Reply to Ghosh et al¹. Comments on Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder

Abstract

We reviewed Ghosh et al. 1 letter based on our active-controlled, double-blind, and randomized trial 2 that demonstrated the therapeutic benefit of Endoxifen in patients with bipolar I disorder. The author's reservations about the sample size estimation, statistical analysis, and missing data handling on the published article are unfounded. The clinical study design, conduct, and analysis were done under required regulatory and Good Clinical Practice guidelines. The non-inferiority margin was chosen based on consideration of our prior study. 3

Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder

“…Time to remission was observed as early as Days 4 with endoxifen versus Days 7 with valproate, though the two interventions had similar response and remission rates at the study endpoint of Day 21. This earlier time to remission in acute mania suggests a somewhat faster mode of action that might be due to endoxifen's direct PKC inhibition (Ahmad et al, 2021).…”

“…Interestingly, a recent randomized, controlled trial investigated endoxifen for the treatment of BD (Ahmad et al, 2021). This agent, which is a metabolite of tamoxifen, crosses the blood-brain barrier and is a direct PKC inhibitor.…”