In the 1940s, experiments showed that major depression can be relieved by injecting testosterone into men with low levels of that hormone. The treatment never caught on because the shots are painful, and effective antidepressant drugs started coming to market. More recently, however, testosterone patches and gels became available. In June 2000, the United States Food and Drug Administration approved a new form of gel for treating muscle loss, decreased sex drive, lack of energy, and other symptoms of so-called hypogonadism or underactivity of the testes.

Pope wondered if the gel might also help males with the combination of low testosterone and depression not treated successfully with drugs...

The first question to answer was how frequently low testosterone occurs in American men with depression that cannot be controlled with drugs. "I requested enough money to screen 150 subjects with the hope of finding about 20 who fit that description," Pope recalls. "To my astonishment, it turned out to be no problem at all."

Out of the first 56 men screened, Pope and his colleagues found 24 who had both low spirits and low levels of the hormone. That's more than 40 percent. "I never would have guessed that the prevalence of low testosterone levels would be so great in men not responding to antidepressant drugs," Pope comments.

At McLean Hospital, a private psychiatric facility affiliated with Harvard Medical School, 12 men received small packets containing 2.5 grams of Testosterone Gel. Another ten subjects received identical packets containing a dummy, or placebo substance. By the end of the experiment, Pope found a significant improvement in mood among those taking testosterone compared to those using the dummy rub.

Ten of the 12 men on the active gel completed the full eight-week study. Three showed almost no improvement, and four experienced only modest relief. However, three enjoyed "striking, dramatic gains," Pope notes. "While this was a very small study, the results clearly justify larger studies to explore the benefits and possible risks of testosterone replacement therapy for men with low levels of the hormone who find antidepressants ineffective."

More muscle, less fat

How many men might that be? Certainly more than everyone thought before the researchers found how common low testosterone levels are in depressed males not being helped sufficiently by the drugs they take.

According to the team's report in the Jan. 1, 2003, issue of the American Journal of Psychiatry, in any given year 8 percent of American men over 30 years old will experience an episode of major depression. A substantial minority of these men will get only partial help, or none at all, from popular antidepressants. "If this refractory subgroup exhibits a 43 percent prevalence of low testosterone levels, as found in our study," notes Pope's report, "then hundreds of thousands of men in a given year might be candidates for further trials of the supplements. Given the size of this population, together with the increased availability and convenience of testosterone gels, it would seem important to assess carefully the benefits and risks of adding hormone replacement to antidepressant drugs."

Normal men who take testosterone usually add muscle and lose fat. That occurred among those in the Harvard study, including subjects whose depression was not reduced. "One man, who got no psychiatric benefit at all, gained about 15 pounds of muscle mass and lost about 8 pounds of fat," Pope notes.

Such results raise the issue of whether the supplements aid only the physical symptoms of depression such as loss of energy, libido, and appetite. To address that, Pope's group analyzed the responses of those who took the testosterone to a battery of psychological tests. They found higher moods, less guilt and anxiety, and a decrease of suicidal thoughts. "These analyses suggest that the hormone can cause improvements in both the mind and body," Pope says.

Evidence also exists that some women may be helped by testosterone supplements. Other studies hint that post-menopausal women, and those who have had their ovaries removed surgically, may reap some benefits in terms of improved mood and energy. But to avoid excess growth of hair, increased muscle mass, and other masculine side effects, doses would have to be much lower than those given to men.

"It's something we should explore in the future," Pope maintains.