Fighting the winter blues with DHEA
This is the sixth in a series of posts on complementary and alternative therapies for depressed mood. Previous posts reviewed the evidence for SAMe, bright light exposure therapy, omega-3 fatty acids, and folate. The topic of this post is dehydroepiandrosterone (DHEA) a molecule that plays many key roles in the human body and brain that has been extensively investigated for its antidepressant and cognitive enhancing benefits.
Multiple mechanisms of action
Dehydroepiandrosterone (DHEA) is a prohormone (i.e. a precursor of both male and female sex hormones) that occurs naturally in the body and brain and plays key roles in mood regulation and the body’s stress response, and has general neuroprotective, antiinflammatory and anti-oxidant effects. DHEA and a related molecule (DHEA-S) are both manufactured in the adrenal cortex and testes, and are later converted to androgens and estrogens–the male and female sex hormones–in peripheral tissues. DHEA-S is the sulfonated form of DHEA and the most abundant steroid hormone in the body. The antidepressant mechanism of DHEA has not been fully elucidated but may involve androgen receptors, estrogen receptors, or well defined neurotransmitter systems including serotonin, GABA, NMDA and norepinephrine. Estrogen manufactured from DHEA affects the synthesis and binding of serotonin at multiple receptors sites. A recent study found that elevated DHEA-S serum levels correlated with higher rates of response to SSRI antidepressants consistent with research findings that supplementation with DHEA has antidepressant benefits and significantly enhances antidepressant efficacy (Hough et al 2017).
Promising research findings when taken alone or together with an antidepressant
Research findings show that DHEA supplementation alone may reduce the severity of depressed mood and can be safely used in conjunction with antidepressants increasing their efficacy. Blood levels of DHEA decline with normal aging. An early study found that physiological replacement doses of DHEA (ie, 30 to 90mg/day, a dose range corresponding to DHEA serum levels that are normal in people younger than age 40) may improve mood in middle-aged or elderly depressed patients (Wolkowitz et al. 1997).
This above findings are consistent with the findings of a small randomized placebo-controlled trial in which individuals with mid-life onset depression experienced significant and sustained improvements in mood following several weeks of supplementation with DHEA (Schmidt et al 2005). In the study 46 moderately depressed adults were randomized to DHEA 90mg/day for three weeks followed by DHEA 450mg/day in three equal doses, for three weeks versus placebo. None of the patients used antidepressants concurrently. A 50% or greater reduction in depressive symptoms was observed in the majority of patients in the DHEA group, which also reported improvements in baseline sexual functioning. Significantly, most patients who responded to DHEA remained asymptomatic at 12 months follow-up.
Two systematic reviews support that DHEA is an effective monotherapy for depressed mood and may be safely combined with antidepressants augmenting their efficacy (Peixoto et al 2018; Peixoto et al 2014). Research findings on DHEA in depressed mood are limited by the small size of many studies, differences in dosages used, and heterogeneous study designs.
DHEA for depressed mood in HIV/AIDS, Alzheimer’s disease and schizophrenia
DHEA may also be an effective treatment of depressed mood individuals with HIV/AIDS. In one study depressed HIV positive patients experienced significant improvements in mood and fatigue when taking DHEA 200 to 500mg/day (Rabkin 2000). Serum testosterone levels and CD4 T-cell counts were not affected. Psychotic or demented patients often experience significant co-morbid depressed mood. In addition to its established antidepressant benefits, emerging findings suggest that DHEA may also reduce symptoms of psychosis, anxiety and cognitive impairment all of which can occur together with depressed mood.
Research findings suggest that DHEA supplementation may reduces the rate of cognitive deterioration in Alzheimer’s disease (Knopman 2003), and may improve anxiety and negative psychotic symptoms (i.e., apathy, withdrawal, paucity of thought) in individuals diagnosed with schizophrenia. In a double-blind placebo-controlled study 30 inpatients diagnosed with schizophrenia treated with DHEA 100mg/day in addition to their antipsychotic medications experienced significant improvements in depressed mood, anxiety and negative psychotic symptoms (Strous 2003). For unclear reasons, women improved more than men.
Most individuals who take DHEA at doses that have been shown to reduce the severity of depressed mood report few mild adverse effects. Case reports show that DHEA can cause hirsutism (i.e. abnormal hair growth) and acne and can interfere with normal blood clotting. DHEA may promote cancer in women who have a history of estrogen receptor positive breast cancer, and should be avoided in this population. However, a metabolite of DHEA called 7-keto-DHEA is not converted into androgens or estrogens and can probably be safely used in this population. Preliminary findings suggest that DHEA supplementation may increase the risk of prostate cancer in men with early or undetected prostate cancer (Arnold 2005).
At dosages established to be effective against depressed mood DHEA has few adverse effects. Combining DHEA with psychiatric medications is a safe and reasonable integrative approach in depressed individuals who fail to respond–or have a partial response–to antidepressant therapy, and in depressed individuals with co-occurring anxiety, psychosis or cognitive symptoms. The beneficial effects of DHEA on libido and sexual functioning is a significant added benefit of DHEA in view of the high percentage of depressed individuals who report reduced libido due to depressed mood or the side effects of antidepressants. Finally, DHEA should be considered when depressed mood occurs together with anxiety, psychosis and cognitive impairment including in patients diagnosed with schizophrenia and Alzheimer’s disease. .
Further research is needed to replicate the findings reported in this post, evaluate the efficacy of DHEA as a monotherapy for severe depressed mood, further elucidate the mechanism for a synergistic or independent antidepressant effect of DHEA and determine optimal safe dosing strategies.