In the 1920s, long before the appearance of modern antidepressants, physicians tried to treat listless men with a serum of ground-up animal testes, which they imagined contained the essence of male virility. In the '40s and '50s, when that essence had been discovered and synthesized in a laboratory, injections of testosterone were prescribed for depression.
Psychiatrists have since abandoned such treatment for newer ideas, first electroshock therapy and then antidepressant drugs such as Prozac and Paxil.
But recently, a small number of research scientists have suggested that those earlier doctors may have been onto something, that a dose of testosterone could effectively treat major depression, especially among men who have not responded to other treatments.
A study published today in the American Journal of Psychiatry examined a group of men who had not responded to antidepressants. Researchers at Harvard-affiliated McLean Hospital in Belmont found that almost half of those men had one thing in common, unusually low testosterone levels.
After 10 men received an eight-week course of testosterone gel, they reported significantly improved mood, less anxiety, better sleep, and heartier appetites on average than nine subjects treated with a placebo gel, the study found.
'What this suggests is that this may be a large unexplored area,' said Dr. Harrison G. Pope Jr., who heads the Biological Psychiatry Laboratory at McLean and was lead author of the study. 'Psychiatrists don't usually go to the trouble of [testing for] testosterone levels on men who are depressed.'
The research is published at a difficult time for hormone- based treatments. Last summer, government agencies halted two major clinical trials involving hormones because of health risks, one a trial of progesterone and estrogen given to post-menopausal women and the other a trial of testosterone given to aging men. Progestin was found to increase the risk of breast cancer, and high levels of testosterone are associated with increased risk of prostate cancer, especially in older men. As a result, there have been no long-term studies of testosterone therapy in older men with low levels of the hormone.
Such risks have not dimmed the growing popularity of testosterone treatment. Doctors prescribe the hormone for muscle loss, sexual dysfunction, and other problems, both in men and women. The appearance two years ago of a gel that allows the hormone to be absorbed through the skin made it easier to prescribe and use testosterone. Since then, anecdotal evidence has mounted in favor of the hormone's mood-elevating properties.
Most remarkable has been the response from HIV-positive men, who were prescribed testosterone for wasting syndrome. Effective for loss of appetite and muscle mass, testosterone 'also made these guys feel better,' according to double-blind studies that tested symptoms of depression, said Pope, who has also studied athletes' use of anabolic steroids.
Psychiatrists still have no 'smoking gun' firmly establishing the relationship between testosterone and depression, said Dr. Stuart N. Seidman, codirector of the Brain-Behavior Clinic at the New York State Psychiatric Clinic, who published research in 2002 on testosterone injections as a treatment for depression.
Seidman's first experiment, published in 1999, involved five men with treatment-resistant depression and low testosterone. All five reported improvement after receiving testosterone injections; three of the four who stopped testosterone therapy relapsed. In 2001, a second study of men not taking antidepressants had more equivocal results: Although half of the subjects on testosterone improved, so did half on a placebo.
Population-based studies have showed that men with unusually low levels of testosterone are much more likely to report symptoms of depression. In a 1999 survey of 4,000 subjects, sociologist Alan Booth of Pennsylvania State University found that men with testosterone levels on the low end of the normal range were five times more likely to be depressed than those with average levels. There was also a link between unusually high testosterone levels and depression, although Booth said that the correlation could be explained because marital strife, unemployment, and involvement in the criminal justice system are higher among men with high testosterone levels.
'I'm pretty confident in ... the link' between low testosterone and depression, said Booth, who has published numerous papers on testosterone and social behavior. 'It's just never been put together in one study.'
Pope's new study, like Seidman's, is one of a handful of recent studies on the effect of testosterone on depression. His results, although in a small sample set, suggest a good and sometimes excellent therapeutic effect.
One subject, a construction worker in his 50s, had been taking the antidepressant Celexa for chronic insomnia, but after a year the pills' effect had virtually disappeared. When Pope tested his testosterone, he found that the man had morning testosterone levels at the low end of normal range of 200 to 1000 nanograms per deciliter. Two weeks after he started taking the gel, his testosterone levels had risen to 700 nanograms per deciliter, on the high side of average, and his sleep problems were gone.
Another subject, a 45-year-old sales representative, said the doses of testosterone had improved his memory and made him far more resilient under stress. Although he had taken the antidepressant Effexor for two years before starting the testosterone treatment, the testosterone treatment was faster and more effective, and he is planning to quit the Effexor, he said.
'I find I can handle situations much better,' said the man, who spoke on condition of anonymity. 'I'm clearer, more focused. I know that's a direct effect of the testosterone. '
Pope said he hopes that larger studies will bear out his working hypothesis: that, although testosterone may not be an effective antidepressant therapy across the board, it could have a striking effect on men with low testosterone levels whose illness has been particularly difficult to treat.
Meanwhile, testosterone is also being explored as a treatment for depression in women whose testosterone level is lower than average. This year, an Australian study of 45 women found that half reported improvement after receiving testosterone supplements.
But pharmaceutical companies have shown little interest in funding large-scale studies, Pope said.
'Testosterone is an old drug; it's been around for half a century,' Pope said. 'That may explain why the pace of research has not picked up until recently.'
One psychiatrist interviewed Dr. Carol A. Bernstein, associate professor of psychiatry at New York University School of Medicine, said she would be wary of using hormones without the assistance of gynecologists or other specialists, because of their complex side effects.
Psychiatrists, unlike endocrinologists or urologists, receive little training during residency in the use of hormones, said Dr. Martin Kafka, a specialist in sexual disorders at McLean Hospital.
Psychiatrists have since abandoned such treatment for newer ideas, first electroshock therapy and then antidepressant drugs such as Prozac and Paxil.
But recently, a small number of research scientists have suggested that those earlier doctors may have been onto something, that a dose of testosterone could effectively treat major depression, especially among men who have not responded to other treatments.
A study published today in the American Journal of Psychiatry examined a group of men who had not responded to antidepressants. Researchers at Harvard-affiliated McLean Hospital in Belmont found that almost half of those men had one thing in common, unusually low testosterone levels.
After 10 men received an eight-week course of testosterone gel, they reported significantly improved mood, less anxiety, better sleep, and heartier appetites on average than nine subjects treated with a placebo gel, the study found.
'What this suggests is that this may be a large unexplored area,' said Dr. Harrison G. Pope Jr., who heads the Biological Psychiatry Laboratory at McLean and was lead author of the study. 'Psychiatrists don't usually go to the trouble of [testing for] testosterone levels on men who are depressed.'
The research is published at a difficult time for hormone- based treatments. Last summer, government agencies halted two major clinical trials involving hormones because of health risks, one a trial of progesterone and estrogen given to post-menopausal women and the other a trial of testosterone given to aging men. Progestin was found to increase the risk of breast cancer, and high levels of testosterone are associated with increased risk of prostate cancer, especially in older men. As a result, there have been no long-term studies of testosterone therapy in older men with low levels of the hormone.
Such risks have not dimmed the growing popularity of testosterone treatment. Doctors prescribe the hormone for muscle loss, sexual dysfunction, and other problems, both in men and women. The appearance two years ago of a gel that allows the hormone to be absorbed through the skin made it easier to prescribe and use testosterone. Since then, anecdotal evidence has mounted in favor of the hormone's mood-elevating properties.
Most remarkable has been the response from HIV-positive men, who were prescribed testosterone for wasting syndrome. Effective for loss of appetite and muscle mass, testosterone 'also made these guys feel better,' according to double-blind studies that tested symptoms of depression, said Pope, who has also studied athletes' use of anabolic steroids.
Psychiatrists still have no 'smoking gun' firmly establishing the relationship between testosterone and depression, said Dr. Stuart N. Seidman, codirector of the Brain-Behavior Clinic at the New York State Psychiatric Clinic, who published research in 2002 on testosterone injections as a treatment for depression.
Seidman's first experiment, published in 1999, involved five men with treatment-resistant depression and low testosterone. All five reported improvement after receiving testosterone injections; three of the four who stopped testosterone therapy relapsed. In 2001, a second study of men not taking antidepressants had more equivocal results: Although half of the subjects on testosterone improved, so did half on a placebo.
Population-based studies have showed that men with unusually low levels of testosterone are much more likely to report symptoms of depression. In a 1999 survey of 4,000 subjects, sociologist Alan Booth of Pennsylvania State University found that men with testosterone levels on the low end of the normal range were five times more likely to be depressed than those with average levels. There was also a link between unusually high testosterone levels and depression, although Booth said that the correlation could be explained because marital strife, unemployment, and involvement in the criminal justice system are higher among men with high testosterone levels.
'I'm pretty confident in ... the link' between low testosterone and depression, said Booth, who has published numerous papers on testosterone and social behavior. 'It's just never been put together in one study.'
Pope's new study, like Seidman's, is one of a handful of recent studies on the effect of testosterone on depression. His results, although in a small sample set, suggest a good and sometimes excellent therapeutic effect.
One subject, a construction worker in his 50s, had been taking the antidepressant Celexa for chronic insomnia, but after a year the pills' effect had virtually disappeared. When Pope tested his testosterone, he found that the man had morning testosterone levels at the low end of normal range of 200 to 1000 nanograms per deciliter. Two weeks after he started taking the gel, his testosterone levels had risen to 700 nanograms per deciliter, on the high side of average, and his sleep problems were gone.
Another subject, a 45-year-old sales representative, said the doses of testosterone had improved his memory and made him far more resilient under stress. Although he had taken the antidepressant Effexor for two years before starting the testosterone treatment, the testosterone treatment was faster and more effective, and he is planning to quit the Effexor, he said.
'I find I can handle situations much better,' said the man, who spoke on condition of anonymity. 'I'm clearer, more focused. I know that's a direct effect of the testosterone. '
Pope said he hopes that larger studies will bear out his working hypothesis: that, although testosterone may not be an effective antidepressant therapy across the board, it could have a striking effect on men with low testosterone levels whose illness has been particularly difficult to treat.
Meanwhile, testosterone is also being explored as a treatment for depression in women whose testosterone level is lower than average. This year, an Australian study of 45 women found that half reported improvement after receiving testosterone supplements.
But pharmaceutical companies have shown little interest in funding large-scale studies, Pope said.
'Testosterone is an old drug; it's been around for half a century,' Pope said. 'That may explain why the pace of research has not picked up until recently.'
One psychiatrist interviewed Dr. Carol A. Bernstein, associate professor of psychiatry at New York University School of Medicine, said she would be wary of using hormones without the assistance of gynecologists or other specialists, because of their complex side effects.
Psychiatrists, unlike endocrinologists or urologists, receive little training during residency in the use of hormones, said Dr. Martin Kafka, a specialist in sexual disorders at McLean Hospital.
