Polymorphisms of estrogen receptors and risk of depression: therapeutic implications.

Accumulating evidence suggests the involvement of estrogen in depression. Estrogen can modulate neurotransmitter turnover, enhancing the levels of serotonin and noradrenaline (norepinephrine), and it is involved in the regulation of serotonin receptor number and function. Across the female reproductive life, fluctuating estrogen levels and low levels have been associated with depressed mood and there is strong support for a beneficial effect of estrogen-containing hormone treatment in depressed peri-menopausal women. Estrogen exerts its biological effects in large part through intracellular activation of its principal receptors, estrogen receptor α (ESR1) and estrogen receptor β (ESR2). Genetic variation in the estrogen receptors may therefore modify estrogen signalling, thus influencing a woman's susceptibility to developing depression. This review provides a synthesis of studies that have examined the association between estrogen receptor polymorphisms and depression-related mood disorders across the lifetime. Studies were identified through a search of the literature from January 1980 until March 2012 using MEDLINE, Web of Knowledge, Cochrane Library and PsycINFO databases. The studies conducted to date have produced inconsistent findings, which likely relates to the large heterogeneity in terms of the populations, study design and depression measures used. It appears unlikely that the common ESR1 variants rs2234693 and rs9340799 are associated with moderate depressive symptoms in women; however, there is some evidence that indicates a significant association with more severe depressive symptoms, major depressive disorder and anxiety. There are too few studies of ESR2 polymorphisms to draw any definite conclusions; however, preliminary evidence suggests that specific variants may modify the risk of depression associated with the use of hormone treatment in women. Few studies have investigated associations in men, and they have focused almost exclusively on ESR1, but all report non-significant findings. Much work is therefore still needed in this field. If it is confirmed that specific estrogen receptor polymorphisms are associated with the risk of depression, this could have important preventive and therapeutic implications, with the potential to develop targeted estrogen receptor agonists and antagonists. Furthermore, it is possible that such therapies may be more effective in treating particular people with depression based on their genetic profile, which is an exciting prospect given that many people do not respond to current antidepressant treatments.