From evidence that unanesthetized rats given long-term lithium chloride demonstrated reduced turnover of arachidonic acid (n-6 polyunsaturated fatty acid [PUFA] but not docosahexaenoic acid (n-3 PUFA) in brain phospholipids, and reduced conversion of arachidonate to prostaglandin E2 by cyclooxygenase2, Rapoport and BosettiArticle hypothesize that lithium and antimanic anticonvulsants act by inhibiting brain arachidonate metabolism. If arachidonate metabolism were functionally hyperactive in mania, a cyclooxygenase 2 inhibitor might help in its treatment. Their hypothesis is consistent with evidence that n-3 PUFAs, which can inhibit brain arachidonate metabolism, may be effective in bipolar disorder.
Elliott et alArticle used functional brain imaging to study depressed patients and controls during performance of a simple cognitive task. Specific regions of the prefrontal cortex responded differently depending on the emotional tone of stimuli, reflecting the cognitive biases reported in previous studies. These findings suggest a crucial role for prefrontal regions in mediating the interaction between mood, cognition, and neurobiology in depression.
Beekman et alArticle characterized the natural history of depression in a large prospective study of elderly individuals (>55 years of age) in the Netherlands. In the depressed cohort, the average symptom severity remained above the 85th percentile for the population for 6 years. In only 14% were the symptoms short-lived, whereas 32% exhibited a chronic course. The remainder experienced a fluctuating course.
Neumeister et alArticle evaluated the behavioral responses to tryptophan depletion in a group of healthy women with and without a first-degree family history of major depression and examined the relationship to the serotonin transporter gene promotor polymorphism (5HTTLPR). The short allele of the 5HTTLPR and a positive family history of depression were shown to be additive risk factors for developing depressive symptoms during tryptophan depletion. In contrast, subjects homozygous for the long allele did not develop depressive symptoms during tryptophan depletion, irrespective of their family history.
New et alArticle used positron emission tomography to examine the regional metabolic activity in response to a serotonergic stimulus, meta-chlorophenylpiperazine (m-CPP), in impulsive-aggressive and normal subjects. Unlike normal subjects, impulsive-aggressive patients did not show activation specifically in the left anteromedial orbital cortex or the anterior cingulate gyrus in response to m-CPP. The decreased activation of inhibitory regions in patients with impulsive aggression in response to a serotonergic stimulus may contribute to their difficulty in modulating aggressive impulses.
Hemby et alArticle present the first single-cell expression analysis of schizophrenia. Using macroarrays, they show that the abundances of various mRNAs differ in cortical layer II/III stellate neurons between control and schizophrenic subjects. Because of the cellular heterogeneity of the central nervous system, the interconnectivity of various neuronal systems, and the relative abundances of mRNAs in different cell types, these data suggest that both whole-tissue and single-cell analysis complement each other in providing a more complete picture of the molecular consequences of schizophrenia.
Abnormal spread of activation through neural networks controlling semantic associations has been proposed as a cause of symptoms in schizophrenia. Four hundred milliseconds after a semantic stimulus, a negative wave (N400) can be recorded by electroencephalogram. Mathalon et alArticle show that subjects with schizophrenia exhibited smaller N400 waves than controls, although the response was normalized when they were provided with a contextual stimulus prior to the semantic stimulus.
Currently there is no consensus on the best therapeutic approach to chronic tic disorders and comorbid attention-deficit/hyperactivity disorder(ADHD). Spencer et alArticle report findings from a controlled trial of desipramine in children and adolescents with chronic tic disorders and ADHD. Desipramine treatment was well tolerated and associated with robust reductions in both tic and ADHD symptoms.
Kupfer et alArticle have identified special challenges to the recruitment and retention of the next generation of physician researchers in mental health and clinical neuroscience. These challenges include the need to interest undergraduate and medical researchers to compete successfully for National Institutes of Health career development(K) awards, to provide bridge support between postdoctoral fellowship training, and successful receipt of pay for mentoring.