The concept of a spectrum of mixed bipolar depression that affects treatment response is supported by findings from two new studies. Goldberg et al. (p. 173) report that subsyndromal manic symptoms were present in 54% of the patients with a bipolar depressive episode entering the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). A full mixed episode was diagnosed in another 15%. Manic symptoms were associated with male gender, bipolar II disorder, rapid cycling, history of suicide attempts, and earlier onset. In a trial of adjunctive antidepressants for depressed patients with bipolar disorder, Frye et al. (p. 164) found that baseline characteristics associated with treatment-emergent mania were higher scores for motor activity, speech, and thought disorder. Assessing these symptoms may help in deciding whether to prescribe antidepressants for patients with bipolar disorder. An editorial by Dr. Christopher Schneck on p. 127 outlines the implications of these findings.

Many elderly adults say they would be willing to participate in research on Alzheimer’s disease even if it would not benefit them and would entail some risk. Karlawish et al. (CME, p. 182) asked 538 medical clinic patients age 65 or older if they would consider advance directives to allow research testing if they develop Alzheimer’s disease. For a study requiring a blood sample, 92% were willing to grant advance consent or would allow a proxy leeway in determining consent. For a lumbar puncture, 75% would grant advance consent or grant leeway to the proxy. Support for participation was strongly related to a favorable attitude toward research but not to experience with Alzheimer’s disease. In an editorial on p. 131, Drs. Spencer Eth and Gregory Leong describe ethical challenges in research with noncompetent subjects.

Three studies examining both clinical measures and brain images in patients with schizophrenia reveal important information about brain dysfunction in this illness. Findings by Wexler et al. (p. 189) suggest that white matter pathology plays a primary role in the cognitive deficits of schizophrenia. Patients with neuropsychological impairments typical of schizophrenia and patients with relatively intact cognition both had smaller gray matter and larger third ventricle volumes than healthy subjects. However, those with preserved cognition had normal white matter volumes. Lui et al. (p. 196) documented volume abnormalities in three brain regions of 68 first-episode, never-treated patients with schizophrenia. Compared to healthy subjects, the patients had lower gray matter volumes in the right superior temporal gyrus, middle temporal gyrus, and anterior cingulate gyrus. Each of these deficits was related to worse functioning and more severe psychotic symptoms. Rasetti et al. (p. 216) report that the deficient reactivity of the amygdala in schizophrenia appears to stem from the illness itself, not genetic risk. Threatening faces elicited less response in the amygdala of patients with schizophrenia than in healthy subjects, whereas patients’ unaffected siblings had normal reactivity. An editorial by Dr. Jason Tregellas on p. 134 examines these findings.

Comparison of the ability to detect two different test odors implicates impairment in a basic intracellular chemical signaling system in schizophrenia. Turetsky and Moberg (p. 226) selected two floral fragrances that differ markedly in the extent to which they activate intracellular cyclic adenosine monophosphate (cAMP). Compared to healthy subjects, patients with schizophrenia and their unaffected relatives were less able to detect the odor that elicits a weaker cAMP response. This odor-specific deficit may indicate a genetically regulated disruption of chemical signals influenced by cAMP, which has been linked to memory, learning, and mood. Dr. Akira Sawa and Nicola Cascella discusses this study in an editorial on p. 137.