Abemaciclib-Associated Psychosis: A Case Report of a Rare Neuropsychiatric Adverse Effect during Breast Cancer Treatment

Abstract

Introduction

Abemaciclib is a cyclin-dependent kinase 4/6 inhibitor widely used in combination with endocrine therapy for the treatment of hormone receptor-positive, HER2-negative advanced and early breast cancer. While generally well-tolerated, neuropsychiatric adverse effects are uncommon but may be clinically significant.

Case Presentation

We report the case of a 72-year-old Caucasian female with stage I endometrial cancer and invasive ductal carcinoma of the breast who developed severe psychotic symptoms approximately 2 weeks after initiating abemaciclib, as part of her adjuvant breast cancer treatment. Her prior treatment had included adjuvant carboplatin and paclitaxel chemotherapy with brachytherapy, and her endocrine therapy was switched from anastrozole to letrozole at the time abemaciclib was added. Despite having a history of anxiety and obsessive-compulsive tendencies, she had no prior psychotic episodes. Her symptoms ultimately required two emergency department visits and a 9-day psychiatric hospitalization. Treatment with mirtazapine, olanzapine, and clonazepam resulted in the complete resolution of psychotic symptoms, and abemaciclib was permanently discontinued. After approximately 9 months, she was able to discontinue psychiatric medications without relapse of her psychotic symptoms.

Conclusion

This case highlights the importance of recognizing rare but serious neuropsychiatric adverse effects of abemaciclib and emphasizes the need for careful monitoring and multidisciplinary management.

Introduction

Abemaciclib is a selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved for the treatment of hormone receptor-positive, HER2-negative breast cancer both in the metastatic and early-stage settings [1]. The drug has demonstrated significant efficacy in combination with endocrine therapy [1]: improved invasive disease-free survival in the adjuvant setting (monarchE [1]) and improved progression-free survival in the advanced-disease setting (MONARCH 2 and MONARCH 3 [2, 3]).Common adverse effects include diarrhea, neutropenia, fatigue, and infections [2, 3]. However, neuropsychiatric adverse effects, particularly psychosis, are rarely reported in the literature [4].

Abemaciclib functions by inhibiting CDK4 and CDK6 kinases, which are critical regulators of the G1/S cell cycle checkpoint [5]. By blocking these kinases, abemaciclib prevents phosphorylation of the retinoblastoma protein, leading to cell cycle arrest in the G1 phase and subsequent apoptosis in cancer cells. The safety profile of abemaciclib has been extensively characterized through multiple phase III clinical trials [2, 3].

The causes of neuropsychiatric adverse effects with CDK4/6 inhibitors are poorly understood in the literature [4]. While fatigue is commonly reported with all agents in this class, affecting approximately 40% of patients [3] – more severe neuropsychiatric manifestations, such as depression, anxiety, or psychosis, are rarely documented [4]. A few isolated case reports have described mood disorders and cognitive impairment with palbociclib, but comprehensive data on the neuropsychiatric safety profile of abemaciclib specifically remains limited [2–4]. The central nervous system penetration of abemaciclib may contribute to its potential for neuropsychiatric effects, as preclinical studies suggest it crosses the blood-brain barrier more readily than other CDK4/6 inhibitors [6]. Here, we report a case of new psychotic symptoms appearing in a patient with no prior history of psychosis within 2 weeks of initiating abemaciclib in the adjuvant treatment setting. A CARE checklist has been completed and is included as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000553560).

Case Presentation

The patient is a 72-year-old woman with a past medical history significant for depression, anxiety, obsessive-compulsive disorder, hypothyroidism and osteopenia who initially presented in October 2023 with postmenopausal vaginal bleeding and was subsequently diagnosed with endometrial cancer. Staging CT imaging revealed not only the primary endometrial malignancy but also incidental findings, including a 1.3 cm left breast nodule concerning for malignancy and a 0.9 cm pancreatic head cystic lesion, likely an intraductal papillary mucinous neoplasm (Fig. 1).

Fig. 1.

Clinical timeline of oncologic and psychiatric events. Two-lane timeline showing oncologic treatment course and neurobehavioral/psychiatric events.

Further evaluation of the breast lesion with dedicated imaging demonstrated a 2.1 cm left breast mass with surrounding non-mass enhancement, creating a total estimated extent of disease of 6.2 cm, though without evidence of axillary adenopathy. Core biopsy of this mass revealed invasive ductal carcinoma that was strongly estrogen and progesterone receptor positive with H-scores of 300 for both, HER2 negative, and demonstrated variable Ki-67 proliferation ranging from 10 to 45% with an average of 27%.

The patient underwent definitive surgical management of her endometrial cancer in December 2023 with hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection. Final pathologic staging revealed pT1a N0 disease with mixed endometrioid and clear cell histology, negative pelvic washings for malignant cells, and three benign lymph nodes. She subsequently completed adjuvant chemotherapy with six cycles of carboplatin and paclitaxel, finishing in April 2024, along with adjuvant brachytherapy completed on April 18, 2024.

Given a low-risk Oncotype DX recurrence score for her breast cancer, the patient was initiated on endocrine therapy with anastrozole in March 2024 as neoadjuvant treatment. She then underwent a left segmental mastectomy with axillary lymph node biopsy in June 2024. Final surgical pathology demonstrated a 2.7 cm tumor with concerning findings, including two of three lymph nodes positive for micrometastatic disease. Notably, the tumor showed minimal response to neoadjuvant aromatase inhibitor therapy, with Ki-67 proliferation index remaining essentially unchanged at an average of 25% compared to the initial 27%.

The lack of robust Ki-67 reduction following 3 months of aromatase inhibitor therapy, combined with the presence of micrometastatic nodal disease and absence of tumor shrinkage, raised concerns about endocrine sensitivity. Based on these worrisome pathologic features suggesting potential endocrine resistance, treatment was modified to switch from anastrozole to letrozole with the addition of abemaciclib at 100 mg twice daily dosing.

At the time abemaciclib was initiated, the patient had been evaluated by a psychiatrist and documented as lucid with normal thought processes. Two weeks later, she presented to the emergency department with an acute onset of delusional thinking that had begun four to five days prior. Her delusions centered on the belief that law enforcement was pursuing her for practicing medicine without a license, that her family members would lose their jobs as a consequence of her alleged actions, and that her family would face lawsuits resulting in the loss of their homes. Despite these prominent psychiatric symptoms, she remained physically well-appearing with a normal neurological examination and was able to engage appropriately in conversation outside of her delusional content. Vital signs were notable for hypertension at 166/77 mm Hg. Workup to exclude acute medical etiologies was unremarkable, and the family requested discharge given a psychiatrist appointment scheduled for the following morning.

At her telemedicine psychiatric evaluation the next day, the patient endorsed anxiety and guilt surrounding the perceived consequences her family would face. She lacked any current psychiatric medication regimen. A safety assessment was negative for suicidal or homicidal ideation. The therapist provided psychoeducation, completed a referral to an intensive outpatient program, and notified the oncology team, who recommended holding abemaciclib until follow-up; her psychosis nonetheless worsened over the subsequent days before improving during inpatient treatment.

Three days later, prior to her scheduled intensive outpatient intake, the patient returned to the emergency department with significantly worsening psychosis accompanied by her husband. Her delusions had become more elaborate; she remained fully convinced of their reality, did not recognize them as delusional, and believed that disclosing her concerns to healthcare providers would accelerate legal action against her. She also endorsed depression, social withdrawal due to chemotherapy-related hair loss, and fleeting passive thoughts of death without plan or intent. Laboratory studies revealed mild hypercalcemia at 10.4 mg/dL, mild hypokalemia, and a reduced eGFR of 49 mL/min/1.73 m²; CT head was negative for intracranial pathology; brain MRI was not performed. While hypercalcemia can produce neuropsychiatric symptoms, the degree of elevation was insufficient to account for the severity and complexity of her presentation. She was admitted voluntarily to the inpatient psychiatric unit under a 201 commitment for severe depression with psychotic features.

Over her 9-day admission, the patient was started on mirtazapine (titrated to 22.5 mg nightly), olanzapine (5 mg nightly), clonazepam (0.5 mg twice daily), and hydroxyzine (25 mg three times daily as needed). Her clinical course showed gradual improvement; by day six her delusions had begun to feel implausible to her, and by day seven she denied them entirely, noting that thoughts about law enforcement “really don’t come to mind anymore.” At discharge on day nine, she demonstrated complete resolution of psychotic symptoms, full mood stabilization, normalized sleep and appetite, and intact insight, with plans for outpatient tapering of clonazepam and eventual discontinuation of olanzapine given long-term metabolic concerns.

At 9-month follow-up, the patient had successfully discontinued all psychiatric medications – olanzapine, 2 months post discharge, clonazepam 1 month post discharge, and mirtazapine by 9 months. She continued psychotherapy and reported functioning above her pre-episode baseline with complete resolution of psychotic symptoms.

Given the temporal relationship between her psychiatric symptoms and abemaciclib initiation, the lack of any prior history of psychosis, and the resolution of symptoms after abemaciclib was held and discontinued (during concurrent antipsychotic treatment), her psychiatry and oncology teams regarded abemaciclib as a possible temporal precipitant of her psychosis. Letrozole was continued while abemaciclib was discontinued, as the abemaciclib initiation coincided with her symptom onset. After discussion with the patient and her husband, her oncologist recommended against restarting abemaciclib or any other CDK4/6 inhibitor, determining that the psychiatric risks outweighed the potential oncologic benefits. Her psychotic symptoms did not recur on letrozole monotherapy after abemaciclib discontinuation, and she remained stable with continued cancer surveillance.

Discussion

This case illustrates a complex interplay between pre-existing psychiatric vulnerability and cancer treatment-induced psychosis in a 72-year-old woman with endometrial and breast cancer. The patient had a documented history of anxiety that she characterized as “OCD-like,” suggesting an underlying predisposition to obsessive and ruminative thinking patterns. This baseline psychiatric vulnerability likely created a foundation upon which acute stressors could precipitate more severe symptoms.

CDK4/6 inhibitors, while generally well-tolerated, have emerging reports of neuropsychiatric side effects that may be underrecognized in clinical practice [4]. To assess the relationship between abemaciclib and this episode, we applied the Naranjo Adverse Drug Reaction Probability Scale (Table 1). The reaction scored within the “possible” range, reflecting a compelling temporal association but a dechallenge confounded by concurrent psychotropic treatment and by several documented alternative contributors. We, therefore, regard abemaciclib as a possible – and temporally plausible – precipitant rather than a definitively established cause.

Table 1.

Naranjo adverse drug reaction probability scale

Naranjo item	Response	Score
1. Previous conclusive reports on this reaction?	Yes (pharmacovigilance + case reports [4])	+1
2. Did the event appear after the drug was given?	Yes (∼2 weeks)	+2
3. Did the reaction improve on dechallenge/antagonist?	Uncertain – symptoms worsened immediately after the hold and resolved only with concurrent antipsychotics	0
4. Did the reaction reappear on rechallenge?	Not rechallenged	0
5. Alternative causes that could on their own explain it?	Yes – documented contributors (dual primaries, recent chemotherapy, psychosocial stress, mild hypercalcemia/hypokalemia, reduced eGFR)	−1
6. Reaction reappear with placebo?	Not applicable	0
7. Drug detected in toxic concentration?	Not measured	0
8. Dose-response relationship?	Not assessed	0
9. Prior similar reaction to this/related drug?	No	0
10. Confirmed by objective evidence?	No (clinical diagnosis; CT negative, no MRI)	0
Total	​	+2 (“possible”)

Several factors beyond abemaciclib may have contributed to this presentation. The patient had received two concurrent cancer diagnoses and had recently completed cytotoxic chemotherapy, both substantial psychosocial and physiologic stressors. At her second presentation she had mild hypercalcemia (10.4 mg/dL) and mild hypokalemia, electrolyte disturbances that can produce neuropsychiatric symptoms [7], together with a reduced eGFR (49 mL/min/1.73 m²). Individually, however, the degree of metabolic derangement was modest and is unlikely to account for the severity, complexity, and abrupt onset of her delusional symptoms. We consider these factors plausible cofactors acting on a background of pre-existing anxiety rather than sufficient independent explanations.

Whether this represents a class effect or an abemaciclib-specific phenomenon is unclear. Neuropsychiatric events – including mood disturbance and cognitive complaints – have been reported with palbociclib [8, 9], and pharmacovigilance analyses have identified psychiatric signals across the CDK4/6 inhibitor class [4]. Abemaciclib exhibits a divergent neuropsychiatric toxicity profile relative to palbociclib [10], with broader class-wide psychiatric signals also documented [11]. Abemaciclib’s greater central nervous system penetration relative to other agents in the class [6] offers a biologically plausible, though unproven, basis for a drug-specific contribution (Table 2).

Table 2.

Published reports of neuropsychiatric adverse events associated with CDK4/6 inhibitors

Agent	Neuropsychiatric event(s)	Study type	Reference
Palbociclib, ribociclib, abemaciclib	Multiple psychiatric AEs (insomnia, depressed mood, eating disorder, stress, sleep disorder; 17 categories)	FAERS pharmacovigilance (ROR, IC)	[4]
Abemaciclib, palbociclib	Headache, dizziness, memory impairment enriched for abemaciclib; CDK6 genetically linked to cognitive performance	Triangulation (FAERS, Mendelian randomization, multi-omics, molecular docking)	[10]
Palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib	Eating disorder, emotional disorder (novel psychiatric safety signals)	FAERS pharmacovigilance (ROR, sensitivity analysis)	[11]
Palbociclib, abemaciclib	Psychiatric and nervous system disorders more frequent with palbociclib; renal disorders with abemaciclib	Comparative pharmacovigilance (VigiBase + FAERS, ROR)	[8, 9]
Palbociclib	Dementia, neurocognitive disorders, hearing/vestibular AEs (age-stratified increase in older patients)	FAERS pharmacovigilance (age-stratified disproportionality analysis)	[8, 9]

The gastrointestinal side effects commonly associated with abemaciclib, particularly diarrhea [3], may have played an additional contributory role through dehydration and electrolyte disturbances that could compound neuropsychiatric symptoms [7]. The combination of medication-induced metabolic changes, pre-existing anxiety vulnerability, and the psychological stress of cancer treatment may all play a role in the subsequent psychiatric pathology. This case underscores the importance of psychiatric support for oncology patients, particularly those with pre-existing anxiety disorders.

This report has several limitations. As a single case, it can establish association but not causation. Abemaciclib was not rechallenged, so the temporal relationship could not be confirmed. The dechallenge was confounded by the simultaneous initiation of mirtazapine, olanzapine, and clonazepam, which limits attribution of symptom resolution to drug withdrawal alone. Brain MRI was not performed, leaving a structural CNS contributor incompletely excluded. Finally, the alternative metabolic and psychosocial factors described above cannot be fully disentangled from a direct drug effect.

Conclusion

This case highlights the importance of recognizing rare neuropsychiatric adverse effects associated with abemaciclib therapy. While psychosis appears to be an uncommon complication, early recognition and appropriate management, including multidisciplinary collaboration between oncology and psychiatry teams, are essential for optimal patient outcomes. Further investigation is warranted to clarify this association: systematic pharmacovigilance and registry capture of neuropsychiatric events across CDK4/6 inhibitors, prospective neuropsychiatric monitoring within clinical trials of these agents, and mechanistic study of how differential central nervous system penetration may shape their neuropsychiatric risk.

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to disclose.

Funding Sources

J.F. is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award No. KL2TR001856. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.C.C. is supported by NIH Grant 5F30CA294839-02.

Author Contributions

A.C.C. conducted the initial compilation of clinical information, prepared the first draft of the manuscript, and participated in editing and revision. J.F. and E.H. contributed to manuscript editing, provided overall supervision, and guided the development of the final version. All authors read and approved the final manuscript.

Funding Statement

J.F. is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award No. KL2TR001856. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.C.C. is supported by NIH Grant 5F30CA294839-02.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.