a disease which itself carries with it significant morbidity and mortality. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population.

Limbic structures and networks in children and adolescents with schizophrenia.

Studies of adults with schizophrenia provide converging evidence for abnormalities in the limbic system. Limbic structures that show consistent patient/control differences in both postmortem and neuroimaging studies include the anterior cingulate and hippocampus, although differences in the amygdala, parahippocampal gyrus, and fornix have also been observed. Studies of white matter in children and adolescents with schizophrenia tend to show findings that are more focal than those seen in adults. Interestingly, these focal abnormalities in early-onset schizophrenia tend to be more localized to limbic regions. While it is unclear if these early limbic abnormalities are primary in the etiology of schizophrenia, there is evidence that supports a developmental progression with early limbic abnormalities evolving over time to match the neuroimaging profiles seen in adults with schizophrenia. Alternatively, the aberrations in limbic structures may be secondary to a more widespread or global pathological processes occurring with the brain that disrupt neural transmission. The goal of this article is to provide a review of the limbic system and limbic network abnormalities reported in children and adolescents with schizophrenia. These findings are compared with the adult literature and placed within a developmental context. These observations from neuroimaging studies enrich our current understanding of the neurodevelopmental model of schizophrenia and raise further questions about primary vs secondary processes. Additional research within a developmental framework is necessary to determine the putative etiologic roles for limbic and other brain abnormalities in early-onset schizophrenia.

Editorial: research progress in early-onset schizophrenia.

A substantial proportion of patients with schizophrenia experience the onset of their illness by age 18. Data from phenomenological, cognitive, neuroimaging, and genetic studies suggest a similar profile of clinical and neurobiological abnormalities between early- and adult-onset patients. However, children and adolescents with schizophrenia have been found to have more severe premorbid neurodevelopmental abnormalities, worse long-term outcome, more cytogenetic anomalies, and potentially greater loading of family histories for schizophrenia and associated spectrum disorders than their adult counterparts. Together, these data support a hypothesis that early-onset schizophrenia may reflect a more severe form of the disorder associated with a greater genetic predisposition. It is anticipated that future imaging and genetic studies of this cohort will provide further insight into the neurodevelopmental origins of schizophrenia and the complexity by which genetic and environmental factors interact to modulate susceptibility and/or disease phenotype. The articles on this theme provide updated findings from brain magnetic resonance imaging, neurocognition, and clinical trials in this unique cohort.