G Model AIMED-50; No. of Pages 7 Advances in Integrative Medicine xxx (2015) xxx–xxx Contents lists available at ScienceDirect Advances in Integrative Medicine journal homepage: www.elsevier.com/locate/aimed A narrative review of the efficacy of DHA for treatment of major depressive disorder and treatment and prevention of postnatal depression Lyra Rinaudo a,*, Malcolm Hopwood b a b University of Melbourne, Australia Albert Road Clinic Professorial Psychiatry Unit, University of Melbourne, Australia A R T I C L E I N F O A B S T R A C T Article history: Available online xxx Objective: To perform a narrative review of the efficacy of docosahexaenoic acid (DHA) supplementation as a treatment for major depressive disorder (MDD) and as prevention and treatment for postnatal depression (PND). Method: Electronic searches of the following databases were preformed: The Cochrane Library and PubMed, published up to September 2014. The search strategy also included cited reference searching. Study results, methodological, potential flaws and study strengths were assessed. Results: Five studies assessing DHA supplementation in MDD and six for PND were found. Due to heterogeneity of study designs results were difficult to compare. Only one MDD study found a statistically significant decrease in depression severity, although this study had noticeable methodological flaws. None of the studies found significant difference in adverse effects from supplementation between the groups. Conclusion: DHA monotherapy does not appear to be beneficial in the treatment of MDD or in the treatment and prevention of PND. ß 2015 Elsevier Ltd. All rights reserved. Keywords: Depression Docosahexaenoic acid Mental health Omega-3 polyunsaturated fatty acids Postnatal depression What is already known about the topic?  Major depression and postnatal depression are severe illnesses with a significant burden of disease.  Conventional antidepressant treatment does not resolve all cases of major depression disorder and postnatal depression.  A correlation exists between DHA intake from fish and the prevalence of depression and postnatal depression.  DHA is depleted during the 3rd trimester of pregnancy.  High level data has found efficacy for omega-3 supplementation in major depressive disorder and preliminary evidence exist for omega-3 supplementation in the treatment of postnatal depression. What this paper adds?  Isolation of DHA only and high DHA n-3 supplementation rather than EPA + DHA omega-3 supplementation at the standard ratio available in most preparations. * Corresponding author. Tel.: +61 400517729. E-mail addresses: lrinaudo@student.unimelb.edu.au (L. Rinaudo), mhopwood@unimelb.edu.au (M. Hopwood).  Consideration of potential flaws and strengths of the current research.  Review of strength of the current body of evidence for DHA only supplementation in major depressive disorder and postnatal depression. 1. Introduction Major depressive disorder (MDD) is a disabling condition, difficult to treat with high reoccurrence rates. It is defined as pervasive low mood and loss of pleasure in normally enjoyable activities present on most days. Accompanied by a significant change in weight, sleep and activity, feelings of guilt, worthlessness or suicide and loss of attention and concentration [1]. In terms of disability-adjusted life years MDD accounts for 3% of global ill health [2]. Approximately, 60% of patients treated with antidepressants do not achieve remission and their symptoms can be ongoing [4]. For this reason continual exploration for novel treatments is warranted. One such treatment currently under investigation is the omega-3 polyunsaturated fatty acid (n-3 PUFA) docosahexaenoic acid (DHA) present in marine fish oil and Antarctic krill. http://dx.doi.org/10.1016/j.aimed.2015.02.004 2212-9588/ß 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: Rinaudo L, Hopwood M. A narrative review of the efficacy of DHA for treatment of major depressive disorder and treatment and prevention of postnatal depression. Adv Integr Med (2015), http://dx.doi.org/10.1016/j.aimed.2015.02.004 G Model AIMED-50; No. of Pages 7 2 L. Rinaudo, M. Hopwood / Advances in Integrative Medicine xxx (2015) xxx–xxx DHA is also under investigation for use in the treatment and prevention of postnatal depression (PND). PND is a mood disorder in which the clinical symptoms of depression arise in the first week to one-year post child birth [5]. In high income countries, such as Australia, point prevalence estimates of mild to severe depressive episodes range from 6.5% to 12.9% [6]. Limited data is available for the effectiveness and safety of conventional antidepressants for PND [7]. Selective serotonin re-uptake inhibitors have been linked to increased risk of low birth weight infants and respiratory distress [8] and long-term behavioural abnormalities in children [9]. N-3 PUFAs appear very safe in pregnancy and breastfeeding [10] and may be a useful alternative to conventional antidepressants in PND. Observational studies show an inverse correlation between n-3 PUFA intake from fish and the incidence of depression in populations [11,12]. MDD suffers have been found to have lower plasma phospholipid DHA levels and a higher omega 6:omega 3 ratio. These parameters are inversely related to depressive symptom manifestation and severity [13–16]. In healthy volunteers there is a significant association between increased plasma DHA and ALA and the personality and cognitive parameters: agreeableness, reduced neuroticism and reduced cognitive impulsivity [17]. Clinical trials have demonstrated that DHA supplementation leads to increased erythrocyte (RBC) DHA concentration which correlates with improvements in depression scores [18]. This observational data suggests that reduced DHA intake may be involved in the pathophysiology of MDD and therefore beneficial effects may be achieved from supplementation. Fewer observational associations exist for PND. There is an inverse correlation between PND prevalence and high n-3 consumption from fish as well as levels of DHA in mother’s milk [19,20]. In the third trimester there is extensive foetal brain development requiring DHA. There is preferential transference of maternal DHA to the foetus potentially resulting in maternal DHA deficiency [21–23]. However, two large observational studies have found no significant correlation between plasma phospholipid DHA levels and the presence of PND measured using the Edinburgh Postnatal Depression Scale (EPDS) [24,25]. A study from Otto et al. [24] measured the ratio of DHA to its metabolite docosapentaenoic acid (n-6DPA, 22:5n-6), which increases in a functional shortage of DHA [26], this ratio is used as a DHA sufficiency index. This index becomes reduced during pregnancy but was found to be significantly higher in non-depressed women, reflecting an improvement in DHA status in the postpartum period in the non-depressed women. Women with a slower increase in the DHA:DPA ratio postpartum (hence a functional shortage of DHA) were at a 10% higher risk for developing PND [24]. Understanding of the functional and structural role of DHA further implicates its potential role in the pathophysiology of depressive disorders. DHA and its shorter chain precursor alphalinolenic acid (ALA) are essential components of the mammalian diet as they cannot be synthesised de novo [27]. DHA is a major structural component of neuronal cell membranes [28] influencing membrane fluidity and permeability. DHA is a precursor for lipid messengers which are required for receptor binding, ion channels, neurotransmission and enzyme activity [29]. The changes in neuronal membrane activity and messenger precursors with higher DHA concentrations influences the modulation of signalling pathways that are involved in sustaining synaptic function and neuronal survival [30]. Lithium, a mood stabiliser, has been shown to increase brain levels of 17-hydroxy-DHA, a neuroprotective DHA metabolite, which may lead to some of its therapeutic action. Leading to the query that DHA supplementation could have a similar effect [31]. Furthermore, the neuroprotective and antidepressant neurotrophin, brain-derived neurotrophic factor, has been found to be decreased with reduced n-3 PUFA intake [32]. Considering the integral structural and functional role of DHA in the central nervous system, a deficiency is implicated in the pathophysiology of MDD and PND and therefore supplementation may provide therapeutic benefits. Currently, high-level evidence exists for the therapeutic benefit of combined EPA and DHA n-3 PUFA supplementation in affective disorders and depressive symptoms as a monotherapy [33] and as an adjuvant to conventional treatments [34]. Minimal evidence is available for the use of DHA alone or high DHA n-3 preparations in MDD and PND. Further observational studies are needed to confirm an association between DHA deficiency and depression and ultimately high quality interventional studies are needed to confirm causation. This review will focus in on the current evidence for DHA only and high DHA n-3 supplementation, as opposed to high EPA:DHA ratio supplementation found in most standard n-3 supplements, for the treatment of MDD and the prevention and treatment of PND. 2. Methods An electronic search of the following online databases was preformed: PubMed and The Cochrane Library for articles published up to September 2014. Articles of interest were identified using the following search terms; ‘‘docosahexaenoic acid’’, OR ‘‘DHA’’, OR ‘‘omega-3’’, OR ‘‘fish oil’’ AND ‘‘depression’’, OR ‘‘post natal depression’’ OR ‘‘post partum depression’’. The search strategy also included cited reference searching. All relevant randomised control trials (RCTs) were included in the review. Trials using EPA were included if a higher DHA:EPA ratio was used. Exclusion criteria included: EPA only therapy, healthy volunteers, children <19 years of age, substance abuse, language other than English, schizophrenia, anxiety disorders, ADHA, peri- and postmenopausal women, acute myocardial infarction, cognitive decline, personality disorders, sleep apnea, obesity, food intervention and animal studies. 3. Results 3.1. DHA in major depressive disorder Four clinical trials were found which assessed DHA only n-3 PUFA supplementation for the treatment of MDD and one which used a combined n-3 PUFA with a high DHA:EPA ratio (see Table 1). Only one study reported a statistically significant treatment effect. Mischoulon et al. [35] designed a three-arm trial assessing the efficacy and dose response pattern of DHA at 1 g, 2 g and 4 g/day. A >50% decrease in Hamilton rating scale for depression (HAM-D) scores was found in two trial arms with DHA doses 1 g and 2 g [35]. Meyer et al. [18] designed a 16-week, placebo controlled RCT with 95 adults on 2 g DHA daily or olive oil placebo. A significant correlation was seen in the intervention group between increase in RBC DHA and depression scores using the HAM-D (p < 0.05), indicating that DHA supplementation may be beneficial in a subset of depressed patients with low DHA. However the overall treatment effect was not significant in comparison to the placebo group. Marangell et al. [36] also found no improvement in Montgomery–Åsberg Depression Rating Scale (MADRAS) scores with DHA supplementation (2 g/day) in an 8-week RCT of 35 adults with MDD. Rogers et al. [37] used a much bigger sample size of 218 subjects with mild to moderate depression, identified using the depression, anxiety, stress scale (DASS) and not receiving standard antidepressant medication. Invention was 630 mg EPA and 850 mg DHA with olive oil. While a small reduction was seen in the DASS, there was no significant improvement in depression or cognition parameters [37]. Mozaffari-Khosravi et al. [38] compared EPA and Please cite this article in press as: Rinaudo L, Hopwood M. A narrative review of the efficacy of DHA for treatment of major depressive disorder and treatment and prevention of postnatal depression. Adv Integr Med (2015), http://dx.doi.org/10.1016/j.aimed.2015.02.004 AIMED-50; No. of Pages 7 Aim Type of study Sample Intervention Exposure assessment Outcome Confounding Findings Marangell et al. [36] Evaluation of the n3 fatty acid DHA for the treatment of major depression Double blinded RCT – 8 weeks 35 adults (18–65 years of age) who met the DSM-IV criteria for MDD DHA 2 g/day, or placebo (not reported) Response rates were 27.8% in the DHA group and 23.5% in the placebo group Determine if tuna oil supplementation correlates with changes in depression scores and RBC DHA Placebo controlled RCT – 16 weeks 95 adult (18–75) HAMD score >16, receiving treatment for MDD 8  1 g capsules per day of n-3 (2 g DHA, 0.6 g EPA and 10 mg Vitamin E) or olive oil (placebo) Differences at baseline – smoking and weight. Baseline RBC DHA in treatment group at normal levels Baseline RBC DHA in treatment group at normal levels Difference in MADRS did not reach statistical significance Meyer et al. [18] 50% reduction in the score on the Montgomery–Åsberg Depression Rating Scale (MADRAS) 17-Item Hamilton rating scale for depression (HAM-D 17) and the Beck Depression Inventory (BDI) Mischoulon et al. [35] The antidepressant efficacy and dose– response pattern of DHA RCT, not placebo controlled – 12 weeks 35 depressed adult outpatients (mean age 42  14 years) with a HAM-D-17 score of >18 Group A (n = 14): 1 g/day DHA group B (n = 11): 2 g/day; and Group C (n = 10): 4 g/day HAM-D-17 score Mozaffari-Khosravi et al. [38] Compare the efficacy of EPA versus DHA as adjuvants to maintenance medication treatments for mild-to-moderate depression 81 mild-to-moderately depressed out-patients. Ages between 18 and 75 years; a Beck Depression Inventory (BDI) score between 10 and 28; a 17-item Hamilton Depression Rating Scale (HDRS) score between 8 and 18 1 g/day of EPA or DHA or placebo (coconut oil) 17-item Hamilton Depression Rating Scale response to treatment (defined as a >50% decrease from the baseline HDRS score) and remission (defined as a final HDRS score of <7) Rogers et al. [37] EPA and DHA supplementation (1.5 g/day) on mood and cognitive function in mild to moderately depressed individuals. Single-centre, randomised, double-blind, placebo-controlled, multi-arm, parallel-group trial – 12 weeks. Concealment of allocation. Modified-ITT analysis Single centre, double-blind randomised controlled – 12 weeks 218 mild to moderately depressed individuals assessed by DASS 630 mg EPA, 850 mg DHA, 850 mg olive oil, 7.5 mg mixed tocopherols and 12 mg orange oil. Placebo: 2360 mg olive oil, 7.5 mg mixed tocopherols and 12 mg orange oil DASS, Beck Depression Inventory (BDI) The General Health Questionnaire. The state anger subscale of the State-Trait Anger Expression Inventory, mood diary The mean changes in scores of depression ( 12.2  2.1 for n-3 and 14.4  2.3 for olive oil). Erythrocyte DHA content rose from 4.1  0.2 to 7.9  0.4% (mean  SEM, p < 0.001) 50% decrease in HAMD-17 score. Group A – 83%. Group B – 40%. Group C – 0% For completers and ITT subjects, plasma DHA increased significantly (p < 0.05) 6 patients receiving EPA HAM-D score reduction >50%, while no one in any of DHA or placebo groups responded to treatment Treatment group: mean DASS reduction 2.5, placebo group 1.4. Difference was not statistically significant N-3 group showed a significant correlation (r = 0.51) between the change in RBC DHA and the change in scores of depression (p < 0.05) Of 35 recruited, 21 dropped out but only 28 were included in ITT analysis. Significant difference in n-3 intake within each group Groups A and B had significant decreases in HAM-D-17 scores (p < 0.05) Low HAM-D entry score less likely to see results from treatment EPA showed a significantly lower mean HAM-D total score at study endpoint compared with those who received DHA (p < 0.001) or placebo (p = 0.002) Olive oil as placebo No significant improvement was found from DHA supplementation in any mood or cognition parameters G Model Reference L. Rinaudo, M. Hopwood / Advances in Integrative Medicine xxx (2015) xxx–xxx Please cite this article in press as: Rinaudo L, Hopwood M. A narrative review of the efficacy of DHA for treatment of major depressive disorder and treatment and prevention of postnatal depression. Adv Integr Med (2015), http://dx.doi.org/10.1016/j.aimed.2015.02.004 Table 1 Comparison of clinical trials for use of DHA in MDD. 3 G Model AIMED-50; No. of Pages 7 4 L. Rinaudo, M. Hopwood / Advances in Integrative Medicine xxx (2015) xxx–xxx DHA monotherapy in MDD. Only the patients receiving EPA showed statistically significant improvements, measured as a >50% decrease in HAM-D compared to the DHA and placebo groups. A summary of each study can be seen in Table 1. 3.2. Postnatal depression Six RCTs were found which used DHA monotherapy or a high DHA:EPA ratio n-3 PUFA supplementation in pregnancy (Table 2). Five assessed the prevention of PND in healthy participants and one tested treatment of existing PND with high DHA fish oil. All the prevention studies used the Edinburgh Post Natal Depression Scale (EPDS) as an exposure assessment. This 10-item self-reporting questionnaire measures the probably of PND, it is not a diagnostic tool [40]. All studies were randomisation, placebo controlled and included intention to treat analysis to deal with dropouts. DHA supplementation ranged between 200 mg and 2 g/day. No statistically significant differences were found in EPDS scores in any of the studies. The only significant finding was in the Mozurkewich et al. [41] trial of 126 pregnant women considered high risk for PND on the bases of EPDS scores. This study found that the Beck Depression Index (BDI), a measure of depression severity, scores at week 34–36 were predictive of serum DHA concentration and capsule compliance. This correlation however was not present in the postpartum period [41]. The two largest trials by Makrides et al. [42] and KraussEtschmann et al. [44] used a dietary intervention design. Makrides et al. [42] conducted the largest trial with 2399 participants, aiming to determine significance via an absolute reduction of 4.2% in depression symptoms measured by the EPDS. No significant reduction was seen [42]. Unfortunately, RBC or serum DHA concentration was not measured at baseline, so correlation of increase in DHA levels and EPDS could not be assessed [43]. KraussEtschmann et al. [44] included 311 pregnant women from three European countries using DHA in conjunction with EPA and folate supplementation. Again no significant difference was seen in EPDS scores between groups [44]. Llorente et al. [45] found some potential evidence for DHA supplementation. Cognitive parameters and depressive symptoms were investigated in 138 pregnant women supplementing with 200 mg DHA daily. Analysis of data from subjects that provided baseline and 4 month BDI scores showed small, but significant difference 0.6 SD (30%) (p < 0.05). However, this data was only assessed in 44 subjects. All other statistical analysis found no significant results [45]. Doornbos et al. [46] used a similar low dose of DHA (200 mg) and a DHA + arachidonic acid (AA) combination in women with low DHA intake with an average frequency of fish intake of 0.94 times per week. Despite low DHA intake, serum DHA levels at baseline were comparable to that of healthy subjects. The supplementation groups did not differ in mean EPDS scores or changes in EPDS scores, or in the incidence or severity of postpartum blues or measures of sleep quality. RBC DHA, AA and DHA/AA ratio also did not correlate with EPDS or blues scores [46]. Only one study investigated the use of DHA as a treatment intervention for PND rather than prevention. Rees et al. [47] assessed 28 women diagnosed with PND supplemented with 8 g of fish oil daily containing 27.3% DHA. Interestingly, both the treatment and placebo group displayed significant improvement in depression scores assessed with the HAM-D and MADRAS. A summary of these studies can be seen in Table 2. 4. Discussion Of the studies reviewed, heterogeneity in terms of dose, duration, exposure outcome and inclusion criteria make comparison difficult. Meyers et al. [18] and Marangell et al. [36] measured baseline RBC DHA as 4% (% by weight of total fatty acids) and 4.15% retrospectively [18,36]. Healthy controls have been found to have a mean RBC DHA percentage between 3.92 and 5.8% [48–50]. While depressed patients showed a mean RBC DHA of 3.25% [48]. Given that the RBC DHA levels in the treatment group were comparable to healthy controls this may explain why no benefit was attained from DHA supplementation. Considering the correlation between low RBC DHA and depression severity, it may be more efficacious to focus the use of DHA supplementation for patients with MDD and known low DHA intake and RBC levels. Mischoulon et al. [35] found statistically significant improvements in HAM-D with DHA supplementation at 1 and 2 g/day. Unfortunately, the validity of these results is questionable due to methodically issues. Specific methodical concerns included, a small sample size (n = 35), absent placebo and variability between the groups at baseline in regards of smoking and dietary n-3. The largest study by Rogers et al. [37] with a sample size of 218 found no significant therapeutic effect. Inclusion criteria for this study included patients with HAM-D scores between 8 and 18 (mild depression) [38], as opposed to >18 (moderate depression) [39] accepted by Meyer et al. [18] and Marangell et al. [36]. The reduced scores at baseline may account for the reduced response rate to treatment as some meta-analysis have found n-3 effectiveness to be related to depression severity [33]. However, the EPA treatment group did show significant improvement in depression scores. Another issue with some of the studies was differences in the type of placebo used, which varied between the trials. Rogers et al. [37] and Meyer et al. [18] both used olive oil which potentially has a therapeutic benefit. Olive oil increases delta 9 desaturase enzyme activity which works to stabilise cell membranes [51] and a potential psychoactive effects have been theorised [52]. Mozurkewich et al. [41] used placebo capsules with a small amount of omega-3 and ALA fatty acids which may have had a potential therapeutic effect. Despite the repeated lack if statistically significant findings for DHA supplementation in MDD, lack of efficacy cannot be confirmed due to small sample sizes, low depression scores at baseline and poor methodology. Issues with variability of baseline DHA levels, not accounting for n-6 intake, not using adequate diagnostic measures to assess subjects at baseline and the use of potential therapeutic placebos greatly impedes the validity of these inconclusive results. Similar issues of heterogeneity and methodological flaws, specifically differences in baseline DHA and symptoms severity, can be identified for the PND studies. Mozurkewich et al. [41] found a significant improvement in BDI scores at weeks 34–36, correlating with plasma DHA levels, but this improvement did not extend to the postpartum period. As rates of replenishment of DHA stores over the postpartum period can be indicative of PND risk [24] it would be interesting to see if the rate of replenishment in these subjects correlated with BDI severity in the postpartum period rather than total DHA levels. The participants in Krauss-Etschmann et al. [44] study had a higher maternal serum DHA at baseline (5.88%) compared to the others studies which reported baseline scores as the following: 3.31  0.70, 3.15  0.78 [45], 4.66%, 4.24%, 3.85% [41]. Higher DHA at baseline may confer a protective effect against DHA depletion during pregnancy. Rees et al. [47] investigated DHA as a treatment for existing PND rather than prevention. No significant improvements were found. Issues with this trial were that all patients currently treated with conventional antidepressants or psychological therapies were excluded. This contributed to the small sample size (n = 26) and the increased number of women in the intervention group with Please cite this article in press as: Rinaudo L, Hopwood M. A narrative review of the efficacy of DHA for treatment of major depressive disorder and treatment and prevention of postnatal depression. Adv Integr Med (2015), http://dx.doi.org/10.1016/j.aimed.2015.02.004 AIMED-50; No. of Pages 7 Aim Trial Type Sample Intervention Exposure Assessment Findings Confounders Outcome Can low dose DHA or DHA plus arachidonic acid (AA) supplementation during pregnancy and lactation prevent depressive symptoms and sleep disturbances in this period Investigate the effect of DHA supplementation on plasma phospholipid DHA content and indices of depression and information processing for breast feeding women To assess whether omega-3 fatty acid treatment is superior to placebo in the treatment of PND The efficacy of EPA and DHA rich fish oils for the prevention of depressive symptoms in pregnant women at an increased risk of PND To determine whether DHA supplementation during the last half of pregnancy will result in fewer women with high levels of depressive symptoms To assess whether fish oil supplementation with or without folate from week 22 to birth has been related to positive pregnancy and infant outcomes RCT 119 healthy pregnant women DHA (220 mg) or DHA + AA (220 mg each) or soy bean oil placebo Edinburgh Postpartum Depression Scale (EPDS), validated sleep diaries and blues score (postpartum depression measure) ITT analysis was not used for the 63 dropouts DHA or DHA and AA supplementation did not improve depressive symptoms or sleep in pregnant and postpartum women Double blind RCT – 4 months 138 pregnant women (18–42 yo) who planned to breastfeed their infants DHA 200 mg/day or placebo (unknown) for the first 4 months after the delivery Plasma phospholipid fatty acid, BDI, EPDS, structural clinical interview for DSM-IV (SCID-CV) Placebo was no reported Plasma phospholipid DHA concentration increased significantly. Depression and cognitive symptoms did not differ between groups Double-blind randomised placebocontrolled trial – 6 weeks 26 women with PND, during pregnancy and perinatal period 8 g fish oil 27.3% DHA, 6.9% EPA or placebo (sunola oil) EPDS, HAM-D 17 and MADRS scores No significant change in EPDS and blues scores. RBC DHA, AA and DHA/AA ratio did not correlate with EPDS or blues scores. Indices of sleep quality did not differ between the groups Plasma phospholipid DHA of the intervention group increased by 8% higher and the placebo group decrease by 31%. No significant difference in BDI, EPDS, SCID-CV, or cognitive tests Mean improvement in all measures was significant (p < 0.001) for both groups Double blind, RCT 126 pregnant women at risk for depression, assessed by a EPDS score of 9–19 or a history of MDD 1060 mg EPA plus 274 mg DHA or 900 mg DHA plus 180 mg EPA or placebo (soy oil) BDI, Mini-International Neuropsychiatric Interview No significant difference in BDI scores between groups or in initiation of antidepressant medication Intensive weekly follow ups, slightly lower baseline HAM-D, EPDS scores in intervention group Subjects who meet the criteria for MDD, received other treatment Soy placebo contained small amount of ALA n-3 PUFA supplementation did not improve depression symptoms in women with PND BDI scores at 34–36 weeks were predictive of BDI at baseline, serum DHA and admission to not taking capsules A double-blind, multicenter, randomised placebo con-trolled trial 2399 women who were less than 21 weeks’ gestation with singleton pregnancies 800 mg/day of DHA and 100 mg/day of EPA or placebo (vegetable oil – rapeseed, sunflower and palm oil) EPDS No difference in high levels depression symptoms (EPDS > 12) between groups DHA serum at baseline and trial end were not measured. Included smokers. Fish intake was not assessed DHA supplementation did not result in lower levels of PND A multicenter, randomised, doubleblind, placebo controlled trial 311 pregnant women 500 g DHA and 150 g EPA 400 g methyltetrahydrofolic acid (MTHF), both, or placebo DHA plasma phospholipid and RBC concentration and EPDS n-3 supplementation significantly increase DHA plasma levels. However no difference in EPDS was found among the intervention groups High maternal serum DHA a baseline compared to some studies DHA and EPA supplementation significantly increased maternal serum DHA levels but did not impact on development of depressive symptoms Llorente et al. [45] Rees et al. [47] Mozurkewich et al. [41] Makrides et al. [42] KraussEtschmann et al. [44] G Model References Doornbos et al. [46] L. Rinaudo, M. Hopwood / Advances in Integrative Medicine xxx (2015) xxx–xxx Please cite this article in press as: Rinaudo L, Hopwood M. A narrative review of the efficacy of DHA for treatment of major depressive disorder and treatment and prevention of postnatal depression. Adv Integr Med (2015), http://dx.doi.org/10.1016/j.aimed.2015.02.004 Table 2 Comparison of clinical trials of DHA as an intervention in prevention and treatment of PND. 5 G Model AIMED-50; No. of Pages 7 6 L. Rinaudo, M. Hopwood / Advances in Integrative Medicine xxx (2015) xxx–xxx milder depression, mean baseline scores HAM-D 19.7 and EPDS 7.3 compared to the placebo group 16.5 and 9.09 retrospectively [47]. Milder disease may have made it harder to detect improvement with treatment. Furthermore, a placebo response in both arms is indicated by the early response times in both groups. Intensive weekly follow up may have had a therapeutic effect activating placebo benefits [47]. Makrides et al. [42] also found that the placebo group had a lower than expected incidence of high level depressive symptoms. This could reflect a common finding in antidepressant studies that contact with health care professionals provides therapeutic improvements making intervention attributable differences between groups more difficult to elucidate. This is a common finding with all depression trials; finding efficacy can be an issue due to the well documented problem of large placebo responses in antidepressant trials with reports of up to 50% in some trials [43]. Placebo run in should be employed to help account for this variable. None of the studies assessed n-6 PUFA consumption. As mentioned, a diet with a high n-6:n-3 ratio has been linked to depression, regardless of n-3 intake [14]. Reports from a 2010 Nurses Health Study of 73,449 participants found an association was only seen for n-3 intake and depression risk when omega-6 intake was adjusted for. Specially, no matter the n-3 intake, if n6:n-3 ratio was increased the risk of depression was not reduced [55]. Omitting consideration of n-6 intake may have limited beneficial outcomes from n-3 supplementation. Doornbos et al. [46] actually included supplementation with the n-6 PUFA AA as part of the therapeutic intervention. Furthermore, lack of significant results in this study may have been due to the high drop out rate; only 119 of 182 women completed the study. Analysis of multiply MDD trials has shown that the therapeutic benefit from fish oil is limited to DSM-diagnosis MDD [33] and that responsiveness to n-3 in PND specifically may be correlated with symptom severity [53]. A number of the MDD trials reviewed studies reported low depression scores at baseline [38,47], excluded subjects if they were on antidepressants or commenced antidepressants during the trial [41] and included mild to moderate depression assessed by DASS rather than a diagnostic tool [37]. Of the PND trials only one of the reviewed studies used the structured clinical interview for DSM-IV to assess outcomes. This was the trial by Llorente et al. [45] which found a positive correlation between serum DHA, compliance and BDI at week 34– 36. The other studies used EPDS which is not a diagnostic tool. Efficacy of DHA supplementation may be elicited if outcomes were measured by adequate diagnostic tools such as the structured clinical interview for DSM-IV rather than EPDS or DASS. Furthermore, considering the correlation between functional DHA and development of PND, DHA:DPA ratio should also be considered in future studies. Considering the results from observational trials and the known high concentration of DHA in neuronal membranes compared to EPA [54] it seems counterintuitive that DHA supplementation would confer no benefit in depression. However, clinical trials show far more favourable results for high EPA:DHA ratio n-3 supplementation compared to DHA. Two RCTs of pregnant and postpartum women with already diagnosed PND found that combined EPA + DHA supplementation significantly reduced depression scores using the EPDS, HAM-D and BDI [56,57]. A number of reviews and meta-analysis have concluded that EPA rather than DHA supplementation is required for efficacy of n-3 supplementation in MDD [58,59]. A meta-analysis of 241 studies concluded that for n-3 to have efficacy in the treatment of primary MDD supplementation it must be 60% EPA in the dose rang of 200–2200 mg/day [60]. None of the studies found significant adverse effects from supplementation between the groups. Of the PND studies no adverse effects were reported for subjects or neonates [41,42,44–46]. Reiterating the safety and tolerability of fish oil supplementation found in other studies [10]. There are a number of limitations to this review that need to be considered. Given the nature of a narrative review, in that it lacks the systematic searching, appraisal and data analysis of a systematic review, the results are far more prone to authors preconceived notions and/or bias. Specifically, unlike a systematic review, the studies in this review were not subjected to rigorous assessment of methodological quality and as such results from poorer quality studies were included. Furthermore, studies were sourced from limited locations, namely PubMed and Cochrane there by not producing an exhaustive summary of current literature. 5. Conclusion There is growing evidence that inadequate intake of n-3 may be associated with the pathophysiology of depressive disorders, specifically a high n-6:n-3 diet. DHA is a major component of neuronal cell membranes, contributing to neuronal cell functional and survival. DHA is also an important nutrient for foetal development and with preferential transference of DHA from the mother to the foetus; pregnancy is a time of increased need therefore increased risk of deficiency. The correlation between DHA deficiency and depression makes DHA a potential therapeutic target for diagnosed MDD and PND. Yet, despite compelling observational data and a clear potential mechanism of action, there does not appear to be a therapeutic role for DHA in depression. There may be selective benefits for those at higher risk, lower n-3 intake and higher n-6:n-3 ratio and for diagnosed MDD and PND, rather than depressive symptoms, but more trials are needed. Additionally, considering the valuable evidence for the use of high EPA n-3 PUFA in MDD and PND and the lack of evidence for DHA maybe it is better to concentrate research efforts on gathering evidence for n-3 supplementation with the standard high EPA:DHA ratio, rather than isolating or increasing the DHA fraction. Conflict of interest None declared. References [1] APA. Diagnostic statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013. [2] World Health Organization (WHO). Global burden of disease; 2014, Available from: http://www.who.int/healthinfo/global_burden_disease/gbd/en/index. html [01.02.14]. [4] Fagiolini A, Kupfer DJ. Is treatment-resistant depression a unique subtype of depression? Biol Psychiatry 2003;53(8):640–8. [5] Gonsalves L, Pearson RL, Sudak D, Murray JL, Alici-Evcimen Y. Postpartum depression; 2011, Available from: https://www-clinicalkey-com-au.ezp.lib. unimelb.edu.au/#!/ContentPlayerCtrl/doPlayContent/21-s2.0-1011044/ {scope:all,query:post%20natal%20depression} [updated 7 April 2011–19 September 2014]. [6] Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T. Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol 2005;106(5 Pt 1):1071–83. [7] Molyneaux E, Howard LM, McGeown HR, Karia AM, Trevillion K. Antidepressant treatment for postnatal depression. Cochrane Database Syst Rev 2014;9: Cd002018. [8] Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006;63(8):898–906. [9] Sie SD, Wennink JM, van Driel JJ, te Winkel AG, Boer K, Casteelen G, et al. Maternal use of SSRIs: SNRIs and NaSSAs: practical recommendations during pregnancy and lactation. Arch Dis Child Fetal Neonatal Ed 2012;97(6):F472–6. [10] Carlson SE, Colombo J, Gajewski BJ, Gustafson KM, Mundy D, Yeast J, et al. DHA supplementation and pregnancy outcomes. Am J Clin Nutr 2013;97(4): 808–15. Please cite this article in press as: Rinaudo L, Hopwood M. A narrative review of the efficacy of DHA for treatment of major depressive disorder and treatment and prevention of postnatal depression. Adv Integr Med (2015), http://dx.doi.org/10.1016/j.aimed.2015.02.004 G Model AIMED-50; No. of Pages 7 L. Rinaudo, M. Hopwood / Advances in Integrative Medicine xxx (2015) xxx–xxx [11] Astorg P, Couthouis A, Bertrais S, Arnault N, Meneton P, Guesnet P, et al. Association of fish and long-chain n-3 polyunsaturated fatty acid intakes with the occurrence of depressive episodes in middle-aged French men and women. Prostaglandins Leukot Essent Fatty Acids 2008;78(3):171–82. [12] Colangelo LA, He K, Whooley MA, Daviglus ML, Liu K. Higher dietary intake of long-chain omega-3 polyunsaturated fatty acids is inversely associated with depressive symptoms in women. Nutrition 2009;25(10):1011–9. [13] Sarri KO, Linardakis M, Tzanakis N, Kafatos AG. Adipose DHA inversely associated with depression as measured by the Beck Depression Inventory. Prostaglandins Leukot Essent Fatty Acids 2008;78(2):117–22. [14] Dinan T, Siggins L, Scully P, O’Brien S, Ross P, Stanton C. Investigating the inflammatory phenotype of major depression: focus on cytokines and polyunsaturated fatty acids. J Psychiatr Res 2009;43(4):471–6. [15] Schiepers OJ, de Groot RH, Jolles J, van Boxtel MP. Plasma phospholipid fatty acid status and depressive symptoms: association only present in the clinical range. J Affect Disord 2009;118(1–3):209–14. [16] Pomponi M, Janiri L, La Torre G, Di Stasio E, Di Nicola M, Mazza M, et al. Plasma levels of n-3 fatty acids in bipolar patients: deficit restricted to DHA. J Psychiatr Res 2013;47(3):337–42. [17] Conklin SM, Harris JI, Manuck SB, Yao JK, Hibbeln JR, Muldoon MF. Serum omega-3 fatty acids are associated with variation in mood, personality and behavior in hypercholesterolemic community volunteers. Psychiatry Res 2007;152(1):1–10. [18] Meyer BJ, Grenyer BF, Crowe T, Owen AJ, Grigonis-Deane EM, Howe PR. Improvement of major depression is associated with increased erythrocyte DHA. Lipids 2013;48(9):863–8. [19] Hibbeln JR. Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affect Disord 2002;69(1–3):15–29. [20] Golding J, Steer C, Emmett P, Davis JM, Hibbeln JR. High levels of depressive symptoms in pregnancy with low omega-3 fatty acid intake from fish. Epidemiology 2009;20(4):598–603. [21] Hornstra G. Essential fatty acids in mothers and their neonates. Am J Clin Nutr 2000;71(5 Suppl.):1262s–9s. [22] Kendall-Tackett K. Long-chain omega-3 fatty acids and women’s mental health in the perinatal period and beyond. J Midwifery Women’s Health 2010;55(6):561–7. [23] Larque E, Gil-Sanchez A, Prieto-Sanchez MT, Koletzko B. Omega 3 fatty acids, gestation and pregnancy outcomes. Br J Nutr 2012;107(Suppl. 2):S77–84. [24] Otto SJ, de Groot RH, Hornstra G. Increased risk of postpartum depressive symptoms is associated with slower normalization after pregnancy of the functional docosahexaenoic acid status. Prostaglandins Leukot Essent Fatty Acids 2003;69(4):237–43. [25] Sallis H, Steer C, Paternoster L, Davey Smith G, Evans J. Perinatal depression and omega-3 fatty acids: a Mendelian randomisation study. J Affect Disord 2014;166:124–31. [26] Makrides M, Neumann MA, Byard RW, Simmer K, Gibson RA. Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants. Am J Clin Nutr 1994;60(2):189–94. [27] Rapoport SI, Rao JS, Igarashi M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot Essent Fatty Acids 2007;77(5/6):251–61. [28] O’Brien JS, Sampson EL. Fatty acid and fatty aldehyde composition of the major brain lipids in normal human gray matter, white matter, and myelin. J Lipid Res 1965;6(4):545–51. [29] Bazan NG. Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor. J Lipid Res 2003;44(12):2221–33. [30] Oster T, Pillot T. Docosahexaenoic acid and synaptic protection in Alzheimer’s disease mice. Biochim Biophys Acta 2010;1801(8):791–8. [31] Basselin M, Kim HW, Chen M, Ma K, Rapoport SI, Murphy RC, et al. Lithium modifies brain arachidonic and docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation. J Lipid Res 2010;51(5):1049–56. [32] Ikemoto A, Nitta A, Furukawa S, Ohishi M, Nakamura A, Fujii Y, et al. Dietary n3 fatty acid deficiency decreases nerve growth factor content in rat hippocampus. Neurosci Lett 2000;285(2):99–102. [33] Grosso G, Pajak A, Marventano S, Castellano S, Galvano F, Bucolo C, et al. Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. PLOS ONE 2014;9(5):e96905. [34] Gertsik L, Poland RE, Bresee C, Rapaport MH. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J Clin Psychopharmacol 2012;32(1):61–4. [35] Mischoulon D, Best-Popescu C, Laposata M, Merens W, Murakami JL, Wu SL, et al. A double-blind dose-finding pilot study of docosahexaenoic acid (DHA) for major depressive disorder. Eur Neuropsychopharmacol 2008;18(9):639–45. [36] Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, Puryear LJ. A doubleblind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry 2003;160(5): 996–8. 7 [37] Rogers PJ, Appleton KM, Kessler D, Peters TJ, Gunnell D, Hayward RC, et al. No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial. Br J Nutr 2008;99(2):421–31. [38] Mozaffari-Khosravi H, Yassini-Ardakani M, Karamati M, Shariati-Bafghi SE. Eicosapentaenoic acid versus docosahexaenoic acid in mild-to-moderate depression: a randomized, double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 2013;23(7):636–44. [39] Hamilton M. A rating scale for depression. J Neurol Neurosur Psychiatry 1960;23:56–62. [40] Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry J Mental Sci 1987;150:782–6. [41] Mozurkewich EL, Clinton CM, Chilimigras JL, Hamilton SE, Allbaugh LJ, Berman DR, et al. The Mothers, Omega-3, and Mental Health Study: a double-blind, randomized controlled trial. Am J Obstet Gynecol 2013;208(4):313.e1–.e9. [42] Makrides M, Gibson RA, McPhee AJ, Yelland L, Quinlivan J, Ryan P. Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. JAMA 2010;304(15):1675–83. [43] Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA 2002;287(14): 1840–7. [44] Krauss-Etschmann S, Shadid R, Campoy C, Hoster E, Demmelmair H, Jimenez M, et al. Effects of fish-oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid: a European randomized multicenter trial. Am J Clin Nutr 2007;85(5):1392–400. [45] Llorente AM, Jensen CL, Voigt RG, Fraley JK, Berretta MC, Heird WC. Effect of maternal docosahexaenoic acid supplementation on postpartum depression and information processing. Am J Obstet Gynecol 2003;188(5):1348–53. [46] Doornbos B, van Goor SA, Dijck-Brouwer DA, Schaafsma A, Korf J, Muskiet FA. Supplementation of a low dose of DHA or DHA + AA does not prevent peripartum depressive symptoms in a small population based sample. Prog Neuropsychopharmacol Biol Psychiatry 2009;33(1):49–52. [47] Rees AM, Austin MP, Parker GB. Omega-3 fatty acids as a treatment for perinatal depression: randomized double-blind placebo-controlled trial. Austr N Z J Psychiatry 2008;42(3):199–205. [48] Edwards R, Peet M, Shay J, Horrobin D. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord 1998;48(2/3):149–55. [49] Pala V, Krogh V, Muti P, Chajes V, Riboli E, Micheli A, et al. Erythrocyte membrane fatty acids and subsequent breast cancer: a prospective Italian study. J Natl Cancer Inst 2001;93(14):1088–95. [50] James MJ, Ursin VM, Cleland LG. Metabolism of stearidonic acid in human subjects: comparison with the metabolism of other n-3 fatty acids. Am J Clin Nutr 2003;77(5):1140–5. [51] Escudero A, Montilla JC, Garcia JM, Sanchez-Quevedo MC, Periago JL, Hortelano P, et al. Effect of dietary (n-9), (n-6) and (n-3) fatty acids on membrane lipid composition and morphology of rat erythrocytes. Biochim Biophys Acta 1998;1394(1):65–73. [52] Puri BK, Richardson AD. The effects of olive oil on omega3 fatty acids and mood disorders. Arch Gen Psychiatry 2000;57(7):715. [53] Wojcicki JM, Heyman MB. Maternal omega-3 fatty acid supplementation and risk for perinatal maternal depression. J Matern Fetal Neonatal Med 2011;24(5):680–6. [54] Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr 2006;83(6 Suppl.): 1467s–76s. [55] Lucas M, Mirzaei F, O’Reilly EJ, Pan A, Willett WC, Kawachi I, et al. Dietary intake of n-3 and n-6 fatty acids and the risk of clinical depression in women: a 10-y prospective follow-up study. Am J Clin Nutr 2011;93(6):1337–43. [56] Freeman MP, Hibbeln JR, Wisner KL, Brumbach BH, Watchman M, Gelenberg AJ. Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression. Acta Psychiatr Scand 2006;113(1):31–5. [57] Su KP, Huang SY, Chiu TH, Huang KC, Huang CL, Chang HC, et al. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2008;69(4): 644–51. [58] Ross BM, Seguin J, Sieswerda LE. Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids Health Dis 2007;6:21. [59] Bloch MH, Hannestad J. Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis. Mol Psychiatry 2012;17(12): 1272–82. [60] Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr 2009;28(5):525–42. Please cite this article in press as: Rinaudo L, Hopwood M. A narrative review of the efficacy of DHA for treatment of major depressive disorder and treatment and prevention of postnatal depression. Adv Integr Med (2015), http://dx.doi.org/10.1016/j.aimed.2015.02.004