The omega-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential components of the human diet and have a broad range of health benefits.  Furthermore, they may also be beneficial for the treatment of mood disorders.  

Outside of  the perinatal period, several studies have demonstrated that omega-3 PUFA supplementation may have antidepressant effects in patients with major depression.  The greatest benefit has been observed in studies using high dosages of the omega-3 fatty acid EPA, possibly due to its anti-inflammatory properties.  

Because during pregnancy omega-3 fatty acids are diverted to the developing fetus, some women may develop a deficiency of omega-3 fatty acids during pregnancy.  Previous studies have shown that pregnant women with lower levels of DHA may be more vulnerable to depressive symptoms (Rees et al, 2009).  Conversely, other studies have demonstrated that women who have diets higher in omega-3 PUFA- containing seafoods and  higher DHA levels may have a lower risk of perinatal depression than women with lower levels of omega-3 fatty acid intake (Hibben et al, 2003).  However, studies investigating the use of omega-3 PUFA supplementation for the treatment or prevention of perinatal depression have yielded mixed results.  

Are Omega-3 Fatty Acids Effective for Perinatal Depression?

A recent meta-analysis from Mocking and colleagues analyzed data from 18 randomized controlled trials (RCTs) of  omega-3 PUFAs versus placebo for depressive symptoms in pregnant and postpartum women. Thirteen RCTs initiated supplementation during pregnancy, three started during the postpartum period, and two included a mixed sample.  Most studies used supplements with both DHA and EPA. Three studies supplemented with DHA only, and no studies supplemented with only EPA. 

The analysis included 4,052 participants, observing a small but statistically significant beneficial effect of omega-3 PUFAs on depressive symptoms compared to placebo, showing a modest effect size of 0.26 (P = .042).  Heterogeneity across the studies was considerable.  

The findings of this meta-analysis were consistent with findings from studies assessing omega-3 PUFAs for the treatment of depression outside the perinatal period, where omega-3 PUFA supplementation appeared to be more effective in patients with an actual major depressive episode than in patients with subclinical depressive symptoms.  The beneficial effect was medium to large in size in postpartum women with depression (SDM = ?0.656) compared to a negligible effect in women treated during pregnancy (SDM = ?0.071).  However, this finding was not statistically significant (P = .214) and was skewed by the inclusion of one study from Iran which had a very large effect size.  

Given that the postpartum period is characterized by activation of the immune system, the authors speculate that the anti-inflammatory properties of the omega-3 fatty acids, particularly EPA, may be responsible for their antidepressant effects during the postpartum period.  In support of this theory, higher omega-6 concentrations (which have a proinflammatory effect) and a higher omega-6/omega-3 ratio have been associated with increased risk for perinatal depression (Lin et al, 2017).

Omega-3 PUFAs in the Prevention of Perinatal Depression

The fact that depressive symptoms were similar in those who were treated with omega-3 PUFAs or placebo suggests that omega-3 did not prevent perinatal depression. However, many of the studies included in the meta-analysis were performed in women drawn from the general obstetric population, whereas some of the studies were carried out in women at increased risk for perinatal depression.  

Two of the studies specifically looked at the capacity of omega-3 fatty acids to attenuate risk in women at increased risk for PPD.   In a study carried out at the University of Michigan (Mozurkewich et al, 2013), 126 pregnant women at high risk for PPD  and less than 20 weeks of gestation were randomized to one of three groups and received the following: a) EPA-rich fish oil supplement (1060 mg EPA plus 274 mg DHA) b) DHA-rich fish oil supplement (900 mg DHA plus 180 mg EPA; or c) a placebo.  EPA-rich fish oil and DHA-rich fish oil supplements did reduce risk for depressive symptoms during pregnancy or the postpartum period.  

In another study from Brazil (Vaz et al, 2017), 60 pregnant women identified as being at risk for PPD were randomly assigned to receive fish oil capsules (1.08 g of EPA and 0.72 g of DHA) or placebo between weeks 22 and 24 of gestation.  Supplementation with 1.8 g of omega-3 PUFAs for 16 weeks did not prevent perinatal depressive symptoms.

Final Thoughts on the Use of Omega-3 Fatty Acids in Perinatal Women

Based on these and other findings, it remains to be determined whether there is a role for omega-3 fatty acids in the treatment and/or prevention of perinatal depression.  It is noteworthy that there have been at least six meta-analyses, three from the past year alone (see below), investigating the use of omega-3 fatty acids for perinatal depression.  It seems that despite some studies suggesting that omega-3 fatty acids may be helpful in the setting, the preponderance of data do not support the efficacy of omega-3 fatty acids for the treatment and/or prevention of perinatal depression.  

There may be a subset of women who may be particularly responsive to treatment with omega-3 fatty acids; however, meta-analyses may not help us to distinguish between responders and non-responders.  Differences between responders and non-responders could potentially be due to underlying inflammatory processes, variations in dietary intake of omega-3 fatty acids, or to genetic differences in omega-3 fatty acid metabolism.  Also, it is unclear if there is a differential effect of omega-3 fatty acids consumed in food, as compared to omega-3 fatty acids contained in supplements.  

While Mocking and colleagues advise against prescribing omega-3 PUFAs for the treatment or prevention of depressive symptoms during pregnancy, an accompanying commentary from Jerome Sarris, PhD, MHSc and Marlene Freeman, MD from the MGH Center for Women’s Mental Health, comment that there may be some settings where omega-3 PUFA supplementation may be beneficial — for example,  in cases of marked dietary deficiency or in cases where there is obesity or comorbid inflammatory conditions. 

It is certainly premature to recommend omega-3 fatty acids as monotherapy for either the acute or preventative treatment of depression.  However, due to the possibility of antidepressant effects and other health benefits for pregnancy, such as increased length of gestation,  many women may opt to take omega-3 fatty acids during pregnancy.  A recent guideline based on a literature review, expert panel, and Delphi process carried out by the International Society for Nutritional Psychiatry Research (ISNPR) supports the use of omega-3 PUFA supplementation for perinatal major depressive episodes (Guu et al, 2020).  

The ISNPR clinical guidelines recommend the following:  

(1) clinicians and other practitioners are advised to conduct a clinical interview to validate clinical diagnoses, physical conditions, and measurement-based psychopathological assessments in the therapeutic settings when recommending O3 in depression treatment; 

(2) with respect to formulation and dosage, both pure EPA or an EPA/docosahexaenoic acid (DHA) combination of a ratio higher than 2 (EPA/DHA > 2) are considered effective, and the recommended dosages should be 1–2 g of net EPA daily, from either pure EPA or an EPA/DHA (> 2:1) formula; 

(3) the quality of n-3 PUFAs may affect therapeutic activity; and 

(4) potential adverse effects, such as gastrointestinal and dermatological conditions, should be monitored, as well as obtaining comprehensive metabolic panels.

 

Ruta Nonacs, MD PhD

 

References:

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Hibbeln JR. Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affect Disord. 2002;69(1–3):15–29.

Lin P-Y, Chang C-H, Chong MF-F, et al. Polyunsaturated fatty acids in perinatal depression: a systematic review and meta-analysis. Biol Psychiatry. 2017;82(8):560–569.

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