Endoxifen in Depressive Phases of Bipolar Disorder: a case series

Introduction:

Endoxifen, 4 hydroxytamoxifen, has received FDA (Food and Drug Administration) approval for the management of manic and mixed episodes of bipolar disorder. It doesn’t per se get approval for the depressive phases of the illness of bipolar affective disorder. On the contrary, tamoxifen has been attributed to causing iatrogenic depression. Four cases are presented here, which comprise this case series. In all the cases, Endoxifen (8 mg/day) was administered orally. Endoxifen is a direct PKC (protein kinase C) inhibitor. ¹

Case vignette 4:

Mr FH, 22 years engineering student presented with dysphoria, irritability, low mood, lack of interest in pleasurable activities for the last 8 months. He had attempted to commit suicide by hanging following up in relationship . He had made past deliberate self-harm attempts on two occasions by hanging two years back (attempted once with moderate risk, lethality and low rescue) and, has a family history of suicide among first-degree relatives.

Table 1 summarizes age, gender, illness variables and responses following treatment of Endoxifen. All the subjects were male and belonged to the younger age group (range 20-28 years). The duration of illness is ranging from 6-48 months. The case 1 had hypothyroidism as medical comorbidity. The case 3 had cannabis abuse and alcohol dependence meeting the criteria as per ICD 10. The case 4 had one deliberate self harm attempt and family history of completed suicide in first degree relative.

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Fig 1

Reduction of YMRS & MADRS scores (Baseline and six weeks) of Case 1.

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Fig 2

Reduction of YMRS & MADRS scores (Baseline and six weeks) of Case 2.

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Fig 3

Reduction of YMRS & MADRS scores (Baseline and six weeks) of Case 3.

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Fig 4

Reduction of YMRS & MADRS scores (Baseline and six weeks) of Case 4.

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Table 1 Summary of cases with demographic, illness variables and response following treatment.

Variables/Parameters	Case 1 (Mr AB)	Case 2 (Mr AP)	Case 3 (Mr AM)	Case 4 (Mr FH)
Age (years)	28	20	24	22
Gender	Male	Male	Male	Male
Duration of illness (months)	48	12	6	8
Comorbidities/Live Events	Subclinical Hypothyroidism	Nil	Cannabis abuse & Alcohol dependence	H/o DSH (Deliberate Self Harm) attempt.
Dose & duration of Endoxifen therapy	Endoxifen 8 mg/d for 6 weeks	Endoxifen 8 mg/d for 6 weeks	Endoxifen 8 mg/d for 6 weeks	Endoxifen 8 mg/d for 6 weeks
Co-prescribing drugs (total dose/day)	Quetiapine (300 mg/d), Lithium (450 mg/d), Divalproex Sod (500 mg/d), Clonazepam (0.25 mg)	Olanzapine (5 mg), Lithium (900 mg), Divalproex Sodium (500mg), Clonazepam (0.5 mg)	Risperidone (3 mg), Divalproex Sod (500mg), Lithium SR (400 mg), Clonazepam (1mg)	Olanzapine (15 mg), Lithium (600 mg), Clonazepam (2mg)
YMRS (Baseline, 42 days)	46, 12	52, 10	44,8	41, 6
MADRS (Baseline, 42 days)	17, 7	15,6	18, 7	20, 5
CGI (Baseline, 42 days)	5,1	5,2	5,1	5,1

Discussion:

In all the above cases the patients were in depressive phases of Bipolar affective disorder. Patients were on antipsychotic drugs and/or Lithium carbonate and Divalproex sodium. None of the patients were put on any antidepressants. Still all the patients responded well with Endoxifen at a dose of 8 mg/day for 6 weeks and there had been improvement in the MADRS and CGI scales.

Endoxifen’s potential role in bipolar disorder is an area of emerging research, though it is not currently a standard treatment for this condition. Here are a few points regarding its exploration in bipolar disorder:

1. Mechanism of Action: Endoxifen is primarily known for its activity as a metabolite of tamoxifen, a medication used in breast cancer treatment. Tamoxifen and its metabolites, including endoxifen, interact with estrogen receptors in the brain and other tissues. Estrogen receptors are known to play a role in mood regulation and may influence pathways implicated in bipolar disorder.

2. Research Studies: Some preliminary studies have investigated the potential use of tamoxifen or endoxifen in bipolar disorder. These studies are small-scale and exploratory, often focusing on understanding the mechanisms through which these compounds might affect mood stabilization.

3. Potential Benefits: Research suggests that endoxifen could modulate neurotransmitter systems involved in mood regulation, potentially offering a novel mechanism for treating bipolar disorder. However, more rigorous clinical trials are needed to establish its safety, efficacy, and optimal dosing regimen for this purpose.

4. Challenges and Considerations: Using endoxifen or tamoxifen in bipolar disorder presents several challenges, including potential side effects associated with long-term use, interactions with other medications, and variability in individual responses. Additionally, the safety profile and long-term effects of tamoxifen or endoxifen for bipolar disorder treatment are not yet well-established.

While there is interest in exploring endoxifen’s potential role in bipolar disorder treatment, it remains investigational. Individuals considering or currently using medications like tamoxifen or endoxifen for other medical conditions should consult with healthcare providers to discuss potential risks, benefits, and alternative treatment options specifically tailored to bipolar disorder management.

Endoxifen, as a metabolite of tamoxifen, has been studied in the context of mood disorders, including bipolar depression, but research in this area is still in its early stages.² Here’s a summary of the current understanding and research findings:

1. Mechanism of Action: Endoxifen, like tamoxifen, acts as a selective estrogen receptor modulator (SERM). Estrogen receptors are present in the brain and are involved in various processes related to mood regulation. It is hypothesized that endoxifen could potentially modulate these receptors and influence neurotransmitter systems implicated in bipolar depression.

2. Research Studies: There have been some preclinical studies and a few small clinical trials exploring the use of tamoxifen or endoxifen in bipolar disorder, particularly in bipolar depression. These studies have shown mixed results, with some indicating potential efficacy in reducing depressive symptoms. 3

3. Clinical Evidences: One small clinical trial conducted in patients with bipolar depression found that adjunctive treatment with tamoxifen, which increases endoxifen levels, led to significant improvements in depressive symptoms compared to placebo. However, larger and more robust clinical trials are needed to confirm these findings and establish the safety and efficacy of endoxifen specifically. 4,5

4. Considerations: Despite the promising initial findings, the use of tamoxifen or endoxifen in bipolar depression is not without challenges. Both substances can have significant side effects, including potential risks related to long-term use. Additionally, individual responses to these medications may vary, and they may interact with other medications commonly used in bipolar disorder treatment.

5. Future Directions: Further research is needed to elucidate the precise mechanisms of action of endoxifen in mood disorders and to establish its role in bipolar depression treatment. This includes larger clinical trials with well-defined patient populations, longer treatment durations, and comprehensive assessments of both efficacy and safety.

Conclusion:

While there is preliminary evidence suggesting a potential benefit of endoxifen in bipolar depression, it remains an investigational treatment. Patients and healthcare providers should carefully weigh the potential benefits and risks before considering the use of tamoxifen or endoxifen for this indication, and decisions should be made based on the latest clinical evidence and individual patient factors.