Omega 3 Fatty Acids in Bipolar DisorderA Preliminary Double-blind, Placebo-Controlled TrialAndrew L. Stoll, MD; W. Emanuel Severus, MD, PhD; Marlene P. Freeman, MD; Stephanie Rueter;Holly A. Zboyan; Eli Diamond; Kimberly K. Cress, MD; Lauren B. Marangell, MDBackground: 3 Fatty acids may inhibit neuronal sig-nal transduction pathways in a manner similar to thatof lithium carbonate and valproate, 2 effective treat-ments for bipolar disorder. The present study was per-formed to examine whether 3 fatty acids also exhibitmood-stabilizing properties in bipolar disorder.Methods: A 4-month, double-blind, placebo-controlled study, comparing 3 fatty acids (9.6 g/d) vsplacebo (olive oil), in addition to usual treatment, in30 patients with bipolar disorder.Results: A Kaplan-Meier survival analysis of thecohort found that the 3 fatty acid patient group had asignificantly longer period of remission thanthe placebo group (P = .002; Mantel-Cox). In addition,for nearly every other outcome measure, the 3fatty acid group performed better than the placebogroup.Conclusion: 3 Fatty acids were well tolerated andimproved the short-term course of illness in this pre-liminary study of patients with bipolar disorder.Arch Gen Psychiatry. 1999;56:407-412BIPOLAR DISORDER (manic-depressive illness) is a com-mon neuropsychiatric ill-ness with a high morbidityand mortality.1Despite avail-able mood-stabilizing drugs, such as lithiumcarbonate and valproate, the illness is char-acterized by high rates of recurrence.1,2Re-cent research suggests that all of the cur-rently available mood-stabilizing drugs haveinhibitory effects on neuronal signal trans-duction systems. These findings have led tothe hypothesis that overactive cell-sig-naling pathways may be involved in thepathophysiological mechanisms underly-ing bipolar disorder.3-6By using this modelof mood stabilizer action based on suppres-sion of neuronal signal transduction mecha-nisms, novel mood-stabilizing agents can berationally developed. One promising groupof compounds is the 3 fatty acids, ob-tained from marine or plant sources.7Among other effects, the ingestion of largeamounts of 3 fatty acids is associated witha general dampening of signal transduc-tion pathways associated with phosphati-dylinositol, arachidonic acid, and other sys-tems.8,9Thus, 3 fatty acids may be usefulin conditions such as bipolar disorder, wherethe pathophysiological process may involveoveractivity of cell signal transduction.We hypothesized that orally admin-istered 3 fatty acids would exhibit in-hibitory effects on signal transductionmechanisms in human neuronal mem-branes, and that high-dose 3 fatty acidswould be an effective mood stabilizer in bi-polar disorder. The goal of this prelimi-nary study was to assess the subacute mood-stabilizing effects of 3 fatty acids in patientswith unstable bipolar disorder.RESULTSThe results for the 30 patients with evalu-able data, as defined above, are presentedherein. There were no significant differ-ences in the demographic and baselineclinical characteristics of the 3 fatty acidand placebo groups (Table 1).Figure 1depicts a Kaplan-Meier survival analysisof the study cohort. The duration of timeremaining in the study was significantlyThis article is also available on ourWeb site: www.ama-assn.org/psych.See also pages 413 and 415ORIGINAL ARTICLEFrom the PsychopharmacologyUnit, Division of Psychiatry,Brigham and Women’s Hospital(Drs Stoll, Severus, andFreeman, Ms Rueter, andMr Diamond), and Departmentof Psychiatry, Harvard MedicalSchool (Drs Stoll andFreeman), Boston, Mass; FreeUniversity of Berlin, Berlin,Germany (Dr Severus); andDepartment of Psychiatry,Baylor College of Medicine,Houston, Tex (Ms Zboyan andDrs Cress and Marangell).Dr Stoll is now with thePsychopharmacology ResearchLaboratory, McLean Hospital,Belmont, Mass, and continueswith the Department ofPsychiatry, HarvardMedical School.ARCH GEN PSYCHIATRY/ VOL 56, MAY 1999407©1999 American Medical Association. All rights reserved.greater in the 3 fatty acid–treated group when com-pared with placebo (P = .002; Mantel-Cox, log-rank sta-tistic, 21= 9.990). The time to a 50% rate of ending thestudy prematurely (“nonresponse”) was 65 days for theplacebo group, reflecting the unstable nature of the studypopulation. A post hoc analysis was also performed forthe subgroup of 8 subjects who entered the studywhile receiving no other mood-stabilizing drugs. Aswas observed in the whole study cohort, the 4 subjectswho received 3 monotherapy remained in remissionfor a significantly longer time than the 4 subjects whoreceived placebo monotherapy (Figure 2; P = .04;Mantel-Cox). Other post hoc analyses showed thatsex, the presence or absence of rapid cycling, and thetype of bipolar disorder (I vs II) did not predictresponse to 3 fatty acids, although the number ofsubjects in each cell was small.Table 1 displays the comparison of the secondaryoutcome measures between the 3 and placebogroups. For nearly every outcome measure, the 3fatty acid group performed better than the placebogroup.PATIENTS AND METHODSOVERVIEWThis was a 4-month, parallel-group, placebo-controlled,double-blind pilot study in which outpatients with bipolardisorder were randomized to receive either 3 fatty acids orplacebo, in addition to their ongoing usual treatment.PATIENTSParticipating subjects were men and women, 18 to 65 yearsold, who met DSM-IV10criteria for bipolar disorder (typesI or II), and were free of notable medical and psychiatriccomorbidity. The diagnosis of bipolar disorder was estab-lished by means of all available clinical information, in-cluding the mood disorder module of the Structured Clini-cal Interview for DSM-IV.11Patients were required to havehad at least 1 manic or hypomanic episode within the pastyear, because the expected high risk of recurrence in thissubgroup1enhanced the power of the study to detect a dif-ference between the 2 treatment groups within the studyperiod. Forty percent of the study cohort had rapid-cycling symptoms, defined as 4 or more mood episodes inthe 1 year before enrollment in the study.12Patients werepermitted to continue with their outpatient psychiatrist orpsychotherapist, but no new psychotherapy treatment wasstarted. Subjects receiving other medications at study en-try continued to receive these medications at constant dos-ages, whether or not they were in the therapeutic range.Table 1 summarizes the demographic
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