TY - JOUR

T1 - Genetic, Clinical, and Sociodemographic Factors Associated With Stimulant Treatment Outcomes in ADHD

AU - Brikell, Isabell

AU - Wimberley, Theresa

AU - Albinana, Clara

AU - Pedersen, Emil Michael

AU - Vilhjalmsson, Bjarni Johann

AU - Agerbo, Esben

AU - Demontis, Ditte

AU - Borglum, Anders D.

AU - Schork, Andrew J.

AU - LaBianca, Sonja

AU - Werge, Thomas

AU - Mors, Ole

AU - Hougaard, David M.

AU - Thapar, Anita

AU - Mortensen, Preben Bo

AU - Dalsgaard, Soren

PY - 2021

Y1 - 2021

N2 - Objective: Stimulant medications are effective for treating attention deficit hyperactivity disorder (ADHD), yet discontinuation and switch to nonstimulant ADHD medications are common. This study aimed to identify genetic, clinical, and sociodemographic factors influencing stimulant treatment initiation, discontinuation, and switch to nonstimulants in individuals with ADHD.Methods: The authors obtained genetic and national register data for 9,133 individuals with ADHD from the Danish iPSYCH2012 sample and defined stimulant treatment initiation, discontinuation, and switch from prescriptions. For each stimulant treatment outcome, they examined associations with polygenic risk scores (PRSs) for psychiatric disorders and clinical and sociodemographic factors using survival analyses, and conducted genome-wide association studies (GWASs) and estimated single-nucleotide polymorphism heritability (h(SNP)(2)).Results: Eighty-one percent of the sample initiated stimulant treatment. Within 2 years, 45% discontinued stimulants and 15% switched to nonstimulants. Bipolar disorder PRS (hazard ratio=1.05, 95% CI=1.02, 1.09) and schizophrenia PRS (hazard ratio=1.07, 95% CI=1.03, 1.11) were associated with discontinuation. Depression, bipolar disorder, and schizophrenia PRSs were marginally but not significantly associated with switch (hazard ratio range, 1.05-1.07). No associations were observed for ADHD and autism PRSs. Individuals diagnosed with ADHD at age 13 or older had higher rates of stimulant initiation, discontinuation, and switch (hazard ratio range, 1.27-2.01). Psychiatric comorbidities generally reduced rates of initiation (hazard ratio range, 0.84-0.88) and increased rates of discontinuation (hazard ratio range, 1.19-1.45) and switch (hazard ratio range, 1.40-2.08). h(SNP)(2) estimates were not significantly different from zero. No GWAS hits were identified for stimulant initiation or discontinuation. A locus on chromosome 16q23.3 reached genome-wide significance for switch.Conclusions: The study findings suggest that individuals with ADHD with higher polygenic liability for mood and/or psychotic disorders, delayed ADHD diagnosis, and psychiatric comorbidities have a higher risk for stimulant treatment discontinuation and switch to nonstimulants. Despite the study's limited sample size, one putative GWAS hit for switch was identified, illustrating the potential of utilizing genomics linked to prescription databases to advance ADHD pharmacogenomics.

AB - Objective: Stimulant medications are effective for treating attention deficit hyperactivity disorder (ADHD), yet discontinuation and switch to nonstimulant ADHD medications are common. This study aimed to identify genetic, clinical, and sociodemographic factors influencing stimulant treatment initiation, discontinuation, and switch to nonstimulants in individuals with ADHD.Methods: The authors obtained genetic and national register data for 9,133 individuals with ADHD from the Danish iPSYCH2012 sample and defined stimulant treatment initiation, discontinuation, and switch from prescriptions. For each stimulant treatment outcome, they examined associations with polygenic risk scores (PRSs) for psychiatric disorders and clinical and sociodemographic factors using survival analyses, and conducted genome-wide association studies (GWASs) and estimated single-nucleotide polymorphism heritability (h(SNP)(2)).Results: Eighty-one percent of the sample initiated stimulant treatment. Within 2 years, 45% discontinued stimulants and 15% switched to nonstimulants. Bipolar disorder PRS (hazard ratio=1.05, 95% CI=1.02, 1.09) and schizophrenia PRS (hazard ratio=1.07, 95% CI=1.03, 1.11) were associated with discontinuation. Depression, bipolar disorder, and schizophrenia PRSs were marginally but not significantly associated with switch (hazard ratio range, 1.05-1.07). No associations were observed for ADHD and autism PRSs. Individuals diagnosed with ADHD at age 13 or older had higher rates of stimulant initiation, discontinuation, and switch (hazard ratio range, 1.27-2.01). Psychiatric comorbidities generally reduced rates of initiation (hazard ratio range, 0.84-0.88) and increased rates of discontinuation (hazard ratio range, 1.19-1.45) and switch (hazard ratio range, 1.40-2.08). h(SNP)(2) estimates were not significantly different from zero. No GWAS hits were identified for stimulant initiation or discontinuation. A locus on chromosome 16q23.3 reached genome-wide significance for switch.Conclusions: The study findings suggest that individuals with ADHD with higher polygenic liability for mood and/or psychotic disorders, delayed ADHD diagnosis, and psychiatric comorbidities have a higher risk for stimulant treatment discontinuation and switch to nonstimulants. Despite the study's limited sample size, one putative GWAS hit for switch was identified, illustrating the potential of utilizing genomics linked to prescription databases to advance ADHD pharmacogenomics.

KW - ATTENTION-DEFICIT/HYPERACTIVITY DISORDER

KW - DRUG-TREATMENT

KW - MEDICATION

KW - CHILDREN

KW - RISK

KW - METHYLPHENIDATE

KW - DISCONTINUATION

KW - SCHIZOPHRENIA

KW - ADOLESCENTS

KW - DIAGNOSIS

U2 - 10.1176/appi.ajp.2020.20121686

DO - 10.1176/appi.ajp.2020.20121686

M3 - Journal article

C2 - 34154395

VL - 178

SP - 854

EP - 864

JO - The American Journal of Psychiatry

JF - The American Journal of Psychiatry

SN - 0002-953X

IS - 9

ER -