Data Sources

In this cohort study, we used administrative claims databases from two U.S. health care organizations with national coverage, Optum Clinformatics and IBM MarketScan. The Clinformatics database consists of medical and pharmacy claims for patients with United Healthcare insurance, with data available for 68 million patients. MarketScan is a similar source for claims from large employers and insurance plans, with data available for 185 million patients. The study used deidentified data and was approved by the institutional review board of Partners HealthCare. Data licensing agreements allowed Partners HealthCare to use the Optum and IBM databases.

Study Population

Figure 1. Figure 1. Study Cohorts. Incident users of methylphenidate or amphetamine were defined as patients who received a new prescription for one of these drugs, with no previous prescription claims for the stimulant during the 12 months before cohort entry. ADHD denotes attention deficit–hyperactivity disorder, and CNS central nervous system.

Eligible patients were 13 to 25 years of age at entry into the cohort, had had one or more outpatient encounters with a diagnosis of ADHD (defined on the basis of International Classification of Diseases, 9th Revision [ICD-9], code 314), and started taking amphetamine or methylphenidate between January 1, 2004, and September 30, 2015. One year of continuous enrollment in medical and prescription drug services before stimulant use was required. The cohort entry date was defined as the date that the stimulant was first dispensed. To eliminate current users and facilitate detection of new-onset psychosis related to treatment, we defined incident use as a new prescription for methylphenidate or amphetamine, with no previous prescription claims for those drugs during the 12 months before cohort entry.13 We excluded patients with unspecified psychosis, hallucinations, delusional disorder, schizophrenia spectrum disorders, drug-induced psychoses, mood disorders with psychotic features, bipolar disorder, central nervous system disease, or narcolepsy. We also excluded patients who were receiving mood stabilizers, antipsychotic medication, or stimulants not typically used for ADHD (phentermine, pemoline, or methamphetamine) during the 12 months before entry into the cohort. Patients who received a prescription for oral glucocorticoids in the 60 days before entry into the cohort were also excluded because of the potential association of these drugs with psychosis (Figure 1).14

Figure 2. Figure 2. Overview of the Study Design. The washout period required that patients be enrolled in medical and prescription drug services for 365 days before initial use of a stimulant. Cohort entry is defined as the date of the first prescription claim for methylphenidate or amphetamine.

The amphetamine group included patients who began receiving amphetamine–dextroamphetamine, dextroamphetamine, or lisdexamfetamine (a prodrug of dextroamphetamine). The methylphenidate group included patients who began receiving methylphenidate or dexmethylphenidate (the d-threo-enantiomer of methylphenidate). Follow-up started 7 days after the date of the initial dispensation of a stimulant drug, because we assumed that psychosis that resulted in antipsychotic treatment within 1 week after a patient started a stimulant was unlikely to be caused by exposure to the medication, since events during the first 7 days are transient and resolve without the need for an antipsychotic medication.15 Data for participants were censored at the time of occurrence of psychosis, discontinuation of the stimulant (defined as 60 days after the end of stimulant treatment), crossover to use of the other stimulant, death, end of enrollment, or end of the study (on December 31, 2016 [15 months after enrollment of the last new patients]), whichever occurred first (Figure 2).

Outcomes

The primary outcome was an ICD-9 or ICD-10 code for a new inpatient or outpatient diagnosis of psychosis and a prescription claim for antipsychotic medication on the same day as the initial diagnosis of psychosis or within 60 days thereafter. The following diagnoses qualified as psychosis: unspecified psychosis, hallucinations, delusional disorder, other stimulant use disorders with psychosis, schizophrenia spectrum disorders, and major depressive disorder or bipolar disorder with psychotic features. (The ICD-9 and ICD-10 codes and the antipsychotic medications used to determine the outcome are provided in Tables S1 and S2 in the Supplementary Appendix, available with the full text of this article at NEJM.org.) This definition of psychosis was based on a validation study conducted with the use of data from an external New England electronic health record database (Partners HealthCare Research Patient Data Registry), which yielded a positive predictive value of 93.1%.

We used two strategies for internal validation of the outcome (details of internal and external validation are provided in the Supplementary Appendix). First, we conducted a claims profile review16,17 in which all claims for medication prescriptions, inpatient hospitalizations, and diagnoses and procedure codes for outpatient visits were ordered by date of service or dispensation of medication. Claims profiles for each patient with a psychotic episode were reviewed by a psychiatrist (who was unaware of the stimulant group) starting with the date the patient began taking the stimulant and ending 180 days after the initial diagnosis of psychosis to determine whether the medical history was consistent with psychosis. This allowed us to identify patients who had a diagnosis code for psychosis and were treated with an antipsychotic medication but were unlikely to have true psychosis. The positive predictive value for the outcome definition (a diagnosis of psychosis and a prescription for an antipsychotic medication within 60 days after the initial diagnosis of psychosis) from this interval validation study was 91.3% across both databases. The percentage of patients who were unlikely to have had true psychosis was similar in the methylphenidate group and the amphetamine group (10.1% and 8.4%, respectively). Second, we performed analyses that used the following additional stringent outcome definitions of psychosis: prescription of an antipsychotic medication within 30 days rather than 60 days after the initial diagnosis, one inpatient or two outpatient encounters with a diagnosis of psychosis, two inpatient or outpatient encounters with diagnoses of psychosis, and one diagnosis of psychosis and two prescriptions for an antipsychotic medication.

Statistical Analysis

To address potential confounders for the primary prespecified analysis, we used propensity-score matching. Each patient who started receiving methylphenidate was matched in a 1:1 ratio with a patient who started receiving amphetamine. Propensity scores were estimated with the use of logistic-regression models to predict assignment of methylphenidate or amphetamine with the use of all prespecified covariates. The maximum permitted difference in propensity score between matched patients was 1%.18

Standardized mean differences were compared before and after propensity-score matching to evaluate how well matching balanced potential confounders for the two stimulant groups.19 Potential confounders were defined during the 365-day baseline period and included year of cohort entry, age at cohort entry, sex, geographic region, and insurance type. Markers of ADHD severity included the number of outpatient visits for ADHD, emergency department or inpatient hospitalization with a diagnosis of ADHD, treatment with nonstimulant medications, coexisting oppositional–defiant or conduct disorder, and asthma (because previous research has reported increased severity of ADHD symptoms in patients with asthma).20 We assessed coexisting psychiatric disorders and medications, substance use disorders, provider type, and overall health care utilization (Table S3 in the Supplementary Appendix). These potential confounders were defined according to ICD-9 codes, National Drug Codes, and Current Procedural Terminology procedure codes. For missing data, indicator variables for missing age, sex, region, and insurance type were included in our models. The percentage of patients with missing data for these variables was low (0.002 to 2.400%).

Hazard ratios and 95% confidence intervals were estimated with Cox proportional-hazards models in the matched population in each database. Power analyses showed at least 80% power to detect a 50% higher risk of psychosis with amphetamine than with methylphenidate. Because of the low rate of psychosis, we chose a priori to pool results from the two databases using a fixed-effects meta-analysis. In a secondary analysis, multivariable Cox proportional-hazards outcome models without propensity-score matching were fitted, with adjustment for covariates. Analysis of Schoenfeld residuals showed no violations of the proportional-hazards assumption.

We conducted additional prespecified sensitivity analyses. We extended the exposure risk window to 90 days after stimulant discontinuation. To reduce potential bias from differential follow-up times between stimulant groups, we limited the maximal follow-up to 100 days. To account for potential overlap between the databases, we adjusted 95% confidence intervals to assume 10%, 20%, or 40% overlap.

Post hoc analyses included starting follow-up 1 day instead of 7 days after initial exposure to the stimulant; limiting maximal follow-up to 180 and 365 days; decreasing the exposure risk window to 30 days; and following patients for 365 days and assessing them according to the initial stimulant group, regardless of whether they switched to the other stimulant or discontinued the stimulant. We also performed subgroup analyses stratified according to type of provider (family medicine or internal medicine physicians, pediatricians, or psychiatrists) and age (precollege [13 to 17 years of age] or college [18 to 25 years of age]). We evaluated the rate of psychosis in patients who were prescribed only extended-release formulations, lisdexamfetamine as compared with extended-release methylphenidate, and immediate-release formulations.

A higher risk of psychosis with amphetamine than with methylphenidate could be explained by a higher rate of substance use or more severe psychiatric illness among amphetamine users, which would not have been captured in claims data. To account for this possibility, we performed negative control analyses, in which differences between the groups in the outcomes of emergency department visits or inpatient hospitalizations for alcohol use disorder, all other substance use disorders combined, cannabis use disorders, opioid use disorders, and major depressive disorder without psychotic features at 100 days of follow-up served as negative controls. We estimated the difference between stimulant groups in the prevalence of an unmeasured confounder (e.g., cannabis use) that would fully explain a higher risk of psychosis in one group than in the other.21 Additional sensitivity analyses are described in the Supplementary Appendix. Analyses were performed with the use of the Aetion platform and R software, version 3.2.1.5, which has previously been validated for a range of studies22,23 and for predicting findings in clinical trials.24