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Personalized Medicine With Omega-3 Fatty Acids for Depression in Children and Pregnant Women and Depression Associated With Inflammation
... Several lines of evidence have suggested the efficacy of n-3 PUFAs as a preventive and treatment strategy in MDD, from epidemiological and case-controlled studies [8,9] to randomized-controlled trials [10][11][12][13][14][15][16][17][18][19][20] and meta-analyses [21][22][23][24][25][26][27][28][29][30]. In addition to clinical studies that examine the efficacy [31,32] and tolerability [33], the mechanisms of n-3 PUFAs' antidepressant effects have also been rigorously studied. Several key mechanisms have been proposed, including neuronal cell plasticity and neurogenesis, neurotransmitter dysregulation, and neuro-inflammation [6,34,35]. ...
... There are no RCTs for antidepressant drugs during pregnancy. To date, the US Food and Drug Administration approves no psychotropic drugs during pregnancy and even issues a black box warning of suicidal risk on antidepressant drugs for children [32]. So far, 3 double-blind, placebo-controlled RCTs of n-3 PUFAs have been published in perinatal women with MDD [14,55,56]. ...
... MDD with Low-Grade Inflammation or Comorbid Obesity Recent work has examined the interrelationship between certain inflammatory biomarkers and treatment response to n-3 PUFAs in MDD [18,32]. A clinical trial comparing EPA, DHA, and placebo found that individuals who had 4-5 elevated baseline inflammatory biomarkers (including high-sensitivity C-reactive protein, interleukin-6, interleukin-1 receptor antagonist, leptin) and decreased adiponectin were more likely to respond to EPA but not to DHA [18], echoing the notion that n-3 PUFAs may be more effective in depression associated with inflammation [32]. ...
Major depressive disorder (MDD) is a complex mental illness with unmet therapeutic needs. The antidepressant effects of ω-3 polyunsaturated fatty acids (n-3 PUFAs) have been widely reported. The subcommittee of the International Society for Nutritional Psychiatry Research organized an expert panel and conducted a literature review and a Delphi process to develop a consensus-based practice guideline for clinical use of n-3 PUFAs in MDD. The guideline focuses on 5 thematic areas: general concepts, acute treatment strategy, depression recurrence monitoring and prevention, use in special populations, and potential safety issues. The key practice guidelines contend that: (1) clinicians and other practitioners are advised to conduct a clinical interview to validate clinical diagnoses, physical conditions, and measurement-based psychopathological assessments in the therapeutic settings when recommending n-3 PUFAs in depression treatment; (2) with respect to formulation and dosage, both pure eicosapentaenoic acid (EPA) or an EPA/docosahexaenoic acid (DHA) combination of a ratio higher than 2 (EPA/DHA >2) are considered effective, and the recommended dosages should be 1-2 g of net EPA daily, from either pure EPA or an EPA/DHA (>2:1) formula; (3) the quality of n-3 PUFAs may affect therapeutic activity; and (4) potential adverse effects, such as gastrointestinal and dermatological conditions, should be monitored, as well as obtaining comprehensive metabolic panels. The expert consensus panel has agreed on using n-3 PUFAs in MDD treatment for pregnant women, children, and the elderly, and prevention in high-risk populations. Personalizing the clinical application of n-3 PUFAs in subgroups of MDD with a low Omega-3 Index or high levels of inflammatory markers might be regarded as areas that deserve future research.
... These two studies, along with other findings (Su et al., 2014), suggest that n-3 PUFAs with high EPA content might be more efficacious in depressed patients with low-grade inflammation compared to those without inflammation. Therefore, several investigators have proposed that new studies testing the antidepressant effect of n-3 PUFAs should use a personalized medicine approach targeting patients with increased inflammation and associated metabolic alterations, such as obesity (Su, 2015;Guu et al., 2019;Wu et al., 2023). ...
... Effect sizes were small-to-modest with low quality of evidence. This meta-analysis did, however, not address the question if n-3 PUFAs are more efficacious in a subtype of depression with low-grade inflammation and associated metabolic alterations such as obesity, as has been suggested by several investigators (Rapaport et al., 2016;Su, 2015;Guu et al., 2019;Wu et al., 2023). In the present study, patients with elevated hs-CRP and better treatment response also had significantly elevated BMI and a trend toward higher age. ...
... Moreover, patients with depression often exhibit a lower level of omega-3 fatty acids than healthy individuals, particularly individuals with MDD who are unresponsive to standard antidepressants [19][20][21]. Therefore, researchers began to investigate the potential of n-3 PUFAs supplementation to augment other therapeutic approaches in alleviating depressive symptoms [19,[22][23][24][25][26]. This builds on evidence from previous research suggesting the use of n-3 PUFAs as an oral supplement to improve depressive symptoms [9,27,28], and a recent cohort study linking n-3 PUFAs levels with protection against developing or experiencing persistent depressive episodes in adults [29]. ...
Objective: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have demonstrated protective effects in major depressive disorder (MDD) patients receiving antidepressant treatment. However, there have been a few double-blind randomized controlled trials focused on n-3 PUFAs as monotherapy in MDD, and the outcomes have been mixed. This study aimed to assess the clinical effects of n-3 PUFAs monotherapy in patients with MDD. Methods: A total of 60 patients with MDD participated in this 12-week double-blind randomized controlled trial. They were randomized to either the n-3 PUFAs group (n = 30; 3.2 g of eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA per day) or the placebo group (n = 30; 3.2 g of soybean oil per day). The severity of depression was evaluated using the Hamilton Rating Scale for Depression (HRSD). Results: The n-3 PUFAs group had a significantly lower HRSD score compared with the placebo group at week 4 (p = 0.004), week 6 (p = 0.006), week 8 (p = 0.004), and week 12 (p = 0.01). The n-3 PUFAs group showed slightly higher rates for both remission (26.7% vs. 10%, p = 0.095) and response (23.3% vs. 6.7%, p = 0.145) compared with the placebo group at week 12, but these differences did not reach statistical significance. Conclusions: These findings suggested that monotherapy of n-3 PUFAs could improve depression and potentially serve as an alternative option for MDD patients.
... Based on the results of three randomized clinical trials, the authors did not detect any significant differences in the reduction of the Beck Depression Inventory scores between the tested groups taking sertraline + omega-3 fatty acids and the control groups on sertraline therapy only. Similarly, individual characteristics of a given patient may be important-it has been demonstrated that patients with higher levels of inflammatory biomarkers (e.g., people with interferon-α-induced depression) may be more prone to respond positively to supplementation with omega-3 fatty acids [140][141][142]. ...
Omega-3 polyunsaturated fatty acids have received considerable attention in the field of mental health, in particular regarding the treatment of depression. This review presents an overview of current research on the role of omega-3 fatty acids in the prevention and treatment of depressive disorders. The existing body of evidence demonstrates that omega-3 fatty acids, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have antidepressant effects that can be attributed to their modulation of neuroinflammation, neurotransmitter function, and neuroplasticity. Nevertheless, clinical trials of omega-3 supplementation have yielded inconsistent results. Some studies have demonstrated significant reductions in depressive symptoms following omega-3 treatment, whereas others have shown minimal to no beneficial impact. A range of factors, encompassing dosage, the ratio of EPA to DHA, and baseline nutritional status, have been identified as having a potential impact on the noted results. Furthermore, it has been suggested that omega-3 fatty acids may act as an adjunctive treatment for those undergoing antidepressant treatment. Notwithstanding these encouraging findings, discrepancies in study designs and variability in individual responses underscore the necessity of further research in order to establish uniform, standardized guidelines for the use of omega-3 fatty acids in the management of depressive disorders.
... Intake of fish and long-chain n-3 PUFAs were proved to lower the odds of depression symptoms, with a U-shape relationship, which means moderate intake (around 0.5-1 g/day) can be beneficial to prevent depression (Sánchez-Villegas et al., 2018). Many clinical trials and studies have also examined the efficacy (Lesp erance et al., 2011;Su et al., 2003Su et al., , 2013Su, 2015) and the tolerability (Chang, Tseng, et al., 2018) of n-3 PUFAs in depression, and abundant evidence supported n-3 PUFAs as a potential alternative treatment strategy in depressive disorders (Lin et al., 2010;Nemets et al., 2002;Peet & Horrobin, 2002). Several meta-analyses (Appleton et al., 2015;Bai et al., 2018;Grosso et al., 2014;Mocking et al., 2016) have also confirmed the efficacy of n-3 PUFAs in different age and clinical groups with MDD, including pregnant women with MDD (Su et al., 2008). ...
Essential fatty acids such as omega-3 polyunsaturated fatty acids (n-3 PUFAs) and omega-6 (n-6) PUFAs are essential for the development and function of the brain. There are three potential mechanisms that link n-3 PUFAs and mental health: (1) Inflammation & Oxidative Stress (2) Microbiota & Immune System (3) Nervous System. In addition, n-3 PUFAs have been used as a treatment for several common psychiatric disorders, including depression, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and dementia. This chapter provides a brief overview of the most updated basic and clinical research findings of n-3 PUFAs in psychiatric disorders. Last but not least, clinical guidelines and the level of evidence of n-3 PUFAs in psychiatric disorders will also be featured in the chapter.
... PUFAs in MDD treatment for pregnant women [45][46][47][48], children, and the elderly, and prevention in high-risk populations [49]. ...
Accumulating evidence suggests that inflammation plays an important role in the pathophysiology and therapeutic mechanism across major psychiatric disorders. “Inflammation theory” might not be the full answer for the big picture of mental disorders, but it might explain the high occurrence of somatic symptoms and comorbidity of physical illness in certain subtypes of the heterogeneous groups. Nutritional psychiatric research has been expanding in the past two decades. Epidemiological studies showed that nutritional deficiency has been associated with an increased prevalence of psychiatric disorders, while nutritional supplementation has been shown to reduce or even play a role in the prevention of psychiatric disorders. Moreover, inflammatory regulation has been suggested to be the possible link between nutritional supplementation and psychiatric disorders. Thus, the aim of this chapter is to discuss the role of nutritional supplementations, including omega-3 polyunsaturated fatty acids (n-3 PUFAs) and prebiotics/probiotics, in two commonly seen psychiatric disorders, major depressive disorder (MDD) and attention deficit hyperactivity disorder (ADHD), with inflammatory regulation as the shared mechanism.
... Several lines of evidence have suggested the efficacy of n-3 LCPUFA as a MDD risk reduction or dietary management strategy in epidemiological and case-controlled studies [98,99], randomized-controlled trials [100][101][102][103][104][105][106][107][108][109][110], and meta-analyses [111][112][113][114][115][116][117][118][119][120]. In addition to clinical studies that have examined efficacy [121,122] and tolerability [123], the mechanisms of the n-3 LCPUFA antidepressant effects have also been thoroughly studied. Several key mechanisms have been proposed, including neuronal cell plasticity and neurogenesis, neurotransmitter dysregulation, and neuro-inflammation [95,124,125]. ...
Long-chain (LC) n-3 polyunsaturated fatty acids (n-3 PUFAs), in particular docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are nutrients involved in many metabolic and physiological processes, and are referred to as n-3 LCPUFA. They have been extensively studied for their effects in human nutrition and health. This paper provides an overview on metabolism, sources, dietary intake, and status of n-3 LCPUFA. A summary of the dietary recommendations for n-3 LCPUFAs for different age groups as well as specific physiological conditions is provided. Evidence for n-3 LCPUFA in cardiovascular diseases, including new studies, is reviewed. Expert recommendations generally support a beneficial effect of n-3 LCPUFA on cardiovascular health and recommend a daily intake of 500 mg as DHA and EPA, or 1-2 servings of fish per week. The role of n-3 LCPUFA on brain health, in particular neurodegenerative disorders and depression, is reviewed. The evidence for beneficial effects of n-3 LCPUFA on neurodegenerative disorders is non-conclusive despite mechanistic support and observational data. Hence, no definite n-3 LCPUFA expert recommendations are made. Data for the beneficial effect of n-3 LCPUFA on depression are generally compelling. Expert recommendations have been established: 200-300 mg/day for depression; up to 1-2 g/day for major depressive disorder. Recent studies support a beneficial role of n-3 LCPUFAs in reducing the risk for premature birth, with a daily intake of 600-800 mg of DHA during pregnancy. Finally, international experts recently reviewed the scientific evidence on DHA and arachidonic acid (ARA) in infant nutrition and concluded that the totality of data support that infant and follow-on formulas should provide both DHA and ARA at levels similar to those in breast milk. In conclusion, the available scientific data support that dietary recommendations for n-3 LCPUFA should be established for the general population and for subjects with specific physiological conditions.
... Omega-3 polyunsaturated fatty acids (ω-3 or n-3 PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential nutritional compounds with potential preventive and therapeutic effects against several psychiatric disorders, especially depression [8][9][10][11][12][13][14][15][16]. Societies that consume a larger amount of omega-3 PUFAs have a lower prevalence of MDD [17]. ...
N-3 polyunsaturated fatty acid supplements improve the symptoms of major depressive disorder (MDD) in randomized-controlled trials and meta-analyses, with the higher efficacy from anti-inflammatory eicosapentaenoic acid (EPA) than brain-dominant docosahexaenoic acid (DHA). To investigate the specific brain mechanisms of the anti-inflammatory anti-depressant nutraceutical compounds, we recruited 24 MDD subjects in this double-blind, head-to-head study with a 12-week EPA or DHA treatment (clinical trial registration number: NCT03871088). The depression severity was assessed by Hamilton depression rating scale (HAM-D). Brain responses to emotional stimuli were measured by a 3-Tesla MRI. The correlation between HAM-D scores and brain responses also were tested. Compared to 18 healthy controls, the brain responses of untreated 24 MDD patients mainly revealed hypoactivity in the regions associated with emotion perception and emotion control when processing positive emotion. After treatment, more remitted MDD patients have been observed in the EPA as compared to the DHA groups. In addition, the EPA, but not DHA, treatment revealed increased activity in the regions associated with emotion perception and cognitive control when processing positive emotion. The correlation analysis further revealed negative correlation between HAM-D scores and brain responses in cognitive control regions. The results of this study may imply the compensatory brain responses of cognitive and emotion controls by EPA but not DHA and underpin personalized medicine with anti-inflammatory nutraceuticals toward depression treatments.
... Other nutrients, such as 3-polyunsaturated fatty acids (PUFAs), are often significantly reduced in serum during pregnancy (Chang et al. 2018). Initial studies suggested that PUFA administration could alleviate the symptoms of PND (Kobayashi et al. 2017;Su 2015); however, findings are not consistent (Freeman 2006). ...
Perinatal depression is the most common complication of pregnancy and affects the mother, fetus, and infant. Recent preclinical studies and a limited number of clinical studies have suggested an influence of the gut microbiome on the onset and course of mental health disorders. In this review, we examine the current state of knowledge regarding genetics, epigenetics, heritability, and neuro-immuno-endocrine systems biology in perinatal mood disorders, with a particular focus on the interaction between these factors and the gut microbiome, which is mediated via the gut-brain axis. We also provide an overview of experimental and analytical methods that are currently available to researchers interested in elucidating the influence of the gut microbiome on mental health disorders during pregnancy and postpartum.
... Omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) are one of emerging safe and tolerable treatment options for MDD and other neuropsychiatric disorders [35][36][37][38][39][40]. Several biological mechanisms of the antidepressant effect of n-3 PUFAs were proposed in our previous reviews, including (1) neurotransmitter regulations, (2) anti-inflammation and anti-oxidation, (3) neuroplasticity effects, and (4) arachidonic acid cascade [7,[40][41][42]. ...
Background:
Circadian rhythm disruption underlies the pathophysiology of psychiatric disorders, especially depression. Both pharmacological and non-pharmacological strategies affecting endogenous circadian rhythms have been developed with specificity to alter the circadian dysfunction. The current management strategy with antidepressants is far from being satisfactory in addressing this issue. In recent years, attempts at discovering new antidepressants focused on a melatonergic system which is known to be altered in depression have led to a potential option for treatment of depression.
Methods:
We reviewed all recently published relevant articles on melatonin and its analogues to look for their implication in the treatment of circadian rhythm disruption and depression.
Results:
Melatonin, a pleiotropic regulator molecule and its analogues (ramelteon, agomelatine, TIK-301, Neu-P11 and tasimelteon) have been observed to resynchronize the circadian rhythm and some were said to alleviate depressive symptoms in depressed subjects.
Conclusion:
This review focuses on substantial advances in the melatonin-based chronobiologic intervention and its responses in the treatment of depression.
... Omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) are one of emerging safe and tolerable treatment options for MDD and other neuropsychiatric disorders [35][36][37][38][39][40]. Several biological mechanisms of the antidepressant effect of n-3 PUFAs were proposed in our previous reviews, including (1) neurotransmitter regulations, (2) anti-inflammation and anti-oxidation, (3) neuroplasticity effects, and (4) arachidonic acid cascade [7,[40][41][42]. ...
... 26 Only one study from 1993 found that omega-3 (3.4 g daily) reduced postpartum depression and anxiety symptoms significantly compared with placebo. 27 Omega-3 supplementation is recognized as safe and benefits overall health and improves obstetric outcomes. 28,29 Based on animal data and the benefits of omega-3 in non-perinatal MDD, it is reasonable to consider adjunctive omega-3 supplementation for perinatal women with MDD or who are at risk for MDD. ...
... The hypothesized mechanisms underlying PUFAs' antidepressant effects are their action on neurotransmission and neuroinflammation (Song et al., 2016;Su, 2009Su, , 2012Su, , 2015b. DHA has been shown to regulate neurotransmitters function, including serotonin, norepinephrine and dopamine (Chalon, 2006;Kodas et al., 2004;Zimmer et al., 2002), which is of relevance to the traditional monoamine theory of depression. ...
Suicide is a multifaceted phenomenon, related to an everlasting interconnection between biological, psychosocial, sociological, philosophical, and cultural aspects of human life. Immune system, which is constantly responding to changing environments and changing in response to them, seems to play a major role in this interaction. Multiple studies have reported increased risk of suicidal behaviours after or during inflammatory conditions. Individuals that engage in suicidal behaviours also have increased concentrations of inflammatory markers, such as interleukins 1β and 6, tumour necrosis factor α, and C-reactive protein, both in blood and the central nervous system (CNS). Stress, which is frequently mentioned among the major risk factors for suicidal behaviours, is also associated with a wide immune system dysregulation, entailing glucocorticoid system disruption and a low-grade inflammation. Mechanisms connecting systemic inflammation and CNS changes include damage to blood-brain barrier and interoceptive alterations, both resulting in changes in the communication between the periphery and the brain. Meanwhile, in CNS, pro-inflammatory cytokines may activate microglia causing a shift in tryptophan metabolism, preferentially generating cellular energy and toxic by-products of kynurenine pathway rather than serotonin. These changes in brain homeostasis lead to anatomical and functional brain alterations, most notably prefrontal cortex and insula, engendering maladaptive behavioural phenotypes, such as anhedonia and impulsivity that may mediate the association between inflammation and suicide. This chapter will provide a condensed overview of this complex association between inflammation and suicidal behaviours, presenting major findings in this area and explaining key pathways linking them.
Given the importance of understanding the role of neuroinflammation in psychiatric illness, including its emergence and progression, it is of practical value to explore the available tools that noninvasively index neuroinflammatory markers in vivo. Various aspects of neuroinflammation can be probed by magnetic resonance imaging (MRI) measures. These aspects include water content accumulation (T2-weighted anatomical MRI, magnetization transfer imaging and diffusion MRI); blood–brain barrier dysfunction and cellular infiltration (contrast-enhanced anatomical MRI); and molecular/metabolic signatures of neuroinflammation (magnetic resonance spectroscopy). This chapter provides a nontechnical overview of these MRI measures, which have been applied to estimate putative neuroinflammatory processes in psychiatric illness.
Introduction:
Prenatal depression (PND) is a common psychiatric disorder in pregnant women and leads to psychosocial dysfunction, high suicidal rate, and adverse childcare. Patients with PND have omega-3 polyunsaturated fatty acid (omega-3 or n-3 PUFAs) deficits, which might link to chronic low-grade inflammatory process and the pathophysiological mechanisms of depression. In this case-control study, we examined the levels of PUFAs and inflammatory cytokines in PND.
Method:
Blood samples were obtained and analyzed from 16 healthy controls and 17 depressed cases (PND group) diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Independent sample t-test and correlation analysis were performed with Statistical Package for the Social Sciences (SPSS) logistics correlation analysis.
Results:
PND group had significantly lower levels of total n-3 (p=0.026), docosahexaenoic acid (DHA) (p=0.020) and eicosapentaenoic (EPA) (p=0.019) but a higher omega-6 (n-6)/n-3 PUFAs ratio (p=0.007) and tumor necrosis factor alpha (TNF-α) (p=0.016) level. Moreover, the duration of current PND episodes were also significantly correlated with DHA, EPA, n-3 PUFAs, n-6/n-3 ratio and TNF-α. In terms of PUFAs and cytokine levels, only DHA was inversely correlated with TNF-α.
Conclusion:
PND is significantly associated with lower DHA, EPA, and total n-3 PUFAs levels and an increased n-6/n-3 PUFAs ratio, while the duration of PND is associated with lower levels of n-3 PUFAs, including DHA and EPA. The correlation of PUFAs levels with depression and TNF-α level grant further investigation into the inflammatory process underlying PND, mediated by PUFAs.
Major depressive disorder (MDD) is predicted to become the top leading cause of disability worldwide by 2020, with a high lifetime prevalence rate of up to one-tenth or possibly even one-fifth [1]. The current psychopharmacologic interventions have had fairly limited success and the development of novel antidepressant medications has had mixed results with several unfortunate failures due to limited efficacy and adverse side effects. With such challenges of prevailing pharmacotherapies towards MDD, a new therapeutic strategy in treatment with omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) supplementation has shown promising outcomes in lowering the risk of depression.
This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ⩾15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were randomized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day(-1), docosahexaenoic acid (DHA)-enriched n-3 900 mg day(-1) or placebo. Outcomes were determined using mixed model repeated measures analysis for 'high' and 'low' inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. Although overall treatment group differences were negligible (ES=-0.13 to +0.04), subjects with any 'high' inflammation improved more on EPA than placebo (ES=-0.39) or DHA (ES=-0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with 'high' IL-1ra or hs-CRP or low adiponectin ('high' inflammation) had medium ES decreases in HAM-D-17 scores vs subjects 'low' on these biomarkers. Subjects with 'high' hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort. Studies are needed to replicate and extend this proof-of-concept work.Molecular Psychiatry advance online publication, 24 March 2015; doi:10.1038/mp.2015.22.
Introduction:
Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) are not synthesized by the human body; they must be derived from dietary sources and they have been known to be involved with neurological, cardiovascular, cerebrovascular, autoimmune and metabolic diseases, and cognitive disorder as well as mood disorders.
Areas covered:
A number of epidemiological and preclinical studies have proven the potential benefit and critical role of omega-3 PUFA in the development and management of major depressive disorder (MDD). In addition, recently independent clinical trials and meta-analyses have also provided superidority of omega-3 PUFA over placebo as monotherapy or augmentation agent in the treatment of MDD. This article presents a brief overview of the evidence to date about the clinical application and biological mechanisms of omega-3 PUFA in the treatment of MDD.
Expert opinion:
Given the potential action mechanism, clinical benefits and currently available clinical trial data, omega-3 PUFAs may deserve greater attention and wider application for treatment of MDD. However, the practical utility of omega-3 PUFA as one of promising alternative agent for treatment of MDD still have many questions unresolved to be fully addressed in near future.
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
Major depressive disorder in children may be more common than previously thought, and its therapeutics are unclear. Because of success in a previous study on omega-3 fatty acids in adult major depressive disorder, the authors planned a pilot study of omega-3 fatty acids in childhood major depression.
Children who entered the study were between the ages of 6 and 12. Ratings were performed at baseline and at 2, 4, 8, 12, and 16 weeks using Children's Depression Rating Scale (CDRS), Children's Depression Inventory (CDI), and Clinical Global Impression (CGI). Children were randomized to omega-3 fatty acids or placebo as pharmacologic monotherapy. Twenty-eight patients were randomized, and 20 completed at least 1 month's ratings.
Analysis of variance showed highly significant effects of omega-3 on symptoms using the CDRS, CDI, and CGI.
Omega-3 fatty acids may have therapeutic benefits in childhood depression.
Perinatal depression is common, and treatment remains challenging. Depression has been reported to be associated with the abnormality of omega-3 polyunsaturated fatty acids (PUFAs). A profound decrease of omega-3 PUFAs in the mother during pregnancy is associated with the higher demand of fetal development and might precipitate the occurrence of depression. In this study, we examined the efficacy of omega-3 PUFA monotherapy for the treatment of depression during pregnancy.
From June 2004 to June 2006, we conducted an 8-week, double-blind, placebo-controlled trial comparing omega-3 PUFAs (3.4 g/d) with placebo in pregnant women with major depressive disorder (DSM-IV criteria). No psychotropic agent was given 1 month prior to or during the study period. The Hamilton Rating Scale for Depression (HAM-D) was scored every other week as the primary measurement of efficacy, while the Edinburgh Postnatal Depression Scale (EPDS) and Beck Depression Inventory (BDI) were secondary measures.
Thirty-six subjects were randomly assigned to either omega-3 PUFAs or placebo, and 33 among them were evaluated in more than 2 visits. A total of 24 subjects completed the study. As compared to the placebo group, subjects in the omega-3 group had significantly lower HAM-D scores at weeks 6 (p = .001) and 8 (p = .019), a significantly higher response rate (62% vs. 27%, p = .03), and a higher remission rate, although the latter did not reach statistical significance (38% vs. 18%, p = .28). At the study end point, subjects in the omega-3 group also had significantly lower depressive symptom ratings on the EPDS and BDI. The omega-3 PUFAs were well tolerated and there were no adverse effects on the subjects and newborns.
Omega-3 PUFAs may have therapeutic benefits in depression during pregnancy. In regard to the safety issue and psychotherapeutic effect, as well as health promotion to mothers and their newborns, it is worthy to conduct replication studies in a larger sample with a broad regimen of omega-3 PUFAs in pregnant women with depression.
clinicaltrials.gov Identifier: NCT00618865.
Background
Interferon (IFN)-α therapy for chronic hepatitis C virus (HCV) infection is frequently associated with depression. The routine prophylaxis with antidepressants might expose patients to adverse effects, hence the need for alternative preventive interventions. Omega-3 polyunsaturated fatty acids (PUFAs) are safe and effective essential nutritional compounds used for the treatment of depression, putatively through an anti-inflammatory action. In addition, lower erythrocyte levels of omega-3 PUFA have been associated with an increased risk of IFN-induced depression.
Methods
We conducted a 2-week, double-blind, placebo-controlled trial, comparing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo, for the prevention of IFN-α-induced depression. A total of 162 patients consented to participate and were randomized to the study, and all of them completed the two-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment, and were included in the analysis.
Results
Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-, but not in DHA-treated patients (10% and 28%, respectively, vs. 30% for placebo, P=0.037). Both EPA and DHA significantly delayed the onset of IFN-induced depression (week of onset: 12.0 and 11.7, respectively, vs. 5.3 for placebo, P=0.002). EPA and DHA were both well tolerated in this population. EPA treatment increased both EPA and DHA erythrocyte levels, but DHA only increased DHA erythrocyte levels.
Conclusions
EPA is effective in the prevention of depression in HCV patients received IFN-α therapy. Our study confirms the notion that anti-inflammatory strategies are effective antidepressants in the context of depression associated with inflammation.
Background: Perinatal depression is common, and treatment remains challenging. Depression has been reported to be associated with the abnormality of omega-3 polyunsaturated fatty acids (PUFAs). A pro- found decrease of omega-3 PUFAs in the mother during pregnancy is associated with the higher demand of fetal development and might precipitate the occurrence of depression. In this study, we examined the efficacy of omega-3 PUFA monotherapy for the treatment of depression during pregnancy.
On the basis of evidence from studies showing the antidepressant effects of omega-3 polyunsaturated fatty acids and the inverse relation between fish consumption and the prevalence of depression, the phospholipid hypothesis seems promising in ascertaining the etiology and treatment of depression. Although several studies have shown lower levels of omega-3 (n-3) polyunsaturated fatty acids in depressive patients, the results of individual polyunsaturated fatty acids, including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and the omega-6 (n-6) polyunsaturated fatty acid arachidonic acid (AA), were inconsistent.
We conducted the meta-analyses of 14 studies comparing the levels of polyunsaturated fatty acids between depressive patients and control subjects. The effect size of each study was synthesized by using a random effects model.
Compared with control subjects, the levels of EPA, DHA, and total n-3 polyunsaturated fatty acids were significantly lower in depressive patients. There was no significant change in AA or total n-6 polyunsaturated fatty acids.
The results showed lower levels of EPA, DHA, and total n-3 polyunsaturated fatty acids in patients with depression, thus implying that n-3 polyunsaturated fatty acids play a role in the pathogenesis of depression. Our findings provide further support to the phospholipid hypothesis of depression and a rationale for using n-3 polyunsaturated fatty acids as an alternative treatment for depression. With these results, future studies examining specific roles of DHA and EPA in different clusters of depressive symptoms are warranted.
Phospholipase A2 (PLA2) and cyclooxygenase 2 (COX2) are the two key enzymes in the metabolism of polyunsaturated fatty acids, which in turn play an important role in cytokine-induced depression and sickness behavior.
Patients with chronic hepatitis C viral infection (n = 132) were assessed to examine the effects of seven single nucleotide polymorphisms in COX2 and PLA2 genes on the development of depression during interferon (IFN)-alpha treatment; a subsample (n = 63) was assessed for the erythrocyte levels of the three main polyunsaturated fatty acids, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid. An independent "replication" sample of patients with major depression unrelated to cytokine treatment (n = 82) was also examined.
Twenty-eight percent of participants developed INF-alpha-induced depression. Participants with the PLA2 BanI GG or the COX2 rs4648308 AG genotypes had a higher risk of IFN-alpha-induced depression (odds ratio = 3.1 and 3.5, respectively). The "at risk" PLA2 genotype was associated with lower EPA levels, and the "at risk" COX2 genotype was associated with lower DHA levels, during IFN-alpha treatment. The PLA2 BanI GG polymorphism was also associated with more somatic symptoms of depression, both in patients with INF-alpha-induced depression and in the replication sample of patients with major depression.
Genetic variations in the COX2 and PLA2 genes increase the risk of IFN-alpha-induced depression, possibly by affecting the levels of EPA and DHA. Moreover, PLA2 genotype is associated with somatic symptoms in depression. Our study confirms the role of inflammatory mechanisms in major depression.
Epidemiological, biological marker and treatment studies, as well as neuroscientific theories, indicate a possible link between omega-3 fatty acids and perinatal depression (PND). Hence the aim of the present study was to assess whether omega-3 fatty acid treatment is superior to placebo in the treatment of PND.
A double-blind randomized placebo-controlled trial was undertaken. Women with major depression during the perinatal period received either fish oil or placebo for six weeks. Changes in depression scores were recorded weekly.
A total of 26 subjects were recruited and there was no significant difference in depression scores between those receiving fish oil and those receiving the placebo.
This is formally a negative study, suggesting that there is no benefit for omega-3 fatty acids over placebo in treating PND. The reason could be that the study was underpowered due to recruitment difficulties and therefore we suggest that it may be unwise to interpret this result as conclusive. Omega-3 is a natural product that is a safe and well-tolerated treatment. Further research is therefore needed in this area to establish whether omega-3 fatty acids are an effective treatment for PND.