Tamoxifen-induced acute mania: A case report

Berker Duman1, Adnan Kus¸man2 , Burc¸in C¸olak2 , Filiz C¸ay S¸enler3 and Hakan Kumbasar1

J Oncol Pharm Practice
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Abstract
Introduction: Tamoxifen is widely used for the treatment of hormone-responsive breast cancer, osteoporosis, and post-menopausal symptoms. Also, tamoxifen is currently under investigation for its anti-manic properties. In this article, we report a case who developed manic episode following the initiation of tamoxifen and remitted with discontinuation of the medication.
Case Report: A 58-year-old woman was diagnosed with breast cancer. Pathologic diagnosis was invasive ductal car- cinoma. Following bilateral total mastectomy operation, trastuzumab was initiated with intervals of 21 days. Five days before the fourth application of trastuzumab, tamoxifen was added. On the sixth day following the initiation of tamox- ifen, manic symptoms were developed and she was diagnosed as acute mania.
Management and Outcome: The oncology department suggested withdrawing tamoxifen due to a possible associ- ation between tamoxifen initiation and behavioral symptoms. Manic symptoms were rapidly (approximately 24 h) improved following cessation of tamoxifen. Psychiatric evaluation on the fifth day following cessation of tamoxifen revealed no manic symptoms. An aromatase inhibitor-exemestane was initiated and she showed no side effects with this medication since then.
Discussion: To our knowledge, this is the first case report of probable tamoxifen-induced mania. Our case report at least indicates that there were possibly some patients who were sensitive to the tamoxifen’s nervous system effects, mainly to manic effects. In conclusion, clinicians should be aware of these rare behavioral adverse effects of tamoxifen.

Keywords
Tamoxifen, mania, breast cancer
Date received: 26 November 2019; revised: 6 March 2020; accepted: 9 March 2020

Introduction
Tamoxifen is a first-generation selective estrogen receptor modulator (SERM) with both agonistic and antagonistic properties.1 SERMs are approved and widely used for the treatment of hormone-responsive breast cancer, oste- oporosis, and post-menopausal symptoms. Tamoxifen has been shown to decrease breast cancer recurrence risk and prolong survival.2 Tamoxifen exhibits its effects via binding to intracellular estrogen receptors in target organs and elicits agonist or antagonist responses, depending on the target tissue and hormonal milieu.3 Recently, tamoxifen has been also investigated for its anti-manic properties with some promising results.4
In this article, we report a case of 58-year-old woman who developed manic episode following initia- tion of tamoxifen and remitted with discontinuation of the medication. To our knowledge, this is the first case report of tamoxifen-induced mania.

Case
A 58-year-old woman was diagnosed with breast cancer six months ago. Pathologic diagnosis was inva- sive ductal carcinoma. Following bilateral total mastec- tomy operation, trastuzumab was initiated with intervals of 21 days. Five days before the fourth

1Division of Consultation-Liaison Psychiatry, Department of Psychiatry, Faculty of Medicine, Ankara University, Ankara, Turkey
2Department of Psychiatry, Faculty of Medicine, Ankara University, Ankara, Turkey
3Department of Medical Oncology, Faculty of Medicine, Ankara University, Ankara, Turkey

Corresponding author:
Burc¸in C¸olak, Department of Psychiatry, Faculty of Medicine, Ankara University, Ankara 06620, Turkey.
Email: [email protected]

2 Journal of Oncology Pharmacy Practice 0(0)

application of trastuzumab, tamoxifen was added. On the sixth day following the initiation of tamoxifen, severe insomnia was reported. For the next three days, euphoria, heightened psychomotor activity, feel- ing energetic despite 1-h sleep daily, distractibility, talk- ativeness, mood lability, irritability, and aggression with clear sensorium were reported without any psy- chotic symptoms. No history of drug abuse was evi- dent. On the fourth day since the onset of behavioral changes, the patient was admitted to the emergency department. Medical examination, laboratory assess- ments, and cranial magnetic resonance imaging did not indicate any significant medical pathology due to cancer or other possible medical conditions. She was consulted with the consultation-liaison psychiatry department and behavioral changes were diagnosed as mania. The oncology department suggested with- drawing tamoxifen due to a possible association between tamoxifen initiation and behavioral symp- toms. Manic symptoms were rapidly (approximately 24 h) improved following cessation of tamoxifen. Psychiatric evaluation on the fifth day following cessa- tion of tamoxifen revealed no manic symptoms. An aromatase inhibitor-exemestane was initiated and she showed no side effects with this medication since then. She had a history of obsessive-compulsive symptoms

which was under partial remission for several years. Several selective serotonin reuptake inhibitor (SSRI) medications (fluoxetine, escitalopram, and sertraline) were used for her obsessive-compulsive symptoms.
The probability of tamoxifen causing acute mania is calculated by using the “Naranjo Adverse Drug Reaction Probability Scale” in Table 1. A total score of 5 indicates that probable adverse reaction.5

Discussion
To our knowledge, this is the first case report of prob- able tamoxifen-induced mania. Interestingly and also paradoxically, tamoxifen is currently under investiga- tion for its anti-manic properties.6 Our patient had also a history of antidepressants use for obsessive- compulsive symptoms without any history of manic/ hypomanic shift. Trastuzumab, another agent in which she is on treatment for a few months seems to be less likely to be responsible for the manic episode, mainly because of lack of a temporal correlation. Another and relatively strong evidence is that following the cessation of tamoxifen, mania symptoms abruptly resolved. This could be a clinical cue of medication- induced acute mania instead of a primary affective epi- sode. Also, the cognitive assessment of the patient at

drug was discontinued or a specific antagonist

drug) that could on their own have caused the reaction?
6. Did the reaction reappear when a placebo was given?
7. Was the drug detected in blood (or other fluids) in concentrations known to be toxic?
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?

–1 þ1 0 0
þ1 0 0 0
þ1 0 0 0

same or similar drugs in any previous

Adverse Drug Reaction Probability Scale is as follows: Certain, >9; Probable, 5–8; Possible, 1–4; Unlikely, 0.

Duman et al. 3

the emergency department excludes delirium and other confusional states. The mechanism of action of tamox- ifen is relatively complex. First, tamoxifen was reported to have differential pharmacodynamic behaviors depending on the availability of tissue-specific estrogen receptors. Different types of estrogen receptors work with coactivator and corepressor proteins, which influ- ence access to nuclear genome.2 Second, tamoxifen is the inhibitor of protein kinase C (PKC). PKC is a family of enzymes that phosphorylate neurotransmitter receptors, intracellular signaling molecules, transcrip- tion factors, and cytoskeletal proteins. Recently, the PKC pathway has been suggested as a potential thera- peutic target for bipolar disorders.7,8 In addition to the estrogen receptor and PKC, other binding sites for tamoxifen include calmodulin and voltage-dependent Caþþ channels which are important mediators of sec- onder message systems.9
To speculate the potential effects via neurotransmit- ter systems of tamoxifen, we should focus on glutama- tergic and dopaminergic neurotransmitters which are complicated with several actions in different brain regions. In general, tamoxifen reduces NMDA activity which could potentially trigger a manic episode. Tamoxifen can increase extracellular dopamine levels especially in striatal regions such as nucleus accumbens which could be associated with bipolar disorders.10
The neurobiological mechanism of action of tamox- ifen on the nervous system remains questionable. Our case report at least indicates that there were possibly some sensitive patients to the tamoxifen’s nervous system effects, mainly to manic effects. In conclusion, clinicians should be aware of these rare behavioral adverse effects of tamoxifen. Possibly, more research is needed to evaluate the safety and efficacy of tamox- ifen to approve as an anti-manic agent.

Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs
Adnan Kus¸man https://orcid.org/0000-0002-0540-4712 Burc¸in C¸olak https://orcid.org/0000-0002-1691-2886

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