Abstract
Impulsivity and substance use frequently co-occur in adolescents with externalizing psychopathology and are often difficult to manage with conventional pharmacological agents. Attention-deficit symptoms, especially those characterized by hyperactivity and impulsivity, are associated with disrupted prefrontal cortical activity, emotional dysregulation, and early-onset risk-taking behaviors. These symptoms may present with co-occurring oppositional behaviors, poor academic functioning, and increasing psychosocial dysfunction. 1 Management becomes further complicated when substance use patterns evolve into dependence, leading to poor adherence, aggression, and difficulty engaging in psychotherapeutic interventions.
Protein kinase C (PKC) has emerged as a key molecular target in the neurobiology of impulsivity and addiction. PKC overactivity disrupts dopaminergic regulation and impairs prefrontal cortex function, contributing to loss of inhibition and executive dysfunction. 2 Specifically, the PKCε isoform plays a critical role in reward-related learning and has been implicated in nicotine and ethanol dependence. 3 ,4 Endoxifen, an active metabolite of tamoxifen, is a selective PKC inhibitor that has demonstrated antimanic, anti-impulsive, and emotion-stabilizing effects in adults. 5 Emerging clinical studies have shown promise for endoxifen in managing behavioral dysregulation in conditions such as bipolar disorder, borderline personality traits, and substance use disorders.6, 7 Although its use in adolescents is limited and largely off-label, case-based evidence suggests that endoxifen may help reduce impulsivity and enhance response to psychotherapy by restoring behavioral control.
In this report, we present a clinically complex case of an adolescent male with persistent attention-deficit symptoms, oppositional defiant disorder (ODD), and polysubstance dependence, in whom conventional treatments failed. The addition of endoxifen was associated with improvements in impulsivity, craving, and treatment engagement. Although ODD was also diagnosed in this patient, the focus of this report is on the management of persistent impulsivity and substance use, which were the primary presenting complaints and therapeutic challenges.
Written informed assent was obtained from the patient, and written informed consent was obtained from both parents in their native language.
Case Report
A 17-year-old male presented with persistent hyperactivity, impulsivity, and oppositional behaviors since early childhood. He was born preterm (8 months) via Cesarean section, with normal developmental milestones. Classroom reports described restlessness, distractibility, and noisy behavior from ages 3 to 9, which gradually evolved into oppositionality and poor frustration tolerance. From age 11, he began lying, stealing, and absconding from home. These behaviors intensified after parental separation at age 15, with increased aggression, school dropout, and legal complaints from neighbors. At age 14, he engaged in rash driving, gambling, and risk-taking activities. Tobacco use began at 12, escalating to 12–15 cigarettes/day. Alcohol use started at 13, and by 16, he was using cannabis daily with peers during bike racing. He reported intense craving, withdrawal symptoms (irritability, restlessness), and failed attempts to reduce usage, suggesting a dependence pattern for tobacco and cannabis, and harmful use of alcohol. “Intoxicated behavior” was defined as disinhibited and confrontational conduct while under the influence, such as breaking household objects, reckless driving, and verbal aggression. In this patient, it specifically included acts like damaging furniture at home during alcohol intoxication, physical fights with peers after cannabis use, and dangerous motorcycle stunts under the influence of substances. Socio-occupational dysfunction was severe, with persistent family conflict, academic dropout, and poor social boundaries. He reported chronic sadness, boredom, and irritability.
He had been treated for attention deficits since age 6, but were poorly adherent. Methylphenidate worsened agitation; clonidine caused sedation; fluoxetine led to suicidal ideation. Atomoxetine (36 mg/day) and bupropion (150 mg/day) showed partial benefit; however, side effects such as nausea, vomiting, and sleep disturbances limited continuation. He remained impulsive, irritable, and unable to engage in therapy.
At presentation, he was on atomoxetine 36 mg, bupropion 150 mg, and valproate 250 mg. Psychometry revealed borderline intelligence (IQ = 79) and, based on Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5), 8 a diagnosis of attention-deficit hyperactivity disorder (314.01), ODD (313.81) and borderline personality traits. Additional diagnoses for this individual were problems with parents or in-laws (Z63.1) and inadequate family support (Z63.2). Assessments included the Conners’ Rating Scales-Revised (CRS-R) 9 and Strengths and Difficulties Questionnaire (SDQ). 10 Conduct disorder was ruled out as the behaviors were not persistent or pervasive enough. However, we acknowledge that some symptoms overlapped with conduct disorder; this remains a diagnostic challenge in cases with severe polysubstance use and impulsivity.
Physical examination was normal. Blood investigations (CBC, LFT, RFT, glucose, lipids, TSH, free T3/T4) were unremarkable except for a mildly elevated TSH (6.2 mIU/L) with normal T3/T4, indicating subclinical hypothyroidism. An endocrinology opinion was sought; currently, supplementation was not advised.
Bupropion was stopped due to side effects. Atomoxetine was increased to 50 mg/day, and sodium valproate to 500 mg/day. After 10 days, attention improved modestly; however, impulsivity, substance craving, and aggression persisted. Tab endoxifen 8 mg once daily was initiated on Day 11. A 14 mg nicotine patch was added. By the end of week 3, the patient reported reduced craving, improved sleep, and better frustration tolerance. By week 4, he started engaging in psychotherapy sessions. After 6 weeks, he was discharged on atomoxetine, valproate, endoxifen, and a nicotine patch. Over the next 5 months, he remained under monthly follow-up. He continued endoxifen throughout, with no major side effects except occasional indigestion and sleep disturbance that were managed symptomatically with proton pump inhibitors and sleep hygiene measures. Oral melatonin spray at a dose of 3 mg (per spray) was used only a needed. Smoking was reduced to two to three cigarettes/day; alcohol was restricted to social occasions; cannabis was discontinued. He resumed studying, had fewer anger outbursts, developed improved insight, and reported better relationships with family members. Gambling has reduced significantly. These changes were corroborated by caregiver interviews.
Discussion
This case highlights the challenges of managing impulsivity, polysubstance dependence, and oppositional traits in adolescents with attention-deficit symptoms. Conventional pharmacotherapy often fails to address the multidimensional nature of such presentations, particularly when impulsivity persists despite stimulant or non-stimulant agents. In this adolescent, the addition of endoxifen was associated with a clinically meaningful improvement in behavioral control, substance craving, and psychosocial functioning—suggesting its potential as an adjunctive strategy.
Impulsivity in adolescents is neurobiologically underpinned by delayed maturation of the prefrontal cortex and altered dopaminergic transmission, which contributes to sensation-seeking, poor judgment, and risk-taking behaviors. 1 Dysfunction in top-down control from the frontal lobes may predispose adolescents to earlier substance experimentation and a faster transition to dependence. 2 When comorbid with externalizing disorders such as ODD, emotional instability, or subthreshold conduct traits, the management becomes even more difficult due to poor treatment adherence and engagement.
PKC, especially the PKCε isoform, plays a central role in modulating dopaminergic signaling, impulsive behavior, and addiction. PKC overactivation has been shown to impair prefrontal cortical regulation of working memory, attention, and behavioral inhibition. 3 In animal models, ethanol exposure increases PKCε expression, disrupting emotion regulation and facilitating substance-seeking behavior. 4 PKCε knockout mice show reduced sensitivity to alcohol and nicotine rewards, suggesting its role in substance reinforcement. 5 Endoxifen, a selective PKC inhibitor and active metabolite of tamoxifen, has shown promise in regulating impulsive and affective symptoms in bipolar disorder and borderline personality disorder. 6 In a randomized controlled trial, endoxifen was superior to placebo in reducing manic symptoms and irritability. 7 Other case reports suggest its utility in reducing substance craving and enhancing affective stability in individuals with comorbid impulsivity.11, 12 Its tolerability profile and non-sedative action make it a viable consideration for adolescent populations where sedation can interfere with academic and social functioning.
The index patient showed significant reductions in cannabis craving, oppositional behavior, and emotional dysregulation within 2–3 weeks of initiating endoxifen, along with improved engagement in psychotherapy. These changes were unlikely to be solely attributable to delayed responses to atomoxetine or valproate, which had been titrated earlier with limited effect. Additionally, the patient had previously failed multiple medications due to side effects or poor adherence, underscoring the clinical utility of a well-tolerated agent like endoxifen.
Limitations of this case include the absence of objective biomarkers of impulsivity (e.g., behavioral inhibition tasks or serum PKC levels), the potential confounding role of psychosocial interventions and the use of a nicotine patch, which may have contributed to reduced craving and smoking. Furthermore, long-term safety and efficacy of endoxifen in adolescents are not yet established, and its use remains off-label in this age group. There is a possibility that an increased dose of other medications could have contributed to the efficacy apart from endoxifen.
Nevertheless, this report adds to the growing body of literature supporting PKC inhibition as a therapeutic strategy for impulsivity and externalizing behaviors, especially when combined with psychotherapy. Future controlled trials in adolescent populations are needed to evaluate the long-term efficacy, safety, and optimal dosing strategies for endoxifen in these complex clinical presentations. 13
Conclusion
Endoxifen may offer a metabolically safe and behaviorally effective option in adolescents with refractory impulsivity, polysubstance use, and oppositional traits. When standard pharmacotherapies fail or are poorly tolerated, endoxifen may improve treatment adherence, emotional control, and psychotherapy engagement. Larger controlled trials are needed to confirm its efficacy and safety in pediatric populations. This case also highlights the need for individualized, multimodal treatment strategies in adolescent psychiatry, especially in cases involving overlapping externalizing symptoms and substance use. Pharmacological interventions like endoxifen, when cautiously used under expert supervision, may complement behavioral therapies to address both neurobiological and psychosocial aspects of impulsivity. While the findings here are preliminary, they suggest a potential therapeutic avenue for adolescents who are otherwise difficult to treat, emphasizing the importance of future research in this area.
Supplemental Material
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Footnotes
Acknowledgements
We acknowledge all the participants of the study and their family members.
Declaration of Conflicting Interests
The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Declaration Regarding the Use of Generative AI
None used.
Ethical Approval and Patient Consent
Informed consent was obtained from all participants. The study adhered to the CARE guidelines for clinical case reporting.
Funding
The author received no financial support for the research, authorship, and/or publication of this article.
Prior Presentations
None.
Simultaneous Submission to Another Journal or Resource
None.
References
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