Improvement in patient functioning has become a yardstick for measuring new treatments for schizophrenia. Mohamed et al. (p. 978) found that patients’ psychiatric symptoms and cognition both contribute to functioning, as reflected in quality of life ratings and employment. In addition, in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), functional changes were related to changes in symptoms and cognition over 18 months of treatment. Two studies of new antipsychotic treatments illustrate this dual outcomes assessment. Shekhar et al. (CME, p. 1033) evaluated xanomeline, a selective agonist of acetylcholine muscarinic receptors. Compared to 10 patients randomly assigned to placebo, the 10 assigned to xanomeline had greater improvement in global outcomes, positive and negative schizophrenia symptoms, verbal learning, and short-term memory. Freedman et al. (p. 1040) compared two doses of a partial α₇ nicotinic cholinergic agonist, DMXB-A, with placebo in a crossover trial. The higher DMXB-A dose was associated with greater improvement in negative symptoms, especially alogia and anhedonia, than placebo. Improvements in attention and working memory occurred with DMXB-A during the first arm of the trial. Dr. Jeffrey Lieberman et al. comments in an editorial on p. 931.

Two comparisons of brain structure in first-episode and chronic schizophrenia suggest declines in both gray and white matter. The meta-analysis by Ellison-Wright et al. (p. 1015) of voxel-based data from 27 MRI studies indicates a progressive decrease of gray matter volume in the frontal, insular, and temporal cortices. Progression of pathology from the hippocampus to the amygdala was not found. Using diffusion tensor imaging, Friedman et al. (p. 1024) examined white matter structure in 80 patients. Those with chronic schizophrenia had modestly lower values than matched healthy subjects, and the differences reached statistical significance in the right forceps minor and left inferior longitudinal fasciculus. First-episode patients did not differ from healthy subjects, but progression was suggested by similarities between first-episode and chronically ill patients in abnormalities in three regions. An editorial by Drs. John Csernansky and Will Cronenwett on p. 937 focuses on these findings.

Most second-generation antipsychotic medications preferentially bind to receptors outside the striatum, but Gründer et al. (p. 988) report that aripiprazole attaches to dopamine receptors throughout the brain. Positron emission tomography also showed that aripiprazole occupied over 80% of dopamine D₂ and D₃ receptors in patients with schizophrenia. Further, these receptors remained saturated for several days after the last dose. Occupancy values correlated with blood levels of aripiprazole but not with daily dose. Dr. Donald Goff examines these characteristics in an editorial on p. 940.

Differing methods revealed similar findings about brain functioning in schizophrenia. Ferrarelli et al. (p. 996) measured electrical activity in the frontal cortex by using direct magnetic stimulation. The evoked gamma-frequency oscillations were markedly less in patients with schizophrenia than in healthy subjects. Both amplitude and synchronization were affected, particularly in the fronto-central region. Activation was also more localized, suggesting impaired connectivity between regions. Yoon et al. (CME, p. 1006) examined the dorsolateral prefrontal cortex during a task requiring cognitive control of contingent behavior. Functional magnetic resonance imaging revealed less activity in the patients with schizophrenia than in matched healthy subjects. The patients also had less connectivity between this region and other task-related brain regions. The changes in prefrontal connectivity were strongly associated with symptoms of disorganization, impaired cognition, and lower social and occupational functioning. An editorial by Drs. Daniel Mathalon and Judith Ford on p. 944 reviews implications of these results.