Letter: Seventeen-Year-Old Develops Neuroleptic Malignant Syndrome after Brief Low-Dose Exposure to Aripiprazole: A Case Report

Case Presentation

The patient was a 17-year-old male with a history of major depressive and generalized anxiety disorders who presented to the emergency department with fever, rigidity, and altered mental status 5 days after starting aripiprazole 2 mg daily. His medication regimen also included bupropion XR 300 mg and duloxetine 20 mg daily, decreased from 30 mg on day 1 of aripiprazole.

On arrival, he was febrile at 39.5C and tachycardic at 120 bpm. Laboratory findings were initially unremarkable. He began lorazepam 2 mg q1 hour and was transferred to the pediatric intensive care unit (PICU) and psychotropic medications were held. He started benztropine 1 mg q6 hour, bromocriptine 2.5 mg q6 hour, dantrolene 1 mg/kg q8 hour, infusions of midazolam and dexmedetomidine as needed, as well as intravenous fluids (IVF). Examination was significant for rigidity to passive range of motion and two beats of clonus at his right ankle. The primary team’s differential diagnosis included NMS versus serotonin syndrome (SS). On day 2, his temperature reached 40.5°C, and he received external cooling and cooled IVF in addition to prior medications, temporarily decreasing his temperature to 36.0°C. Creatinine kinase rose to 346. On day 3, he was intubated for hypercarbic respiratory failure in the setting of benzodiazepine and dantrolene treatment, subsequently complicated by Methicillin-susceptible Staphylococcus aureus ventilator-associated tracheitis. He was then placed on morphine, midazolam, and dexmedetomidine drips. He continued to have fluctuating fevers requiring external cooling. On day 13, he was successfully extubated.

On day 14, Psychiatry was consulted for restarting his psychotropic medications. His mother reported that he had clonus at his ankles and tremor, low muscle tone, myopia, scoliosis, and joint hypermobility at baseline. He had been seeing a neurologist for several years and underwent genetic testing for drug metabolism. His pharmacokinetic gene profile revealed intermediate metabolizers at CYP2CP and CYP2D6, as well as ultrarapid metabolizer at UGT1A4. He had no surgical history, and he denied any substance use. He had been started on selective serotonin reuptake inhibitors for major depressive and generalized anxiety disorders at about 8 years old, ultimately finding the most relief on bupropion. He started duloxetine several months prior to presentation, but did not find this medication helpful and was tapering down with a plan of ultimately discontinuing it.

Examination was notable for normal tone, no cogwheel or paratonic rigidity, four beats of clonus at the ankles, and brisk and symmetrical reflexes. He was initially drowsy, which improved over the course of conversation (he was receiving dexmedetomidine 0.9 mg/kg, morphine 2 mg/h, diazepam 15 mg q6 hour), thick to fluent speech, vague but related thoughts, no delusions, and future oriented. There was no flushing or diaphoresis.

Impression was NMS. We advised against using any dopamine-blocking/modifying agents, dopamine agonists, and against resuming psychotropic medications during his hospitalization. Over the course of the week, he remained afebrile and continued to improve. The primary team transitioned him from morphine to methadone, and he was discharged to physical rehabilitation on diazepam, clonidine, and methadone with tapering off schedule in place. He was scheduled to follow-up with an outpatient psychiatrist.

Discussion

Here we report a 17-year-old male with a history of major depressive and generalized anxiety disorders who presented with NMS secondary to brief, low-dose aripiprazole. NMS is known to be an uncommon but life-threatening medical emergency that is important to identify and treat promptly.

NMS and SS are both potentially life threatening. Although there is some overlap, this patient’s distinguishing features on hospitalization included having recently started a partial dopamine agonist, baseline clonus, absence of hyperreflexia or gastrointestinal symptoms, and slow resolution of symptoms, which make NMS the more appropriate diagnosis (Prakash et al., 2021). The patient’s duloxetine dose was decreased when he started taking aripiprazole, thereby reducing serotonergic effects. Parts of his treatment on arrival to the PICU included bromocriptine, dantrolene, and benztropine. Although bromocriptine and dantrolene are appropriate to treat NMS, along with supportive measures, benztropine is an anticholinergic, which could impair thermoregulation.

This case also highlights how cytochrome P450 enzymes may be important to consider when selecting psychotropic medication and their potential tolerability in patients, especially when patients are prescribed other medications for mood disorders. Interestingly, our patient was on bupropion, a CYP2D6 inhibitor, and aripiprazole, which is metabolized by CYP2D6. His pharmacokinetic gene profile revealed that CYP2D6 was an intermediate metabolizer. Thus, aripiprazole would be metabolized more slowly, thereby prolonging its effect. This case suggests the importance of considering hepatic enzymes when deciding between which psychotropic medications may be most tolerable to the patient, which may benefit from further research.

Consent

Written informed consent was obtained.