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Disappointing Data Confound Claims For DHEA Effectiveness

In a small pilot study, DHEA doesn’t look promising as a treatment for Alzheimer’s disease, regardless of widespread claims that the neurosteroid has far-reaching neuroprotective effects.

Dehydroepiandrosterone (DHEA) does not significantly improve cognitive performance or overall ratings of change in severity of Alzheimer’s disease, according to a small-scale pilot study.

DHEA and its sulfate metabolite, DHEA-S, are the most abundant adrenal and gonadal steroids found in humans. Also synthesized in brain tissue, they are often referred to as "neurosteroids" and are known to bind to N-methyl-D-aspartate (NMDA) receptors as well as gamma-amino-butyric acid type A (GABA-A) receptors. Previous laboratory and animal studies had yielded some evidence that DHEA may provide neuroprotection by decreasing oxidative stress and blocking excitatory neurotoxicity, as well as blocking corticosteroid-induced neuronal damage. In addition, some preliminary clinical trials with DHEA have indicated that it may have antidepressant qualities. Lastly, DHEA has also been associated with increased levels of hippocampal release of acetylcholine, known to be important in memory.

"We know that as we age, levels of DHEA begin to fall after about age 20 or so," said the current study’s lead author, Owen Wolkowitz, M.D., a professor of psychiatry at the University of California at San Francisco. "And by about age 65, those levels have fallen to 10 to 20 percent of those found in healthy young adults. Because of preclinical studies linking DHEA to neuroprotective effects and animal studies showing that higher levels of DHEA improve memory, we wanted to look at what effect the hormone would have in clinically diagnosed Alzheimer’s patients."

Wolkowitz and his colleagues conducted a multisite, double-blind, placebo-controlled study of DHEA in 58 patients with Alzheimer’s over six months.

"The patients we studied were not allowed to be on any other drugs—cholinesterase inhibitors, and so on—that could confound the results, so that limited our patient population," Wolkowitz told Psychiatric News. Patients who were receiving any other steroid, including estrogen, were also excluded, as were patients with severe dementia (those with a Mini-Mental State Exam score of less than eight).

Twenty-eight patients were blindly chosen to receive 50 mg of DHEA twice a day for six months, and 30 patients received an identical-looking placebo. The dose of DHEA, Wolkowtiz said, was targeted to achieve blood levels of the hormone at or slightly above the top of the normal range of DHEA levels found in healthy young adults.

"Although we weren’t thinking that an age-dependent decline in DHEA was directly tied to the pathology of Alzheimer’s," Wolkowitz said, "we hypothesized that perhaps by boosting levels of the hormone back up to those seen when people are young and healthy, we might be able to harness some of the hormone’s inherent neuroprotective effects."

The main outcome variables were the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) and the Clinician’s Interview Based Impression of Change With Caregiver Input (CIBIC-Plus).

"What we saw was that numerically, DHEA did have a benefit on cognitive ratings, but overall, on the CIBIC-Plus, there was no significant benefit shown," Wolkowotz said. Specifically, Wolkowitz and his colleagues showed that at three months, the DHEA group, compared with placebo, showed a trend toward improvement on the ADAS-Cog, but the improvement only narrowly missed being statistically significant. On the CIBIC-Plus, no significant differences were noted between the DHEA and the placebo group.

"Obviously we were limited on the number of patients we were looking at, so that limited our statistical power," Wolkowitz told Psychiatric News. "But also, DHEA may simply not be effective as a stand-alone agent in Alzheimer’s."

Wolkowitz and his fellow investigators want to follow up these preliminary results with a larger study, potentially looking at the use of DHEA as an adjunct medication with a cholinesterase inhibitor like donepezil. In addition Wolkowitz would like to study DHEA’s reported antiglucocorticoid effects. In particular, DHEA has been reported to reduce cortisol, the so-called "stress hormone," which in response to stress is released in large quantities that have been linked to neuronal stress and damage.

An abstract of "DHEA Treatment of Alzheimer’s Disease: A Randomized, Double-Blind, Placebo-Controlled Study" is posted on the Web at www.neurology.org/cgi/content/abstract/60/7/1071.

Neurology 2003 60 1071[Abstract/Free Full Text]

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