Women with bipolar disorder often experience fluctuating mood symptoms across the menstrual cycle, typically reporting an exacerbation of symptoms during the premenstrual phase of the cycle (Rasgon et al, 2003, 2005).  Other studies have indicated that women with bipolar disorder have more affective instability as they transition into the menopause, when there are pronounced fluctuations in levels of estrogen and progestin levels (Marsh et al, 2012).  These findings have led researchers to infer that for some women with bipolar disorder, hormonal changes may affect mood stability.

This hypothesis is supported by case reports demonstrating improvement in mania with treatments that reduce estradiol levels by inducing anovulation with drugs such as danazol and medroxyprogesterone acetate (MPA: Chouinard et al, 1987). Other studies have used tamoxifen,  a selective oestrogen receptor modulator (SERM), which has anti-estrogenic effects throughout the brain and have shown that tamoxifen may be clinically beneficial in the treatment of acute mania in both female and male patients with bipolar disorder (Bebchuk et al, 2000; Amrollahi et al, 2011; Yildiz et al, 2011).

In a recent double blind, placebo controlled trial, researchers tested the efficacy of MPA and tamoxifen in the treatment of acute mania in a group of women with bipolar disorder.   Eligible women were aged between 18 and 65, had a diagnosis of schizoaffective disorder or bipolar disorder, and were taking a mood stabilizer (lithium, sodium valproate or carbamazepine) and/or a mood–stabilizing antipsychotic.  Participants were randomized to receive tamoxifen 40 mg ( n = 15); MPA 20 mg daily ( n = 18); or placebo ( n = 18).  Mania was assessed at baseline and then weekly for four weeks using the Clinician Administered Rating Scale for Mania (CARS-M).

Adjunctive treatment with MPA, but not tamoxifen, was beneficial in treating acute mania. Women in the MPA group had a greater reduction in symptoms and responded more rapidly.  The authors noted that the lack of effect in the tamoxifen group may have reflected the dosage of tamoxifen used.  In order to limit side effects, they used tamoxifen at 40 mg daily.   However, other studies which described significant improvements in mania used a tamoxifen dosage of 60–80 mg/day of started at 40 mg and increased the dose as needed.  Thus, larger doses of tamoxifen may be necessary to see a treatment effect.

Further studies are needed in order to determine which women are likely to benefit from this sort of adjunctive treatment.  It is also possible to note that, since estrogen and progestin levels vary across the menstrual cycle, treatment may be affected by the phase of menstrual cycle.  (This study was not able to obtain this information because the women were very ill, and over half of the women did not have regular menstrual cycles.)  Nonetheless, MPA may be a reasonable adjunctive treatment for women with refractory mania.

Ruta Nonacs, MD PhD

Kulkarni J, Berk M, Wang W, et al.  A four week randomised control trial of adjunctive medroxyprogesterone and tamoxifen in women with mania.  Psychoneuroendocrinology. 2014 May; 43:52-61.