The Impact of Omega-3 Fatty Acids on Depressive Disorders and Suicidality: Can We Reconcile 2 Studies With Seemingly Contradictory Results?
Investigation into the psychotropic efficacy of the omega-3 fatty acids has grown tremendously in the past decade and a half. Since publication of the Stoll et al1 study of omega-3 for treatment of bipolar disorder, many clinical trials, in adults and children, have examined the omega-3s in unipolar major depressive disorder (MDD), postpartum depression, bipolar disorder, attention-deficit disorder, psychotic disorders, obsessive-compulsive disorder, and borderline personality disorder.2-5 Psychiatric clinical trials of omega-3 fatty acids in mood disorders now number in the 30s, and various meta-analyses and systematic reviews have generally, but not unequivocally, suggested benefit.2,6-16 These efficacy findings are consistent with what is being learned about antidepressants in general, with the growing availability of unpublished studies and databases.17
Interpretation of the omega-3 data is complicated by several factors:
1. Preparations of the psychiatrically relevant omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), range from pure EPA or DHA to combinations of the 2 at different ratios. Most studies have used EPA alone or a combination of EPA and DHA2; few studies have used pure DHA.18,19 The possible EPA to DHA ratios are varied, and thus far there is no clear advantage for any 1 preparation.
2. Doses in studies have ranged from less than 1,000 mg/d to 10 g/d. With regard to unipolar depression, the data generally support doses in the range of 1-2 g/d,2 although studies with higher doses have also shown benefit. Optimal doses have yet to be characterized.
3. The EPA to DHA ratio, which varies widely in commercial preparations, may be important when considering the clinical effects of omega-3, but we do not know whether there is an optimal ratio for humans. Likewise, omega-6 fatty acids, which people from industrialized countries consume in high levels, may also be relevant. Some studies that have found therapeutic windows for EPA and DHA suggest an optimal omega-6/omega-3 ratio for humans. For example, our study of EPA monotherapy20 found an association between lowering of the omega-6/omega-3 ratio and clinical improvement in subjects who received EPA, but we did not find a significant association in our smaller study of DHA.19
4. The omega-3 fatty acids are vulnerable to oxidation and may be affected by dietary and consumptive practices. Investigators often attempt to control for this by excluding smokers and people who already consume high amounts of omega-3 in the diet.21,22 However, these methods are not 100% reliable; patients may lie or may minimize or exaggerate lifestyle factors to be admitted into studies.
5. Diagnostic criteria vary, with some studies requiring DSM-IV MDD and others having more liberal diagnostic requirements; depressive severity may also vary; and certain comorbid conditions and concurrent medications may or may not determine exclusion.
The body of omega-3 data is therefore heterogeneous, which makes it difficult to compare and contrast studies in a systematic manner that provides practical information for investigators and clinicians, not to mention the general public.
The Journal of Clinical Psychiatry recently published 2 excellent, meticulously crafted reports online examining the clinical impact of omega-3 fatty acids. Both of these reports are included in the current issue of The Journal. Lewis and colleagues23 performed a case-control study of suicide deaths among active-duty military, in which higher serum DHA demonstrated a protective effect against suicide; surprisingly, EPA appeared to confer no significant protective effect. A meta-analysis by Sublette and colleagues24 examined the relative effects of EPA and DHA for MDD and found that EPA, rather than DHA, appeared to have the main antidepressant effect.
Can these seemingly contradictory findings be reconciled? Let us first contrast the 2 studies:
1. Lewis and colleagues23 selected a specific, unambiguous outcome: suicide death. In contrast, Sublette and colleagues24 examined depressive improvement, an outcome more subject to patient and investigator bias.
2. Lewis and colleagues23 examined a narrow segment of the population: active-duty, predominantly male military personnel serving during the post-9/11 era—a population that may be especially vulnerable to psychiatric disorders. Sublette and colleagues,24 on the other hand, examined studies with depressed individuals of both genders (presumably with a more balanced distribution than in the Lewis sample) and from many walks of life, which would make their sample more representative of the general population with depression, although not necessarily of the population as a whole, since their reviewed studies did not include healthy controls.
3. While Lewis and colleagues23 focused on dietary serum levels of omega-3, Sublette and colleagues24 examined a wide range of omega-3 supplementation regimens, including monotherapy, augmentation (including 1 study with psychotherapy as the baseline treatment), different doses and EPA to DHA ratios, and different treatment durations. Diagnoses included MDD of different severities, bipolar disorder, dysthymia, depressive episode, Parkinson’s , and coronary heart disease. Again, this heterogeneity may limit generalizability with regard to MDD per se.
4. Both studies reported difficulty controlling for medical and psychiatric comorbidity, including substance abuse and posttraumatic stress disorder, which may be especially relevant in a military population. Soldiers who had witnessed extreme violence, for example, had a greater suicide risk than those who had not. Although access to comorbidity data was limited in the Sublette meta-analysis,24 the studies reviewed typically allowed some comorbid disorders (except for active substance abuse), provided that they did not constitute the primary complaint. We cannot be sure whether substance abuse and/or posttraumatic stress disorder were contributing factors to suicide in the Lewis study.
5. Lewis and colleagues23 broke down their serum omega-3 findings into octiles, allowing for a wide range of comparisons. The authors observed that their sample had an unusually low serum DHA status compared to the general population, which may make detection of an association more difficult and yield results less generalizable to the population at large. Sublette and colleagues24 designed their meta-analysis with a binary dose schedule: EPA at levels of greater than or less than 60%, relative to DHA. They provide a strong rationale for their dichotomy, based on the observation that all significant positive studies had at least 60% EPA and all studies with less than 60% EPA were negative. They could not, however, examine the impact of blood levels of omega-3, which were not obtained in many of their studies. It is not clear how blood levels may relate to levels in the brain, where the omega-3s presumably carry out their psychotropic effects.
These issues make the studies difficult to compare on a head-to-head basis and could explain any apparent differences in their findings. But are these findings contradictory? One study says that DHA is protective against suicide and EPA is not; the other says that EPA is more effective than DHA for alleviating depression.
These findings of Lewis et al23 and Sublette et al24 are not mutually exclusive:
1. Although the relationship between depressive disorders and suicide is well established, suicidal ideation or completed suicide should not be considered as a proxy measure for MDD. Only 15% of people with depression will commit suicide,25 and at least 40% of suicides consist of people without diagnosed depression.26 Suicide may be influenced by many factors, eg, situational stressors that can be difficult to systematically assess and quantify in study samples. Therefore, conclusions about suicide and about depression cannot necessarily be commingled.
2. Although EPA did not significantly associate with suicide in the Lewis study,23 there was a trend toward significance (P < .08), suggesting that EPA may in fact have a benefit, albeit more modest. Other fatty acids that are seemingly unrelated to mood also appeared to have protective effects against suicide: dihomo-γ-linolenic acid, palmitoleic acid, cis-vaccinic acid, and stearic acid. Therefore, the overall clinical impact of the different fatty acids and their ratios, in oral preparations and in the blood, is difficult to fully elucidate within the limitations of these studies.
3. Serum levels of omega-3 may not necessarily reflect brain levels; EPA is a precursor of DHA and may indirectly increase brain DHA or cause secondary effects, such as in the inflammatory system, that could ultimately impact on the brain. While Sublette and colleagues24 suggest that DHA could block the effects of EPA, this scenario seems unlikely given everything else that is known about DHA’s impact on mood and suicidality.
4. Posttraumatic stress disorder in the Lewis sample, even if not formally diagnosed, may have influenced suicidality. Also, psychiatric pathology in general, measured indirectly by a greater number of outpatient and inpatient mental health visits, may have also conferred a greater suicide risk for these soldiers. Interestingly, substance abuse visits were not associated with increased suicide risk, although it is possible that many individuals were underdiagnosed in this regard.
Considering the above, these studies should not be viewed as contradictory and can in fact be reconciled. EPA may have benefits for the overall constellation of symptoms known as DSM-IV MDD that exceed those of DHA. On the other hand, DHA may impact the mechanism(s) in the brain that regulate suicidal behavior, independent of MDD status. These findings should encourage investigators who study omega-3s, as well as other antidepressants, to closely scrutinize suicidal symptoms in addition to performing standard efficacy analyses based on depressive symptoms as a whole.
On a final note, our group at Massachusetts General Hospital, in collaboration with Emory University, is nearing completion of a 3-arm randomized clinical trial comparing EPA, DHA, and placebo for MDD, including analysis of plasma polyunsaturated fatty-acid levels as moderators and mediators of response. We hope that our findings will help to shed further light on the comparative efficacy of EPA and DHA.
Author affiliations: Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston.
Potential conflicts of interest: Dr Mischoulon has received research support from Nordic Naturals and Ganeden; has served as a consultant to Bristol-Myers Squibb; has received speaking and writing honoraria from Pamlab and Nordic Naturals; has received royalties from Back Bay Scientific for PMS Escape and from Lippincott Williams & Wilkins for the textbook Natural Medications for Psychiatric Disorders: Considering the Alternatives, of which he is co-editor; and has received honoraria from Reed Medical Education, a company working as a logistics collaborator for the Massachusetts General Hospital (MGH) Psychiatry Academy (the education programs conducted by the MGH Psychiatry Academy were supported through independent medical education grants from pharmaceutical companies cosupporting programs along with participant tuition; commercial entities currently supporting the MGH Psychiatry Academy are listed on the Academy’s Web site at www.mghcme.org).
Funding/support: Supported in part by grant R01 MH074085 to Dr Mischoulon from the National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
REFERENCES
1. 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(5):407-412. PubMed doi:10.1001/archpsyc.56.5.407
2. Freeman MP, Hibbeln JR, Wisner KL, et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry. 2006;67(12):1954-1967. PubMed doi:10.4088/JCP.v67n1217
3. Fux M, Benjamin J, Nemets B. A placebo-controlled cross-over trial of adjunctive EPA in OCD. J Psychiatr Res. 2004;38(3):323-325. PubMed doi:10.1016/S0022-3956(03)00077-3
4. Nemets H, Nemets B, Apter A, et al. Omega-3 treatment of childhood depression: a controlled, double-blind pilot study. Am J Psychiatry. 2006;163(6):1098-1100. PubMed doi:10.1176/appi.ajp.163.6.1098
5. Wozniak J, Biederman J, Mick E, et al. Omega-3 fatty acid monotherapy for pediatric bipolar disorder: a prospective open-label trial. Eur Neuropsychopharmacol. 2007;17(6-7):440-447. PubMed doi:10.1016/j.euroneuro.2006.11.006
6. Lee S, Gura KM, Kim S, et al. Current clinical applications of omega-6 and omega-3 fatty acids. Nutr Clin Pract. 2006;21(4):323-341. PubMed doi:10.1177/0115426506021004323
7. Appleton KM, Hayward RC, Gunnell D, et al. Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials. Am J Clin Nutr. 2006;84(6):1308-1316. PubMed
8. Severus WE. Effects of omega-3 polyunsaturated fatty acids on depression. Herz. 2006;31(suppl 3):69-74. PubMed
9. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007;68(7):1056-1061. PubMed doi:10.4088/JCP.v68n0712
10. Montgomery P, Richardson AJ. Omega-3 fatty acids for bipolar disorder. Cochrane Database Syst Rev. 2008;(2):CD005169. PubMed
11. Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr. 2009;28(5):525-542. PubMed
12. Appleton KM, Rogers PJ, Ness AR. Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr. 2010;91(3):757-770. PubMed doi:10.3945/ajcn.2009.28313
13. Lin PY, Huang SY, Su KP. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol Psychiatry. 2010;68(2):140-147. PubMed doi:10.1016/j.biopsych.2010.03.018
14. Freeman MP, Mischoulon D, Tedeschini E, et al. Complementary and alternative medicine for major depressive disorder: a meta-analysis of patient characteristics, placebo-response rates, and treatment outcomes relative to standard antidepressants. J Clin Psychiatry. 2010;71(6):682-688. PubMed doi:10.4088/JCP.10r05976blu
15. Sarris J, Mischoulon D, Schweitzer I. Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression [published online ahead of print August 9, 2011]. J Clin Psychiatry. PubMed
16. Sarris J, Mischoulon D, Schweitzer I. Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: a systematic review of clinical trials. Bipolar Disord. In press.
17. Pigott HE, Leventhal AM, Alter GS, et al. Efficacy and effectiveness of antidepressants: current status of research. Psychother Psychosom. 2010;79(5):267-279. PubMed doi:10.1159/000318293
18. Marangell LB, Martinez JM, Zboyan HA, et al. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry. 2003;160(5):996-998. PubMed doi:10.1176/appi.ajp.160.5.996
19. Mischoulon D, Best-Popescu C, Laposata M, et al. A double-blind dose-finding pilot study of docosahexaenoic acid (DHA) for major depressive disorder. Eur Neuropsychopharmacol. 2008;18(9):639-645. PubMed doi:10.1016/j.euroneuro.2008.04.011
20. Mischoulon D, Papakostas GI, Dording CM, et al. A double-blind, randomized controlled trial of ethyl-eicosapentaenoate for major depressive disorder. J Clin Psychiatry. 2009;70(12):1636-1644. PubMed doi:10.4088/JCP.08m04603
21. Politi P, Rocchetti M, Emanuele E, et al. Randomized placebo-controlled trials of omega-3 polyunsaturated fatty acids in psychiatric disorders: a review of current literature [published online ahead of print August 15, 2011]. Curr Drug Discov Technol. PubMed
22. Sublette ME, Segal-Isaacson CJ, Cooper TB, et al. Validation of a food frequency questionnaire to assess intake of n-3 polyunsaturated fatty acids in subjects with and without major depressive disorder. J Am Diet Assoc. 2011;111(1):117-123. PubMed
23. Lewis MD, Hibbeln JR, Johnson JE, et al. Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison [published online ahead of print August 23, 2011]. J Clin Psychiatry. 2011;72(12):1585-1590. PubMed
24. Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression [published online ahead of print September 6, 2011]. J Clin Psychiatry. 2011;72(12):1577-1584. PubMed
25. Boardman AP, Healy D. Modelling suicide risk in affective disorders. Eur Psychiatry. 2001;16(7):400-405. PubMed doi:10.1016/S0924-9338(01)00597-1
26. Oquendo MA, Ellis SP, Greenwald S, et al. Ethnic and sex differences in suicide rates relative to major depression in the United States. Am J Psychiatry. 2001;158(10):1652-1658. PubMed doi:10.1176/appi.ajp.158.10.1652
