Eicosapentaenoic acid versus docosahexaenoic acid in mild-to-moderate depression: A randomized, double-blind, placebo-controlled trial

Abstract

Controversy exists as to whether eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) or both are responsible for the efficacy of n-3 polyunsaturated fatty acids in depression. We conducted a single-center, randomized, double-blind, placebo-controlled, multi-arm, parallel-group trial, comparing the efficacy of EPA versus DHA as adjuvants to maintenance medication treatments for mild-to-moderate depression. Eighty-one mild-to-moderately depressed outpatients were randomly assigned to receive either 1 g/d of EPA or DHA or placebo (coconut oil) for 12 weeks. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS) final score in the modified intention-to-treat population, which comprised of all randomized patients with at least 1 post-randomization observation (n=62; 61.3% female; mean age 35.1±1.2 years). Allocated treatments were well tolerated. Although there was no significant difference between groups at baseline, patients in the EPA group showed a significantly lower mean HDRS score at study endpoint compared with those in the DHA (p<0.001) or placebo (p=0.002) groups. Furthermore, response to treatment (defined as a ≥50% decrease from the baseline HDRS score) was only observed in 6 patients receiving EPA, while no one in any of DHA or placebo groups responded to treatment. Overall, these data suggest greater efficacy of EPA compared to DHA or placebo as an adjunctive treatment in mild-to-moderate depression. However, further, randomized controlled trials are needed to support these findings.

Introduction

Depression is a serious public health concern with a lifetime prevalence of about 16% (Kessler et al., 2003), and is associated with substantial morbidity, mortality, and health care costs (Andrade et al., 2003). In Iran, the prevalence of depression is also considerable and it is more common among females than males (Sadeghirad et al., 2010). Although, at the individual level, disability from subclinical or mild-to-moderate depression is lower than for major depressive disorder (MDD), it is of major public health significance due to its greater prevalence (Judd et al., 2002) and associated increased risk of mortality (Cuijpers and Smit, 2002), coronary heart disease (Rugulies, 2002), and developing subsequent MDD (Cuijpers and Smit, 2004). Generally, existing treatments for depression have limited efficacy (Bech et al., 2000) and despite the development of new antidepressant medications with improved side-effect profiles, approximately, 60% of patients treated with antidepressants do not achieve remission (Fagiolini and Kupfer, 2003). Therefore, novel approaches to the management of depression need to be found.

The n-3 polyunsaturated fatty acids (n-3 PUFAs) found in fish and marine derivates, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been suggested to provide an alternative to antidepressant medications with fewer side effects. Lower dietary intakes of fish or n-3 PUFAs have been significantly correlated with world-wide prevalence of depression (Hibbeln, 1998, Hibbeln and Salem, 1995). Moreover, there is increasing evidence from epidemiological and clinical studies that EPA and/or DHA have beneficial effects in those suffering from mood disorders, especially depression (Sontrop and Campbell, 2006).

Thus far, a large number of studies have examined the antidepressant efficacy of n-3 PUFAs (mostly as an adjunctive treatment) in patients with unipolar MDD, resulting in positive (da Silva et al., 2008, Jazayeri et al., 2008, Mischoulon et al., 2008, Nemets et al., 2002, Peet and Horrobin, 2002, Rondanelli et al., 2010, Su et al., 2003) and negative (Bot et al., 2010, Carney et al., 2009, Chiu et al., 2008, Grenyer et al., 2007, Lucas et al., 2009, Marangell et al., 2003, Mischoulon et al., 2009, Silvers et al., 2005) findings. However, the potential antidepressant effects of n-3 PUFAs on mild-to-moderately depressed patients are not yet well studied and findings from the rare previous trials conducted on these patients are contradicting, yielding in positive (Frangou et al., 2006, Tajalizadekhoob et al., 2011) and negative (Rogers et al., 2008) results. These mixed findings may be due to methodological differences including the use of different combinations (i.e. EPA, DHA, or EPA+DHA) or doses (ranging from 0.2 to 9.6 g/d) of n-3 PUFAs. Furthermore, to our knowledge, no previous study has compared the efficacy of EPA versus DHA for the treatment of depression and controversy exists as to whether EPA or DHA or both are responsible for the observed beneficial effects of n-3 PUFAs in depressed patients. Therefore, we conducted a randomized, double-blind, placebo-controlled trial to compare the efficacy of EPA versus DHA as adjuvants to maintenance antidepressant medications for the treatment of mild-to-moderate depression.