title: A pharmacokinetic and clinical evaluation of switching patients with bipolar I disorder from delayed-release to extended-release divalproex.
abstract: OBJECTIVE
  To determine the optimal strategy for converting stable bipolar patients from twice-daily divalproex delayed release (DR) to once-daily divalproex extended release (ER).
  
  
  METHODS
  This prospective, open-label, crossover study compared 4 divalproex regimens in euthymic outpatients with bipolar I disorder (DSM-IV diagnosis confirmed by Mini-International Neuropsychiatric Interview). Serum valproic acid levels were collected 12, 16, 20, and 24 hours after the last bedtime dose of the following regimens: DR twice daily (DR b.i.d.) during week 1; total daily DR dose once daily (DR q.h.s.) during week 2; once-daily ER at equal daily DR dose (ER 1:1) during week 3; and once-daily ER with the dose increased by 500 mg (ER + 500) during week 4. Patients continued on ER + 500 for 4 additional weeks after the pharmacokinetic phase. Side effects and psychiatric symptoms were assessed at weeks 1 through 4, 6, and 8. Twenty-one patients were enrolled from July 2002 to July 2004.
  
  
  RESULTS
  Of the regimens tested, DR q.h.s. produced the widest fluctuations in valproic acid levels, with the highest 12-hour (82 mug/mL) and lowest 24-hour (44 mug/mL) levels. The ER + 500 dose was the only regimen that maintained the mean minimum valproic acid concentration above 50 mug/mL. Each regimen was well tolerated, and no significant changes in psychometric indices were observed.
  
  
  CONCLUSIONS
  When converting stable bipolar patients from twice-daily divalproex DR to once-daily ER, we recommend increasing the total daily dose by 250 to 500 mg to ensure maintenance of therapeutic valproic acid levels.
authors.affiliation: Research and Development Department, Tuscaloosa VA Medical Center, Tuscaloosa, AL 35404, USA. lori.davis@va.gov
authors.forename: Lori L
authors.initials: LL
authors.lastname: Davis
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Al A
authors.initials: AA
authors.lastname: Bartolucci
authors.forename: Raela B
authors.initials: RB
authors.lastname: Williford
authors.forename: Joette S
authors.initials: JS
authors.lastname: Lowe
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D001714:Bipolar Disorder / Q000188:drug therapy*; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D011594:Psychometrics; D014635:Valproic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D014635:Valproic Acid