Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression

Altered striatal function in a mutant mouse lacking D1A dopamine receptors.

Of the five known dopamine receptors, D1A and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D1A receptors expressed by direct output neurons and D2 receptors expressed by indirect output neurons. To further examine the interaction of D1A and D2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D1A receptors (D1A-/-). D1A-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D1A receptor binding was absent in striatal sections from D1A-/- mice. Striatal neurons normally expressing functional D1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D2 receptors, are unaffected. These findings show that D1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway

Dopamine Receptors in the Subthalamic Nucleus: Identification and Localization of D5 Receptors

International audienceHerein we present methodological approaches for the identification and characterization of dopamine receptors in the subthalamic nucleus, a component nucleus of the basal ganglia, at pre-and postsynaptic locations and of their roles with an emphasis given to the dopamine D5 receptor subtype. This chapter focuses on the possible sources of divergence between electrophysiological studies and describes the pharmacological tools available for functional studies of this receptor. The procedures for single-cell reverse transcription PCR (polymerase chain reaction) identification of dopamine D5 receptor mRNA and the immunochemical detection of the receptor at cellular and subcellular levels are presented

D3 dopamine receptor regulation of D5 receptor expression and function in renal proximal tubule cells

Dopamine receptor, via D 1-like and D 2-like receptors, increases sodium excretion in kidney. We have reported positive interactions between D 3 and D 1 receptors in renal proximal tubule (RPT) cells. These reports, however do not preclude that there may be also interaction between D 3 and D 5 receptors, because of the lack of selective D 1 and D 5 receptor agonists or antagonists. We hypothesize that D 3 receptors can regulate D 5 receptors, and that D 3 receptor regulation of D 5 receptors in RPTs is impaired in spontaneously hypertensive rats (SHRs). It showed that a D 3 receptor agonist, PD128907, by the activation of protein kinase C activity, increased the expression of D 5 receptors in a concentration- and time-dependent manner in RPT cells from Wistar-Kyoto (WKY) rats. The stimulatory effect of the D 3 receptor on D 5 receptor expression was impaired in RPT cells from SHRs. The effect of D 3 receptor on D 5 receptor is functionally relevant; stimulation of D 5 receptor decreases Na +-K + adenosine triphosphatase (ATPase) activity in WKY cells. Pretreatment with D 3 receptor agonist for 24 h enhances the D 5 receptor expression and D 5 receptor-mediated inhibitory effect on Na +-K + ATPase activity in WKY cells, but decreases them in SHR cells. The effect of D 3 receptor on D 5 receptor expression and function was also confirmed in the D 5 receptor-transfected HEK293 cells. It indicates that activation of D 3 receptor increases D 5 receptor expression and function. Altered regulation of D 3 receptor on D 5 receptors may have a role in the pathogenesis of hypertension. © 2012 The Japanese Society of Hypertension All rights reserved

D 3 dopamine receptor regulation of D 5 receptor expression and function in renal proximal tubule cells.

Dopamine receptor, via D 1-like and D 2-like receptors, increases sodium excretion in kidney. We have reported positive interactions between D 3 and D 1 receptors in renal proximal tubule (RPT) cells. These reports, however do not preclude that there may be also interaction between D 3 and D 5 receptors, because of the lack of selective D 1 and D 5 receptor agonists or antagonists. We hypothesize that D 3 receptors can regulate D 5 receptors, and that D 3 receptor regulation of D 5 receptors in RPTs is impaired in spontaneously hypertensive rats (SHRs). It showed that a D 3 receptor agonist, PD128907, by the activation of protein kinase C activity, increased the expression of D 5 receptors in a concentration- and time-dependent manner in RPT cells from Wistar-Kyoto (WKY) rats. The stimulatory effect of the D 3 receptor on D 5 receptor expression was impaired in RPT cells from SHRs. The effect of D 3 receptor on D 5 receptor is functionally relevant; stimulation of D 5 receptor decreases Na +-K + adenosine triphosphatase (ATPase) activity in WKY cells. Pretreatment with D 3 receptor agonist for 24 h enhances the D 5 receptor expression and D 5 receptor-mediated inhibitory effect on Na +-K + ATPase activity in WKY cells, but decreases them in SHR cells. The effect of D 3 receptor on D 5 receptor expression and function was also confirmed in the D 5 receptor-transfected HEK293 cells. It indicates that activation of D 3 receptor increases D 5 receptor expression and function. Altered regulation of D 3 receptor on D 5 receptors may have a role in the pathogenesis of hypertension. © 2012 The Japanese Society of Hypertension All rights reserved