Testosterone: A Great Antidepressant!

Written by Dave Palumbo

March 10, 2008 – Researchers have uncovered a link between low free testosterone levels and depression. Their study, which appears in the March issue of the Archives of General Psychiatry, shows that older men with abnormally low free testosterone levels, or hypogonadism, were, on average, 271% more likely to display clinically significant signs of depression than men with higher testosterone levels. “Importantly, these results could not be explained by increasing age, education level, smoking, obesity or poor physical health – all factors that are known to dampen testosterone and are associated with depression,” said lead author Osvaldo P. Almeida, MD, PhD, director of research, Western Australian Centre for Health and Ageing, and professor and chair of geriatric psychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia. The results of this study could have important implications for the treatment of depression in certain men, he said. “Older men with depression should be assessed for hypogonadism, and older hypogonadal men who fail to respond to standard antidepressant therapy may benefit from testosterone replacement,” said Dr. Almeida.

Results Independent of Physical Health The study sample of 3987 men aged 71 to 89 years was taken from a community sample of older male residents of Perth, Western Australia, who were part of the larger prospective Health in Men Study. To determine their physical health, the researchers used the weighted Charlson index, which takes into account 17 common medical conditions including myocardial infarction, congestive hart failure, peripheral arterial disease, cerebrovascular disease, and chronic pulmonary disease. They retrieved linked data for all participants from the Health in Men Study. As well, the participants used the 36-Item Short Form Health Survey to rate their own health. The men were screened for cognitive impairment and depression, completing the Standardized Mini-Mental State Examination and the 15-Item Geriatric Depression Scale (GDS-15). In the sample, 203 (5.1%) had a total GDS-15 score within the depression range (scores ?‰? 7). Men with depression were older than their counterparts without depression, had lower educational levels, and were more likely to be former or current smokers and to have a body mass index (BMI) of 30 kg/m2 or greater. Researchers took blood samples to test serum concentrations of total and free testosterone and divided the men into quintiles according to these concentrations.

Compared with men in the highest quintile, the odds ratio for depression in men in the lowest quintile for total testosterone levels was 1.94. However, the association between depression and total testosterone levels was not significant after the analysis was adjusted for age, educational level, smoking, BMI, and other factors. Link With Free Testosterone Levels Remained Significant When Adjusted When the researchers looked at free testosterone levels, they found that men in the lowest quintile also had an increased risk for depression in relationship to men in the highest quintile (odds ratio, 3.12). However, this association remained significant after the analysis was adjusted for age, educational level, smoking, BMI, and other factors (odds ratio, 2.71). “The findings of this study are compelling in suggesting a causal relationship between low free testosterone and depression in older men,” Dr. Almeida told Medscape Psychiatry in an email.

“The association is biologically plausible; there is evidence from lab work that testosterone may increase the bioavailability of serotonin and noradrenaline in the brain and this could explain its antidepressogenic effect.” Current evidence suggests that free testosterone, or testosterone that is not bound to the proteins albumin and sex hormone-binding globulin, is biologically active (also called bioavailable testosterone). “In other words, if we wish to clarify what testosterone does, we need to look at free testosterone,” said Dr. Almeida. Twenty Percent of Men Older Than 70 Years Develop Hypogonadism The study results do not mean that all older men should receive testosterone replacement therapy, but they do suggest that this therapy should be considered for the significant number of older men with low male hormone levels, said Dr. Almeida. “The association between depression and free testosterone is limited to hypogonadal men or men with abnormally low free testosterone,” he added. “After age 70 years, approximately 20% of men develop hypogonadism. This particular group may benefit from testosterone replacement.” Dr. Almeida added that randomized trials are now needed to determine if testosterone replacement is effective and safe to treat depression in this group. He stressed that the association between free testosterone levels and depression is a “risk” association rather than a cause-consequence effect. “Not all older men with depression are hypogonadal, and not all hypogonadal men have depression. But there is a dramatic increase in the risk of depression among hypogonadal men.” As the population ages, there is likely to be an increase in the number of men with hypogonadism, said Dr. Almeida. He noted, too, that although depression is more prevalent among women, the gap between the sexes “all but disappears” later in life. “Our findings may partly explain why that is so,” he said. The study was supported by grants from the National Health and Medical Research Council of Australia. Biochemical analyses were funded by a Sylvia and Charles Viertel Charitable Foundation Clinical Investigator Award. The study authors have disclosed no relevant financial relationships. Arch Gen Psychiatry. 2008;65:283-289.

Clinical Context
Depression is a leading cause of disability worldwide, affecting 2% to 5% of the population. The prevalence of depression in women is higher vs men throughout the lifespan, but sex differences disappear after the age of 65 years. Serum concentrations of gonadal hormones have been associated with various measures of well-being. In men, relative androgen deficiency in later life has been linked to decreased lean mass and increased fat mass, osteopenia, decreased muscle strength, fatigue, decreased hematocrit values, systemic illness, increased risk for coronary heart disease, and poor concentration. It has been postulated that the association of low testosterone concentrations and mood is confounded by concurrent physical morbidity. The aim of this study was to determine whether the association between serum testosterone concentrations and mood in older men is independent of physical comorbidity.

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