Testosterone–The next blockbuster anti-depressant?

Researchers suggests hormone replacement might help raise mood in some men

by Jim Schnabel

April 18, 2008

Australian researchers have reported finding a significant association between depression and low testosterone levels in a large group of elderly men. The study is one of several in recent years that have suggested testosterone replacement as a possible therapy for some cases of depression.

The Australian study, reported in the March issue of the Archives of General Psychiatry, included nearly 4,000 elderly men enrolled in a wider health survey in the west coast city of Perth. Among the approximately five percent of the study group who showed evidence of depression according to a standard measure used for the elderly, average blood testosterone levels were significantly lower than they were among the non-depressed men.

The study seems to confirm a relationship between low testosterone levels and depression that has been suspected by researchers for at least six decades. But analyses of this apparent relationship have never been easy.

“It’s not a nice, simple, clean relationship,” says Harrison Pope, a Harvard psychiatry professor. Researchers still disagree on the best laboratory measure to use to determine the level of testosterone that is biologically available, he says. A host of confounding factors also muddy the relationship between testosterone and depression, including the fact that depression itself can lower testosterone levels. “So it becomes difficult to answer the simple question about how much depression is attributable to low testosterone levels because you have all these different directions of causality, all happening at the same time,” Pope says.

Some of these complicating factors were evident in the recent Australian study. The investigators reported that the depressed group, in addition to showing lower testosterone levels, also was more likely to be older, overweight and have smoking habits. After controlling for these factors, a significant link between low testosterone and depression remained, but only for the fraction of testosterone known as “free testosterone” (because it is not bound to protein in the blood). Low “total testosterone,” which Pope says is a more common clinical measure, showed a much weaker relationship with depression in the study.

But Pope believes a relationship is there, even if it tends to be obscured by the “background noise” of current measurement techniques. In 2003 he reported on a small pilot study of AndroGel, a testosterone gel, in middle-aged men with low or borderline low testosterone levels. The men were depressed but did not respond well to the usual anti-depressant medications.

When the men were given AndroGel in addition to their usual medications, the response was “all over the map, with some people displaying quite dramatic effects, and others displaying absolutely no effect,” Pope says. “And again, this is probably attributable to all these numerous confounding variables.”

Tens of millions of people are estimated to have depression in the United States and other Western countries, so even the fraction that seem more likely to respond to testosterone comprise a very large population, Pope says.

“Between a third and a half of men with depression don’t display a really adequate response to conventional anti-depressant treatment,” he says. Of these roughly one-third have low or borderline-low testosterone levels—and in his pilot study, about one-third of these men responded dramatically to testosterone gel treatment.

Pope is currently running an NIH-sponsored clinical trial of AndroGel in 100 patients, and expects to submit results for publication by the end of 2008.