Psychiatry and Clinical Psychopharmacology 2021;31(3):344-352

REVIEW ARTICLE
DOI:10.5152/pcp.2021.21817

The Use of Tamoxifen as a Potential Treatment for Bipolar

Disorder
Noy Bagdadi1 , Abed N. Azab2,3 , Rachel Shvartsur2,3

1
Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Israel; 2Department of Clinical
Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Israel; 3Department of Nursing, Ben-Gurion University of
the Negev, Israel

ABSTRACT ARTICLE HISTORY

Bipolar disorder (BD) is a chronic mental disease that substantially affects the patient’s quality of life Received: April 3, 2021
and causes significant morbidity and mortality. Although there are a variety of available treatments, Accepted: April 18, 2021
therapeutic intervention is not beneficial in many cases and recurrence rates remain high. Recent data
suggested tamoxifen, a drug with a wide range of activities, as a potential treatment for reducing
manic symptoms of BD. Tamoxifen’s therapeutic effect on bipolar mania has not been fully elucidated, KEYWORDS: Antimanic
but it is believed to biochemically operate on protein kinase C (PKC) inhibition. In this article, we treatment, bipolar disorder,
review preclinical and clinical studies investigating the efficacy of tamoxifen as a potential treatment mania, protein kinase C,
for bipolar manic patients. tamoxifen

BIPOLAR DISORDER

Bipolar disorder (BD) is a chronic mental disease, well as for preventing recurrence of mood symptoms
characterized by alternating episodes of mania and (maintenance therapy). Occasionally, other treatments are
depression of varying severity, each radical state impairing added to help stabilize the patient during the acute and
social and personal functioning.1 The manic episodes the chronic phases of the disease.1,5-7
include symptoms such as euphoria, aggressive behavior, A variety of cellular pathways are affected by mood-
and increased motor and sexual activity. Depression modulating drugs,1,8-10 making it difficult to elucidate which
episodes are characterized by feelings of worthlessness, of them is most relevant to their therapeutic efficacy. Given
suicidal thoughts, altered appetite, and decreased interest that the mechanism of mood-modulating drugs is poorly
in pleasurable activities, among other features.1 BD affects understood, the development of better-suited medication
approximately 1% of the world population and is the sixth is complex.
leading cause of disability.2 The substantial morbidity and
Although medications such as lithium, valproate, and
mortality rates associated with BD are not only a result of
antipsychotic drugs were proven as effective agents
the illness itself and its immediate ramifications, but are
in treating bipolar patients,1,5,6,11 there are many
also due to the rampant comorbidity quotient among this
patients who do not respond to these treatments, some
population; they are high risk for a wide range of medical
experiencing severe side effects increasing the burden
illnesses, especially cardiovascular diseases and metabolic
of the disease, and in turn, impelling low-adherence
disorders.3,4 Several hypotheses have been proposed
to treatment.12,13 Many patients suffer high recurrence
explaining the biological basis of BD; however, a clear
rates and chronicity of symptoms.5-7,14 In addition, the
pathophysiological mechanism remains elusive.
effectiveness of most of these medications is minimal in
The pharmacotherapy of BD consists of various some areas, such as ameliorating cognitive function and
medications, including salts of the monovalent suicidal thoughts.15 Thus, finding adequate and better-
cation lithium, antiepileptic drugs (e.g., valproate, tolerated treatments for BD is an urgent need.16 In
carbamazepine, and lamotrigine), and antipsychotics recent years, intracellular signaling cascades have been
(e.g., chlorpromazine, haloperidol, clozapine, olanzapine, studied extensively, revealing that the protein kinase
and quetiapine).1,5-7 Mood-stabilizers and antipsychotic C (PKC) signaling pathway is an important factor in the
drugs are given during acute episodes of the disease as pathophysiology and treatment of BD.17-26 In this review,

Corresponding author: Rachel Shvartsur, e-mail: shvartsu@post.bgu.ac.il

Cite this article as: Bagdadi N, Azab AN, Shvartsur R. The use of tamoxifen as a potential treatment for bipolar disorder. Psychiatr Clin
Psychopharmacol. 2021;31(3):344-352.

Content of this journal is licensed under a Creative Commons

Attribution-NonCommercial 4.0 International License.
 Psychiatry and Clinical Psychopharmacology

we focus on the non-selective PKC inhibitor tamoxifen as a the calmodulin-cAMP phosphodiesterase suggest different
potential treatment for BD. pathways of biological processes that are not estrogen
receptor-dependent.46
PKC
METHODS
PKC is a family of kinases among the largest superfamilies
of several highly conserved proteins regulating a vast This is a narrative review. The search strategy was
range of cellular activities.27 Proteins from this family are designed by the authors and conducted based on criteria
widely distributed throughout the human body. Abnormal as follows: using the keyword tamoxifen in conjunction
activity in PKC signaling may result in severe alterations in with each one of the following words: BD, mania,
physiological functions, leading to diseases such as cancer, depression, mental illness, psychiatry, PKC. We searched
Parkinson’s disease, Alzheimer’s disease, immune and for published articles in PubMed, Google, and Google
infectious disorders, among others.28 Scholar up to December 2020. The search was limited to
studies published in English.
Numerous studies have shown that there is an association
between alterations in the PKC signaling pathway and
the pathophysiology of BD.29-31 PKC regulates neuronal ANTI-MANIC EFFECTS OF TAMOXIFEN
signaling by affecting excitability, neurotransmitter
release, receptor regulation, synaptic remodeling, and Preclinical Studies
gene expression.32 It was found to be highly expressed in There are several animal behavioral models that mimic
the prefrontal cortex, hippocampus, and amygdala––brain human mania. Mania-like behavior is achieved by
regions that are involved in regulation of emotions and pharmacological (administration of stimulants such as
mood.33 amphetamine), environmental (rodent sleep deprivation,
the resident intruder test, and the dominant–submissive
TAMOXIFEN behavior paradigms), and genetic interventions.47
Although these models do not fulfill all validity criteria,
Tamoxifen is an effective antitumor agent with low they are considered a valuable tool for the screening of
toxicity,34,35 and as such, it is an extensively used drug new mood-stabilizing compounds.28 Several studies have
in all stages of breast cancer and is also given in cases shown that treatment with tamoxifen decreased mania-
where women are at high risk for breast cancer.36 It like effects induced by amphetamine in rats, similar to
was first approved by the United States Food and Drug lithium and valproate.48-50 Tamoxifen-treated rats showed
Administration in 1977 for the treatment of women a decrease in PKC activity, which was accompanied by
in advanced stages of breast cancer.37 The antitumor a reduction in amphetamine-induced hyperactivity and
properties of tamoxifen are attributed to its competitive risk-taking behavior (a parameter of mania-like behavior
blocking of estrogen receptors.38 As a result of tamoxifen in rodents).48-51 It was found that amphetamine enhanced
binding to the estrogen receptor, there is consequent the activity of PKC, whereas pretreatment with tamoxifen
inhibition of estrogen-regulated gene expression; eliminated the effect of amphetamine on PKC and on
growth factors and angiogenic factors that are normally rats’ behavior.48 Another substrate of PKC that plays an
regulated by estrogen are demonstrably inhibited as well. important role in manic-like behavior is myristoylated
The result of this cascade is blocking of the cell cycle alanine-rich C kinase substrate (MARCKS).52 Rats submitted
in the G1 phase and an interruption in cell proliferation to amphetamine induction and sleep deprivation showed
rate.39,40 an increase in MARCKS phosphorylation in the frontal
In synthesis with its effect on estrogen receptors, tamoxifen cortex, suggestive of an important role of MARCKS in
appears to have additional cellular causata. For example, manic-like behavior.52 Valvassori et al.53 demonstrated
at certain concentrations, tamoxifen inhibits PKC.41 The that intracerebroventricular injection of ouabain, a
inhibition of PKC activity is by two independent pathways–– specific inhibitor of the Na+/K+-adenosine-triphosphatase,
allosteric inhibition, and inhibition of the fully stimulated caused an increase in MARCKS phosphorylation in the
enzyme through binding to its active site instead of frontal cortex and hippocampus of rats, inducing manic-
ATP.41 Tamoxifen was also found to be a competitive like behavior. Tamoxifen reversed the ouabain-induced
inhibitor of calmodulin-dependent enzymes such as cAMP increase in MARCKS phosphorylation in rats’ frontal
phosphodiesterase.42 The mechanism of this inhibition is cortex and the behavioral changes.53 Subsequent studies
not yet clear, and it is not known whether tamoxifen binds showed that despite the positive effects of tamoxifen on
to calmodulin itself or to the calmodulin binding site of ouabain-induced mania-like behavior, it did not reverse
cAMP phosphodiesterase.43 Both PKC and calmodulin play the oxidative damage caused by ouabain.54 These results
critical roles in transmembrane signaling and cell growth suggest that the antimanic effects of tamoxifen are not
regulation.44,45 The interactions of tamoxifen with PKC and due to inhibition of oxidative stress.

345
 Bagdadi et al.

Moreover, the administration of amphetamine is reduction of cell proliferation in the hippocampus were
associated with mitochondrial damage and inhibition of seen after chronic administration of tamoxifen in healthy
creatine kinase.55-58 Treatment with tamoxifen reversed rats.66
the mitochondrial damage and inhibition of creatine
Furthermore, it was shown that amphetamine induces
kinase induced by amphetamine.49 Interestingly, the mood
50 kHz ultrasonic vocalizations (USV) in rats,67-69 and
stabilizers lithium and valproate—which conjointly inhibit
that treatment with lithium, tamoxifen, and myricitrin
PKC8,22—also attenuated mitochondrial damage,59 but did
(a PKC inhibitor) reversed amphetamine-induced USV,
not reverse the inhibition of creatine kinase.56 It was shown
suggesting that USV may serve as a sensitive marker to
that creatine kinase is involved in the estrogen receptor
model exaggerated euphoric mood.70 Another possible
cascade, indicating that tamoxifen may treat mania via
positive therapeutic effect of tamoxifen in relation to BD
PKC inhibition and via estrogen receptor as well.60 However,
treatment was observed in the study by Tinsgov et al.,71 in
Pereira et al.61 showed that, in contrast to tamoxifen,
which tamoxifen attenuated lithium-induced polyuria in
other anti-estrogenic drugs (such as medroxyprogesterone
rats. This suggests that tamoxifen might represent a novel
and clomiphene) did not reverse amphetamine-induced
therapeutic approach for patients with lithium-induced
hyperactivity, either in acute or in chronic administration,
nephrogenic diabetes insipidus.
suggesting that the antimanic effect of tamoxifen derives
mainly from its PKC inhibitory activity rather than its anti- Clinical Studies
estrogenic effect.
The results of the included clinical studies are presented
A possible explanation for the link between mitochondrial in Table 1. The first study conducted on patients with
damage and BD may be the fact that mitochondrial acute mania was carried out in 2000 by Bebchuk et al.72
activity is coupled with the tricarboxylic acid (TCA) cycle. It included 5 male and 2 female subjects, aged 18-65
Hence, the inactivation of any step in the cycle can impair years, diagnosed with BD and bearing no other psychiatric
mitochondrial activity. Valvassori et al.62 showed that the disorders. Treatment with tamoxifen (up to 80 mg daily)
administration of amphetamine inhibited the TCA cycle showed a significant decrease in manic symptoms rated by
enzymes and that tamoxifen treatment reversed this the Young Mania Rating Scale (YMRS). Five of 7 patients
effect of amphetamine. In addition, a negative correlation had more than a 50% decrease in the YMRS score. The
between amphetamine-induced hyperactivity and the Hamilton Depression Rating Scale (HAMD) did not show
activity of TCA cycle enzymes was observed. a consistent change over time. Overall, the treatment
was well tolerated; only 1 patient reported flushing
Evaluation of other biochemical targets of lithium, such
during dose titration.72 The second study, by Kulkarni et
as glycogen synthase kinase (GSK)-3β, PKC, protein kinase
al.,73 included 13 women with acute BD episodes who
A (PKA), cAMP response element-binding protein (CREB),
participated in a comparative 28-day trial. All patients had
brain-derived neurotrophic factor (BDNF), and nerve
a baseline treatment that consisted of lithium, valproate,
growth factor (NGF) in the amygdala and in different
or both. In this trial, tamoxifen (40 mg/day) was added
areas of the anterior limbic brain showed increased PKC
to the standard treatment and compared to a synthetic
and GSK-3β levels and decreased phospho-GSK-3β, PKA,
progesterone medroxyprogesterone acetate (MPA) (20 mg/
NGF, BDNF, and CREB levels in amphetamine-treated
day), and a placebo. The tamoxifen group showed a
mice.51 Treatment with lithium and tamoxifen reversed
significant decrease in mania symptoms in comparison
these amphetamine-induced effects, indicating their
to the placebo group. The MPA group also showed an
influence on cellular plasticity cascades in addition to their
improvement.73 In the next study, 16 patients with BD
effect on behavior.51 Contrastingly, a study evaluating the
(14 men and 2 women), aged 18-65 years, were divided
effects of long-term treatment (28 days) with tamoxifen
randomly into 2 groups.74 One group received tamoxifen
reported decreased levels of BDNF in the hippocampus of
(up to 140 mg/day) and the other received a placebo.
both male and female rats and decreased levels of NGF in
On day 5, the tamoxifen-treated group started to show
the hippocampus of female rats, suggesting that long-term
a significant improvement from baseline, demonstrating
tamoxifen treatment may lead to negative cellular effects
the rapid effect of tamoxifen in comparison to previously
and possibly cognitive impairments.63
shown effects of mood stabilizers. At the end of the trial,
The effect of tamoxifen on mania-like behavior was also 5 of the 8 patients in the tamoxifen group had more than
examined under the paradoxical sleep deprivation (PSD)- 50% improvement in the YMRS score, while in the placebo
induced hyperactivity model. Tamoxifen and lithium group only 1 patient showed a similar improvement. The
administrated separately and combined reversed PSD- treatment was overall well tolerated, except for the loss
induced hyperactivity.64 PSD was also found to trigger of appetite which was significantly higher in the tamoxifen
hippocampal cell proliferation deficits and the effect group.74 Another study75 included 66 patients, aged 18-60
was reversed by the PKC inhibitors tamoxifen and years, diagnosed with bipolar 1 disorder and randomly
chelerythrine.65 Interestingly, depressive-like behavior and divided into 2 groups: 1 group received tamoxifen (up

346
 Table 1. Clinical Studies on the Efficacy of Tamoxifen in the Treatment of Bipolar Disorder
Duration,
Study Disorder Study Design Sample Size Drug Test Adverse Effects Outcome
Weeks
Ahmad et al.79 (2016) Manic or mixed Double-blind, 84 Endoxifen or valproate 3 YMRS No reports The efficcacy of
episode active- endoxifen was similar
controlled trial to that of valproate
Fallah et al.81 (2016) Manic episode Double-blind 44 Tamoxifen+lithium or 3 YMRS Dry mouth Lithium+tamoxifen was
Children, placebo- placebo+lithium superior to
adolescents controlled RCT lithium+placebo
Kulkarni et al.78 Manic episode or 3-arm, double- 51 Tamoxifen/MPA or 4 CARS-M No reports Tamoxifen was superior
(2014) schizoaffective blind RCT placebo adjunct to to placebo. The effect
disorder lithium or valproate occurred significantly
faster in the MPA
group in comparison
to the tamoxifen/
control group
Amrollahi et al.77 Manic episode Double-blind, 40 Tamoxifen+lithium or 6 YMRS Fatigue Lithium+tamoxifen was
(2011) placebo- placebo+lithium superior to
controlled RCT lithium+placebo
Yildiz et al.75 (2008) Manic or mixed Double-blind RCT 66 Tamoxifen or placebo 3 YMRS No reports Tamoxifen was superior
episode to placebo for the
treatment of acute
mania
Zarate et al.74 (2007) Manic or mixed Double-blind RCT 16 Tamoxifen or placebo 3 YMRS, PANSS Loss of appetite Tamoxifen was superior
episode to placebo for the
treatment of acute
mania
Kulkarni et al.73 Manic episode 3-arm, double- 13 Tamoxifen/MPA or 4 CARS-M No reports Tamoxifen demonstrated
(2006) blind RCT placebo adjunct to antimanic effects
lithium or valproate superior to placebo
Bebchuk et al.72 Manic episode Single-blind, 7 Tamoxifen 2 YMRS Flushing during Preliminary results.
(2000) open-label, (monotherapy or dose titration Tamoxifen may have
add-on add-on) efficacy for the
treatment of acute
mania
MPA, synthetic progesterone medroxyprogesterone acetate; YMRS, Young Mania Rating Scale; CARS-M, Clinician-Administered Rating Scale for Mania; PANSS, Positive and Negative
Syndrome Scale.
Psychiatry and Clinical Psychopharmacology

347
 Bagdadi et al.

to 80 mg/day) and the other received a placebo. The affinity and specificity to estrogen receptors. Moreover,
tamoxifen group showed a decrease in YMRS every week endoxifen has a 4-fold higher potency in inhibiting PKC
while the placebo group showed an increase. At the activity compared with tamoxifen.80 In the Ahmad et al.79
end of the trial, 48% of the tamoxifen group had a 50% trial, 84 patients with mania or mixed state were treated
or more decrease in YMRS score, as compared to 5% in for 21 days with endoxifen (4 or 8 mg/day) or valproate
the placebo group.75 Significant improvements were also (extended release tablets of 1000 mg/day) in a 2 : 1 ratio,
seen in the Positive and Negative Syndrome Scale (PANSS). respectively. A significant decrease in YMRS score was
However, no significant improvements were observed in observed in the endoxifen group from day 4 of treatment.
HAMD-17 and Montgomery-Åsberg Depression Rating Scale The effect remained significant throughout 21 days. The
(MADRS). Overall, the treatment was well tolerated and efficcacy of endoxifen in mitigating manic symptoms was
there were no reports of any serious adverse events.75 An found similar to that of valproate. Additionally, endoxifen
interesting case report supported the previous findings was well tolerated by patients.80
attesting for the mood-stabilizing effect of tamoxifen.76 A
The aforementioned studies explored the effects of
44-year-old woman with a diagnosis of a schizoaffective
tamoxifen in adult patients. In this regard, a study was
disorder which manifested after the birth of her second
conducted aiming to measure the effect of tamoxifen
child participated in a 28-day trial of tamoxifen (40 mg/
in children and adolescents as an adjunctive treatment
day) treatment. The woman stopped taking her usual
of lithium.81 Totally 44 patients aged 9-20 years and
medications 3 weeks prior to the beginning of the trial.
diagnosed with acute mania were randomly allocated
At the beginning of the trial, she had moderate manic
to treatment with lithium+tamoxifen (up to 40 mg/
symptoms and moderate depressive symptoms. After 1
day) or lithium+placebo. A significant decrease in YMRS
week, a reduction in her manic symptoms was observed,
score was observed in the adjunctive tamoxifen treatment
and by week 4, the reduction was significant. In addition,
group compared to the placebo treatment group. The
the patient’s depressive symptoms remained stable (did
significant difference between the groups was observed
not increase) during the trial.76
after the first week and remained until the end of the
trial. No side effects were reported, except dry mouth,
Amrollahi et al.77 tested the efficacy of tamoxifen as an
in the lithium+tamoxifen group.81 Two meta-analyses of
adjunctive treatment to lithium.77 In the study, 40 patients
5 randomized controlled trials that evaluated the efficacy
aged 19-49 years with current manic episodes were randomly
of tamoxifen on manic episodes concluded that tamoxifen
assigned to 2 groups for a 6-week trial. The first group
as monotherapy or add-on to the standard therapy is
received lithium+tamoxifen (80 mg/day) and the second
efficacious and generally well tolerated.30,82 However,
group received lithium+placebo. At the end of the trial, the
the total number of participants was relatively low
lithium+tamoxifen group showed a significant improvement
(N = 186) with only short duration of follow-up (3-6 weeks).
in their YMRS scores compared to the lithium+placebo
The authors therefore conclude that more studies are
group. There was also a significant difference in the
needed in order to establish its long-term efficacy, side
percentage of patients who showed a reduction of 50%
effects, and effective doses.30,82
or more in the YMRS score; this difference was observed
as early as week 1 (50% in the lithium+tamoxifen group,
15% in the lithium+placebo group) and at the end of the DISCUSSION
trial (95% in the lithium+tamoxifen group, 70% in the
lithium+placebo group). At week 6, a significant difference The results of the studies summarized above support
was observed in the PANSS, but not in the HAMD-17 score. the hypothesis that the PKC inhibitor tamoxifen has an
Side effects did not differ significantly between the anti-manic effect in BD patients. Overall, tamoxifen
groups, except for fatigue that occurred more frequently was well tolerated and no severe side effects were
in the lithium+tamoxifen group.77 Another study by reported. Mostly, the therapeutic effects of tamoxifen
Kulkarni et al.78 reported surprising results. In this 28-day appeared more rapidly than those seen with lithium
trial, 51 women with a diagnosis of schizoaffective disorder or valproate. Although the results of the preclinical
or BD were divided randomly to receive tamoxifen (40 mg/ and clinical studies are promising, there is a need for
day), MPA (20 mg/day), or a placebo. The experimental future randomized, placebo-controlled studies with
treatment was given in addition to standard treatment. larger sample sizes to test the efficacy of tamoxifen
All groups showed a reduction in symptoms over time, monotherapy among BD patients. Moreover, since mood
however, this decrease occurred significantly faster in the disorders require continued pharmacological treatment
MPA group in comparison to the tamoxifen and the control throughout patients’ lives, it is important to examine
group.78 In 2016, Ahmad et al.79 performed a double-blind, the long-term effects of tamoxifen on various body
active-controlled trial to study the efficacy and safety systems. For example, it is necessary to examine the
of endoxifen in the treatment of patients with BD I. effects of tamoxifen on the occurrence of endometrial
Endoxifen is an active metabolite of tamoxifen with higher cancer,83-87 depressive symptoms,88-90 cognitive

348
 Psychiatry and Clinical Psychopharmacology

impairment,91-94 and increased risk of thromboembolic REFERENCES

events.84,87 For instance, it has been reported that
tamoxifen treatment was associated with an increased 1. Belmaker RH. Bipolar disorder. N Engl J Med.
risk of endometrial cancer.83-87 A meta-analysis of the 2004;351:476-486. [CrossRef]
breast cancer prevention trials found that tamoxifen 2. Murray CJ., Lopez A. D . The Global burden of disease :
a comprehensive assessment of mortality and disability
therapy increased the risk of endometrial cancer about
from diseases, injuries, and risk factors in 1990 and
2.4-fold when compared with placebo treatment.84 In projected to 2020 . 1996. Boston: Harvard School of
addition, endometrial cancers appear sooner in those Public Health. https://apps.who.int/iris/handle/10665/
administered tamoxifen than in non-tamoxifen users.86 41842.
Research literature addressing the association between 3. Krishnan KRR. Psychiatric and medical comorbidities of
depression and tamoxifen suggests that this relationship bipolar disorder. Psychosom Med. 2005;67:1-8.
may exist. Tamoxifen has been reported to affect mood, [CrossRef]
with some patients needing to discontinue tamoxifen 4. Kupfer DJ. The increasing medical burden in bipolar
treatment secondary to depression.88-90 In contrast, disorder. J Am Med Assoc. 2005;293:2528-2530. [CrossRef]
5. Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder.
other studies found no association between tamoxifen
Lancet. 2016;387:1561-1572. [CrossRef]
and depression.95-98 The potential effects of tamoxifen on 6. Sachs GS, Dupuy JM, Wittmann CW. The pharmacologic
cognition are uncertain.91-94,99 Few studies have suggested treatment of bipolar disorder. J Clin Psychiatry.
an association between tamoxifen and cognitive problems 2011;72:704-715. [CrossRef]
in women treated for breast cancer.91-94 Women on long- 7. Baldessarini RJ, Tondo L, Vázquez GH. Pharmacological
term tamoxifen treatment reported diminished cognitive treatment of adult bipolar disorder. Mol Psychiatry.
functioning.94 Furthermore, tamoxifen users showed 2019;24:198-217. [CrossRef]
specific impairments in processing speed,92 verbal 8. Chen G, Manji HK, Hawver DB, Wright CB, Potter WZ.
memory,92,93 and executive functioning,93 compared to Chronic sodium valproate selectively decreases protein
kinase C α and ε in vitro. J Neurochem. 1994 ;63:2361-
healthy post-menopausal women. However, contradicting
2364. [CrossRef]
findings have also been published.99 Studies evaluating 9. Manji HK, Moore GJ, Chen G. Lithium at 50: Have the
the side effects of tamoxifen in male breast cancer neuroprotective effects of this unique cation been
patients reported a higher tendency to experience side overlooked? Biol Psychiatry. 1999;46:929-940. [CrossRef]
effects and as a result, higher discontinuation rates.100- 10. Phiel CJ, Zhang F, Huang EY, et al. Histone deacetylase
102
The most common side effects were a decrease in is a direct target of valproic acid, a potent anticonvulsant,
libido, weight gain, and hot flashes, followed by mood mood stabilizer, and teratogen. J Biol Chem.
alterations, depression, insomnia, and deep venous 2001;276:36734-36741. [CrossRef]
thrombosis.100-102 A fifth of the patients terminated 11. Goodwin FK, Jamison KR. Manic-Depressive Illness :
Bipolar Disorders and Recurrent Depression. 2nd ed.
tamoxifen treatment in less than 1 year due to these side
Oxford University Press; Oxford; 2007:729-785.
effects.100-102 Therefore, further exploration of the effects 12. Gitlin M. Treatment-resistant bipolar disorder. Mol
of tamoxifen is necessary in order to provide a broader Psychiatry. 2006 March;11:227-240. [CrossRef]
understanding of its therapeutic effect and toxicity 13. Nierenberg AA. A critical appraisal of treatments for
profile before it can be recommended as a mainstream bipolar disorder. Prim Care Companion J Clin Psychiatry.
treatment for BD. 2010;12:23-29. [CrossRef]
14. Calabrese JR, Shelton MD, Rapport DJ, et al. A 20-month,
CONCLUSION double-blind, maintenance trial of lithium versus
divalproex in rapid-cycling bipolar disorder. Am J
Tamoxifen may be a possible therapeutic intervention in Psychiatry. 2005;162:2152-2161. [CrossRef]
manic bipolar patients. Randomized, placebo-controlled, 15. Alda M, Hajek T, Calkin C, O’Donovan C. Treatment of
bipolar disorder: New perspectives. Ann Med.
double-blind trials are nessecary to determine the long-
2009;41:186-196. [CrossRef]
term efficacy and safety of tamoxifen as a treatment for 16. Machado-Vieira R, Salvadore G, DiazGranados N, et al.
manic bipolar patients. New therapeutic targets for mood disorders.
ScientificWorldJournal. 2010;10:713-726. [CrossRef]
Peer Review: Externally peer-reviewed. 17. Wang HY, Friedman E. Lithium inhibition of protein
Author Contributions: Literature Search - N.B., A.N.A, kinase C activation-induced serotonin release.
R.S.; Writing - N.B., A.N.A, R.S.; Critical Reviews - N.B., Psychopharmacol (Berl). 1989;99:213-218. [CrossRef]
A.N.A, R.S. 18. Giambalvo CT. Protein kinase C and dopamine transport-2.
Effects of amphetamine in vitro. Neuropharmacology.
Conflict of Interest: The authors have no conflicts of 1992 ;31:1211-1222. [CrossRef]
interest to declare. 19. Giambalvo CT. Protein kinase C and dopamine transport-1.
Financial Disclosure: The authors declared that this study Effects of amphetamine in vivo. Neuropharmacology.
has received no financial support. 1992 ;31:1201-1210. [CrossRef]

349
 Bagdadi et al.

20. Friedman E, Hoau-Yan-Wang, Levinson D, Connell TA, derivatives. Eur J Med Chem. 2018 ;143:515-531.
Singh H. Altered platelet protein kinase C activity in [CrossRef]
bipolar affective disorder, manic episode. Biol Psychiatry. 36. Jordan VC. Tamoxifen: a personal retrospective. Lancet
1993;33:520-525. [CrossRef] Oncol. 2000;1:43-49. [CrossRef]
21. Gnegy ME, Hong P, Ferrell ST. Phosphorylation of 37. Cohen MH, Hirschfeld S, Flamm Honig SF, et al. Drug
neuromodulin in rat striatum after acute and repeated, approval summaries: arsenic trioxide, tamoxifen citrate,
intermittent amphetamine. Brain Res Mol Brain Res. Anastrazole, paclitaxel, bexarotene. Oncologist.
1993;20:289-298. [CrossRef] 2001;6:4-11. [CrossRef]
22. Manji HK, Etcheberrigaray R, Chen G, Olds JL. Lithium 38. Osborne C, Elledge R, SAW F. Estrogen receptors in
decreases membrane‐associated protein kinase C in breast cancer therapy. Sci Med. 1996;3:32-41.
hippocampus: selectivity for the α isozyme. J Neurochem. 39. Arteaga CL, Osborne CK. Growth factors as mediators
1993 ;61:2303-2310. [CrossRef] of estrogen/antiestrogen action in human breast
23. Manji HK, Bersudsky Y, Chen G, Belmaker RH, Potter WZ. cancer cells. Cancer Treat Res. 1991;53:289-304.
Modulation of protein kinase C isozymes and substrates [CrossRef]
by lithium: the role of myo-inositol. 40. Lippman ME., Dickson RB, eds. Regulatory mechanisms
Neuropsychopharmacology. 1996 ;15:370-381. in breast cancer. Cancer Treat Res. Kluwer Academic
[CrossRef] Publishers, Boston. 2012.
24. Cervo L, Mukherjee S, Bertaglia A, Samanin R. Protein 41. O’brian CA, Ward NE, Anderson BW. Role of specific
kinases A and C are involved in the mechanisms interactions between protein kinase C and
underlying consolidation of cocaine place conditioning. triphenylethylenes in inhibition of the enzyme. J Natl
Brain Res. 1997;775:30-36. [CrossRef] Cancer Inst. 1988;80:1628-1633. [CrossRef]
25. Birnbaum SG, Yuan PX, Wang M, et al. Protein kinase C 42. Huai-De S, Mazzei GJ, Vogler WR, kuo JF. Effect of
overactivity impairs prefrontal cortical regulation of tamoxifen, a nonsteroidal antiestrogen, on phospholipid/
working memory. Science. 2004;306:882-884. [CrossRef] calcium-dependent protein kinase and phosphorylation
26. Lenox RH, Watson DG, Patel J, Ellis J. Chronic lithium of its endogenous substrate proteins from the rat brain
administration alters a prominent PKC substrate in rat and ovary. Biochem Pharmacol. 1985;34:3649-3653.
hippocampus. Brain Res. 1992;570:333-340. [CrossRef] [CrossRef]
27. Kazi JU, Kabir NN, Soh JW. Bioinformatic prediction and 43. Lam HYP. Tamoxifen is a calmodulin antagonist in the
analysis of eukaryotic protein kinases in the rat genome. activation of cAMP phosphodiesterase. Biochem Biophys
Gene. 2008;410:147-153. [CrossRef] Res Commun. 1984;118:27-32. [CrossRef]
28. Armani F, Andersen ML, Galduróz JCF. Tamoxifen use for 44. O’Brian CA, Liskamp RM, Solomon DH, Weinstein IB.
the management of mania: a review of current preclinical Inhibition of protein kinase C by tamoxifen . Cancer Res.
evidence. Psychopharmacol (Berl). 2014;231:639-649. 1985;45:2462-2465.
[CrossRef] 45. Means AR, Tash JS, Chafouleas JG. Physiological
29. Manji HK, Lenox RH. Long‐term action of lithium: a role implications of the presence, distribution, and regulation
for transcriptional and posttranscriptional factors of calmodulin in eukaryotic cells. Physiol Rev. 1982;
regulated by protein kinase C. Synapse. 1994;16:11-28. 62:1-39. [CrossRef]
[CrossRef] 46. O’Brian CA, Ioannides CG, Ward NE, Liskamp RM.
30. Talaei A, Pourgholami M, Khatibi-Moghadam H, et al. Inhibition of protein kinase C and calmodulin by the
Tamoxifen: a protein kinase C inhibitor to treat mania geometric isomers cis‐ and trans‐tamoxifen. Biopolymers.
a systematic review and meta-analysis of randomized, 1990 ;29:97-104. [CrossRef]
placebo-controlled trials. J Clin Psychopharmacol. 47. Sharma AN, Fries GR, Galvez JF, et al. Modeling mania
2016;36:272-275. [CrossRef] in preclinical settings: a comprehensive review. Prog
31. Zarate CA, Manji HK. Protein kinase C inhibitors: Neuropsychopharmacol Biol Psychiatry. 2016;66:22-34.
rationale for use and potential in the treatment of [CrossRef]
bipolar disorder. CNS Drugs. 2009;23:569-582. [CrossRef] 48. Einat H, Yuan P, Szabo ST, Dogra S, Manji HK. Protein
32. Amadio M, Battaini F, Pascale A. The different facets of kinase C inhibition by tamoxifen antagonizes manic-like
protein kinases C: old and new players in neuronal signal behavior in rats: implications for the development of
transduction pathways. Pharmacol Res. Academic Press; novel therapeutics for bipolar disorder.
Cambridge. 2006;54:317-325. [CrossRef] Neuropsychobiology. 2007;55:123-131. [CrossRef]
33. Naik MU, Benedikz E, Hernandez I, et al. Distribution of 49. Moretti M, Valvassori SS, Steckert AV, et al. Tamoxifen
protein kinase M? and the complete protein kinase C effects on respiratory chain complexes and creatine
isoform family in rat brain. J Comp Neurol. 2000;426:243- kinase activities in an animal model of mania. Pharmacol
258. [CrossRef] Biochem Behav. 2011 April ;98:304-310. [CrossRef]
34. Powles TJ, Hardy JR, Ashley SE, et al. A pilot trial to 50. Steckert AV, Valvassori SS, Mina F, et al. Protein kinase
evaluate the acute toxicity and feasibility of tamoxifen C and oxidative stress in an animal model of mania. Curr
for prevention of breast cancer. Br J Cancer. 1989; Neurovasc Res. 2012;9:47-57. [CrossRef]
60:126-131. [CrossRef] 51. Cechinel-Recco K, Valvassori SS, Varela RB, et al. Lithium
35. Shagufta A. I., Ahmad I. Tamoxifen a pioneering drug: and tamoxifen modulate cellular plasticity cascades in
an update on the therapeutic potential of tamoxifen

350
 Psychiatry and Clinical Psychopharmacology

animal model of mania. J Psychopharmacol. 2012;26:1594- of mania. Int J Neuropsychopharmacol. 2014;18:1-11.

1604. [CrossRef] [CrossRef]
52. Szabo ST, Machado-Vieira R, Yuan P, et al. Glutamate 66. Abrial E, Etievant A, Bétry C, et al. Protein kinase C
receptors as targets of protein kinase C in the regulates mood-related behaviors and adult hippocampal
pathophysiology and treatment of animal models of cell proliferation in rats. Prog Neuropsychopharmacol
Mania. Neuropharmacology. 2009;56:47-55. [CrossRef] Biol Psychiatry. 2013;43:40-48. [CrossRef]
53. Valvassori SS, Dal-Pont GC, Resende WR, et al. Lithium 67. Burgdorf J, Knutson B, Panksepp J, Ikemoto S. Nucleus
and tamoxifen modulate behavior and protein kinase C accumbens amphetamine microinjections unconditionally
activity in the animal model of mania induced by elicit 50-kHz ultrasonic vocalizations in rats. Behav
ouabain. Int J Neuropsychopharmacol. 2017;20:877-885. Neurosci. 2001;115:940-944. [CrossRef]
[CrossRef] 68. Thompson B, Leonard KC, Brudzynski SM. Amphetamine-
54. Dal-Pont GC, Resende WR, Bianchini G, et al. Tamoxifen induced 50 kHz calls from rat nucleus accumbens: a
has an anti-manic effect but not protect the brain quantitative mapping study and acoustic analysis. Behav
against oxidative stress in an animal model of mania Brain Res. 2006;168:64-73. [CrossRef]
induced by ouabain. J Psychiatr Res. 2019;113:181-189. 69. Wright JM, Gourdon JC, Clarke PBS. Identification of
[CrossRef] multiple call categories within the rich repertoire of
55. Andreazza AC, Shao L, Wang JF, Young LT. Mitochondrial adult rat 50-kHz ultrasonic vocalizations: effects of
complex I activity and oxidative damage to mitochondrial amphetamine and social context. Psychopharmacol
proteins in the prefrontal cortex of patients with bipolar (Berl). 2010;211:1-13. [CrossRef]
disorder. Arch Gen Psychiatry. 2010;67:360-368. [CrossRef] 70. Pereira M, Andreatini R, Schwarting RKW, Brenes JC.
56. Streck EL, Amboni G, Scaini G, et al. Brain creatine Amphetamine-induced appetitive 50-kHz calls in rats: a
kinase activity in an animal model of mania. Life Sci. marker of affect in mania? Psychopharmacol (Berl).
2008;82:424-429. [CrossRef] 2014;231:2567-2577. [CrossRef]
57. Clay HB, Sillivan S, Konradi C. Mitochondrial dysfunction 71. Tingskov SJ, Hu S, Frøkiær J, et al. Tamoxifen attenuates
and pathology in bipolar disorder and schizophrenia. Int development of lithium-induced nephrogenic diabetes
J Dev Neurosci. 2011;29:311-324. [CrossRef] insipidus in rats. Am J Physiol Ren Physiol. 2018;
58. Gigante AD, Andreazza AC, Lafer B, et al. Decreased 314:F1020-F1025. [CrossRef]
mRNA expression of uncoupling protein 2, a mitochondrial 72. Bebchuk JM, Arfken CL, Dolan-Manji S, et al. A preliminary
proton transporter, in post-mortem prefrontal cortex investigation of a protein kinase C inhibitor in the
from patients with bipolar disorder and schizophrenia. treatment of acute mania. Arch Gen Psychiatry. 2000;
Neurosci Lett. 2011;505:47-51. [CrossRef] 57:95-97. [CrossRef]
59. Valvassori SS, Rezin GT, Ferreira CL, et al. Effects of 73. Kulkarni J, Garland KA, Scaffidi A, et al. A pilot study
mood stabilizers on mitochondrial respiratory chain of hormone modulation as a new treatment for mania
activity in brain of rats treated with d-amphetamine. J in women with bipolar affective disorder.
Psychiatr Res. 2010;44:903-909. [CrossRef] Psychoneuroendocrinology. 2006;31:543-547.
60. Somjen D, Katzburg S, Sharon O, et al. The effects of [CrossRef]
estrogen receptors α- and β-specific agonists and 74. Zarate CA, Singh JB, Carlson PJ, et al. Efficacy of a
antagonists on cell proliferation and energy metabolism protein kinase C inhibitor (tamoxifen) in the treatment
in human bone cell line. J Cell Biochem. 2011;112:625- of acute mania: a pilot study. Bipolar Disord. 2007;9:561-
632. [CrossRef] 570. [CrossRef]
61. Pereira M, Martynhak BJ, Baretta IP, et al. Antimanic-like 75. Yildiz A, Guleryuz S, Ankerst DP, Öngür D, Renshaw PF.
effect of tamoxifen is not reproduced by acute or chronic Protein kinase C inhibition in the treatment of mania: a
administration of medroxyprogesterone or clomiphene. double-blind, placebo-controlled trial of tamoxifen.
Neurosci Lett. 2011;500:95-98. [CrossRef] Arch Gen Psychiatry. 2008;65:255-263. [CrossRef]
62. Valvassori SS, Bavaresco D V., Budni J, et al. Effects of 76. Kulkarni J, Gurvich C, Gilbert H, et al. Hormone
tamoxifen on tricarboxylic acid cycle enzymes in the modulation: a novel therapeutic approach for women
brain of rats submitted to an animal model of mania with severe mental illness. Aust N Z J Psychiatry.
induced by amphetamine. Psychiatry Res. 2014;215:483- 2008;42:83-88. [CrossRef]
487. [CrossRef] 77. Amrollahi Z, Rezaei F, Salehi B, et al. Double-blind,
63. Valvassori SS, Borges CP, Varela RB, et al. The different randomized, placebo-controlled 6-week study on the
effects of lithium and tamoxifen on memory formation efficacy and safety of the tamoxifen adjunctive to
and the levels of neurotrophic factors in the brain of lithium in acute bipolar mania. J Affect Disord.
male and female rats. Brain Res Bull. 2017;134:228-235. 2011;129:327-331. [CrossRef]
[CrossRef] 78. Kulkarni J, Berk M, Wang W, et al. A four week randomised
64. Armani F, Andersen ML, Andreatini R, et al. Successful control trial of adjunctive medroxyprogesterone and
combined therapy with tamoxifen and lithium in a tamoxifen in women with mania.
paradoxical sleep deprivation-induced mania model. Psychoneuroendocrinology. 2014;43:52-61. [CrossRef]
CNS Neurosci Ther. 2012;18:119-125. [CrossRef] 79. Ahmad A, Sheikh S, Shah T, et al. Endoxifen, a new
65. Abrial E, Bétourné A, Etiévant A, et al. Protein kinase C treatment option for mania: a double-blind, active-
inhibition rescues manic-like behaviors and hippocampal controlled trial demonstrates the antimanic efficacy of
cell proliferation deficits in the sleep deprivation model endoxifen. Clin Transl Sci. 2016;9:252-259. [CrossRef]

351
 Bagdadi et al.

80. Ali SM, Ahmad A, Shahabuddin S, et al. Endoxifen is a 92. Jenkins V, Shilling V, Fallowfield L, Howell A, Hutton S.
new potent inhibitor of PKC: a potential therapeutic Does hormone therapy for the treatment of breast cancer
agent for bipolar disorder. Bioorg Med Chem Lett. have a detrimental effect on memory and cognition? a
2010;20:2665-2667. [CrossRef] pilot study. Psycho Oncol. 2004;13:61-66. [CrossRef]
81. Fallah E, Arman S, Najafi M, Shayegh B. Effect of 93. Schilder CM, Seynaeve C, Beex LV, et al. Effects of
tamoxifen and lithium on treatment of acute mania tamoxifen and exemestane on cognitive functioning of
symptoms in children and adolescents. Iran J Child postmenopausal patients with breast cancer: results
Neurol. 2016 ;10:16-25. from the neuropsychological side study of the tamoxifen
82. Palacios J, Yildiz A, Young AH, Taylor MJ. Tamoxifen for and exemestane adjuvant multinational trial. J Clin
bipolar disorder: systematic review and meta-analysis. Oncol. 2010;28:1294-1300. [CrossRef]
J Psychopharmacol. 2019;33:177-184. [CrossRef] 94. Boele FW, Schilder CMT, De Roode ML, Deijen JB,
83. Kedar RP, Bourne TH, Powles TJ, et al. Effects of Schagen SB. Cognitive functioning during long-term
tamoxifen on uterus and ovaries of postmenopausal tamoxifen treatment in postmenopausal women with
women in a randomised breast cancer prevention trial. breast cancer. Menopause. 2015;22:17-25. [CrossRef]
Lancet. 1994;343:1318-1321. [CrossRef] 95. Love RR, Cameron L, Connell BL, Leventhal H. Symptoms
84. Cuzick J, Powles T, Veronesi U, et al. Overview of the associated with tamoxifen treatment in postmenopausal
main outcomes in breast-cancer prevention trials. women. Arch Intern Med. 1991;151:1842-1847.
Lancet. 2003;361:296-300. [CrossRef] 96. Day R, Ganz PA, Costantino JP. Tamoxifen and depression:
85. Cohen I. Endometrial pathologies associated with more evidence from the national surgical adjuvant
postmenopausal tamoxifen treatment. Gynecol Oncol. breast and bowel project’s breast cancer prevention
2004;94:256-266. [CrossRef] (p-1) randomized study. J Natl Cancer Inst. 2001;93:1615-
86. Slomovitz BM, Sun CC, Ramirez PT, et al. Does tamoxifen 1623. [CrossRef]
use affect prognosis in breast cancer patients who 97. Fallowfield L, Fleissig A, Edwards R, et al. Tamoxifen for
develop endometrial cancer? Obstet Gynecol. the prevention of breast cancer: psychosocial impact on
2004;104:255-260. [CrossRef] women participating in two randomized controlled
87. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen trials. J Clin Oncol. 2001;19:1885-1892. [CrossRef]
for the prevention of breast cancer: current status of 98. Lee KC, Ray GT, Hunkeler EM, Finley PR. Tamoxifen
the national surgical adjuvant breast and bowel project treatment and new-onset depression in breast cancer
P-1 study. J Natl Cancer Inst. 2005;97:1652-1662. patients. Psychosomatics. 2007;48:205-210. [CrossRef]
[CrossRef] 99. Cella D, Land SR, Chang CH, et al. Symptom measurement
88. Cathcart CK, Jones SE, Pumroy CS, et al. Clinical in the Breast Cancer Prevention Trial (BCPT) (P-1):
recognition and management of depression in node psychometric properties of a new measure of symptoms
negative breast cancer patients treated with tamoxifen. for midlife women. Breast Cancer Res Treat.
Breast Cancer Res Treat. 1993;27:277-281. [CrossRef] 2008;109:515-526. [CrossRef]
89. Thompson DS, Spanier CA, Vogel VG. The relationship 100. Anelli TF, Anelli A, Tran KN, Lebwohl DE, Borgen PI.
between tamoxifen, estrogen, and depressive symptoms. Tamoxifen administration is associated with a high rate
Breast J. 1999;5:375-382. [CrossRef] of treatment-limiting symptoms in male breast cancer
90. Bourque F, Karama S, Looper K, Cohen V. Acute tamoxifen- patients. Cancer. 1994;74:74-77. [CrossRef]
induced depression and its prevention with venlafaxine. 101. Visram H, Kanji F, Dent SF. Endocrine therapy for male
Psychosomatics. 2009;50:162-165. [CrossRef] breast cancer: rates of toxicity and adherence. Curr
91. Paganini-Hill A, Clark LJ. Preliminary assessment of Oncol. 2010;17:17-21. [CrossRef]
cognitive function in breast cancer patients treated with 102. Pemmaraju N, Munsell MF, Hortobagyi GN, Giordano SH.
tamoxifen. Breast Cancer Res Treat. 2000;64:165-176. Retrospective review of male breast cancer patients:
[CrossRef] analysis of tamoxifen-related side-effects. Ann Oncol.
2012;23:1471-1474. [CrossRef]

352