General Hospital, Boston, MA

for major depressive disorder associated with the menopausal transition. Secondary outcomes

were assessed for vasomotor symptoms (or hot flashes).

open-label omega-3 fatty acid capsules (eicosapentaenoic acid and docosahexaenoic acid, 2 g/d).

The Montgomery-Asberg Depression Rating Scale (MADRS) was the primary outcome measure.

Hot flashes were monitored prospectively using daily diaries and the Hot Flash Related Daily

Interference Scale. Blood samples for plasma pretreatment and post treatment essential fatty acid

assays were obtained. Because of the small sample size, data were analyzed using nonparametric

techniques.

None discontinued because of adverse effects. The pretreatment and final mean MADRS scores

were 24.2 and 10.7, respectively, reflecting a significant decrease in MADRS scores (P G 0.0001).

The response rate was 70% (MADRS score decrease of Q50%), and the remission rate was 45%

(final MADRS score of e7). Responders had significantly lower pretreatment docosahexaenoic

acid levels than nonresponders did (P = 0.03). Hot flashes were present in 15 (75%) participants.

Among those with hot flashes at baseline, the number of hot flashes per day improved

significantly from baseline (P = 0.02) and Hot Flash Related Daily Interference Scale scores

decreased significantly (P = 0.006).

disorder and hot flashes in women during the menopausal transition.

Address correspondence to: Marlene P. Freeman, MD, Massachusetts General Hospital, Perinatal and Reproductive Psychiatry

Program, 185 Cambridge Street, Boston, MA 02114., mfreeman@partners.org.

*Shared last author.

Financial disclosure/conflicts of interest: Marlene P. Freeman, MDVresearch support from investigator-initiated trials: Forest, GSK,

and Lilly. CME support of program: Pam Lab. Stipend for medical editing: DSM Nutritionals. Speaking: none. Consulting: none.

Stock: none. Hadine Joffe, MD, MScVresearch support to the Perinatal and Reproductive Psychiatry Program: Bayer HealthCare

Pharmaceuticals, Forest Laboratories, Inc., and GSK. Speaking/honoraria: none. Advisory/consulting: Sanofi-Aventis and Pfizer.

Royalty/patent, other income: None. Lee S. Cohen, MDresearch support: Astra-Zeneca Pharmaceuticals, Bayer HealthCare

Pharmaceuticals, Bristol-Myers Squibb, Forest Laboratories, Inc., GSK, National Institute on Aging, National Institutes of Health,

National Institute of Mental Health, Ortho-McNeil Janssen, and Pfizer Inc. Advisory/consulting: Eli Lilly & Company and Noven.

Honoraria: none. Royalty/patent, other income: None. Michael Silver, Joseph Hibbeln, Amy Yule, April Hirschberg, Betty Wang,

Laura Petrillo, Erica Pascuillo, Nicole Economou nothing to disclose.

NIH Public Access

Published in final edited form as:

NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Depression; Major depressive disorder; Omega-3 fatty acids; Menopause; Eicosapentaenoic acid;

Docosahexaenoic acid

A significant number of women have major depressive disorder (MDD) and hot flashes

associated with the menopausal transition. The lifetime prevalence of MDD in women is

greater than 20%, and hot flashes affect up to 80% of women during the menopausal

transition.1, 2 Prospective studies have demonstrated an increased risk of onset of MDD

during the menopausal transition,3, 4 and persistent mood symptoms have been

demonstrated to affect 15% to18% of perimenopausal women, compared with 8% to 12% of

premenopausal women.5 Depression and hot flashes commonly co-occur during the

menopausal transition, and women with hot flashes are at increased risk for MDD.6 Many

women prefer nonhormonal therapies to treat menopause-related symptoms in light of the

demonstrated or perceived risks of hormone therapy. Interest in other treatments has

increased since the publication of the results of the Women’s Health Initiative study, which

failed to demonstrate some of the preventive medical benefits thought to be associated with

hormone therapy and also suggested some risks associated with these treatments.7 Standard

antidepressants have also been studied as a treatment for both the mood and vasomotor

symptoms (VMS) in perimenopausal and postmenopausal women, but many women are

reluctant to use these because of their adverse effectprofiles.8 Complementary and

alternative medicine (CAM) treatments are widely used and often easily accessible. Most

remain understudied in the treatment of MDD and menopausal symptoms. The use of CAM

therapies has increased over the past several decades. A recent report from the National

Center for Complementary and Alternative Medicine demonstrated that more than 40% of

the adult population in the United States used at least one CAM treatment over the previous

year, with women more likely than men to use CAM.9,10 CAM use is most prevalent

among adults aged 30 to 69 years.9 In 2007, US adults spent more than $33.9 billion as outof-

pocket medical costs on CAM therapies, with 44% of that amount (almost $15 billion)

spent on nonvitamin, nonmineral, natural products like omega-3 fatty acids.11 This pattern

of utilization highlights the need for CAM treatment research for depression in women, as

women are both more likely than men to have MDD and to use CAM treatments,9

especially midlife women with depression. Omega-3 fatty acids are a CAM therapy worthy

of further systematic study in perimenopausal and postmenopausal women who have MDD.

Omega-3 fatty acids are among the most widely used CAM therapies and are associated

with well established health benefits. Omega-3 fatty acids are polyunsaturated fatty acids,

and as essential fatty acids, they are an important dietary component, because they must be

consumed and cannot be made by the human body. The typical American diet is composed

of a relative excess amount of omega-6 fatty acids compared with omega-3 fatty acids.12

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 fatty acids

found in fish and marine sources. A significant benefit for omega-3 fatty acids has been

found compared with placebo in several independent meta-analyses, although omega-3 fatty

acids have been used as an adjunctive therapy in most published randomized controlled

trials.13-15 There have been few systematic controlled trials of CAM therapies for hot

flashes. In a recent double-blind, placebo-controlled study comparing black cohosh,

multibotanicals, soy, and estrogen therapy for the treatment of VMS, none of the CAM

therapies showed any benefit over placebo, whereas hormone therapy did demonstrate more

benefits for VMS.16 Preclinical data suggest a role for omega-3 fatty acids in the treatment

of VMS. Omega-3 fatty acids seem to affect serotonergic transmission, as do

antidepressants, which have been demonstrated to diminish VMS.17-19 One placebo-

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controlled study has been published suggesting that omega-3 fatty acids are efficacious in

the treatment of hot flashes in women 40 to 55 years old who were experiencing

psychological distress at baseline.20 In an 8-week study, 120 women were enrolled and

received 1,200 mg/day of EPA and DHA (1,050 mg EPA and 150 mg DHA per day). There

was significantly greater benefit on hot flashes in the omega-3 fatty acids group compared

with the placebo group. For depressive symptoms, women had depressive symptoms at

baseline, although only 24% met the criteria for MDD. Both the omega-3 fatty acid and

placebo groups experienced improved quality-of-life scores throughout the study, without

demonstrated benefit of the omega-3 fatty acids over placebo.20 In the present study, we

sought to determine if an 8-week intervention with omega-3 fatty acids significantly reduces

(1) depressive symptoms and (2) VMS in perimenopausal and postmenopausal women with

MDD.

We conducted an open-label study of omega-3 fatty acids for the treatment of MDD in

women who were perimenopausal or postmenopausal. After a 1-week single-blind placebo

lead-in, participants received 8 weeks of treatment with open-label omega-3 fatty acids. The

study was approved by the institutional review board at Massachusetts General Hospital. An

Investigational New Drug exemption from the US Food and Drug Administration was

obtained before the use of this omega-3 fatty acid preparation for the treatment of MDD in

perimenopausal and postmenopausal women. All participants provided written informed

consent forms. In total, 24 eligible women provided informed consent forms and were

enrolled between November 2008 and April 2009.

Women were eligible to participate if they met all of the following criteria: (1) 40 years or

older, (2) met perimenopause or postmenopause status as defined by the standardized Stages

of Reproductive Aging Workshop criteria,21 (3) met criteria for MDD, verified by the Mini-

International Neuropsychiatric Interview (MINI), and (4) had a minimum score of 19 on the

Montgomery-Asberg Depression Rating Scale (MADRS) at the screening visit.22 Women

were ineligible if any of the following criteria were present: (1) currently pregnant (urine

human chorionic gonadotropin obtained at the screening visit), breast-feeding, or trying to

conceive, (2) currently being treated with an antidepressant, hormone treatment (hormone

therapies, hormonal contraceptives), or omega-3 fatty acid supplements or recently treated

with one of the preceding treatments within 1 month of study entry, (3) acute suicidal

ideation, (4) current or recent (past month) diagnosis of panic disorder or obsessive

compulsive disorder or any lifetime history of psychosis, mania, or hypomania, as assessed

by the MINI, (5) diagnosis of treatment-resistant MDD, defined as treatment with two or

more therapeutic courses of antidepressant medication without remission of symptoms for

the current episode of depression, and (6) presence of a known allergy to fish or fish oil.

Women who responded to placebo (950% decrease in MADRS) were withdrawn from the

study.

Participants received open-label Lovaza 2 g/day (given as 2 capsules per day). Lovaza

(GlaxoSmithKline, Philadelphia, PA, and Research Triangle Park, NC) is a brand of

omega-3 fatty acids with Food and Drug Administration indication for hypertriglyceridemia,

supplied as 1-g transparent soft gelatin capsules. Each 1-g capsule of Lovaza (omega-3 acid

ethyl esters) contains 840 mg of the ethyl esters of omega-3 fatty acids, provided as a

combination of ethyl esters of EPA (approximately 465 mg per capsule) and DHA

(approximately 375 mg per capsule). Small amounts of other omega-3 fatty acids composed

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the remaining 160 mg in each capsule, including docosapentaenoic acid, stearidonic acid,

Before inclusion in the study, women were assessed with the MINI to verify a diagnosis of

MDD and to exclude diagnoses that would determine ineligibility. Medical symptom rating

scales were completed at each of the six visits throughout the study to measure depressive

symptoms and VMS. The instrument used to measure mood at each visit was the MADRS.

22 VMS (hot flashes) were not required at baseline but were experienced by most of the

participants and were monitored throughout the study. VMS were tracked and quantified

prospectively using a daily hot flash diary, completed throughout the study, as well as a selfreport

Hot Flash Related Daily Interference Scale (HFRDIS), completed every other visit.

Hot flash diaries were completed daily by participants prospectively throughout the study.

The diary used was adapted from the 7-day North Central Cancer Treatment Group Diary, a

self-report tool for VMS.23 The diary was adapted so that nocturnal and daytime hot flashes

could be recorded both together and separately. Scores were calculated to incorporate

frequency and severity.23 The HFRDIS is a 10-item self-report questionnaire that measures

the degree to which hot flashes interfere with daily activities and quality of life during the

prior week.24 Blood was drawn to measure essential fatty acid assays before treatment and

after 8 weeks of open-label omega-3 fatty acid treatment. Each participant’s intake of

additional omega-3 fatty acids, including food containing omega-3 fatty acids, was

monitored starting at baseline using a food questionnaire modified from the National Health

and Nutrition Examination Survey study.25 Participants were asked to continue their fish

and seafood intake as usual throughout the study. No significant changes in fish and/or

seafood consumption were noted in any of the participants.

Our primary objective was to determine if an 8-week treatment intervention with omega-3

fatty acids would decrease depressive symptoms in perimenopausal and postmenopausal

women with MDD. Depressive symptoms were measured using MADRS. The secondary

outcome was change in hot flashes from beginning to end of the study, as measured by hot

flash diary and HFRDIS scores. We also sought to determine if baseline DHA or EPA levels

or changes in their levels across the study were associated with response to treatment. This

was a completers’ analysis using a nonparametric approach. The primary outcome measure

(changes in MADRS scores from screening to end of study) was assessed with the Wilcoxon

signed rank test. The same nonparametric procedure was used to examine differences in

HFRDIS scores and hot flash diary from baseline to end of study. Statistical significance

was established at the > = 0.05 level for all analyses.

Of 30 women who consented to participate, 24 were eligible. Three women withdrew during

the placebo run-in (two were no longer interested, one began disallowed medication).

Another woman was a placebo responder after the 1-weekplacebo lead-in. Of the 20

participants who started omega-3fatty acids, 19 (95%) completed the 8-week study. None

discontinued the study because of adverse effects or adverse events. The participant who

began open-label omega-3 fatty acids but did not complete withdrew because of scheduling

difficulties. The mean (SD) age of the participants was 52.5 (4.9) years (range, 42-64 y).

The majority were white (66.7%), non-Hispanic (87.5%), and employed (62.5%). Their

menopause status included a mixture of perimenopausal (37.5%), naturally postmenopausal

(54.2%), and surgically postmenopausal (8.3%) women. See Table 1 for additional

demographic characteristics.

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Table 2 presents the mean MADRS scores at baseline, pretreatment, and posttreatment.

There was a significant effect of treatment on depression symptoms. Mean MADRS scores

decreased from 22.4 to 10.7 after 8 weeks of treatment. The MADRS scores improved

significantly from pretreatment to study end (P G 0.0001). The response rate was 70%

(14/20), and the remission rate was 45% (9/20). Hot flash symptom outcomes Table 2 also

shows baseline, pretreatment, and posttreatment hot flash measures and changes in hot

flashes. Hot flashes improved significantly with treatment, as evident in hot flash diary

scores and HFRDIS scores. On the diary, there was a significant improvement in the mean

frequency of hot flashes reported over a 24-hour period (P = 0.02) and when separated by

day (P = 0.05) and night (P = 0.002). The HFRDIS scores also decreased significantly (P =

0.006). Comparisons of hot flash outcomes between MDD treatment responders and

nonresponders Participants who were responders to treatment on depression measures were

significantly more likely to have decreased hot flash diary scores than were nonresponders

(P = 0.029). This association was also observed when VMS were analyzed separately on the

diary by night time symptoms (P = 0.02), with a weaker association for daytime symptoms

(P = 0.11). Participants who experienced remission of MDD had a significant decrease on

the HFRDIS compared with those who did not experience remission (P = 0.04), although the

difference between depression treatment responders and nonresponders on the HFRDIS was

not significant (P = 0.37).

There was a significant increase in both plasma DHA and EPA levels from baseline to

endpoint (P = 0.0005 and P <0.0001, respectively). MDD treatment responders had

significantly lower pretreatment DHA plasma levels (P = 0.03) compared with

nonresponders. No other fatty acid measures were associated with response to treatment.

There was a trend for MDD treatment responders having a greater increase in plasma EPA

levels than nonresponders (P = 0.08). The changes in DHA levels were not significant

between MDD treatment responders and nonresponders (P = 0.9).

No serious adverse events occurred during the study. All adverse effects were mild in

severity, and no one withdrew because of adverse events. While taking single-blind placebo,

one participant reported an increase in hot flashes, one participant reported experiencing

gastrointestinal discomfort, and one participant reported diarrhea. In the open treatment

phase with omega-3 fatty acids, the following were reported: gas and/or bloating (n = 3),

mild rash (n = 2), puffiness in her face (n = 1), and flulike symptoms (n = 1), which were

assessed by the investigator to be unrelated to the study medication.

More data are needed to inform the treatment of women who experience MDD and hot

flashes during the menopausal transition. Given the significant number of perimenopausal

and postmenopausal women who experience MDD, the potential risks of hormone therapy

and antidepressants, and the broad acceptability of CAM therapies, omega-3 fatty acids are

an important potential treatment alternative. These preliminary data support further study of

omega-3 fatty acids for MDD and VMS during the menopausal transition. In this open trial,

we found promising evidence that omega-3 fatty acids may be efficacious for the treatment

of MDD and hot flashes. Our finding of reduced hot flashes is consistent with the findings of

Lucas et al,20,26 who observed improvement in hot flashes in a randomized placebo

controlled trial of omega-3 fatty acids. However, Lucas et al did not observe a significantly

greater decrease in depressive symptoms with omega-3 fatty acids compared with placebo

Freeman et al. Page 5

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among their participants who were recruited with psychological distress, although only a

minority of their participants had diagnoses of MDD. It may be that a lack of improvement

in mood between groups in that study was due to the fact that the population included

participants with mild to moderate depressive symptoms, who may have been less likely to

respond significantly to treatment, and that nonspecific effects of study participation

attributed to a placebo response. Several different putative mechanisms of action have been

proposed for central nervous system effects of omega-3 fatty acids.14,15,27 The fluctuating

and intermittently lowered levels of estrogen may contribute to the increased prevalence of

depression in perimenopause.28 Treatment with estrogen compounds, such as oral estrogen

therapy or oral contraceptive pills, has been shown to increase levels of DHA in women,

theoretically from the up-regulation of DHA synthesis from dietary precursors.29 Hormone

therapy has been demonstrated to increased EPA and DHA in plasma and has been

hypothesized to contribute to a role in antidepressant effects.30 If a decline in endogenous

estrogen levels were found to lower the amount of omega-3 fatty acids available to the brain,

increased consumption of omega-3 fatty acids during the menopausal transition may be of

particular importance in the treatment of MDD in perimenopausal and postmenopausal

women.

The strengths of the current trial include validated diagnoses of MDD at baseline, specified

severity at baseline, and clear outcome criteria for depressive symptoms in terms of

validated ratings and remission and response criteria. In addition, we monitored VMS

frequency and severity. This study also had important limitations. These included the small

sample size and the lack of a placebo control group. A randomized, well-powered, placebocontrolled

trial of omega-3 fatty acids will be important to ascertain a definitive role of

omega-3 fatty acids in perimenopausal and postmenopausal women with MDD. In addition,

the potential role of omega-3 fatty acids as an adjunct to hormonal therapies and

antidepressant medications would be important to elucidate. The favorable tolerability and

risk-benefit profile of omega-3 fatty acids make them a clinically important treatment option

warranting further study.

In this preliminary study, omega-3 fatty acids seemed to reduce depressive symptoms and

VMS in women who presented with MDD related to the menopausal transition. These data

suggest that larger controlled trials are justified to more definitively assess the role of

omega-3 fatty acids in the treatment of MDD in women during the menopausal transition.

had no input on the study implementation, data analysis, or manuscript preparation. This work was completed at

Massachusetts General Hospital.

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Freeman et al. Page 8

Demographics of enrolled subjects (n=24)

Age, mean ± SD 52.5 ± 4.9

Marital Status

Married/living with partner 8 (33.3%)

Single (never married) 6 (25.0%)

Widowed/divorced 10 (41.7%)

Employment Status

Full time 12 (50.0%)

Part time 3 (12.5%)

Home maker 2 (8.3%)

Student 1 (0.2%)

Disabled 1 (4.2%)

Unemployed 3 (12.5%)

Retired 1 (4.2%)

Other 1 (4.2%)

Education

Attended graduate school 5 (20.8%)

College graduate 5 (20.8%)

Attended some college 11 (45.8%)

High school diploma or GED 2 (8.3%)

Ethnicity

Hispanic/Latina 2 (8.3%)

Non-Hispanic/Non-Latina 21 (87.5%)

Decline to Answer 1 (4.2%)

Race

White/Caucasian 16 (66.7%)

Black/African American 5 (20.8%)

Asian/Pacific Islander 1 (4.2%)

Other 2 (8.3%)

Menopausal Status

Perimenopausal 9 (37.5%)

Naturally Postmenopausal 13 (54.2%)

Surgically Postmenopausal 2 (8.3%)

History of previous major depressive episode*

Yes 8 (33.3%)

No 15 (62.5%)

No answer 1 (4.2%)

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Freeman et al. Page 9

Changes in depression and hot flash scores from baseline to end point

HFRDIS 15 36.9 ± 27.7 14.1 ± 24.2 22.9 27.5 20.0 44.0 0.37

N=20, number of participants who started omega-3 fatty acids after the one-week placebo lead in N=15, number of participants who had hot flashes at baseline and could be included in the hot flash

analyses