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Archives of General Psychiatry current issue

ABOUT THIS JOURNAL: About This Journal
Mon, 05 Jan 2009 00:00:00 -0000

THIS MONTH IN ARCHIVES OF GENERAL PSYCHIATRY: This Month in Archives of General Psychiatry
Mon, 05 Jan 2009 00:00:00 -0000

ART AND IMAGES IN PSYCHIATRY: The Convalescent
Harris, J. C. Mon, 05 Jan 2009 00:00:00 -0000

ORIGINAL ARTICLE: Elevated Striatal Dopamine Function Linked to Prodromal Signs of Schizophrenia
Howes, O. D., Montgomery, A. J., Asselin, M.-C., Murray, R. M., Valli, I., Tabraham, P., Bramon-Bosch, E., Valmaggia, L., Johns, L., Broome, M., McGuire, P. K., Grasby, P. M. Mon, 05 Jan 2009 00:00:00 -0000
Context  A major limitation on the development of biomarkers and novel interventions for schizophrenia is that its pathogenesis is unknown. Although elevated striatal dopamine activity is thought to be fundamental to schizophrenia, it is unclear when this neurochemical abnormality develops in relation to the onset of illness and how this relates to the symptoms and neurocognitive impairment seen in individuals with prodromal symptoms of schizophrenia. Objectives  To determine whether striatal dopamine function is elevated in individuals with prodromal symptoms of schizophrenia before the onset of psychosis and to assess how this relates to the symptoms and neurocognitive impairment. Design  Case-control study of in vivo striatal dopaminergic function. Setting  Academic research. Patients  Patients were recruited from a community mental health service. Twenty-four patients having prodromal symptoms of schizophrenia were compared with 7 patients having schizophrenia and with 12 matched healthy control subjects from the same community. Main Outcome Measure  Striatal 6-fluoro–l-dopa F 18–dopa uptake measured using positron emission tomographic 18F-dopa imaging. Results  Striatal 18F-dopa uptake was elevated in patients with prodromal symptoms of schizophrenia (effect size, 0.75) to an intermediate degree compared with that in patients with schizophrenia (effect size, 1.25). The elevation was localized in the associative striatum in both groups. Moreover, striatal 18F-dopa uptake in patients with prodromal symptoms of schizophrenia was correlated with the severity of prodromal psychopathologic and neuropsychological impairment but not with the severity of anxiety or depressive symptoms. Conclusions  These findings indicate that dopamine overactivity predates the onset of schizophrenia in individuals with prodromal psychotic symptoms, is predominantly localized in the associative striatum, and is correlated with the severity of symptoms and neurocognitive dysfunction.
ORIGINAL ARTICLE: Alternative Splicing, Methylation State, and Expression Profile of Tropomyosin-Related Kinase B in the Frontal Cortex of Suicide Completers
Ernst, C., Deleva, V., Deng, X., Sequeira, A., Pomarenski, A., Klempan, T., Ernst, N., Quirion, R., Gratton, A., Szyf, M., Turecki, G. Mon, 05 Jan 2009 00:00:00 -0000
Context  Although most of the effort to understand the neurobiology of depressive states and suicide has focused on neuronal processes, recent studies suggest that astroglial dysfunction may play an important role. A truncated variant of the tropomyosin-related kinase B (TrkB.T1) is expressed in astrocytes, and brain-derived neurotrophic factor–TrkB signaling has been linked to mood disorders. Objective  To test the hypothesis that TrkB.T1 expression is downregulated in suicide completers and that this downregulation is mediated by an epigenetic process. Design  Postmortem case-control study. Patients, Setting, and Main Outcome Measures  Thirty-nine French Canadian men underwent screening at the Douglas Hospital Research Institute using the HG-U133 plus 2 microarray chip. Nine frontal cortical regions and the cerebellum were assessed using a microarray screening approach for extreme expression differences across subjects and a conventional screening approach. Results were validated by quantitative polymerase chain reaction and Western blot analyses. Animal experiments were performed to control for drug and alcohol effects. Genetic and epigenetic studies were performed by means of direct sequencing and bisulfite mapping. Results  We found that 10 of 28 suicide completers (36%) demonstrated significant decreases in different probe sets specific to TrkB.T1 in Brodmann areas 8 and 9. These findings were generalizable to other frontal regions but not to the cerebellum. The decrease in TrkB expression was specific to the T1 splice variant. Our results were not accounted for by substance comorbidity or by reduction in astrocyte number. We found no effect of genetic variation in a 2500–base pair promoter region or at relevant splice junctions; however, we detected an effect of methylation state at particular CpG dinucleotides on TrkB.T1 expression. Conclusion  A reduction of TrkB.T1 expression in the frontal cortex of a subpopulation of suicide completers is associated with the methylation state of the promoter region.
ORIGINAL ARTICLE: Effects of HTR1A C(-1019)G on Amygdala Reactivity and Trait Anxiety
Fakra, E., Hyde, L. W., Gorka, A., Fisher, P. M., Munoz, K. E., Kimak, M., Halder, I., Ferrell, R. E., Manuck, S. B., Hariri, A. R. Mon, 05 Jan 2009 00:00:00 -0000
Context  Serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating serotonin signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C[–1019]G) in the human 5-HT1A gene (HTR1A) represents 1 potential source of such interindividual variability. Both in vitro and in vivo, –1019G blocks transcriptional repression, leading to increased autoreceptor expression. Thus, –1019G may contribute to relatively decreased serotonin signaling at postsynaptic forebrain target sites via increased negative feedback. Objectives  To evaluate the effects of HTR1A C(–1019)G on amygdala reactivity and to use path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that –1019G, which potentially results in decreased serotonin signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety. Design  Imaging genetics in participants from an archival database. Participants  Eighty-nine healthy adults. Results  Consistent with prior findings, –1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism that affects serotonin signaling, 5-HTTLPR. While there were no direct genotype effects on trait anxiety, HTR1A C(–1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity. Conclusions  Our findings further implicate relatively increased serotonin signaling, associated with a genetic variation that mediates increased 5-HT1A autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation indirectly affects emergent behavioral processes related to psychiatric disease risk by biasing the response of underlying neural circuitries.

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