Duloxetine compared with fluoxetine and venlafaxine: use of meta-regression analysis for indirect comparisons

BACKGROUND: Data comparing duloxetine with existing antidepressant treatments is limited. A comparison of duloxetine with fluoxetine has been performed but no comparison with venlafaxine, the other antidepressant in the same therapeutic class with a significant market share, has been undertaken. In the absence of relevant data to assess the place that duloxetine should occupy in the therapeutic arsenal, indirect comparisons are the most rigorous way to go. We conducted a systematic review of the efficacy of duloxetine, fluoxetine and venlafaxine versus placebo in the treatment of Major Depressive Disorder (MDD), and performed indirect comparisons through meta-regressions. METHODS: The bibliography of the Agency for Health Care Policy and Research and the CENTRAL, Medline, and Embase databases were interrogated using advanced search strategies based on a combination of text and index terms. The search focused on randomized placebo-controlled clinical trials involving adult patients treated for acute phase Major Depressive Disorder. All outcomes were derived to take account for varying placebo responses throughout studies. Primary outcome was treatment efficacy as measured by Hedge's g effect size. Secondary outcomes were response and dropout rates as measured by log odds ratios. Meta-regressions were run to indirectly compare the drugs. Sensitivity analysis, assessing the influence of individual studies over the results, and the influence of patients' characteristics were run. RESULTS: 22 studies involving fluoxetine, 9 involving duloxetine and 8 involving venlafaxine were selected. Using indirect comparison methodology, estimated effect sizes for efficacy compared with duloxetine were 0.11 [-0.14;0.36] for fluoxetine and 0.22 [0.06;0.38] for venlafaxine. Response log odds ratios were -0.21 [-0.44;0.03], 0.70 [0.26;1.14]. Dropout log odds ratios were -0.02 [-0.33;0.29], 0.21 [-0.13;0.55]. Sensitivity analyses showed that results were consistent. CONCLUSION: Fluoxetine was not statistically different in either tolerability or efficacy when compared with duloxetine. Venlafaxine was significantly superior to duloxetine in all analyses except dropout rate. In the absence of relevant data from head-to-head comparison trials, results suggest that venlafaxine is superior compared with duloxetine and that duloxetine does not differentiate from fluoxetine

Synchronising oestrus with oestradiol benzoate after using a two-dose prostaglandin treatment to synchronise luteolysis in dairy heifers

Objective: To compare the reproductive performance and pattern of onset of oestrus in dairy heifers in which oestrous cycles were synchronised with two doses of prostaglandin (PG) F2aL and oestrus was synchronised with oestradiol benzoate (ODB).\ud \ud Procedure: Dairy heifers in two herds (herd A, n=192; herd B, n = 267) were treated with two doses of an analogue of PGF2aL (cloprostenol, 375 mUg, IM) 12 days apart. Heifers not detected in oestrus 48 h after the last dose of PGF2aL were either left untreated (No ODB, n=147) or treated with ODB (0.75 mg IM, n = 126). Onset of oestrus was monitored at 0, 24, 48, 80, 96 and 120 h after the last dose of PGF2aL Heifers were inseminated on detection of oestrus.\ud \ud Results: After the last dose of PGF2aL, oestrous detection rates at 80 h (43.5 vs 72.6%, P < 0.001), 96 h (74.1 vs 84.9%, P=0.025) and 120 h (78.2 vs 86.3%, P=0.082) were less in the No ODB compared to the ODB heifers, respectively. Conception rates (percentage pregnant that were inseminated) were greater in the No ODB compared to the ODB heifers (64.3% vs 47.6%, respectively; P=0.006), while pregnancy rates (percentage pregnant that were treated) were also greater in the No ODB compared to the ODB heifers, but differences were not significant (50.3% vs 41.1%, respectively; P = 0.068).\ud \ud Conclusion: Administration of ODB to heifers not in oestrus 48 h after a two-dose PGF2aL treatment increases the percentage of heifers detected in oestrus by 80 h, 96 h and 120 h after treatment, by an estimated 29%, 11% and 8%, respectively. However, administration of ODB decreases conception rates by an estimated 17%, and may decrease pregnancy rates (estimated 9% difference). Results are consistent with the hypothesis that ODB can increase submission rates but reduce conception rates following a two dose treatment with PGF2aL

Meta-analysis of 32 genome-wide linkage studies of schizophrenia

A genome scan meta-a nalysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P SR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for aggregate genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies. © 2009 Nature Publishing Group

DAT1 polymorphism is associated with risk taking in the Balloon Analogue Risk Task (BART)

Twin-studies suggest that a significant portion of individual differences in the propensity to take risks resides in people's genetic make-up and there is evidence that variability in dopaminergic systems relates to individual differences in risky choice. We examined the link between risk taking in a risk taking task (the Balloon Analogue Risk Task, BART) and a variable number tandem repeat (VNTR) polymorphism in the 3'UTR of the dopamine transporter gene (SLC6A3/DAT1). Behavior in BART is known to be associated with activity in striatal reward-processing regions, and DAT1 is assumed to modulate striatal dopamine levels. We find that carriers of DAT1 alleles, which presumably result in lower striatal dopamine availability, showed more risk taking, relative to carriers of the alleles associated with higher striatal dopamine availability. Our analyses suggest that the mechanism underlying this association is diminished sensitivity to rewards among those who take more risks. Overall, our results support the notion that a behavioral genetic approach can be helpful in uncovering the basis of individual differences in risk taking