Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder

Ahmad, Ateeq; Sheikh, Saifuddin; Khan, Mubeen; Chaturvedi, Alok; Patel, Piyush M.; Patel, Ronak; Buch, Bakul Chandrakant; Anand, Rajendra Someshwar; Shah, Timirkumar Chandrakant; Vora, Vaishal N.; Ramasubramanian, Vikhram; Rao, Satyanarayana; Kumar, Narendra; Prasad, B S V; Ramanathan, Sathianathan; Verma, Kamal; Jhanwar, Venu Gopal; Kumar, Nand; Shah, Sandip; Dalal, Pronob Kumar; Sindhu, Brahmdeep; Talukdar, Payel; Ahmad, Imran

doi:10.1111/bdi.13041

Cited by 18 publications

(17 citation statements)

References 45 publications

(46 reference statements)

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“…Early time to remission of the disease was observed with endoxifen compared to divalproex. 10 The recommended dose of endoxifen is 8 mg once daily and there are no studies about doses above 8 mg. 10 However, a study demonstrated dose proportionality in peak drug concentrations in plasma (C max ) and area under the concentration-time curve of endoxifen. 9 This is the first case in which a dose of 8 mg BID was administered, aiming at achieving a better response in a patient with Dubey V. Int J Adv Med.…”

Section: Discussionmentioning

confidence: 99%

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

Dubey

2022

Int J Adv Med

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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.

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Section: Discussionmentioning

confidence: 99%

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

Dubey

2022

Int J Adv Med

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“…Numerous preclinical and clinical studies have demonstrated encouraging results of tamoxifen in mania, a relatively selective PKC inhibitor [12][13][14]. Endoxifen, an active metabolite of tamoxifen and a direct PKC inhibitor is fourfold potent than tamoxifen [15]. Results of a multicentre, double-blind, active-controlled phase III study using a daily dose of 8 mg endoxifen in patients with BPD I acute manic episodes with/without mixed features significantly (p < 0:0001) reduced the total YMRS score (from 33.1 to 17.8) and was well-tolerated for 3 weeks [15].…”

Section: Discussionmentioning

confidence: 99%

“…Endoxifen, an active metabolite of tamoxifen and a direct PKC inhibitor is fourfold potent than tamoxifen [ 15 ]. Results of a multicentre, double-blind, active-controlled phase III study using a daily dose of 8 mg endoxifen in patients with BPD I acute manic episodes with/without mixed features significantly ( p < 0.0001) reduced the total YMRS score (from 33.1 to 17.8) and was well-tolerated for 3 weeks [ 15 ]. In the present case, although guideline-driven treatment was given for a year, the patient did not show any improvement, and thus, endoxifen at a dose of 8 mg once daily was initiated.…”

Section: Discussionmentioning

confidence: 99%

Real-World Long-Term Experience on Endoxifen in Bipolar Disorder with Psychotic Symptoms

Thanvi¹

2022

Case Reports in Psychiatry

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Evidence suggests that inhibition of protein kinase C (PKC) signalling may have a contributing role in the treatment of bipolar affective disorder (BPAD). Endoxifen, an active metabolite of tamoxifen, is a potent direct PKC inhibitor. This report presents a severe case of a BPAD patient with a baseline Young Mania Rating Scale (YMRS) score of 49, associated family history and addiction to psychostimulants, with no improvement by the first and second-generation antipsychotics. Treatment with endoxifen 8 mg once a day showed improvement in manic symptoms with a YMRS score of 4 and a reduction in the use of psychostimulants as well as other antipsychotic concomitant medications. No adverse effects were noted up to 8-month follow-up. Long-term treatment with endoxifen is safe and effective in severe BPAD.

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“…Endoxifen, an active metabolite of tamoxifen with a four-fold PKC inhibitory activity compared with tamoxifen, was recently tested in a phase III double-blind, divalproex-controlled RCT with acutely manic patients. The trial demonstrated efficacy of endoxifen in reducing manic symptoms and faster action as compared to divalproex with a good short-term adverse events profile [ 78 , 79 ].…”

Section: Emerging Approaches To the Treatment Of Maniamentioning

confidence: 99%

Existing and emerging pharmacological approaches to the treatment of mania: A critical overview

et al. 2022

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Manic episodes are a defining, frequent and dramatically disabling occurrence in the course of Bipolar Disorder type I. Current pharmacotherapy of mania lists a good number of agents, but differences in efficacy and safety profiles among these agents must be considered in order to tailor personalized therapies, especially when the long-term course of the illness is considered. There is wide room and need to ameliorate current pharmacological approaches to mania, but ongoing pharmacological research on the topic is scant. In this work we try to critically assess clinical factors and patients’ characteristics that may influence the treatment choice for manic episodes. In addition, we conduct a narrative review on experimental pharmacology of bipolar mania and psychotic disorders, presenting a critical overview on agents which could represent treatment alternatives for a manic episode in the next future. Results show limited novel or ongoing research on agents acting as mood stabilizers (Ebselen, Valnoctamide and Eslicarbazepine did not reach statistical significance in demonstrating antimanic efficacy). As for the emerging experimental antipsychotic, some of them (including KarXT, SEP-363856, RO6889450, ALKS3831) have demonstrated good antipsychotic efficacy and a favorable safety profile, but little is known about their use in patients with bipolar disorder and specifically designed trials are needed. Lastly, some benefits for the treatment of mania could be expected to come in the next future from non-mood stabilizers/non-antipsychotic agents (especially PKC inhibitors like Endoxifen): long-term trials are needed to confirm positive results in terms of long-term efficacy and safety.

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Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder

Cited by 18 publications

References 45 publications

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

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

Real-World Long-Term Experience on Endoxifen in Bipolar Disorder with Psychotic Symptoms

Existing and emerging pharmacological approaches to the treatment of mania: A critical overview

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