Archives of general psychiatry最新文献

CONTEXT Schizophrenic symptoms are linked to a dysfunction of dopamine neurotransmission and the brain reward system. However, it remains unclear whether antipsychotic treatment, which blocks dopamine transmission, improves, alters, or even worsens the reward-related abnormalities. OBJECTIVE To investigate changes in reward-related brain activations in schizophrenia before and after antipsychotic monotherapy with a dopamine D2/D3 antagonist. DESIGN Longitudinal cohort study. SETTING Psychiatric inpatients and outpatients in the Capital Region of Denmark. PARTICIPANTS Twenty-three antipsychotic-naive patients with first-episode schizophrenia and 24 healthy controls initially matched on age, sex, and parental socioeconomic status were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task. INTERVENTIONS Patients were treated for 6 weeks with the antipsychotic compound amisulpride. Controls were followed up without treatment. MAIN OUTCOME MEASURES Task-related blood oxygen level-dependent activations as measured by functional magnetic resonance imaging before and after antipsychotic treatment. RESULTS At baseline, patients, as compared with controls, demonstrated an attenuation of brain activation during reward anticipation in the ventral striatum, bilaterally. After 6 weeks of treatment, patients showed an increase in the anticipation-related functional magnetic resonance imaging signal and were no longer statistically distinguishable from healthy controls. Among the patients, there was a correlation between the improvement of positive symptoms and normalization of reward-related activation. Those who showed the greatest clinical improvement in positive symptoms also showed the greatest increase in reward-related activation after treatment. CONCLUSIONS To our knowledge, this is the first controlled, longitudinal study of reward disturbances in schizophrenic patients before and after their first antipsychotic treatment. Our results demonstrate that alterations in reward processing are fundamental to the illness and are seen prior to any treatment. Antipsychotic treatment tends to normalize the response of the reward system; this was especially seen in the patients with the most pronounced treatment effect on the positive symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01154829.

CONTEXT Prospective studies of childhood attention-deficit/hyperactivity disorder (ADHD) have not extended beyond early adulthood. OBJECTIVE To examine whether children diagnosed as having ADHD at a mean age of 8 years (probands) have worse educational, occupational, economic, social, and marital outcomes and higher rates of ongoing ADHD, antisocial personality disorder (ASPD), substance use disorders (SUDs), adult-onset psychiatric disorders, psychiatric hospitalizations, and incarcerations than non-ADHD comparison participants at a mean age of 41 years. DESIGN Prospective, 33-year follow-up study, with masked clinical assessments. SETTING Research clinic. PARTICIPANTS A total of 135 white men with ADHD in childhood, free of conduct disorder, and 136 men without childhood ADHD (65.2% and 76.4% of original cohort, respectively). MAIN OUTCOME MEASURES Occupational, economic, and educational attainment; marital history; occupational and social functioning; ongoing and lifetime psychiatric disorders; psychiatric hospitalizations; and incarcerations. RESULTS Probands had significantly worse educational, occupational, economic, and social outcomes; more divorces; and higher rates of ongoing ADHD (22.2% vs 5.1%, P < .001), ASPD (16.3% vs 0%, P < .001), and SUDs (14.1% vs 5.1%, P = .01) but not more mood or anxiety disorders (P = .36 and .33) than did comparison participants. Ongoing ADHD was weakly related to ongoing SUDs (ϕ = 0.19, P = .04), as well as ASPD with SUDs (ϕ = 0.20, P = .04). During their lifetime, probands had significantly more ASPD and SUDs but not mood or anxiety disorders and more psychiatric hospitalizations and incarcerations than comparison participants. Relative to comparisons, psychiatric disorders with onsets at 21 years or older were not significantly elevated in probands. Probands without ongoing psychiatric disorders had worse social, but not occupational, functioning. CONCLUSIONS The multiple disadvantages predicted by childhood ADHD well into adulthood began in adolescence, without increased onsets of new disorders after 20 years of age. Findings highlight the importance of extended monitoring and treatment of children with ADHD.

CONTEXT Brain-derived neurotrophic factor (BDNF) is suspected of being a causative factor in psychiatric disorders based on case reports or studies involving large structural anomalies. OBJECTIVE To determine the involvement of BDNF in human psychopathology. DESIGN Case-control study. SETTING Microarray-based comparative genomic hybridization data from 7 molecular diagnostic centers including 38 550 affected subjects and 28 705 unaffected subjects. PATIENTS Subjects referred to diagnostic screening centers for microarray-based comparative genomic hybridization for physical or cognitive impairment. MAIN OUTCOME MEASURES Genomic copy number gains and losses. RESULTS We report 5 individuals with psychopathology and genomic deletion of a critical region including BDNF. The defined critical region was never disrupted in control subjects or diagnostic cases without developmental abnormalities. CONCLUSION Hemizygosity of the BDNF region contributes to variable psychiatric phenotypes including anxiety, behavioral, and mood disorders.

CONTEXT Neural substrates that may be responsible for the high prevalence of depression in type 1 diabetes mellitus (T1DM) have not yet been elucidated. OBJECTIVE To investigate neuroanatomic correlates of depression in T1DM. DESIGN Case-control study using high-resolution brain magnetic resonance images. SETTINGS Joslin Diabetes Center and McLean Hospital, Massachusetts, and Seoul National University Hospital, South Korea. PARTICIPANTS A total of 125 patients with T1DM (44 subjects with ≥1 previous depressive episodes [T1DM-depression group] and 81 subjects who had never experienced depressive episodes [T1DM-only group]), 23 subjects without T1DM but with 1 or more previous depressive episodes (depression group), and 38 healthy subjects (control group). MAIN OUTCOME MEASURES Spatial distributions of cortical thickness for each diagnostic group were compared with the control group using a surface-based approach. Among patients with T1DM, associations between metabolic control measures and cortical thickness deficits were examined. RESULTS Thickness reduction in the bilateral superior prefrontal cortical regions was observed in the T1DM-depression, T1DM-only, and depression groups relative to the control group at corrected P < .01. Conjunction analyses demonstrated that thickness reductions related to the influence of T1DM and those related to past depressive episode influence were observed primarily in the superior prefrontal cortical region. Long-term glycemic control levels were associated with superior prefrontal cortical deficits in patients with T1DM (β = -0.19, P = .02). CONCLUSIONS This study provides evidence that thickness reduction of prefrontal cortical regions in patients with T1DM, as modified by long-term glycemic control, could contribute to the increased risk for comorbid depression.

CONTEXT Schizophrenia remains a highly disabling disorder, but the specific determinants and pathways that lead to functional impairment are not well understood. It is not known whether these key determinants of outcome lie on 1 or multiple pathways. OBJECTIVE To evaluate theoretically based models of pathways to functional outcome starting with early visual perception. The intervening variables were previously established determinants of outcome drawn from 2 general categories: ability (ie, social cognition and functional capacity) and beliefs/motivation (ie, defeatist beliefs, expressive and experiential negative symptoms). We evaluated an integrative model in which these intervening variables formed a single pathway to poor outcome. DESIGN This was a cross-sectional study that applied structural equation modeling to evaluate the relationships among determinants of functional outcome in schizophrenia. SETTING Assessments were conducted at a Veterans Administration Medical Center. PARTICIPANTS One hundred ninety-one clinically stable outpatients with schizophrenia or schizoaffective disorder were recruited from the community. RESULTS A measurement model showed that the latent variables of perception, social cognition, and functional outcome were well reflected by their indicators. An initial untrimmed structural model with functional capacity, defeatist beliefs, and expressive and experiential negative symptoms had good model fit. A final trimmed model was a single path running from perception to ability to motivational variables to outcome. It was more parsimonious and had better fit indices than the untrimmed model. Further, it could not be improved by adding or dropping connections that would change the single path to multiple paths. The indirect effect from perception to outcome was significant. CONCLUSIONS The final structural model was a single pathway running from perception to ability to beliefs/motivation to outcome. Hence, both ability and motivation appear to be needed for community functioning and can be modeled effectively on the same pathway.

CONTEXT Schizophrenia is a common, highly heritable, neurodevelopmental mental illness, characterized by genetic heterogeneity. OBJECTIVE To identify abnormalities in the transcriptome organization among older persons with schizophrenia and controls. DESIGN Weighted gene coexpression network analysis based on microarray transcriptomic profiling. SETTING Research hospital. PATIENTS Postmortem brain tissue samples from 4 different cerebrocortical regions (the dorsolateral prefrontal cortex, the middle temporal area, the temporopolar area, and the anterior cingulate cortex) from 21 persons with schizophrenia and 19 controls. MAIN OUTCOME MEASURES Results from gene expression microarray analysis, from analysis of coexpression networks, and from module eigengene, module preservation, and enrichment analysis of schizophrenia-related genetic variants. RESULTS The oligodendrocyte, microglial, mitochondrial, and neuronal (GABAergic and glutamatergic) modules were associated with disease status. Enrichment analysis of genome-wide association studies in schizophrenia and other illnesses demonstrated that the neuronal (GABAergic and glutamatergic) and oligodendrocyte modules are enriched for genetically associated variants, whereas the microglial and mitochondrial modules are not, providing independent support for more direct involvement of these gene expression networks in schizophrenia. Interregional coexpression network analysis showed that the gene expression patterns that typically differentiate the frontal, temporal, and cingulate cortices in controls diminish significantly in persons with schizophrenia. CONCLUSIONS These results support the existence of convergent molecular abnormalities in schizophrenia, providing a molecular neuropathological basis for the disease.