Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome.

A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg-1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.

Effects of cocaine and withdrawal on the mouse nucleus accumbens transcriptome.

Genetic association studies, pharmacological investigations and analysis of mice-lacking individual genes have made it clear that Cocaine administration and Withdrawal have a profound impact on multiple neurotransmitter systems. The GABAergic medium spiny neurons of the nucleus accumbens (NAc) exhibit changes in the expression of genes encoding receptors for glutamate and in the signaling pathways triggered by dopamine binding to G-protein-coupled dopamine receptors. Deep sequence analysis provides a sensitive, quantitative and global analysis of the effects of Cocaine on the NAc transcriptome. RNA prepared from the NAc of adult male mice receiving daily injections of Saline or Cocaine, or Cocaine followed by a period of Withdrawal, was used for high-throughput sequence analysis. Changes were validated by quantitative polymerase chain reaction or Western blot. On the basis of pathway analysis, a preponderance of the genes affected by Cocaine and Withdrawal was involved in the cadherin, heterotrimeric G-protein and Wnt signaling pathways. Distinct subsets of cadherins and protocadherins exhibited a sustained increase or decrease in expression. Sustained down-regulation of several heterotrimeric G-protein ß- and γ-subunits was observed. In addition to altered expression of receptors for small molecule neurotransmitters, neuropeptides and endocannabinoids, changes in the expression of plasma membrane transporters and vesicular neurotransmitter transporters were also observed. The effects of chronic Cocaine and Withdrawal on the expression of genes essential to cholinergic, glutamatergic, GABAergic, peptidergic and endocannabinoid signaling are as profound as their effects on dopaminergic transmission. Simultaneous targeting of multiple Withdrawal-specific changes in gene expression may facilitate development of new therapeutic approaches that are better able to prevent relapse.

How family practice patients view their utilization of mental health services.

This study examines to what extent family practice patients perceive themselves as being willing to seek help for personal problems. The study further explores whether this willingness is related to various demographic characteristics. Finally, it investigates family practice patients' preferences in their choice of a source of help for personal problems. Patients in the waiting room of a private family practice center were approached to participate in the study at random times during one month (n = 145). For each item of a list of common personal problems, patients were asked to judge how likely they would be to seek professional help, their preferred setting for this help, and their preference of a professional provider. Respondents' sex was found to be the only demographic characteristic that affected willingness to seek help. "The family physician's office" and "the family physician" were the preferred choices mainly for personal problems associated with physical manifestations. Other providers were chosen for predominantly social or emotional problems. Most respondents stated that they would be more likely to seek help from a mental health professional who worked along with the family physician than they would be to seek help from a professional housed elsewhere.

Studies in B12-deficient monkeys with combined system disease. I. B12-deficient patterns in bone marrow deoxyuridine suppression tests without morphologic or functional abnormalities.

A colony of rhesus monkeys made vitamin B12 deficient through dietary deprivation has been maintained since 1970. Deficient animals regularly develop neurologic lesions histologically, ultrastructurally, and topographically indistinguishable from those of human subacute combined degeneration but have failed to develop overt hematologic changes. No megaloblastic alterations, other evidence of impaired blood cell production, or subtle differences in mean red cell size are found. dU suppression tests on bone marrow were performed to determine whether functional B12 deficiency existed. All B12-deficient monkeys had markedly abnormal dU suppression test results after more than 10 months of B12 depviation, corrected by addition of B12 in vitro, whereas controls remained normal. Reasons for these disparate findings are considered, including species differences in metabolism of cobalamin analogues, cobalamin, and transcobalamins; the sensitivity of the dU test; the fact that ability to utilize preformed nucleotides may be greater in monkeys than in humans.