Methylphenidate-Induced Neuroleptic Malignant Syndrome

Abstract

Sir: Methylphenidate is a piperidine derivative, structurally related to amphetamines. It reaches peak blood concentration in 2 hours and has a short half-life of 1 to 2 hours. Its onset of action occurs shortly after dosing, and it can cause increased wakefulness, energy, alertness, and physical and mental performance. Its side effects include anorexia, weight loss, slow growth, insomnia, dysphoria, tics, and psychosis. There is a single case report of methylphenidate causing neuroleptic malignant syndrome (NMS) in a 1-year-old child with encephalomalacia.1 We report the first case of methylphenidate causing increased creatine kinase levels and possible neuroleptic malignant syndrome in a patient who had autistic disorder in the absence of any brain malformation. Case report. A 10-year-old African American boy with autistic disorder (DSM-IV criteria) was admitted in 2002 to the child psychiatry inpatient unit as a crisis intervention measure to stabilize his numerous behavioral problems. The behavior of the patient was characterized by constant fidgetiness, restlessness, kicking, biting, and spitting. He also was throwing things and trying to run away. The patient was started on treatment with risperidone and clonazepam without success—he spit out his medications. In view of the escalation of the patient's behavioral problems, intramuscular haloperidol and lorazepam were tried on an as-needed basis. After 2 injections each of haloperidol (5 mg) and lorazepam (2 mg) over 1 to 2 days, the patient had a dystonic reaction and was treated with diphenhydramine. However, after the patient received an additional 4 doses each of haloperidol (total of 20 mg) and lorazepam (total of 8 mg) by intramuscular injection over 2 days, he developed signs and symptoms suggestive of NMS, including fever, tachycardia, elevated white blood cell count, and creatine kinase (CK) levels elevated to over 8000 U/L. The patient was transferred to the pediatric intensive care unit and treated appropriately by stopping haloperidol and starting intravenous hydration and sedation. The patient was transferred back to the psychiatric unit after his CK level, showing a downward trend, had decreased to 2000 U/L. However, the behavioral problems in the form of aggression, spitting, and throwing things continued, and the patient was also constantly fidgety and restless. At this stage, a trial of methylphenidate was considered with the hope of decreasing the patient's restlessness and fidgetiness. After he received the first and only dose of methylphenidate, 5 mg, he was noted to be relatively calm and less fidgety. However, the patient subsequently developed a fever, and his CK level increased from 690 U/L at the time of methylphenidate administration to 1033 U/L 5 hours after methylphenidate administration. During this time, the patient was not agitated and not restrained and received no intramuscular injections that might explain the elevation of CK levels. One day after the administration of methylphenidate, the patient's fever subsided and his CK level dropped to 618 U/L and continued to drop further. No further doses of methylphenidate were administered. Neuroleptic malignant syndrome is a potentially life-threatening condition that presents with hyperthermia, mental status changes, oculogyric crisis, autonomic instability, and increased CK levels. Potential risk factors are previous episodes of NMS, psychomotor agitation, dehydration, rapid increase of neuroleptic medication, and parenteral routes of administration. Conventional and atypical antipsychotics have been implicated in its causation, as are any agents that possess dopaminergic antagonistic action. In the present, we do not know if the patient would have developed all the signs and symptoms of NMS if he had continued to receive methylphenidate. However, he certainly had a significant CK level elevation that was related to methylphenidate. Since elevated CK levels are seen in about 95% of patients with NMS,2 it is likely that he might have developed a full-blown NMS. It is possible that patients who have a propensity to develop NMS with antipsychotic medication are also likely to develop NMS with methylphenidate. Typically, NMS is caused by blockade of dopaminergic receptors. However, methylphenidate acts by inhibiting reuptake of dopamine, and therefore the mechanism by which it caused elevation of CK levels is not known. Prior to this report, there has been only 1 case report describing neuroleptic malignant syndrome following methylphenidate administration, and that was in a 1-year-old child with encephalomalacia.1 This is the first case of NMS in a person without brain malformation. Methylphenidate should be used with caution in patients who have had an adverse reaction to antipsychotics. We believe that further experience is required before we can come to a definite conclusion that methylphenidate indeed can cause NMS and also before we can determine the mechanism by which it does so.