Omega-3 fatty acids and perinatal depression: A review of the literature and recommendations for future research

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Prostaglandins, Leukotrienes and Essential Fatty Acids 75 (2006) 291–297 www.elsevier.com/locate/plefa

Omega-3 fatty acids and perinatal depression: A review of the literature and recommendations for future research M.P. Freeman Women’s Mental Health Program, Departments of Psychiatry, Obstetrics and Gynecology, and Nutritional Sciences, University of Arizona College of Medicine, 1501 N. Campbell Avenue, PO Box 245002, Tucson, AZ 85724-5002, USA

Abstract Introduction: Perinatal depression refers to major depression in the context of pregnancy and postpartum. In consideration of its prevalence and consequences, the treatment and prevention of perinatal depression should be important public health priorities. Omega-3 fatty acids are attractive for consideration in perinatal women, due to known health benefits for the mother and baby. Antidepressant medications may pose risks in utero and in breastfeeding. Methods: MEDLINE and manual searches were conducted. Results: Epidemiological and preclinical data support a role of omega-3 fatty acids in perinatal depression. Two studies failed to support a role of omega-3 fatty acids for postpartum depression prophylaxis, although one included a small sample, and the other utilized a low dosage. Two pilot studies suggest good tolerability and potential efficacy in the acute treatment of perinatal depression. Conclusions: Further research studies are warranted to determine the role of omega-3 fatty acids in the treatment of perinatal depression. r 2006 Elsevier Ltd. All rights reserved.

1. Introduction 1.1. Perinatal depression: scope of the problem and standard treatments Perinatal depression refers to major depression in the context of pregnancy and the postpartum. Perinatal depression is common, and the treatment of perinatal depression presents distinctive challenges. Depression during pregnancy: Major depression during pregnancy is common, affecting between 10% and 20% of pregnant women [1,2]. Untreated maternal depression increases the risk of negative pregnancy outcomes [3–5]. Randomized controlled trials of antidepressants have not been conducted for depression during pregnancy. Most data regarding tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) do not Tel.: +1 520 626 6509; fax: +1 520 626 6050.

E-mail address: [email protected]. 0952-3278/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2006.07.007

suggest that antidepressants increase the risk of major malformations or miscarriage [5]. However, recent data regarding the SSRI paroxetine suggest an association between its use in pregnancy and cardiac teratogenicty [6]. There is a growing concern regarding a neonatal syndrome associated with late pregnancy antidepressant use, making antidepressant use in pregnancy more controversial [7]. There are few data regarding longterm effects of in utero exposure to antidepressants, although this must be balanced against the risks of untreated maternal depression. Postpartum depression: Postpartum depression (PPD) is defined in the DSM-IV as a major depressive episode with onset within 4 weeks of delivery, although the literature in this area supports a broader definition that includes onset later during the postpartum year [8,9]. Ten to 20% of postpartum women experience PPD [10,11]. PPD has been referred to as the ‘‘the most under-recognized, under-diagnosed, and under-treated obstetrical complication in America’’ [12]. PPD affects

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the individual and her family, with negative impact upon several aspects of child development, including attachment, cognitive development, and behavior [13–15]. Antidepressant medications are often used for PPD, although only one placebo-controlled trial of an antidepressant has been published in women with PPD [16]. Small, open-label studies suggest that several antidepressant medications may be efficacious in the treatment of PPD [17–21]. An analysis of the two studies that assess antidepressant medications to prevent PPD was inconclusive as to whether antidepressants prevent PPD when started after delivery in women at risk [22]. While some studies demonstrate low levels of medication exposure to infants who are breastfed during maternal antidepressant treatment, there are some case reports of suspected adverse events [23]. Although a limited literature supports the efficacy of antidepressants in PPD, some women are unwilling to accept antidepressant medications in the context of breastfeeding. Psychotherapeutic interventions have also been studied for the prevention and acute treatment of PPD and appear beneficial, although more studies are warranted [24–27]. Unfortunately, many women have financial and time constraints that limit participation in psychotherapy. In consideration of its prevalence and consequences, the prevention and treatment of perinatal depression should be important public health priorities. 1.2. Omega-3 fatty acids: rationale for study in perinatal depression: Optimal treatments for perinatal depression would be safe for both the mother and baby, in utero and while breastfeeding. Omega-3 fatty acids are nutritional compounds with widely established health benefits. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 fatty acids found in fish and marine sources. As essential fatty acids, they are an important dietary component. The typical American diet is comprised of a relatively excess amount omega-6 fatty acids when compared to omega-3 fatty acids [28]. Omega-3 fatty acids in major depression: Studies of the epidemiology of mood disorders support a role of omega-3 fatty acids in depression. In a cross-national study, Hibbeln [29] demonstrated an inverse association between risk of major depression and per capita fish consumption. Several studies demonstrated lower total omega-3 fatty acid content in erythrocyte membranes and plasma among subjects with depression than controls [30–33]. Proposed mechanisms of antidepressant action include: (1) alteration of protein phosphorylation and impact upon protein kinases [34,35], (2) impact upon protein kinase C [36], (3) decreased phosphatidylinositol-associated second messenger activity [37], (4) effects on serotonergic and dopaminergic

neurotransmission [38], (5) immunological effects [39– 43], (6) vagal mechanisms [44], (7) heightened dendritic arborization and synapse genesis [45], and (8) regulation of gene expression [46,47]. Treatment data in major depressive disorder also support a role for omega-3 fatty acids. Three doubleblind, placebo-controlled trials have demonstrated the benefit of omega-3 fatty acids as an adjunctive treatment in major depressive disorder [48–50]. Not all data are consistent in terms of significant benefits of omega-3 fatty acids in major depression. One randomized trial of omega-3 fatty acids as an adjuctive treatment did not show a significant difference from placebo [51]. In the only published randomized, placebo-controlled trial of omega-3 fatty acids as a monotherapy for major depressive disorder, Marangell et al. [52] did not detect a significant difference between DHA and placebo. As noted in Table 1, the interpretation of these studies is hampered by the utilization of different particular omega-3 fatty acids or their combinations and widespread dosing differences. Omega-3 fatty acids in pregnancy and postpartum: Omega-3 fatty acids are particularly attractive for consideration in perinatal women, as depletion of maternal stores occurs during pregnancy to ensure adequate an supply for the baby’s central nervous system development [53–56]. And as assessed in 2000, dietary intake of omega-3 fatty acids by pregnant and postpartum women in the US falls short of recommended levels [57]. Also, as demonstrated by a study in rats, maternal brain DHA levels are significantly reduced following birth when fed diets low in omega-3 fatty acids during pregnancy [58]. However, the US Food and Drug Administration (FDA) has issued mercury warnings, the first issued in 2003, regarding fish intake in pregnancy that specify that pregnant women should avoid fish that contain high levels of mercury, including tilefish, swordfish, shark, and king mackerel [59]. The recommendations also state that women should restrict intake of other seafood to 12 ounces per week to avoid excessive mercury exposure. The main concerns about mercury exposure in pregnant women stem from the association of mercury and central nervous system teratogenicity. Since the US FDA advisory, fish consumption among pregnant women has fallen below previous levels [60]. In addition, concerns regarding contaminants in farm-raised salmon have been raised [61]. Despite the recent concerns about fish intake and mercury, Oken et al. [62] recently found that higher fish intake in pregnancy was associated with higher infant cognitive function. While apprehension about mercury in fish has become widespread in the US, fish oil supplements do not appear to contain significant levels of mercury [63]. Fish oil capsules undergo a refining process to reduce contaminants, including mercury and polychlorinated

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Table 1 Randomized placebo-controlled trials of Omega-3 fatty acids for major depressive disorder Study design

N

Omega-3 constituent, dose

Length of trial

Outcome

Peet and Horrobin (2002)

Adjunctive therapy to antidepressant medication

N ¼ 70

EPA 1,2, or 4 g/day

12 weeks

EPA significantly more effective than placebo (best response with lowest dose)

Nemets et al. (2002)

Adjunctive therapy to antidepressant medication

N ¼ 20

EPA, 2 g/day

4 weeks

EPA significantly more effective than placebo

Marangell et al. (2003)

Monotherapy

N ¼ 36

DHA, 2 g/day

6 weeks

DHA not significantly more effective than placebo

Su et al. (2003)

Adjunctive therapy to antidepressant medication

N ¼ 28

EPA+DHA, 6.6 g/day

8 weeks

EPA+DHA significantly more effective than placebo

Silvers et al. (2005)

Adjunctive therapy to antidepressant medication

N ¼ 77

EPA+DHA, 8 g/day

12 weeks

EPA+DHA not significantly more effective than placebo

Study

biphenyls (PCBs) [64]. In an analysis conducted by Consumer Reports in July 2003, 16 brands of fish oil were tested and found to contain nondetectable quantities of mercury, dioxin, and PCBs [65]. Omega-3 fatty acid supplementation in pregnant women appears to have beneficial effects regarding pregnancy outcome and infant development. Diets low in omega-3 fatty acids during pregnancy are associated with an increased risk of prematurity [66]. Supplementation may protect against preterm delivery, as demonstrated in a double-blind, placebo-controlled study conducted by Olsen and colleagues (1992) [67]. They found that omega-3 fatty acid supplementation in a dosage of 2.7 g/day resulted in longer gestational periods without negative consequences for fetal growth and childbirth. Additionally, preeclampsia may be associated with low levels of maternal omega-3 fatty acid intake, suggested by a cross-sectional case-control study [68]. Furthermore, in one study, higher omega-3 fatty acid intake during pregnancy was associated with reduced a risk of cerebral palsy [69]. Presently, many infant formulas are supplemented with omega-3 fatty acids, and DHA-supplemented formulas are especially recommended in premature infants [70,71]. Unlike in utero or neonatal antidepressant medication exposure, which is considered of potential risk, omega-3 fatty acids are known to play an important role in neurodevelopment [72]. Therefore, there is a general paucity of data regarding standard treatments for perinatal depression and possible risks of pharmacologic interventions in pregnancy and breastfeeding. We urgently need to study potentially safe and effective treatment options for perinatal depression. Omega-3 fatty acids appear to be a well-suited candidate, considering the data in major

depression and the beneficial effects in the perinatal period. The aim of this review is to determine what is currently known about omega-3 fatty acids and perinatal depression. Directions for future research in this area are discussed.

2. Methods A literature search was conducted of MEDLINE journals from 1965 to present. Manual literature searches were also conducted. Keywords included Omega-3 fatty acids, pregnancy, postpartum, depression, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).

3. Results 3.1. Perinatal depression Epidemiological and laboratory data support a role of omega-3 fatty acids in perinatal depression. In a crossnational analysis, Hibbeln [73] found that per capita seafood intake was significantly inversely correlated with scores on the Edinburgh Postnatal Depression Scale (EPDS) in postpartum women, with higher seafood intake associated with lower levels of depressive symptoms. In the same report, a similar inverse relationship was also found between DHA levels in breastmilk and depressive symptoms. In another study, Otto et al. [74] assessed plasma phospholipids in women at delivery and then again at 32 weeks postpartum. They also assessed maternal depressive symptoms with the EPDS at 32 weeks postpartum. They

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found a significantly lower ratio of DHA to omega-6 fatty acids among the group with higher EPDS scores. As summarized in Table 2, four studies were found that assess omega-3 fatty acids in the treatment of perinatal depression. Two studies evaluated efficacy in PPD prophylaxis, and two were acute treatment studies. Two published studies do not confirm efficacy of omega-3 fatty acids as a prophylactic measure for postpartum depression. In a small open trial with seven subjects, Marangell et al. [75] reported that fish oil supplementation (a combination of EPA and DHA, 2.96 g per day), starting between 34 and 36 weeks of pregnancy, did not prevent the occurrence of PPD in women who had experienced it after previous pregnancies. They observed postpartum depressive episodes in four of seven subjects. The expected rate of recurrence of postpartum depression is reported to be 20–60% [76,77]. Llorente et al. [78] assessed 138 healthy mothers who received either DHA (200 mg per day) or placebo for four months starting after delivery. They found no differences in depression scores between groups after the supplementation period. In these studies, omega-3 fatty acid supplementation was only started either in the third trimester or after delivery, perhaps too late to result in prevention of PPD. The limiting aspects of these studies include the small sample size in the first study, and the small daily dose of DHA in the second, which as monotherapy has not appeared effective in the treatment of major depression [52]. There have not been adequate studies of omega-3 fatty acids as an intervention for acute perinatal depression. Our group has completed two pilot studies of omega-3 fatty acids as an intervention for perinatal

depression. The first was a small open-label, flexibledose trial of a combination of EPA and DHA (ratio of 1.5:1) for the treatment of major depression during pregnancy in 15 subjects [79]. The mean final dose of omega-3 fatty acids was 1.9 g/d. Duration of participation in the trial was variable. Subjects were enrolled at any point in the pregnancy after the first trimester, due to considerations of morning sickness. Subjects were permitted to continue treatment throughout their pregnancy and assessed every two weeks, with a mean duration of participation of 8.3 weeks (SD+7.1). The mean reduction in EPDS scores was 40.9%. For subjects who completed at least 8 weeks in the study, the mean decrease from baseline on the EPDS was 49.2%. In the second trial for acute perinatal depression, the efficacy of omega-3 fatty acids for PPD was assessed in an 8-week randomized dose-ranging study. Subjects were randomized to daily doses of a combination of EPA and DHA, 0.5 g (N ¼ 6), 1.4 g (N ¼ 3), or 2.8 g (N ¼ 7) [80]. The ratio of EPA:DHA in the study capsules was 1.5:1. There was no placebo-only group in this study. Subjects all received the same number of capsules per day, regardless of dose assignment. There were no significant differences in response between the dosage groups, although subjects in this trial, all of whom received EPA and DHA in doses ranging from 0.5 to 2.8 g/day, improved significantly. Overall, mean decreases on the EPDS and HAM-D were 52% and 49%, respectively. Changes from baseline after treatment were significant among all groups. Omega-3 fatty acid supplementation was well tolerated in both pilot trials. Both studies were limited by small sample size and lack of placebo group. However, these results support

Table 2 Omega-3 fatty acids for perinatal depression: treatment studies Study

Study design

N

Omega-3 constituent, dose

Length of trial

Outcome

Llorente et al. (2003)

Double-blind, placebo-controlled study for PPD prophylaxis

N ¼ 138

DHA, 200 mg

Four months (starting after delivery)

No significant differences in depression scores

Marangell et al. (2004)

PPD prophylaxis, open-label

N¼7

EPA and DHA, 2.96 g per day

Variable, starting between 34 and 36 weeks of pregnancy

4/7 subjects experienced a postpartum depressive episode

Freeman et al. (2006)

Open label, flexible dose for major depression in pregnancy

N ¼ 15

EPA and DHA, flexible dose study; mean final dose 1.9 g per day

Variable, mean participation 8.3 weeks

40.9% mean decrease in depressive symptoms on the EPDS

Freeman et al. (2006)

Randomized doseranging trial for postpartum depression

N ¼ 16

EPA and DHA, randomization to daily doses of 0.5 g, 1.4 g, or 2.8

8 weeks

No significant differences between groups; overall mean percent decreases on the EPDS and HRSD were 51.5% and 48.8%, respectively

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further studies of omega-3 fatty acids as a treatment for perinatal depression.

4. Discussion Perinatal depression is common and has serious consequences for a woman and her family. Pregnant and nursing women and their health care providers must wrestle with the risks and benefits of various treatments and the possible side effects of psychotropic medications. These concerns are highlighted by recent data regarding a neonatal syndrome after in utero antidepressant exposure and data suggestive of teratogenicity with paroxetine use [6,7]. An intervention such as omega-3 fatty acids that has positive effects on an individual’s overall health are attractive to many patients and their health care providers. Moreover, an intervention for perinatal depression that provides health benefits to the baby is exciting and ideal. These considerations apply broadly in the treatment of mood disorders. Major depression is a debilitating condition that affects women more frequently than men [81]. The course is often chronic or recurrent, necessitating long-term treatment for many individuals. The majority of women have children, and at least half of pregnancies in the US are unplanned or mistimed [82]. Hence, women of reproductive age are likely to become pregnant during the course of treatment for depression, and pregnant and postpartum women are often in need of treatment for depression. Further research is warranted to ascertain the potential role of omega-3 fatty acids in the treatment of perinatal depression. Large, randomized controlled treatment trials are necessary to determine whether omega-3 fatty acids are efficacious for acute major depressive episodes in pregnant and postpartum women. Furthermore, controlled dose-ranging trials would be useful to determine if omega-3 fatty acid supplementation may be utilized to prevent PPD in women at risk. Also, as supported by treatment trials in major depressive disorder, omega-3 fatty acids may be an important adjunctive treatment in perinatal women, a strategy that may allow some women to stay well while using lower doses of antidepressant medications. Perinatal depression is an area that deserves special emphasis for research with omega-3 fatty acids as an intervention, due to maternal depletion of omega-3 fatty acids during pregnancy and the unique risk of antidepressant medication exposure in this population.

Acknowledgement Dr. Freeman has received research support from: National Institute for Mental Health, US Food and

295

Drug Administration, Arizona Disease Control Research Commission, Institute for Mental Health Research (Arizona), Forest, Pronova Biocare; Consultant: Ther-Rx, Reliant; Speaking/Honoraria: Pfizer, Lilly, Astra Zeneca

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