Summary
Major depressive disorder is perhaps the most well-known form of depression, typically characterized by at least a depressed mood most of the day or a loss of pleasure and interest. Although no biological cause is known, studies indicate that low levels of DHA negatively correlate with this disorder prevalence and symptoms. Moreover, a promising trial has shown positive effects of DHA supplementation in relation to symptom severity of major depressive disorder. 
 
Introduction
When it comes to disorders and conditions that have a severe negative impact on the quality of life, major depressive disorder (MDD) is perhaps one of the most well-known burdens people can be affected by. For people that have experienced the destructive effect of depressive disorders, either personally or in one’s surroundings, the importance of countering this extremely burdensome disorder is crystal clear. Because depressive disorders are experienced differently between individuals with a large variety of possible symptoms, biomarkers and universally effective treatments remain elusive. The most commonly used way to classify depressive disorders is by the Diagnostic & Statistical Manual for Mental Disorders (DSM). This manual for the classification of mental disorders was first established in the 1950s by the American Psychological Association, but has seen many revisions since. MDD was first entered as a diagnostic category in the third edition of the DSM, published in 1980. MDD is colloquially referred to as simply depression, the current diagnostic criteria for this disorder (according to the latest version of the DSM) are perhaps what most people think of when they hear the term “depression”. A person with MDD has one of more major depressive episodes without a history of mania or hypomania. Major depressive episodes last for a minimum of two weeks, during which the affected individual must have 5 of the symptoms below (and at least one of the two first symptoms):

1. Depressed mood most of the day, nearly every day, OR
2. Loss of interest/pleasure (anhedonia).
3. Significant weight loss/gain, or change in appetite.
4. Insomnia or hypersomnia.
5. Psychomotor agitation or retardation (observable by others).
6. Fatigue or loss of energy.
7. Feelings of worthlessness or excessive/inappropriate guilt.
8. Diminished concentration, indecisiveness.
9. Recurrent thoughts of death, suicidal ideation, or suicide attempt.

 
Unlike physical disorders and conditions, psychiatric disorders are not typically defined by physical changes in the brain, but rather by a person’s experience of their life. Nevertheless, many studies aiming to understand and treat depressive disorders such as MDD look at the brain to explain and counter depressive disorders. Previously discovered changes in the brain of (certain) persons with MDD, such as neuroinflammation, has allowed for the development of therapeutic strategies, and are currently even being used to identify biomarkers that can aid in diagnosis. As around 15-20% of the brain’s total fatty acids are DHA, it only makes sense that researchers have investigated if DHA plays an important role in MDD, either as potential biomarker or as therapeutic target. This has led to interesting findings that have put forward low DHA levels as a possible indicator of MDD. Moreover, trials where DHA was used as a treatment strategy have accordingly showed promising results in terms of relieving the symptom burden of MDD. Some of these studies are outlined below.  
 
Research findings
Neuroinflammation is increasingly recognized to play a role in some cases of MDD. Unfortunately, certain medication can increase the risk of neuroinflammation and thereby MDD. An example of this is IFN-α treatment (a pro-inflammatory cytokine given to persons with hepatitis C); a common side-effect of this treatment is the triggering of a depressive episode. As DHA has anti-inflammatory effects, Lotrich and collaborators investigated the role of DHA levels in hepatitis C patients receiving IFN-α treatment (Lotrich, Sears, and McNamara 2013). The authors followed hepatitis C patients during their IFN-α treatment, including a group of 99 men and women. At the start and end of treatment they took blood samples and conducted psychiatric assessments of depression using the Montgomery-Asperg Depression Rating Scale (MADRS). Hepatitis C patients who at the beginning of their IFN-α treatment had lower levels of DHA, or EPA + DHA relative to the pro-inflammatory arachidonic acid, had a higher susceptibility of having depressive episodes as scored by the MADRS. As such, it is likely the case that persons with low levels of circulating DHA have an increased risk of being burdened by depressive episodes when their immune system is affected by an inflamed state. 
 
In line with the findings of Lotrich, Sears and McNamara (2013), Omori and colleagues set out to study the relationship between the bioactive form of DHA (LPA 22:6) in cerebrospinal fluid and symptomatic scores of MDD (Omori et al. 2021). In the brain, DHA is contained within lysophospholipids; this represents the bioactive form of DHA in the central nervous system which Lotrich and colleagues investigated in their study. [JG1]  Cerebrospinal fluid is present in and around our brain to absorb shocks, but also regulates delivery of nutrients and disposal of waste. This fluid is often used to look for biomarkers, as it can contain indicators regarding the nutrient and health status of the brain. The authors assessed levels of lysophospholipids harbouring polyunsaturated fatty acids (such as EPA and DHA) in cerebrospinal fluid to see if any of these related to the symptomatic scores of persons with schizophrenia or depression. The authors found that compared to healthy controls, persons with  MDD or schizophrenia had significantly lower levels of LPA-DHA in their cerebrospinal fluid. Moreover, in the study participants with MDD, several clinical symptomatic scores of MDD negatively correlated with levels of LPA-DHA in their cerebrospinal fluid. This means that low levels of the bioactive LPA-DHA could potentially be used as a biomarker for MDD presence and symptom severity.
 
As mentioned above, pro-inflammatory cytokines such as IL1β or IFN-α are associated with (neuro)inflammation that can negatively impact MDD. Borsini and fellow scientists published a study wherein they examined the effects of DHA on pro-inflammatory cytokines. They investigated this both in cell cultures, and in a clinical intervention trial with MDD patients (Borsini et al. 2021). Their first reported finding is that in a human neuronal cell culture, pretreatment of cells with either DHA or EPA was able to prevent the neuroinflammatory effects of IL1β or IFN-α. Studying this further, they found that this effect was dependent on the metabolization of EPA and DHA by lipid mediators called lipoxygenase (LOX) and cytochrome P450 (CYP450), as blocking the activity of these mediators resulted in a loss of the protective effect of EPA and DHA. The authors then moved to translate these findings in a small intervention trial with persons diagnosed with MDD. In brief, 22 adults with MDD received either 3g per day of EPA or 1.4g per day of DHA for a period of 12 weeks. At baseline and the end of the intervention, blood plasma samples were taken and MDD severity was assessed using the Hamilton Depression Rating Scale (HAM-D). It was found that in both intervention groups, depression severity decreased after the 12 week intervention period. Critically, this decrease in depression severity correlated with the levels of (LOX and CYP-450 mediated) metabolites of DHA or EPA in their respective groups. This means that persons with higher levels of these DHA or EPA metabolites had greater decreases in depression severity. 
 
Conclusion
The studies above highlight a consistent pattern in which low levels of DHA, whether circulating in the blood or present in its bioactive form in the cerebrospinal fluid, are associated with greater susceptibility to and severity of major depressive disorder. The work by Lotrich, Sears, and McNamara (2013) suggests that insufficient DHA may increase vulnerability to depressive episodes in the context of heightened immune activation, while Omori et al. (2021) demonstrate that reductions in LPA-DHA (the bioactive form in the brain) may relate to both the presence and severity of depressive symptoms. Extending these observations, Borsini and colleagues (2021) provide mechanistic and clinical evidence that DHA and EPA can counteract neuroinflammation through their LOX- and CYP450-derived metabolites, and that these pathways are directly linked to improvements in depression severity during supplementation. Taken together, these findings not only underscore the importance of DHA in the pathophysiology of MDD but also point toward its potential utility as both a biomarker and therapeutic target in the management of depressive disorders.
 
References
Borsini, Alessandra, Anna Nicolaou, Dolores Camacho-Muñoz, Alexandra C. Kendall, Maria Grazia Di Benedetto, Juliette Giacobbe, Kuan-Pin Su, and Carmine M. Pariante. 2021. ‘Omega-3 Polyunsaturated Fatty Acids Protect against Inflammation through Production of LOX and CYP450 Lipid Mediators: Relevance for Major Depression and for Human Hippocampal Neurogenesis’. Molecular Psychiatry 26(11):6773–88. doi:10.1038/s41380-021-01160-8.

Lotrich, Francis E., Barry Sears, and Robert K. McNamara. 2013. ‘Elevated Ratio of Arachidonic Acid to Long-Chain Omega-3 Fatty Acids Predicts Depression Development Following Interferon-Alpha Treatment: Relationship with Interleukin-6’. Brain, Behavior, and Immunity 31:48–53. doi:10.1016/j.bbi.2012.08.007.

Omori, Wataru, Kuniyuki Kano, Kotaro Hattori, Naoto Kajitani, Mami Okada-Tsuchioka, Shuken Boku, Hiroshi Kunugi, Junken Aoki, and Minoru Takebayashi. 2021. ‘Reduced Cerebrospinal Fluid Levels of Lysophosphatidic Acid Docosahexaenoic Acid in Patients With Major Depressive Disorder and Schizophrenia’. International Journal of Neuropsychopharmacology 24(12):948–55. doi:10.1093/ijnp/pyab044.
 

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