- Email: [email protected]
Complementary and alternative medicine for perinatal depression
Journal of Affective Disorders 112 (2009) 1 – 10 www.elsevier.com/locate/jad
Review
Complementary and alternative medicine for perinatal depression Marlene P. Freeman ⁎,1 Women's Mental Health Center, University of Texas Southwestern Medical Center, 6363 Forest Park, Suite 800, Dallas, TX 75235-9086, United States Received 14 March 2008; received in revised form 17 June 2008; accepted 24 June 2008 Available online 8 August 2008
Abstract Introduction: Perinatal Major Depressive Disorder (MDD) is common and poses particular treatment dilemmas. Complementary and Alternative Medicine (CAM) treatments are widely used, accessible, and understudied for well-defined psychiatric indications. Women are more likely than men to both suffer from MDD and use CAM. Methods: A PubMed/Medline search was conducted to assess the evidence base for commonly utilized CAM treatments, MDD, and perinatal depression. Results: Among CAM treatments, omega-3 fatty acids have received the most specific study in terms of epidemiological, preclinical, and clinical research for perinatal depression. Three randomized placebo-controlled trials have been conducted in which investigators assessed omega-3 fatty acids vs. placebo for perinatal depression, with conflicting results. CAM interventions that can be easily added to a treatment plan with little risk and general health benefits for most women include omega-3 fatty acids, exercise, and folate, although data are insufficient at this time to recommend any of these as monotherapy for perinatal depression. S-adenosyl-methionine (SAMe) and bright light therapy may be reasonable to consider based on the evidence in MDD. St. John's Wort requires further study with regard to safety in pregnancy, and drug interactions can be a potential problem. Discussion: Further study is required to elucidate the role of CAM treatments for perinatal depression, and the clinical context of perinatal depression requires safe, effective, and accessible treatment options. © 2008 Elsevier B.V. All rights reserved. Keywords: Pregnant; Postpartum; Perinatal; Depression; Omega-3; Exercise; Acupuncture; S-adenosyl-methionine; St. John's Wort; Light therapy
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . Methods . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . 3.1. Omega-3 fatty acids. . . . . 3.1.1. Perinatal depression
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⁎ Massachusetts General Hospital, Simches Research Building, Floor 2 185 Cambridge Street, Boston, MA 02114, USA. Tel.: +1 617 724 8020; fax: +1 617 643 3080. E-mail address: [email protected]. 1 PLEASE NOTE: after August 2008, I will be changing institutions to Massacusetts General Hospital, Boston, MA. 0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.06.017
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3.2.
S-adenosyl-methionine (SAMe) . . . . . . . 3.2.1. Perinatal depression considerations . 3.3. Folate . . . . . . . . . . . . . . . . . . . . 3.3.1. Perinatal depression considerations . 3.4. Bright light therapy . . . . . . . . . . . . . 3.4.1. Perinatal depression considerations . 3.5. Exercise . . . . . . . . . . . . . . . . . . . 3.5.1. Perinatal depression considerations . 3.6. St. John's Wort . . . . . . . . . . . . . . . 3.6.1. Perinatal depression considerations . 3.7. Acupuncture . . . . . . . . . . . . . . . . . 3.7.1. Perinatal depression data . . . . . . 4. Discussion. . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Perinatal depression, the occurrence of Major Depressive Disorder (MDD) during pregnancy or postpartum, is common and often presents treatment dilemmas. MDD during pregnancy increases the risk of pregnancy complications (Gavin et al., 2005; Wisner et al., 2000). Postpartum depression (PPD) affects 10– 20% of women after childbirth, and is defined in the DSM-IV as Major Depressive Disorder (MDD) with onset within one month of childbirth, with depressive symptoms often starting during pregnancy (Gavin et al., 2005; American Psychiatric Association, 1994; Stowe et al., 2005; Altshuler et al., 1998). Many aspects of child development are negatively affected by PPD, including effects on attachment, behavior, and neurocognitive development (Moses-Kolko and Roth, 2004). Balancing the risks and benefits of antidepressant medications with the risk of untreated MDD is difficult during pregnancy and lactation. Recently available data have raised concerns about the safety of antidepressants for the fetus during pregnancy (Misri and Kendrick, 2007). However, discontinuation of antidepressants for a pregnancy is associated with an increased risk of maternal relapse (Cohen et al., 2006). The treatment challenges involve minimizing fetal and infant exposure to both medications and untreated maternal depression. There are no controlled studies that systematically assess efficacy of antidepressants during pregnancy, and few in the area of postpartum depression. A limited number of studies support that psychotherapy is effective for the acute treatment
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and prevention of perinatal depression (Dennis and Hodnett, 2007). Complementary and Alternative Medicine (CAM) treatments are widely used, accessible, and understudied for well-defined psychiatric indications (Eisenberg et al., 1998; Tindle et al., 2005). Women are more likely than men both to suffer from MDD and use CAM (Mackenzie et al., 2003; Weissman et al., 1984). In a cross-sectional survey, Wu et al. (2007) assessed CAM use by women in the U.S. In a subsample with diagnosed depression, more than half endorsed the use of a CAM treatment over a one-year period. In another study of patients hospitalized for psychiatric indications, 63% reported the use of a CAM treatment within the past year (Elkins et al., 2005). Notably, depressive disorders were the most associated with CAM use, the majority of CAM users were women, and most had not disclosed CAM use to their psychiatrist. Unutzer et al. (2000) demonstrated that individuals with MDD were significantly more likely than those without MDD to use CAM therapies. Previous reviews have addressed CAM treatments for depression in women (Manber et al., 2002; Freeman et al., 2004), although new studies have been subsequently published. In consideration of the prevalence of perinatal MDD, the complicated risks/benefit analysis of treatments in pregnancy and breastfeeding, and the popularity of CAM treatments, a greater understanding of the evidence base for CAM in perinatal depression is important. The objective of this review is to assess the available efficacy and safety data that may be applied to perinatal depression for commonly utilized CAM treatments.
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2. Methods A PubMed/Medline search was conducted using the following terms: pregnancy, postpartum, perinatal, depression, acupuncture, exercise, Hypericum, omega3, St. John's Wort, S-adenosyl-methionine (SAMe), light therapy, tryptophan, inositol, and folate. Therapies that have received the most rigorous study in randomized controlled trials were included, with clinical considerations for pregnancy and the postpartum also considered for relevance.
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2006; Hibbeln et al., 2007). In rats, maternal brain DHA levels decrease when omega-3 fatty acid intake is deficient during pregnancy (Levant et al., 2006). Despite increased demand for omega-3 fatty acids during pregnancy, dietary intake by pregnant and postpartum women in the U.S. has been noted as deficient, with dietary intake during pregnancy even more diminished after U.S. Food and Drug Administration issuances of mercury advisories regarding fish intake during pregnancy (Benisek et al., 2000; Oken et al., 2003). Fish oil capsules appear free of significant levels of mercury or other contaminants (Foran et al., 2003).
3. Results As reviewed by Thachil et al. (2007) in a comprehensive review of CAM treatments for MDD, interventions with the highest rating of evidence included St. John's Wort, tryptophan, S-adenosyl-methionine, folate, inositol, acupuncture, and exercise. Omega-3 fatty acids were also included based on the randomized controlled studies in perinatal depression and MDD, with the studies in perinatal depression having been published after the Thachil et al. review. These were all included as search terms, and inositol and tryptophan were not included for full review due to lack of specific clinical study in pregnancy and the postpartum. Modalities selected for this review were included based on 1) randomized controlled trials in MDD and 2) widespread use with important clinical safety or health information relevant to pregnancy and the postpartum. 3.1. Omega-3 fatty acids Among CAM treatments, omega-3 fatty acids have received the most specific study in terms of epidemiological, preclinical, and clinical research for perinatal depression. Omega-3 fatty acids are nutritional compounds with well established benefits for human health and particular benefits for fetal and infant development (Kris-Etherton et al., 2003; Freeman, 2006; McGregor et al., 2001). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are two crucial omega-3 fatty acids found in fish. Meta-analyses of randomized controlled trials demonstrate a statistically significant antidepressant benefit of omega-3 fatty acids in mood disorders overall, but there has been noted heterogeneity in study designs and results, and they are best studied as an augmentation treatment (Parker et al., 2006; Freeman et al., 2006a,b,c). Despite mixed results in treatment studies of mood disorders, the benefits of maternal omega-3 fatty acid intake have been established as regards obstetrical and infant outcomes (McGregor et al., 2001; Dunstan et al.,
3.1.1. Perinatal depression considerations In a cross-national epidemiological study, Hibbeln (2002) demonstrated that per capita seafood intake was significantly inversely associated with depressive symptoms in postpartum women. However, Browne et al. (2006) did not find an association between prenatal fish consumption and PPD. Our group conducted an open-label study of omega-3 fatty acids in depression during pregnancy, and a randomized dose-finding study of omega-3 fatty acids in postpartum women (Freeman et al., 2006c,b). Both provided promising preliminary data regarding feasibility, tolerability, and efficacy (please see Table 1). Three randomized placebo-controlled trials have been conducted in which investigators assessed omega-3 fatty acids vs. placebo for perinatal depression (please see Table 1). In two, investigators did not detect a difference between omega-3 fatty acids and placebo (Rees et al., 2008; Freeman et al., 2008). However, Su et al. demonstrated a significant benefit of omega-3 fatty acids compared with placebo in antenatal depression (Su et al., 2008). The randomized controlled trials conducted to date have several limitations. All included relatively small numbers of subjects and were of short duration (up to 8weeks). In the two studies that failed to find a difference between placebo, both omega-3 fatty acid and placebo groups improved significantly from study entry, suggesting that other factors related to study participation were associated with improvement (Rees et al., 2008; Freeman et al., 2008). Dose may be especially important for further study, as the positive study by Su et al. (2008) utilized the highest dose. Omega-3 fatty acid supplements have been well tolerated by perinatal women (Freeman and Sinha, 2007). 3.2. S-adenosyl-methionine (SAMe) S-adenosyl-methionine (SAMe) is naturally occurring and integral for the methylation of biological
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Table 1 Treatment studies of omega-3 fatty acids for perinatal depression Study
Study design
Freeman Open-label, flexible-dose et al. (2006b) for MDD in pregnancy Freeman et al. (2006c)
Randomized dose-ranging trial for postpartum MDD
N
Omega-3 dose
Length of trial
12 EPA and DHA, flexible-dose; mean final dose 1.9g/day 16 EPA and DHA, 0.5g, 1.4g, or 2.8g/day
Su et al. Double-blind, placebo-controlled 36 EPA and DHA, (2008) trial MDD in pregnancy 3.4g/day Freeman et al. Double-blind, placebo-controlled 59 EPA and DHA, (2008) trial for MDD in pregnant and 1.9 g/day postpartum women (all received supportive psychotherapy) Rees et al. Double-blind, placebo-controlled 26 6 weeks (2008) trial for MDD in pregnant and postpartum women
Outcome
Mean participation 8.3weeks 40.9% mean decrease in depressive (protocol allowed for symptoms on the EPDS variable duration) 8 weeks Mean % decreases on the EPDS and HRSD 51.5% and 48.8%, respectively (no significant differences between groups) 8 weeks Significantly higher response, remission rates in omega-3 group 8 weeks No significant difference between omega-3 fatty acids and placebo 6 g fish oil per day; provided No significant difference 1.6 g DHA; 0.4 g EPA between omega-3 fatty (2 g DHA and EPA) acids and placebo
EPDS = Edinburgh Postnatal Depression Scale. HRSD = Hamilton Rating Scale for Depression.
constituents with important implications for mood disorders, including neurotransmitters, phospholipids, and cellular receptors and channels (Mischoulon and Fava, 2002; Papakostas et al., 2005). The Agency for Healthcare Research and Quality (AHRQ) conducted a systematic assessment of SAMe use for MDD, and found an evidence base that supports further research with SAMe for depression (AHRQ, 2002). Several reviews and meta-analyses document SAMe efficacy for the treatment of MDD (Bressa, 1994; Delle Chiaie et al., 2002; Mischoulon and Fava, 2002). SAMe has been demonstrated to be generally well tolerated, and better tolerated than tricyclic antidepressants. Infrequently reported side effects include mild gastrointestinal symptoms, sweating, dizziness, and anxiety; mania has been reported in cases when used for bipolar depression (Alpert et al., 2004; Delle Chiaie et al., 2002; Mischoulon and Fava, 2002). 3.2.1. Perinatal depression considerations In a placebo-controlled study of postpartum women, Cerutti et al. (1993) found significant decreases in depressive symptoms with SAMe. Diagnoses of MDD were not established in that study, although the investigators observed significantly greater improvement in depressive symptoms in the SAMe group compared to the placebo group after 10days of treatment. No data are available regarding the efficacy of SAMe in antenatal depression. There have been no reports of side effects or adverse events in infants who are breastfed during maternal use of SAMe. Animal data
assessing sulphate-p-toluene sulphonate salt of SAMe have not been demonstrated to alter reproductive function, result in teratogenic effects, or affect neonates adversely with large dose administration (Cozens et al., 1988). SAMe has been used in clinical studies in pregnant women for cholestasis in pregnancy. SAMe may have a protective role in liver functioning and in the treatment of liver diseases. In the AHRQ report on SAMe, 8 studies were identified that assessed SAMe for cholestasis in pregnancy. Five systematically reported tolerability and side effects, without observed side effects for mothers or babies (AHRQ, 2002). 3.3. Folate Folate has been assessed as a predictor of antidepressant medication response and as an adjunct to MDD treatment. Folate is involved in the methylation of homocysteine, which is SAMe (Botez et al., 1979). Lower folate blood levels are associated with poorer and slower response to fluoxetine for MDD (Papakostas et al., 2004; Papakostas et al., 2005; Alpert et al., 2003). A systematic review of randomized, placebo-controlled studies found evidence to suggest that folate may have a role as an augmenting antidepressant agent, even in patients with normal serum folate levels (Taylor et al., 2003). Additionally, individuals with low folate levels may be less likely to respond to SSRI therapy (Fava et al., 1997). Folate may have particular advantages for women compared with men in its effects on depressive symptoms (Coppen and Bailey, 2000). Women were
M.P. Freeman / Journal of Affective Disorders 112 (2009) 1–10
observed to experience a larger decrease (p b 0.001) in mean depression scores when folate 500mg per day was provided compared with placebo in women treated with fluoxetine for MDD. This benefit was not found for men. Also, folate appeared to improve tolerability of fluoxetine, as medication-related side effects were lower in those receiving folate compared to the placebo group. 3.3.1. Perinatal depression considerations There has been no specific study of folate as an intervention for perinatal depression. However, women who are pregnant or planning to become pregnant are advised to take 0.4–1mg of folate daily to decrease birth defects, particularly neural tube defects (McDonald et al., 2003). Data are inadequate to suggest that folate is efficacious as a monotherapy for MDD or PPD, and modest evidence supports folate as an augmentation strategy. However, one epidemiological study did not find a relationship between folate intake and postpartum depression (Miyake et al., 2006). An attractive risk/ benefit profile suggests that folate can be considered a reasonable adjunctive treatment for MDD that carries little risk and may decrease birth defects in women who become pregnant during the course of treatment. 3.4. Bright light therapy Bright light therapy was first assessed as a treatment for seasonal MDD, but appears effective for nonseasonal MDD as well (Eastman et al., 1998; Terman et al., 1989; Kripke et al., 1992; Sumaya et al., 2001). Although many studies in this area have some methodological limitations, the more rigorous studies demonstrate a significant benefit of bright light therapy in seasonal MDD and nonseasonal MDD (Golden et al., 2005). Hypomania has been reported as an adverse event with light therapy (Golden et al., 2005). 3.4.1. Perinatal depression considerations In one open study of light therapy for antenatal MDD, pregnant women received treatment with 60min of bright light therapy in the morning (Oren et al., 2002). In the 16 women who completed at least three weeks of treatment, depression scores improved by an average of 49%. In the seven subjects who completed two more weeks (five weeks), scores improved by 59%. Withdrawal of light therapy resulted in a relapse of depressive symptoms in the majority. In a double-blind study of antenatal depression, ten pregnant women were randomized to either bright light therapy or a dim light placebo (Epperson et al., 2004). One patient experienced hypomania with bright light. After ten weeks, bright
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light therapy produced a significantly greater antidepressant response than placebo, with differences reaching significance after five weeks. In a study of women with PPD (N = 15), participants were assigned randomly to bright light or a dim light placebo (Corrall et al., 2007). After six weeks, both groups experienced significant improvement, without a difference between groups. Although limited by small sample sizes, the evidence supports the potential use of bright light therapy as an efficacious therapy for MDD in pregnant women and deserves further study in perinatal women. 3.5. Exercise Exercise is important in achieving and maintaining good health. Most studies in this area support at least a modest benefit for depressive symptoms in normal individuals and those with MDD. Epidemiological data support an association between exercise and a decreased risk of depressive symptoms (Strawbridge et al., 2002; Penninx et al., 2002). Research challenges include selection of appropriate control conditions and difficulty blinding treatment assignment. The “dose” of exercise and adherence to a regimen may be particularly important to assess (Dunn et al., 2005). Several treatment studies support an antidepressant effect of aerobic exercise (Trivedi et al., 2006; Otto et al., 2007). 3.5.1. Perinatal depression considerations In one study of pregnant women without MDD, participants collected prospective data each trimester on mood, anxiety, stress, and exercise (Da Cost et al., 2003). Exercisers reported significantly less depressive symptoms in the first and second trimesters than those who did not exercise, a difference not found later in pregnancy. The women were not randomized to condition, introducing cofounding variables. In studies of pregnant and postpartum women (Koltyn and Schultes, 1997; Polman et al., 2007), the effects of a single aerobic exercise session appear to have more beneficial mood effects than control conditions. In a randomized study of 80 postpartum women who had depression scores indicative of PPD at 6weeks postpartum, investigators randomly assigned women to either three exercise sessions per week or treatment as usual (Heh et al., 2008). Women who were assigned to exercise did significantly better after five months postpartum than controls. Exercise is attractive due to its low cost, availability, and broad health advantages. The American College of Obstetricians and Gynecologists recommend 30min of moderate exercise on most days for pregnant women, unless medical contraindications exist (Artal and O'Toole, 2003).
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3.6. St. John's Wort St. John's Wort (usually studied as Hypericum extract) is an herbal remedy that is extremely popular in Europe (Cott, 1995). In placebo-controlled studies of St. John's Wort in the treatment of MDD, results have yielded conflicting results, especially in more severe MDD. Shelton et al. (2001) and Davidson et al. (2002) did not find a significant difference between St. John's Wort and placebo in large studies. Lecrubier et al. (2002), however, demonstrated a significant difference between St. John's Wort and placebo in mild to moderate depression. Additionally, several randomized studies have shown non-inferiority compared to standard antidepressants, with some advantage of St. John's Wort in terms of side effects (Whiskey et al., 2001). Drug–drug interactions are an important consideration, as St. John's Wort has effects on drug metabolism via the cytochrome P450 system (most notably CYP3A4), and may interact with medications such as SSRIs, oral contraceptives, and hormones
replacement therapy (Roby et al., 2000). The possible increased metabolism of oral contraceptives with St. John's Wort may increase the risk of unwanted pregnancy, and unwanted pregnancies resulting from suspected drug interactions have been reported (Schwarz et al., 2003). Therefore, St. John's Wort may be a reasonable treatment, especially more mild to moderate MDD, and safety issues include potential for drug interactions. 3.6.1. Perinatal depression considerations Only a small amount of data inform the safety profile in pregnancy and postpartum. In case reports of breastfeeding mothers (Klier et al., 2002, 2006), the measurement of two active constituents of Hypericum (hyperforin and hypericin) in breastmilk demonstrated low levels in breastmilk, suggesting minimal exposure to the breastfed infant. Infants did not have detectable plasma levels, and no adverse effects were observed. In one study of pregnant women (N = 33) treated with Hypericum, newborns were reported to experience increased rates of
Table 2 CAM modalities: considerations in MDD and perinatal depression CAM modality
Evidence in MDD and dose ranges
Omega-3 fatty acids Placebo-controlled studies support efficacy in MDD, mainly as an adjunctive treatment to antidepressants; doses range from 0.5–3.4 g in studies specific to perinatal depression SAMe
Folate
Good evidence for efficacy; effective doses range from 800–1600 mg in studies of oral administration
May be especially important for women as an augmentation strategy for MDD; dose of 0.5–1 mg of folate daily based on MDD research and prevention of birth defects St. John's Wort Substantial number of placebo-controlled trials support efficacy for mild to moderate depression; less convincing evidence for severe MDD; doses range from 500–1800 mg per day in randomized controlled trials Acupuncture Mixed findings of efficacy in studies for MDD; methodological difficulties of study in terms of adequate placebo control Bright light therapy Appears effective for MDD; dose is usually up to 10,000 lx delivered for 30–60 min/day by light box Exercise Appears to have antidepressant benefits; duration of 30 min per day consistent with ACOG recommendations and depression literature
Specific comments regarding perinatal depression
Other comments
Provision in utero associated with neurocognitive developmental benefits; treatment studies have demonstrated mixed findings regarding efficacy as monotherapy for perinatal MDD Unlikely to pose risk; has been studied in pregnancy as a treatment for liver disease without apparent adverse events; more study needed No known risks; may help with overall nutritional status and prevention of birth defects
General health benefits and data regarding benefits in mood disorders support omega-3 fatty acids as part of treatment plan
General health benefits and data regarding benefits in mood disorders support folate as part of treatment plan Insufficient study in breastfeeding and Drug interactions; may decrease for PPD; one study suggests a neonatal efficacy of oral contraceptives; syndrome after in utero exposure requires careful study before it may be recommended in pregnancy
No specific study in PPD; some points may stimulate uterine contractions or hasten labor and delivery One small negative study in PPD; positive pilot trials in pregnancy Recommended for general health General health benefits and data benefits unless known contraindication regarding benefits in mood disorders support exercise as part of treatment plan
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colic, drowsiness, and lethargy compared to infants of matched depressed and non-depressed control mothers (Lee et al., 2003). Five were noted to experienced adverse effects, although none required medical intervention. It is possible that the neonatal syndrome described with antidepressants is also an issue with St. John's Wort, although this has not received specific study. One study of administration in rats during pregnancy and breastfeeding suggests that the potential for teratogenic and toxic effects, and human safety during pregnancy and breastfeeding has not received adequate study (Gregoretti et al., 2004; Dugoua et al., 2006). St. John's Wort shows some evidence of efficacy, but further studies need to be done to evaluate safety for use in perinatal and postpartum depression, particularly its effects on the unborn fetus. 3.7. Acupuncture In Traditional Chinese Medicine, acupuncture is thought to impact the imbalance of energy which is thought to result from trauma and cause disease. Mixed results have been demonstrated in controlled trials of acupuncture for MDD (Allen et al., 1998; Luo et al., 1998; Quah-Smith et al., 2005; Gallagher et al., 2001). Assessment of the evidence base for acupuncture is challenging, as many reports are in Asian languages and often overlooked in the Western literature, and study designs often reflect conceptually challenging aspects, such as variability in diagnosis and implementation of interventions across studies (Halbreich, 2008). 3.7.1. Perinatal depression data Special caution is required for pregnant women, as some acupuncture points may cause uterine stimulation and advancement of labor and delivery (Motl, 2002; Rabl et al., 2001). In one pilot trial for pregnant women with depression, investigators randomized 61 women with MDD to active acupuncture, active control acupuncture, or massage for 8weeks (Manber et al., 2004). Response rates were higher for active acupuncture (69%) compared to the control acupuncture (47%) or massage groups (32%). 4. Discussion Antenatal and postpartum MDD are common, with serious consequences for a woman and her family. There are potential risks of psychotropic medications in pregnancy and breastfeeding, and a limited evidence base from which to make treatment decisions. Further study is required so that psychiatrists and other health care providers can offer safe, effective, and accessible
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treatment options for perinatal depression. Although CAM treatments are often easily accessible and available without prescription, women who experience perinatal depression should be encouraged to have a comprehensive assessment and discussion about all available treatment options. Psychiatrists and other physicians need to be educated about CAM modalities and discuss these actively and nonjudgmentally with patients, as many patients will not spontaneously disclose use of CAM treatments (Eisenberg et al., 2001). Some CAM treatments offer general health benefits and low risk, provided that appropriate assessments and standard treatments are also provided or accessible. The accessibility and popularity of some interventions raises the concern that needed evaluation and treatment will be prematurely dismissed in lieu of CAM. CAM interventions that can be easily added to a treatment plan with low risk and general health benefits for most women include omega-3 fatty acids, exercise, and folate, although data are insufficient at this time to recommend any of these as monotherapy for perinatal depression. SAMe and bright light therapy may be reasonable to consider, and there is evidence to support monotherapy in MDD. Data regarding the efficacy of acupuncture in MDD are conflicting. Bright light therapy, St. John's Wort, and SAMe might increase the risk of hypomania in women who are predisposed to experience bipolar-spectrum mood episodes. St. John's Wort can be best recommended for mild to moderate depression, with possible drug–drug interactions kept in mind. St. John's Wort requires further study with regard to efficacy and safety in perinatal depression. At this time, further study is necessary to delineate the role of specific CAM therapies in perinatal depression. Role of funding source Dr. Freeman's time was supported by the UT Southwestern Medical Center and the Meadows Foundation. Neither had any input into this manuscript.
Conflict of interest Research support: U.S. FDA, Eli Lilly, Forest (pending), Reliant/ GlaxoSmithKline (pending), the Meadows Foundation, UT Southwestern Medical Center; CME honorarium Chatham Institute (sponsored by grant from KV Pharmaceuticals, pending). Dr. Freeman's time was supported by UT Southwestern Medical Center and the Meadows Foundation. Neither had any input into this manuscript.
Acknowledgements The author wishes to thank Scott A. Freeman, M.D., and Dorothy Kelly, Ph.D. for editorial suggestions.
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References Agency for Healthcare Research and Quality, 2002. S-Adenosyl-LMethionine (SAMe) for Depression, Osteoarthritis, and Liver Disease, Structured Abstract. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/tp/sametp.htm. Allen, J.J.B., Schnyer, R.N., Hitt, S.K., 1998. The efficacy of acupuncture in the treatment of major depressive disorder in women. Psychol. Sci. 9, 397–401. Alpert, M., Silva, R.R., Pouget, E.R., 2003. Prediction of treatment response in geriatric depression from baseline folate level: interaction with an SSRI or a tricyclic antidepressant. J. Clin. Psychopharmacol. 23 (3), 309–313. Alpert, J.E., Papakostas, G., Mischoulon, D., Worthington III, J.J., Petersen, T., Mahal, Y., Burns, A., Bottiglieri, T., Nierenberg, A.A., Fava, M., 2004. S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J. Clin. Psychopharmacol. 24 (6), 661–664. Altshuler, L.L., Hendrich, V., Cohen, L.S., 1998. Course of mood and anxiety disorders during pregnancy and the postpartum period. J. Clin. Psychiatry 59, 29–33. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Association, Washington, DC. Artal, R., O'Toole, M., 2003. Guidelines of the American College of Obstetricians and Gynecologists for exercise during pregnancy and the postpartum period. Br. J. Sports Med. 37 (1), 6–12. Benisek, D., Shabert, J., Skornik, R., 2000. Dietary intake of polyunsaturated fatty acids by pregnant or lactating women in the United States. Obstet. Gynecol. 95, 7778. Botez, M.I., Young, S.N., Bachevalier, J., Gauthier, S., 1979. Folate deficiency decreased brain 5-hydroxytryptamine synthesis in man and rat. Nature 278, 182–183. Bressa, G.M., 1994. S-adenosyl-L-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol. Scand Suppl. 154, 7–14. Browne, J.C., Scott, K.M., Silvers, K.M., 2006. Fish consumption in pregnancy and omega-3 status after birth are not associated with postnatal depression. J. Affect Disord. 90 (2–3), 131–139. Cerutti, R., Sichel, M.P., Perin, M., Grusso, P., Zulian, O., 1993. Psychological distress during the puerperium: a novel therapeutic approach using S-adenosylmethionine. Curr. Ther. Res. 53, 707–716. Cohen, L.S., Altshuler, L.L., Harlow, B.L., Nonacs, R., Newport, D.J., Viguera, A.C., Suri, R., Burt, V.K., Hendrick, V., Remnick, A.M., Loughead, A., Vitonis, A.F., Stowe, Z.N., 2006. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 295 (5), 499–507. Coppen, A., Bailey, J., 2000. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomized, placebo-controlled trial. J. Affect. Disord. 60 (2), 121–130. Corral, M., Wardrop, A.A., Zhang, H., Grewal, A.K., Patton, S., 2007. Morning light therapy for postpartum depression. Arch Womens Ment. Health 10 (5), 221–224. Cott, J., 1995. Natural product formulations available in Europe for psychotropic indications. Psychopharmacol. Bull. 31 (4), 745–751. Cozens, D.O., Barton, S.J., Clark, R., Gibson, W.A., Hughs, E.W., Masters, R.E., Offer, J.M., Perkins, C.J., 1988. Stramentinoli G. Reproductive toxicity studies of ademetionine. Arzneimittelforschung 38, 1625–1629.
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Review
Complementary and alternative medicine for perinatal depression Marlene P. Freeman ⁎,1 Women's Mental Health Center, University of Texas Southwestern Medical Center, 6363 Forest Park, Suite 800, Dallas, TX 75235-9086, United States Received 14 March 2008; received in revised form 17 June 2008; accepted 24 June 2008 Available online 8 August 2008
Abstract Introduction: Perinatal Major Depressive Disorder (MDD) is common and poses particular treatment dilemmas. Complementary and Alternative Medicine (CAM) treatments are widely used, accessible, and understudied for well-defined psychiatric indications. Women are more likely than men to both suffer from MDD and use CAM. Methods: A PubMed/Medline search was conducted to assess the evidence base for commonly utilized CAM treatments, MDD, and perinatal depression. Results: Among CAM treatments, omega-3 fatty acids have received the most specific study in terms of epidemiological, preclinical, and clinical research for perinatal depression. Three randomized placebo-controlled trials have been conducted in which investigators assessed omega-3 fatty acids vs. placebo for perinatal depression, with conflicting results. CAM interventions that can be easily added to a treatment plan with little risk and general health benefits for most women include omega-3 fatty acids, exercise, and folate, although data are insufficient at this time to recommend any of these as monotherapy for perinatal depression. S-adenosyl-methionine (SAMe) and bright light therapy may be reasonable to consider based on the evidence in MDD. St. John's Wort requires further study with regard to safety in pregnancy, and drug interactions can be a potential problem. Discussion: Further study is required to elucidate the role of CAM treatments for perinatal depression, and the clinical context of perinatal depression requires safe, effective, and accessible treatment options. © 2008 Elsevier B.V. All rights reserved. Keywords: Pregnant; Postpartum; Perinatal; Depression; Omega-3; Exercise; Acupuncture; S-adenosyl-methionine; St. John's Wort; Light therapy
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . Methods . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . 3.1. Omega-3 fatty acids. . . . . 3.1.1. Perinatal depression
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⁎ Massachusetts General Hospital, Simches Research Building, Floor 2 185 Cambridge Street, Boston, MA 02114, USA. Tel.: +1 617 724 8020; fax: +1 617 643 3080. E-mail address: [email protected]. 1 PLEASE NOTE: after August 2008, I will be changing institutions to Massacusetts General Hospital, Boston, MA. 0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.06.017
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3.2.
S-adenosyl-methionine (SAMe) . . . . . . . 3.2.1. Perinatal depression considerations . 3.3. Folate . . . . . . . . . . . . . . . . . . . . 3.3.1. Perinatal depression considerations . 3.4. Bright light therapy . . . . . . . . . . . . . 3.4.1. Perinatal depression considerations . 3.5. Exercise . . . . . . . . . . . . . . . . . . . 3.5.1. Perinatal depression considerations . 3.6. St. John's Wort . . . . . . . . . . . . . . . 3.6.1. Perinatal depression considerations . 3.7. Acupuncture . . . . . . . . . . . . . . . . . 3.7.1. Perinatal depression data . . . . . . 4. Discussion. . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Perinatal depression, the occurrence of Major Depressive Disorder (MDD) during pregnancy or postpartum, is common and often presents treatment dilemmas. MDD during pregnancy increases the risk of pregnancy complications (Gavin et al., 2005; Wisner et al., 2000). Postpartum depression (PPD) affects 10– 20% of women after childbirth, and is defined in the DSM-IV as Major Depressive Disorder (MDD) with onset within one month of childbirth, with depressive symptoms often starting during pregnancy (Gavin et al., 2005; American Psychiatric Association, 1994; Stowe et al., 2005; Altshuler et al., 1998). Many aspects of child development are negatively affected by PPD, including effects on attachment, behavior, and neurocognitive development (Moses-Kolko and Roth, 2004). Balancing the risks and benefits of antidepressant medications with the risk of untreated MDD is difficult during pregnancy and lactation. Recently available data have raised concerns about the safety of antidepressants for the fetus during pregnancy (Misri and Kendrick, 2007). However, discontinuation of antidepressants for a pregnancy is associated with an increased risk of maternal relapse (Cohen et al., 2006). The treatment challenges involve minimizing fetal and infant exposure to both medications and untreated maternal depression. There are no controlled studies that systematically assess efficacy of antidepressants during pregnancy, and few in the area of postpartum depression. A limited number of studies support that psychotherapy is effective for the acute treatment
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and prevention of perinatal depression (Dennis and Hodnett, 2007). Complementary and Alternative Medicine (CAM) treatments are widely used, accessible, and understudied for well-defined psychiatric indications (Eisenberg et al., 1998; Tindle et al., 2005). Women are more likely than men both to suffer from MDD and use CAM (Mackenzie et al., 2003; Weissman et al., 1984). In a cross-sectional survey, Wu et al. (2007) assessed CAM use by women in the U.S. In a subsample with diagnosed depression, more than half endorsed the use of a CAM treatment over a one-year period. In another study of patients hospitalized for psychiatric indications, 63% reported the use of a CAM treatment within the past year (Elkins et al., 2005). Notably, depressive disorders were the most associated with CAM use, the majority of CAM users were women, and most had not disclosed CAM use to their psychiatrist. Unutzer et al. (2000) demonstrated that individuals with MDD were significantly more likely than those without MDD to use CAM therapies. Previous reviews have addressed CAM treatments for depression in women (Manber et al., 2002; Freeman et al., 2004), although new studies have been subsequently published. In consideration of the prevalence of perinatal MDD, the complicated risks/benefit analysis of treatments in pregnancy and breastfeeding, and the popularity of CAM treatments, a greater understanding of the evidence base for CAM in perinatal depression is important. The objective of this review is to assess the available efficacy and safety data that may be applied to perinatal depression for commonly utilized CAM treatments.
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2. Methods A PubMed/Medline search was conducted using the following terms: pregnancy, postpartum, perinatal, depression, acupuncture, exercise, Hypericum, omega3, St. John's Wort, S-adenosyl-methionine (SAMe), light therapy, tryptophan, inositol, and folate. Therapies that have received the most rigorous study in randomized controlled trials were included, with clinical considerations for pregnancy and the postpartum also considered for relevance.
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2006; Hibbeln et al., 2007). In rats, maternal brain DHA levels decrease when omega-3 fatty acid intake is deficient during pregnancy (Levant et al., 2006). Despite increased demand for omega-3 fatty acids during pregnancy, dietary intake by pregnant and postpartum women in the U.S. has been noted as deficient, with dietary intake during pregnancy even more diminished after U.S. Food and Drug Administration issuances of mercury advisories regarding fish intake during pregnancy (Benisek et al., 2000; Oken et al., 2003). Fish oil capsules appear free of significant levels of mercury or other contaminants (Foran et al., 2003).
3. Results As reviewed by Thachil et al. (2007) in a comprehensive review of CAM treatments for MDD, interventions with the highest rating of evidence included St. John's Wort, tryptophan, S-adenosyl-methionine, folate, inositol, acupuncture, and exercise. Omega-3 fatty acids were also included based on the randomized controlled studies in perinatal depression and MDD, with the studies in perinatal depression having been published after the Thachil et al. review. These were all included as search terms, and inositol and tryptophan were not included for full review due to lack of specific clinical study in pregnancy and the postpartum. Modalities selected for this review were included based on 1) randomized controlled trials in MDD and 2) widespread use with important clinical safety or health information relevant to pregnancy and the postpartum. 3.1. Omega-3 fatty acids Among CAM treatments, omega-3 fatty acids have received the most specific study in terms of epidemiological, preclinical, and clinical research for perinatal depression. Omega-3 fatty acids are nutritional compounds with well established benefits for human health and particular benefits for fetal and infant development (Kris-Etherton et al., 2003; Freeman, 2006; McGregor et al., 2001). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are two crucial omega-3 fatty acids found in fish. Meta-analyses of randomized controlled trials demonstrate a statistically significant antidepressant benefit of omega-3 fatty acids in mood disorders overall, but there has been noted heterogeneity in study designs and results, and they are best studied as an augmentation treatment (Parker et al., 2006; Freeman et al., 2006a,b,c). Despite mixed results in treatment studies of mood disorders, the benefits of maternal omega-3 fatty acid intake have been established as regards obstetrical and infant outcomes (McGregor et al., 2001; Dunstan et al.,
3.1.1. Perinatal depression considerations In a cross-national epidemiological study, Hibbeln (2002) demonstrated that per capita seafood intake was significantly inversely associated with depressive symptoms in postpartum women. However, Browne et al. (2006) did not find an association between prenatal fish consumption and PPD. Our group conducted an open-label study of omega-3 fatty acids in depression during pregnancy, and a randomized dose-finding study of omega-3 fatty acids in postpartum women (Freeman et al., 2006c,b). Both provided promising preliminary data regarding feasibility, tolerability, and efficacy (please see Table 1). Three randomized placebo-controlled trials have been conducted in which investigators assessed omega-3 fatty acids vs. placebo for perinatal depression (please see Table 1). In two, investigators did not detect a difference between omega-3 fatty acids and placebo (Rees et al., 2008; Freeman et al., 2008). However, Su et al. demonstrated a significant benefit of omega-3 fatty acids compared with placebo in antenatal depression (Su et al., 2008). The randomized controlled trials conducted to date have several limitations. All included relatively small numbers of subjects and were of short duration (up to 8weeks). In the two studies that failed to find a difference between placebo, both omega-3 fatty acid and placebo groups improved significantly from study entry, suggesting that other factors related to study participation were associated with improvement (Rees et al., 2008; Freeman et al., 2008). Dose may be especially important for further study, as the positive study by Su et al. (2008) utilized the highest dose. Omega-3 fatty acid supplements have been well tolerated by perinatal women (Freeman and Sinha, 2007). 3.2. S-adenosyl-methionine (SAMe) S-adenosyl-methionine (SAMe) is naturally occurring and integral for the methylation of biological
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Table 1 Treatment studies of omega-3 fatty acids for perinatal depression Study
Study design
Freeman Open-label, flexible-dose et al. (2006b) for MDD in pregnancy Freeman et al. (2006c)
Randomized dose-ranging trial for postpartum MDD
N
Omega-3 dose
Length of trial
12 EPA and DHA, flexible-dose; mean final dose 1.9g/day 16 EPA and DHA, 0.5g, 1.4g, or 2.8g/day
Su et al. Double-blind, placebo-controlled 36 EPA and DHA, (2008) trial MDD in pregnancy 3.4g/day Freeman et al. Double-blind, placebo-controlled 59 EPA and DHA, (2008) trial for MDD in pregnant and 1.9 g/day postpartum women (all received supportive psychotherapy) Rees et al. Double-blind, placebo-controlled 26 6 weeks (2008) trial for MDD in pregnant and postpartum women
Outcome
Mean participation 8.3weeks 40.9% mean decrease in depressive (protocol allowed for symptoms on the EPDS variable duration) 8 weeks Mean % decreases on the EPDS and HRSD 51.5% and 48.8%, respectively (no significant differences between groups) 8 weeks Significantly higher response, remission rates in omega-3 group 8 weeks No significant difference between omega-3 fatty acids and placebo 6 g fish oil per day; provided No significant difference 1.6 g DHA; 0.4 g EPA between omega-3 fatty (2 g DHA and EPA) acids and placebo
EPDS = Edinburgh Postnatal Depression Scale. HRSD = Hamilton Rating Scale for Depression.
constituents with important implications for mood disorders, including neurotransmitters, phospholipids, and cellular receptors and channels (Mischoulon and Fava, 2002; Papakostas et al., 2005). The Agency for Healthcare Research and Quality (AHRQ) conducted a systematic assessment of SAMe use for MDD, and found an evidence base that supports further research with SAMe for depression (AHRQ, 2002). Several reviews and meta-analyses document SAMe efficacy for the treatment of MDD (Bressa, 1994; Delle Chiaie et al., 2002; Mischoulon and Fava, 2002). SAMe has been demonstrated to be generally well tolerated, and better tolerated than tricyclic antidepressants. Infrequently reported side effects include mild gastrointestinal symptoms, sweating, dizziness, and anxiety; mania has been reported in cases when used for bipolar depression (Alpert et al., 2004; Delle Chiaie et al., 2002; Mischoulon and Fava, 2002). 3.2.1. Perinatal depression considerations In a placebo-controlled study of postpartum women, Cerutti et al. (1993) found significant decreases in depressive symptoms with SAMe. Diagnoses of MDD were not established in that study, although the investigators observed significantly greater improvement in depressive symptoms in the SAMe group compared to the placebo group after 10days of treatment. No data are available regarding the efficacy of SAMe in antenatal depression. There have been no reports of side effects or adverse events in infants who are breastfed during maternal use of SAMe. Animal data
assessing sulphate-p-toluene sulphonate salt of SAMe have not been demonstrated to alter reproductive function, result in teratogenic effects, or affect neonates adversely with large dose administration (Cozens et al., 1988). SAMe has been used in clinical studies in pregnant women for cholestasis in pregnancy. SAMe may have a protective role in liver functioning and in the treatment of liver diseases. In the AHRQ report on SAMe, 8 studies were identified that assessed SAMe for cholestasis in pregnancy. Five systematically reported tolerability and side effects, without observed side effects for mothers or babies (AHRQ, 2002). 3.3. Folate Folate has been assessed as a predictor of antidepressant medication response and as an adjunct to MDD treatment. Folate is involved in the methylation of homocysteine, which is SAMe (Botez et al., 1979). Lower folate blood levels are associated with poorer and slower response to fluoxetine for MDD (Papakostas et al., 2004; Papakostas et al., 2005; Alpert et al., 2003). A systematic review of randomized, placebo-controlled studies found evidence to suggest that folate may have a role as an augmenting antidepressant agent, even in patients with normal serum folate levels (Taylor et al., 2003). Additionally, individuals with low folate levels may be less likely to respond to SSRI therapy (Fava et al., 1997). Folate may have particular advantages for women compared with men in its effects on depressive symptoms (Coppen and Bailey, 2000). Women were
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observed to experience a larger decrease (p b 0.001) in mean depression scores when folate 500mg per day was provided compared with placebo in women treated with fluoxetine for MDD. This benefit was not found for men. Also, folate appeared to improve tolerability of fluoxetine, as medication-related side effects were lower in those receiving folate compared to the placebo group. 3.3.1. Perinatal depression considerations There has been no specific study of folate as an intervention for perinatal depression. However, women who are pregnant or planning to become pregnant are advised to take 0.4–1mg of folate daily to decrease birth defects, particularly neural tube defects (McDonald et al., 2003). Data are inadequate to suggest that folate is efficacious as a monotherapy for MDD or PPD, and modest evidence supports folate as an augmentation strategy. However, one epidemiological study did not find a relationship between folate intake and postpartum depression (Miyake et al., 2006). An attractive risk/ benefit profile suggests that folate can be considered a reasonable adjunctive treatment for MDD that carries little risk and may decrease birth defects in women who become pregnant during the course of treatment. 3.4. Bright light therapy Bright light therapy was first assessed as a treatment for seasonal MDD, but appears effective for nonseasonal MDD as well (Eastman et al., 1998; Terman et al., 1989; Kripke et al., 1992; Sumaya et al., 2001). Although many studies in this area have some methodological limitations, the more rigorous studies demonstrate a significant benefit of bright light therapy in seasonal MDD and nonseasonal MDD (Golden et al., 2005). Hypomania has been reported as an adverse event with light therapy (Golden et al., 2005). 3.4.1. Perinatal depression considerations In one open study of light therapy for antenatal MDD, pregnant women received treatment with 60min of bright light therapy in the morning (Oren et al., 2002). In the 16 women who completed at least three weeks of treatment, depression scores improved by an average of 49%. In the seven subjects who completed two more weeks (five weeks), scores improved by 59%. Withdrawal of light therapy resulted in a relapse of depressive symptoms in the majority. In a double-blind study of antenatal depression, ten pregnant women were randomized to either bright light therapy or a dim light placebo (Epperson et al., 2004). One patient experienced hypomania with bright light. After ten weeks, bright
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light therapy produced a significantly greater antidepressant response than placebo, with differences reaching significance after five weeks. In a study of women with PPD (N = 15), participants were assigned randomly to bright light or a dim light placebo (Corrall et al., 2007). After six weeks, both groups experienced significant improvement, without a difference between groups. Although limited by small sample sizes, the evidence supports the potential use of bright light therapy as an efficacious therapy for MDD in pregnant women and deserves further study in perinatal women. 3.5. Exercise Exercise is important in achieving and maintaining good health. Most studies in this area support at least a modest benefit for depressive symptoms in normal individuals and those with MDD. Epidemiological data support an association between exercise and a decreased risk of depressive symptoms (Strawbridge et al., 2002; Penninx et al., 2002). Research challenges include selection of appropriate control conditions and difficulty blinding treatment assignment. The “dose” of exercise and adherence to a regimen may be particularly important to assess (Dunn et al., 2005). Several treatment studies support an antidepressant effect of aerobic exercise (Trivedi et al., 2006; Otto et al., 2007). 3.5.1. Perinatal depression considerations In one study of pregnant women without MDD, participants collected prospective data each trimester on mood, anxiety, stress, and exercise (Da Cost et al., 2003). Exercisers reported significantly less depressive symptoms in the first and second trimesters than those who did not exercise, a difference not found later in pregnancy. The women were not randomized to condition, introducing cofounding variables. In studies of pregnant and postpartum women (Koltyn and Schultes, 1997; Polman et al., 2007), the effects of a single aerobic exercise session appear to have more beneficial mood effects than control conditions. In a randomized study of 80 postpartum women who had depression scores indicative of PPD at 6weeks postpartum, investigators randomly assigned women to either three exercise sessions per week or treatment as usual (Heh et al., 2008). Women who were assigned to exercise did significantly better after five months postpartum than controls. Exercise is attractive due to its low cost, availability, and broad health advantages. The American College of Obstetricians and Gynecologists recommend 30min of moderate exercise on most days for pregnant women, unless medical contraindications exist (Artal and O'Toole, 2003).
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3.6. St. John's Wort St. John's Wort (usually studied as Hypericum extract) is an herbal remedy that is extremely popular in Europe (Cott, 1995). In placebo-controlled studies of St. John's Wort in the treatment of MDD, results have yielded conflicting results, especially in more severe MDD. Shelton et al. (2001) and Davidson et al. (2002) did not find a significant difference between St. John's Wort and placebo in large studies. Lecrubier et al. (2002), however, demonstrated a significant difference between St. John's Wort and placebo in mild to moderate depression. Additionally, several randomized studies have shown non-inferiority compared to standard antidepressants, with some advantage of St. John's Wort in terms of side effects (Whiskey et al., 2001). Drug–drug interactions are an important consideration, as St. John's Wort has effects on drug metabolism via the cytochrome P450 system (most notably CYP3A4), and may interact with medications such as SSRIs, oral contraceptives, and hormones
replacement therapy (Roby et al., 2000). The possible increased metabolism of oral contraceptives with St. John's Wort may increase the risk of unwanted pregnancy, and unwanted pregnancies resulting from suspected drug interactions have been reported (Schwarz et al., 2003). Therefore, St. John's Wort may be a reasonable treatment, especially more mild to moderate MDD, and safety issues include potential for drug interactions. 3.6.1. Perinatal depression considerations Only a small amount of data inform the safety profile in pregnancy and postpartum. In case reports of breastfeeding mothers (Klier et al., 2002, 2006), the measurement of two active constituents of Hypericum (hyperforin and hypericin) in breastmilk demonstrated low levels in breastmilk, suggesting minimal exposure to the breastfed infant. Infants did not have detectable plasma levels, and no adverse effects were observed. In one study of pregnant women (N = 33) treated with Hypericum, newborns were reported to experience increased rates of
Table 2 CAM modalities: considerations in MDD and perinatal depression CAM modality
Evidence in MDD and dose ranges
Omega-3 fatty acids Placebo-controlled studies support efficacy in MDD, mainly as an adjunctive treatment to antidepressants; doses range from 0.5–3.4 g in studies specific to perinatal depression SAMe
Folate
Good evidence for efficacy; effective doses range from 800–1600 mg in studies of oral administration
May be especially important for women as an augmentation strategy for MDD; dose of 0.5–1 mg of folate daily based on MDD research and prevention of birth defects St. John's Wort Substantial number of placebo-controlled trials support efficacy for mild to moderate depression; less convincing evidence for severe MDD; doses range from 500–1800 mg per day in randomized controlled trials Acupuncture Mixed findings of efficacy in studies for MDD; methodological difficulties of study in terms of adequate placebo control Bright light therapy Appears effective for MDD; dose is usually up to 10,000 lx delivered for 30–60 min/day by light box Exercise Appears to have antidepressant benefits; duration of 30 min per day consistent with ACOG recommendations and depression literature
Specific comments regarding perinatal depression
Other comments
Provision in utero associated with neurocognitive developmental benefits; treatment studies have demonstrated mixed findings regarding efficacy as monotherapy for perinatal MDD Unlikely to pose risk; has been studied in pregnancy as a treatment for liver disease without apparent adverse events; more study needed No known risks; may help with overall nutritional status and prevention of birth defects
General health benefits and data regarding benefits in mood disorders support omega-3 fatty acids as part of treatment plan
General health benefits and data regarding benefits in mood disorders support folate as part of treatment plan Insufficient study in breastfeeding and Drug interactions; may decrease for PPD; one study suggests a neonatal efficacy of oral contraceptives; syndrome after in utero exposure requires careful study before it may be recommended in pregnancy
No specific study in PPD; some points may stimulate uterine contractions or hasten labor and delivery One small negative study in PPD; positive pilot trials in pregnancy Recommended for general health General health benefits and data benefits unless known contraindication regarding benefits in mood disorders support exercise as part of treatment plan
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colic, drowsiness, and lethargy compared to infants of matched depressed and non-depressed control mothers (Lee et al., 2003). Five were noted to experienced adverse effects, although none required medical intervention. It is possible that the neonatal syndrome described with antidepressants is also an issue with St. John's Wort, although this has not received specific study. One study of administration in rats during pregnancy and breastfeeding suggests that the potential for teratogenic and toxic effects, and human safety during pregnancy and breastfeeding has not received adequate study (Gregoretti et al., 2004; Dugoua et al., 2006). St. John's Wort shows some evidence of efficacy, but further studies need to be done to evaluate safety for use in perinatal and postpartum depression, particularly its effects on the unborn fetus. 3.7. Acupuncture In Traditional Chinese Medicine, acupuncture is thought to impact the imbalance of energy which is thought to result from trauma and cause disease. Mixed results have been demonstrated in controlled trials of acupuncture for MDD (Allen et al., 1998; Luo et al., 1998; Quah-Smith et al., 2005; Gallagher et al., 2001). Assessment of the evidence base for acupuncture is challenging, as many reports are in Asian languages and often overlooked in the Western literature, and study designs often reflect conceptually challenging aspects, such as variability in diagnosis and implementation of interventions across studies (Halbreich, 2008). 3.7.1. Perinatal depression data Special caution is required for pregnant women, as some acupuncture points may cause uterine stimulation and advancement of labor and delivery (Motl, 2002; Rabl et al., 2001). In one pilot trial for pregnant women with depression, investigators randomized 61 women with MDD to active acupuncture, active control acupuncture, or massage for 8weeks (Manber et al., 2004). Response rates were higher for active acupuncture (69%) compared to the control acupuncture (47%) or massage groups (32%). 4. Discussion Antenatal and postpartum MDD are common, with serious consequences for a woman and her family. There are potential risks of psychotropic medications in pregnancy and breastfeeding, and a limited evidence base from which to make treatment decisions. Further study is required so that psychiatrists and other health care providers can offer safe, effective, and accessible
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treatment options for perinatal depression. Although CAM treatments are often easily accessible and available without prescription, women who experience perinatal depression should be encouraged to have a comprehensive assessment and discussion about all available treatment options. Psychiatrists and other physicians need to be educated about CAM modalities and discuss these actively and nonjudgmentally with patients, as many patients will not spontaneously disclose use of CAM treatments (Eisenberg et al., 2001). Some CAM treatments offer general health benefits and low risk, provided that appropriate assessments and standard treatments are also provided or accessible. The accessibility and popularity of some interventions raises the concern that needed evaluation and treatment will be prematurely dismissed in lieu of CAM. CAM interventions that can be easily added to a treatment plan with low risk and general health benefits for most women include omega-3 fatty acids, exercise, and folate, although data are insufficient at this time to recommend any of these as monotherapy for perinatal depression. SAMe and bright light therapy may be reasonable to consider, and there is evidence to support monotherapy in MDD. Data regarding the efficacy of acupuncture in MDD are conflicting. Bright light therapy, St. John's Wort, and SAMe might increase the risk of hypomania in women who are predisposed to experience bipolar-spectrum mood episodes. St. John's Wort can be best recommended for mild to moderate depression, with possible drug–drug interactions kept in mind. St. John's Wort requires further study with regard to efficacy and safety in perinatal depression. At this time, further study is necessary to delineate the role of specific CAM therapies in perinatal depression. Role of funding source Dr. Freeman's time was supported by the UT Southwestern Medical Center and the Meadows Foundation. Neither had any input into this manuscript.
Conflict of interest Research support: U.S. FDA, Eli Lilly, Forest (pending), Reliant/ GlaxoSmithKline (pending), the Meadows Foundation, UT Southwestern Medical Center; CME honorarium Chatham Institute (sponsored by grant from KV Pharmaceuticals, pending). Dr. Freeman's time was supported by UT Southwestern Medical Center and the Meadows Foundation. Neither had any input into this manuscript.
Acknowledgements The author wishes to thank Scott A. Freeman, M.D., and Dorothy Kelly, Ph.D. for editorial suggestions.
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