Endoxifen for the management of bipolar disorder with comorbid substance use disorder: A report of two cases

Case 1

A 35-year-old male with no history of depressive or obsessive-compulsive symptoms or any other psychiatric illness reported experiencing a first manic episode 2–3 weeks prior. The patient was irritable with occasional outbursts of violent anger, excessive grandiose talks, unnecessary spending, poor sleep, increased alcohol consumption and smoking throughout the day.

The patient had a history of alcohol consumption for over 15 years and consumed eight to ten pegs of whiskey daily for 6–7 months. He smoked 20 cigarettes daily and made no attempts to abstain from smoking or alcohol. His father and brother also consumed alcohol, while his mother was being treated for depression. The patient was married and belonged to the middle socioeconomic status.

The patient was diagnosed with bipolar I disorder, alcohol use disorder, and nicotine use disorder. Investigations revealed normal hematology, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated gamma-glutamyl transferase, normal findings on ultrasonography of the abdomen, normal echocardiography, and magnetic resonance imaging of the brain. The CGI score has been added using the Insert tool 6.^[3]

The patient was hospitalized and was prescribed thiamine and multivitamins for alcohol withdrawal. Lorazepam 12–14 mg daily was initiated. The patient was prescribed Tab. Endoxifen 8 mg once daily and Tab. Olanzapine 15 mg daily in divided doses. Intramuscular haloperidol and promethazine were reserved for emergencies, as needed.

After 10 days, there was complete remission of manic symptoms and alcohol withdrawal. The CGI score has been added using the Insert tool 1. The patient was prescribed Endoxifen 8 mg once daily, Olanzapine 10 mg/day in two divided doses, Lorazepam 2 mg once daily at bedtime, and multivitamins once daily. Remission was maintained at 2 weeks post-discharge and the patient remained sober. CGI Score at 1 and 2 weeks was 1. CGI global improvement at 1 and 2 weeks was 1 while CGI efficacy index at 1 and 2 weeks was 1.

At 33 days after presentation, the patient was stable on Endoxifen 8 mg once daily, Olanzapine 5 mg twice daily, Lorazepam 2 mg at bedtime, and multivitamins once daily. CGI severity score was 1, CGI global improvement was 1 [Figure 1], and CGI efficacy index was 1. No side effects were reported. The patient was adherent to therapy. Vegetative functions had normalized and the patient reported minimal craving for alcohol and nicotine during 42 days of Endoxifen use. The treatment details for Case 1 are described in Table 1.

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Figure 1:

Change in clinical global impression severity score for case 1.

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Case 2

A 30-year-old male taxi driver presented with complaints of lack of sleep for 1 week, wandering during the night, abusing his family members, and making tall claims. The patient had a history of use of cannabis, nicotine, and alcohol. The patient was married. The CGI score has been added using the Insert tool 6.

The patient was diagnosed with the bipolar affective disorder with comorbid substance use disorder. The patient was prescribed sodium valproate 750 mg twice daily (cross-tapered with Endoxifen later), Olanzapine 20 mg nightly, Clonazepam 1 mg nightly for 3 months, and Lithium 300 mg thrice daily.

There was no clinical improvement after 4 weeks, with minimal change in YMRS scores. The patient denied undergoing electroconvulsive therapy. Therefore, Endoxifen 8 mg once daily in the morning was initiated. After 1 week, the patient showed clinical improvement and change in YMRS ratings. Sodium valproate was tapered and stopped.

Remission began 1 week after initiating Endoxifen treatment. Symptom severity was reduced, as indicated by a CGI score of 2. CGI score was one at the end of 3 months [Figure 2]. No side effects attributed to Endoxifen were observed. Mild rigidity due to concomitant antipsychotic medication was reported, which resolved with 2 weeks of Trihexyphenidyl treatment. The patient resumed his driving job and did not resume substance usage with Endoxifen treatment at 3 months of follow-up. The treatment details for Case 2 are described in Table 1.

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Figure 2:

Change in clinical global impression severity score for case 2.

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Protein kinase C (PKC) as a common thread

There may be a shared mechanism between BI and addictions,^[4] possibly regulated by PKC. Overactive PKC intracellular signalling is associated with mania. Endoxifen inhibits PKC up to 80% and could, thus, play a key role in managing BI.^[6] Furthermore, chronic exposure to ethanol increases the activity of PKC and the expression levels of PKC isozymes. A PKC isotype is involved in nicotine addiction.^[3,7,8] Therefore, Endoxifen, a PKC inhibitor, could play an important therapeutic role.^[6]

In vitro studies have demonstrated that chronic exposure to ethanol increases the activity of PKC^[7] and it is suggested that selective inhibition of PKC epsilon could reduce excessive consumption of alcohol.^[9] Concerning nicotine addiction, PKC epsilon regulates reward signalling via nicotinic receptors, thus indicating the potential for PKC epsilon as a target for treating comorbid nicotine addiction.^[8]

Role of Endoxifen

Clinical studies have demonstrated the efficacy of Endoxifen. Treatment with Endoxifen 8 mg/day led to a nearly 60% reduction in YMRS score, similar to that achieved with Tab. Divalproex 1000 mg/day.^[3] In patients with bipolar I disorder, Endoxifen, and Divalproex co-treatment for 21 days led to comparable changes in YMRS score, Montgomery-Åsberg Depression Rating Scale score, and CGI CGI-BP ratings. Endoxifen led to earlier remission (by day 4) compared with divalproex; unlike divalproex, Endoxifen did not increase levels of thyroid-stimulating hormone or decrease levels of platelets.^[10]

The current case series highlights the benefits of Endoxifen with substances such as cannabis and nicotine. PKC inhibitors such as Endoxifen can be considered a new comprehensive treatment option in mania with comorbid substance abuse, where it can bring dual benefits by controlling both conditions.