Risk of Newly Diagnosed Psychotic Symptoms in Youth Receiving Medications for Attention-Deficit/Hyperactivity Disorder

Objective

Epidemiological studies suggest that patients with attention-deficit/hyperactivity disorder (ADHD) treated with amphetamines have an increased risk of newly diagnosed psychosis. This risk in youth is poorly understood. This investigation studied the potential risk of newly diagnosed psychotic symptoms associated with exposure to 4 classes of ADHD medications.

Method

This retrospective study used a medical records–linkage system from a cohort of youth (age 6-18 years) with diagnosed ADHD who were prescribed amphetamines, methylphenidate, atomoxetine, or α-2 agonists. Cohort members with any diagnosis of psychosis before their first ADHD medication were excluded. The primary outcome was newly diagnosed psychotic symptoms. The risk for psychotic symptoms for each medication (vs the remaining medication classes combined) was estimated using a multivariable time-varying covariate Cox proportional hazard regression model that adjusted for sex and age at ADHD diagnosis.

Results

Of 5,171 youth (68.6% male), 134 (2.6 %) had newly diagnosed psychotic symptoms. Exposure to amphetamine (vs amphetamine nonexposure, hazard ratio 1.41, 95% CI 1.15-2.26) and atomoxetine (vs atomoxetine nonexposure, hazard ratio 2.01, 95% CI 1.38-2.92) was associated with increased risk of newly diagnosed psychotic symptoms. Secondary analysis showed that the frequency of newly diagnosed psychotic symptoms was higher with atomoxetine/stimulant lifetime combination therapy (12.5% with amphetamines, 7.7% with methylphenidate) than atomoxetine monotherapy (1.2%).

Conclusion

Risk of newly diagnosed psychotic symptoms was low. These results suggest that cumulative exposure to amphetamines or atomoxetine/stimulant lifetime combination therapy may be associated with an increased risk of newly diagnosed psychotic symptoms in youth with ADHD.

Plain language summary

This retrospective study, using the Rochester Epidemiology Project, looked at the risk of developing newly diagnosed psychotic symptoms in youth (n = 5,171 between 6- to 18-years-old) with attention-deficit/hyperactivity disorder (ADHD) treated with 4 different classes of US FDA approved medications. The authors found that the overall absolute risk of psychosis was low. The risk of newly diagnosed psychotic symptoms was higher in youth treated with amphetamines and atomoxetine. In addition, this risk was observed when atomoxetine was combined with methylphenidate, amphetamine, or both. Authors suggest that this association may be related to attentional difficulties presenting as a prodromal symptom of psychosis or related to polypharmacy in youth with treatment-resistant ADHD.

Diversity & Inclusion Statement

We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.