Omega-3 fatty acids in major depressive disorder: A preliminary double-blind, placebo-controlled trial
Introduction
WHO (World Health Organization) estimates that major depressive disorder will become the second leading cause of disability worldwide by 2020, which is only second to ischemic heart disease, and the leading cause in developing regions (Murray and Lopez, 1997). The annual prevalence of major depressive disorder shows nearly a 60-fold variation across countries (Weissman et al., 1996). It is similar to the cross-national difference in mortality from coronary artery disease, which might suggest that similar dietary risk factors could be important (Hibbeln, 1998). Based on the epidemiological data, societies with a high consumption of fish, which contain more omega-3 PUFAs, appear to have a lower prevalence of major depressive disorder (Hibbeln, 1998, Tanskanen et al., 2001).
Polyunsaturated fatty acids (PUFAs) have been reported recently to be effective in treatment of various psychiatric disorders. A mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in a high dosage was effective in a case of a pregnant schizophrenic woman (Su et al., 2001). EPA has been reported to have positive effects for patients with schizophrenia in several studies (Peet et al., 2001, Peet and Horrobin, 2002a, Emsley et al., 2002). However, one study on EPA (Fenton et al., 2001) and the arm of DHA in another study (Peet et al., 2001) showed no effect. In their preliminary trial, Stoll et al. (1999) concluded that omega-3 PUFAs could improve the 4-month course of illness in patients with bipolar disorder. We further found, from Stoll’s data, that omega-3 PUFAs seem to prevent depression but not mania among the patients with bipolar disorder (Su et al., 2000).
The PUFAs are classified mainly into omega-3 (or n−3) and omega-6 (or n−6) groups, of which the parent essential fatty acid is α-linolenic acid (ALA; C18:3n−3) and linoleic acid (LA; C18:2n−6). As we know that cerebral cell membranes are composed of certain PUFAs, which cannot be synthesized and must be obtained from the diet. Therefore, the abnormalities of PUFA composition in cell membranes can alter membrane microstructure, and then result in abnormal signal transduction and immunological regulation. There are studies revealing abnormalities in PUFA composition may vary in different major psychiatric disorders (Chiu et al., 2003a). In depressive disorders, the major abnormality is seen as lower erythrocyte membrane omega-3 PUFAs, including significant decrease of EPA and DHA levels (Adams et al., 1996, Maes et al., 1996, Edwards et al., 1998, Peet et al., 1998, Maes et al., 1999). EPA monotherapy was then reported its antidepressant effect in a case of treatment-resistant major depressive disorder (Puri et al., 2002). Benefits of omega-3 PUFAs augmentation with antidepressant medications were also reported in the recent studies (Nemets et al., 2002, Peet and Horrobin, 2002b), though the dietary frequency and erythrocyte omega-3 fatty acid composition were not measured then. In addition, we suggest that the patients in the placebo group should also receive tertiary butylhydroquinone and tocopherols as they did in the omega-3 fatty acids group, to avoid the possible therapeutic effect from these compound as a confounding factor (Su et al., 2000).
To provide more evidence to uncover the relation between pathogenesis in major depression and omega-3 PUFAs and then establish an efficient treatment for it, we conducted an 8-week, preliminary double-blind, placebo-controlled trial. Our hypothesis is that giving a high dosage of DHA and EPA is effective when treating depressive symptoms.
Section snippets
Method
Participants were outpatients, ranging from 18 to 60 years old, referred by Taipei Medical University–Wan Fang Hospital. They were enrolled if they met the following criteria: (1) they were diagnosed with DSM-IV as major depressive disorder and had no other comorbid Axis I or Axis II psychiatric disorders, (2) they were rated over 18 on the 21-item Hamilton Rating Scale for Depression (HRSD), (3) there was no change in their medications or psychotherapy 4 weeks before the enrollment, (4) they
Results
Thirty-two patients were enrolled in this study, but four were excluded at the stage of placebo lead-in. Twenty-eight patients were randomized to either omega-3 PUFAs (n=14) or placebo (n=14), while 22 patients (12 of the omega-3 group and 10 of the placebo group) completed this 8-week study. Six patients dropped out prior to Week 8. Of the six, two received omega-3 (one was lost in follow-up and the other was lost due to noncompliance), and four received placebo (three were lost in follow-up
Discussion
Although this study is limited by its small sample size and the possible confounding factor of uncontrolled combined medications, the findings do provide a rationale perspective to conduct further large-scale trials of omega-3 PUFAs monotherapy.
It is interesting to notice that EPA, but not DHA, improves schizophrenic symptoms (Peet et al., 2001, Peet and Horrobin, 2002a, Emsley et al., 2002) and major depressive disorder (Marangell et al., 2000, Nemets et al., 2002, Peet and Horrobin, 2002b) as
Acknowledgments
The work was supported by the grants of NSC 90-2314-B-109-005, NSC 90-2320-B-039-042 and NSC 91-2320-B-039-010 from the National Science Council, and China Chemical and Pharmaceutical Company, Taipei, Taiwan. The authors thank Miss Chin-Hua Liu for data collection.
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