Long term safety of ADHD medication in patients with schizophrenia spectrum disorders

Attention-deficit hyperactivity disorder (ADHD) is frequently comorbid with schizophrenia spectrum disorders (SSDs) and is associated with poorer outcomes. Yet, its pharmacological treatment in patients with SSDs has been hampered by safety concerns. We therefore examined whether psychiatric, cardiovascular and other medical outcomes are associated with the use of ADHD medications in people with SSDs (N = 131,476). The main outcome was all-cause hospitalization/mortality. Secondary outcomes were hospitalization for psychosis, somatic hospitalization, and cardiovascular hospitalization. Adjusted hazard ratios (aHRs) were calculated for the association between the outcomes and the different exposure categories (compared with non-use of ADHD medication) using within-individual Cox regression analyses. Lisdexamphetamine was associated with a decreased risk of all-cause hospitalization/mortality (aHR = 0.89, 95%CI = 0.84-0.94) and methylphenidate with a slightly increased risk (aHR = 1.04 [1.01-1.08]), while for the other exposures the 95%CI of the HRs encompassed 1. Atomoxetine was associated with a reduced risk of hospitalization for psychosis (aHR = 0.87 [0.78-0.98]), lisdexamphetamine with a reduced risk of somatic hospitalizations (aHR = 0.70 [0.58-0.84]), and ADHD polytherapy with an increased risk of somatic hospitalizations (aHR = 1.37 [1.07-1.74]). No other statistically significant associations were found between the exposures and outcomes (including cardiovascular hospitalizations). Furthermore, increased all-cause hospitalization/mortality risks for methylphenidate were only found with doses ≥95 mgs/day (aHR 1.08 [1.03-1.14]) or during use periods of this agent without concomitant use of an antipsychotic (aHR = 1.06 [1.01-1.12]). Finally, for methylphenidate and lisdexamphetamine, we found evidence of U-shaped associations between doses used and risks of all-cause hospitalization/mortality and psychosis. In conclusion, we find that for people with SSDs, the use of ADHD medication (particularly lisdexamphetamine in all dosages and long-acting methylphenidate in low to medium doses) is safer than generally conceived. The benefits of its use for patients with SSD and comorbid ADHD should therefore be weighed against the risks in a shared decision-making process aimed at improving patients' chances of recovery.