Chemotherapy-Induced Psychosis Treated With Clozapine in an Adolescent With Metastatic Nasopharyngeal Carcinoma

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CASE REPORT

“Mr Devon” is a Black 16-year-old young man with past psychiatric history of autism spectrum disorder and oppositional defiant disorder. He has a past medical history of recently diagnosed nasopharyngeal carcinoma with metastatic disease to left cervical lymph node (Tis, N2b, M0-stage IVA per NCCN and T1, N1, M0-stage IIB per AJCC staging). Mr Devon recently developed religious delusions, command auditory hallucinations, thoughts of auto-enucleation and coprophagia, and disorganizations of speech and behavior during chemotherapy with cisplatin and 5-fluorouracil.

Oncology Medical History

Mr Devon noticed a neck mass in May 2022 but did not report his symptoms until 6 months later. He also experienced a 20-pound weight loss and persistent symptoms of rhinorrhea and hemoptysis from nasal bleeding. ENT examined Mr Devon, conducted CT imaging, and a neck mass fine needle aspiration revealed indeterminate pathology which necessitated further evaluation. NM PET CT whole body, x-ray chest, MRI orbit face neck w/wo contrast, and MRI brain w/wo contrast ultimately showed hypermetabolic activity in the nasopharynx, suspicious lymph nodes, and a small, heterogeneously enhancing soft tissue mass in the posterior nasopharynx, likely representing nasopharyngeal carcinoma. The large 5.3 cm left level 2A nodal mass most likely metastatic disease.

Pediatric hematology oncology initiated treatment according to ARAR0331 protocol. In April 2023, Mr Devon completed cycle 1 chemotherapy. He received 80.46 mg/m2 of cisplatin on days (D) 1; 1,005.747 mg/m2 of 5 fluorouracil on day (D) 1-5. Peripheral intravenous line administering promethazine (25 mg every 6 hr prn) D1-5 and dexamethasone hydrocortisone sodium succinate (0.9677 mg/kg per day) was placed to for antiemetic management due to continuous chemotherapy. He had mild and asymptomatic chemo-induced anemia, but otherwise tolerated it well. However, the left neck lymphadenopathy had continued to increase in size (2 to 3 cm) compared with prior assessments and the lymph node showed poor response to chemotherapy. Mr Devon underwent an excision of the left neck lymph node in June prior to further chemotherapy. Ten days later, he completed chemotherapy induction cycle 2 and was medically stable for discharge. He received 80 mg/m2 of cisplatin on days (D) 1; 1000 mg/m2 of 5 fluorouracil on day (D) 1-5.

Psychiatric Interventions

Mr Devon was absent for cycle 3 chemotherapy induction in early July; he eloped from his home during the time of the scheduled appointment and was observed by a neighbor to be walking in his neighborhood barefoot in the sweltering 100+ degree heat, not responding to his name. The police were called for a welfare check, and he was brought to the emergency department (ED) for further evaluation, where he interfaced with the pediatric psychiatry consult service for the first time.

On exam, he was observed to be internally preoccupied, disoriented to date and situation, withdrawn with flat affect, and exhibiting thought latency—an acute change from his baseline mental status. Although normally a bright and thoughtful young man, Mr Devon did not know what school or grade he attended, the date, and was scanning the room suspiciously. When asked, he confirmed that he was hearing voices of “a God” telling him to refuse further cancer treatment and to no longer listen to the treating physicians.

His family had noticed an acute change in his behavior approximately 2 weeks prior to his presentation to the ED, including disruption in sleep, bizarre behavior of standing and staring in place, and talking of resisting treatment. His family history is notable for schizophrenia in a first degree relative and an older sibling with bipolar disorder. The patient had no previous episodes of psychosis, hospitalizations, nor medication trials. He had been diagnosed with autism spectrum disorder and opposition defiant disorder in the outpatient mental health clinic around the age of 10. His mother noted him to be uninterested in religion prior to his presentation.

Mr Devon was admitted to the floor and further diagnostic tests were conducted, revealing no acute intracranial findings on a CT head, but an ultrasound identified an irregular fluid collection in the neck with an accompanying lymph node. He was started on aripiprazole 10 mg daily for psychosis and agitation for 3 days, however he was switched to olanzapine 10 mg twice daily as he continued to exhibit agitation towards himself and others. Olanzapine was increased to 15 mg twice daily and he showed some improvement of psychosis, but remained internally preoccupied. Due to lack of insurance coverage for long-acting injectable formulations of medication, he was given 100 mg haloperidol decanoate and discharged to home with oral haloperidol overlap instructions and antibiotics. Two days later, he was readmitted to the hospital after refusing oral medications at home and physically assaulting a family member due to delusional thinking.

Mr Devon’s psychiatric condition continued to substantially disrupt the progression of his medical treatment. The auditory hallucinations were telling him to eat his own feces as a form of religious punishment. He also was preoccupied with removing his right eye as it had “caused him sin.” He remained fixated on reading old testament passages of the Bible. The voices began to “speak through” him, and he would change his tone of voice to match the voices that he heard. He would consult with hallucinated individuals in the room: “I can make them astral project.”

Mr Devon would hold himself in strange, fixed positions on the hospital bed; for example, standing for several minutes on a single foot while gazing at the wall. For 3 days in a row, he also tried to force his way into the food and nutrition room so that he could find a plastic spoon to “gouge my sinful eyes out.” If the water faucet turned on or if something appeared on the TV screen, Mr Devon would say, “He did that. He is announcing his presence.” Mr Devon required a 1:1 sitter to always be in place, sometimes a security officer, and he was only allowed to eat with paper utensils on a safe tray.

Mr Devon eventually completed his last cycle of chemotherapy cycle 3 on July 16, 2023, while admitted to the floor. He received 80 mg/m2 of cisplatin on days (D) 1; 1000 mg/m2 of 5 fluorouracil on day (D) 1-5. Oral haloperidol was increased to 10 mg BID with complications of dystonia managed by oral diphenhydramine and benztropine. We attempted placement at several inpatient psychiatric facilities, all whom refused him on the basis of medical complexity and having a G-button in place. A positive response to chemotherapy emerged from the MRI assessment a week later, reinforcing discussions about radiation treatment. During this period, the management of elevated creatinine levels led to consultation with nephrology, alongside reiterated plans for 25 cycles of radiation treatment that required hospital admission.

Due to the severity of the psychosis that seemed to develop during chemotherapy treatment, neurology was consulted for further evaluation. A lumbar puncture was scheduled to assess cerebrospinal fluid for encephalopathy and autoimmune/paraneoplastic etiologies. Continuous video EEG monitoring yielded normal results, ruling out the presence of epileptic activity. Cerebrospinal fluid studies showed no definitive markers of autoimmune encephalitis, thereby discounting initial suspicions of an autoimmune etiology underlying his psychiatric symptoms. MRI of the brain revealed no significant intracranial abnormality.

Due to persistent dystonia and lack of efficacy on 20 mg haloperidol daily for 2 weeks, risperidone 0.5 mg BID was initiated and Haldol PO halted due to continued dystonia. Shortly thereafter , risperidone was increased to 1 mg QAM and 2 mg QHS for psychosis management. Oral valproate at 500 mg twice daily was also trialed to assist with management of agitation, however he developed ataxia and worsening sedation. Despite this treatment protocol, he continued to be internally preoccupied and had increasing episodes of reported agitation and acute worsening of mental status. He frequently threatened to kill staff, sometimes via “divine intervention and wrath.” The decision was finally made to discontinue risperidone and valproate and begin treatment with clozapine and lithium due to the severity of his psychosis, preoccupation with self harm, and his preponderance toward extrapyramidal side effects. Lithium was initiated to assist with mood, agitation, and to help bolster his absolute neutrophil count (ANC) as his ANC fluctuated from a normal range to less than 1500 with each radiation treatment.

As all local facilities continued to reject Mr Devon due to his medical complications and need for radiation therapy for treatment of the malignancy, our psychiatry consult service continued to evaluate and treat the patient while admitted to the floor over the following 6 weeks. Clozapine was ultimately increased to 50 mg twice daily, lithium to 600 mg at bedtime with serum blood level of 0.8, and aripiprazole was restarted and increased to 15 mg daily. His mood improved and his agitation and EPS symptoms resolved. He continued to endorse auditory hallucinations and would vacillate between talking in the first and third person, but his outward delusional thought content of religious persecution and beliefs that he needed to harm himself and refuse treatment of his malignancy finally ceased. It was determined that the patient, while nearing the end of his cancer treatment, would need continued treatment at an inpatient facility or potentially state hospitalization once his medical contraindications resolved.

Discussion

The patient's case is particularly noteworthy due to the convergence of multiple factors: his medical history of EBV+ nasopharyngeal carcinoma with metastatic disease, his psychiatric history of autism and ODD, and his family's strong psychiatric history. The patient's acute onset psychosis in the context of his medical illness and potential neurotoxicity from chemotherapy raises several important considerations. First, the interaction between his malignancy and treatment, specifically EBV+ malignancy, cisplatin, and 5-FU, and his psychosis is rare and complex. Second, the patient's family psychiatric history, including first degree relatives with legitimate bipolar disorder and schizophrenia suggest a genetic predisposition for psychiatric disorders. Third, although his presentation exuded prodromal symptoms of schizophrenia, he clearly developed these symptoms during his chemotherapy course, as noted by his abrupt change in mental status by observant parents. This case also highlights the challenges of treating psychotic disorders in the setting of existing malignancy necessitating chemotherapy and radiation treatment. Although the patient finally exhibited a substantial treatment response to clozapine, his ANC count would drop after each radiation treatment, and we nearly had to discontinue clozapine at least twice in accordance with the clozapine REMS system, potentially compromising the treatment of his psychotic disorder.

Existing literature offers some parallels to this case. Notably, instances of chemotherapy-induced acute psychosis have been documented in germ cell tumor patients, as seen in a 2015 study about a 25-year-old woman showing acute psychosis post-chemotherapy.¹ A similar case was presented in 2011 discussing an adolescent with a testicular germ cell tumor.² Although many cancer patients experience depression and anxiety, only a few develop psychotic symptoms. For example, Harter et al's study found that just 10 out of 517 adult patients with cancer manifested psychotic disorders.³ Pediatric cancer associated psychosis cases are even rarer, mostly related to central nervous system malignancies or leukemia.⁴ Intriguingly, the literature does not extensively correlate Epstein-Barr virus (EBV) nasopharyngeal carcinoma with psychosis, and despite cisplatin's neurotoxic properties, no direct links to psychiatric complications have been established.

The potential etiological influence of viral infections, particularly herpes simplex and EBV, on the emergence of psychotic symptoms has been highlighted in several scientific investigations. For example, a case report in 2017 discussed a psychotic disorder that emerged after the reactivation of a herpes simplex infection, set against the background of mannose-binding lecithin (MBL) deficiency, a history of childhood EBV infection, and intense psychosocial stress.⁵

The hypothesis that viral infections might play a role in triggering psychotic disorders is not new. Menninger, as early as 1926, postulated that influenza viral infections could potentially be a causative factor in schizophrenia.⁶ Subsequent reports have also indicated associations between psychotic disorders and infections like the EBV and herpes simplex. Another study provided further depth by investigating the correlation between antibodies to infectious agents and the subclinical positive symptoms of psychosis in adolescents, averaging around 16 years of age, from the general populace.⁷ Their findings suggest a significant association between serological reactions to EBV and male adolescents; however, this connection was not observed in females. This research stands out as it's among the first to delve into the serological evidence of infections with human herpes viruses and their relationship to the subclinical positive dimension of psychosis in a healthy adolescent cohort.

Ms Young is a current fourth year medical student at Texas A&M Health Science Center College of Medicine located in Bryan College Station, TX. Dr Hodges is a current PGY-4 child and adolescent fellow at Baylor Scott and White Hospital in Temple, TX. Dr Ansari is a current child and adolescent psychiatrist at Baylor Scott and White Hospital in Temple, TX.

References

1. Puangthong U, Pongpirul K. Chemotherapy-induced acute psychosis in a patient with malignant germ cell tumour. BMJ Case Rep. 2015;2015:bcr2014208982.

2. Campbell BA, Panicker J. New onset psychosis in an adolescent during treatment of testicular germ cell tumor. J Pediatr Hematol Oncol. 2011;33(3):e125-126.

3. Härter M, Reuter K, Aschenbrenner A, et al. Psychiatric disorders and associated factors in cancer: results of an interview study with patients in inpatient, rehabilitation and outpatient treatment. Eur J Cancer. 2001;37(11):1385-1393.

4. Ducore JM, Waller DA, Emslie G, Bertolone SJ. Acute psychosis complicating induction therapy for acute lymphoblastic leukemia. J Pediatr. 1983;103(3):477-480.

5. Asogwa K, Buabeng K, Kaur A. Psychosis in a 15-year-old female with herpes simplex encephalitis in a background of mannose-binding lecithin deficiency. Case Rep Psychiatry. 2017;2017:1429847.

6. Menninger KA. Influenza and schizophrenia: an analysis of post-influenzal ‘dementia precox’, as of 1918 and five years later. Am J Psychiatry. 1994;151(6 suppl):182-187.

7. Wang H, Yolken RH, Hoekstra PJ, et al. Antibodies to infectious agents and the positive symptom dimension of subclinical psychosis: the TRAILS study. Schizophr Res. 2011;129(1):47-51.