A Pharmacokinetic and Clinical Evaluation of Switching Patients With Bipolar I Disorder From Delayed-Release to Extended-Release Divalproex

Lori L. Davis, M.D.; Xiaohua Li, M.D., Ph.D.; Al A. Bartolucci, Ph.D.; Raela B. Williford, Pharm.D.; and Joette S. Lowe, Pharm.D.

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).

Method: 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 mg/mL) and lowest 24-hour (44 mg/mL) levels. The ER + 500 dose was the only regimen that maintained the mean minimum valproic acid concentration above 50 mg/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.

(J Clin Psychiatry 2007;68:1546-1551)

Received Oct. 2, 2006; accepted Jan. 23, 2007. From the Research and Development Department, Tuscaloosa VA Medical Center, Tuscaloosa (Drs. Davis and Williford); the Department of Psychiatry, University of Alabama School of Medicine, Birmingham (Drs. Davis and Li); the Department of Biostatistics, University of Alabama at Birmingham, Birmingham (Dr. Bartolucci); and Pharmacy Benefits, Southeast Network, Veterans Health Administration, Tuscaloosa (Dr. Lowe), Ala.

This study was supported by an investigator-initiated grant from Abbott Laboratories, Chicago, Ill. The authors acknowledge the support of VA Research and Development, Tuscaloosa VA Medical Center, Tuscaloosa, and the Department of Psychiatry and Behavioral Neurobiology, University of Alabama School of Medicine, Birmingham, Ala.

An interim analysis was presented at the 43rd annual New Clinical Drug Evaluation Unit meeting, May 28, 2003, Boca Raton, Fla.

The authors appreciate the technical nursing assistance of Sandra Ambrose, M.S.N., University of Alabama, Tuscaloosa, and Elizabeth Waldrop, R.N., Tuscaloosa VA Medical Center, as well as the editing support of Kaplan Communications, LLC, Fairfield, Conn.

Financial disclosure appears at the end of the article.

Corresponding author and reprints: Lori L. Davis, M.D., VA Medical Center, 3701 Loop Rd. E., Tuscaloosa, AL 35404 (e-mail: lori.davis@va.gov).