title: Randomized, placebo-controlled trial of flax oil in pediatric bipolar disorder.
abstract: OBJECTIVE
  This clinical trial evaluated whether supplementation with flax oil, containing the omega-3 fatty acid alpha-linolenic acid (alpha-LNA), safely reduced symptom severity in youth with bipolar disorder.
  
  
  METHODS
  Children and adolescents aged 6-17 years with symptomatic bipolar I or bipolar II disorder (n = 51), manic, hypomanic, mixed, or depressed, were randomized to either flax oil capsules containing 550 mg alpha-LNA per 1 gram or an olive oil placebo adjunctively or as monotherapy. Doses were titrated to 12 capsules per day as tolerated over 16 weeks. Primary outcomes included changes in the Young Mania Rating Scale, Child Depression Rating Scale-Revised, and Clinical Global Impressions-Bipolar ratings using Kaplan-Meier survival analyses.
  
  
  RESULTS
  There were no significant differences in primary outcome measures when compared by treatment assignment. However, clinician-rated Global Symptom Severity was negatively correlated with final serum omega-3 fatty acid compositions: %alpha-LNA (r = -0.45, p < 0.007), % eicosapentaenoic acid (EPA) (r = -0.47, p < 0.005); and positively correlated with final arachidonic acid (AA) (r = 0.36, p < 0.05) and docosapentaenoic acid (DPA) n-6 (r = 0.48, p < 0.004). The mean duration of treatment for alpha-LNA was 11.8 weeks versus 8 weeks for placebo; however, the longer treatment duration for alpha-LNA was not significant after controlling for baseline variables. Subjects discontinued the study for continued depressive symptoms.
  
  
  CONCLUSIONS
  Studies of essential fatty acid supplementation are feasible and well tolerated in the pediatric population. Although flax oil may decrease severity of illness in children and adolescents with bipolar disorder who have meaningful increases in serum EPA percent levels and/or decreased AA and DPA n-6 levels, individual variations in conversion of alpha-LNA to EPA and docosahexaenoic acid as well as dosing burden favor the use of fish oil both for clinical trials and clinical practice. Additionally, future research should focus on adherence and analysis of outcome based on changes in essential fatty acid tissue compositions, as opposed to group randomization alone.
authors.affiliation: Department of Psychiatry, University of Rochester Medical Center/Strong Memorial Hospital, Laboratory for Mood Disorders in Children and Adolescents, Rochester, NY 14642, USA. barbara_gracious@urmc.rochester.edu
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Gracious
authors.forename: Madalina C
authors.initials: MC
authors.lastname: Chirieac
authors.forename: Stefan
authors.initials: S
authors.lastname: Costescu
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Finucane
authors.forename: Eric A
authors.initials: EA
authors.lastname: Youngstrom
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Hibbeln
mesh_terms: D000293:Adolescent; D016718:Arachidonic Acid / Q000097:blood; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000523:psychology; D002648:Child; D003863:Depression / Q000188:drug therapy; D015118:Eicosapentaenoic Acid / Q000097:blood; D015525:Fatty Acids, Omega-3 / Q000097:blood; D005231:Fatty Acids, Unsaturated / Q000097:blood; D005260:Female; D006801:Humans; D008043:Linseed Oil / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use*; D008297:Male; D011569:Psychiatric Status Rating Scales; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D017962:alpha-Linolenic Acid / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D017962:alpha-Linolenic Acid; D016718:Arachidonic Acid; D008043:Linseed Oil; D015118:Eicosapentaenoic Acid; C026219:docosapentaenoic acid
references.citation: J Am Acad Child Adolesc Psychiatry. 2005 May;44(5):409-17
references.pmid: 15843762
references.citation: Psychiatry Res. 1999 Mar 22;85(3):275-91
references.pmid: 10333380
references.citation: J Affect Disord. 1996 Apr 26;38(1):35-46
references.pmid: 8735157
references.citation: Am J Psychiatry. 2006 Jun;163(6):1098-100
references.pmid: 16741212
references.citation: World Rev Nutr Diet. 2009;99:17-30
references.pmid: 19136836
references.citation: Mol Genet Metab. 2001 May;73(1):38-45
references.pmid: 11350181
references.citation: J Clin Psychiatry. 2007 Jul;68(7):1056-61
references.pmid: 17685742
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2002 Nov;67(5):311-8
references.pmid: 12445491
references.citation: Am J Psychiatry. 2005 Jan;162(1):58-64
references.pmid: 15625202
references.citation: Biol Psychiatry. 2004 Oct 1;56(7):490-6
references.pmid: 15450784
references.citation: J Proteome Res. 2008 Oct;7(10):4266-77
references.pmid: 18778095
references.citation: Psychopharmacol Bull. 1994;30(2):199-202
references.pmid: 7831455
references.citation: Am J Psychiatry. 2003 Dec;160(12):2222-7
references.pmid: 14638594
references.citation: Biol Psychiatry. 2006 Nov 1;60(9):1020-2
references.pmid: 16814257
references.citation: Psychiatr Serv. 2002 Jun;53(6):730-7
references.pmid: 12045311
references.citation: J Am Acad Child Adolesc Psychiatry. 1997 Jul;36(7):980-8
references.pmid: 9204677
references.citation: Am J Psychiatry. 2006 Jun;163(6):969-78
references.pmid: 16741195
references.citation: J Affect Disord. 1998 Mar;48(2-3):149-55
references.pmid: 9543204
references.citation: J Am Acad Child Adolesc Psychiatry. 2007 Jan;46(1):107-125
references.pmid: 17195735
references.citation: Int J Vitam Nutr Res. 1998;68(3):159-73
references.pmid: 9637947
references.citation: Lipids. 1996 Mar;31 Suppl:S157-61
references.pmid: 8729112
references.citation: Lipids. 2001 Sep;36(9):945-59
references.pmid: 11724467
references.citation: Am J Clin Nutr. 2008 May;87(5):1156-62
references.pmid: 18469234
references.citation: Biol Psychiatry. 2007 Jul 1;62(1):17-24
references.pmid: 17188654
references.citation: J Clin Psychiatry. 2006 Dec;67(12):1954-67
references.pmid: 17194275
references.citation: J Clin Psychiatry. 2005 Jun;66(6):726-9
references.pmid: 15960565
references.citation: Eur J Clin Nutr. 2006 Aug;60(8):1016-23
references.pmid: 16482070
references.citation: Am J Clin Nutr. 2003 Jul;78(1):40-6
references.pmid: 12816769
references.citation: Lipids. 2008 Nov;43(11):1031-8
references.pmid: 18781353
references.citation: Eur Neuropsychopharmacol. 2007 May-Jun;17(6-7):440-7
references.pmid: 17258897
references.citation: Biol Psychiatry. 1981 Sep;16(9):837-50
references.pmid: 7028146
references.citation: Br J Psychiatry. 1978 Nov;133:429-35
references.pmid: 728692
references.citation: Br J Psychiatry. 2006 Jan;188:46-50
references.pmid: 16388069
references.citation: Biometrics. 1974 Mar;30(1):89-99
references.pmid: 4813387
references.citation: Arterioscler Thromb Vasc Biol. 1997 Jun;17(6):1163-70
references.pmid: 9194769
references.citation: Hum Mol Genet. 2006 Jun 1;15(11):1745-56
references.pmid: 16670158
references.citation: Pediatrics. 2005 May;115(5):1360-6
references.pmid: 15867048
references.citation: JAMA. 1993 Nov 3;270(17):2096-7
references.pmid: 8411578
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2004 Jun;70(6):495-501
references.pmid: 15120712
references.citation: Biol Psychiatry. 1998 Mar 1;43(5):315-9
references.pmid: 9513745
references.citation: Pediatrics. 1979 Oct;64(4):442-50
references.pmid: 492809
references.citation: J Am Coll Nutr. 1993 Oct;12(5):501-4
references.pmid: 7903324
references.citation: Nutr J. 2005 Feb 09;4:6
references.pmid: 15703073
references.citation: Psychosom Med. 2007 Dec;69(9):932-4
references.pmid: 17991818
references.citation: Behav Res Methods. 2007 May;39(2):175-91
references.pmid: 17695343
references.citation: Curr Opin Investig Drugs. 2008 Jan;9(1):57-64
references.pmid: 18183532
references.citation: Am J Clin Nutr. 2006 Jun;83(6 Suppl):1483S-1493S
references.pmid: 16841858
references.citation: Psychiatry Res. 2008 Sep 30;160(3):285-99
references.pmid: 18715653
references.citation: Child Adolesc Psychiatr Clin N Am. 2009 Apr;18(2):455-69, x
references.pmid: 19264273
references.citation: Arch Gen Psychiatry. 1999 May;56(5):407-12
references.pmid: 10232294
references.citation: Psychiatry Res. 1997 Dec 5;73(3):159-71
references.pmid: 9481807
references.citation: Bipolar Disord. 2007 Nov;9(7):759-65
references.pmid: 17988367