Hormonal Treatments for Bipolar Disorder: A Review of the Literature

Tuong-Vi Nguyen, Nancy C. P. Low

Department of Psychiatry, McGill University, Montreal, Canada.

DOI: 10.4236/jbbs.2012.21006                

Abstract

Hormonal therapies may play a role in the treatment of bipolar disorder. Preliminary evidence suggests that: 1) tamoxifen has anti-manic properties; 2) hormone replacement therapy represents a good augmentation strategy in treatment-resistant peri-menopausal depression; and 3) certain oral contraceptives could prevent menstrual exacerbations of affective symptoms. Potential neurobiological mechanisms of the anti-manic effects of tamoxifen include the inhibition of protein kinase C in addition its anti-estrogenic effects. Estrogen is a serotonergic and adrenergic agonist as well as an agent promoting neurogenesis in the hippocampus through glutamatergic synaptic formation, which may be the basis of its antidepressant activity. Progesterone appears to decrease serotonergic and adrenergic tone and activity, while increasing GABAA receptor activation through its active metabolite allopregnanolone, which may be the basis of its anxiolytic, sedative, and potentially anti-manic properties. Although there is consistency between the evidence for clinical efficacy and neurobiological mechanisms of hormonal treatments, the current state of knowledge relies on studies with several methodological limitations. On the other hand, benefits of hormonal treatment include protection from osteoporosis and several gynecological cancers, as well as safe contraception in a population at-risk for unplanned pregnancy. Nonetheless, hormonal treatments should be reserved for treatment-resistant bipolar depression or mania, or when contra-indications to other psychotropic medications are present. Institution of regular monitoring for medical complications and drug-drug interactions are essential to minimize risks and maximize benefits.

Keywords

Tamoxifen; Hormone Replacement Therapy; Oral Contraceptives; Mood; Mania; Depression

1. Introduction

Reproductive hormones appear to impact the course of bipolar disorder in women, particularly in the premenstrual, post-partum and perimenopausal phases [1-3]. Manic and depressive symptoms have been found to occur more frequently during the premenstrual (late luteal) phase; post-partum mood episodes were found to occur in 67% of bipolar mothers; and a significant proportion of bipolar women have reported a worsening of mood symptoms, primarily depressive, in the periand/or post-menopausal period [3]. Interestingly, tamoxifen, a known anti-cancer hormonal agent, was recently listed as a third-line option in the acute treatment of mania in the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines, based on evidence of efficacy in recent trials with a purported mechanism of action similar to that of lithium and valproate [4,5]. In addition, the World Federation of Societies of Biological Psychiatry (WFSBP) rated the evidence for the anti-manic effect of tamoxifen as a category B and gave it a recommendation grade of 3, just below the grade given to carbamazepine and olanzapine [6]. This raises questions regarding the role of hormonal treatments such as: 1) tamoxifen; 2) hormone replacement therapy (HRT); and 3) oral contraceptives (OCs) in the treatment of bipolar disorder, as preliminary evidence suggests these agents may possess mood stabilizing properties, primarily in terms of efficacy in: 1) acute mania; 2) acute depression; or 3) prevention of mood fluctuations across the menstrual cycle. Clinical interest in hormonal treatments first stemmed from studies in samples treated for other medical, non-psychiatric conditions. Unexpected effects of these treatments on mood came to light through these studies in women and men with no psychiatric history.

1.1. Tamoxifen

Tamoxifen is a selective estrogen receptor modulator, and acts as an estrogen agonist at some sites and an estrogen antagonist at other sites, such as breast tissue [7,8]. However, its effect in the central nervous system appears more complex, with possible agonist effects in some areas of the brain and antagonist effects in others [9]. Tamoxifen is commonly used as an adjuvant for the prevention of breast cancer recurrence in high-risk women and the treatment of estrogen-receptor positive breast cancer in post-menopausal women and metastatic estrogen-receptor positive breast cancer in both men and women [7]. Yet despite several years of tamoxifen use in non-psychiatric populations, its effect on mood remains uncertain. In addition to the new use of tamoxifen in mania, several case reports have reported tamoxifen-induced depression symptoms in breast cancer patients, but a large placebocontrolled randomized trial and a retrospective cohort study in the same population found no difference between the tamoxifen and control groups in terms of depressive symptoms [10-12].

1.2. Hormone Replacement Therapy

HRT is prescribed for the short-term treatment of moderate to severe peri-/post-menopausal vasomotor symptoms [13-16]. There are few reports of adverse mood symptoms with HRT in samples with no psychiatric history. One case report described the induction of mania with HRT use (estrogen only for 3 weeks and estrogen/progesterone for one week every month) in one 85 year-old post-menopausal women with no prior history of bipolar disorder [17]. On the other hand, studies have consistently shown increased rates of depression in the perimenopausal/menopausal period, even in women with no prior history of depression [18,19]. Measures of follicle-stimulating hormone (FSH), luteinizing hormone [20] and estradiol in an 8-year prospective cohort study revealed that greater variability in estradiol and FSH at the time of menopause was associated with increased incidence of depressed mood and depression in women with no prior history of depression [19].

1.3. Oral Contraceptives

In addition to being used for regular contraception, oral contraceptives (OCs) are also prescribed to relieve acne, dysmenorrhea, premenstrual dysphoric disorder, endometriosis, menorrhagia, uterine leiomyomas, pelvic inflammatory disease, and to regulate the menstrual cycle in women suffering from polycystic ovarian syndrome [21, 22]. In samples of women with no current/prior psychiatric history, studies of OCs yielded mixed results, with older studies finding more adverse mood effects while more recent studies found some evidence of decreased mood fluctuations across the menstrual cycle [23-26]. This is thought to be due to changes in OCs formulation over time [23].

2. Objectives

Given the wide range of indications and prevalent use of hormonal treatments throughout the lifespan and recent findings on the potential novel use of tamoxifen in mania, it is timely to review the evidence of these treatments in bipolar disorder. The main objectives of this review are to: 1) summarize the current evidence for potential mood stabilization effects of tamoxifen, hormone replacement therapy and oral contraceptives; 2) review theoretical neurobiological mechanisms of hormonal treatments in bipolar disorder; and 3) discuss the medical benefits, adverse effects and pharmacological interactions of hormonal treatments with mainstay bipolar treatment (mood stabilizers, antipsychotics, antidepressants).

3. Methods

A literature search was conducted through EMBASE and MEDLINE from 1980 to 2010. This time period was chosen because hormonal replacement therapy received its first clinical indication for osteoporosis in the 1980s [27]. The following terms were used for the literature search: “tamoxifen”, “hormone replacement therapy”, “oral contraceptives”, “bipolar disorder”, ”depression”, “mania”, “mood stabilizers”, “antidepressants”, “antidepressive agents”, “anticonvulsants”, “lithium”, “antipsychotic agents”, and “side effects”. Manual literature searches based on bibliographies of relevant articles were also conducted. The main search using the terms “tamoxifen”, “hormone replacement therapy”, and “oral contraceptives” combined with “bipolar disorder”, yielded 12 studies for tamoxifen, 12 studies for HRT, 14 studies for OCs through MEDLINE; the same search through EMBASE yielded 60 studies for tamoxifen, 30 studies for HRT and 124 studies for OCs. After careful review of the abstracts and elimination of duplicate studies, 25 studies were retained for review. Randomized controlled trials and non-randomized prospective clinical trials pertaining to hormonal treatments in bipolar disorder were prioritized. When such studies were not available or were few in number, observational studies, reviews and case reports of bipolar subjects were included.

4. Results

4.1. Evidence of Mood Stabilization

4.1.1. Tamoxifen in Women and Men with Bipolar Disorder

As detailed in Table 1, several studies demonstrate the anti-manic properties of tamoxifen in bipolar disorder, as adjunctive or monotherapy. Two 3-week randomized, double-blind placebo-controlled (RCTs) monotherapy trials of 66 and 16 bipolar subjects found an anti-manic effect of tamoxifen [28,29]. However, worsening of the placebo groups in both trials over the course of the study partially accounted for treatment differences. This calls into question the generalizability of these two RCTs, as worsening of the placebo group is not typical of trials targeting mania [28,29]. In a non-randomized, doubleblind, placebocontrolled 4-week study involving 13 women, Kulkarni et al. observed a significant decrease in both manic and psychotic symptoms in the tamoxifen group [30]. In this study, tamoxifen or placebo were added to an ongoing regimen of lithium and/or valproic acid [30]. Finally, in a non-randomized, single-blind study of 7 subjects, Bebchuck et al. observed a significant decrease in Youth Mania Rating Scale (YMRS) ratings [31]. Two of these patients were on other psychotropic agents [31]. Of note, no randomized controlled trials to date have shown a worsening or improvement of depresssive symptoms in bipolar patients associated with the use of tamoxifen [5].

4.1.2. Hormone Replacement Therapy in Women with Bipolar Disorder

As detailed in Table 2, there are few controlled studies assessing the mood stabilizing (predominantly antidepressant) effect of hormone replacement therapy in bipolar patients. In a prospective observational study of 170 depressed unipolar and bipolar post-menopausal women, HRT use was associated with significantly greater response to a selective serotonin reuptake inhibitor (83.7%. vs. 63.2% for non-HRT users) [32]. No significant differences were observed between estrogen-only and estrogen-progesterone users; surprisingly, there were also no significant differences in response between unipolar and bipolar populations [32]. In a retrospective study of 22 bipolar women, non-HRT users were significantly more likely than HRT users to report worsening in mood symptoms in the perimenopause/menopause period [1]. Chouinard et al. reported on 2 case reports of women in their 50s with treatment-resistant bipolar disorder, mainly consisting of depressive/mixed symptoms, who responded to a combination of estrogen and progesterone, while estrogen alone induced mania in one of these women [33]. In another case report, this time involving a

Table 1. Summary of studies examining the mood stabilizing effect of tamoxifen in bipolar disorder.

Table 2. Summary of studies examining the mood stabilizing effect of hormonal replacement therapy in bipolar disorder.

treatment-resistant post-partum mania, Huang et al. reported the effectiveness of HRT in combination with lithium and valproic acid [34]. The patient remained in remission after the withdrawal of HRT 2 months after treatment initiation [34].

4.1.3. Oral Contraceptives in Women with Bipolar Disorder

To our knowledge, there is one only study to date in bipolar subjects examining the mood stabilizing effects of oral contraceptives. In a non-randomized sample of women with bipolar disorder, Rasgon et al. observed 17 subjects (6 OC users, 11 non-OC users) over the course of 3 months and found less mood variability/fluctuations across the menstrual cycle in OC users [35]. Bias due to selfselection into the OC group and continuation of other medications such as mood stabilizers and antidepressants over the course of the study constitute significant limitations [35].

4.2. Potential Neurobiological Mechanisms Underlying Mood Stabilizing Effects

4.2.1. Tamoxifen

Tamoxifen is a selective protein kinase C inhibitor as well as a partial estrogen antagonist, with agonist properties in endometrial tissue and antagonist properties in breast tissue [7,8]. However, its effects on the central nervous system appear are complex: it appears to act as a serotonergic antagonist, while promoting cholinergic and adrenergic activity [9,36].

Tamoxifen trials were initiated in manic subjects on the basis of its inhibition of protein kinase C (PKC), a mechanism that is also thought to be partially responsible for the mood stabilizing properties of lithium and valproic acid [5]. Unfortunately, preliminary studies of tamoxifen in humans were not adequately powered or methodologically designed to distinguish the effect of PKC inhibition of tamoxifen from its effect on estrogen [5]. The only head-to-head study of tamoxifen with the anti-estrogen agent medroxyprogesterone in humans did not find significant differences between these medications in terms of their anti-manic effect [30]. One animal study using an amphetamine-induced manic model in mice found a greater anti-manic effect of lithium, tamoxifen or chelerythrine (a selective PKC inhibitor) monotherapy when compared to medroxyprogesterone, suggesting that the anti-manic effect of tamoxifen is distinct from its anti-estrogen effect [37]. Of note, both animal and human studies were either not adequately powered to control for sex or have not shown any difference between sexes in response to tamoxifen [28-31,37].

4.2.2. Hormone Replacement Therapy and Oral Contraceptives

Evidence from RCTs in depressed periand post-menopausal women suggest that mood disorders in the perimenopausal phase are due to hormonal changes (acute withdrawal or fluctuations) in the early perimenopausal period rather than chronic hormone-deficient states in women who have been post-menopausal for more than 5- 10 years [18]. Therefore, the primary aim of hormone replacement therapy is to stabilize hormonal levels in perimenopausal women.

Oral contraceptives are also thought to result in more stable levels of hormones throughout the menstrual cycle [25]. This is relevant in women with bipolar disorder, as they not only commonly experience an exacerbation of their affective symptoms in the late luteal phase, but also appear to show greater hormonal fluctuations across the menstrual cycle, a difference that remains significant after controlling for comorbidities and treatment effects [38].

Estrogen appears to have widespread effects in the brain, and it has been noted to act on serotonergic, adrenergic, dopaminergic, and basal forebrain cholinergic pathways [9,39,40,42,43] . It has also been found to be implicated in the formation of new NMDA synapses in the CA1 region of the hippocampus, possibly potentiating long-term memory but also decreasing seizure threshold [9]. Among the various neurotransmitters, the relationship between estrogen and the serotonergic system has been most thoroughly studied, and in this case, may relate directly to its antidepressant effect. These effects are complex: estrogen appears to increase genomic expression of tryptophan hydroxylase and decrease the activity of monoamine oxidase in animal studies, potentially leading to increased serotonin synthesis [9,41,44]; it has also been found to increase the activity of the serotonin transporter gene, leading to increased serotonin turnover [44]. In addition, estrogen appears to increase the sensitivity of post-synaptic 5-HT1a receptors and to decrease the sensitivity of pre-synaptic 5-HT1a autoreceptors [44]. There have also been reports of estrogen-related increases in density of post-synaptic 5-HT2a receptors in the amygdala, hippocampus, nucleus accumbens and a number of cortical areas [9]. These various neuronbiological changes seem to lead overall to an increase in serotonergic activity and turnover, while a decrease in serotonergic tone and activity, associated with increased pre-synaptic 5-HT1a autoreceptor binding, has been reported in bipolar depression [45]. In addition, estrogen appears to increase norepinephrine turnover and decrease norepinephrine reuptake, though this is not as well documented than the effects on the serotonergic system [9]. Both serotonergic and adrenergic effects could therefore underlie estrogen’s antidepressant effect, as well as the less common, but reported induction of mania with the administration of estrogen [1,17,32,33]. Other effects of estrogen, such as a possible antidopaminergic effect by blocking D2 receptors, similar to the mechanism of action of antipsychotics, or the increase in frontal release of acetylcholine and decreased catabolism of this neurontransmitter, may be associated with other beneficial psychotropic effects of estrogen, but direct implications with regards to bipolar depression and mania are not evident.

In contrast to estrogen, progesterone appears to decrease 5-HT1a binding potential and to downregulate the formation of NMDA synapses in the hippocampus [9,39]. In addition, progesterone seems to mainly act on the central nervous system through one of its metabolites, allopregnanolone, and its agonistic effects on GABA_A receptors [46]. Progesterone also decreases the activity of nicotinic cholinergic receptors, and reduces noradrenergic tone by decreasing receptor sigma-1 activity as well as increasing catabolism of this neurotransmitter [42]. Thus it is believed to have anxiolytic and sedating effects, though depressogenic and adverse cognitive effects have also been reported [9,39,42,46]. On the other hand, effects on the dopaminergic system are complex, differing depending on the regions of the cortex or subcortical structures, and are not clearly associated with bipolar depression or mania [42].

It appears that estrogen and progesterone act, at least partly, on the same neurotransmitter systems, though in a mostly antagonistic manner [9,39,42]. This interaction is complex, as estrogen also increases the expression of progesterone receptors [9,39]. Nonetheless, it appears that estrogen has potential antidepressant effects, while progesterone appears to have depressogenic and anxiolytic effects [9]. The combination of both estrogen and progesterone could therefore have mood stabilizing properties. Few studies have been designed to answer this question. Kurshan et al. report that combining estrogen and progesterone reduces levels of dehydroepiandrosterone-sulfate (DHEAS), a GABA_A receptor antagonist [46]. This effect has been hypothesized to be partly responsible for the mood stabilizing effect of estrogen-progesterone combinations, but these considerations remain speculative [46].

4.3. Medical Benefits, Adverse Effects and Pharmacological Interactions

Table 3 summarizes advantages, adverse effects and drug interactions of tamoxifen, hormonal replacement therapy and oral contraceptives.

Conflicts of Interest

The authors declare no conflicts of interest.

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