Endoxifen augmentation in treatment-resistant rapid cycling bipolar disorder: A case series in elderly females

INTRODUCTION

Rapid cycling affective disorder (RCAD) is a particularly severe and treatment-resistant subtype of bipolar disorder (BD), characterized by four or more mood episodes per year, with alternating manic/hypomanic and depressive phases.^[1] RCAD accounts for approximately 10–20% of BD cases and is more frequently observed in females.^[2] Individuals with RCAD experience approximately a sevenfold greater mean number of (hypo)manic episodes and a twofold increase in depressive episodes compared to those with non-rapid cycling BD,^[3] leading to higher morbidity, functional impairment, and suicidality.^[4] The pharmacological management of RCAD remains complex and poses challenges, with no single agent proving consistently effective across patient populations. Despite the use of over 16 different pharmacological interventions – including mood stabilizers, atypical antipsychotics, and antidepressants – treatment resistance remains common.^[5] Sodium valproate, a broad-spectrum mood stabilizer, has shown moderate efficacy in controlling manic episodes in RCAD.^[6] Aripiprazole or quetiapine is often added to valproate; however, especially in chronic cases with decades-long illness durations, sometimes remission is not achieved.

Emerging evidence suggests that hormonal and neuroendocrine modulation may be a key to improving treatment response in female patients with BD.^[7] Endoxifen, a potent active metabolite of tamoxifen, is a selective estrogen receptor modulator (SERM) and protein kinase C (PKC) inhibitor. It has shown promise in isolated case reports and small series as a novel mood stabilizer in BD, particularly in acute mania.^[8,9] However, a recent meta-analysis found 5 randomized controlled trials (RCTs) of tamoxifen in acute manic patients, 3 as add-on, and 2 as monotherapy.^[10] Results of the studies homogeneously indicate evidence of efficacy for tamoxifen over placebo in reducing manic symptoms. However, its utility in RCAD has not been explored in refractory or in combination with valproate for effectiveness and long-term safety. This case series presents three female patients with over four decades of chronic RCAD, who had failed multiple pharmacotherapies and only partially responded to valproate. The addition of 8 mg/day of endoxifen to 1000 mg/day of sodium valproate led to sustained remission for over 8–12 months. These findings suggest a possible synergistic interaction between valproate and endoxifen in modulating mood stability at a molecular level, warranting further investigation in larger controlled trials for this re-emerging approach.

Figure 1 depicts mood episodes and remission duration of all three cases after endoxifen augmentation.

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Figure 1:

The significant drop in episodes and corresponding remission duration for all three cases after endoxifen augmentation to valproate and aripiprazole.

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CASE SERIES

DISCUSSION

This case series presents three female patients with chronic RCAD of over three to four decades’ duration, all of whom had failed to achieve sustained remission despite multiple pharmacological trials, including long-term sodium valproate therapy. Remarkably, the introduction of endoxifen (8 mg/day) alongside valproate (1000 mg/day) resulted in complete remission sustained over a 10–12-month period. None of the patients discontinued endoxifen, reflecting good tolerability and safety of 8 mg (low doses compared to 160 mg used for breast cancer). These findings raise important questions about the role of endoxifen and the potential for synergistic effects in mood stabilization. Previous literature has shown that RCAD patients experience significantly more mood episodes – especially (hypo) manic ones – compared to non-rapid cycling counterparts, and are less likely to achieve remission or functional recovery.^[3,4] Sodium valproate, though effective in acute mania and partially beneficial in RCAD, often fails to maintain long-term mood stability when used alone.^[6] In these treatment-resistant cases, novel pharmacological strategies become necessary.

Endoxifen, a SERM and PKC inhibitor, has been reported in the context of BD, though largely in isolated case reports and small studies focusing on acute mania.^[8,9] Its application in RCAD, however, has not been previously documented to our knowledge. The mechanism of its mood-stabilizing effect is believed to involve the inhibition of PKC, which plays a role in intracellular signaling pathways implicated in mania and affective dysregulation. Interestingly, both valproate and endoxifen have been independently shown to exert PKC-inhibitory effects, raising the possibility of a synergistic molecular interaction when used together. In addition to PKC modulation, the hormonal and neuroendocrine actions of endoxifen may be particularly relevant in female patients. Estrogen has been shown to influence serotonergic and dopaminergic pathways, both of which are central to mood regulation.^[7] The chronic fluctuating mood states in all our 3 old-age female RCAD patients may, in part, be modulated by hormonal variability. Endoxifen’s estrogen receptor modulation could therefore represent a targeted approach for this subgroup. Both valproate and endoxifen significantly decrease phosphorylated PKC in the hippocampus, prefrontal cortex, amygdala, and striatum.^[11]

This case series has thus moved toward the need for identifying more precise neurobiological targets that, in turn, may help develop personalized approaches and more reliable biomarkers for treatment prediction in poor responders of RCAD. The combination of endoxifen and valproate was well-tolerated in all three patients, with no significant side effects or laboratory abnormalities reported during the last 10–12-month follow-up (normal LFT). The data are limited regarding the efficacy and safety of endoxifen 8 mg for long-term maintenance treatment, and only two previous reports suggest its use till 8 months.^[12,13] This suggests that ours is one of the first cases wherein we continued endoxifen for a 12-month follow-up, and we found the regimen safe for long-term use; all 3 patients’ hepatic functions were within normal range. We intend to stop endoxifen in all 3 patients after 12 months and wonder if remission will be sustained or not. The limitations of this case series include the small sample size and lack of a control group, as well as the inclusion of only female RCAD patients, which restricts generalizability and therefore provides insufficient evidence to recommend the clinical use of endoxifen in all treatment-refractory RCAD cases. However, the chronicity and treatment resistance of three cases highlight the clinical significance of the observed outcomes. These findings warrant further exploration through RCTs to assess the efficacy and safety of endoxifen as an augmenting agent in RCAD, particularly in female patients.

CONCLUSION

To the best of our knowledge, this is the first case series or report to be published on the use of endoxifen in the management of chronic long-standing treatment-resistant RCAD. All three patients tolerated endoxifen for more than 8 months without any discernible adverse effects and surprisingly showed sustained remission. Endoxifen may represent a novel adjunctive treatment for RCAD, especially in patients with longstanding, treatment-refractory illness. The observed sustained remission in these three patients supports the hypothesis of a synergistic interaction with sodium valproate, offering new hope in an otherwise therapeutically limited condition.