The Safety of Psychostimulants or Atomoxetine for Patients With Psychotic Disorders

Nicholas Distefano, MD;Bransen Guild, DO;David Wilton, MD;Mullen,Mark;Tampi,Rajesh;

A monthly column dedicated to reviewing the literature and sharing clinical implications.

Available evidence indicates that children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have a more than 4-fold increased risk of schizophrenia spectrum and other psychotic disorders (SZSPD) in adulthood compared with the general population. Additionally, ADHD is associated with worse clinical, social, occupational, and treatment outcomes among individuals with SZSPD. It has been unclear whether the risk of psychotic relapse among individuals with SZSPD is higher when they are treated with ADHD medications, including amphetamines, methylphenidate, and atomoxetine.

Janssen (division of Johnson & Johnson) and the Ministère de l’Économie, de l’Innovation et de l’Énergie

This retrospective cohort study was conducted to examine the risk of hospital admission for psychosis among individuals with SZSPD during the year following the introduction of psychostimulants or atomoxetine compared with the year before.

The researchers extracted data from the Régie de l’assurance maladie du Québec health databases to get cohort data on individuals with SZSPD. Data was extracted from January 1, 2002, to December 31, 2017. Individuals included in the study were those with SZSPD of any age who initiated a psychostimulant or atomoxetine between January 1, 2010, and December 31, 2016, with continuous Public Prescription Drug Insurance Plan coverage 1 year before and 1 year after initiation of treatment. Patients were excluded if they were not prescribed an antipsychotic medication 30 days before and after initiation of a psychostimulant. A person was considered exposed/taking medications from the date that the drug was picked up from their outpatient pharmacy.

The primary dependent variable was the time until a hospital admission for psychosis 1 year after psychostimulant or atomoxetine initiation. The secondary dependent variable was the time until hospital admission for mental disorders other than psychosis. Multiple different covariables were analyzed including sex at birth, low socioeconomic status, age at psychostimulant or atomoxetine initiation, psychosis duration, initial prescriber of psychostimulant or atomoxetine initiation (psychiatrist or other clinician), prescriber of the antipsychotic near the index date (psychiatrist or other clinician), substance use disorder during the 12-month period prior to psychostimulant or atomoxetine initiation, personality disorder diagnosis, hospital admissions for reasons other than psychosis (psychiatric or medical), number of ambulatory visits, and comorbidity index. Investigators also assessed the use of other psychotropic medication including lithium, valproic acid, lamotrigine, antidepressant, or benzodiazepines.

Multiple statistical analyses were done on the data. State sequence analysis was used to demonstrate psychostimulant and/or atomoxetine use trajectories, antipsychotic utilization trajectories before and after ADHD medication initiation, and hospital admission trajectories. Cox regression modeling was performed with time-dependent psychostimulant or atomoxetine and antipsychotic drug variables, including all the covariables. The McNemar nonparametric test for paired data was used to analyze the prevalence of hospital admission for nonmental disorders in the year prior to ADHD medication initiation with the prevalence the following year. Post hoc analysis was conducted to examine whether individuals who started ADHD medication were comparable with the population of individuals with SZSPD without ADHD medication use. Up to 4 controls were extracted for each member of the study cohort, matched for sex, year of birth, date of psychosis onset, and antipsychotic use.

Study Strengths

1. The study answered an important clinical question, looking specifically at individuals with a diagnosis of SZSPD who were previously believed to be negatively impacted by psychostimulant/atomoxetine prescription use.

2. This was the first North American study of this type.

3. The study drew data from a large cohort that was representative of a real-world population.

There were 235,027 identified individuals diagnosed with SZSPD between January 2002 and December 2017. Of those, 11,391 individuals had utilized psychostimulants or atomoxetine. After applying all inclusion and exclusion criteria, the final study population consisted of 2219 individuals: 1589 (71.6%) who were initiated on methylphenidate, 339 (15.3%) who were initiated on amphetamines, and 291 (13.1%) who were initiated on atomoxetine.

Study Limitations

1. No information was obtained about the specific therapeutic indication for psychostimulant or atomoxetine prescription.

2. There was no information about the mean/median dose of psychostimulant/atomoxetine used.

3. The results may not be widely applicable in populations that are demographically different from the cohort population.

Utilization of psychostimulants and atomoxetine followed a similar trajectory: initial continuous use followed by a decrease in medication adherence over the following year, with approximately 50% of participants not continuously covered by ADHD medication 1 year after its initiation. Antipsychotic adherence remained high throughout the following year, with an early spike immediately following the initiation of ADHD medication. There was an overall reduction in hospital admission rates for psychosis and for mental disorders other than psychosis for all individuals in the year following ADHD medication initiation compared with the previous year. The combination of both methylphenidate (adjusted HR [aHR], 0.37; 95% CI, 0.24-0.57; P < .0001) or atomoxetine (aHR, 0.29; 95% CI, 0.16-0.51; P < .0001) and antipsychotics was associated with a decreased risk of hospital admission for psychosis. A similar trend was seen with amphetamines, although this was not statistically significant (aHR, 0.60; 95% CI, 0.36-1.01; P = .0528). Additionally, hospital admission for psychosis decreased from 15.6% to 11.2% (P < .0001), and hospital admission for mental disorders other than psychosis decreased from 13.7% to 13.1% (P < .0001).

Many individuals with SZSPD may also have comorbid ADHD. Based on this study, the coprescription of psychostimulants or atomoxetine and antipsychotics among these individuals may be safer than has been previously hypothesized/reported.

When individuals with SZSPD are being treated with an antipsychotic medication, it may be beneficial to consider the addition of a psychostimulant medication or atomoxetine when they present with symptoms of ADHD. This study demonstrated that the addition of a psychostimulant medication or atomoxetine among individuals prescribed an antipsychotic medication can decrease the likelihood of inpatient psychiatric hospitalizations for psychosis and for mental disorders other than psychosis in the first year after initiation of the psychostimulant medication or atomoxetine compared with the previous year.

Psychostimulants and atomoxetine, when used in combination with antipsychotics among individuals with SZSPD, decreased the rates of hospital admission for psychosis and for other mental disorders in the first year after their initiation compared with the previous year.

Dr Distefano is a fourth-year psychiatry resident at Creighton University in Omaha, Nebraska. Dr Guild is a fourth-year psychiatry resident at Creighton University. Dr Wilton is a third-year psychiatry resident at Creighton University. Dr Mullen is a fourth-year psychiatry resident at Creighton University. Dr Tampi is a professor and chairman of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut, and he is a member of the Psychiatric Times Editorial board.