Another St John's Wort preparation shown to be better than placebo in major depression

The evidence base for use of St John's Wort (SJW) in depression is improved by publication of this reasonably-sized placebo-controlled trial, which found a significant benefit over placebo. A difficulty in using SJW is that as a natural product with many different preparations available, results from a clinical trial using one preparation cannot necessarily be extrapolated to a different preparation; there are also limited data on effective doses. This study aimed to compare the effect of two different doses of SJW WS 5570 (a preparation previously compared to paroxetine BMJ 2005; 330: 503) against placebo. It involved 332 patients with mild to moderate major depression who were randomised in a 3:3:2 ratio to treatment with SJW 600mg daily (n=123), 1200mg daily (n=127), or placebo (n=82). Standard rating scales were used to measure the effect of treatment, and the primary outcome was change in score on the HAM-D 17 scale. Study duration was six weeks, and responders were offered continuation treatment in a 16-week double-blind maintenance phase.

The results at six weeks showed improvement in all three groups, with a significantly greater improvement in the SJW groups compared to placebo: HAM-D 17 score decreases were 11.6 (SJW 1200mg daily), 10.8 (SJW 600mg daily), and 6.0 (placebo), p<0.001 vs. placebo. Patients in the SJW groups also showed greater improvements in secondary outcomes. All treatments were well tolerated, with adverse events in the SJW groups being similar in incidence and consistent with those known for SJW. Based on their results, the authors conclude that both doses of SJW were safe and more effective than placebo in the treatment of mild to moderate major depressive illness, with comparable efficacy for the two doses.

Resource link: http://www.biomedcentral.com/1741-7015/4/14/abstract

Gene-regulating Enzyme Is Also A Target For Anti-depressive Drugs, Anti-cancer Possibilities

In 2005, professor Ramin Shiekhattar, Ph.D., at The Wistar Institute and his colleagues reported details about an enzyme involved in appropriately repressing sets of neuronal genes in non-neuronal cells.

At the time, the scientists noted that the enzyme appeared to fit into the same extended enzyme family that includes monoamine oxidases, psychoactive enzymes that oxidize dopamine and norepinephrin. Inhibitors of these enzymes have long been used to treat depression, certain other psychiatric and emotional disorders, and Parkinson's disease.

Now, in a study published online today in the June 26 issue of Chemistry & Biology, Shiekhattar and his team show that the enzyme is itself a target for certain monoamine oxidase inhibitors used to treat depression. One member of this family of drugs in particular, called tranylcypromine (brand name Parnate®, manufactured by GlaxoSmithKline), was seen to inhibit the enzyme most strongly. The findings suggest that these anti-depressive drugs may have additional applications in other medically relevant areas.

For example, Shiekhattar notes that the enzyme studied exists in a complex with another type of gene-regulating enzyme that has been implicated in the development of cancer. Inhibitors of that second enzyme are currently in clinical trails as cancer therapies.

"Might particular monoamine oxidase inhibitors, currently used primarily to treat depression, have anti-cancer activity too?" Shiekhattar says. "Our findings indicate this could be the case, and we are currently screening these drugs against many different types of cancer to answer that question."

Because the primary role of the enzyme is to repress sets of related genes, many other areas of potential influence for the monoamine oxidase inhibitors are possible too, according to Shiekhattar. At the very least, he says, the drugs will likely prove to be useful laboratory tools for answering fundamental questions about genetic expression.

The enzyme in question is called BHC110/LSD1, and it was the first human histone demethylase identified. The enzyme's function is to remove methyl groups from small molecules called histones to modify them in ways that trigger gene repression. The second enzyme found in complex with BHC110/LSD1, acts in a similar way. Called a deacetylase, this enzyme removes acetyl groups from histones to repress gene expression.

In the body's scheme for safely storing genes away until needed, DNA is tightly looped around the histones, kept secure by enzymes similar to the ones studied by the Wistar team until made accessible by the activity of other enzymes responsible for gene expression. Eight histones comprise a nucleosome, and long strings of nucleosomes coil in turn into chromatin, the basic material of chromosomes.

The lead author on the Chemistry & Biology study is Min Gyu Lee. Christopher Wynder is a coauthor. Additional coauthors at the University of Pennsylvania School of Medicine are Dawn M. Schmidt and Dewey G. McCafferty. Senior author Ramin Shiekhattar is a professor in two programs at Wistar, the gene expression and regulation program and molecular and cellular oncogenesis program. Support for the research was provided by the National Institutes of Health.

Source: The Wistar Institute, http://www.sciencedaily.com/releases/2006/06/060623174358.htm

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