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 LETTERS TO THE EDITOR

Effect of omega-3 fatty acids on valproate plasma protein binding

Heather M. Brandt, PharmD*

Wilson N. Jones Medical Center, Sherman, TX, USA

Sarah J. Popish, PharmD*

College of Pharmacy, Touro University, Mare Island, Vallejo, CA, USA

Rex S. Lott, PharmD

Department of Pharmacy Practice and Administrative Sciences, Idaho State University College of Pharmacy, Boise Veterans Affairs Medical Center, Boise, ID, USA

* At the time of this study, Dr. Brandt was Clinical Assistant Professor, Department of Pharmacy Practice and Administrative Sciences, Idaho State University College of Pharmacy, Pocatello, ID, and Dr. Popish was Psychopharmacy Resident, Idaho State University College of Pharmacy and Boise Veterans Affairs Medical Center, Boise, ID.

KEYWORDS: valproate, omega-3 fatty acids, protein binding

ANNALS OF CLINICAL PSYCHIATRY 2010;22(4):280–282

TO THE EDITOR:

Valproate plasma concentration is commonly used to adjust or optimize dosages of valproic acid or divalproex during treatment of bipolar disorder. Valproate is extensively bound (90% to 95%) to plasma albumin.1 Plasma concentrations measured clinically include both bound and unbound drug. Decreased valproate binding—following either reductions in albumin concentration or competition with other drugs or substances for albumin binding sites—results in an increased free fraction (percent unbound) of valproate.

Valproate clearance is restrictive and directly proportional to plasma free fraction.1 Thus, decreases in valproate binding are followed by reductions in total plasma concentrations, whereas unbound concentrations are unchanged.2 However, reduced total valproate concentrations that result from decreased binding may be misinterpreted as reflecting an inadequate dosage, which may lead to unnecessary dosage adjustments.

Augmentation of mood stabilizers with omega-3 fatty acids (O3FA) may enhance therapeutic outcomes in bipolar disorder3,4 and other psychiatric disorders.5,6 Mental health benefits of O3FA have also been described in lay publications. Therefore, it is likely that patients taking valproate are receiving concomitant treatment with O3FA, either prescribed or self-administered.

Dietary fatty acids alter valproate binding,1 which may partially explain observed day-to-day variability in valproate plasma concentrations. Likewise, O3FA may potentially alter valproate binding. Changes in valproate pharmacokinetics have not been described following administration of O3FA, but no systematic pharmacokinetic evaluation of this combination has, to our knowledge, been reported. We investigated the effect of single doses of O3FA on valproate protein binding in outpatients with DSM-IV-TR Axis I disorders.

Following approval by the Institutional Review Boards of Idaho State University and the Boise VA Medical Center and review and approval by the Research and Development Committee of the Boise VA Medical Center, 21 outpatients (18 men, 3 women; mean age, 47 ± 9.3 years) from the Boise VA Medical Center who were taking valproic acid consented to participate. All met eligibility criteria: they were at least 18 years old, were apparently adherent to prescribed valproic acid regimens, were not already taking O3FA supplements, and had normal plasma albumin concentrations. Patients taking divalproex were not enrolled, because delayed absorption of divalproex dosage forms may hamper determination of consistent trough plasma concentrations. Patients taking anticoagulants (including aspirin) or those who started or stopped any medication during the study also were excluded.

DSM-IV-TR Axis I diagnoses among study participants were: bipolar disorder (16 patients), posttraumatic stress disorder (6 patients), major depressive episode or disorder (4 patients), schizoaffective disorder (3 patients), generalized anxiety disorder (1 patient), and attention-deficit/hyperactivity disorder (1 patient). Several patients had multiple Axis I diagnoses. Only 1 patient had a seizure disorder that was comorbid with bipolar disorder.

Concomitant psychotropic medications included selective serotonin reuptake inhibitors, other mood stabilizers (eg, lithium or lamotrigine), and antipsychotics. Most patients were being treated for medical conditions (eg, chronic obstructive pulmonary disease, hypertension, etc.) with stable medication regimens. No concomitant medications were known to influence valproate protein binding. The mean valproic acid dose was 1,310 ± 647 mg/d, and the mean albumin concentration was 4.38 ± 0.24 g/dL.

On 3 consecutive mornings, study participants withheld morning doses of medication until after blood samples were obtained. Adherence to prescribed medications and to the study protocol was evaluated each morning. Blood samples drawn on each study day were immediately immersed in ice water. Plasma was separated in a refrigerated centrifuge and frozen until analysis. After blood sampling on day 2, participants ingested 3 capsules of a dietary supplement containing 300 mg O3FA per capsule (Kirkland Signature Fish Oil Concentrate, 1000 mg, softgel capsules; Costco Wholesale, Issaquah, WA). To assess dietary fatty acid intake, participants were asked to record all foods and beverages consumed for the following 24 hours. Dietary records were collected on day 3, after final blood samples were drawn. No patient experienced adverse effects from O3FA during the study.

Valproate concentrations were measured by capillary gas chromatography. Unbound concentrations were determined after ultrafiltration using a Centrifree Micropartition system (Millipore, Billerica, MA). The lower limit of detection for both unbound and total valproate was 1 mcg/mL. Interday and intraday coefficients of variation were less than 5%.7

Mean total and unbound concentrations from days 1 and 2 were used to establish each participant’s baseline free fraction; these were compared with free fractions determined following administration of O3FA. Mean total and unbound valproate concentrations before and after administration of O3FA also were compared. Two-way analysis of variance (ANOVA) without replication was used for comparisons.

Mean valproate free fraction (10.9% vs 10.8%; P = .64; FIGURE) as well as total (58.2 mcg/mL vs 60.3 mcg/mL; P = .28) and unbound (7.09 mcg/mL vs 7.27 mcg/mL; P = .67) valproate concentrations were not significantly changed following O3FA administration. Although not statistically significant, some participants exhibited substantial variability in total valproate concentrations between study days 1 and 2.

These results suggest that O3FA treatment does not alter the relationship between valproate plasma concentrations and clinical response. Other factors, however, may have contributed to these negative findings. Small sample size and intrapatient variability in baseline valproate concentrations may have caused this study to be statistically underpowered. Doses of O3FA administered may not have produced plasma concentrations adequate to displace valproate. Additionally, O3FA are rapidly incorporated into plasma lipids, potentially decreasing their ability to displace valproate.8 Variability in baseline valproate concentrations may have resulted from improper dose timing, poor medication adherence, or inaccurate patient reporting. Dietary fatty acids also could have contributed to this variability. Dietary records only covered 24 hours and were inadequate to allow assessment of variation in fatty acid intake throughout the study period.

Clinicians should remain alert for possible evidence that O3FA may displace valproate from binding. Further research is needed to fully evaluate this potential plasma-binding interaction.

FIGURE Valproate free fraction: Baseline vs post–omega-3 fatty acid

FF: free fraction; O3FA: omega-3 fatty acid.

ACKNOWLEDGEMENTS: This study was supported in part by the resources and facilities at the Boise Veterans Affairs Medical Center, Boise, ID. This research was supported by Grant No. 935 from the Faculty Research Committee, Idaho State University, Pocatello, ID.

DISCLOSURES: The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

    REFERENCES

  1. Levy RH, Shen DD. Valproic acid. Absorption, distribution, and excretion. In: Levy RH, Mattson RH, Meldrum SS, eds. Antiepileptic drugs. 4th ed. New York, NY: Raven Press, Ltd.; 1995:605–619.
  2. DeVane CL. Clinical significance of drug binding, protein binding, and binding displacement drug interactions. Psychopharmacol Bull. 2002;36:5–21.
  3. Stoll AL, Severus WE, Freeman MP, et al. Omega-3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1999;56:407–412.
  4. Martinez JM, Marangell LB. Omega-3 fatty acids: do ‘fish oils’ have a therapeutic role in psychiatry? Current Psychiatry. 2004;3:25–52.
  5. Kraguljac NV, Montori VM, Pavuluri M, et al. Efficacy of omega-3 fatty acids in mood disorders - a systematic review and metaanalysis. Psychopharmacol Bull. 2009;42:39–54.
  6. Shelton RC, Osuntokun O, Heinloth AN, et al. Therapeutic options for treatment-resistant depression. CNS Drugs. 2010;24:131–161.
  7. Semmes RLO, Shen DD. Capillary gas chromatographic assay for valproic acid and its 2-desaturated metabolite in brain and plasma. J Chromatogr. 1988;432:185–197.
  8. Zuijdgeest-van Leeuwen SD, Dagnelie PC, Rietveld T, et al. Incorporation and washout of orally administered n-3 fatty acid ethyl esters in different plasma lipid fractions. Br J Nutr. 1999;82:481–488.

CORRESPONDENCE:Rex S. Lott, PharmD, Idaho State University College of Pharmacy, Boise VA Medical Center, 500 W. Fort St. (119A), Boise, ID 83702 USA, E-MAIL: lott@otc.isu.edu