A narrative review of the efficacy of DHA for treatment of major depressive disorder and treatment and prevention of postnatal depression
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.
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], [14], [15], [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], [22], [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 alpha-linolenic 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.
Section snippets
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
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
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], [49], [50]. While depressed patients showed a mean RBC DHA of 3.25% [48]. Given that the RBC DHA levels in the treatment
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
Conflict of interest
None declared.
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