From Pages to Practice

By Angela Castellanos, MD

Published May 1, 2019


Jay is a 14-year-old boy who comes with his dad to your primary care office for a follow-up to a school evaluation for attention deficit–hyperactivity disorder (ADHD). He has been struggling in school for the last few years, and his parents have noted that he has trouble staying on task at home as well. He underwent a comprehensive examination with a school psychologist and, along with the psychologist’s assessment, your assessment, and teacher reports, meets the Diagnostic and Statistical Manual of Mental Disorders criteria for ADHD.

You recommend that Jay start a stimulant medication in conjunction with the tutoring and support he is currently receiving at school. His father is reluctant to start Jay on stimulant medications because of potential side effects and mentions that he heard about a study that suggests these medications can “make you psychotic.” Jay’s father wants to know the dangers associated with ADHD medications.

In an observational study published in March in NEJM, Moran and colleagues used a large insurance claims database from 2004 to 2015 to investigate the prevalence of new diagnoses of psychosis requiring antipsychotic treatment after the initiation of prescription stimulants in adolescents and young adults (ages 13–25 years). Although an observational study cannot demonstrate causality because of unmeasured confounders, the results did demonstrate a small increased risk of new-onset psychosis in patients receiving prescription stimulants. Notably, this small risk was about double the risk found in patients who were started on methylphenidate.

The finding of a small risk associated with amphetamines does not negate the importance and benefit of ADHD treatment in the thousands of children and young adults diagnosed each year. The results add to the evidence in support of a preference for initiating methylphenidate over amphetamines. 

The following NEJM Journal Watch summary further explains the study and its findings.


Small Risk for Psychosis After Stimulant Prescription for ADHD

Nevertheless, rates are twice as high with amphetamine as with methylphenidate.

Psychotic adverse effects from stimulants are well documented in stimulant abusers but have been infrequently studied in individuals prescribed stimulants for attention-deficit/hyperactivity disorder (ADHD). These researchers examined insurance claims during 2004–2015 for adolescents and young adults (age range, 13–25) with new stimulant prescriptions for ADHD and no psychosis diagnoses or treatments.

Propensity scores were used to match people taking methylphenidate (MPH) and those taking amphetamine (110,923 in each group), with 143,286 person-years of follow-up (which ended with psychosis diagnosis, stimulant discontinuation, or study end). The primary outcome (a new diagnostic code for psychosis plus antipsychotic prescription) was met by a significantly higher percentage of the amphetamine group than the MPH group (0.21% vs. 0.10%). Incident rate of psychosis was 1.78/1000 patient-years in the MPH group and 2.83/1000 patient-years in the amphetamine group, yielding a hazard ratio of 1.65 with amphetamine. Median time to psychosis was 128 days. Psychosis risk was lower in patients treated by psychiatrists and higher with extended-release than with immediate-release compounds and in the youngest participants.

Comment: These observational data indicate that the risk for psychosis with stimulants is small. Causality could not be determined due to unmeasured confounding. While stimulant abuse could not be directly controlled for, its role as a confounder seems unlikely given that risk was highest in younger patients, who were less likely to abuse drugs than college-age patients, and was higher with less-abused extended-release compounds. Lower psychosis rates when psychiatrists prescribe might relate to their greater skills in noticing subtle psychosis risk factors or their caution with more psychiatrically ill referred patients. As the editorialist discusses, since stimulant discontinuation is often sufficient to resolve psychosis and to allow consideration of rechallenge, MPH would likely be the preferred stimulant to try.

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Angela Castellanos is a general pediatrician and editorial fellow at the NEJM.