REVIEW OF: Ray WA et al, J Child Adolesc Psychopharmacol 2024;34(9):397–406

STUDY TYPE: Retrospective cohort study

Neuroleptic malignant syndrome (NMS) is one of the most feared complications of antipsychotic treatment, but its true incidence in children has been hard to pin down.

Using Medicaid data from all 50 states, researchers followed 1.66 million children and young adults ages 2–24 who started oral antipsychotics and examined how risk varied by medication type, dose, timing, and co-prescribed drugs. NMS was uncommon, with an overall incidence of about 5 cases per 100,000 person-years of antipsychotic exposure. Risk was highest in the first 30 days after starting treatment and increased with higher initial doses.

First-generation antipsychotics carried a slightly higher risk than second-generation agents, with haloperidol standing out. Concomitant lithium use was the strongest risk factor, tripling the likelihood of NMS. Risk did not differ meaningfully by sex; however, five factors were associated with increased risk: (1) age 18–24, (2) first-generation drugs, (3) doses of at least 200 mg chlorpromazine-equivalent, (4) schizophrenia spectrum disorders, and (5) neurodevelopmental disorders. Moreover, only about one-third of identified cases received classic NMS treatments such as dantrolene or bromocriptine, suggesting delayed recognition or inconsistent management.

CARLAT TAKE
This correlation study cannot prove causation, but it should raise our awareness, particularly given the study’s scope (oral antipsychotics, Medicaid, and a wide age range). NMS is rare in youth but can appear early, during initiation or rapid titration (or reduction), especially with high-potency antipsychotics or lithium, and in patients with schizophrenia spectrum or neurodevelopmental disorders. Start low, titrate thoughtfully, and slow down when combining agents. During the first few weeks, educate families about red flags (rigidity, confusion, high fever) and have a low threshold for medical evaluation. You may rarely see NMS, but recognizing it fast is what matters.