In many preliminary studies, including one presented at the recent 2nd World Congress on Women's Mental Health, the naturally occurring steroid dehydroepiandrosterone has been shown to be an effective treatment for mild-to-moderate midlife depression. Questions remain, however, as to its mechanism of action, the risk of side effects and its interactions with medications.
Dehydroepiandrosterone (DHEA) replacement therapy may be efficacious in treating mild-to-moderate midlife depression, particularly where traditional antidepressant treatment has failed, is undesired by the patient or is not well tolerated, an expert in behavioral endocrinology reported in March. Robert J. Daly, MB, MRCPsych, senior lecturer at the Royal College of Surgeons in Ireland, described findings from a study on DHEA sponsored by the National Institute of Mental Health at the 2nd World Congress on Women's Mental Health in Washington, D.C. Daly was formerly a senior staff fellow in NIMH's Behavioral Endocrinology Branch.
While DHEA is found naturally in the body as a steroid hormone secreted by the adrenal cortex, its supplement form is extracted from the barbasco root or wild Mexican yam. In the United States, DHEA is one of the most commonly used dietary supplements, according to Daly. Supplement marketers claim it is capable of alleviating depression, slowing aging, improving memory, boosting energy and building muscle mass. Several countries, however, have banned over-the-counter (OTC) DHEA sales. Last April, the U.S. House of Representatives Energy and Commerce Committee unanimously approved the Anabolic Steroid Control Act of 2004 (HR 3866), which would make 43 steroid precursors controlled substances instead of OTC supplements, but DHEA was exempted from the list. Still, as a precaution, the bill requires the U.S. Attorney General to evaluate the health risks of dietary supplements similar to anabolic steroids not included in HR 3866 and issue a report within the next two years.
Daly said that DHEA and its sulfate metabolite, DHEA-S, are the most abundant adrenal and gonadal steroids found in humans. Dehydroepiandrosterone acts as a prohormone or hormonal precursor; specifically, it is a precursor to testosterone and estrogen.
Concentrations of DHEA are generally higher in men than women. Blood levels of DHEA and DHEA-S begin dropping when individuals are in their 20s. By the time they are in their 40s and 50s, levels of DHEA and DHEA-S have dropped by about 50%. Low DHEA levels have been associated with a variety of adverse biological consequences, including increased cardiovascular disease, decreased immune function, decreased bone density, negative lipid profile and increased fat-to-muscle ratio.
Daly, who is a consultant psychiatrist with the Beaumont Private Clinic in Dublin, Ireland, explained that a relationship between DHEA and depression has been suggested by reports of alterations (both decreases and increases) in plasma DHEA levels in depression (Jozuka et al., 2003; Young et al., 2002) and by initial reports of antidepressant-like effects of DHEA either as monotherapy or combined with traditional antidepressant agents.
"[Other researchers] have demonstrated the beneficial effects of DHEA administration, both in depressed and nondepressed men and women," Daly said. "So we carried out a study seeking to answer the following question: Is DHEA administration efficacious in treatment of midlife-onset depression?"
Daly and colleagues (2004) studied men (n=23) and women (n=23) ages 40 to 65 with midlife-onset depression. All individuals enrolled in the study met the criteria for minor or major depression. The design was a double-blind, randomized, placebo-controlled, crossover treatment study. Initially, there was a six-week screening period, following which individuals were randomized to either six weeks of DHEA treatment or placebo. Then there was a two-week washout period, followed by a crossover where individuals received a further six weeks of either DHEA or placebo. During the active phase of treatment, DHEA was administered in divided doses totaling 90 mg/day for the first three weeks, followed by doses totaling 450 mg/day for the next three weeks. The primary outcome measures included the 17-item Hamilton Rating Scale for Depression (HAM-D), Center for Epidemiologic Studies Depression Scale (CES-D) and Derogatis Sexual Functioning Inventory (DSFI). Results were analyzed by ANOVA and Bonferonni t-tests.
"The administration of DHEA during the study was marked by a dramatic increase in DHEA levels. In men and women, there was an overall sevenfold increase in DHEA levels. Also of note, during the washout period, there was a normalization of DHEA back to levels seen at baseline and placebo periods," Daly said. "Sexual dimorphism was maintained in the DHEA treatment phase, whereby DHEA levels in men were somewhat greater than those seen in women."
Overall, Daly and his colleagues observed beneficial effects of DHEA on mood. In both men and women taking DHEA, significant improvement was seen on the HAM-D in depression severity compared to both baseline (p<0.01) and placebo conditions (p<0.01). During the placebo phase, there was no significant difference observed in depressive symptoms on the HAM-D scores from baseline. In addition to DHEA's beneficial effects on mood, the researchers also observed beneficial effects on symptoms of loss of libido.
"DHEA administration resulted in an improvement overall in sexual functioning compared with baseline and placebo, and this improvement was in parallel with improvements in mood," Daly added.
Although it appears to be an effective monotherapy, predictors of a therapeutic response to DHEA remain to be determined, Daly said.
"One of the reasons we decided to employ a crossover model for our study was that it would allow us to search for possible factors that might predict response to DHEA in [study participants]. We examined a number of factors including age, gender and reproductive status. However, no predictors of response to DHEA were identified. Specifically, neither baseline nor posttreatment DHEA levels predicted response. Thus, successful DHEA treatment is not felt to be due to simple physiological replacement of DHEA levels," he added.
One of the primary metabolites of DHEA is testosterone, and Daly said the investigators observed marked increases in plasma testosterone levels in women in the study. During the active DHEA treatment phase of the study, plasma testosterone levels increased by more than 500% above baseline in women and about 20% above baseline in men. He noted that these changes in testosterone may be one factor that mediates mood and libido responses. These findings are similar to other initial studies.
A pilot study looked at the efficacy of DHEA in the treatment of midlife-onset dysthymia (Bloch et al., 1999). The double-blind, randomized, crossover treatment study was similar in design to the Daly et al. study: three weeks on 90 mg/day DHEA, three weeks on 450 mg/day DHEA and six weeks on placebo. Outcome measures included cross-sectional self-ratings (e.g., Beck Depression Inventory [BDI] and visual analogue symptom scales), objective ratings (e.g., HAM-D and the Cornell Dysthymia Rating Scale [CDRS]) and a cognitive test battery. Positive response was defined as a 50% reduction from baseline in either the HAM-D or BDI.
Participants were 17 men and women ages 45 to 63 with midlife-onset dysthymia. In completers (n=15), a robust effect of DHEA on mood was observed compared with placebo. At the end of the six-week treatment period, 60% of participants responded to DHEA compared to 20% on placebo. After three weeks of treatment on 90 mg/day DHEA, a significant response was seen. The most significant improvement was seen in symptoms of anhedonia, such as loss of energy, lack of motivation, emotional "numbness," sadness, inability to cope and worry.
In a six-week, double-blind study, DHEA was both an adjunct to treatment and a monotherapy (Wolkowitz et al., 1999). Participants were 22 individuals with major depression (20 with unipolar depression and two with bipolar II disorder, depressed phase) meeting DSM-IV criteria and pre-study ratings of greater than or equal to 16 on the HAM-D. Participants were also medication-free or had been stabilized on an antidepressant medication for greater than or equal to 2 months. Five of the 11 patients treated with DHEA showed a 50% or greater decrease in depressive symptoms; however, this was not seen in the 11 patients given placebo. No differential effect of sex or pre-existing medication status (medication-free versus stabilized antidepressant regimen) was found through subgroup analyses.
Wolkowitz et al. (1999) explained that the mechanisms by which DHEA might have mood-elevating or antidepressant effects were unclear but suggested some possibilities. Dehydroepiandrosterone is partially metabolized to testosterone and estrogen, both of which may have mood effects of their own. Also, DHEA may modulate the bioavailability of testosterone by means of allosteric changes in albumin's affinity for testosterone. In discussing other possible mechanisms of action, Legrain and Girard (2003) noted, "[DHEA-S] is a neurosteroid which modulates neuronal excitability via specific interactions with neurotransmitter receptors and DHEA is an activator of calcium-gated potassium channels."
Beyond treating depression, Binello and Gordon (2003) have noted that evidence is accruing in support of DHEA supplementation for schizophrenia, adrenal insufficiency, hypopituitarism, osteoporosis and systemic lupus erythematosus.
Strous and colleagues (2003), in a double-blind trial, investigated the efficacy of DHEA in the management of negative symptoms of schizophrenia. Significant improvement was found in individuals receiving DHEA in negative symptoms (p<0.001) as well as in depressive (p<0.05) and anxiety (p<0.001) symptoms.
Baulieu and colleagues (2000) conducted a double-blind, placebo-controlled, one-year trial of oral DHEA 50 mg/day with 280 men and women ages 60 to 79 (the so-called "DHEAge Study") and found some effects on bone turnover, skin and libido. In addition to the re-establishment of a "young" concentration of DHEA-S, small increases in testosterone and estradiol were noted, particularly in women. In women who were older than 70, bone turnover improved selectively as assessed by the dual-energy X-ray absorptiometry (DEXA) technique, and there was a decrease of osteoclastic activity. Also in these older women, a significant increase in most libido parameters was found. In terms of hydration, epidermal thickness, sebum production and pigmentation, improvement of skin status was observed, again particularly in women. The investigators concluded that a number of biological indices confirmed "the lack of harmful consequences of this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects of aging, but does not create 'supermen/women' (doping)."
Genelabs Technologies, Inc., has funded several studies of a synthetic form of DHEA (Prestara) for the potential treatment of systemic lupus erythematosus. In August of 2002, the U.S Food and Drug Administration issued an approvable letter for the Prestara New Drug Application. Additionally, the National Institutes of Health is studying DHEA as an alternative HIV/AIDS therapy (Heavey, 2004).
Side effects of DHEA therapy in women have included increased facial hair, weight gain, acne, temporary breast tenderness, loss of head hair and skin rash (Munarriz et al., 2002). Doses above 1500 mg/day have been known to result in insulin resistance in humans and pre-neoplastic pancreatic lesions in rats (Alternative Medicine Review, 2001). Potential interactions between DHEA and pharmaceuticals include enhanced sedation seen in patients on benzodiazepines and related central nervous system active drugs.
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