Elsevier

Psychoneuroendocrinology

Volume 43, May 2014, Pages 52-61
Psychoneuroendocrinology

A four week randomised control trial of adjunctive medroxyprogesterone and tamoxifen in women with mania

https://doi.org/10.1016/j.psyneuen.2014.02.004Get rights and content

Summary

Emerging research has suggested that hormone treatments such as selective oestrogen receptor modulators (SERMs) or progestins may be useful in the treatment of mania. The current pilot study compared the use of the SERM tamoxifen and the progestin medroxyprogesterone acetate (MPA), as an adjunct to mood stabiliser medications, for the treatment of mania symptoms in 51 women in a 28-day double blind, placebo controlled study. The primary outcome was the change between baseline and day 28 mania scores as measured by the Clinician Administered Rating Scale for Mania (CARS-M). Adjunctive MPA treatment provided greater and more rapid improvement in mania symptoms compared with adjunctive placebo and tamoxifen treatment. Adjunctive therapy with MPA may be a potentially useful new treatment for persistent mania, leading to a greater and more rapid resolution of symptoms compared with mood stabiliser treatment alone.

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).

References (40)

  • H.-Y.P. Lam

    Tamoxifen is a calmodulin antagonist in the activation of cAMP phosphodiesterase

    Biochem. Biophys. Res. Commun.

    (1984)
  • H.K. Manji et al.

    Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness

    Biol. Psychiatry

    (1999)
  • J.L. Payne et al.

    Reproductive cycle-associated mood symptoms in women with major depression and bipolar disorder

    J. Affect. Disord.

    (2007)
  • M. Pereira et al.

    Antimanic-like effect of tamoxifen is not reproduced by acute or chronic administration of medroxyprogesterone or clomiphene

    Neurosci. Lett.

    (2011)
  • N.L. Rasgon et al.

    Longitudinal evaluation of reproductive function in women treated for bipolar disorder

    J. Affect. Disord.

    (2005)
  • American Psychiatric Association

    Diagnostics and Statistical Manual of Mental Disorders, text revised

    (2000)
  • J.M. Bebchuk et al.

    A preliminary investigation of a protein kinace C inhibitor in the treatment of acute mania

    Arch. Gen. Psychiatry

    (2000)
  • A.B. Berenson et al.

    Continuation rates and complications of intrauterine contraception in women diagnosed with bipolar disorder

    Obstet. Gynecol.

    (2011)
  • G. Chouinard et al.

    Estrogen–progesterone combination: another mood stabilizer?

    Am. J. Psychiatry

    (1987)
  • M.C. Craig

    Should psychiatrists be prescribing oestrogen therapy to their female patients?

    Br. J. Psychiatry

    (2013)
  • Cited by (27)

    • Lithium treatment of Bipolar disorder in adults: A systematic review of randomized trials and meta-analyses

      2022, European Neuropsychopharmacology
      Citation Excerpt :

      Three studies that reported on combinations of mood stabilizing agents (including lithium) with haloperidol vs. haloperidol monotherapy were equivocal as the outcome depended on the haloperidol dosage (Chou et al., 1999; Garfinkel et al., 1980; Klein et al., 1984). The addition of asenapine, olanzapine, risperidone, haloperidol and tamoxifen but not gabapentin and medroxyprogesterone on lithium or valproate was superior to lithium or valproate alone (Kulkarni et al., 2014, 2006; Pande et al., 2000; Sachs et al., 2002; Szegedi et al., 2012; Xu et al., 2015; Yatham et al., 2003). Taking into consideration the data concerning combination treatment, it seems that only specific combinations of lithium (with asenapine, olanzapine, risperidone, quetiapine, carbamazepine, tamoxifen, lorazepam, allopurinolare more efficacious than monotherapy.

    • Menopause in women with schizophrenia, schizoaffective disorder and bipolar disorder

      2021, Maturitas
      Citation Excerpt :

      In a separate trial, it was proposed that medroxyprogesterone acetate (MPA) as adjunct treatment to regular therapy can provide greater and more rapid improvement in the control of manic symptoms compared with an adjunctive placebo and tamoxifen. Adjunct therapy with MPA may be a potentially useful new treatment option for persistent mania, leading to a greater and more rapid resolution of symptoms compared to using mood stabilizers alone83. HRT has well documented anti-depressive effects, and can thus be a powerful tool in the management of depressive symptoms exhibited by patients with bipolar disorder, and as an augmentation strategy in treatment-resistant peri-menopausal depression80.

    • Neuropsychiatric effects of tamoxifen: Challenges and opportunities

      2020, Frontiers in Neuroendocrinology
      Citation 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.

    • Antipsychotic effects of sex hormones and atypical hemispheric asymmetries

      2020, Cortex
      Citation 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).

    View all citing articles on Scopus
    View full text