A four week randomised control trial of adjunctive medroxyprogesterone and tamoxifen in women with mania
Introduction
Mania is characterised by a prolonged period of excessively elevated or irritable mood (American Psychiatric Association, 2000). It is the hallmark of bipolar affective disorder (BPAD) and is also seen in schizoaffective disorder. Currently, the biological processes involved in mania pathophysiology are unclear, and its treatment remains complex (Geddes and Miklowitz, 2013). Women with BPAD experience fluctuating mood across the menstrual cycle, with an exacerbation of symptoms reported during the premenstrual period (Rasgon et al., 2003, Rasgon et al., 2005, Payne et al., 2007, Dias et al., 2011). Further, evidence suggests that women with BPAD have an increased risk of mood disorder during menopause, a time of decreasing oestrogen levels (Freeman et al., 2002, Marsh et al., 2012). Thus, in women, there is suggestive evidence that endogenous oestrogen levels may mediate manic symptoms.
In previous work, we found that a small subgroup of schizoaffective women with acute mania who received 50 mcg of adjunctive transdermal estradiol for 28 days experienced a worsening of manic symptoms (Kulkarni et al., 2001). We hypothesised this as the effect of an increase in Central Nervous System (CNS) oestrogen exposure. This hypothesis is supported by case reports of improvement in mania with treatments that reduce estradiol levels by inducing anovulation, such as danazol (Goldstein, 1986, Nelson, 1988) and medroxyprogesterone acetate (MPA: Chouinard et al., 1987). In early animal studies, MPA has been shown to cause down regulation of oestrogen receptors in the hypothalamus and pituitary (Blaustein and Brown, 1984) and has an ‘anti-estrogenic’ effect in the brain generally (Irwin et al., 2011).
Tamoxifen is a selective oestrogen receptor modulator (SERM), with tissue specific effects on oestrogen receptors as well as second messenger pathways (Lam, 1984). Tamoxifen has mainly ‘anti-estrogenic’ effects in many parts of the CNS, although studies are largely inconclusive (Paganini-Hill and Clark, 2000, Buwalda and Schagen, 2013). Several small studies have also demonstrated a clinical benefit of tamoxifen in the treatment of mania (Manji and Lenox, 1999, Bebchuk et al., 2000, Zarate et al., 2007, DiazGranados and Zarate, 2008, Yildiz et al., 2008, Amrollahi et al., 2011, Yildiz et al., 2011). A small study found tamoxifen to be superior to MPA and clomiphene in preventing amphetamine induced hyper locomotion in an animal model of mania (Pereira et al., 2011).
Our group has previously reported results of a three arm pilot study comparing adjunctive tamoxifen, MPA and placebo in the treatment of 13 women with manic symptoms (Kulkarni et al., 2006). The women treated with tamoxifen had a greater improvement than the MPA group, and both groups showed a greater improvement than placebo. While both tamoxifen and MPA have oestrogen antagonism effects, tamoxifen is also known to be a potent protein kinase-C (PKC) inhibitor. Elevated PKC levels are seen in mania, and the resolution of mania is associated with reductions in PKC levels (Friedman et al., 1993, Kulkarni et al., 2006, Einat et al., 2007, DiazGranados and Zarate, 2008).
The study reported here expands our pilot study. The aim was to compare the use of two adjunctive agents (tamoxifen and MPA) in a 28-day three-arm double blind, placebo-controlled study in the treatment of acute mania or hypomania to further explore dosing effects in larger sample. Extrapolating from our pilot results, we hypothesised that tamoxifen therapy would be associated with a significant reduction in mania symptoms compared to the MPA and placebo groups. We also attempted to understand more about the mechanisms underpinning any reduction in mania symptoms. In particular, we were interested in exploring whether tamoxifen reduced mania symptoms through PKC inhibition or by oestrogen antagonism. To do this we included the MPA arm as a direct comparator for an “anti -estrogen” effect, and examined for changes in PKC levels across the trial.
Section snippets
Method
This three arm double blind randomised controlled trial was approved by The Alfred Hospital Ethics Committee and Barwon Health Research and Ethics Advisory Committee (Alfred Project Number 77/02). All participants provided written informed consent. The registration number of this trial (at clinicaltrials.gov) is NCT00206544.
Descriptive analyses
There were no significant differences in mean age, diagnosis, age at illness onset or number of hospitalisations between the treatment groups (Table 1), nor were there significant differences in the distribution of women taking mood stabilisers (χ2(8) = 13.18, p = 0.11) or antipsychotics (χ2(2) = 1.81, p = 0.40) at baseline.
Primary outcome measures: CARS-M total and subscale analyses
There were no significant differences in CARS-M total score at baseline. The CARS-M Total score and CARSMANIA Sub-scale means scores decreased across the treatment period in the
Discussion
This study suggests that adjunctive MPA, but not tamoxifen, was beneficial in treating acute mania in women. Women in the MPA group had a greater reduction in symptoms and responded more rapidly. No statistically significant effect was seen in women treated with adjunctive tamoxifen. These findings are different to our original, smaller pilot study, which indicated adjunctive tamoxifen to be superior to MPA and placebo (Kulkarni et al., 2006). We suspect that the differences between our earlier
Role of the funding sources
The Stanley Medical Research Institute, Washington USA, Grant ID: 03T-415. National Health and Medical Research Council Grant ID: 284319.
Conflicts of interest
ES was supported by the Royce Abbey Postdoctoral Fellow (Australian Rotary Health). MB is supported by a NHMRC SPRF.
Acknowledgements
The authors would like to acknowledge the financial support of the NHMRC (Australia) and Stanley Medical Research Institute (Washington).
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2020, Frontiers in NeuroendocrinologyCitation Excerpt :When these trials were combined in a recent meta-analysis, tamoxifen was found to have a substantial treatment effect over placebo, but with similar tolerability (Palacios et al., 2019). Importantly, all of these studies used participants across the adult lifespan and, with the exception of two (Kulkarni et al., 2014, 2006), tested tamoxifen’s effects in men and women suggesting that it would be a potential treatment regardless of sex and hormonal status. It should be noted that these trials were only conducted for 4–6 weeks, so long-term effects of tamoxifen are still unknown and no studies have yet to test tamoxifen’s effects in bipolar depression.
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2020, CortexCitation Excerpt :As such, a limited number of small clinical trials have been conducted to investigate sex hormones as adjunctive therapies in bipolar disorder (Meinhard, Kessing, & Vinberg, 2014). Kulkarni et al. (2014) demonstrated that both adjunctive medroxyprogesterone and tamoxifen, a selective estrogen receptor modulator (SERM) that lacks the possible negative effects of estrogen on breast and uterine tissue, were associated with greater symptom improvement, and medroxyprogesterone was associated with faster improvements in symptoms compared to adjunctive tamoxifen and mood stabilisers alone. Other studies also found anti-manic effects in women with bipolar disorder after SERM treatment (Amrollahi et al., 2011; Yildiz, Guleryuz, Ankerst, Öngür, & Renshaw, 2008; Zarate et al., 2007).