Depression has many forms, from pregnancy-related depression, event-related depression such as following death, unemployment, failed relationships, to the poetic state of tristesse to clinical states and psychosis. Whilst depression can be a natural, temporary state, it can also stagnate and lead to hopelessness, lethargy and a feeling of pointlessness. The severity of depression can vary from mild to a clinical diagnosis of Major Depressive Disorder or MDD.

Depression is one of the most common mental disorders. An EU report makes for sombre reading; chronic depression in the EU during a 12-month study period was estimated at 7% of the population, whilst depressive symptoms regardless of severity was experienced by slightly more than 20% of the EU population during the 2 weeks before the survey [1]. The US CDC reports 18.5% of adults having had a diagnosis of depression during their lifetime with the highest prevalence in the age group 18-25[2].

The biology of depression

Depression is a complex interaction of genetics, brain biochemistry, physical status and psychology.

Assistant Professor of Psychology, Alex Vuckovic of Harvard Medical School explains that depression can result from a myriad of reasons ranging from events in our lives to genetic or biochemical disorder or disturbance. At the same time, the individual can experience a range of depression severity from every day “blues” to severe MDD. But there is no association between the different causes and depression severity. Clinicians have to make case by case judgements as to what is the root cause and treat them accordingly.

The end result is that management of depression may need several points of attack including one or more medications, therapy or counselling, good family and friends, stress management and correct nutrition.

Nutrition may be especially relevant to depression because of the aetiological complexity of the condition. This means the more complex the problem, the less likely specific targeted solutions will work. And drugs are often very specific. Let’s explain this by first looking at how drugs work.

The main class of anti-depressant drugs act by increasing serotonin levels in the brain. This happens by limiting serotonin re-uptake by neurons. These drugs are known as SSRIs (selective serotonin reuptake inhibitors) and are the most common anti-depressive drugs in use, and place serotonin as a central player in depression, at least as far as drugs are concerned.

For many people, SSRIs offer relief and are an important contributor to their well-being. However, whilst they are effective for some people, in the complex world of depression, hitting one factor may not be enough, and remission (cure) rates start at 33% with initial treatments and increase to 50% with a second treatment regimen [1]. This still leaves considerable numbers with partial or no response. Side effects can hit up to 50% of patients, which include dizziness, stomach problems, and sexual dysfunction[3].

Biochemically, there is more than just serotonin levels affecting our mood. Neuro-inflammation is also thought to be a key promoter of depression by disruption of nerve cell function. Use of anti-inflammatory drugs shows some efficacy with depression [2].

It´s this complexity that gives nutrition an interesting edge. Nutritional compounds often have broad effects on multiple organs and molecular systems and omega-3 fatty acids are a great example of this. Omega-3 fatty acids are essential components of the brain. They are anti-inflammatory, promote anti-oxidants, neuroprotective and contribute to brain development and brain health.

How omega-3 fatty acids can play a role in depression and well-being

Omega-3 is anti-inflammatory, and it is here that most researchers consider fish oil to be effective in depression. Omega-3 fatty acids are converted to Specialised Pro-resolving Mediators (SPMs) that are a broad family of molecules that are active in the resolution of inflammation. This includes down-regulating levels of inflammatory cytokines, reducing neutrophil infiltration and removing dead cells and bacteria from the inflammatory site. SPMs are one of the hot areas within omega-3 research and are considered to be responsible for much of the anti-inflammatory activity of fish oils.

Omega-3 fatty acids also compete and down regulate the omega-6-arachidonic acid pathway leading to reduced levels of inflammatory prostaglandins and leukotrienes. Many of us know that COX-2 inhibitors are powerful analgesics (e.g., aspirin). COX-2 acts on a pathway that starts with omega-6 arachidonic acid and is hijacked by omega-3. This is also a great example of how a drug (aspirin) is very effective, but usually used in acute situations, whereas fish oils are mildly effective but able to be taken over prolonged periods of time and therefore well suited for reducing chronic inflammation.

Oxidative stress is a result of metabolic activity, stress and damage. In the brain this is of importance since brain cells are unable to regenerate. In the brain. omega-3 fatty acids induce the pathways that increase anti-oxidant enzymes such as superoxide dismutase and catalase [3, 4].

If cells are irreparably damaged, they enter a phase of programmed cell death. This process is known as apoptosis and is carefully orchestrated by the cell in contrast to senescence which is unplanned cell death. Omega-3 fatty acids inhibit apoptosis which may be beneficial during traumas to the brain such as during concussion or in disease states such as Alzheimer´s Disease [3].

Omega-3 fatty acids are also precursors to endocannabinoids. This family of lipids is less well discussed in the omega-3 world. The cannabinoids most famous member is the psychoactive cannabis derivative THC. Cannabinoids made by the body (endocannabinoids, eCB) are not psychoactive and are derived from DHA (DHA-EA or synaptamide), EPA (EPA-EA) and omega-6.  The endocannabinoid system is one of the most ubiquitously expressed signalling systems in the brain, contributing to the regulation of stress response, anxiety, memory, pain, and motivated behaviour [5]. The role of eCBs in depression is supported by deficiency measured in a clinical population and mechanistic studies supporting neuroprotective and anti-inflammatory activity. However, more work is required to fully understand the role in depression, but eCBs potentially offer another means by which inflammation and neurological health is maintained by omega-3 [6].

Does omega-3 supplementation reduce depression?

Epidemiological studies are those that measure population habits and outcomes. These studies show that higher intake of seafood or omega-3 is associated with less depression. A Japanese study looking at childbirth related depression in approximately 82,000 women showed significant reductions in depression and mental illness in those with high vs low omega-3 [7].

Maybe most important is a finding from a Finnish meta-analysis of 14 studies demonstrating that individuals with depression had significantly lower blood levels of EPA, DHA than a control group [8] suggesting that depression may be associated with a reduction or deficiency of omega-3.

Omega-3 intervention studies are also largely positive for improving symptoms of depression. Our review of 10 meta-analyses of omega-3 intervention studies in depression shows that 8 report benefits from omega-3 intervention [9-16] and 2 report a neutral effect [17, 18].

In a so-called umbrella analysis (a meta-analysis of meta-analyses) the effect of omega-3 was assessed from 13 RCTs including 1,233 subjects. Significant and dose related benefits of EPA in MDD were shown whether as a stand-alone or adjunct to anti-depressives. The effect of EPA was best in subjects with systemic inflammation and with formulations >50% EPA [9].

Taking epidemiological, mechanistic and intervention studies together, the evidence provides strong support for the role of omega-3 in the management of depression.

One exciting twist in the omega-3 story is that EPA seems to be of more importance than DHA [19], although 90% of the brains PUFA content is DHA and EPA is almost unmeasurable. Researchers believe the EPA is rapidly converted to other molecules such as SPMs that are important in regulating inflammation.

Dose response studies demonstrate that an EPA dose should be at a minimum of 1g per day [9, 10] . This is a relatively high amount and suggests that depression may cause a particular need for EPA.

Nutritional guidelines for depression

The data for omega-3 supplementation is sufficiently strong to influence dietary guidelines for depression.

Guidelines recommending omega-3 for management of depression are:

• The International Society for Nutritional Psychiatry Research [20]
• Clinical Psychopharmacology and Neuroscience [21]
• Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce [22].

These guidelines recommend 1-2g of EPA and an EPA:DHA ratio of at least 2:1.

Other nutrients

The guideline provided by Sarris et al. provides support for omega-3, Vitamin D, methylfolate, and S-adenosylmethionine for the management of depression, these and other nutrients are further supported in a number of reviews and meta-analyses [11, 23, 24].

Folate and methylfolate

An interesting nutrient proposed for use in depression is folate. Up to 70% of people with MDD have a genetic variation (called a single nucleotide polymorphism or SNP) that reduces their ability to convert folate to methylfolate which is the form able to enter the brain. Supplementation with methylfolate has been demonstrated to reduce symptoms of depression. Folate has both an anti-inflammatory activity and plays a role in the 1-carbon cycle, important in neurotransmitter synthesis (particularly for dopamine, serotonin and noradrenalin (known in the US as norepinephrine)).

Vitamin D

Vitamin D is a pluripotent vitamin with effects on the immune system and bone health as key areas of interest. Vitamin D is thought to play a role in serotonin signalling. Vit D receptors are found throughout the brain and Vitamin D has activity in neuroprotection and brain development. Low blood levels of Vitamin D are associated with depression and a retrospective study of Vitamin D use in US Veterans showed an impressive 48% reduction in self-harm amongst those taking supplementation [25].  

Microbiota

The microbiota describes the bacteria, fungi and viruses that live symbiotically in our guts and on our skin. The ability of the gut microbiome to affect brain function is known as the gut-brain axis and is one of the hottest areas of research in nutrition. What is currently known is that omega-3 supplementation has a positive effect on an “anti-inflammatory” gut. It´s also known that the gut microbiome has a role in depression, ADHD, and autoimmune conditions such as Multiple Sclerosis. Research is now trying to connect these dots with the exciting question – can omega-3 affect brain function via the gut? It´s early days, but exciting days, and worthy to keep an eye on future developments.  

Conclusion

• Depression is a complex disease with many casual factors and many clinical forms.
• Medicines have an important role in alleviating symptoms for many people, but up to half of treated patients show limited benefit or poor tolerability.
• There is considerable evidence from epidemiological, mechanistic and interventions studies supporting omega-3 use in depression.
• Guidelines recommend at least 1g of EPA daily and that there should be at least a 2:1 EPA:DHA ratio.

Back to our film scenario: your love is over, the depression sets in, you sit down to watch your film, you take your tub of ice cream. Seems superficial but there are a lot of positive messages here:  Take depression seriously, give yourself time to de-stress, focus on what makes you happy, read this report, take a spoon of ice cream and plan a nutrient rich future.  

References

1.            Gaynes, B.N., et al., The STAR*D study: treating depression in the real world. Cleve Clin J Med, 2008. 75(1): p. 57-66.

2.            Bai, S., et al., Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry, 2020. 91(1): p. 21-32.

3.            Ajith, T.A., A Recent Update on the Effects of Omega-3 Fatty Acids in Alzheimer's Disease. Curr Clin Pharmacol, 2018. 13(4): p. 252-260.

4.            Wang, L., et al., Protective effects of omega-3 fatty acids against Alzheimer's disease in rat brain endothelial cells. Brain Behav, 2018. 8(11): p. e01037.

5.            Haney, M., Cannabis Use and the Endocannabinoid System: A Clinical Perspective. Am J Psychiatry, 2022. 179(1): p. 21-25.

6.            Gorzalka, B.B. and M.N. Hill, Putative role of endocannabinoid signaling in the etiology of depression and actions of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry, 2011. 35(7): p. 1575-85.

7.            Hamazaki, K., et al., Dietary intake of fish and n-3 polyunsaturated fatty acids and risk of postpartum depression: a nationwide longitudinal study - the Japan Environment and Children's Study (JECS). Psychol Med, 2020. 50(14): p. 2416-2424.

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9.            Firth, J., et al., The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta-review of meta-analyses of randomized controlled trials. World Psychiatry, 2019. 18(3): p. 308-324.

10.         Liao, Y., et al., Efficacy of omega-3 PUFAs in depression: A meta-analysis. Transl Psychiatry, 2019. 9(1): p. 190.

11.         Sarris, J., et al., Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. Am J Psychiatry, 2016. 173(6): p. 575-87.

12.         Mocking, R.J., et al., Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Transl Psychiatry, 2016. 6(3): p. e756.

13.         Yang, J.R., et al., Combined application of eicosapentaenoic acid and docosahexaenoic acid on depression in women: a meta-analysis of double-blind randomized controlled trials. Neuropsychiatr Dis Treat, 2015. 11: p. 2055-61.

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17.         Zhang, L., et al., Omega-3 fatty acids for the treatment of depressive disorders in children and adolescents: a meta-analysis of randomized placebo-controlled trials. Child Adolesc Psychiatry Ment Health, 2019. 13: p. 36.

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19.         Mozaffari-Khosravi, H., et al., Eicosapentaenoic acid versus docosahexaenoic acid in mild-to-moderate depression: a randomized, double-blind, placebo-controlled trial. Eur Neuropsychopharmacol, 2013. 23(7): p. 636-44.

20.         Guu, T.W., et al., International Society for Nutritional Psychiatry Research Practice Guidelines for Omega-3 Fatty Acids in the Treatment of Major Depressive Disorder. Psychother Psychosom, 2019. 88(5): p. 263-273.

21.         Chang, J.P. and K.P. Su, Nutritional Neuroscience as Mainstream of Psychiatry: The Evidence- Based Treatment Guidelines for Using Omega-3 Fatty Acids as a New Treatment for Psychiatric Disorders in Children and Adolescents. Clin Psychopharmacol Neurosci, 2020. 18(4): p. 469-483.

22.         Sarris, J., et al., Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J Biol Psychiatry, 2022: p. 1-32.

23.         Hoepner, C.T., R.S. McIntyre, and G.I. Papakostas, Impact of Supplementation and Nutritional Interventions on Pathogenic Processes of Mood Disorders: A Review of the Evidence. Nutrients, 2021. 13(3).

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