Psychopharmacology

, Volume 231, Issue 4, pp 639–649

Tamoxifen use for the management of mania: a review of current preclinical evidence

Authors

  • Fernanda Armani
    • Departamento de PsicobiologiaUniversidade Federal de São Paulo
  • Monica Levy Andersen
    • Departamento de PsicobiologiaUniversidade Federal de São Paulo
    • Departamento de PsicobiologiaUniversidade Federal de São Paulo
Review

DOI: 10.1007/s00213-013-3397-x

Cite this article as:
Armani, F., Andersen, M.L. & Galduróz, J.C.F. Psychopharmacology (2014) 231: 639. doi:10.1007/s00213-013-3397-x

Abstract

Rationale

Preliminary data on the efficacy of tamoxifen in reducing manic symptoms of bipolar disorder (BD) suggest that this agent may be a potential treatment for the management of this psychiatric disorder. However, the antimanic properties of tamoxifen have not been fully elucidated, hampering the development and/or use of mood-stabilising drugs that may share its same therapeutic mechanisms of action. Notably, we may gain a greater understanding of the neurobiological and therapeutic properties of tamoxifen by using suitable animal models of mania.

Objectives

Here, we review the preclinical studies that have evaluated the effects of tamoxifen to provide an overview of the current progress in our understanding of its antimanic actions, highlighting the critical role of protein kinase C (PKC) as a therapeutic target for the treatment of BD.

Conclusions

To date, this field has struggled to make significant progress, and the organisation of an explicit battery of tests is a valuable tool for assessing a number of prominent facets of BD, which may provide a greater understanding of the entire scope of this disease.

Keywords

Bipolar disorderManiaTamoxifenProtein kinase C (PKC)Animal modelsAntimanic treatment

Introduction

Bipolar disorder (BD) is a severe psychiatric disease that is clinically characterised by recurrent mood switches, including mania, mixed states and depression. A manic episode, regarded as the clinical hallmark of BD, is defined by euphoria, hyperactivity, impulsivity, increased risk-taking behaviour, increased reward seeking and a decreased need for sleep, whereas a depressive episode consists of sadness, guilt, sleep disturbances and anhedonia (APA 2013). Its association with high rates of medical comorbidities, recurrence and suicide contributes to BD being considered one of the world's ten most disabling conditions (Krishnan 2005; Kupfer 2005).

Although lithium, valproate and atypical antipsychotic drugs remain the standard pharmacological agents to treat acute states and prevent new episodes of BD mania (Goodwin and Jamison 2007), many patients do not tolerate or respond adequately to these therapies (Gitlin 2006; Nierenberg 2010). Additionally, these medications only minimally target aspects such as cognitive function and suicidal ideation, which should be taken into account for effective therapeutic management (Alda et al. 2009). Therefore, there is a clear need to develop novel mood stabilisers to address these clinical challenges (Machado-Vieira et al. 2010).

Unfortunately, progress in discovering new antimanic drugs has been hampered by the lack of accurate knowledge about the neurobiological mechanisms underlying the pathophysiology and therapeutics involved in mania. Elucidating the most effective antimanic agents that share common therapeutically relevant targets will provide a better understanding of the underlying biology of this disease. Several independent groups have recognised a class of enzymes, the protein kinase C (PKC) family, as a direct biochemical target of BD pharmacological agents (for review, see DiazGranados and Zarate 2008; Einat et al. 2004; Zarate and Manji 2009). Collectively, these data provide evidence that PKC inhibition attenuates manic signals in a similar manner as antimanic and mood-stabilising drugs, whereas PKC activation is related with manic states. These studies demonstrating the involvement of PKC in the pathophysiology and therapeutics of BD are summarised in Table 1.
Table 1

Evidence implicating protein kinase C (PKC) in the pathophysiology and treatment of bipolar disorder

Study

PKC-related evidence

Bitran et al. (1990)

Chronic lithium treatment attenuates agonist-, PMA-mediated stimulation of Na+/H+ antiporter activity in HL-60 cells, suggesting PKC pathway inhibition

Giambalvo (1992a, b)

Increased particulate PKC activity in synaptosomes incubated with amphetamine (1–10 μmol/L)

Friedman et al. (1993)

Ratios of platelet membrane-bound to cytosolic PKC activities were augmented in manic subjects. Additionally, serotonin-elicited platelet PKC translocation was enhanced in subjects with mania. Those alterations were normalised following lithium treatment

Gnegy et al. (1993)

Amphetamine increased the phosphorylation of neural-specific calmodulin-binding protein GAP-43 (involved in neurotransmitter release in the purified synaptic plasma membrane of female rat striatum

Manji et al. (1993)

Chronic lithium treatment for 5 weeks resulted in a 30 % reduction in [3H]PDbu binding in the subiculum and CA1 regions of the rat hippocampus

Immunoblot analysis of hippocampal PKC with isozyme-specific antibodies showed a 30 % reduction in membrane-associated PKCα

Chen et al. (1994)

Chronic exposure (6–7 days) of rat C6 glioma cells to “therapeutic” concentrations of valproate (0.6 mmol/L) decreased PKC activity in both membrane and cytosolic fractions and increased the cytosol/membrane ratio of PKC activity. Western blot analysis revealed isozyme-selective decreases in the levels of PKCα and PKCε in both the membrane and cytosolic fractions after long-term valproate exposure

Manji et al. (1996)

Chronic myoinositol administration attenuated lithium-induced decreases in PKCα, MARCKS and GAP-43 in rat hippocampus and frontal cortex

Cervo et al. (1997)

PKC was involved in the mechanism underlying consolidation of conditioned place preference (CPP) in rats

Birnbaum et al. (2004)

High levels of PKC activity in the prefrontal cortex markedly impair behavioural and electrophysiological measures of working memory in rats. Chronic treatment with lithium or valproate for 6 weeks abolished exogenous activation of PKC signalling

Wang and Friedman (1989)

Chronic treatment with lithium in rats significantly decreased PKC stimulation-induced release in response to phorbol esters in the cortex, hypothalamus and hippocampus. Exposure of brain slices obtained from lithium-treated rats to depolarisation and PKC stimulation markedly reduced the translocation of PKC from the cytoplasm to the membrane compartment

Lenox et al. (1992)

Immunoblot analysis revealed that chronic lithium treatment reduced in vivo levels of MARCKS in the rat hippocampus, an effect that was not immediately reversed following lithium discontinuation

Steketee (1993, 1994)

Intra-A10 administration of a PKC inhibitor, H7, inhibited cocaine-induced behavioural sensitisation in rats

Wang and Friedman (1996)

Brain membrane-associated PKC activity was higher in bipolar subjects vs. controls. PKC isozymes in cortical homogenates showed that cytosolic PKCα and membrane-associated PKCγ isozymes were elevated in the cortices of subjects with bipolar disorder

Watson and Lenox (1996)

Chronic lithium treatment downregulated MARCKS protein in a dose- and time-dependent manner in immortalised rat hippocampus cells

Browman et al. (1998)

Behavioural and tissue studies indicate that injection of a PKC inhibitor, Ro31-8220, into the nucleus accumbens in rats attenuates the acute response to amphetamine

Wang et al. (1999)

In a basal state, manic subjects had higher membrane PKC activity than depressed subjects and controls; the ratio of membrane to cytosol PKC activity was significantly higher in manic subjects compared with controls, depressed or schizophrenic subjects; stimulation of platelets with serotonin in vitro resulted in a greater membrane-to-cytosol ratio in manic subjects compared with other groups

Hahn and Friedman (1999)

Long-term lithium treatment significantly reduced PKC activation in rat brains, as measured by the translocation of cytoplasmic PKC to the membrane component or quantitative binding of the PKC ligand PDBu. Alterations in platelet PKC were observed in bipolar patients during manic states of illness. Compared with patients with major depressive disorder, schizophrenia or healthy controls, PKC activity was significantly increased in manic patients and was suppressed following mood-stabilising treatment

Soares et al. (2000)

Lithium-treated euthymic bipolar patients had lower levels of cytosolic PKCα compared with healthy subjects

Wang et al. (2001)

In slices of rat brain cortex, chronic lithium treatment reduced phorbol-induced PKC translocation from the cytosol to membrane without affecting basal membrane or cytosolic PKC activity; immunoblotting revealed that chronic lithium treatment reduced cytosolic PKCα and PKCδ

Wang and Friedman (2001)

Increased association of RACK1 with membrane PKCγ and PKCζ was increased under basal conditions in bipolar disorder relative to control brains; stimulation with phorbol esters increased the amount of RACK1 that coimmunoprecipitated with αPKC, βPKC, γPKC, δPKC and εPKC isozymes in the frontal cortex of subjects with bipolar disorder

Einat et al. (2007)

Tamoxifen significantly reduced amphetamine-induced hyperactivity in a large open field without affecting spontaneous activity and normalised amphetamine-induced increase in visits to the centre of an open field (representing risk-taking behaviour); tamoxifen attenuated amphetamine- induced phosphorylation of GAP-43

Kurita et al. (2007)

At therapeutic concentrations, sodium valproate inhibited PKC in human astrocytoma cells

Kantor and Gnegy (1998)

PKC inhibitors blocked amphetamine-mediated dopamine release in rat striatal slices

Pandey et al. (2008)

PKC βI and PKC βII, but not PKCα or PKCδ, were significantly decreased in both the membrane and cytosolic fractions of platelets obtained from nonmedicated patients with bipolar disorder compared with healthy controls; pharmacotherapy significantly increased PKC activity, but not PKC isozyme levels

Modified from Zarate and Manji (2009)

PMA phorbol-12-myristate13-acetate, PKC protein kinase C, GAP-43 growth-associated protein of 43 kDa, MARKS myristoylated alanine-rich C kinase substrate, PKC protein kinase C, RACK1 receptor for activated C kinase-1

Tamoxifen, the only known centrally active PKC inhibitor available for humans (Zarate and Manji 2009), has emerged as a promising alternative antimanic agent. Preliminary clinical trials have demonstrated that tamoxifen treatment significantly decreased manic symptoms in BD patients (Bebchuk et al. 2000; Kulkarni et al. 2006), and these findings were confirmed in double-blind, placebo-controlled clinical studies (Amrollahi et al. 2011; Yildiz et al. 2008; Zarate et al. 2007), as summarised in Table 2. Despite increasing evidence in favour of the use of tamoxifen for the management of mania, reinforcing the role of PKC as a therapeutic target of mood stabilisers, its exact mechanisms of action are not yet fully elucidated, which prevents the development and/or use of drugs that share its similar therapeutic mechanisms of action.
Table 2

Clinical studies on the efficacy of tamoxifen in the treatment of bipolar disorder

Clinical studies

Outcome

Bebchuk et al. (2000)

Preliminary data from a single-blind, open-label, add-on (some patients were on no other medications) study suggest that tamoxifen may have efficacy for the treatment of acute mania

Kulkarni et al. (2006)

In a 28-day, three-arm, double-blind, lithium and/or valproate add-on study, the tamoxifen (40 mg/day) (n = 5) demonstrated antimanic effects superior to placebo (n = 4)

Zarate et al. (2007)

In a 3-week, double-blind, placebo-controlled study (n = 16), tamoxifen (up to 140 mg/day) was superior to placebo for the treatment of acute mania; lorazepam (up to 2 mg/day) was permitted for the first 10 days of the blinded phase. A significant improvement was observed as early as day 5 in YMRS scores; no significant improvement was observed in MADRS scores

Yildiz et al. (2008)

In a 3-week, double-blind, placebo-controlled study (n = 66), tamoxifen (up to 80 mg/day) was superior to placebo for the treatment of acute mania; lorazepam (up to 5 mg/day) was permitted for the entire duration of the study. A significant improvement in YMRS was reported at week 3; significant improvement was also observed in CGI and PANSS total and positive subscale scores; no significant improvement was observed with HAMD-17 and MADRS scores; individualised food preferences and enriched recreational activities were allowed

Amrollahi et al. (2011)

In a 6-week, double-blind, placebo-controlled study (n = 40), lithium (1–1.2 mEq/L) + tamoxifen (80 mg/day) was superior to lithium (1–1.2 mEq/L) + placebo for the treatment of acute mania. A significant improvement in YMRS was reported at week 6; a significant improvement was also observed in Positive and Negative Syndrome Scale total score at week 6

Modified from Zarate and Manji (2009)

CGI Clinical Global Impression Scale, HAMD-17 17-Item Hamilton Depression Rating Scale, MADRS Montgomery–Åsberg Depression Rating Scale, PANSS Positive and Negative Syndrome Scale, YMRS Young Mania Rating Scale

Animal models provide an essential tool for screening several aspects of potentially new antimanic drugs and translating these novel compounds to the behavioural realm of a whole organism (Kara and Einat 2013). Suitable animal models also allow for greater comprehension of the underlying neurobiology of a disease and/or the mechanisms by which effective medications exert their therapeutic actions (Andreatini 2002; Andreatini et al. 2006; Gould and Einat 2007). To date, we identified only eight studies in animal models of mania that have investigated the effect of tamoxifen on behavioural parameters and correlated them with biochemical aspects (identifying alterations on its direct target, PKC, or other molecular pathways) (Abrial et al. 2012; Armani et al. 2012; Cechinel-Recco et al. 2012; Einat et al. 2007; Moretti et al. 2011; Pereira et al. 2011; Sabioni et al. 2008; Steckert et al. 2012) (Table 3).
Table 3

Preclinical studies on the effects of tamoxifen in the current animal models of mania

Preclinical studies

Manipulation

Spp.

Treatment

Outcome

Einat et al. (2007)

Acute or chronic AMPH-induced ↑activity, ↑risk-taking behaviour and ↑GAP-43 phosphorylation

Rats

Acute tamoxifen

Reduced AMPH-induced ↑activity, ↑risk-taking behaviour and ↑GAP-43 phosphorylation

Sabioni et al. (2008)

Acute AMPH-induced ↑activity

Mice

Acute tamoxifen, chelerythrine and MPA

Attenuated ↑activity induced by AMPH

Pereira et al. (2011)

Acute MPH-induced ↑activity

Mice

Acute or chronic tamoxifen, MPA and clomiphene

Reversion of AMPH-induced ↑activity by tamoxifen

Moretti et al. (2011)

Chronic AMPH-induced ↑activity and ↓energy metabolism

Rats

Chronic tamoxifen

Reversed and protected AMPH-induced ↑activity, ↓activity of mitochondrial respiratory chain complexes; reversed AMPH-induced ↓creatine kinase

Armani et al. (2012)

Chronic PSD-induced ↑activity

Mice

Acute or chronic tamoxifen and lithium

Reduced PSD-induced hyperactivity

Steckert et al. (2012)

Chronic AMPH-induced ↑activity and oxidative damage

Rats

Chronic tamoxifen

Reversed and protected AMPH-induced ↑activity, ↑oxidative stress and ↓antioxidant defence parameters

Cechinel-Recco et al. (2012)

Chronic AMPH-induced ↑activity and changes on therapeutically relevant targets of lithium

Rats

Chronic tamoxifen

Reversed and protected AMPH-induced ↑activity, ↑GSK-3 and ↑PKC levels and ↓pGSK-3, ↓PKA, ↓NGF, ↓BDNF and ↓CREB levels

Abrial et al. (2012)

Acute AMPH-induced ↑activity and ↑risk-taking behaviour; acute PMA-induced ↑activity and antidepressant-like effect

Rats

Acute or chronic tamoxifen and chelerythrine

Reduced AMPH-induced ↑activity and ↑risk-taking behaviour; long-term treatment caused depressive-like behaviour and ↓hippocampal cell proliferation

Spp. specie, AMPH amphetamine, MPH methylphenidate, PSD paradoxical sleep deprivation, MPA medroxyprogesterone, GAP-43 growth-associated protein of 43 kDa, PKC protein kinase C, PMA phorbol 12-myristate 13-acetate, GSK-3 glycogen synthase kinase 3, pGSK-3 phosphorylated glycogen synthase kinase 3, PKA protein kinase A, NGF nerve growth factor, BDNF brain-derived neurotrophic factor, CREB cyclic adenosine monophosphate response element-binding protein

Thus, we aimed to describe and integrate the findings from all these preclinical studies to promote an overview of the current progress in understanding the antimanic actions of tamoxifen, highlighting the potentially important role of PKC as a therapeutic target for BD. To this end, we provide a brief prospective of the current animal models of mania and discuss possible avenues that would enhance their ability to predict potential antimanic agents that target PKC as a biochemically relevant target to treat BD mania. We also outline the involvement of PKC signalling in normal and pathological conditions, emphasising the properties of tamoxifen as a PKC inhibitor.

Animal models of mania

Animal models of psychiatric disorder are crucial for translational research, providing an efficient screening of safety, tolerability and efficacy of new medications (Kara and Einat 2013; Machado-Vieira et al. 2004). Despite its importance, modelling human neuropsychiatry diseases in other animal species is extremely difficult due to the higher cognitive aspects involved in their presentations allied with the problematic concept of modelling affect in nonhumans, the lack of biomarkers and objective diagnostic tests and the lack of complete elucidation of their aetiology and pathology. This challenge is even more pronounced in modelling BD because the oscillatory nature of the disease impairs the development of models that elicit both extreme poles, which are frequently assessed in separate models of mania or depression (Machado-Vieira et al. 2004; Nestler and Hyman 2010)

Considering that mania is a complex and heterogeneous disease comprising a much broader set of facets, a practical approach is to reduce and dissect its signs and symptoms and evaluate them separately in existing animal models (Einat 2007b). Among the different symptoms of mania, most studies have assessed increased activity in laboratory animals to model mania. Although this parameter has some limitations in modelling mania (Dencker and Husum 2010; Goodwin and Jamison 2007), hyperactivity is an objective behavioural factor that can be quickly induced, can be easily measured and is reliable in its response to the prototypic mood stabilisers lithium (Lerer et al. 1984; Smith 1981) and valproate (Kuruvilla and Uretsky 1981; Post and Weiss 1989; Shaldubina et al. 2002). Moreover, augmented activity is present in nearly all acute manic states and it is a diagnostic criterion of DSM-V for considering an individual as a manic subject (APA 2013), in addition to being a common denominator in distinct manic subgroups (Perry et al. 2009, 2010).

While hyperactivity is an important component of manic behaviour, it does not represent the entire scope of the illness (Einat 2007a, b). In this sense, the organisation of an explicit battery of tests that assess BD and other domains could encompass a number of its facets and provide a broader resemblance of this illness (Einat 2006, 2007b; Flaisher-Grinberg et al. 2009; Geyer 2008). A multiple approach is also a critical tool to filter out false-positive drugs in the hope of identifying effective antimanic agents (Einat 2007b). One aspect of mania that should be part in animal models is the cognitive domain, given that cognitive impairment has been linked to the functional outcome of mania (Torres et al. 2010), and the therapeutic efficiency of antimanic drugs is commonly evaluated by the subjective measures of rating scales (Smith et al. 2007). Objective neurocognitive domains (e.g. attention, memory and executive functioning) could then be easily and reliably rated in laboratory animals (Burdick et al. 2007; Torres et al. 2010). Additionally, BD is a highly heritable and heterogeneous disorder involving multiple genes, supporting the idea that assessing alterations in the expression of genes and proteins that are implicated in this disorder could provide a better understanding of the aetiology of BD (Gould and Einat 2007; Kato 2008; Malkesman et al. 2009).

Notably, all current animal models of mania used to evaluate the effect of tamoxifen focus only on motor activity as the univariate measurement for manic state, which impairs the assessment of its therapeutic properties on other domains of this multifaceted illness.

PKC

PKC signalling in normal or pathological conditions

PKC is a family of structurally related protein kinases that are heterogeneously distributed throughout the body. According to its distinct activation requirements (for review, see Wu-Zhang and Newton 2013), PKC was classified into at least 12 isoforms that differ in structure, subcellular localisation, tissue and substrate specificity and mode of action (Casabona 1997; Tanaka and Nishizuka 1994). Such specificity leads this enzyme to be involved in selective cellular functions (Hahn and Friedman 1999; Ohno et al. 1987), including cell cycle progression, proliferation, differentiation and apoptosis (for review, see Mellor and Parker 1998). Interestingly, PKC isozymes have unique and sometimes opposing functions in both normal signalling and disease states (Chen et al. 2001; Murriel and Mochly-Rosen 2003), allowing it to play contrasting roles in the same cell depending on the stimulation context (Basu and Pal 2010).

Growing evidence supports the key role of abnormal PKC signalling in the pathophysiology of several important human diseases (Mochly-Rosen et al. 2012). The first disease condition related to PKC isoforms and their modulation was cancer (Mackay and Twelves 2007; Totoń et al. 2011). Since then, the function of PKC has been examined in many other diseases, including cardiovascular (Churchill et al. 2008; Ferreira et al. 2011; Inagaki et al. 2006), pulmonary (Dempsey et al. 2007), immune and infectious disease (Aksoy et al. 2004; Zanin-Zhorov et al. 2011), diabetes mellitus (Das Evcimen and King 2007; Geraldes and King 2010), psoriasis (Maioli and Valacchi 2010), Parkinson's disease (Burguillos et al. 2011; Zhang et al. 2007), Alzheimer's disease (Garrido et al. 2002) and, more recently, bipolar disorder (Manji and Lenox 2000; Zarate and Manji 2009). The major challenge of these studies lies in whether a particular PKC isozyme participates in the aberrant cellular signalling of those pathologies. Importantly, elucidating PKC isoform specificity in disease is relevant to drug development, as directly targeting certain isoforms could provide a more efficient therapeutic effect (e.g. antimanic) in a discrete region, minimising adverse effects (Mochly-Rosen et al. 2012).

Protein kinase C and bipolar disorder

PKC is highly enriched in the brain, where it plays a major role in regulating neuronal excitability, neurotransmitter release, long-term alterations in gene expression and synaptic plasticity and various forms of learning and memory (Huang 1990; MacDonald et al. 2001; Newton 1995; Nishizuka 1992; Nishizuka and Nakamura 1995; Nogues 1997; Ramakers et al. 1997; Stabel and Parker 1991). Consequently, those functions regulate survival signals in a variety of cell types, including neurons (Zarate and Manji 2009). The PKC cellular signalling pathway also controls the morphology of dendritic spines in cultured neuronal synaptic preparations (Calabrese and Halpain 2005; Craske et al. 2005).

The critical role of PKC in the central nervous system (CNS) led clinical and preclinical studies to confirm the involvement of abnormal PKC activity and its substrates in the aetiology of BD, whereas the therapeutic effects of antimanic and mood-stabilising drugs could be, at least in part, due to the inhibition of PKC function (Table 1). Notably, the identification of polymorphisms that confer susceptibility to BD in the gene encoding the η isoform of diacylglycerol kinase (DGKH), which regulates members of the PKC signalling cascade, supports the involvement of PKC in this disease (Baum et al. 2008). It is also worth noting that the administration of amphetamine, a psychostimulant that elicits manic states in susceptible individuals (Fibiger 1995; Mamelak 1978; Peet and Peters 1995) and behaviours related to mania in animals (Einat 2006; Machado-Vieira et al. 2004), induces enhancement of PKC and its substrates in rodents (Cechinel-Recco et al. 2012; Einat et al. 2007; Giambalvo 1992a, b; Gnegy et al. 1993). Excessive PKC activation was suggested to inhibit prefrontal cortical behaviour regulation, possibly contributing to symptoms such as distractibility, impaired judgment and disorganised thoughts, which are characteristics of individuals affected by BD, particularly in the manic phase (Birnbaum et al. 2004).

Tamoxifen as a protein kinase C inhibitor

Several of the previously discussed reports suggest that compounds that inhibit PKC activity have antimanic actions and could be used in the treatment of BD. However, we have identified only one CNS selective inhibitor of PKC available for human use, tamoxifen. This agent has been used safely in women, men and children (Jordan 2003; Pollack et al. 1997) for the treatment of malignant glioma, a CNS disorder (Couldwell et al. 1996; Mastronardi et al. 1998), and it is fairly well tolerated, even at high doses (up to 200 mg/day) (Tang et al. 2006).

Although accumulating data have suggested that PKC inhibition is an important mechanism underlying the action of tamoxifen and is likely to be responsible for its antimanic effects, this agent is also an estrogen receptor modulator, and this female sexual hormone has been implicated in the regulation of mood and anxiety states both in woman and female rodents (for review, see Meinhard et al. 2013; Morgan et al. 2004; Walf and Frye 2006). Walf and Frye (2006) provided a detailed description of the distinct actions of estrogen levels on gender and hormonal differences and lifespan. Estrogen treatment has consistently been shown to induce hyperactivity, a behaviour associated with the manic state (Becker et al. 1987; Wade 1972; Morgan and Pfaff 2001, 2002). While the possibility that the antiestrogenic actions of tamoxifen contribute to its antimanic properties cannot be ruled out, the superiority of this agent over antiestrogenic drugs in reversing mania-like behaviour under the same experimental conditions suggests that its ability to inhibit PKC is more important for its antimanic effects (Pereira et al. 2011; Sabioni et al. 2008).

Supporting this data, administration of a more specific PKC inhibitor in different contexts also reversed mania-like behaviours (Browman et al. 1998; Cervo et al. 1997; Steketee 1993, 1994, 1997). A selective PKC inhibitor also demonstrated efficacy in nonhuman primate studies investigating cognitive deficits similar to those observed in mania (Birnbaum et al. 2004). Therefore, the contributions of antiestrogenic effects to the antimanic properties of tamoxifen seem to be minimal compared to PKC inhibition. In this sense, an overview of the current status of knowledge on tamoxifen antimanic properties may provide a view of how much is currently known and an idea of how much we still need to learn so that BD patients may benefit from treatment with PKC inhibitors.

Effects of tamoxifen in animal models of mania

Eight preclinical studies investigated the effects of tamoxifen on the behavioural and/or biochemical parameters associated with mania. Einat and colleagues (2007) carried out the first studies, which indicated the crucial role of PKC inhibition for the therapeutic effects of tamoxifen on mania-like states. They showed that amphetamine-induced activity, risk-taking behaviour and phosphorylation of the PKC substrate, growth-associated protein of 43 kDa (GAP-43), in rat striatum were reversed by tamoxifen administration. Because tamoxifen is also an estrogen modulator, two subsequent studies assessed whether its antimanic properties were due to antiestrogenic activity and/or inhibition of PKC. The fact that lithium, tamoxifen and chelerythrine (all drugs with PKC inhibition properties) completely blocked amphetamine-induced hyperlocomotion, while medroxyprogesterone (MPA, an antiestrogenic drug) only partially reduced this mania-related behaviour, suggests that PKC plays a major role in the antimanic effects of tamoxifen (Sabioni et al. 2008). Furthermore, acute or chronic treatment with MPA or clomiphene (an estrogenic receptor antagonist) was unable to reverse methylphenidate-induced hyperlocomotion, whereas both acute and chronic tamoxifen treatments effectively reversed this behaviour, suggesting that these antiestrogenic drugs had no antimanic effects in this paradigm (Pereira et al. 2011).

Data from our group also demonstrated that tamoxifen reduces hyperactivity in the paradoxical sleep deprivation (PSD) paradigm as an animal model of mania. Moreover, augmented activity as a behaviour associated with mania was normalised following combined treatment with lithium and tamoxifen at subeffective doses. This effect could be explained by the fact that both of these agents block the PKC signalling pathway (Armani et al. 2012). These results are in accordance with clinical data demonstrating that the combination of tamoxifen and lithium was superior to lithium alone for the rapid reduction of manic symptoms (Amrollahi et al. 2011).

It should be emphasised that sleep disruption is a core pathophysiological aspect of mania that exacerbates manic attacks or causes a switch from depression to mania in BD patients (Barbini et al. 1996; Colombo et al. 1999; Wehr 1991; Wehr et al. 1982, 1987). Periods of sleep deprivation can also induce PKC overactivity, leading to alterations in neuroplasticity that may contribute to the pathogenesis of a manic episode (Manji 2008; Schloesser et al. 2007; Szabo et al. 2009). In this context, the PSD paradigm has proven to be a useful tool for examining neurobiological correlates between manic reactions and sleep loss (Armani et al. 2012; Benedetti et al. 2008; Gessa et al. 1995).

The following studies proposed to assess the effects of tamoxifen on etiological factors involved in BD as a strategy to further elucidate the mechanisms underlying its therapeutic actions and pathophysiology. Based on the knowledge that reduced mitochondrial function impairs cellular energy production in BD aetiology, Moretti and colleagues (2011) reported that tamoxifen normalised the amphetamine-induced reduction in mitochondrial respiratory chain complex activity and creatine kinase activity (a pivotal enzyme related to energetic metabolism) in some brain areas. Those actions might be related to the dual role of tamoxifen as an uncoupling agent and a powerful inhibitor of electron transport, resulting in a collapse of membrane potential, and/or its estrogen restoring actions on mitochondrial respiratory function (Moretti et al. 2011; Tuquet et al. 2000; Zhao et al. 2006).

Similarly, the implication of free radical generation exceeding the capacity of antioxidant defence in the pathogenesis of BD (Kuloglu et al. 2002; Ozcan et al. 2004; Ranjekar et al. 2003) led Steckert and colleagues (2012) to investigate the potential antimanic actions of tamoxifen against cellular function impairment. They demonstrated that tamoxifen reversed and prevented amphetamine-induced locomotor activity and risk-taking behaviour, corroborating previous findings (Einat et al. 2007; Moretti et al. 2011). Additionally, increased levels of oxidative damage parameters, including superoxide, thiobarbituric acid reactive species (TBARS) and carbonyl and catalase activity in conjunction with a reduction of antioxidant enzyme superoxide dismutase, in response to amphetamine in most brain structures were reversed and prevented by tamoxifen. The neuroprotective effects of this drug against oxidative damage might be partially due to its free radical-scavenging action and antioxidant activity (Cardoso et al. 2002, 2004; Obata 2006), and/or its ability to attenuate free radical generation by normalising psychostimulant-induced dopamine oxidative catabolism (Burrows et al. 2000; Cadet et al. 2005; Deng et al. 2002), among others (Kimelberg et al. 2000; Zhao et al. 2006).

PKC inhibition by tamoxifen also modulates behaviour, neurotrophic and apoptosis pathways in common, relevant targets of lithium (Cechinel-Recco et al. 2012). Its administration attenuated the increased activity and levels of glycogen synthase kinase-3β (GSK-3) and PKC and the decreased pGSK-3, protein kinase A (PKA), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and cAMP response element-binding protein (CREB) levels induced by amphetamine in the brain. Notably, these intracellular signalling components, which are targets of mood-stabilising drugs such as lithium and valproate, have been implicated in controlling synaptic plasticity and cellular resilience of brain regions implicated in BD neurobiology. Therefore, tamoxifen targets elements involved in the emotional regulation of specific brain areas, such as anterior limbic structures (Schloesser et al. 2007).

Recently, long-term treatment with tamoxifen was reported to cause depressive-like behaviour, raising the issue of whether chronic PKC inhibition could induce depression-related effects, or a switch from mania to depression (Abrial et al. 2012). In fact, although this agent has been used continually and safely as a hormonal therapy for the prophylactic treatment of breast cancer (Jordan 1992; Karn et al. 2010), its long-term effects on mood states warrant deeper investigation. Chronic administration of tamoxifen also decreased hippocampal cell proliferation in rats, which could be explained by reduced neurons and/or glia density (Abrial et al. 2012) such as that reported in the hippocampus of postmortem brains from bipolar subjects (Benes et al. 1998; Rajkowska 2002).

Overall, the preclinical studies noted above demonstrate that tamoxifen decreases mania-like behaviours after both acute (Einat et al. 2007; Pereira et al. 2011; Sabioni et al. 2008) and chronic treatments (Abrial et al. 2012; Armani et al. 2012; Moretti et al. 2011; Steckert et al. 2012), supporting its antimanic properties and corroborating clinical trial data (Amrollahi et al. 2011; Bebchuk et al. 2000; Kulkarni et al. 2006; Yildiz et al. 2008; Zarate et al. 2007). The ability of tamoxifen to reverse manic behaviours was independent of whether the inducing agent was a psychostimulant (Einat et al. 2007; Pereira et al. 2011; Sabioni et al. 2008) or PSD (Armani et al. 2012). The reproducible ability of tamoxifen to normalise hyperactivity under the same experimental protocols and mimic the acute treatment or prevention phase of BD, named reversion and prevention treatment, respectively (Frey et al. 2006), supports the robustness of its antimanic properties (Cechinel-Recco et al. 2012; Moretti et al. 2011; Steckert et al. 2012). However, the fact that all of the animal models of mania currently used to evaluate the antimanic properties of tamoxifen rely on motor activity as the primary behavioural outcome may bias the assessment of its systemic effects on other BD domains.

Tamoxifen administration per se induces alterations on parameters of energetic metabolism (Moretti et al. 2011), oxidative stress measures (Steckert et al. 2012) and therapeutically relevant targets of lithium (Cechinel-Recco et al. 2012), which may contribute to the lack of its full antimanic effects on these etiological factors. For a drug to be considered a treatment agent, it should reverse a stimulant-induced pathological symptom, such as normalisation of hyperactivity, rather than simply reduce this facet irrespective of prior treatment (Young et al. 2011). Thus, it is difficult to assume that the tamoxifen-mediated effects of PKC inhibition on psychostimulant-treated animals were due to the reversal or preventative effects or simply nonspecific modification on these markers.

Ultimately, additional studies are required to elucidate the antimanic effects of tamoxifen and to develop and/or use drugs that share its therapeutic properties, specifically regarding the ability of this agent to inhibit PKC as a relevant therapeutic target for treating BD.

Conclusions

Tamoxifen has proven to be a potential antimanic agent in both clinical and preclinical studies, and several studies have related this therapeutic action to PKC inhibition. Despite our progress in understanding the mechanisms underlying the neurobiology and antimanic properties of tamoxifen by assessing the effects of tamoxifen on the behaviour and biochemical parameters related to BD mania in animal models, its systemic actions, including PKC inhibition, on BD domains other than motor activity remain unclear. In this sense, additional studies conducting an organised and explicit battery of tests that are able to assess a different set of mania facets, including neurocognitive and genetic factors, might provide a broader understanding of the antimanic effects of tamoxifen. Further knowledge of this subject may benefit patients suffering from BD through the use of current or novel drugs that share the same therapeutically relevant target of tamoxifen, PKC.

Acknowledgments

We would like to declare our deepest appreciation for the critical input and contributions of Prof. Roberto Frussa-Filho (in memoriam).

Conflict of interest

All researchers listed in the present study reported no biomedical financial interests or potential conflicts of interest.

Copyright information

© Springer-Verlag Berlin Heidelberg 2014