Polyunsaturated Fatty Acids and Mental Health

Docosahexaenoic acid (DHA), one of the polyunsaturated fatty acids, has been linked in the past to psychosis. However, the longitudinal trajectories of polyunsaturated fatty acids in the general population have not been thoroughly characterized, and their specific relationships with psychosis spectrum outcomes during early adulthood remain uncertain. In this study by Mongan et al. (2024), the authors utilized nuclear magnetic spectroscopy to measure plasma omega-6:omega-3 ratio and DHA levels (represented as a percentage of total fatty acids) in participants of the Avon Longitudinal Study of Parents and Children (ALSPAC, ages 7, 15, 17, and 24 years old). By utilizing the Psychosis-Like Symptoms questionnaire (n = 3,635; 61.8% female), 24-year-olds' psychotic experiences (PEs), at-risk mental state status, and Community Assessment of Psychic Experiences (n = 3,484; 62.0% female), diagnoses of psychotic disorders, the quantity of PEs, and negative symptoms were evaluated. Statistical adjustments were made to account alcohol use, cumulative smoking, parental socioeconomic status, sex, and ethnicity. Initial findings indicated that consistently high trajectories of omega-6 to omega-3 ratio were linked to elevated odds of experiencing PEs and psychotic disorders. However, these associations were weakened after accounting for covariates. Similar patterns were observed for persistently low DHA. After adjustment, persistently high omega-6 to omega-3 ratio and low DHA were associated with an increased number of PEs and higher negative symptoms scores. Further investigation into optimizing polyunsaturated fatty acid status during development is warranted to better understand its relationship with psychotic symptoms in early adulthood. [NPID: ALSPAC, negative symptoms, omega-3, plasma, polyunsaturated fatty acid, psychosis]

In order to examine the effects of eicosapentaenoic acid (EPA) at three different dosages vs placebo on inflammatory biomarkers and depressed symptoms, Mischoulon et al. (2022) conducted this study. Sixty-one adults who were not taking medication (75% female; average age 45.5 ± 13.8 years), had a body mass index over 25 kg/m2, were diagnosed with DSM-5 major depressive disorder (MDD), and had a plasma high-sensitivity C-reactive protein (hs-CRP) level of 3.0 mg/L or higher, were randomly assigned to receive EPA at doses of 1 g/d, 2 g/d, or 4 g/d, or a placebo for a 12-week period. The study endpoints included a reduction in plasma inflammatory markers interleukin (IL)-6, cytokines in peripheral blood mononuclear cells (PBMCs), and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. A reduction of at least 50% in the IDS-C30 (Clinian-Rated version of the Inventory of Depressive Symptomatology) scores was considered a response to treatment. Outcomes were compared across the three EPA doses and placebo. Among the 45 participants who completed the study, only PBMC TNF levels showed a median decrease with EPA 2 g/d. The authors noted that none of the EPA dosages being investigated lead to a significant reduction in plasma IL-6 or mitogen-stimulated TNF. The response rates for EPA 4 g/d were 64%, EPA 1 g/d was 38%, EPA 2 g/d was 36%, and the placebo group was 40%. The fact that these differences did not become statistically significant is notable, however. A strong connection was seen between the reduction in IDS-C30 symptoms at 12 weeks and the percentage drop in plasma hs-CRP when EPA 4 g/d was administered. When compared to a placebo, EPA at a dosage of 4 g/d had a moderate impact size on response rates. This suggests that this higher dose of EPA may be beneficial in alleviating MDD symptoms in overweight individuals with elevated inflammatory markers, and reductions in hs-CRP levels may be associated with clinical improvement. [NPID: Eicosapentaenoic acid, EPA, major depressive disorder, inflammatory biomarkers, placebo-controlled trial, depressive symptoms, hs-CRP, PBMC cytokines, treatment response, overweight individuals]

Cognitive problems linked to major depressive disorder (MDD) are widespread, debilitating, and currently lack effective treatments. Dysregulated inflammatory processes are considered a potential underlying mechanism and a target for therapy. In a 12-week randomized placebo-controlled trial involving individuals with MDD and a pro-inflammatory profile, Mac Giollabhui et al. (2023) investigated three main aspects: (i) the connection between dysregulated inflammation and initial cognitive impairment, (ii) changes in cognitive function following treatment, and (iii) how baseline inflammatory markers relate to cognitive improvements during treatment. The authors enrolled 61 unmedicated adults (75% female, mean age = 45.50 years, C-reactive protein [CRP] ≥3.0 mg/L, body mass index >25 kg/m2) that satisfy DSM-5 criteria for MDD. Participants were randomized to receive daily doses of omega-3 polyunsaturated fatty acids (ω-3-FA) at 1 g, 2 g, or 4 g, or a placebo. Data analysis involved 45 participants who finished the study and underwent assessment of their inflammatory biomarkers, which encompassed interleukin-6 (IL-6), CRP, tumor necrosis factor-α (TNFα), and TNFα and IL-6 levels stimulated by lipopolysaccharide (LPS) in peripheral blood mononuclear cells (PBMCs), with a focus on participants receiving the highest dose of omega-3 fatty acids (4 g daily; n = 11) compared to controls (n = 10). Validated self-report measures were used to assess cognitive impairment, including motivational symptoms and higher-order cognitive functioning. At baseline, lower IL-6 levels in LPS-stimulated PBMCs were associated with more severe impairment in higher-order cognitive functions across all participants. Subsequent investigation revealed that, in comparison to those on a placebo, those on 4 g/day of ω-3-FA enjoyed substantial improvements in motivational symptoms. Lower initial TNFα levels in LPS-stimulated PBMCs correlated with notable enhancement in motivational symptoms after treatment among individuals receiving 4 g/day of omega-3 fatty acids. According to this preliminary clinical investigation, giving depressed people with inflammatory profiles 4 g of ω-3-FA daily may improve their motivational symptoms. [NPID: Cognitive impairment, major depressive disorder, inflammatory physiology, omega-3, randomized trial, motivational symptoms]

Essential for cognitive function are omega-3 fatty acids. It is becoming more well-accepted that adolescence plays a crucial role in brain susceptibility to nutritional influence. However, it is unknown if walnuts, an omega-3 alpha-linolenic acid (ALA) source, may help with teenage neurodevelopment. To determine if eating walnuts has positive impacts on the cognitive and behavioral development of teenagers, Pinar-Martí et al. (2023) undertook a 6-month multi-school randomized controlled nutrition intervention experiment, recruiting 771 healthy adolescents 11-16 years old who were randomly assigned to either an intervention or control group. The intervention group was given 30 g/day of raw walnut kernels to add to their diet for six months. At baseline and during the intervention, many major outcomes relating to neuropsychological (working memory, executive function, attention, and fluid intelligence) and behavioral (socio-emotional and attention deficit hyperactivity disorder [ADHD] symptoms) development were evaluated. As a gauge of compliance, the red blood cell (RBC) ALA level was assessed at baseline and after six months. Analysis of the results revealed that, for all major outcomes, there were no statistically significant differences in the intervention group compared to controls at six months in intention-to-treat analyses. Only the intervention group's RBC ALA (%) substantially increased. The per-protocol (adherence-adjusted) effect on improvement in attention score (hit reaction time variability) was 11.26 ms for the intervention group in comparison to the control group, with an improvement in fluid intelligence score by 1.78 and a reduction in ADHD symptom score at 2.18. Thus, the authors demonstrated that healthy teenagers' neurophysiological functions did not improve after being advised to eat walnuts for six months. However, those who adhered better to the walnut intervention showed improvements in sustained attention, fluid intelligence, and ADHD symptoms. The authors comment that their study lays the groundwork for future clinical and epidemiological studies on the impact of walnuts and ALA on adolescent neurodevelopment. [NPID: Adolescent health, cognitive function, neuropsychology, randomized nutritional intervention, public health, walnut intake]

Antidepressant drugs enhanced with omega-3 polyunsaturated fatty acids (n-3 PUFAs) have demonstrated significant promise in the prevention and treatment of severe depressive disorders (MDD). Yang et al. (2022) examined the impact of venlafaxine combined with n-3 PUFAs in a population of 72 individuals with newly diagnosed, drug-naive depression. Throughout more than 12 weeks, either 2.4 g/day of n-3 PUFAs or a placebo with venlafaxine was administered. The Hamilton Depression Scale (HAMD), the Beck Depression Inventory (BDI), the Hamilton Anxiety Scale (HAMA), and the Self-Rating Anxiety Scale (SAS) were used to evaluate the results. When compared to baseline, both groups showed improvement in clinical features at weeks 4 and 12. In week 4, the rate of responders for anxiety in the n-3 PUFAs group was substantially greater than that in the placebo group, but week 12 did not demonstrate a difference between the groups. There was no discernible difference between the two groups in the rate of respondents for depression at either week 4 or week 12. Upon further investigation, it was shown that the Childhood Trauma Questionnaire (CTQ) exhibited a positive association with SAS, HAMA, BDI, and HAMD scores. SAS and BDI showed a negative relationship with the Social Support Rating Scale (SSRS). The authors conclude that supplementing with n-3 PUFAs instead of venlafaxine reduced anxiety symptoms rather than depressive ones over the first four weeks of therapy for newly diagnosed, drug-naive depressed individuals. This benefit, however, vanished over prolonged therapy. Additionally, the clinical and biochemical aspects of depression are tightly linked to childhood trauma and social support. Lack of social support and early trauma may both be indicators of a bad prognosis for depression. [NPID: Antidepressant, childhood abuse, major depressive disorders, nutrient intervention, omega 3, polyunsaturated fatty acids, social support]

Current research evidence points to the beneficial impacts of fish oils (such as Eicosapentaenoic acid [EPA] and Docosahexaenoic acid [DHA]) and omega-3 fatty acids on chronic diseases like rheumatoid arthritis, cardiovascular diseases, and more recently, Alzheimer’s disease (AD). Ajith (2018) discusses the recently available findings in the use of omega-3 fatty acids to treat AD in this review. DHA in particular plays an important role in brain and retinal development. These dietary components are metabolized in the lipooxygenase, cyclooxygenase, and hepatic cytochrome P450 isoenzymes. Omega-3 fatty acids are thought to elicit their beneficial properties due to their anti-inflammatory, antioxidant, neurotrophic and antiapoptotic characteristics. In conclusion, DHA and EPA could enhance cognitive function in major depressive disorder and mild AD and help elevate nerve growth factor levels. [NPID: Alzheimer's disease, Docosahexaenoic acid, dementia, Eicosapentaenoic acid, neurodegenerative diseases, polyunsaturated fatty acids]

Depression is the most prevalent mental health disorder affecting adults, and is projected to be the second leading cause of illness by 2020. The negative impacts of depression reach several systems, especially the central nervous system, and these impacts potentiate with advancing age. Depression involves several etiological factors and an equally complex myriad of pathophysiological mechanisms, with several human and animals studies revealing the links between depression and neurotransmitter disproportion, hypothalamic-pituitary-adrenal axis dysregulation, changes in brain volume, dysfunctional neurogenesis and inflammatory pathway disturbance, not to mention the influence gut microbiome disturbance has on mental health disorders and vice versa. Depression is certainly not an expected complication of advancing age, however, experiencing symptoms of depression is more prevalent with aging, and is often underdiagnosed or misdiagnosed in geriatric populations. If left untreated, it can lead to a multitude of complications, including reduction of life expectancy, deterioration in overall health, encumberment of healthcare systems and an increase in the incidence of suicide in older populations. Depression in older patients is a condition that remains to be fully understood, where the use of pharmaceutical interventions remains the current standard of therapy. However, as sedentary lifestyles and penurious nutrition became topics of growing interest in the pathogenesis, course and treatment of depression, Vecchioli et al. (2018) conducted this review to investigate the impact of physical activity and omega-3 fatty acids intake on depression in older patients. Through their results, the authors highlight that a growing body of literature alludes to a positive impact on mental health exerted by physical activity and improvement of nutritional status, and conclude that maintaining sufficient nutrition and activity levels may be utilized as a low-cost therapeutic intervention to combat depression in older patients. [NPID: Aging, depression, diet, exercise, late-life depression, mood disorders, omega-3 fatty acids, physical activity]

With rising COVID-19 infections to well above 20 million patients and north of 778,000 deaths across the world, a notable rising trend in psychiatric disorders, such as anxiety and depression, was concurrently observed. In tandem with continued research on preventive and therapeutic interventions to combat COVID-19, a renewed spotlight has been shed on strengthening host immunity to stop the clinical progression of COVID-19, and on immunity-boosting nutritional supplements like omega-3 polyunsaturated fatty acids (n-3 PUFAs). n-3 PUFAs have additionally exhibited a significant positive impact on mood disorders, thus, Chang et al. (2020) highlight the necessity to investigate whether n-3 PUFAs could potentially improve both host physical and mental defenses against COVID-19. [NPID: Covid-19, immunomodulation, omega-3]

Omega-3 polyunsaturated fatty acids are a family of dietary fats that have several health benefits and include several members such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish, and α-linolenic acid which is found in perilla oil. As per Hamazaki (2019), following a landmark study in Greenland more than five decades ago, the protective effects of EPA in cardiovascular conditions were established, and it became available as a nutritional supplement during the 1990s. In this article, the author presents the growing body of epidemiological literature and clinical trials that investigate EPA and its use in mental health conditions, particularly, in depressive disorders. [NPID: Clinical trials, depression, epidemiological studies, omega-3 polyunsaturated fatty acids]

Despite a growing body of research probing the use of omega-3 fatty acids (abundant in fish) in borderline personality disorder (BPD), a lack of clarity remains on their impact on disease outcomes. Through their work, Karaszewska et al. (2021) attempted to appraise the impact of using omega-3 fatty acids in BPD through meta-analyses employing an a priori differentiation (i.e., based on theoretical rather than clinical observation) of affected psychological symptom domains in BPD patients. Through a literature search of several databases (EMBASE, PsycINFO, MEDLINE), and selecting five studies encompassing a 137 BPD patient cohort, the authors discovered a comprehensive impact of omega-3 fatty acids deficiency was found to be linked to increased BPD symptom severity. In particular, omega-3 fatty acid deficiency leads to patients being unable to tolerate negative emotions or events, and may cause them to lose adequate control over impulsive behaviors, compared to controls. The authors conclude that their work highlights the positive impact of marine-derived omega-3 fatty acids on BPD, and determines that they could be evaluated as adjuvant treatments in the course of BPD. [NPID: Omega-3 fatty acids, Borderline Personality Disorder, affective disorder, impulsive behavior, cognition, perception]

According to DiNicolantonio & O’Keefe (2020), most humans are deficient in long-chain marine omega-3s, and most importantly, in docosahexaenoic acid (DHA), which plays a key part in healthy cerebral and ocular development. Furthermore, DHA is important for mental health in children and adults, cellular membrane function, and cerebral neurotransmitter secretion. Studies have shown that a nutritional deficiency of marine omega-3 fatty acids leads to raising the odds of several mental health conditions, such as Attention Deficit Hyperactivity Disorder (ADHD), autism, bipolar disorder, depression, and risk of suicide, in addition to a supportive growing body of evidence on the positive impact of marine omega-3 fatty acid supplements on mental health. In this paper, the authors summarize the literature exploring the relationship between marine omega-3 fatty acids and mental health disorders. [NPID: Omega-3, fish oil, brain, mood, attention, depression]

Nursing is a depression-prone healthcare profession. Despite a significant underdiagnosis of depression, nurses continue to endure depression and anxiety, resulting in a negative impact on the patient care they are able to deliver. A lack of evidence to support mental health preventative strategies for this vulnerable population remains noticeable. After conducting a literature review, Watanabe et al. (2015) investigated the potential approach of using omega-3 fatty acids and a mindfulness-based stress management program to aid 120 hospital ward-employed junior nursing staff. Nurses participating in the study underwent four 30-minute individual mindfulness cognitive therapy sessions and received either a 1,200 mg/day of eicosapentaenoic acid and 600 mg/day of docosahexaenoic acid supplement or a placebo, for 90 days. Response to the intervention was gauged using the Hospital Anxiety and Depression Scale (HADS), and the nurses were evaluated for major depressive episodes, severity of depression, anxiety, insomnia, burnout, and productivity. Utility scores and unexpected medical problems were assessed at 13, 26, and 52 weeks. The authors present their work as a recommendation of the necessary background and methods required for conducting a randomized trial aimed to evaluate the efficacy of supportive programs utilizing omega-3 fatty acids and mindfulness-based stress management to reduce depression suffered by nursing staff. [NPID: Anxiety, behavior therapy, depression, fatty acids, omega-3, mindfulness, prevention and control]

In this work, Sánchez-Villegas et al. (2018) intended to discover the links between seafood consumption, omega-3 polyunsaturated fatty acids (ω-3 PUFA), and the pervasiveness of depression, by analyzing data from the PREDIMED-Plus trial. In a sample of 6,587 participants (where 1,367 of which were found to suffer from depression), dietary intake of seafood and ω-3 PUFA was evaluated using a validated food-frequency questionnaire, while the Beck Depression Inventory-II was used to evaluate symptoms of depression. In their results, the authors discovered no relationship between seafood consumption and depression, while moderate consumption of long-chain ω-3 PUFA (approximately 0.5–1 g/day) was linked to a substantial decrease in the pervasiveness of depression. The authors conclude that moderate dietary intake of fish and long-chain ω-3 PUFAs leads to a decrease in the prevalence of depression. [NPID: Fish, omega-3, eicosapentaenoic acid, docosahexaenoic acid, depression]

Several studies have demonstrated the link between inflammation, depression, lower omega-3 (n-3) polyunsaturated fatty acids (PUFAs), and higher omega-6 (n-6) PUFAs levels, however, the evidence from randomized control trials (RCTs) remains unclear. In their works, Kiecolt-Glaser et al. (2011) examined 68 medical students to understand if n-3 supplementation reduced proinflammatory cytokine production and symptoms of anxiety and/or depression in a parallel group, placebo-controlled, double-blind 12-week RCT. The participants were given either n-3 (2.5 g/d, 2085 mg eicosapentaenoic acid and 348 mg docosahexaenoic acid) or equi-caloric placebo capsules, and had blood samples drawn on lower and higher stress intervals (days prior to scheduled exams). The authors observed that students receiving n-3 showed a 14% reduction in lipopolysaccharide (LPS)-stimulated interleukin 6 (IL-6) and a reduction of 20% in symptoms of anxiety compared to controls. No substantial impact was observed on symptoms of depression in either group. To account for potential variabilities in absorption, metabolism, and adherence to n-3 PUFA intervention, the authors analyzed plasma n-6:n-3 ratio, demonstrating that a lower n-6:n-3 ratio correlated with a reduction in anxiety symptoms and in stimulated IL-6 and tumor necrosis factor alpha (TNF-α) release. The authors comment that these findings postulate a role of n-3 PUFA in decreasing inflammation and anxiety in healthy young adults and that n-3 may be explored as an anxiolytic intervention in individuals regardless of prior diagnosis of anxiety disorder. [NPID: Fish oil, omega-3, omega-6, inflammation, interleukin-6, tumor necrosis factor alpha, psychoneuroimmunology, nutritional neuroscience, anxiety]

Amongst all organs in the human body, the brain is by far the most complex and plays the most critical role in regulation of body homeostasis. Studies have shown that specific dietary nutrients contribute to overall brain well-being, especially omega fatty acids. However, the impact of omega fatty acids throughout the duration of human life has not been fully understood. In this systematic review, Derbyshire (2018) compiled 25 randomized control trials (with a total of 3,633 participants) to investigate omega fatty acids further. The results showed that omega-3 supplementation led to a significant beneficial impact on several blood biomarkers in distinct populations, including those with lower baseline fatty acids, breastfeeding mothers, and neuropsychiatric patients. The author comments that, despite evidence suggesting the benefit of omega fatty acids in neurodegenerative conditions afflicting the geriatric population, further research is necessary to investigate their impact in the period prior to clinical diagnosis, which would help present omega supplementation as a low-cost adjunctive therapy to help support geriatric brain health and address related escalating healthcare costs. Further work using standardized methods is necessary to outline dosage requirements, ratios of different omega fatty acids to be included, and duration of treatment, in order to set universal treatment guidelines. [NPID: Brain health, omega-3 fatty acids, cognition, learning, mindfulness]

High levels of omega-3 fatty acids correlate with longer DNA telomeres, lower inflammatory markers, and improved sympathetic and cardiovascular responses to stress. However, the impact of omega-3 supplements on telomerase, serum cortisol levels, and systemic inflammation remains poorly understood. In this randomized controlled trial by Madison et al. (2021), the authors investigated the effect of omega-3 supplementation on cellular aging-related serological markers after being subjected to a laboratory speech stressor, in a sample of 138 participants (sedentary, overweight, and middle-aged, 93 women and 45 men). The participants were given a 2.5 g/d of omega-3, 1.25 g/d of omega-3, or a placebo for 4 months, and performed the Trier Social Stress Test before starting the trial and after its conclusion. Saliva and blood samples helped evaluate salivary cortisol, telomerase found in peripheral blood lymphocytes, anti-inflammatory (interleukin-10; IL-10), and pro-inflammatory (interleukin-6; IL-6, interleukin-12, tumor necrosis factor-alpha) cytokines. Analysis of the results, with respect to variables like stress reactivity prior to supplementation, age, abdominal contour, and sex, revealed an improvement in telomerase and IL-10 stress reactivity in both supplement groups compared to the decline seen in the placebo group after the induction of stress. Furthermore, omega-3 supplementation decreased overall cortisol and IL-6 levels in the 2.5 g/d group compared to placebo. The authors comment that by reducing overall inflammation and cortisol levels due to stress and enhancing cellular repair during recovery, omega-3s could potentially decelerate aging and lower the risk of depression. [NPID: Aging population, cytokines, dietary supplements, fatty acids, omega-3, stress]

Cognitive disorders, such as mild cognitive impairment (MCI) and age-related cognitive decline (ARCD), are prevalent in the elderly population across the world. Dietary components like n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are thought to enhance cognitive status and potentiate treatment against cognitive decline in the elderly, however, the evidence to the efficacy of n-3 LCPUFA in cognitive decline remains insufficient. In this systematic review by Moral & Fortique (2019), the authors examined the links between n-3 LCPUFA and cognitive decline in an elderly population to elucidate any potential enhancement of cognitive status using n-3 LCPUFA supplements, and whether these enhancements are affected by treatment duration, baseline cognitive status, dosage, or other variables. Through a PRISMA guidelines-compliant search of available randomized controlled trials (RCTs, Pubmed January 2010 - December 2017), researchers investigated the links between cognitive impairment and n-3 LCPUFA supplements (containing docosahexaenoic acid, eicosapentaenoic acid, or combinations). From a total of 14 RCTs, 10 demonstrated an improvement of at least one domain of cognition (working memory, executive function, verbal memory, short-term memory, or perceptual speed) with the use of n-3 LCPUFA. The authors thus state that their review demonstrates how n-3 LCPUFA supplements may improve cognitive function in the elderly, and recommend their potential use as preventative supplements or as therapeutic interventions in the elderly population suffering from cognitive decline. [NPID: Cognitive decline, omega-3, fatty acids, elderly, aging]

Current therapeutic interventions against major depressive disorder (MDD) remain lacking. ω–3 polyunsaturated fatty acids (n–3 PUFAs) were among researched nutritional components with proven antidepressant properties. In this literature review, Guu et al. (2019) present forth the findings produced by the subcommittee of the International Society for Nutritional Psychiatry Research, aimed at outlining clinical practice guidelines governing the use of n–3 PUFAs in MDD. The resultant guidelines engrossed five domains, namely: “general concepts, acute treatment strategy, depression recurrence monitoring and prevention, use in special populations, and potential safety issues.” These guidelines asserted the following, first: that professionals in clinical practice should authenticate the diagnosis, condition, and psychopathological assessment of their patients prior to considering n–3 PUFAs. Second, regarding n–3 PUFA prescription, administering pure eicosapentaenoic acid (EPA) or a EPA/docosahexaenoic acid (DHA) mixture where EPA/DHA >2:1, at a dose of 1–2 g of net EPA daily, is of substantial potency. Third, therapeutic response is liable to fluctuate depending on n–3 PUFAs quality. Finally, n–3 PUFAs are safe for use during pregnancy and in extremes of age (children, geriatrics), however, side effects (such as gastrointestinal or dermatological) should be monitored and addressed. The authors conclude that customizing treatment plans for MDD patients with low levels of n–3 PUFAs or high inflammatory biomarkers are significant topics of interest that require future research. [NPID: Omega-3 polyunsaturated fatty acids, Docosahexaenoic acid, Eicosapentaenoic acid, guideline, Major Depressive Disorder]

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