Adjunctive Endoxifen in a Middle-aged Man with Persistent Manic Symptoms Despite Standard Antimanic Agents: A Case Report of Early Clinical Response

Case Report

A 54-year-old male with bipolar I disorder, current episode manic, with psychotic symptoms (ICD-11: 6A60.1), ⁴ with an illness duration of 33 years, presented with a three-month history of irritability, reduced sleep, psychomotor agitation, and persecutory delusions. His index manic episode at age 21, which lasted about 4–6 weeks, had no identifiable precipitant but caused significant functional deterioration requiring hospitalization. Although precise recall was limited, available history suggested that the patient had experienced approximately 7–8 episodes of mania over the years. These episodes had lasted 3–4 weeks and were well controlled on lithium carbonate 800 mg/day and quetiapine 100 mg/day.

He had Type 2 diabetes mellitus, controlled with metformin 1,000 mg/day, lived with family, and maintained good occupational functioning before this episode. There was no relevant family psychiatry history.

On examination, the patient exhibited an elevated mood, irritability, pressured speech, increased psychomotor activity, and decreased need for sleep (3–4 hours per night) and persecutory delusions. The Young Mania Rating Scale (YMRS) score, ⁵ was 28, consistent with moderate mania severity. No rigidity or tremors were observed, although he reported drooling of saliva and constipation.

He presented to our outpatient clinic on an extensive regimen of lithium 800 mg/day, quetiapine 100 mg/day, risperidone 8 mg/day, clozapine 300 mg/day, haloperidol 20 mg/day, trihexyphenidyl 6 mg/day, and lorazepam 2 mg/day, prescribed at another facility in an attempt to manage persistent agitation and psychotic symptoms. But despite this polypharmacy, his symptoms remained uncontrolled. MRI brain was normal, and serum lithium was therapeutic (0.8 mEq/L). The patient’s family declined inpatient management despite repeated psychoeducation. On the day of presentation, sodium valproate 1,000 mg/day was added, as it is a commonly used, generally well-tolerated outpatient initiation dose for acute mania in adults. After one week, there was minimal clinical improvement.

Given the constraints of outpatient management and the need for a treatment option with potentially faster onset of action, adjunctive endoxifen 8 mg/day was initiated on the eighth day after discussing the evidence, expected benefits, and cost considerations with his caregivers. Within 5–7 days, sleep improved to 6–7 hours per night, irritability and agitation subsided, and his family reported a calmer affect and better cooperation. The patient described his mind as clearer, with fewer crowded thoughts, and his persecutory fears diminished. No sedation, thromboembolic events, or hepatic/renal dysfunction were observed. The YMRS score improved from 28 to 7 by the fourteenth day.

From approximately Day 14 to Day 28 following presentation, clozapine, hal-operidol, and valproate were gradually tapered and discontinued because they had not contributed meaningfully to symptom control during the acute phase and were producing anticholinergic adverse effects. His drooling and constipation resolved thereafter. Liver and renal function tests were periodically reviewed and remained normal throughout. At the four-week follow-up, he remained euthymic on a simplified regimen of lithium 800 mg, quetiapine 100 mg, risperidone 8 mg, endoxifen 8 mg, trihexyphenidyl 4 mg, and lorazepam 2 mg. Further tapering of risperidone, trihexyphenidyl, and lorazepam was planned as part of ongoing rationalization, as these medications had been inherited from his previous regimen and were not essential for maintaining remission; however, the dose reductions were deferred to a subsequent visit to ensure stability following recent medication changes.

Discussion

This case illustrates the potential utility of endoxifen as an adjunct in mania persisting despite multiple antimanic agents. The rapid improvement within one-week parallels prior evidence supporting PKC inhibition as a mechanistic pathway for antimanic effects. Recent real-world case reports^6,7 of endoxifen have docu-mented favorable outcomes in treatment-refractory mania. Our patient’s course demonstrates that endoxifen may be beneficial even in complex polypharmacy situations where conventional agents fail.

Conclusions

Although limited by its single-case design, short follow-up, and the absence of serum valproate levels, this report contributes real-world evidence from Indian clinical practice. It further underscores the need to rationalize polypharmacy and explore targeted mechanisms, such as PKC inhibition. Larger naturalistic studies are needed to clarify the role of endoxifen in refractory mania.

Supplemental Material