title: Attention-deficit hyperactivity disorder, its pharmacotherapy, and the risk of developing bipolar disorder: A nationwide population-based study in Taiwan.
abstract: In this study, we aimed to evaluate the relationship between attention-deficit/hyperactivity disorder (ADHD) during childhood and subsequent diagnoses of bipolar disorder (BD), as well as to determine whether the pharmacotherapy for ADHD (methylphenidate and atomoxetine) influence the risks of developing BD. A nationwide cohort of patients newly diagnosed with ADHD (n = 144,920) and age- and gender-matching controls (n = 144,920) were found in Taiwan's National Health Insurance database from January 2000 to December 2011. Both patients and controls were observed until December 31, 2011. To determine the effect that the duration of methylphenidate and atomoxetine exposure had on BD, the difference in the risk of developing BD was compared among non-users, short-term users (≤ 365 days), and long-term users (>365 days). In comparison to the control group, the ADHD group showed a significantly increased risk of developing BD (ADHD: 2.1% vs.
  
  
  METHODS
  0.4%; aHR: 7.85, 95% CI: 7.09-8.70), and had a younger mean age at the time of first diagnosis (ADHD: 12.0 years vs.
  
  
  METHODS
  18.8 years). Compared to ADHD patients that had never taken methylphenidate, patients with long-term use of methylphenidate were less likely to be diagnosed with BD (aOR: 0.72, 95% CI: 0.65-0.80). However, the duration of exposure to atomoxetine did not have a significant relationship to a BD diagnosis. The results suggested that a previous diagnosis of ADHD was a powerful indicator of BD, particularly juvenile-onset BD. Nevertheless, the exact mechanisms of the relationships among ADHD, its pharmacotherapy, and BD require further clarification in the future.
authors.affiliation: Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Liang-Jen
authors.initials: LJ
authors.lastname: Wang
authors.affiliation: Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan.
authors.forename: Yu-Chiau
authors.initials: YC
authors.lastname: Shyu
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Shin-Sheng
authors.initials: SS
authors.lastname: Yuan
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan; Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan; Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Kang-Chung
authors.initials: KC
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States.
authors.forename: Tung-Liang
authors.initials: TL
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Psychiatry, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan. Electronic address: shirleylee.ncku@gmail.com.
authors.forename: Sheng-Yu
authors.initials: SY
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000069445:Atomoxetine Hydrochloride / Q000627:therapeutic use; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000453:epidemiology*; D001714:Bipolar Disorder / Q000453:epidemiology*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D002648:Child; D015331:Cohort Studies; D015897:Comorbidity; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use; D012306:Risk; D016019:Survival Analysis; D013624:Taiwan / Q000453:epidemiology
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride
keywords: ADHD; Cohort study; Comorbidity; Epidemiology; Mood disorders; Stimulant