Evidence-Based Reviews

Bipolar disorder: New strategy for checking serum valproate

Current Psychiatry. 2005 December;4(12):31-44

References

1. Glauser TA, Pippenger CE. Controversies in blood-level monitoring: reexamining its role in the treatment of epilepsy. Epilepsia 2000;41(suppl 8):S6-S15.

2. Pellock JM, Willmore LJ. A rational guide to routine blood monitoring in patients receiving antiepileptic drugs. Neurology 1991;41:961-4.

3. Jannuzzi G, Cian P, Fattore C, et al. A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy. Epilepsia 2000;41:222-30.

4. AmericanPsychiatric Association Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 2002;159(suppl 4):1-50.

5. Depakote (divalproex sodium) package insert Abbott Park, IL: Abbott Laboratories; October 2005.

6. Pope HG, Jr, McElroy SL, Keck PE, Jr, Hudson JI. Valproate in the treatment of acute mania. A placebo-controlled study. Arch Gen Psychiatry 1991;48:62-8.

7. Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA 1994;271:918-24.

8. Bowden CL, Janicak PG, Orsulak P, et al. Relation of serum valproate concentration to response in mania. Am J Psychiatry 1996;153:765-70.

9. Allen MH, Baker J, Wozniak PJ. Relationship of serum valproate level to response in mania (abstract presentation). New York: American Psychiatric Association annual meeting, 2004.

10. Keck PE, Jr, McElroy SL, Tugrul KC, Bennett JA. Valproate oral loading in the treatment of acute mania. J Clin Psychiatry 1993;54:305-8.

11. Hirschfeld RM, Allen MH, McEvoy JP, et al. Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry 1999;60:815-18.

12. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000;57:481-9.

13. Keck PE, Jr, Bowden CL, Meinhold JM, et al. Relationship between serum valproate and lithium levels and efficacy and tolerability in bipolar maintenance therapy. Int J Psychiatry Clin Pract (in press).

14. Davis LL, Bartolucci A, Petty F. Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord 2005;85:259-66.

15. Sachs GS, Collins MA, Altshuler LL, et al. Divalproex sodium versus placebo for the treatment of bipolar depression (abstract presentation). San Juan, PR: American College of Neuropsychopharmacology annual meeting, 2001.

16. Wilder BJ. Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 1992;12(suppl 1):64S-68S.

In the loading dose study by Hirschfeld et al,¹¹ patients receiving divalproex, 20 to 30 mg/kg/d, did not experience a higher frequency or severity of side effects compared with patients receiving standard titration. Keck et al¹⁰ also reported minimal valproate-related side effects in their open-label study. Neither study suggested an upper-limit valproate level associated with increased side effects.

Discussion. Serum valproate >125 mcg/mL has been associated with increased side effects (Table 2), but more studies are needed.

Table 2

For bipolar disorder, suggested serum valproate therapeutic ranges*

	Serum valproate (mcg/mL)
	Lower level	Upper level	Comments
Acute mania	45 to 50	125	Upper level based on tolerability, not efficacy
Maintenance	75	100	Levels based primarily on retrospective analysis
Acute bipolar	Not established	Not established
* Based on available data

Clinical recommendations

Carefully consider when to monitor serum valproate levels in your patients with bipolar disorder:

Obtaining routine serum levels can be expensive, and no data support the cost-effectiveness of this approach in bipolar disorder.
Individualize valproate dosing; a specific patient’s therapeutic range may differ from another’s or from those published in the literature or used by a clinical laboratory.
Monitoring serum valproate levels does not replace the need to adjust dosages based on patients’ therapeutic response and tolerance.

Related resources

American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry2002; 159(suppl 4):1–50.
Depression and Bipolar Support Alliance. www.dbsalliance.org.

Drug brand names

Carbamazepine • Tegretol, Equetro
Divalproex sodium • Depakote
Felbamate • Felbatol
Phenytoin • Dilantin

Disclosures

Dr. Kaneria reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Patel is a consultant to and speaker for Eli Lilly and Co. and a speaker for Pfizer.

Dr. Keck receives research support from or is a consultant to or advisor for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Co., Organon, Ortho-McNeil Pharmaceutical, Merck & Co., Pfizer, Shire, and UCB Pharma.