Researchers identify factors that influence stimulant discontinuation, switch in ADHD

Several factors increased risk for stimulant treatment discontinuation and switch to nonstimulants among people with ADHD, according to study results published in American Journal of Psychiatry.

These included having higher polygenic liability for mood and/or psychotic disorders, delayed ADHD diagnosis and psychiatric comorbidities.

“Despite the high efficacy of stimulants, many patients discontinue treatment or switch to nonstimulant ADHD medications, with the most common reasons reported being poor treatment response and adverse effects,” Isabell Brikell, PhD, of the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) in Denmark, and colleagues wrote. “Because stimulant treatment has been associated with positive effects on important functional outcomes, it is of clinical importance to identify genetic, clinical and sociodemographic factors that influence stimulant treatment initiation, discontinuation and switch to nonstimulant medications in ADHD. Genetics likely contribute to stimulant treatment response and risk of adverse treatment effects, yet few genetic variants have been robustly linked to stimulant treatment outcomes in ADHD.”

The researchers sought to address this research gap by analyzing genetic and national register data of 9,133 individuals with ADHD who were included in the Danish iPSYCH2012 sample. They used survival analyses to assess associations with polygenic risk scores for psychiatric disorder and clinical and sociodemographic factors for each stimulant treatment outcome. Further, they conducted genome-wide association studies and estimated single-nucleotide polymorphism heritability.

Results showed stimulant treatment initiation among 81% of the sample. A total of 45% discontinued stimulants and 15% switched to nonstimulants within 2 years. The researchers noted an association between discontinuation and bipolar disorder (HR = 1.05; 95% CI, 1.02-1.09) and schizophrenia polygenic risk scores (HR = 1.07; 95% CI, 1.03-1.11). They also noted a marginal but not significant association between switch and depression, bipolar disorder and schizophrenia polygenic risk scores (HR range, 1.05-1.07). However, they reported no associations for ADHD and autism polygenic risk scores. Those diagnosed with ADHD at age 13 years or older had higher rates of stimulant initiation, discontinuation and switch (HR range, 0.84-0.88), as well as higher rates of discontinuation (HR range, 1.19-1.45) and switch (HR range, 1.4-2.08). Single-nucleotide polymorphism heritability estimates did not exhibit significant difference from zero. The researchers identified no genome-wide association study hits for stimulant initiation or discontinuation. They noted a locus on chromosome 16q23.3 reached genome-wide significance for switch.

“Identifying individuals with ADHD at high risk of suboptimal treatment outcomes will likely depend on multifactorial prediction, including both genetic and clinical risk factors,” Brikell and colleagues wrote. “Our GWASs illustrate the potential of utilizing genomics linked to EHRs to identify genetic variants underlying stimulant treatment outcomes in ADHD.”