Drugs that increase brain levels of the neurotransmitter acetylcholine can enhance cognitive functioning. Cholinergic enhancers are, in fact, the most used pharmacological therapy for patients with Alzheimer’s disease. In young adults asked to remember faces, these drugs increase activity in brain areas specific to visual processing and decrease activity in the prefrontal cortex, where information is maintained and manipulated. The activated brain regions are somewhat different in older adults. Freo et al. (p. 2061) examined whether the brains of young and old adults would respond differently to physostigmine, a cholinergic-enhancing drug, during an exercise involving short-term memory of faces. Without physostigmine, task-related activation occurred in different prefrontal subregions in old and young subjects. Physostigmine reduced activation in these age-specific areas, enhanced activity in visual cortical areas, and improved task performance. Apparently, structural and functional changes during aging can shape the way a drug affects the brain.

Many people with diagnosed dementia are still capable of voting. In Doe v. Rowe, a federal district court ruled that people are incompetent to vote only if they "lack the capacity to understand the nature and effect of voting such that they cannot make an individual choice." Appelbaum et al. (p. 2094) developed a short test containing three questions assessing the Doe criteria—understanding and choice—and two questions assessing reasoning and appreciation of what voting signifies. The test was administered to 33 people with Alzheimer’s disease. Higher scores on the three Doe questions were associated with better performance on a test of cognitive functioning. Participants with mild dementia had high scores, people with severe dementia had low scores, and people with moderate dementia varied. The reasoning and appreciation questions yielded similar findings but are more demanding than the Doe court’s criteria. The questions based on the Doe standard appear to be an efficient screening tool.

Both schizophrenia and bipolar disorder show associations with the DAOA/G30 gene locus on chromosome 13. Given the apparent role of DAOA/G30 in the neurochemistry of psychosis, Schulze et al. (p. 2101) postulated that this locus could be associated with psychotic symptoms, rather than the diagnostic categories. Among 300 German patients with bipolar disorder, specific psychotic features were tested individually: persecutory delusions emerged as the only significant discriminatory variable for the risk genotype. This finding was replicated in an independent sample of Polish patients with bipolar disorder, who did not show an overall association with the DAOA/G30 locus but did so when only the cases with a history of persecutory delusions were considered. The consistency of this genetic association illustrates the value of refining patient symptom profiles to produce more phenotypically homogeneous samples.

In many adults with bipolar disorder, the dorsolateral region of the prefrontal cortex has low levels of N-acetylaspartate, which is an indicator of neuronal health. This could be the result of long-term medication, however. Children and adolescents with bipolar disorder have taken less psychoactive medication than adults and provide a glimpse into brain functioning early in the disease. Sassi et al. (p. 2109) used magnetic resonance spectroscopy to measure three metabolites in the dorsolateral prefrontal cortex of 14 bipolar subjects ages 10–21 years and 18 healthy subjects. The levels of N-acetylaspartate were lower in the bipolar subjects than in the healthy subjects. This supports the presence of prefrontal neuronal abnormality early in bipolar disorder. It could be due to underdevelopment of neuronal branching and synaptic connections; long-term degeneration seems unlikely in these young patients.

Poor response to lithium is common among patients with bipolar disorder whose episodes alternate rapidly. Divalproex has been effective in short-term maintenance treatment of this condition, and so Calabrese et al. (p. 2152) compared it to lithium in a 20-month maintenance trial. Patients with rapid-cycling bipolar disorder were first stabilized with a combination of lithium and divalproex sodium over 6 months. Then one medication was withdrawn. The relapse rates during the subsequent 20-month trial did not differ significantly between the groups taking divalproex (50%) and lithium (56%), nor did the intervals of stability preceding relapse. Lithium produced higher rates of tremors and polyuria or polydipsia. The overall rates of study discontinuation were 71% and 84% for divalproex and lithium, respectively, which suggest that single-agent therapy for rapid-cycling bipolar disorder is likely to have a poor outcome.F1

George Engel, M.D. (1913–1999) (p. 2039)F2