Search

Context: Neurocognitive impairment in schizophrenia is severe and is an important predictor of functional outcome. The relative effect of the second-generation (atypical) antipsychotic drugs and older agents on neurocognition has not been comprehensively determined., Objective: To compare the neurocognitive effects of several second-generation antipsychotics and a first-generation antipsychotic, perphenazine., Design: Randomized, double-blind study of patients with schizophrenia assigned to receive treatment with olanzapine, perphenazine, quetiapine fumarate, or risperidone for up to 18 months as reported previously by Lieberman et al. Ziprasidone hydrochloride was included after its approval by the Food and Drug Administration., Setting: Fifty-seven sites participated, including academic sites and treatment mental health facilities representative of the community., Patients: From a cohort of 1460 patients in the treatment study, 817 completed neurocognitive testing immediately prior to randomization and then after 2 months of treatment., Main Outcome Measures: The primary outcome was change in a neurocognitive composite score after 2 months of treatment. Secondary outcomes included neurocognitive composite score change at 6 months and 18 months after continued treatment and changes in neurocognitive domains., Results: At 2 months, treatment resulted in small neurocognitive improvements of z = 0.13 for olanzapine (P<.002), 0.25 for perphenazine (P<.001), 0.18 for quetiapine (P<.001), 0.26 for risperidone (P<.001), and 0.12 for ziprasidone (P<.06), with no significant differences between groups. Results at 6 months were similar. After 18 months of treatment, neurocognitive improvement was greater in the perphenazine group than in the olanzapine and risperidone groups. Neurocognitive improvement predicted longer time to treatment discontinuation, independently from symptom improvement, in patients treated with quetiapine or ziprasidone., Conclusions: After 2 months of antipsychotic treatment, all groups had a small but significant improvement in neurocognition. There were no differences between any pair of agents, including the typical drug perphenazine. These results differ from the majority of previous studies, and the possible reasons are discussed.

Context: Several neurobiological models of obsessive-compulsive disorder (OCD) posit a primary role for dysfunction of the anterior cingulate gyrus. Both functional and structural neuroimaging studies have implicated anterior cingulate gray matter abnormalities in the pathophysiology of OCD, but there has been little investigation of the anterior cingulate white matter in this disorder., Objective: To test the hypothesis that patients with OCD have abnormal white matter microstructure in the anterior cingulate gyrus compared with healthy volunteers as inferred from diffusion tensor imaging. Additional analyses examined group differences in white matter integrity across the entire brain., Design, Setting, and Participants: Fifteen patients with a DSM-IV diagnosis of OCD and 15 healthy volunteers matched for age, sex, and handedness underwent diffusion tensor imaging and structural magnetic resonance imaging examinations. Fractional anisotropy (FA), a robust intravoxel measure of water self-diffusion, was compared between groups on a voxel-by-voxel basis in the anterior cingulate white matter after standardization in Talairach space., Main Outcome Measures: Clinical ratings of symptom severity (ie, Yale-Brown Obsessive-Compulsive Scale) and FA., Results: Compared with healthy volunteers, patients demonstrated significantly lower FA bilaterally in 3 areas of the anterior cingulate gyrus white matter. Additional analyses conducted across the rest of the brain white matter revealed lower FA bilaterally in the parietal region (supramarginal gyri), right posterior cingulate gyrus, and left occipital lobe (lingual gyrus). No areas of significantly higher FA were observed in patients compared with healthy volunteers. Lower FA in the parietal region correlated significantly with higher Yale-Brown Obsessive-Compulsive Scale scores., Conclusions: These preliminary findings provide evidence of an abnormality that involves the anterior cingulate white matter in the pathogenesis of OCD and are consistent with neurobiological models that posit a defect in connectivity in the anterior cingulate basal ganglia-thalamocortical circuit. White matter abnormalities in other brain regions may also be implicated in the neurobiology of OCD.

Background: Deficits in working memory (WM) have been reported in patients with schizophrenia, but WM is a complex construct dependent on several subprocesses, including input representation (perceptual competency) and holding stimuli on-line (maintenance). A visual delayed match-to-sample task (DMST) was developed to isolate perceptual competency from maintenance during delays. It was hypothesized that patients in the first episode of schizophrenia would exhibit dissociable deficits in both WM domains., Methods: Performance on the DMST was assessed in 57 patients in the first episode of schizophrenia or schizoaffective disorder and 22 healthy comparison subjects. In phase 1 of the DMST, a complex visual stimulus (target) was followed immediately by a forced choice between 2 test stimuli, and item difficulty (differences between the test stimuli) was titrated until each subject achieved a consistent accuracy (80%-90%) in this no-delay condition. In phase 2, a delay of 4 or 8 seconds with a mask of randomly illuminated pixels was introduced between target and test stimuli; test stimuli were fixed in difficulty level based on phase 1 titration. Main outcome measures were mean item difficulty attained in the no-delay condition and mean accuracy in matching after delay., Results: Compared with controls, patients attained a lower level of difficulty in the no-delay condition (P =.001) and significantly lower accuracy with delay (P =.002)., Conclusions: Deficits in both domains of WM suggest abnormality in the posterior and prefrontal cortexes. These deficits can be observed in a task involving complex visual pattern stimuli using only a brief delay and are present even in unmedicated patients in the first episode of illness.

Background: Functional neuroimaging studies have implicated the frontal lobes and the hippocampus-amygdala complex in the pathophysiology of obsessive-compulsive disorder (OCD). These brain regions have not been well investigated in patients with OCD, however, using magnetic resonance imaging., Methods: Volumes of the superior frontal gyrus, anterior cingulate gyrus, orbital frontal region, hippocampus, and amygdala were computed from contiguous magnetic resonance images in a sample of 26 patients with OCD and 26 healthy comparison subjects., Results: Patients with OCD had significantly reduced bilateral orbital frontal and amygdala volumes compared with healthy comparison subjects and lacked the normal hemispheric asymmetry of the hippocampus-amygdala complex. Neither brain structure volumes nor asymmetry indices were significantly correlated with total illness duration or length of current OCD episode., Conclusions: Findings of reduced orbital frontal and amygdala volumes in patients implicate a structural abnormality of these brain regions in the pathophysiology of OCD. Absence of the normal hemispheric asymmetry of the hippocampus-amygdala complex in patients is consistent with an anomalous neurodevelopmental process.

In vivo brain imaging and postmortem investigations have demonstrated structural anomalies in the brains of schizophrenic patients. However, previous studies have not established clear relationships between the characteristic symptoms of the disorder and neuropathologic changes in specific brain regions. We have obtained high-resolution magnetic resonance brain images of first-episode schizophrenic and normal control subjects and, with a computerized mensuration system, determined the volumes of the different components of the entire ventricular system. Volumes of ventricular segments were significantly larger in patients than controls (differences ranged from 17% to 40%). Temporal horn enlargement consistently demonstrated significant correlations with a broad range of schizophrenic symptoms. Our data indicate that anomalies of limbic structures in the medial temporal lobe surrounding the temporal horn play a crucial pathophysiologic role in schizophrenia.