Long-term effectiveness and safety of endoxifen in the treatment of bipolar mania: a case report

Vaibhav Dubey


Bipolar disorder (BD) displays abnormalities in protein kinase C (PKC) signaling, and evidence suggests that inhibiting PKC may help treat mania. Endoxifen a potent inhibitor of the PKC signaling pathway, is effective in controlling acute bipolar mania, at doses of 8 mg OD, for a period of 3-weeks. Here we present the case of a patient with severe mania, increased alcohol consumption administered endoxifen 8 mg BID for a period of 3-months, to achieve a better response. High-dose, long-term treatment with endoxifen was efficacious in controlling manic symptoms, with no adverse effects. Additionally, the patient didn’t consume alcohol during the course of treatment. This case showed the long-term effectiveness and safety of high-dose endoxifen to control mania in a patient with BD.


Endoxifen, Bipolar mania, Severe mania, Long-term use, Safety, Effectiveness

Full Text:



Kishi T, Ikuta T, Matsuda Y, Sakuma K, Okuya M, Nomura I et al. Pharmacological treatment for bipolar mania: a systematic review and network meta-analysis of double-blind randomized controlled trials. Mol Psychiatry. 2021;1-9.

Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20:97-170.

Fountoulakis KN, Yatham L, Grunze H, Vieta E, Young A, Blier P et al. The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 2: review, grading of the evidence, and a precise algorithm. Int J Neuropsychopharmacol. 2017;20:121-79.

Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes T, Cipriani A et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30:495-553.

Saxena A, Scaini G, Bavaresco DV, Leite C, Valvassori SS, Carvalho AF et al. Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature. Mol Neuropsychiatry. 2017;3:108-24.

Talaei A, Pourgholami M, Khatibi-Moghadam H, Faridhosseini F, Farhoudi F, Askari-Noghani A et al. Tamoxifen: A Protein Kinase C Inhibitor to Treat Mania: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials. J Clin Psychopharmacol. 2016;36:272-5.

Ahmad A, Sheikh S, Shah T, Reddy MS, Prasad B, Verma KK et al. Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen. Clin Transl Sci. 2016;9:252-9.

Butler M, Urosevic S, Desai P, Sponheim SR, Popp J, Nelson VA et al. Treatment for Bipolar Disorder in Adults: A Systematic Review. Rockville (MD): Agency for Healthcare Research and Quality (US). 2018.

Ahmad A, Shahabuddin S, Sheikh S, Kale P, Krishnappa M, Rane RC, et al. Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects. Clin Pharmacol Ther. 2010;88:814-7.

Ahmad A, Sheikh S, Khan MA, Chaturvedi A, Patel P, Patel R et al. Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder. Bipolar Disord. 2021;23:595-603.

Yildiz A, Guleryuz S, Ankerst DP, Ongür D, Renshaw PF. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry. 2008;65:255-63.

Sonne SC, Brady KT. Bipolar Disorder and Alcoholism. Alcohol Res Health. 2002;26:103-8.

Pakri Mohamed RM, Mokhtar MH, Yap E, Hanim A, Abdul Wahab N, Jaffar FHF et al. Ethanol-Induced Changes in PKCε: From Cell to Behavior. Front Neurosci. 2018;12:244.

Maiya R, McMahon T, Wang D, Kanter B, Gandhi D, Chapman HL et al. Selective chemical genetic inhibition of protein kinase C epsilon reduces ethanol consumption in mice. Neuropharmacology. 2016;107:40-8.